Obesity

LOS ANGELES – More than 20 years ago, Roy Taylor, MD, began working to further understand the pathogenesis of hepatic insulin resistance in people with type 2 diabetes. It became clear that the main determinant was the amount of fat in the liver.

Vidyard Video

“If you reduced the amount of fat, the resistance went down,” Dr. Taylor, professor of medicine and metabolism at Newcastle University (England), said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “We had a very clear picture of what might be controlling this awful matter of fasting glucose being too high.”

Then, Dr. Taylor read a study from Caterina Guidone, MD, and colleagues in Italy, which found that 1 week after patients with type 2 diabetes underwent gastric bypass surgery, their fasting plasma glucose levels became normal (Diabetes. 2006;55[7]:2025-31). “I was sitting at my desk and I thought, ‘This really changes type 2 diabetes,’ ” Dr. Taylor said. “It set in process a series of thoughts as to what was controlling what.”

This inspired ongoing work that Dr. Taylor termed the “twin-cycle hypothesis,” which postulates that chronic calorie excess leads to accumulation of liver fat, which spills over into the pancreas (Diabetologia. 2008;51[10]:1781-9).

“People with type 2 diabetes have been in positive calorie balance for a number of years,” he said. “That’s going to lead to an excess of fat in the body, and liver fat levels tend to rise with increasing body weight. If a person has normal insulin sensitivity in muscle tissue, then dealing with a meal is quite easy. Some 30 years ago, we showed using MR spectroscopy that you will have stored the carbohydrate from your breakfast in muscle, to the extent of about one-third of your breakfast, and the peak will be about 5 hours after breakfast. If you had your corn flakes at seven in the morning, by noon there will be peak in muscle, nicely stored away. However, if you happen to be insulin resistant in muscle, that doesn’t happen. There’s only one other pathway that the body can use, and that’s lipogenesis. The body can turn this very toxic substance [glucose] into safe storage [fat]. A lot of that happens in the liver. This means that people with insulin resistance tend to build up liver fat more rapidly than others.”

To test the twin-cycle hypothesis, Dr. Taylor and colleagues launched an 8-week study known as Counterpoint, which set out to induce negative calorie balance using a very low–calorie diet – about one-quarter of an average person’s daily food intake – in 11 people with diabetes (Diabetologia. 2011;54[10]:2506-14). The diet included consuming three packets of liquid formula food each day (46.4% carbohydrate, 32.5% protein, and 20.1% fat; plus vitamins, minerals, and trace elements), supplemented with portions of nonstarchy vegetables such that total energy intake was about 700 calories a day.

“On a liquid-formula diet, hunger is not a problem after the first 36 hours,” Dr. Taylor said. “This is one of the best-kept secrets of the obesity field. Our low-calorie diet was designed as something that people would be able to do in real life. We included nonstarchy vegetables to keep the bowels happy. That was important. It also fulfilled another point. People didn’t want just a liquid diet. They missed the sensation of chewing.”

The researchers also developed three-point Dixon MRI to measure pancreas and liver triacylglycerol content. “The pancreas was particularly challenging, and the full resources of the magnetic resonance physics team were needed to crack the technical problems,” he said.

After just 1 week of restricted energy intake, the fasting plasma glucose level normalized in the diabetic group, going from 9.2 to 5.9 mmol/L (P = .003), while insulin suppression of hepatic glucose output improved from 43% to 74 % (P = .003). By week 8, pancreatic triacylglycerol decreased from 8.0% to 1.1% (P = .03), and hepatic triacylglycerol content fell from 12.8% to 2.9% (P = .003).

“Within 7 days, there was a 30% drop in liver fat, and hepatic insulin resistance had disappeared,” Dr. Taylor said. “This is not a significant change – it’s a disappearance. For one individual, the amount of fat in the liver decreased from 36% to 2%. In fact, 2% [fat in the liver] was the average in the whole group. But what was simply amazing was the change in first-phase insulin response. It gradually increased throughout the 8 weeks of the study to become similar to the normal control group. We knew right away that a low-calorie diet would start correcting this central abnormality of type 2 diabetes.”

After the results from Counterpoint were published, Dr. Taylor received a “tsunami” of emails from researchers and from members of the public. “Some of the medical experts said it was a flash in the pan – interesting, but not relevant,” he said. “People with diabetes learned of it by the media, and it was talked about as a crash diet, which is unfortunate. First, it wasn’t a crash diet. This diet has to be very carefully planned, and people need to think about it in advance. They need to talk about it with their nearest and dearest, because it’s the spouse, the partner, the friends who will be supporting the individual through this journey. That’s critically important. People don’t eat as isolated individuals, they often eat as a family. We’re not talking about cure. We’re talking about reversal of the processes underpinning diabetes, with the aim of achieving remission.”

Dr. Taylor created a website devoted to providing information for clinicians and patients about the low-calorie diet and other tips on how to reverse type 2 diabetes. Soon afterward, he started to receive emails from people telling him about their experiences with the diet. “In the comfort of their own kitchens these people had lost the same amount of weight as in our trial subjects – about 33 pounds,” Dr. Taylor said. “Most of them had gotten rid of their type 2 diabetes. This was not something artificial as part of a research project. This was something that real people would do if the motivation was strong enough.”

To find out if the results from the Counterpoint study were sustainable, Dr. Taylor and his associates launched the Counterbalance study in 30 patients with type 2 diabetes who had a positive calorie imbalance and whom the researchers followed for 6 months. The 8-week diet consisted of consuming three packets of liquid formula a day comprising 43.0% carbohydrates, 34.0% protein, and 19.5% fat, as well as up to 240 g of nonstarchy vegetables (Diabetes Care. 2016;39[5]:808-15). “This was followed for a 6-month period of normal eating: Eating whatever foods they liked but in quantities to keep their weight steady,” Dr. Taylor explained. “These people gained no weight over the 6-month follow-up period. They achieved normalization of liver fat, and it remained normal.”

The patients’ hemoglobin A_1c levels fell from an average of 7.1% at baseline to less than 6.0%, and stayed at less than 6.0%. Patients who didn’t respond tended to have a longer duration of diabetes. Their beta cells had fallen to a level beyond that capable of recovery. “So the durability of the return to normal metabolic function was not in question, at least up to 6 months,” he said. “This study also gave us the opportunity to look at changes in pancreas fat. Was it likely that the liver fat was driving the pancreas fat? Yes.”

During the weight-loss period, the researchers found that there was the same degree of reduction of pancreas fat in the Counterbalance study as there’d been in the Counterpoint study. “Remarkably, it decreased slightly during the 6 months of follow-up,” Dr. Taylor said. “Those changes were significant. Type 2 diabetes seems to be caused by about a half a gram of fat within the cells of the pancreas.”

To investigate if a very low–calorie diet could be used as a routine treatment for type 2 diabetes, Dr. Taylor collaborated with his colleague, Mike Lean, MD, in launching the randomized controlled Diabetes Remission Clinical Trial (DiRECT) at 49 primary care practices in the United Kingdom (Diabetologia. 2018;61[3]:589-98). In all, 298 patients were randomized to either best-practice diabetes care alone (control arm) or with an additional evidence-based weight-management program (intervention arm). Remission was defined as having a hemoglobin A_1c level of less than 6.5% for at least 2 months without receiving glucose-lowering therapy.

At 1 year, 46% of patients in the intervention arm achieved remission, compared with 4% in the control arm (Lancet Diabetes Endocrinol. 2019;7[5]:344-55). At 2 years, 36% of patients in the intervention arm achieved remission, compared with 2% in the control arm. “The most common comment from study participants was, ‘I feel 10 years younger,’ ” Dr. Taylor said. “That’s important.”

The percentage of patients who achieved remission was 5% in those who lost less than 11 lb (5 kg), 29% in those who lost between 11 lb and 22 lb (5-10 kg), 60% in those who lost between 22 lb and 33 lb (10-15 kg), and 70% in those who lost 33 lb (15 kg) or more.

The researchers found that 62 patients achieved no remission at 12 or 24 months, 15 achieved remission at 12 but not at 24 months, and 48 achieved remission at 12 and 24 months. “We haven’t got this perfectly right yet,” Dr. Taylor said. “There is more work to do in understanding how to achieve prevention of weight gain, maybe with behavioral interventions and/or other agents such as [glucagonlike peptide–1] agonists. This is the start of a story, not the end of it.”

He and his associates also observed that delivery of fat from the liver to the rest of the body was increased in study participants who relapsed. “What effect did that have on the pancreas fat? The people who continued to be free of diabetes showed a slight fall in pancreatic fat between 5 and 24 months,” Dr. Taylor said. “In sharp contrast, the relapsers had a complete increase. Over the whole period of the study, the relapsers had not changed from baseline. It appears beyond reasonable doubt that excess pancreas fat seems to be driving the beta-cell problem underlying type 2 diabetes.”

Dr. Taylor reported that he has received lecture fees from Novartis, Lilly, and Janssen. He has also been an advisory board member for Wilmington Healthcare.

dbrunk@mdedge.com

LOS ANGELES – More than 20 years ago, Roy Taylor, MD, began working to further understand the pathogenesis of hepatic insulin resistance in people with type 2 diabetes. It became clear that the main determinant was the amount of fat in the liver.

Vidyard Video

“If you reduced the amount of fat, the resistance went down,” Dr. Taylor, professor of medicine and metabolism at Newcastle University (England), said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “We had a very clear picture of what might be controlling this awful matter of fasting glucose being too high.”

Then, Dr. Taylor read a study from Caterina Guidone, MD, and colleagues in Italy, which found that 1 week after patients with type 2 diabetes underwent gastric bypass surgery, their fasting plasma glucose levels became normal (Diabetes. 2006;55[7]:2025-31). “I was sitting at my desk and I thought, ‘This really changes type 2 diabetes,’ ” Dr. Taylor said. “It set in process a series of thoughts as to what was controlling what.”

This inspired ongoing work that Dr. Taylor termed the “twin-cycle hypothesis,” which postulates that chronic calorie excess leads to accumulation of liver fat, which spills over into the pancreas (Diabetologia. 2008;51[10]:1781-9).

“People with type 2 diabetes have been in positive calorie balance for a number of years,” he said. “That’s going to lead to an excess of fat in the body, and liver fat levels tend to rise with increasing body weight. If a person has normal insulin sensitivity in muscle tissue, then dealing with a meal is quite easy. Some 30 years ago, we showed using MR spectroscopy that you will have stored the carbohydrate from your breakfast in muscle, to the extent of about one-third of your breakfast, and the peak will be about 5 hours after breakfast. If you had your corn flakes at seven in the morning, by noon there will be peak in muscle, nicely stored away. However, if you happen to be insulin resistant in muscle, that doesn’t happen. There’s only one other pathway that the body can use, and that’s lipogenesis. The body can turn this very toxic substance [glucose] into safe storage [fat]. A lot of that happens in the liver. This means that people with insulin resistance tend to build up liver fat more rapidly than others.”

To test the twin-cycle hypothesis, Dr. Taylor and colleagues launched an 8-week study known as Counterpoint, which set out to induce negative calorie balance using a very low–calorie diet – about one-quarter of an average person’s daily food intake – in 11 people with diabetes (Diabetologia. 2011;54[10]:2506-14). The diet included consuming three packets of liquid formula food each day (46.4% carbohydrate, 32.5% protein, and 20.1% fat; plus vitamins, minerals, and trace elements), supplemented with portions of nonstarchy vegetables such that total energy intake was about 700 calories a day.

“On a liquid-formula diet, hunger is not a problem after the first 36 hours,” Dr. Taylor said. “This is one of the best-kept secrets of the obesity field. Our low-calorie diet was designed as something that people would be able to do in real life. We included nonstarchy vegetables to keep the bowels happy. That was important. It also fulfilled another point. People didn’t want just a liquid diet. They missed the sensation of chewing.”

The researchers also developed three-point Dixon MRI to measure pancreas and liver triacylglycerol content. “The pancreas was particularly challenging, and the full resources of the magnetic resonance physics team were needed to crack the technical problems,” he said.

After just 1 week of restricted energy intake, the fasting plasma glucose level normalized in the diabetic group, going from 9.2 to 5.9 mmol/L (P = .003), while insulin suppression of hepatic glucose output improved from 43% to 74 % (P = .003). By week 8, pancreatic triacylglycerol decreased from 8.0% to 1.1% (P = .03), and hepatic triacylglycerol content fell from 12.8% to 2.9% (P = .003).

“Within 7 days, there was a 30% drop in liver fat, and hepatic insulin resistance had disappeared,” Dr. Taylor said. “This is not a significant change – it’s a disappearance. For one individual, the amount of fat in the liver decreased from 36% to 2%. In fact, 2% [fat in the liver] was the average in the whole group. But what was simply amazing was the change in first-phase insulin response. It gradually increased throughout the 8 weeks of the study to become similar to the normal control group. We knew right away that a low-calorie diet would start correcting this central abnormality of type 2 diabetes.”

After the results from Counterpoint were published, Dr. Taylor received a “tsunami” of emails from researchers and from members of the public. “Some of the medical experts said it was a flash in the pan – interesting, but not relevant,” he said. “People with diabetes learned of it by the media, and it was talked about as a crash diet, which is unfortunate. First, it wasn’t a crash diet. This diet has to be very carefully planned, and people need to think about it in advance. They need to talk about it with their nearest and dearest, because it’s the spouse, the partner, the friends who will be supporting the individual through this journey. That’s critically important. People don’t eat as isolated individuals, they often eat as a family. We’re not talking about cure. We’re talking about reversal of the processes underpinning diabetes, with the aim of achieving remission.”

Dr. Taylor created a website devoted to providing information for clinicians and patients about the low-calorie diet and other tips on how to reverse type 2 diabetes. Soon afterward, he started to receive emails from people telling him about their experiences with the diet. “In the comfort of their own kitchens these people had lost the same amount of weight as in our trial subjects – about 33 pounds,” Dr. Taylor said. “Most of them had gotten rid of their type 2 diabetes. This was not something artificial as part of a research project. This was something that real people would do if the motivation was strong enough.”

To find out if the results from the Counterpoint study were sustainable, Dr. Taylor and his associates launched the Counterbalance study in 30 patients with type 2 diabetes who had a positive calorie imbalance and whom the researchers followed for 6 months. The 8-week diet consisted of consuming three packets of liquid formula a day comprising 43.0% carbohydrates, 34.0% protein, and 19.5% fat, as well as up to 240 g of nonstarchy vegetables (Diabetes Care. 2016;39[5]:808-15). “This was followed for a 6-month period of normal eating: Eating whatever foods they liked but in quantities to keep their weight steady,” Dr. Taylor explained. “These people gained no weight over the 6-month follow-up period. They achieved normalization of liver fat, and it remained normal.”

The patients’ hemoglobin A_1c levels fell from an average of 7.1% at baseline to less than 6.0%, and stayed at less than 6.0%. Patients who didn’t respond tended to have a longer duration of diabetes. Their beta cells had fallen to a level beyond that capable of recovery. “So the durability of the return to normal metabolic function was not in question, at least up to 6 months,” he said. “This study also gave us the opportunity to look at changes in pancreas fat. Was it likely that the liver fat was driving the pancreas fat? Yes.”

During the weight-loss period, the researchers found that there was the same degree of reduction of pancreas fat in the Counterbalance study as there’d been in the Counterpoint study. “Remarkably, it decreased slightly during the 6 months of follow-up,” Dr. Taylor said. “Those changes were significant. Type 2 diabetes seems to be caused by about a half a gram of fat within the cells of the pancreas.”

To investigate if a very low–calorie diet could be used as a routine treatment for type 2 diabetes, Dr. Taylor collaborated with his colleague, Mike Lean, MD, in launching the randomized controlled Diabetes Remission Clinical Trial (DiRECT) at 49 primary care practices in the United Kingdom (Diabetologia. 2018;61[3]:589-98). In all, 298 patients were randomized to either best-practice diabetes care alone (control arm) or with an additional evidence-based weight-management program (intervention arm). Remission was defined as having a hemoglobin A_1c level of less than 6.5% for at least 2 months without receiving glucose-lowering therapy.

At 1 year, 46% of patients in the intervention arm achieved remission, compared with 4% in the control arm (Lancet Diabetes Endocrinol. 2019;7[5]:344-55). At 2 years, 36% of patients in the intervention arm achieved remission, compared with 2% in the control arm. “The most common comment from study participants was, ‘I feel 10 years younger,’ ” Dr. Taylor said. “That’s important.”

The percentage of patients who achieved remission was 5% in those who lost less than 11 lb (5 kg), 29% in those who lost between 11 lb and 22 lb (5-10 kg), 60% in those who lost between 22 lb and 33 lb (10-15 kg), and 70% in those who lost 33 lb (15 kg) or more.

The researchers found that 62 patients achieved no remission at 12 or 24 months, 15 achieved remission at 12 but not at 24 months, and 48 achieved remission at 12 and 24 months. “We haven’t got this perfectly right yet,” Dr. Taylor said. “There is more work to do in understanding how to achieve prevention of weight gain, maybe with behavioral interventions and/or other agents such as [glucagonlike peptide–1] agonists. This is the start of a story, not the end of it.”

He and his associates also observed that delivery of fat from the liver to the rest of the body was increased in study participants who relapsed. “What effect did that have on the pancreas fat? The people who continued to be free of diabetes showed a slight fall in pancreatic fat between 5 and 24 months,” Dr. Taylor said. “In sharp contrast, the relapsers had a complete increase. Over the whole period of the study, the relapsers had not changed from baseline. It appears beyond reasonable doubt that excess pancreas fat seems to be driving the beta-cell problem underlying type 2 diabetes.”

Dr. Taylor reported that he has received lecture fees from Novartis, Lilly, and Janssen. He has also been an advisory board member for Wilmington Healthcare.

dbrunk@mdedge.com

LOS ANGELES – More than 20 years ago, Roy Taylor, MD, began working to further understand the pathogenesis of hepatic insulin resistance in people with type 2 diabetes. It became clear that the main determinant was the amount of fat in the liver.

Vidyard Video

“If you reduced the amount of fat, the resistance went down,” Dr. Taylor, professor of medicine and metabolism at Newcastle University (England), said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “We had a very clear picture of what might be controlling this awful matter of fasting glucose being too high.”

Then, Dr. Taylor read a study from Caterina Guidone, MD, and colleagues in Italy, which found that 1 week after patients with type 2 diabetes underwent gastric bypass surgery, their fasting plasma glucose levels became normal (Diabetes. 2006;55[7]:2025-31). “I was sitting at my desk and I thought, ‘This really changes type 2 diabetes,’ ” Dr. Taylor said. “It set in process a series of thoughts as to what was controlling what.”

This inspired ongoing work that Dr. Taylor termed the “twin-cycle hypothesis,” which postulates that chronic calorie excess leads to accumulation of liver fat, which spills over into the pancreas (Diabetologia. 2008;51[10]:1781-9).

“People with type 2 diabetes have been in positive calorie balance for a number of years,” he said. “That’s going to lead to an excess of fat in the body, and liver fat levels tend to rise with increasing body weight. If a person has normal insulin sensitivity in muscle tissue, then dealing with a meal is quite easy. Some 30 years ago, we showed using MR spectroscopy that you will have stored the carbohydrate from your breakfast in muscle, to the extent of about one-third of your breakfast, and the peak will be about 5 hours after breakfast. If you had your corn flakes at seven in the morning, by noon there will be peak in muscle, nicely stored away. However, if you happen to be insulin resistant in muscle, that doesn’t happen. There’s only one other pathway that the body can use, and that’s lipogenesis. The body can turn this very toxic substance [glucose] into safe storage [fat]. A lot of that happens in the liver. This means that people with insulin resistance tend to build up liver fat more rapidly than others.”

To test the twin-cycle hypothesis, Dr. Taylor and colleagues launched an 8-week study known as Counterpoint, which set out to induce negative calorie balance using a very low–calorie diet – about one-quarter of an average person’s daily food intake – in 11 people with diabetes (Diabetologia. 2011;54[10]:2506-14). The diet included consuming three packets of liquid formula food each day (46.4% carbohydrate, 32.5% protein, and 20.1% fat; plus vitamins, minerals, and trace elements), supplemented with portions of nonstarchy vegetables such that total energy intake was about 700 calories a day.

“On a liquid-formula diet, hunger is not a problem after the first 36 hours,” Dr. Taylor said. “This is one of the best-kept secrets of the obesity field. Our low-calorie diet was designed as something that people would be able to do in real life. We included nonstarchy vegetables to keep the bowels happy. That was important. It also fulfilled another point. People didn’t want just a liquid diet. They missed the sensation of chewing.”

The researchers also developed three-point Dixon MRI to measure pancreas and liver triacylglycerol content. “The pancreas was particularly challenging, and the full resources of the magnetic resonance physics team were needed to crack the technical problems,” he said.

After just 1 week of restricted energy intake, the fasting plasma glucose level normalized in the diabetic group, going from 9.2 to 5.9 mmol/L (P = .003), while insulin suppression of hepatic glucose output improved from 43% to 74 % (P = .003). By week 8, pancreatic triacylglycerol decreased from 8.0% to 1.1% (P = .03), and hepatic triacylglycerol content fell from 12.8% to 2.9% (P = .003).

“Within 7 days, there was a 30% drop in liver fat, and hepatic insulin resistance had disappeared,” Dr. Taylor said. “This is not a significant change – it’s a disappearance. For one individual, the amount of fat in the liver decreased from 36% to 2%. In fact, 2% [fat in the liver] was the average in the whole group. But what was simply amazing was the change in first-phase insulin response. It gradually increased throughout the 8 weeks of the study to become similar to the normal control group. We knew right away that a low-calorie diet would start correcting this central abnormality of type 2 diabetes.”

After the results from Counterpoint were published, Dr. Taylor received a “tsunami” of emails from researchers and from members of the public. “Some of the medical experts said it was a flash in the pan – interesting, but not relevant,” he said. “People with diabetes learned of it by the media, and it was talked about as a crash diet, which is unfortunate. First, it wasn’t a crash diet. This diet has to be very carefully planned, and people need to think about it in advance. They need to talk about it with their nearest and dearest, because it’s the spouse, the partner, the friends who will be supporting the individual through this journey. That’s critically important. People don’t eat as isolated individuals, they often eat as a family. We’re not talking about cure. We’re talking about reversal of the processes underpinning diabetes, with the aim of achieving remission.”

Dr. Taylor created a website devoted to providing information for clinicians and patients about the low-calorie diet and other tips on how to reverse type 2 diabetes. Soon afterward, he started to receive emails from people telling him about their experiences with the diet. “In the comfort of their own kitchens these people had lost the same amount of weight as in our trial subjects – about 33 pounds,” Dr. Taylor said. “Most of them had gotten rid of their type 2 diabetes. This was not something artificial as part of a research project. This was something that real people would do if the motivation was strong enough.”

To find out if the results from the Counterpoint study were sustainable, Dr. Taylor and his associates launched the Counterbalance study in 30 patients with type 2 diabetes who had a positive calorie imbalance and whom the researchers followed for 6 months. The 8-week diet consisted of consuming three packets of liquid formula a day comprising 43.0% carbohydrates, 34.0% protein, and 19.5% fat, as well as up to 240 g of nonstarchy vegetables (Diabetes Care. 2016;39[5]:808-15). “This was followed for a 6-month period of normal eating: Eating whatever foods they liked but in quantities to keep their weight steady,” Dr. Taylor explained. “These people gained no weight over the 6-month follow-up period. They achieved normalization of liver fat, and it remained normal.”

The patients’ hemoglobin A_1c levels fell from an average of 7.1% at baseline to less than 6.0%, and stayed at less than 6.0%. Patients who didn’t respond tended to have a longer duration of diabetes. Their beta cells had fallen to a level beyond that capable of recovery. “So the durability of the return to normal metabolic function was not in question, at least up to 6 months,” he said. “This study also gave us the opportunity to look at changes in pancreas fat. Was it likely that the liver fat was driving the pancreas fat? Yes.”

During the weight-loss period, the researchers found that there was the same degree of reduction of pancreas fat in the Counterbalance study as there’d been in the Counterpoint study. “Remarkably, it decreased slightly during the 6 months of follow-up,” Dr. Taylor said. “Those changes were significant. Type 2 diabetes seems to be caused by about a half a gram of fat within the cells of the pancreas.”

To investigate if a very low–calorie diet could be used as a routine treatment for type 2 diabetes, Dr. Taylor collaborated with his colleague, Mike Lean, MD, in launching the randomized controlled Diabetes Remission Clinical Trial (DiRECT) at 49 primary care practices in the United Kingdom (Diabetologia. 2018;61[3]:589-98). In all, 298 patients were randomized to either best-practice diabetes care alone (control arm) or with an additional evidence-based weight-management program (intervention arm). Remission was defined as having a hemoglobin A_1c level of less than 6.5% for at least 2 months without receiving glucose-lowering therapy.

At 1 year, 46% of patients in the intervention arm achieved remission, compared with 4% in the control arm (Lancet Diabetes Endocrinol. 2019;7[5]:344-55). At 2 years, 36% of patients in the intervention arm achieved remission, compared with 2% in the control arm. “The most common comment from study participants was, ‘I feel 10 years younger,’ ” Dr. Taylor said. “That’s important.”

The percentage of patients who achieved remission was 5% in those who lost less than 11 lb (5 kg), 29% in those who lost between 11 lb and 22 lb (5-10 kg), 60% in those who lost between 22 lb and 33 lb (10-15 kg), and 70% in those who lost 33 lb (15 kg) or more.

The researchers found that 62 patients achieved no remission at 12 or 24 months, 15 achieved remission at 12 but not at 24 months, and 48 achieved remission at 12 and 24 months. “We haven’t got this perfectly right yet,” Dr. Taylor said. “There is more work to do in understanding how to achieve prevention of weight gain, maybe with behavioral interventions and/or other agents such as [glucagonlike peptide–1] agonists. This is the start of a story, not the end of it.”

He and his associates also observed that delivery of fat from the liver to the rest of the body was increased in study participants who relapsed. “What effect did that have on the pancreas fat? The people who continued to be free of diabetes showed a slight fall in pancreatic fat between 5 and 24 months,” Dr. Taylor said. “In sharp contrast, the relapsers had a complete increase. Over the whole period of the study, the relapsers had not changed from baseline. It appears beyond reasonable doubt that excess pancreas fat seems to be driving the beta-cell problem underlying type 2 diabetes.”

Dr. Taylor reported that he has received lecture fees from Novartis, Lilly, and Janssen. He has also been an advisory board member for Wilmington Healthcare.

dbrunk@mdedge.com

LOS ANGELES – Patients who took the sodium-glucose cotransporter-2 inhibitor canagliflozin after undergoing metabolic surgery experienced reductions in blood glucose, body mass index, and truncal body fat, results from a small pilot study have shown.

Doug Brunk/MDedge News

“We hypothesized that canagliflozin would be a good choice for these patients, because these drugs work independently of insulin,” the study’s principal investigator, Sangeeta R. Kashyap, MD, said in an interview at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “They help promote weight loss and improve blood pressure. [After] bariatric surgery, patients have an issue with weight regain, and sometimes their diabetes comes back.”

In what she said is the first prospective, randomized, controlled trial of its kind, Dr. Kashyap, an endocrinologist at the Cleveland Clinic, and her colleagues enrolled 11 women and 5 men with type 2 diabetes who had undergone Roux-en-Y gastric bypass or sleeve gastrectomy to study the effects of canagliflozin on clinical parameters over a period of 6 months. At baseline, the patients’ mean body mass index was 39.2 kg/m² and their mean hemoglobin A_1c level was 7.4%. The researchers used maximum likelihood estimation in a linear mixed-effect model to deduce differences between the treatment and placebo groups. Patients randomized to the study drug were assigned a 6-month course of canagliflozin, starting on 100 mg for 2 weeks titrated up to 300 mg daily.

At 6 months, fasting glucose was significantly reduced in the canagliflozin group, compared with baseline (from 163 to 122 mg/dL; P = .007), but it rose in the placebo group (from 164 to 192 mg/dL), a between-group difference that fell short of statistical significance (P = .12). In addition, C-reactive protein in the treatment group fell from 8.9 mg/L to 3.9 mg/L, but rose from 1.6 mg/L to 4.7 mg/L in the placebo group, a between-group difference that trended toward significance (P = .07).

During the 6-month study period, the mean BMI fell from 39.6 kg/m² to 38 kg/m² in the canagliflozin group but increased from 38 to 41 in the placebo group, a between-group difference that reached statistical significance (P = .014). Mean changes in body fat (a reduction of 1.82%), truncal fat (a reduction of 2.67%), and android fat (a reduction of 3%) also reached statistical significance in the treatment group, compared with the placebo group. Reductions in adiponectin, leptin, and high–molecular weight adiponectin did not reach statistical significance.

“I think these drugs have a place in post–bariatric surgery care,” Dr. Kashyap said. “Canagliflozin after metabolic surgery improved weight-loss outcomes and blood sugar levels. It also improved abdominal fat levels, and in this way might even lower cardiovascular disease risk in these patients.”

She acknowledged the study’s small sample size and single-center design as limitations. “It was very difficult to recruit patients for this study,” she said. “Not many patients have recurrent diabetes after bariatric surgery.”

Janssen provided funding to Dr. Kashyap for the trial.

dbrunk@mdedge.com

LOS ANGELES – Patients who took the sodium-glucose cotransporter-2 inhibitor canagliflozin after undergoing metabolic surgery experienced reductions in blood glucose, body mass index, and truncal body fat, results from a small pilot study have shown.

Doug Brunk/MDedge News

“We hypothesized that canagliflozin would be a good choice for these patients, because these drugs work independently of insulin,” the study’s principal investigator, Sangeeta R. Kashyap, MD, said in an interview at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “They help promote weight loss and improve blood pressure. [After] bariatric surgery, patients have an issue with weight regain, and sometimes their diabetes comes back.”

In what she said is the first prospective, randomized, controlled trial of its kind, Dr. Kashyap, an endocrinologist at the Cleveland Clinic, and her colleagues enrolled 11 women and 5 men with type 2 diabetes who had undergone Roux-en-Y gastric bypass or sleeve gastrectomy to study the effects of canagliflozin on clinical parameters over a period of 6 months. At baseline, the patients’ mean body mass index was 39.2 kg/m² and their mean hemoglobin A_1c level was 7.4%. The researchers used maximum likelihood estimation in a linear mixed-effect model to deduce differences between the treatment and placebo groups. Patients randomized to the study drug were assigned a 6-month course of canagliflozin, starting on 100 mg for 2 weeks titrated up to 300 mg daily.

At 6 months, fasting glucose was significantly reduced in the canagliflozin group, compared with baseline (from 163 to 122 mg/dL; P = .007), but it rose in the placebo group (from 164 to 192 mg/dL), a between-group difference that fell short of statistical significance (P = .12). In addition, C-reactive protein in the treatment group fell from 8.9 mg/L to 3.9 mg/L, but rose from 1.6 mg/L to 4.7 mg/L in the placebo group, a between-group difference that trended toward significance (P = .07).

During the 6-month study period, the mean BMI fell from 39.6 kg/m² to 38 kg/m² in the canagliflozin group but increased from 38 to 41 in the placebo group, a between-group difference that reached statistical significance (P = .014). Mean changes in body fat (a reduction of 1.82%), truncal fat (a reduction of 2.67%), and android fat (a reduction of 3%) also reached statistical significance in the treatment group, compared with the placebo group. Reductions in adiponectin, leptin, and high–molecular weight adiponectin did not reach statistical significance.

“I think these drugs have a place in post–bariatric surgery care,” Dr. Kashyap said. “Canagliflozin after metabolic surgery improved weight-loss outcomes and blood sugar levels. It also improved abdominal fat levels, and in this way might even lower cardiovascular disease risk in these patients.”

She acknowledged the study’s small sample size and single-center design as limitations. “It was very difficult to recruit patients for this study,” she said. “Not many patients have recurrent diabetes after bariatric surgery.”

Janssen provided funding to Dr. Kashyap for the trial.

dbrunk@mdedge.com

LOS ANGELES – Patients who took the sodium-glucose cotransporter-2 inhibitor canagliflozin after undergoing metabolic surgery experienced reductions in blood glucose, body mass index, and truncal body fat, results from a small pilot study have shown.

Doug Brunk/MDedge News

“We hypothesized that canagliflozin would be a good choice for these patients, because these drugs work independently of insulin,” the study’s principal investigator, Sangeeta R. Kashyap, MD, said in an interview at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “They help promote weight loss and improve blood pressure. [After] bariatric surgery, patients have an issue with weight regain, and sometimes their diabetes comes back.”

In what she said is the first prospective, randomized, controlled trial of its kind, Dr. Kashyap, an endocrinologist at the Cleveland Clinic, and her colleagues enrolled 11 women and 5 men with type 2 diabetes who had undergone Roux-en-Y gastric bypass or sleeve gastrectomy to study the effects of canagliflozin on clinical parameters over a period of 6 months. At baseline, the patients’ mean body mass index was 39.2 kg/m² and their mean hemoglobin A_1c level was 7.4%. The researchers used maximum likelihood estimation in a linear mixed-effect model to deduce differences between the treatment and placebo groups. Patients randomized to the study drug were assigned a 6-month course of canagliflozin, starting on 100 mg for 2 weeks titrated up to 300 mg daily.

At 6 months, fasting glucose was significantly reduced in the canagliflozin group, compared with baseline (from 163 to 122 mg/dL; P = .007), but it rose in the placebo group (from 164 to 192 mg/dL), a between-group difference that fell short of statistical significance (P = .12). In addition, C-reactive protein in the treatment group fell from 8.9 mg/L to 3.9 mg/L, but rose from 1.6 mg/L to 4.7 mg/L in the placebo group, a between-group difference that trended toward significance (P = .07).

During the 6-month study period, the mean BMI fell from 39.6 kg/m² to 38 kg/m² in the canagliflozin group but increased from 38 to 41 in the placebo group, a between-group difference that reached statistical significance (P = .014). Mean changes in body fat (a reduction of 1.82%), truncal fat (a reduction of 2.67%), and android fat (a reduction of 3%) also reached statistical significance in the treatment group, compared with the placebo group. Reductions in adiponectin, leptin, and high–molecular weight adiponectin did not reach statistical significance.

“I think these drugs have a place in post–bariatric surgery care,” Dr. Kashyap said. “Canagliflozin after metabolic surgery improved weight-loss outcomes and blood sugar levels. It also improved abdominal fat levels, and in this way might even lower cardiovascular disease risk in these patients.”

She acknowledged the study’s small sample size and single-center design as limitations. “It was very difficult to recruit patients for this study,” she said. “Not many patients have recurrent diabetes after bariatric surgery.”

Janssen provided funding to Dr. Kashyap for the trial.

dbrunk@mdedge.com

Performing fecal microbiota transplantation in medically uncompromised obese individuals did not result in weight loss nor an increase of the gut hormone glucagon-like peptide 1 (GLP-1) at 12 weeks, but it did contribute to a decrease in primary bile acids as well as alterations in the stool microbiome.

“Currently, fecal microbiota transplantation [FMT] can only be performed clinically in the US to treat recurrent Clostridium difficile infection,” lead study author Jessica R. Allegretti, MD, MPH, said during a media briefing in advance of the annual Digestive Disease Week.

“However, there is ongoing research to find out whether FMT works for other health conditions such as obesity, a condition which affects millions of people worldwide. [It’s] a condition that also increases the risk of developing many other illnesses, including diabetes, heart disease, and certain cancers. In my clinical practice, we regularly see patients who have not yet developed some of these other conditions related to obesity, but really do have difficulty losing weight. Through our research we wanted to focus on a population we call the medically uncompromised obese, and understand if FMT might be a viable treatment option for them,” she said.

Dr. Allegretti, director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston, conducted a parallel study of 22 patients with a body mass index of 35 kg/m² or higher who were metabolically healthy – defined as having no type 2 diabetes, nonalcoholic steatohepatitis (NASH), or metabolic syndrome. They randomized study participants 1:1 to receive 30 FMT capsules followed by two doses of 12 capsules over a 12-week period, or identical placebo capsules. A single healthy lean donor with a BMI of 17 kg/m² was used.

The researchers assessed patients with a mixed meal tolerance test at baseline, week 6, and week 12 post-FMT, at which biomarkers GLP-1 and leptin were measured. Stool was collected at baseline and at one, four, six, eight, and 12 weeks post-FMT. The primary outcomes were safety and change in the area under the curve for GLP-1 at 12 weeks compared to baseline. Secondary endpoints include gut microbiome profiles and diversity as well as bile acid profiles at 12 weeks post FMT. Additional endpoints include a decrease in BMI and waist circumference at week 12. Standard stool microbiome and bile acid analysis was performed.

The mean age of the patients at baseline was 43 years, and their mean BMI was 41 kg/m². Between baseline and week 12, the research observed no increase of GLP-1 in either group, while the change in leptin revealed an increase in the placebo group only (P less than .001). At week 12, no early changes in BMI were noted in either group (P = .51). No serious adverse events occurred in either arm.

Dr. Allegretti and her colleagues observed global signals of donor community engraftment following FMT, including an increase in alpha diversity and increased similarity to stool samples from the FMT donor – trends that were not observed in the placebo arm. In addition, bile acid analysis suggested a sustained decrease in taurocholic acid in the FMT arm, comparable with the donor – an effect that was not seen in the placebo arm. “We know that what leads to the germination of C. diff. spores is brought out by bile acids,” she said. “That’s one of the critical components of pathogenesis in that disease. My group has been able to show that after FMT, you regain bile acid homeostasis.”

Dr. Allegretti concluded her remarks by noting that the current study “adds an encouraging first step in trying to understand the role that the gut microbiome is playing in the pathogenesis of medically uncompromised obese patients. As a next step, we plan to seek more sensitive measures of GLP-1, as well as conduct additional research into varied doses of FMT capsules, as well as potentially investigating other microbial pathways to better understand the role the microbiome is playing in obesity.”

Somerville, Mass.–based Finch Therapeutics provided funding for the research. Dr. Allegretti reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Allegretti J et al. DDW 2019. Abstract 621.

Performing fecal microbiota transplantation in medically uncompromised obese individuals did not result in weight loss nor an increase of the gut hormone glucagon-like peptide 1 (GLP-1) at 12 weeks, but it did contribute to a decrease in primary bile acids as well as alterations in the stool microbiome.

“Currently, fecal microbiota transplantation [FMT] can only be performed clinically in the US to treat recurrent Clostridium difficile infection,” lead study author Jessica R. Allegretti, MD, MPH, said during a media briefing in advance of the annual Digestive Disease Week.

“However, there is ongoing research to find out whether FMT works for other health conditions such as obesity, a condition which affects millions of people worldwide. [It’s] a condition that also increases the risk of developing many other illnesses, including diabetes, heart disease, and certain cancers. In my clinical practice, we regularly see patients who have not yet developed some of these other conditions related to obesity, but really do have difficulty losing weight. Through our research we wanted to focus on a population we call the medically uncompromised obese, and understand if FMT might be a viable treatment option for them,” she said.

Dr. Allegretti, director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston, conducted a parallel study of 22 patients with a body mass index of 35 kg/m² or higher who were metabolically healthy – defined as having no type 2 diabetes, nonalcoholic steatohepatitis (NASH), or metabolic syndrome. They randomized study participants 1:1 to receive 30 FMT capsules followed by two doses of 12 capsules over a 12-week period, or identical placebo capsules. A single healthy lean donor with a BMI of 17 kg/m² was used.

The researchers assessed patients with a mixed meal tolerance test at baseline, week 6, and week 12 post-FMT, at which biomarkers GLP-1 and leptin were measured. Stool was collected at baseline and at one, four, six, eight, and 12 weeks post-FMT. The primary outcomes were safety and change in the area under the curve for GLP-1 at 12 weeks compared to baseline. Secondary endpoints include gut microbiome profiles and diversity as well as bile acid profiles at 12 weeks post FMT. Additional endpoints include a decrease in BMI and waist circumference at week 12. Standard stool microbiome and bile acid analysis was performed.

The mean age of the patients at baseline was 43 years, and their mean BMI was 41 kg/m². Between baseline and week 12, the research observed no increase of GLP-1 in either group, while the change in leptin revealed an increase in the placebo group only (P less than .001). At week 12, no early changes in BMI were noted in either group (P = .51). No serious adverse events occurred in either arm.

Dr. Allegretti and her colleagues observed global signals of donor community engraftment following FMT, including an increase in alpha diversity and increased similarity to stool samples from the FMT donor – trends that were not observed in the placebo arm. In addition, bile acid analysis suggested a sustained decrease in taurocholic acid in the FMT arm, comparable with the donor – an effect that was not seen in the placebo arm. “We know that what leads to the germination of C. diff. spores is brought out by bile acids,” she said. “That’s one of the critical components of pathogenesis in that disease. My group has been able to show that after FMT, you regain bile acid homeostasis.”

Dr. Allegretti concluded her remarks by noting that the current study “adds an encouraging first step in trying to understand the role that the gut microbiome is playing in the pathogenesis of medically uncompromised obese patients. As a next step, we plan to seek more sensitive measures of GLP-1, as well as conduct additional research into varied doses of FMT capsules, as well as potentially investigating other microbial pathways to better understand the role the microbiome is playing in obesity.”

Somerville, Mass.–based Finch Therapeutics provided funding for the research. Dr. Allegretti reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Allegretti J et al. DDW 2019. Abstract 621.

Performing fecal microbiota transplantation in medically uncompromised obese individuals did not result in weight loss nor an increase of the gut hormone glucagon-like peptide 1 (GLP-1) at 12 weeks, but it did contribute to a decrease in primary bile acids as well as alterations in the stool microbiome.

“Currently, fecal microbiota transplantation [FMT] can only be performed clinically in the US to treat recurrent Clostridium difficile infection,” lead study author Jessica R. Allegretti, MD, MPH, said during a media briefing in advance of the annual Digestive Disease Week.

“However, there is ongoing research to find out whether FMT works for other health conditions such as obesity, a condition which affects millions of people worldwide. [It’s] a condition that also increases the risk of developing many other illnesses, including diabetes, heart disease, and certain cancers. In my clinical practice, we regularly see patients who have not yet developed some of these other conditions related to obesity, but really do have difficulty losing weight. Through our research we wanted to focus on a population we call the medically uncompromised obese, and understand if FMT might be a viable treatment option for them,” she said.

Dr. Allegretti, director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston, conducted a parallel study of 22 patients with a body mass index of 35 kg/m² or higher who were metabolically healthy – defined as having no type 2 diabetes, nonalcoholic steatohepatitis (NASH), or metabolic syndrome. They randomized study participants 1:1 to receive 30 FMT capsules followed by two doses of 12 capsules over a 12-week period, or identical placebo capsules. A single healthy lean donor with a BMI of 17 kg/m² was used.

The researchers assessed patients with a mixed meal tolerance test at baseline, week 6, and week 12 post-FMT, at which biomarkers GLP-1 and leptin were measured. Stool was collected at baseline and at one, four, six, eight, and 12 weeks post-FMT. The primary outcomes were safety and change in the area under the curve for GLP-1 at 12 weeks compared to baseline. Secondary endpoints include gut microbiome profiles and diversity as well as bile acid profiles at 12 weeks post FMT. Additional endpoints include a decrease in BMI and waist circumference at week 12. Standard stool microbiome and bile acid analysis was performed.

The mean age of the patients at baseline was 43 years, and their mean BMI was 41 kg/m². Between baseline and week 12, the research observed no increase of GLP-1 in either group, while the change in leptin revealed an increase in the placebo group only (P less than .001). At week 12, no early changes in BMI were noted in either group (P = .51). No serious adverse events occurred in either arm.

Dr. Allegretti and her colleagues observed global signals of donor community engraftment following FMT, including an increase in alpha diversity and increased similarity to stool samples from the FMT donor – trends that were not observed in the placebo arm. In addition, bile acid analysis suggested a sustained decrease in taurocholic acid in the FMT arm, comparable with the donor – an effect that was not seen in the placebo arm. “We know that what leads to the germination of C. diff. spores is brought out by bile acids,” she said. “That’s one of the critical components of pathogenesis in that disease. My group has been able to show that after FMT, you regain bile acid homeostasis.”

Dr. Allegretti concluded her remarks by noting that the current study “adds an encouraging first step in trying to understand the role that the gut microbiome is playing in the pathogenesis of medically uncompromised obese patients. As a next step, we plan to seek more sensitive measures of GLP-1, as well as conduct additional research into varied doses of FMT capsules, as well as potentially investigating other microbial pathways to better understand the role the microbiome is playing in obesity.”

Somerville, Mass.–based Finch Therapeutics provided funding for the research. Dr. Allegretti reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Allegretti J et al. DDW 2019. Abstract 621.

LOS ANGELES – On the male fertility front, obesity seems to hurt semen quality. So does weight-loss surgery reverse the trend? A new review of existing research suggests that there may be an effect, but the findings aren’t conclusive.

“We found something,” said Sikarin Upala, MD, a second-year endocrinology fellow at the University of Chicago, who pointed out that three of the four reports he and his colleagues reviewed suggested improvement in semen motility. “But we still need to study more about whether bariatric surgery will affect infertility,” he continued.

Dr. Upala, who led the systematic review and meta-analysis of research into bariatric surgery and semen quality, spoke in an interview after his presentation at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

Researchers have linked obesity to infertility in men, but it’s not entirely clear how excess weight and sperm deficiencies are connected. As researchers explained in a 2018 report, “conflicting results have been observed in studies evaluating the correlation between [body mass index] and sperm parameters, such as sperm concentration and total sperm count.” However, they noted that it is “generally accepted” that men with obesity seem to be at higher risk of having a low sperm count or having azoospermia, which is the total lack of sperm in semen.

It’s also not clear whether weight loss directly improves male fertility. “We do know that androgen levels improve after weight-loss surgery, and that might be one factor among several that may contribute to improved male fertility,” Edward Lin, DO, MBA, FACS, professor of surgery and chief of gastrointestinal and general surgery at Emory University, Atlanta, said in an interview.

In their review, Dr. Upala and his colleagues analyzed four studies published between 2012 and 2018 that evaluated the effect of bariatric surgery on semen quality. All of the studies examined semen volume and sperm morphology and motility, and three examined sperm concentration.

A meta-analysis found that motility and volume improved after surgery; however, some of the studies (two for volume, one for motility) failed to show a statistically significant change.

There was no statistically significant difference in sperm morphology or concentration overall, although one study showed a statistically significant improvement in both categories.

Overall, “there might be a little bit of positive effect, but we couldn’t reach a good conclusion because there were too few studies,” Dr. Upala said.

Dr. Lin, director of the Emory Bariatrics Center, agreed that the review findings are limited. He said that although the findings hint at a positive effect on semen quality, “the jury is still out” when it comes to a link between bariatric surgery and male infertility.

“Multiple factors contribute to semen quality,” he added, pointing to vitamin deficiencies, micronutrient levels in the body, enzyme signaling pathways, and sperm chromatin integrity. “In fact, surgically or diet-induced weight loss may be associated with permissive malnutrition, which further exacerbates these deficiencies. Deficiencies in these areas can sometimes take months, if not years, to correct by taking vitamin D or copper or zinc, for example.”

Dr. Lin referred to a small study in which reporters observed semen abnormalities and subfertility after weight-loss surgery despite improvements in androgenic and quality of life levels.

Dr. Upala reported having no relevant disclosures.

LOS ANGELES – On the male fertility front, obesity seems to hurt semen quality. So does weight-loss surgery reverse the trend? A new review of existing research suggests that there may be an effect, but the findings aren’t conclusive.

“We found something,” said Sikarin Upala, MD, a second-year endocrinology fellow at the University of Chicago, who pointed out that three of the four reports he and his colleagues reviewed suggested improvement in semen motility. “But we still need to study more about whether bariatric surgery will affect infertility,” he continued.

Dr. Upala, who led the systematic review and meta-analysis of research into bariatric surgery and semen quality, spoke in an interview after his presentation at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

Researchers have linked obesity to infertility in men, but it’s not entirely clear how excess weight and sperm deficiencies are connected. As researchers explained in a 2018 report, “conflicting results have been observed in studies evaluating the correlation between [body mass index] and sperm parameters, such as sperm concentration and total sperm count.” However, they noted that it is “generally accepted” that men with obesity seem to be at higher risk of having a low sperm count or having azoospermia, which is the total lack of sperm in semen.

It’s also not clear whether weight loss directly improves male fertility. “We do know that androgen levels improve after weight-loss surgery, and that might be one factor among several that may contribute to improved male fertility,” Edward Lin, DO, MBA, FACS, professor of surgery and chief of gastrointestinal and general surgery at Emory University, Atlanta, said in an interview.

In their review, Dr. Upala and his colleagues analyzed four studies published between 2012 and 2018 that evaluated the effect of bariatric surgery on semen quality. All of the studies examined semen volume and sperm morphology and motility, and three examined sperm concentration.

A meta-analysis found that motility and volume improved after surgery; however, some of the studies (two for volume, one for motility) failed to show a statistically significant change.

There was no statistically significant difference in sperm morphology or concentration overall, although one study showed a statistically significant improvement in both categories.

Overall, “there might be a little bit of positive effect, but we couldn’t reach a good conclusion because there were too few studies,” Dr. Upala said.

Dr. Lin, director of the Emory Bariatrics Center, agreed that the review findings are limited. He said that although the findings hint at a positive effect on semen quality, “the jury is still out” when it comes to a link between bariatric surgery and male infertility.

“Multiple factors contribute to semen quality,” he added, pointing to vitamin deficiencies, micronutrient levels in the body, enzyme signaling pathways, and sperm chromatin integrity. “In fact, surgically or diet-induced weight loss may be associated with permissive malnutrition, which further exacerbates these deficiencies. Deficiencies in these areas can sometimes take months, if not years, to correct by taking vitamin D or copper or zinc, for example.”

Dr. Lin referred to a small study in which reporters observed semen abnormalities and subfertility after weight-loss surgery despite improvements in androgenic and quality of life levels.

Dr. Upala reported having no relevant disclosures.

LOS ANGELES – On the male fertility front, obesity seems to hurt semen quality. So does weight-loss surgery reverse the trend? A new review of existing research suggests that there may be an effect, but the findings aren’t conclusive.

“We found something,” said Sikarin Upala, MD, a second-year endocrinology fellow at the University of Chicago, who pointed out that three of the four reports he and his colleagues reviewed suggested improvement in semen motility. “But we still need to study more about whether bariatric surgery will affect infertility,” he continued.

Dr. Upala, who led the systematic review and meta-analysis of research into bariatric surgery and semen quality, spoke in an interview after his presentation at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

Researchers have linked obesity to infertility in men, but it’s not entirely clear how excess weight and sperm deficiencies are connected. As researchers explained in a 2018 report, “conflicting results have been observed in studies evaluating the correlation between [body mass index] and sperm parameters, such as sperm concentration and total sperm count.” However, they noted that it is “generally accepted” that men with obesity seem to be at higher risk of having a low sperm count or having azoospermia, which is the total lack of sperm in semen.

It’s also not clear whether weight loss directly improves male fertility. “We do know that androgen levels improve after weight-loss surgery, and that might be one factor among several that may contribute to improved male fertility,” Edward Lin, DO, MBA, FACS, professor of surgery and chief of gastrointestinal and general surgery at Emory University, Atlanta, said in an interview.

In their review, Dr. Upala and his colleagues analyzed four studies published between 2012 and 2018 that evaluated the effect of bariatric surgery on semen quality. All of the studies examined semen volume and sperm morphology and motility, and three examined sperm concentration.

A meta-analysis found that motility and volume improved after surgery; however, some of the studies (two for volume, one for motility) failed to show a statistically significant change.

There was no statistically significant difference in sperm morphology or concentration overall, although one study showed a statistically significant improvement in both categories.

Overall, “there might be a little bit of positive effect, but we couldn’t reach a good conclusion because there were too few studies,” Dr. Upala said.

Dr. Lin, director of the Emory Bariatrics Center, agreed that the review findings are limited. He said that although the findings hint at a positive effect on semen quality, “the jury is still out” when it comes to a link between bariatric surgery and male infertility.

“Multiple factors contribute to semen quality,” he added, pointing to vitamin deficiencies, micronutrient levels in the body, enzyme signaling pathways, and sperm chromatin integrity. “In fact, surgically or diet-induced weight loss may be associated with permissive malnutrition, which further exacerbates these deficiencies. Deficiencies in these areas can sometimes take months, if not years, to correct by taking vitamin D or copper or zinc, for example.”

Dr. Lin referred to a small study in which reporters observed semen abnormalities and subfertility after weight-loss surgery despite improvements in androgenic and quality of life levels.

Dr. Upala reported having no relevant disclosures.

BALTIMORE – Neural networks are the building blocks of machine learning and artificial intelligence, and researchers from the University of Minnesota have identified a panel of “simple, readily known” preoperative patient factors that they fed into an artificial neural network model that can be predictive of 30-day outcomes after laparoscopic sleeve gastrectomy, one of the researchers reported at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

“The biggest limitation to using neural networks clinically is the fact that they’re algorithmic complex,” said Eric S. Wise, MD, of the University of Minnesota, Minneapolis, in presenting the research. “There is an underlying algorithm that’s developed, but it’s very difficult to understand.” He called it “a black box problem.”

Nonetheless, the researchers drew upon 101,721 laparoscopic sleeve gastrectomy cases from the 2016 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program national database to extract factors that were associated with postoperative complications. “More pertinently, we wanted to optimize predictability of a panel of readily obtainable, easily qualifiable preoperative factors and maximize the variants that are contained within those variables to predict the outcome of 30-day morbidity and mortality,” Dr. Wise said.

Essentially, neural networks recognize patterns through a machine-learning process in a manner modeled on the human brain. As Dr. Wise explained, they first emerged in the 1960s to simulate the human brain’s psychological-neurologic systems.

Through bivariate and multivariate analyses, the research identified eight preoperative variables strongly associated with the 30-day endpoints. After univariate analysis, seven of those variables were statistically significant: older age (P = .03), nonwhite race, higher initial body mass index, severe hypertension, history of diabetes, nonindependent functional status, and previous foregut/bariatric surgery (all P less than .001). “Gender was the only factor that was not predictive,” Dr. Wise said.

The factors held up under logistic regression modeling. “We were able to use a traditional logistic regression model that came up with a reasonable area under the curve of 0.572,” he said. Using artificial neural network analysis, the training set, which comprised 80% of patients, was more accurate than logistic regression, with an area under the curve of 0.582.

One limitation was that this was a “small study,” Dr. Wise said, influenced by selection bias inherent in any retrospective data selection. Other major factors that may exist were not considered.

However, he noted, “in the past we’ve had some success translating neural networks into something that’s clinically useful.” His group at Vanderbilt University published a report of artificial neural network modeling to identify five factors predictive of weight loss after Roux-en-Y gastric bypass 2 years ago (Surg Endosc. 2016;30:480-8). “There are ways to translate neural networks clinically,” Dr. Wise said.

Dr. Wise had no financial relationships to disclose.

SOURCE: Wise ES et al. SAGES 2019, Abstract S053.

BALTIMORE – Neural networks are the building blocks of machine learning and artificial intelligence, and researchers from the University of Minnesota have identified a panel of “simple, readily known” preoperative patient factors that they fed into an artificial neural network model that can be predictive of 30-day outcomes after laparoscopic sleeve gastrectomy, one of the researchers reported at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

“The biggest limitation to using neural networks clinically is the fact that they’re algorithmic complex,” said Eric S. Wise, MD, of the University of Minnesota, Minneapolis, in presenting the research. “There is an underlying algorithm that’s developed, but it’s very difficult to understand.” He called it “a black box problem.”

Nonetheless, the researchers drew upon 101,721 laparoscopic sleeve gastrectomy cases from the 2016 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program national database to extract factors that were associated with postoperative complications. “More pertinently, we wanted to optimize predictability of a panel of readily obtainable, easily qualifiable preoperative factors and maximize the variants that are contained within those variables to predict the outcome of 30-day morbidity and mortality,” Dr. Wise said.

Essentially, neural networks recognize patterns through a machine-learning process in a manner modeled on the human brain. As Dr. Wise explained, they first emerged in the 1960s to simulate the human brain’s psychological-neurologic systems.

Through bivariate and multivariate analyses, the research identified eight preoperative variables strongly associated with the 30-day endpoints. After univariate analysis, seven of those variables were statistically significant: older age (P = .03), nonwhite race, higher initial body mass index, severe hypertension, history of diabetes, nonindependent functional status, and previous foregut/bariatric surgery (all P less than .001). “Gender was the only factor that was not predictive,” Dr. Wise said.

The factors held up under logistic regression modeling. “We were able to use a traditional logistic regression model that came up with a reasonable area under the curve of 0.572,” he said. Using artificial neural network analysis, the training set, which comprised 80% of patients, was more accurate than logistic regression, with an area under the curve of 0.582.

One limitation was that this was a “small study,” Dr. Wise said, influenced by selection bias inherent in any retrospective data selection. Other major factors that may exist were not considered.

However, he noted, “in the past we’ve had some success translating neural networks into something that’s clinically useful.” His group at Vanderbilt University published a report of artificial neural network modeling to identify five factors predictive of weight loss after Roux-en-Y gastric bypass 2 years ago (Surg Endosc. 2016;30:480-8). “There are ways to translate neural networks clinically,” Dr. Wise said.

Dr. Wise had no financial relationships to disclose.

SOURCE: Wise ES et al. SAGES 2019, Abstract S053.

BALTIMORE – Neural networks are the building blocks of machine learning and artificial intelligence, and researchers from the University of Minnesota have identified a panel of “simple, readily known” preoperative patient factors that they fed into an artificial neural network model that can be predictive of 30-day outcomes after laparoscopic sleeve gastrectomy, one of the researchers reported at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

“The biggest limitation to using neural networks clinically is the fact that they’re algorithmic complex,” said Eric S. Wise, MD, of the University of Minnesota, Minneapolis, in presenting the research. “There is an underlying algorithm that’s developed, but it’s very difficult to understand.” He called it “a black box problem.”

Nonetheless, the researchers drew upon 101,721 laparoscopic sleeve gastrectomy cases from the 2016 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program national database to extract factors that were associated with postoperative complications. “More pertinently, we wanted to optimize predictability of a panel of readily obtainable, easily qualifiable preoperative factors and maximize the variants that are contained within those variables to predict the outcome of 30-day morbidity and mortality,” Dr. Wise said.

Essentially, neural networks recognize patterns through a machine-learning process in a manner modeled on the human brain. As Dr. Wise explained, they first emerged in the 1960s to simulate the human brain’s psychological-neurologic systems.

Through bivariate and multivariate analyses, the research identified eight preoperative variables strongly associated with the 30-day endpoints. After univariate analysis, seven of those variables were statistically significant: older age (P = .03), nonwhite race, higher initial body mass index, severe hypertension, history of diabetes, nonindependent functional status, and previous foregut/bariatric surgery (all P less than .001). “Gender was the only factor that was not predictive,” Dr. Wise said.

The factors held up under logistic regression modeling. “We were able to use a traditional logistic regression model that came up with a reasonable area under the curve of 0.572,” he said. Using artificial neural network analysis, the training set, which comprised 80% of patients, was more accurate than logistic regression, with an area under the curve of 0.582.

One limitation was that this was a “small study,” Dr. Wise said, influenced by selection bias inherent in any retrospective data selection. Other major factors that may exist were not considered.

However, he noted, “in the past we’ve had some success translating neural networks into something that’s clinically useful.” His group at Vanderbilt University published a report of artificial neural network modeling to identify five factors predictive of weight loss after Roux-en-Y gastric bypass 2 years ago (Surg Endosc. 2016;30:480-8). “There are ways to translate neural networks clinically,” Dr. Wise said.

Dr. Wise had no financial relationships to disclose.

SOURCE: Wise ES et al. SAGES 2019, Abstract S053.

LOS ANGELES – After a simple educational initiative was implemented, the proportion of internal medicine residents who discussed the topic of overweight and obesity with patients improved from 17% to 69%, results from a single center have demonstrated.

Doug Brunk/MDedge News

“Everybody knows about the obesity epidemic, but nobody’s talking about it,” Hassan Mehmood, MD, said in an interview at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “They’re not doing enough to treat obesity. The United States Preventive Services Task Force [USPSTF] recommends screening all adults over the age of 18 years for obesity.”

In an effort to determine how often internal medicine residents are discussing obesity with patients, Dr. Mehmood and colleagues retrospectively reviewed the medical charts of 301 adults with a body mass index of 30 kg/m² or greater who were seen at Temple University/Conemaugh Memorial Medical Center in Johnstown, Pa., between May and June of 2018. They recorded the total number of problems addressed, type of visit, whether obesity was discussed, and the resources used by the residents and attendings for management.

Between July and December of 2018, residents received education through lectures and conferences on obesity screening and management tools. The educational initiative included placement of posters in the clinic about obesity, and all physicians were encouraged to schedule separate visits to discuss the topic with patients. To evaluate the effects of the initiative, the researchers collected data on 255 adults with a BMI of 30 or greater who were seen in the clinic between May and June of 2018.

The mean age of patients in the study sample was between 40 and 50 years, 61% were women, and 91% of the office visits were for follow-up. The patients’ average BMI was 38, they had an average of two comorbidities, and residents most often addressed five diagnoses. From preintervention to postintervention, the researchers observed a statistically significant improvement in the frequency with which residents addressed general health maintenance with patients (from 62% to 83%; P less than .0005) and obesity (from 17% to 69%; P less than .0005). The discussions around obesity included talking about lifestyle modification, medication management, or bariatric surgical intervention.

Before the intervention, many residents reported not being aware of the USPSTF recommendations to screen all patients aged 18 years or older for obesity. They also felt pinched for time during office visits.

“They have only 30 minutes for treatment of chronic problems, so they didn’t find time to talk about obesity,” said Dr. Mehmood, who is a third-year resident at the medical center. “If residents don’t find time for talking about obesity, they can ask patients to return for a separate visit to talk about obesity and give management options to patients. Patients should know what their BMI is so that they can discuss it with their physician.”

He acknowledged that few patients are comfortable talking about their weight, and he suggested starting the conversation by asking “How do you feel about your weight?” during office visits. “That is the best question you can ask,” he said. “[It] helps open the conversation.”

Dr Mehmood reported having no financial disclosures.

dbrunk@mdedge.com

LOS ANGELES – After a simple educational initiative was implemented, the proportion of internal medicine residents who discussed the topic of overweight and obesity with patients improved from 17% to 69%, results from a single center have demonstrated.

Doug Brunk/MDedge News

“Everybody knows about the obesity epidemic, but nobody’s talking about it,” Hassan Mehmood, MD, said in an interview at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “They’re not doing enough to treat obesity. The United States Preventive Services Task Force [USPSTF] recommends screening all adults over the age of 18 years for obesity.”

In an effort to determine how often internal medicine residents are discussing obesity with patients, Dr. Mehmood and colleagues retrospectively reviewed the medical charts of 301 adults with a body mass index of 30 kg/m² or greater who were seen at Temple University/Conemaugh Memorial Medical Center in Johnstown, Pa., between May and June of 2018. They recorded the total number of problems addressed, type of visit, whether obesity was discussed, and the resources used by the residents and attendings for management.

Between July and December of 2018, residents received education through lectures and conferences on obesity screening and management tools. The educational initiative included placement of posters in the clinic about obesity, and all physicians were encouraged to schedule separate visits to discuss the topic with patients. To evaluate the effects of the initiative, the researchers collected data on 255 adults with a BMI of 30 or greater who were seen in the clinic between May and June of 2018.

The mean age of patients in the study sample was between 40 and 50 years, 61% were women, and 91% of the office visits were for follow-up. The patients’ average BMI was 38, they had an average of two comorbidities, and residents most often addressed five diagnoses. From preintervention to postintervention, the researchers observed a statistically significant improvement in the frequency with which residents addressed general health maintenance with patients (from 62% to 83%; P less than .0005) and obesity (from 17% to 69%; P less than .0005). The discussions around obesity included talking about lifestyle modification, medication management, or bariatric surgical intervention.

Before the intervention, many residents reported not being aware of the USPSTF recommendations to screen all patients aged 18 years or older for obesity. They also felt pinched for time during office visits.

“They have only 30 minutes for treatment of chronic problems, so they didn’t find time to talk about obesity,” said Dr. Mehmood, who is a third-year resident at the medical center. “If residents don’t find time for talking about obesity, they can ask patients to return for a separate visit to talk about obesity and give management options to patients. Patients should know what their BMI is so that they can discuss it with their physician.”

He acknowledged that few patients are comfortable talking about their weight, and he suggested starting the conversation by asking “How do you feel about your weight?” during office visits. “That is the best question you can ask,” he said. “[It] helps open the conversation.”

Dr Mehmood reported having no financial disclosures.

dbrunk@mdedge.com

LOS ANGELES – After a simple educational initiative was implemented, the proportion of internal medicine residents who discussed the topic of overweight and obesity with patients improved from 17% to 69%, results from a single center have demonstrated.

Doug Brunk/MDedge News

“Everybody knows about the obesity epidemic, but nobody’s talking about it,” Hassan Mehmood, MD, said in an interview at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “They’re not doing enough to treat obesity. The United States Preventive Services Task Force [USPSTF] recommends screening all adults over the age of 18 years for obesity.”

In an effort to determine how often internal medicine residents are discussing obesity with patients, Dr. Mehmood and colleagues retrospectively reviewed the medical charts of 301 adults with a body mass index of 30 kg/m² or greater who were seen at Temple University/Conemaugh Memorial Medical Center in Johnstown, Pa., between May and June of 2018. They recorded the total number of problems addressed, type of visit, whether obesity was discussed, and the resources used by the residents and attendings for management.

Between July and December of 2018, residents received education through lectures and conferences on obesity screening and management tools. The educational initiative included placement of posters in the clinic about obesity, and all physicians were encouraged to schedule separate visits to discuss the topic with patients. To evaluate the effects of the initiative, the researchers collected data on 255 adults with a BMI of 30 or greater who were seen in the clinic between May and June of 2018.

The mean age of patients in the study sample was between 40 and 50 years, 61% were women, and 91% of the office visits were for follow-up. The patients’ average BMI was 38, they had an average of two comorbidities, and residents most often addressed five diagnoses. From preintervention to postintervention, the researchers observed a statistically significant improvement in the frequency with which residents addressed general health maintenance with patients (from 62% to 83%; P less than .0005) and obesity (from 17% to 69%; P less than .0005). The discussions around obesity included talking about lifestyle modification, medication management, or bariatric surgical intervention.

Before the intervention, many residents reported not being aware of the USPSTF recommendations to screen all patients aged 18 years or older for obesity. They also felt pinched for time during office visits.

“They have only 30 minutes for treatment of chronic problems, so they didn’t find time to talk about obesity,” said Dr. Mehmood, who is a third-year resident at the medical center. “If residents don’t find time for talking about obesity, they can ask patients to return for a separate visit to talk about obesity and give management options to patients. Patients should know what their BMI is so that they can discuss it with their physician.”

He acknowledged that few patients are comfortable talking about their weight, and he suggested starting the conversation by asking “How do you feel about your weight?” during office visits. “That is the best question you can ask,” he said. “[It] helps open the conversation.”

Dr Mehmood reported having no financial disclosures.

dbrunk@mdedge.com

LOS ANGELES – There are plenty of options available if you’re looking to use medication to help your patient with diabetes lose weight, including existing diabetes drugs. Newer medications are much more powerful, but they come with cautions – insurer coverage can be a hurdle, and there are significant gaps in knowledge about their risks for patients with heart disease, Ken Fujioka, MD, told colleagues at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

Dr. Fujioka, of Scripps Clinic in San Diego, shared some tips with his peers about using medications to reduce weight.

Diabetes drugs help, but may need a boost

Metformin can reduce weight by as much as 3%, Dr. Fujioka said. And there may be another benefit related to long-term weight loss maintenance, he said, citing a 15-year study of overweight or obese patients at high risk for diabetes who either received metformin, underwent an intensive lifestyle intervention, or took a placebo. Of the participants with weight loss of at least 5% after the first year, those originally assigned to receive metformin had the greatest weight loss during years 6-15. Older age, the amount of weight initially lost, and continued used of metformin were predictors of long-term weight loss maintenance, according to the researchers (Ann Intern Med. 2019 Apr 23. doi: 10.7326/M18-1605).

There are other options among diabetes drugs. Sodium-glucose cotransporter 2 (SGLT2) inhibitors – a class of drugs that includes canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have a striking effect on weight loss, Dr. Fujioka said. They can cause 300 calories to be flushed out in the urine each day. But that typically doesn’t translate into weight loss of more than 20 pounds, he said, because the body doesn’t fully adjust to fewer calories.

“The patients begin to eat more,” he said. “They have to take in more calories to make up for [the loss]. They’re not consciously trying to do this. It’s a metabolic adaptation, so 2%-3% [weight loss] is about all you’ll get. You won’t get 10% or 20%.”

To drive up weight loss, Dr. Fujioka recommended adding the glucagonlike peptide–1 [GLP1] receptor diabetes drug exenatide (Byetta; Bydureon) or the appetite suppressant phentermine (Adipex-p; Lomaira) to an SGLT2 inhibitor. Recent studies have shown that the drug combinations have a greater impact on weight loss than when taken separately (Lancet Diabetes Endocrinol. 2016 Dec;4[12]:1004-16; Diabetes Care. 2017 May;40[5]:632-9).

In regard to phentermine, which acts similarly to amphetamine, Dr. Fujioka advised colleagues to be aware that “15 mg or less is really safe, but you drive pulse and heart rate beyond that.”

Consider insurance coverage and other factors

Often, insurers will pay for GLP1-receptor and SGLT2-inhibitor medications in patients with diabetes, even if their hemoglobin A_1c is in the healthy range, Dr. Fujioka said, but they’ll balk at paying for specific weight-loss medications, although that can vary by the region of the country. He added that cash discount cards are available for several weight-loss drugs.

Newer weight-loss drugs ...

Dr. Fujioka highlighted a quartet of weight-loss drugs that have been approved in recent years.

• Lorcaserin (Belviq), a selective serotonin 2C receptor agonist, has shown unique benefits in patients with diabetes. A large, multinational, randomized controlled trial found that the drug reduced the risk for incident diabetes, induced remission of hyperglycemia, and reduced the risk of microvascular complications in obese and overweight patients (Lancet. 2018 Nov 24;392[10161]:2269-79).
• Phentermine/topiramate (Qsymia), a combination of an antiseizure medication (topiramate) and an appetite suppressant (phentermine). A 2014 study found that the drug, together with lifestyle modification, effectively promoted weight loss and improved glycemic control in obese or overweight patients with type 2 diabetes (Diabetes Care. 2014 Dec;37[12]:3309-16).
• Naltrexone/bupropion (Contrave), a combination of an addiction drug (naltrexone) and an antidepressant (bupropion). Findings from a 2013 study reported that the drug “in overweight/obese patients with type 2 diabetes induced weight loss... was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes.” (Diabetes Care. 2013 Dec;36[12]:4022-9).
• Liraglutide, an injectable GLP1 agonist that has been approved for diabetes (Victoza) and weight loss (Saxenda). Dr. Fujioka was coauthor for a study in which the findings suggested that the drug could prevent prediabetes from turning into diabetes. (Lancet. 2017 Apr 8;389[10077]:1399-409).

... but watch out for safety in patients with heart disease

Two of the newer weight-loss drugs are OK to prescribe for diabetic patients with heart disease, Dr. Fujioka said, but two are not, because no cardiac safety trials have been completed for them.

Liraglutide (at a dose of 3.0 mg) is considered safe based on previous data (Diabetes Obes Metab. 2018 Mar;20[3]:734-9), Dr. Fujioka said. Likewise, findings from a trial with lorcaserin in which 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors received either lorcaserin (10 mg twice daily) or placebo, suggested that lorcaserin helped sustain weight loss without a higher rate of major cardiovascular events compared with placebo (N Engl J Med. 2018 Sep 20;379[12]:1107-17).However, no such cardiac safety trials have been completed for naltrexone/bupropion or phentermine/topiramate, said Dr. Fujioka. As a result, he said he could not recommend either of them for patients with high-risk cardiovascular disease.

Dr. Fujioka disclosed relationships of various types with Novo Nordisk, Eisai, Gelesis, KVK Tech, Amgen, Sunovion, Boehringer Ingelheim, and Janssen Global Services.
 

LOS ANGELES – There are plenty of options available if you’re looking to use medication to help your patient with diabetes lose weight, including existing diabetes drugs. Newer medications are much more powerful, but they come with cautions – insurer coverage can be a hurdle, and there are significant gaps in knowledge about their risks for patients with heart disease, Ken Fujioka, MD, told colleagues at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

Dr. Fujioka, of Scripps Clinic in San Diego, shared some tips with his peers about using medications to reduce weight.

Diabetes drugs help, but may need a boost

Metformin can reduce weight by as much as 3%, Dr. Fujioka said. And there may be another benefit related to long-term weight loss maintenance, he said, citing a 15-year study of overweight or obese patients at high risk for diabetes who either received metformin, underwent an intensive lifestyle intervention, or took a placebo. Of the participants with weight loss of at least 5% after the first year, those originally assigned to receive metformin had the greatest weight loss during years 6-15. Older age, the amount of weight initially lost, and continued used of metformin were predictors of long-term weight loss maintenance, according to the researchers (Ann Intern Med. 2019 Apr 23. doi: 10.7326/M18-1605).

There are other options among diabetes drugs. Sodium-glucose cotransporter 2 (SGLT2) inhibitors – a class of drugs that includes canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have a striking effect on weight loss, Dr. Fujioka said. They can cause 300 calories to be flushed out in the urine each day. But that typically doesn’t translate into weight loss of more than 20 pounds, he said, because the body doesn’t fully adjust to fewer calories.

“The patients begin to eat more,” he said. “They have to take in more calories to make up for [the loss]. They’re not consciously trying to do this. It’s a metabolic adaptation, so 2%-3% [weight loss] is about all you’ll get. You won’t get 10% or 20%.”

To drive up weight loss, Dr. Fujioka recommended adding the glucagonlike peptide–1 [GLP1] receptor diabetes drug exenatide (Byetta; Bydureon) or the appetite suppressant phentermine (Adipex-p; Lomaira) to an SGLT2 inhibitor. Recent studies have shown that the drug combinations have a greater impact on weight loss than when taken separately (Lancet Diabetes Endocrinol. 2016 Dec;4[12]:1004-16; Diabetes Care. 2017 May;40[5]:632-9).

In regard to phentermine, which acts similarly to amphetamine, Dr. Fujioka advised colleagues to be aware that “15 mg or less is really safe, but you drive pulse and heart rate beyond that.”

Consider insurance coverage and other factors

Often, insurers will pay for GLP1-receptor and SGLT2-inhibitor medications in patients with diabetes, even if their hemoglobin A_1c is in the healthy range, Dr. Fujioka said, but they’ll balk at paying for specific weight-loss medications, although that can vary by the region of the country. He added that cash discount cards are available for several weight-loss drugs.

Newer weight-loss drugs ...

Dr. Fujioka highlighted a quartet of weight-loss drugs that have been approved in recent years.

• Lorcaserin (Belviq), a selective serotonin 2C receptor agonist, has shown unique benefits in patients with diabetes. A large, multinational, randomized controlled trial found that the drug reduced the risk for incident diabetes, induced remission of hyperglycemia, and reduced the risk of microvascular complications in obese and overweight patients (Lancet. 2018 Nov 24;392[10161]:2269-79).
• Phentermine/topiramate (Qsymia), a combination of an antiseizure medication (topiramate) and an appetite suppressant (phentermine). A 2014 study found that the drug, together with lifestyle modification, effectively promoted weight loss and improved glycemic control in obese or overweight patients with type 2 diabetes (Diabetes Care. 2014 Dec;37[12]:3309-16).
• Naltrexone/bupropion (Contrave), a combination of an addiction drug (naltrexone) and an antidepressant (bupropion). Findings from a 2013 study reported that the drug “in overweight/obese patients with type 2 diabetes induced weight loss... was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes.” (Diabetes Care. 2013 Dec;36[12]:4022-9).
• Liraglutide, an injectable GLP1 agonist that has been approved for diabetes (Victoza) and weight loss (Saxenda). Dr. Fujioka was coauthor for a study in which the findings suggested that the drug could prevent prediabetes from turning into diabetes. (Lancet. 2017 Apr 8;389[10077]:1399-409).

... but watch out for safety in patients with heart disease

Two of the newer weight-loss drugs are OK to prescribe for diabetic patients with heart disease, Dr. Fujioka said, but two are not, because no cardiac safety trials have been completed for them.

Liraglutide (at a dose of 3.0 mg) is considered safe based on previous data (Diabetes Obes Metab. 2018 Mar;20[3]:734-9), Dr. Fujioka said. Likewise, findings from a trial with lorcaserin in which 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors received either lorcaserin (10 mg twice daily) or placebo, suggested that lorcaserin helped sustain weight loss without a higher rate of major cardiovascular events compared with placebo (N Engl J Med. 2018 Sep 20;379[12]:1107-17).However, no such cardiac safety trials have been completed for naltrexone/bupropion or phentermine/topiramate, said Dr. Fujioka. As a result, he said he could not recommend either of them for patients with high-risk cardiovascular disease.

Dr. Fujioka disclosed relationships of various types with Novo Nordisk, Eisai, Gelesis, KVK Tech, Amgen, Sunovion, Boehringer Ingelheim, and Janssen Global Services.
 

LOS ANGELES – There are plenty of options available if you’re looking to use medication to help your patient with diabetes lose weight, including existing diabetes drugs. Newer medications are much more powerful, but they come with cautions – insurer coverage can be a hurdle, and there are significant gaps in knowledge about their risks for patients with heart disease, Ken Fujioka, MD, told colleagues at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

Dr. Fujioka, of Scripps Clinic in San Diego, shared some tips with his peers about using medications to reduce weight.

Diabetes drugs help, but may need a boost

Metformin can reduce weight by as much as 3%, Dr. Fujioka said. And there may be another benefit related to long-term weight loss maintenance, he said, citing a 15-year study of overweight or obese patients at high risk for diabetes who either received metformin, underwent an intensive lifestyle intervention, or took a placebo. Of the participants with weight loss of at least 5% after the first year, those originally assigned to receive metformin had the greatest weight loss during years 6-15. Older age, the amount of weight initially lost, and continued used of metformin were predictors of long-term weight loss maintenance, according to the researchers (Ann Intern Med. 2019 Apr 23. doi: 10.7326/M18-1605).

There are other options among diabetes drugs. Sodium-glucose cotransporter 2 (SGLT2) inhibitors – a class of drugs that includes canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) – have a striking effect on weight loss, Dr. Fujioka said. They can cause 300 calories to be flushed out in the urine each day. But that typically doesn’t translate into weight loss of more than 20 pounds, he said, because the body doesn’t fully adjust to fewer calories.

“The patients begin to eat more,” he said. “They have to take in more calories to make up for [the loss]. They’re not consciously trying to do this. It’s a metabolic adaptation, so 2%-3% [weight loss] is about all you’ll get. You won’t get 10% or 20%.”

To drive up weight loss, Dr. Fujioka recommended adding the glucagonlike peptide–1 [GLP1] receptor diabetes drug exenatide (Byetta; Bydureon) or the appetite suppressant phentermine (Adipex-p; Lomaira) to an SGLT2 inhibitor. Recent studies have shown that the drug combinations have a greater impact on weight loss than when taken separately (Lancet Diabetes Endocrinol. 2016 Dec;4[12]:1004-16; Diabetes Care. 2017 May;40[5]:632-9).

In regard to phentermine, which acts similarly to amphetamine, Dr. Fujioka advised colleagues to be aware that “15 mg or less is really safe, but you drive pulse and heart rate beyond that.”

Consider insurance coverage and other factors

Often, insurers will pay for GLP1-receptor and SGLT2-inhibitor medications in patients with diabetes, even if their hemoglobin A_1c is in the healthy range, Dr. Fujioka said, but they’ll balk at paying for specific weight-loss medications, although that can vary by the region of the country. He added that cash discount cards are available for several weight-loss drugs.

Newer weight-loss drugs ...

Dr. Fujioka highlighted a quartet of weight-loss drugs that have been approved in recent years.

• Lorcaserin (Belviq), a selective serotonin 2C receptor agonist, has shown unique benefits in patients with diabetes. A large, multinational, randomized controlled trial found that the drug reduced the risk for incident diabetes, induced remission of hyperglycemia, and reduced the risk of microvascular complications in obese and overweight patients (Lancet. 2018 Nov 24;392[10161]:2269-79).
• Phentermine/topiramate (Qsymia), a combination of an antiseizure medication (topiramate) and an appetite suppressant (phentermine). A 2014 study found that the drug, together with lifestyle modification, effectively promoted weight loss and improved glycemic control in obese or overweight patients with type 2 diabetes (Diabetes Care. 2014 Dec;37[12]:3309-16).
• Naltrexone/bupropion (Contrave), a combination of an addiction drug (naltrexone) and an antidepressant (bupropion). Findings from a 2013 study reported that the drug “in overweight/obese patients with type 2 diabetes induced weight loss... was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes.” (Diabetes Care. 2013 Dec;36[12]:4022-9).
• Liraglutide, an injectable GLP1 agonist that has been approved for diabetes (Victoza) and weight loss (Saxenda). Dr. Fujioka was coauthor for a study in which the findings suggested that the drug could prevent prediabetes from turning into diabetes. (Lancet. 2017 Apr 8;389[10077]:1399-409).

... but watch out for safety in patients with heart disease

Two of the newer weight-loss drugs are OK to prescribe for diabetic patients with heart disease, Dr. Fujioka said, but two are not, because no cardiac safety trials have been completed for them.

Liraglutide (at a dose of 3.0 mg) is considered safe based on previous data (Diabetes Obes Metab. 2018 Mar;20[3]:734-9), Dr. Fujioka said. Likewise, findings from a trial with lorcaserin in which 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors received either lorcaserin (10 mg twice daily) or placebo, suggested that lorcaserin helped sustain weight loss without a higher rate of major cardiovascular events compared with placebo (N Engl J Med. 2018 Sep 20;379[12]:1107-17).However, no such cardiac safety trials have been completed for naltrexone/bupropion or phentermine/topiramate, said Dr. Fujioka. As a result, he said he could not recommend either of them for patients with high-risk cardiovascular disease.

Dr. Fujioka disclosed relationships of various types with Novo Nordisk, Eisai, Gelesis, KVK Tech, Amgen, Sunovion, Boehringer Ingelheim, and Janssen Global Services.
 

LOS ANGELES – Longer duration of type 2 diabetes and any use of medication for the disease are risk factors for short-term bone fracture, results from a large community-based study have shown.

“Osteoporotic fractures are a significant public health burden, causing high morbidity, mortality, and associated health care costs,” Elizabeth J. Samelson, PhD, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “Risk of fractures are higher in patients with type 2 diabetes. Further, outcomes are worse in type 2 diabetes patients, with greater frequency of complications following a fracture.”

Given the projected increase in type 2 diabetes in the U.S. population, Dr. Samelson, an associate scientist at the Marcus Institute for Aging Research at Hebrew SeniorLife and Harvard Medical School, Boston, and colleagues set out to evaluate the short- and long-term risks of bone fractures associated with the disease. They drew from 2,105 women and 1,130 men who participated in the Framingham Original and Offspring Cohorts and whose baseline osteoporosis visit was around 1990. Type 2 diabetes was defined as having a fasting plasma glucose of greater than 125 mg/dL or being on treatment for the disease. Incident fractures excluded finger, toe, skull, face, and pathologic fractures, and the researchers used repeated measures analyses to estimate hazard ratios for the association between type 2 diabetes, type 2 diabetes medication use, and type 2 diabetes duration and incident fracture, adjusted for age, sex, height, and weight.

The mean age of the study participants was 67 years, and the mean follow-up was 9 years. The prevalence of type 2 diabetes in women and men was 7% and 13%, respectively, and 63% and 51% of those were on medication for the disease. The mean duration of diabetes was 8 years.

Dr. Samelson and colleagues found that the cumulative incidence of fracture was 37% in women with type 2 diabetes and 30% in those without the disease. Meanwhile, the cumulative incidence of fracture was 11% in men with type 2 diabetes and 16% in those without the disease. The researchers also found that type 2 diabetes was associated with 1-year fracture risk in women (hazard ratio, 2.23), but not in men.

In the entire study population, longer duration of type 2 diabetes increased the 2-year fracture risk (HR, 1.28), as did the use of any type 2 diabetes medication (HR, 1.70). The researchers observed no statistically significant differences between type 2 diabetes and long-term incidence of fracture.

“Previous studies have contributed to understanding the higher incidence of fractures and worse outcomes in type 2 diabetes, [but] the current study demonstrated that patients [with type 2 diabetes] have 50% to 100% higher short-term [1- to 2-year] risk of fracture independent of clinical risk factors, whereas long-term [10-year] risk of fracture was similar in [patients with] type 2 diabetes and those who do not have [the disease],” Dr. Samelson said. “The current study has some inherent limitations of observational studies, including a lack of definitive determination of causality and that the results are not generalizable to patients with similar demographics. The study, however, is robust in the availability of detailed clinical information, which allows for control of multiple confounding variables.”

Dr. Samelson reported having no financial disclosures. Coauthors Setareh Williams, PhD, and Rich Weiss, MD, are employees and shareholders of Radius Health Inc.

dbrunk@mdedge.com

LOS ANGELES – Longer duration of type 2 diabetes and any use of medication for the disease are risk factors for short-term bone fracture, results from a large community-based study have shown.

“Osteoporotic fractures are a significant public health burden, causing high morbidity, mortality, and associated health care costs,” Elizabeth J. Samelson, PhD, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “Risk of fractures are higher in patients with type 2 diabetes. Further, outcomes are worse in type 2 diabetes patients, with greater frequency of complications following a fracture.”

Given the projected increase in type 2 diabetes in the U.S. population, Dr. Samelson, an associate scientist at the Marcus Institute for Aging Research at Hebrew SeniorLife and Harvard Medical School, Boston, and colleagues set out to evaluate the short- and long-term risks of bone fractures associated with the disease. They drew from 2,105 women and 1,130 men who participated in the Framingham Original and Offspring Cohorts and whose baseline osteoporosis visit was around 1990. Type 2 diabetes was defined as having a fasting plasma glucose of greater than 125 mg/dL or being on treatment for the disease. Incident fractures excluded finger, toe, skull, face, and pathologic fractures, and the researchers used repeated measures analyses to estimate hazard ratios for the association between type 2 diabetes, type 2 diabetes medication use, and type 2 diabetes duration and incident fracture, adjusted for age, sex, height, and weight.

The mean age of the study participants was 67 years, and the mean follow-up was 9 years. The prevalence of type 2 diabetes in women and men was 7% and 13%, respectively, and 63% and 51% of those were on medication for the disease. The mean duration of diabetes was 8 years.

Dr. Samelson and colleagues found that the cumulative incidence of fracture was 37% in women with type 2 diabetes and 30% in those without the disease. Meanwhile, the cumulative incidence of fracture was 11% in men with type 2 diabetes and 16% in those without the disease. The researchers also found that type 2 diabetes was associated with 1-year fracture risk in women (hazard ratio, 2.23), but not in men.

In the entire study population, longer duration of type 2 diabetes increased the 2-year fracture risk (HR, 1.28), as did the use of any type 2 diabetes medication (HR, 1.70). The researchers observed no statistically significant differences between type 2 diabetes and long-term incidence of fracture.

“Previous studies have contributed to understanding the higher incidence of fractures and worse outcomes in type 2 diabetes, [but] the current study demonstrated that patients [with type 2 diabetes] have 50% to 100% higher short-term [1- to 2-year] risk of fracture independent of clinical risk factors, whereas long-term [10-year] risk of fracture was similar in [patients with] type 2 diabetes and those who do not have [the disease],” Dr. Samelson said. “The current study has some inherent limitations of observational studies, including a lack of definitive determination of causality and that the results are not generalizable to patients with similar demographics. The study, however, is robust in the availability of detailed clinical information, which allows for control of multiple confounding variables.”

Dr. Samelson reported having no financial disclosures. Coauthors Setareh Williams, PhD, and Rich Weiss, MD, are employees and shareholders of Radius Health Inc.

dbrunk@mdedge.com

LOS ANGELES – Longer duration of type 2 diabetes and any use of medication for the disease are risk factors for short-term bone fracture, results from a large community-based study have shown.

“Osteoporotic fractures are a significant public health burden, causing high morbidity, mortality, and associated health care costs,” Elizabeth J. Samelson, PhD, said in an interview in advance of the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “Risk of fractures are higher in patients with type 2 diabetes. Further, outcomes are worse in type 2 diabetes patients, with greater frequency of complications following a fracture.”

Given the projected increase in type 2 diabetes in the U.S. population, Dr. Samelson, an associate scientist at the Marcus Institute for Aging Research at Hebrew SeniorLife and Harvard Medical School, Boston, and colleagues set out to evaluate the short- and long-term risks of bone fractures associated with the disease. They drew from 2,105 women and 1,130 men who participated in the Framingham Original and Offspring Cohorts and whose baseline osteoporosis visit was around 1990. Type 2 diabetes was defined as having a fasting plasma glucose of greater than 125 mg/dL or being on treatment for the disease. Incident fractures excluded finger, toe, skull, face, and pathologic fractures, and the researchers used repeated measures analyses to estimate hazard ratios for the association between type 2 diabetes, type 2 diabetes medication use, and type 2 diabetes duration and incident fracture, adjusted for age, sex, height, and weight.

The mean age of the study participants was 67 years, and the mean follow-up was 9 years. The prevalence of type 2 diabetes in women and men was 7% and 13%, respectively, and 63% and 51% of those were on medication for the disease. The mean duration of diabetes was 8 years.

Dr. Samelson and colleagues found that the cumulative incidence of fracture was 37% in women with type 2 diabetes and 30% in those without the disease. Meanwhile, the cumulative incidence of fracture was 11% in men with type 2 diabetes and 16% in those without the disease. The researchers also found that type 2 diabetes was associated with 1-year fracture risk in women (hazard ratio, 2.23), but not in men.

In the entire study population, longer duration of type 2 diabetes increased the 2-year fracture risk (HR, 1.28), as did the use of any type 2 diabetes medication (HR, 1.70). The researchers observed no statistically significant differences between type 2 diabetes and long-term incidence of fracture.

“Previous studies have contributed to understanding the higher incidence of fractures and worse outcomes in type 2 diabetes, [but] the current study demonstrated that patients [with type 2 diabetes] have 50% to 100% higher short-term [1- to 2-year] risk of fracture independent of clinical risk factors, whereas long-term [10-year] risk of fracture was similar in [patients with] type 2 diabetes and those who do not have [the disease],” Dr. Samelson said. “The current study has some inherent limitations of observational studies, including a lack of definitive determination of causality and that the results are not generalizable to patients with similar demographics. The study, however, is robust in the availability of detailed clinical information, which allows for control of multiple confounding variables.”

Dr. Samelson reported having no financial disclosures. Coauthors Setareh Williams, PhD, and Rich Weiss, MD, are employees and shareholders of Radius Health Inc.

dbrunk@mdedge.com

A 48-year-old man presents to his primary care physician because of progressively decreasing energy and gradual decline in both libido and erectile function for the past 18 months. He has noticed decreased morning erections as well. He rates his libido at 3 to 4 on a scale of 10 for the past 6 months. He also reports poor motivation, depressed mood, impaired concentration, and sleep disturbances. He reports no hair loss, headache, or dizziness, and no decrease in shaving frequency. Review of his systems is otherwise unremarkable.

He has had dyslipidemia for 3 years and is not known to have hypertension or diabetes. His medications include atorvastatin, vitamin E, and multivitamins.

He is married with 3 children and does not wish to have more. He works as a software engineer and leads a sedentary lifestyle. He is a nonsmoker and occasionally drinks alcohol on the weekends.

On physical examination, he is alert and oriented and appears well. His height is 5 feet 10 inches (178 cm), weight 230 lb (104 kg), and body mass index (BMI) 32.8 kg/m². His blood pressure is 115/83 mm Hg and pulse rate is 82 beats per minute and regular. Findings on cardiovascular and pulmonary examination are normal. He has large fatty breasts but without palpable glandular tissue.

Genitourinary examination reveals normal hair distribution, a normal-sized penis, and slightly soft testes with testicular volume of 18–20 mL bilaterally.

His primary care physician suspects that he has low testosterone and orders some basic laboratory tests; the results are normal except for a low total testosterone level (Table 1).

FURTHER TESTING

1. Which of the following tests should his physician order next?

• Repeat total testosterone measurement
• Free testosterone measurement by commercial assay
• Calculated free testosterone
• Bioavailable testosterone measurement
• Serum inhibin B measurement

This patient presents with several nonspecific symptoms. But collectively they suggest testosterone deficiency (hypogonadism).

Together, erectile dysfunction, low libido, and decreased morning erections strongly suggest hypogonadism.² Loss of body hair and decreased shaving frequency are specific symptoms of hypogonadism; however, they require years to develop.³ Gynecomastia can also occur due to loss of the inhibitory action of testosterone on breast growth and a relative increase in estradiol. This occurs more in primary hypogonadism, due to the increase in luteinizing hormone (LH), which stimulates the remaining Leydig cells to secrete estradiol rather than testosterone.⁴

To diagnose hypogonadism in men and to start treatment for it, current guidelines recommend that the patient should have clinical features as well as laboratory evidence of low testosterone.^5,6

Measuring testosterone: Total, free, bound, and bioavailable

Testosterone, a steroid hormone, circulates in the serum either as free testosterone or bound to several plasma proteins, mainly sex-hormone binding globulin (SHBG) and albumin.

Total testosterone includes both the free and bound fractions, whereas bioavailable testosterone includes both free and the portion bound to albumin, which has low affinity and can dissociate and be used at the tissue level.¹¹

Low levels of total testosterone do not necessarily reflect a hypogonadal state, as a man with altered SHBG levels or binding capabilities can have low total but normal free testosterone levels and no manifestations.¹² Several conditions can alter the levels of SHBG, including obesity, diabetes, aging, thyroid dysfunction, and others.^5,13

Because our patient is obese, his total testosterone level is not a reliable indicator of hypogonadism, and repeating its measurement will not add diagnostic value.

Therefore, an alternative measurement should be used to accurately reflect the testosterone levels. From a physiologic point of view, bioavailable testosterone is the active form of testosterone and is the most accurate to be measured in a patient with hypogonadism. Nevertheless, because of technical difficulties in its measurement and lack of evidence correlating bioavailable testosterone with the clinical picture of hypogonadism, it is recommended that the level of free testosterone be used.⁵

The gold standard for direct measurement of serum free testosterone is equilibrium dialysis, but this is expensive and time-consuming.¹⁴ Commercial assays for free testosterone exist but have been deemed unreliable.^14,15 It is recommended that free testosterone be measured by equilibrium dialysis or calculated using equations based on total testosterone, SHBG, and albumin levels.⁵ These equations are reliable and give results very close to the values obtained by equilibrium dialysis.¹⁵ Therefore, in our patient, it would be suitable to calculate the free testosterone level next.

Serum levels of free testosterone vary according to several factors. Diurnal variation of testosterone has been established: levels are highest in the morning and decline throughout the day.¹⁶ Food decreases testosterone levels.¹⁷ In addition, there is considerable day-to-day variation.¹8 Therefore, at least 2 readings of fasting morning testosterone on 2 separate days are recommended for the diagnosis of hypogonadism.⁵

Inhibin B is a hormone produced by Sertoli cells in the testes in response to follicle-stimulating hormone (FSH) stimulation. In turn, it acts as negative feedback, together with testosterone, to inhibit FSH release from the pituitary. Inhibin B has been shown to reflect spermatogenesis in the testes and therefore fertility.¹⁹ Inhibin B levels were found to be low in patients with central hypogonadism, due to less FSH release; however, they did not correlate with testosterone levels.²⁰

The patient’s physician orders morning fasting total testosterone, SHBG, and albumin testing and calculates the free testosterone level, which yields a value of 3 ng/dL (reference range 4.5–17). This is confirmed by a repeat measurement, which yields a value of 2.9 ng/dL. Laboratory test results combined with his clinical presentation are consistent with hypogonadism.

2. What is the most appropriate next step?

• Measurement of serum LH and FSH
• Measurement of serum prolactin
• Scrotal ultrasonography
• Gonadotropin-releasing hormone (GnRH) stimulation test
• Semen analysis

After hypogonadism is diagnosed, it is important to distinguish if it is primary or central. This is achieved by measuring serum LH and FSH.⁵ All biotin supplements should be stopped at least 72 hours before measuring LH and FSH, as biotin can interfere with the assays, yielding false values.²¹

Secretion of FSH and LH from the anterior pituitary is under the influence of pulsatile release of GnRH from the hypothalamus. LH acts on Leydig cells in the testes to produce testosterone, whereas FSH acts on Sertoli cells, together with testosterone, to bring about spermatogenesis in the seminiferous tubules. Testosterone acts centrally as negative feedback to decrease the release of LH and FSH.

Primary hypogonadism occurs due to testicular failure, ie, the testes themselves fail to produce testosterone, leading to hypogonadism. The decrease in testosterone levels, together with inhibin B if Sertoli cells are damaged, lead to loss of negative feedback on the hypothalamus and pituitary, and therefore increased levels of LH and FSH. This is termed hypergonadotropic hypogonadism. Testicular failure may also result in impaired spermatogenesis and infertility due to destruction of testicular structures, in which case fertility cannot be restored.

Central hypogonadism occurs when the pituitary fails to produce LH and FSH (secondary hypogonadism) or when the hypothalamus fails to produce GnRH and subsequently the lack of secretion of LH and FSH from the pituitary (tertiary hypogonadism). The lack of LH will result in no stimulation of Leydig cells to produce testosterone, and therefore its deficiency. Serum hormone levels in central hypogonadism will reveal low testosterone, with either low or inappropriately normal gonadotropins (LH and FSH). This is termed hypogonadotropic hypogonadism. The lack of FSH, together with testosterone deficiency will also result in decreased spermatogenesis and therefore infertility. Testicular structures are preserved, however, and fertility can be restored with appropriate therapy, as discussed below.

Prolactin should be measured only if the patient has central hypogonadism. Its measurement is not warranted at this point in the patient’s workup. The implications of prolactin and its relationship to hypogonadism will be discussed later.

Although, this stepwise approach is not convenient for many patients, some physicians follow it because it is cost-effective, especially in those who are not insured. However, other physicians order FSH, LH, and sometimes prolactin with the confirmatory low testosterone measurement. Laboratories can also be instructed to wait to measure the pituitary hormones and to do so only if low testosterone is confirmed.

Varicocele, a possible cause of male infertility, can also impair Leydig cell function and cause low testosterone. In fact, surgical repair of varicocele has been demonstrated to increase serum testosterone.²² Scrotal ultrasonography is used to diagnose varicocele, but this also should be ordered at a later stage in the workup if primary hypogonadism is diagnosed.

The GnRH stimulation test is important for the diagnosis and evaluation of precocious or delayed puberty in children. In boys with delayed puberty, a poorer response to GnRH stimulation indicates central hypogonadism rather than constitutional delay.²³ It has no role in the evaluation of postpubertal or adult-onset hypogonadism.

Semen analysis is important to evaluate fertility if the patient is interested in further procreation.⁵ Low testosterone levels may result in impaired spermatogenesis and therefore infertility. On the other hand, treatment with exogenous testosterone will also result in infertility, by feedback inhibition of LH and FSH and therefore inhibition of spermatogenesis. If the patient wishes to preserve fertility, treatment options other than testosterone should be considered; examples include clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin.^23,24

Our patient has no desire to expand his family; therefore, a semen analysis and attempts to preserve spermatogenesis are not indicated.

His physician orders testing of serum LH and FSH, yielding the following values:

• LH 1.6 mIU/mL (reference range 1.8–12)
• FSH 1.9 mIU/mL (reference range 1.5–12.5).

The diagnosis of central hypogonadism is established.

3. Which investigation is the least appropriate in the further evaluation of this patient?

• 
  Serum free thyroxine (T₄) and morning cortisol measurement
• Serum prolactin measurement
• Serum ferritin measurement
• Pituitary magnetic resonance imaging (MRI)
• Chromosomal karyotyping

The diagnosis of central hypogonadism warrants evaluation for possible causes. These are summarized in Table 4.

Serum free thyroxine and morning cortisol

Since this patient’s LH and FSH values are abnormal, it is important to evaluate the status of other anterior pituitary hormones. In patients with pituitary abnormalities, serum free T₄ is a more reliable test for assessing thyroid function than thyroid-stimulating hormone (TSH), because of loss of the negative feedback of thyroid hormones on the diseased pituitary. In contrast, serum TSH is considered the best single thyroid test to assess primary thyroid dysfunction.

Other measurements include prolactin and morning cortisol (reflecting adrenocorticotropic hormone status).

Prolactin measurement

Prolactin measurement is important to evaluate for hyperprolactinemia, as this will lead to hypogonadism by inhibition of GnRH secretion.²⁵ Different pathologic, pharmacologic, and physiologic conditions can result in hyperprolactinemia, including prolactinomas, other pituitary and hypothalamic lesions, primary hypothyroidism, and medications such as antipsychotics.²⁵ Dopamine agonists are the mainstay treatment for hyperprolactinemia.

Ferritin measurement

Ferritin measurement is indicated to diagnose iron overload conditions such as hemochromatosis, which can result in primary hypogonadism via testicular damage or in secondary hypogonadism via pituitary damage.²⁶

Pituitary MRI with contrast

Pituitary MRI with contrast is used to diagnose structural lesions of the pituitary or hypothalamus. This diagnostic modality is indicated for patients with pituitary dysfunction, including central hypogonadism, manifestations of a mass effect (headache, visual field defects), persistent hyperprolactinemia, and panhypopituitarism, among others. To improve the diagnostic yield of pituitary MRI, the Endocrine Society guidelines recommend it for men with serum total testosterone levels below 150 ng/dL.⁵ However, some clinicians have a lower threshold for ordering pituitary MRI for patients with central hypogonadism. Physician judgment and expertise should be exercised and the decision made on an individual basis.

Chromosomal karyotyping

Chromosomal karyotyping is not indicated in our patient. It is reserved for those with primary hypogonadism to diagnose Klinefelter syndrome, which has a karyotype of 47,XXY.

CASE RESUMED: MOSH SYNDROME

Our patient’s prolactin, free T₄, morning cortisol, and ferritin levels are measured, yielding normal values. No abnormalities are seen on pituitary MRI. A clinical reevaluation is conducted, revealing no history of head trauma or head and neck radiation. The lack of an obvious cause in our patient’s clinical presentation and workup, together with his obesity (BMI 32.8 kg/m²) supports the diagnosis of obesity as the cause of his hypogonadism.

Obesity can be a cause of secondary hypogonadism, which has led to the term “MOSH” (male obesity-associated secondary hypogonadism) syndrome. In fact, a cross-sectional study has demonstrated that 40% of nondiabetic obese (BMI ≥ 30 kg/m²) men over age 45 have low serum free testosterone levels, compared with 26% for lean (BMI < 25 kg/m²) men.²⁷ Moreover, obesity has been found to be a strong predictor of testosterone replacement therapy.²⁸ Other studies have also found an inverse relationship between BMI and testosterone levels.²⁹

Several mechanisms interact in the pathogenesis of MOSH syndrome. Adipose tissue possesses aromatase activity, which converts androgens into estrogens.³⁰ Peripheral estrogen production can in turn exert feedback inhibition on pituitary gonadotropin secretion.³¹ In obese men, increased adipose tissue leads to increased aromatase activity and more estrogen, so more feedback inhibition on the pituitary and subsequently secondary hypogonadism. 


Leptin, a hormone produced by adipocytes, is also increased in obesity, and was found to be inversely correlated with serum testosterone.³² Studies have demonstrated that leptin has an inhibitory effect on the enzymatic pathway that synthesizes testosterone in Leydig cells.³³

Proinflammatory cytokines have also been implicated, as central obesity is associated with an increase in these cytokines, which in turn act negatively on the hypothalamus and impair GnRH release leading to lower testosterone.^34,35

Treating obesity-related hypogonadism

In a pilot study,³⁶ lifestyle attempts to reduce obesity were shown to improve hormonal levels. Bariatric surgery has also been demonstrated to be successful.³⁷

Clomiphene citrate, a selective estrogen receptor modulator, increases endogenous testosterone secretion by inhibiting the negative feedback of estrogen on the hypothalamus and pituitary and thus increasing LH and FSH. It also preserves endogenous testosterone production, since it does not suppress the hypothalamic-pituitary-testicular axis.³⁸ This made clomiphene citrate a potential treatment for men with central hypogonadism including those with MOSH.³⁹

Nevertheless, there are no randomized trials to prove its safety and efficacy in the management of central hypogonadism.⁵ Regarding its use in men wishing to preserve fertility, most studies did not show improvement. However, a meta-analysis demonstrated statistically significant increased pregnancy rates in partners of men with idiopathic infertility if the men used 50 mg of clomiphene citrate daily.⁴⁰

Testosterone deficiency can be a marker of metabolic syndrome, which needs to be managed more urgently than hypogonadism. A cross-sectional study found not only an association between metabolic syndrome and low serum testosterone, but also with each individual component of metabolic syndrome on its own, all of which need to be addressed.¹⁰

The physician counsels the patient regarding the implications, potential adverse outcomes, and available treatments for his obesity, including lifestyle modification and bariatric surgery. The patient declines surgery and wishes to adopt a weight-reducing diet and exercise program, for which he is referred to a dietitian.

In addition, in view of the patient’s clinically and biochemically proven hypogonadism, his physician offers testosterone replacement therapy. He orders a serum prostate-specific antigen (PSA) level, which is 1.3 ng/dL (reference range < 4 ng/dL). The patient is prescribed 5 g of 1% testosterone gel daily.

TESTOSTERONE REPLACEMENT THERAPY

4. Which is the most common adverse effect of testosterone replacement therapy?

• Cardiovascular events
• Erythrocytosis
• Prostate cancer
• Infertility
• Obstructive sleep apnea

Clinicians should be very cautious in initiating testosterone replacement therapy in any patient with an unstable medical condition.

There are several formulations of testosterone replacement therapy, including intramuscular injections, transdermal gels or patches, buccal tablets, an intranasal gel, and oral tablets. Of note, there are 2 different forms of oral testosterone preparations: testosterone undecanoate and 17-alpha alkylated testosterone. The former is unavailable in the United States and the latter is not recommended for use due to its proven hepatic toxicity.⁴¹

Testosterone and erythrocytosis

Meta-analyses have concluded that the most frequent adverse event of testosterone replacement therapy is a significant rise in hematocrit.⁴² This rise was found to be dose-dependent and was more marked in older men.⁴³ Although all preparations can cause erythrocytosis, parenteral forms have been observed to raise it the most, particularly short-term injectables.^44,45

The mechanism behind this increase is attributed to increased erythropoietin levels and improved usage of iron for red blood cell synthesis.⁴⁶ In fact, testosterone replacement therapy has been shown to improve hemoglobin levels in patients with anemia.⁴⁷ On the other hand, increasing hematocrit levels may lead to thrombotic and vasoocclusive events.⁴⁴

Testosterone and prostate cancer

The relationship between testosterone treatment and prostate cancer has long been studied. Historically, testosterone replacement therapy was believed to increase the risk of prostate cancer; however, recent studies and meta-analyses have shown that this is not the case.^42,48 Nevertheless, clinical guidelines still recommend prostate monitoring for men on testosterone replacement therapy.^5,6

Testosterone and cardiovascular risk

The evidence regarding this issue has been contradictory and inconsistent. Meta-analyses have demonstrated that low testosterone is associated with higher risk of major adverse cardiovascular events.⁵⁰ These studies argue for the use of testosterone replacement therapy in hypogonadal men to decrease the risk. However, other studies and meta-analyses have found that testosterone replacement therapy is associated with increased cardiovascular risk and have concluded that major adverse cardiac events are in fact a risk of testosterone replacement therapy.⁵¹

Current recommendations advocate against the use of testosterone replacement therapy in men with uncontrolled heart failure or with cardiovascular events in the past 3 to 6 months.^5,6 Cardiovascular risk factors should be addressed and corrected, and patients should be educated on cardiovascular symptoms and the need to report them if they occur.

Testosterone and infertility

As described earlier, testosterone replacement therapy increases negative feedback on the pituitary and decreases LH and FSH production, leading to less spermatogenesis. Other treatment options should be sought for hypogonadal men wishing to preserve fertility.

Other adverse effects

Other adverse effects of testosterone replacement therapy include acne, oily skin, obstructive sleep apnea, gynecomastia, and balding.

Given all the adverse events that can be associated with testosterone replacement therapy, the risks and benefits of treating hypogonadism in each patient should be taken into consideration, and an individualized approach is required.

The patient presents 3 months later for follow-up. He reports significant improvement in his presenting symptoms including energy, libido, and erectile function. He also reports some improvement in his mood and concentration. He has lost 12 lb (5.4 kg) and is still trying to improve his diet and exercise program. He is compliant with his testosterone gel therapy.

His serum calculated free testosterone level is 7.8 ng/dL (4.5–17), and his hematocrit is 46%. The patient is instructed to continue his treatment and to return after 9 months for further follow-up.

TAKE-HOME POINTS

• Men with hypogonadism usually present with nonspecific manifestations, so clinicians should keep a high index of suspicion.
• Both clinical and biochemical evidence of hypogonadism should be present to diagnose and start treatment for it.
• Low levels of serum total testosterone do not necessarily reflect hypogonadism.
• The hormonal profile of central hypogonadism reveals low serum testosterone with low or inappropriately normal serum LH and FSH levels.

Obesity can cause central hypogonadism and should be suspected after pituitary and other systemic causes are excluded.

A 48-year-old man presents to his primary care physician because of progressively decreasing energy and gradual decline in both libido and erectile function for the past 18 months. He has noticed decreased morning erections as well. He rates his libido at 3 to 4 on a scale of 10 for the past 6 months. He also reports poor motivation, depressed mood, impaired concentration, and sleep disturbances. He reports no hair loss, headache, or dizziness, and no decrease in shaving frequency. Review of his systems is otherwise unremarkable.

He has had dyslipidemia for 3 years and is not known to have hypertension or diabetes. His medications include atorvastatin, vitamin E, and multivitamins.

He is married with 3 children and does not wish to have more. He works as a software engineer and leads a sedentary lifestyle. He is a nonsmoker and occasionally drinks alcohol on the weekends.

On physical examination, he is alert and oriented and appears well. His height is 5 feet 10 inches (178 cm), weight 230 lb (104 kg), and body mass index (BMI) 32.8 kg/m². His blood pressure is 115/83 mm Hg and pulse rate is 82 beats per minute and regular. Findings on cardiovascular and pulmonary examination are normal. He has large fatty breasts but without palpable glandular tissue.

Genitourinary examination reveals normal hair distribution, a normal-sized penis, and slightly soft testes with testicular volume of 18–20 mL bilaterally.

His primary care physician suspects that he has low testosterone and orders some basic laboratory tests; the results are normal except for a low total testosterone level (Table 1).

FURTHER TESTING

1. Which of the following tests should his physician order next?

• Repeat total testosterone measurement
• Free testosterone measurement by commercial assay
• Calculated free testosterone
• Bioavailable testosterone measurement
• Serum inhibin B measurement

This patient presents with several nonspecific symptoms. But collectively they suggest testosterone deficiency (hypogonadism).

Together, erectile dysfunction, low libido, and decreased morning erections strongly suggest hypogonadism.² Loss of body hair and decreased shaving frequency are specific symptoms of hypogonadism; however, they require years to develop.³ Gynecomastia can also occur due to loss of the inhibitory action of testosterone on breast growth and a relative increase in estradiol. This occurs more in primary hypogonadism, due to the increase in luteinizing hormone (LH), which stimulates the remaining Leydig cells to secrete estradiol rather than testosterone.⁴

To diagnose hypogonadism in men and to start treatment for it, current guidelines recommend that the patient should have clinical features as well as laboratory evidence of low testosterone.^5,6

Measuring testosterone: Total, free, bound, and bioavailable

Testosterone, a steroid hormone, circulates in the serum either as free testosterone or bound to several plasma proteins, mainly sex-hormone binding globulin (SHBG) and albumin.

Total testosterone includes both the free and bound fractions, whereas bioavailable testosterone includes both free and the portion bound to albumin, which has low affinity and can dissociate and be used at the tissue level.¹¹

Low levels of total testosterone do not necessarily reflect a hypogonadal state, as a man with altered SHBG levels or binding capabilities can have low total but normal free testosterone levels and no manifestations.¹² Several conditions can alter the levels of SHBG, including obesity, diabetes, aging, thyroid dysfunction, and others.^5,13

Because our patient is obese, his total testosterone level is not a reliable indicator of hypogonadism, and repeating its measurement will not add diagnostic value.

Therefore, an alternative measurement should be used to accurately reflect the testosterone levels. From a physiologic point of view, bioavailable testosterone is the active form of testosterone and is the most accurate to be measured in a patient with hypogonadism. Nevertheless, because of technical difficulties in its measurement and lack of evidence correlating bioavailable testosterone with the clinical picture of hypogonadism, it is recommended that the level of free testosterone be used.⁵

The gold standard for direct measurement of serum free testosterone is equilibrium dialysis, but this is expensive and time-consuming.¹⁴ Commercial assays for free testosterone exist but have been deemed unreliable.^14,15 It is recommended that free testosterone be measured by equilibrium dialysis or calculated using equations based on total testosterone, SHBG, and albumin levels.⁵ These equations are reliable and give results very close to the values obtained by equilibrium dialysis.¹⁵ Therefore, in our patient, it would be suitable to calculate the free testosterone level next.

Serum levels of free testosterone vary according to several factors. Diurnal variation of testosterone has been established: levels are highest in the morning and decline throughout the day.¹⁶ Food decreases testosterone levels.¹⁷ In addition, there is considerable day-to-day variation.¹8 Therefore, at least 2 readings of fasting morning testosterone on 2 separate days are recommended for the diagnosis of hypogonadism.⁵

Inhibin B is a hormone produced by Sertoli cells in the testes in response to follicle-stimulating hormone (FSH) stimulation. In turn, it acts as negative feedback, together with testosterone, to inhibit FSH release from the pituitary. Inhibin B has been shown to reflect spermatogenesis in the testes and therefore fertility.¹⁹ Inhibin B levels were found to be low in patients with central hypogonadism, due to less FSH release; however, they did not correlate with testosterone levels.²⁰

The patient’s physician orders morning fasting total testosterone, SHBG, and albumin testing and calculates the free testosterone level, which yields a value of 3 ng/dL (reference range 4.5–17). This is confirmed by a repeat measurement, which yields a value of 2.9 ng/dL. Laboratory test results combined with his clinical presentation are consistent with hypogonadism.

2. What is the most appropriate next step?

• Measurement of serum LH and FSH
• Measurement of serum prolactin
• Scrotal ultrasonography
• Gonadotropin-releasing hormone (GnRH) stimulation test
• Semen analysis

After hypogonadism is diagnosed, it is important to distinguish if it is primary or central. This is achieved by measuring serum LH and FSH.⁵ All biotin supplements should be stopped at least 72 hours before measuring LH and FSH, as biotin can interfere with the assays, yielding false values.²¹

Secretion of FSH and LH from the anterior pituitary is under the influence of pulsatile release of GnRH from the hypothalamus. LH acts on Leydig cells in the testes to produce testosterone, whereas FSH acts on Sertoli cells, together with testosterone, to bring about spermatogenesis in the seminiferous tubules. Testosterone acts centrally as negative feedback to decrease the release of LH and FSH.

Primary hypogonadism occurs due to testicular failure, ie, the testes themselves fail to produce testosterone, leading to hypogonadism. The decrease in testosterone levels, together with inhibin B if Sertoli cells are damaged, lead to loss of negative feedback on the hypothalamus and pituitary, and therefore increased levels of LH and FSH. This is termed hypergonadotropic hypogonadism. Testicular failure may also result in impaired spermatogenesis and infertility due to destruction of testicular structures, in which case fertility cannot be restored.

Central hypogonadism occurs when the pituitary fails to produce LH and FSH (secondary hypogonadism) or when the hypothalamus fails to produce GnRH and subsequently the lack of secretion of LH and FSH from the pituitary (tertiary hypogonadism). The lack of LH will result in no stimulation of Leydig cells to produce testosterone, and therefore its deficiency. Serum hormone levels in central hypogonadism will reveal low testosterone, with either low or inappropriately normal gonadotropins (LH and FSH). This is termed hypogonadotropic hypogonadism. The lack of FSH, together with testosterone deficiency will also result in decreased spermatogenesis and therefore infertility. Testicular structures are preserved, however, and fertility can be restored with appropriate therapy, as discussed below.

Prolactin should be measured only if the patient has central hypogonadism. Its measurement is not warranted at this point in the patient’s workup. The implications of prolactin and its relationship to hypogonadism will be discussed later.

Although, this stepwise approach is not convenient for many patients, some physicians follow it because it is cost-effective, especially in those who are not insured. However, other physicians order FSH, LH, and sometimes prolactin with the confirmatory low testosterone measurement. Laboratories can also be instructed to wait to measure the pituitary hormones and to do so only if low testosterone is confirmed.

Varicocele, a possible cause of male infertility, can also impair Leydig cell function and cause low testosterone. In fact, surgical repair of varicocele has been demonstrated to increase serum testosterone.²² Scrotal ultrasonography is used to diagnose varicocele, but this also should be ordered at a later stage in the workup if primary hypogonadism is diagnosed.

The GnRH stimulation test is important for the diagnosis and evaluation of precocious or delayed puberty in children. In boys with delayed puberty, a poorer response to GnRH stimulation indicates central hypogonadism rather than constitutional delay.²³ It has no role in the evaluation of postpubertal or adult-onset hypogonadism.

Semen analysis is important to evaluate fertility if the patient is interested in further procreation.⁵ Low testosterone levels may result in impaired spermatogenesis and therefore infertility. On the other hand, treatment with exogenous testosterone will also result in infertility, by feedback inhibition of LH and FSH and therefore inhibition of spermatogenesis. If the patient wishes to preserve fertility, treatment options other than testosterone should be considered; examples include clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin.^23,24

Our patient has no desire to expand his family; therefore, a semen analysis and attempts to preserve spermatogenesis are not indicated.

His physician orders testing of serum LH and FSH, yielding the following values:

• LH 1.6 mIU/mL (reference range 1.8–12)
• FSH 1.9 mIU/mL (reference range 1.5–12.5).

The diagnosis of central hypogonadism is established.

3. Which investigation is the least appropriate in the further evaluation of this patient?

• 
  Serum free thyroxine (T₄) and morning cortisol measurement
• Serum prolactin measurement
• Serum ferritin measurement
• Pituitary magnetic resonance imaging (MRI)
• Chromosomal karyotyping

The diagnosis of central hypogonadism warrants evaluation for possible causes. These are summarized in Table 4.

Serum free thyroxine and morning cortisol

Since this patient’s LH and FSH values are abnormal, it is important to evaluate the status of other anterior pituitary hormones. In patients with pituitary abnormalities, serum free T₄ is a more reliable test for assessing thyroid function than thyroid-stimulating hormone (TSH), because of loss of the negative feedback of thyroid hormones on the diseased pituitary. In contrast, serum TSH is considered the best single thyroid test to assess primary thyroid dysfunction.

Other measurements include prolactin and morning cortisol (reflecting adrenocorticotropic hormone status).

Prolactin measurement

Prolactin measurement is important to evaluate for hyperprolactinemia, as this will lead to hypogonadism by inhibition of GnRH secretion.²⁵ Different pathologic, pharmacologic, and physiologic conditions can result in hyperprolactinemia, including prolactinomas, other pituitary and hypothalamic lesions, primary hypothyroidism, and medications such as antipsychotics.²⁵ Dopamine agonists are the mainstay treatment for hyperprolactinemia.

Ferritin measurement

Ferritin measurement is indicated to diagnose iron overload conditions such as hemochromatosis, which can result in primary hypogonadism via testicular damage or in secondary hypogonadism via pituitary damage.²⁶

Pituitary MRI with contrast

Pituitary MRI with contrast is used to diagnose structural lesions of the pituitary or hypothalamus. This diagnostic modality is indicated for patients with pituitary dysfunction, including central hypogonadism, manifestations of a mass effect (headache, visual field defects), persistent hyperprolactinemia, and panhypopituitarism, among others. To improve the diagnostic yield of pituitary MRI, the Endocrine Society guidelines recommend it for men with serum total testosterone levels below 150 ng/dL.⁵ However, some clinicians have a lower threshold for ordering pituitary MRI for patients with central hypogonadism. Physician judgment and expertise should be exercised and the decision made on an individual basis.

Chromosomal karyotyping

Chromosomal karyotyping is not indicated in our patient. It is reserved for those with primary hypogonadism to diagnose Klinefelter syndrome, which has a karyotype of 47,XXY.

CASE RESUMED: MOSH SYNDROME

Our patient’s prolactin, free T₄, morning cortisol, and ferritin levels are measured, yielding normal values. No abnormalities are seen on pituitary MRI. A clinical reevaluation is conducted, revealing no history of head trauma or head and neck radiation. The lack of an obvious cause in our patient’s clinical presentation and workup, together with his obesity (BMI 32.8 kg/m²) supports the diagnosis of obesity as the cause of his hypogonadism.

Obesity can be a cause of secondary hypogonadism, which has led to the term “MOSH” (male obesity-associated secondary hypogonadism) syndrome. In fact, a cross-sectional study has demonstrated that 40% of nondiabetic obese (BMI ≥ 30 kg/m²) men over age 45 have low serum free testosterone levels, compared with 26% for lean (BMI < 25 kg/m²) men.²⁷ Moreover, obesity has been found to be a strong predictor of testosterone replacement therapy.²⁸ Other studies have also found an inverse relationship between BMI and testosterone levels.²⁹

Several mechanisms interact in the pathogenesis of MOSH syndrome. Adipose tissue possesses aromatase activity, which converts androgens into estrogens.³⁰ Peripheral estrogen production can in turn exert feedback inhibition on pituitary gonadotropin secretion.³¹ In obese men, increased adipose tissue leads to increased aromatase activity and more estrogen, so more feedback inhibition on the pituitary and subsequently secondary hypogonadism. 


Leptin, a hormone produced by adipocytes, is also increased in obesity, and was found to be inversely correlated with serum testosterone.³² Studies have demonstrated that leptin has an inhibitory effect on the enzymatic pathway that synthesizes testosterone in Leydig cells.³³

Proinflammatory cytokines have also been implicated, as central obesity is associated with an increase in these cytokines, which in turn act negatively on the hypothalamus and impair GnRH release leading to lower testosterone.^34,35

Treating obesity-related hypogonadism

In a pilot study,³⁶ lifestyle attempts to reduce obesity were shown to improve hormonal levels. Bariatric surgery has also been demonstrated to be successful.³⁷

Clomiphene citrate, a selective estrogen receptor modulator, increases endogenous testosterone secretion by inhibiting the negative feedback of estrogen on the hypothalamus and pituitary and thus increasing LH and FSH. It also preserves endogenous testosterone production, since it does not suppress the hypothalamic-pituitary-testicular axis.³⁸ This made clomiphene citrate a potential treatment for men with central hypogonadism including those with MOSH.³⁹

Nevertheless, there are no randomized trials to prove its safety and efficacy in the management of central hypogonadism.⁵ Regarding its use in men wishing to preserve fertility, most studies did not show improvement. However, a meta-analysis demonstrated statistically significant increased pregnancy rates in partners of men with idiopathic infertility if the men used 50 mg of clomiphene citrate daily.⁴⁰

Testosterone deficiency can be a marker of metabolic syndrome, which needs to be managed more urgently than hypogonadism. A cross-sectional study found not only an association between metabolic syndrome and low serum testosterone, but also with each individual component of metabolic syndrome on its own, all of which need to be addressed.¹⁰

The physician counsels the patient regarding the implications, potential adverse outcomes, and available treatments for his obesity, including lifestyle modification and bariatric surgery. The patient declines surgery and wishes to adopt a weight-reducing diet and exercise program, for which he is referred to a dietitian.

In addition, in view of the patient’s clinically and biochemically proven hypogonadism, his physician offers testosterone replacement therapy. He orders a serum prostate-specific antigen (PSA) level, which is 1.3 ng/dL (reference range < 4 ng/dL). The patient is prescribed 5 g of 1% testosterone gel daily.

TESTOSTERONE REPLACEMENT THERAPY

4. Which is the most common adverse effect of testosterone replacement therapy?

• Cardiovascular events
• Erythrocytosis
• Prostate cancer
• Infertility
• Obstructive sleep apnea

Clinicians should be very cautious in initiating testosterone replacement therapy in any patient with an unstable medical condition.

There are several formulations of testosterone replacement therapy, including intramuscular injections, transdermal gels or patches, buccal tablets, an intranasal gel, and oral tablets. Of note, there are 2 different forms of oral testosterone preparations: testosterone undecanoate and 17-alpha alkylated testosterone. The former is unavailable in the United States and the latter is not recommended for use due to its proven hepatic toxicity.⁴¹

Testosterone and erythrocytosis

Meta-analyses have concluded that the most frequent adverse event of testosterone replacement therapy is a significant rise in hematocrit.⁴² This rise was found to be dose-dependent and was more marked in older men.⁴³ Although all preparations can cause erythrocytosis, parenteral forms have been observed to raise it the most, particularly short-term injectables.^44,45

The mechanism behind this increase is attributed to increased erythropoietin levels and improved usage of iron for red blood cell synthesis.⁴⁶ In fact, testosterone replacement therapy has been shown to improve hemoglobin levels in patients with anemia.⁴⁷ On the other hand, increasing hematocrit levels may lead to thrombotic and vasoocclusive events.⁴⁴

Testosterone and prostate cancer

The relationship between testosterone treatment and prostate cancer has long been studied. Historically, testosterone replacement therapy was believed to increase the risk of prostate cancer; however, recent studies and meta-analyses have shown that this is not the case.^42,48 Nevertheless, clinical guidelines still recommend prostate monitoring for men on testosterone replacement therapy.^5,6

Testosterone and cardiovascular risk

The evidence regarding this issue has been contradictory and inconsistent. Meta-analyses have demonstrated that low testosterone is associated with higher risk of major adverse cardiovascular events.⁵⁰ These studies argue for the use of testosterone replacement therapy in hypogonadal men to decrease the risk. However, other studies and meta-analyses have found that testosterone replacement therapy is associated with increased cardiovascular risk and have concluded that major adverse cardiac events are in fact a risk of testosterone replacement therapy.⁵¹

Current recommendations advocate against the use of testosterone replacement therapy in men with uncontrolled heart failure or with cardiovascular events in the past 3 to 6 months.^5,6 Cardiovascular risk factors should be addressed and corrected, and patients should be educated on cardiovascular symptoms and the need to report them if they occur.

Testosterone and infertility

As described earlier, testosterone replacement therapy increases negative feedback on the pituitary and decreases LH and FSH production, leading to less spermatogenesis. Other treatment options should be sought for hypogonadal men wishing to preserve fertility.

Other adverse effects

Other adverse effects of testosterone replacement therapy include acne, oily skin, obstructive sleep apnea, gynecomastia, and balding.

Given all the adverse events that can be associated with testosterone replacement therapy, the risks and benefits of treating hypogonadism in each patient should be taken into consideration, and an individualized approach is required.

The patient presents 3 months later for follow-up. He reports significant improvement in his presenting symptoms including energy, libido, and erectile function. He also reports some improvement in his mood and concentration. He has lost 12 lb (5.4 kg) and is still trying to improve his diet and exercise program. He is compliant with his testosterone gel therapy.

His serum calculated free testosterone level is 7.8 ng/dL (4.5–17), and his hematocrit is 46%. The patient is instructed to continue his treatment and to return after 9 months for further follow-up.

TAKE-HOME POINTS

• Men with hypogonadism usually present with nonspecific manifestations, so clinicians should keep a high index of suspicion.
• Both clinical and biochemical evidence of hypogonadism should be present to diagnose and start treatment for it.
• Low levels of serum total testosterone do not necessarily reflect hypogonadism.
• The hormonal profile of central hypogonadism reveals low serum testosterone with low or inappropriately normal serum LH and FSH levels.

Obesity can cause central hypogonadism and should be suspected after pituitary and other systemic causes are excluded.

A 48-year-old man presents to his primary care physician because of progressively decreasing energy and gradual decline in both libido and erectile function for the past 18 months. He has noticed decreased morning erections as well. He rates his libido at 3 to 4 on a scale of 10 for the past 6 months. He also reports poor motivation, depressed mood, impaired concentration, and sleep disturbances. He reports no hair loss, headache, or dizziness, and no decrease in shaving frequency. Review of his systems is otherwise unremarkable.

He has had dyslipidemia for 3 years and is not known to have hypertension or diabetes. His medications include atorvastatin, vitamin E, and multivitamins.

He is married with 3 children and does not wish to have more. He works as a software engineer and leads a sedentary lifestyle. He is a nonsmoker and occasionally drinks alcohol on the weekends.

On physical examination, he is alert and oriented and appears well. His height is 5 feet 10 inches (178 cm), weight 230 lb (104 kg), and body mass index (BMI) 32.8 kg/m². His blood pressure is 115/83 mm Hg and pulse rate is 82 beats per minute and regular. Findings on cardiovascular and pulmonary examination are normal. He has large fatty breasts but without palpable glandular tissue.

Genitourinary examination reveals normal hair distribution, a normal-sized penis, and slightly soft testes with testicular volume of 18–20 mL bilaterally.

His primary care physician suspects that he has low testosterone and orders some basic laboratory tests; the results are normal except for a low total testosterone level (Table 1).

FURTHER TESTING

1. Which of the following tests should his physician order next?

• Repeat total testosterone measurement
• Free testosterone measurement by commercial assay
• Calculated free testosterone
• Bioavailable testosterone measurement
• Serum inhibin B measurement

This patient presents with several nonspecific symptoms. But collectively they suggest testosterone deficiency (hypogonadism).

Together, erectile dysfunction, low libido, and decreased morning erections strongly suggest hypogonadism.² Loss of body hair and decreased shaving frequency are specific symptoms of hypogonadism; however, they require years to develop.³ Gynecomastia can also occur due to loss of the inhibitory action of testosterone on breast growth and a relative increase in estradiol. This occurs more in primary hypogonadism, due to the increase in luteinizing hormone (LH), which stimulates the remaining Leydig cells to secrete estradiol rather than testosterone.⁴

To diagnose hypogonadism in men and to start treatment for it, current guidelines recommend that the patient should have clinical features as well as laboratory evidence of low testosterone.^5,6

Measuring testosterone: Total, free, bound, and bioavailable

Testosterone, a steroid hormone, circulates in the serum either as free testosterone or bound to several plasma proteins, mainly sex-hormone binding globulin (SHBG) and albumin.

Total testosterone includes both the free and bound fractions, whereas bioavailable testosterone includes both free and the portion bound to albumin, which has low affinity and can dissociate and be used at the tissue level.¹¹

Low levels of total testosterone do not necessarily reflect a hypogonadal state, as a man with altered SHBG levels or binding capabilities can have low total but normal free testosterone levels and no manifestations.¹² Several conditions can alter the levels of SHBG, including obesity, diabetes, aging, thyroid dysfunction, and others.^5,13

Because our patient is obese, his total testosterone level is not a reliable indicator of hypogonadism, and repeating its measurement will not add diagnostic value.

Therefore, an alternative measurement should be used to accurately reflect the testosterone levels. From a physiologic point of view, bioavailable testosterone is the active form of testosterone and is the most accurate to be measured in a patient with hypogonadism. Nevertheless, because of technical difficulties in its measurement and lack of evidence correlating bioavailable testosterone with the clinical picture of hypogonadism, it is recommended that the level of free testosterone be used.⁵

The gold standard for direct measurement of serum free testosterone is equilibrium dialysis, but this is expensive and time-consuming.¹⁴ Commercial assays for free testosterone exist but have been deemed unreliable.^14,15 It is recommended that free testosterone be measured by equilibrium dialysis or calculated using equations based on total testosterone, SHBG, and albumin levels.⁵ These equations are reliable and give results very close to the values obtained by equilibrium dialysis.¹⁵ Therefore, in our patient, it would be suitable to calculate the free testosterone level next.

Serum levels of free testosterone vary according to several factors. Diurnal variation of testosterone has been established: levels are highest in the morning and decline throughout the day.¹⁶ Food decreases testosterone levels.¹⁷ In addition, there is considerable day-to-day variation.¹8 Therefore, at least 2 readings of fasting morning testosterone on 2 separate days are recommended for the diagnosis of hypogonadism.⁵

Inhibin B is a hormone produced by Sertoli cells in the testes in response to follicle-stimulating hormone (FSH) stimulation. In turn, it acts as negative feedback, together with testosterone, to inhibit FSH release from the pituitary. Inhibin B has been shown to reflect spermatogenesis in the testes and therefore fertility.¹⁹ Inhibin B levels were found to be low in patients with central hypogonadism, due to less FSH release; however, they did not correlate with testosterone levels.²⁰

The patient’s physician orders morning fasting total testosterone, SHBG, and albumin testing and calculates the free testosterone level, which yields a value of 3 ng/dL (reference range 4.5–17). This is confirmed by a repeat measurement, which yields a value of 2.9 ng/dL. Laboratory test results combined with his clinical presentation are consistent with hypogonadism.

2. What is the most appropriate next step?

• Measurement of serum LH and FSH
• Measurement of serum prolactin
• Scrotal ultrasonography
• Gonadotropin-releasing hormone (GnRH) stimulation test
• Semen analysis

After hypogonadism is diagnosed, it is important to distinguish if it is primary or central. This is achieved by measuring serum LH and FSH.⁵ All biotin supplements should be stopped at least 72 hours before measuring LH and FSH, as biotin can interfere with the assays, yielding false values.²¹

Secretion of FSH and LH from the anterior pituitary is under the influence of pulsatile release of GnRH from the hypothalamus. LH acts on Leydig cells in the testes to produce testosterone, whereas FSH acts on Sertoli cells, together with testosterone, to bring about spermatogenesis in the seminiferous tubules. Testosterone acts centrally as negative feedback to decrease the release of LH and FSH.

Primary hypogonadism occurs due to testicular failure, ie, the testes themselves fail to produce testosterone, leading to hypogonadism. The decrease in testosterone levels, together with inhibin B if Sertoli cells are damaged, lead to loss of negative feedback on the hypothalamus and pituitary, and therefore increased levels of LH and FSH. This is termed hypergonadotropic hypogonadism. Testicular failure may also result in impaired spermatogenesis and infertility due to destruction of testicular structures, in which case fertility cannot be restored.

Central hypogonadism occurs when the pituitary fails to produce LH and FSH (secondary hypogonadism) or when the hypothalamus fails to produce GnRH and subsequently the lack of secretion of LH and FSH from the pituitary (tertiary hypogonadism). The lack of LH will result in no stimulation of Leydig cells to produce testosterone, and therefore its deficiency. Serum hormone levels in central hypogonadism will reveal low testosterone, with either low or inappropriately normal gonadotropins (LH and FSH). This is termed hypogonadotropic hypogonadism. The lack of FSH, together with testosterone deficiency will also result in decreased spermatogenesis and therefore infertility. Testicular structures are preserved, however, and fertility can be restored with appropriate therapy, as discussed below.

Prolactin should be measured only if the patient has central hypogonadism. Its measurement is not warranted at this point in the patient’s workup. The implications of prolactin and its relationship to hypogonadism will be discussed later.

Although, this stepwise approach is not convenient for many patients, some physicians follow it because it is cost-effective, especially in those who are not insured. However, other physicians order FSH, LH, and sometimes prolactin with the confirmatory low testosterone measurement. Laboratories can also be instructed to wait to measure the pituitary hormones and to do so only if low testosterone is confirmed.

Varicocele, a possible cause of male infertility, can also impair Leydig cell function and cause low testosterone. In fact, surgical repair of varicocele has been demonstrated to increase serum testosterone.²² Scrotal ultrasonography is used to diagnose varicocele, but this also should be ordered at a later stage in the workup if primary hypogonadism is diagnosed.

The GnRH stimulation test is important for the diagnosis and evaluation of precocious or delayed puberty in children. In boys with delayed puberty, a poorer response to GnRH stimulation indicates central hypogonadism rather than constitutional delay.²³ It has no role in the evaluation of postpubertal or adult-onset hypogonadism.

Semen analysis is important to evaluate fertility if the patient is interested in further procreation.⁵ Low testosterone levels may result in impaired spermatogenesis and therefore infertility. On the other hand, treatment with exogenous testosterone will also result in infertility, by feedback inhibition of LH and FSH and therefore inhibition of spermatogenesis. If the patient wishes to preserve fertility, treatment options other than testosterone should be considered; examples include clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin.^23,24

Our patient has no desire to expand his family; therefore, a semen analysis and attempts to preserve spermatogenesis are not indicated.

His physician orders testing of serum LH and FSH, yielding the following values:

• LH 1.6 mIU/mL (reference range 1.8–12)
• FSH 1.9 mIU/mL (reference range 1.5–12.5).

The diagnosis of central hypogonadism is established.

3. Which investigation is the least appropriate in the further evaluation of this patient?

• 
  Serum free thyroxine (T₄) and morning cortisol measurement
• Serum prolactin measurement
• Serum ferritin measurement
• Pituitary magnetic resonance imaging (MRI)
• Chromosomal karyotyping

The diagnosis of central hypogonadism warrants evaluation for possible causes. These are summarized in Table 4.

Serum free thyroxine and morning cortisol

Since this patient’s LH and FSH values are abnormal, it is important to evaluate the status of other anterior pituitary hormones. In patients with pituitary abnormalities, serum free T₄ is a more reliable test for assessing thyroid function than thyroid-stimulating hormone (TSH), because of loss of the negative feedback of thyroid hormones on the diseased pituitary. In contrast, serum TSH is considered the best single thyroid test to assess primary thyroid dysfunction.

Other measurements include prolactin and morning cortisol (reflecting adrenocorticotropic hormone status).

Prolactin measurement

Prolactin measurement is important to evaluate for hyperprolactinemia, as this will lead to hypogonadism by inhibition of GnRH secretion.²⁵ Different pathologic, pharmacologic, and physiologic conditions can result in hyperprolactinemia, including prolactinomas, other pituitary and hypothalamic lesions, primary hypothyroidism, and medications such as antipsychotics.²⁵ Dopamine agonists are the mainstay treatment for hyperprolactinemia.

Ferritin measurement

Ferritin measurement is indicated to diagnose iron overload conditions such as hemochromatosis, which can result in primary hypogonadism via testicular damage or in secondary hypogonadism via pituitary damage.²⁶

Pituitary MRI with contrast

Pituitary MRI with contrast is used to diagnose structural lesions of the pituitary or hypothalamus. This diagnostic modality is indicated for patients with pituitary dysfunction, including central hypogonadism, manifestations of a mass effect (headache, visual field defects), persistent hyperprolactinemia, and panhypopituitarism, among others. To improve the diagnostic yield of pituitary MRI, the Endocrine Society guidelines recommend it for men with serum total testosterone levels below 150 ng/dL.⁵ However, some clinicians have a lower threshold for ordering pituitary MRI for patients with central hypogonadism. Physician judgment and expertise should be exercised and the decision made on an individual basis.

Chromosomal karyotyping

Chromosomal karyotyping is not indicated in our patient. It is reserved for those with primary hypogonadism to diagnose Klinefelter syndrome, which has a karyotype of 47,XXY.

CASE RESUMED: MOSH SYNDROME

Our patient’s prolactin, free T₄, morning cortisol, and ferritin levels are measured, yielding normal values. No abnormalities are seen on pituitary MRI. A clinical reevaluation is conducted, revealing no history of head trauma or head and neck radiation. The lack of an obvious cause in our patient’s clinical presentation and workup, together with his obesity (BMI 32.8 kg/m²) supports the diagnosis of obesity as the cause of his hypogonadism.

Obesity can be a cause of secondary hypogonadism, which has led to the term “MOSH” (male obesity-associated secondary hypogonadism) syndrome. In fact, a cross-sectional study has demonstrated that 40% of nondiabetic obese (BMI ≥ 30 kg/m²) men over age 45 have low serum free testosterone levels, compared with 26% for lean (BMI < 25 kg/m²) men.²⁷ Moreover, obesity has been found to be a strong predictor of testosterone replacement therapy.²⁸ Other studies have also found an inverse relationship between BMI and testosterone levels.²⁹

Several mechanisms interact in the pathogenesis of MOSH syndrome. Adipose tissue possesses aromatase activity, which converts androgens into estrogens.³⁰ Peripheral estrogen production can in turn exert feedback inhibition on pituitary gonadotropin secretion.³¹ In obese men, increased adipose tissue leads to increased aromatase activity and more estrogen, so more feedback inhibition on the pituitary and subsequently secondary hypogonadism. 


Leptin, a hormone produced by adipocytes, is also increased in obesity, and was found to be inversely correlated with serum testosterone.³² Studies have demonstrated that leptin has an inhibitory effect on the enzymatic pathway that synthesizes testosterone in Leydig cells.³³

Proinflammatory cytokines have also been implicated, as central obesity is associated with an increase in these cytokines, which in turn act negatively on the hypothalamus and impair GnRH release leading to lower testosterone.^34,35

Treating obesity-related hypogonadism

In a pilot study,³⁶ lifestyle attempts to reduce obesity were shown to improve hormonal levels. Bariatric surgery has also been demonstrated to be successful.³⁷

Clomiphene citrate, a selective estrogen receptor modulator, increases endogenous testosterone secretion by inhibiting the negative feedback of estrogen on the hypothalamus and pituitary and thus increasing LH and FSH. It also preserves endogenous testosterone production, since it does not suppress the hypothalamic-pituitary-testicular axis.³⁸ This made clomiphene citrate a potential treatment for men with central hypogonadism including those with MOSH.³⁹

Nevertheless, there are no randomized trials to prove its safety and efficacy in the management of central hypogonadism.⁵ Regarding its use in men wishing to preserve fertility, most studies did not show improvement. However, a meta-analysis demonstrated statistically significant increased pregnancy rates in partners of men with idiopathic infertility if the men used 50 mg of clomiphene citrate daily.⁴⁰

Testosterone deficiency can be a marker of metabolic syndrome, which needs to be managed more urgently than hypogonadism. A cross-sectional study found not only an association between metabolic syndrome and low serum testosterone, but also with each individual component of metabolic syndrome on its own, all of which need to be addressed.¹⁰

The physician counsels the patient regarding the implications, potential adverse outcomes, and available treatments for his obesity, including lifestyle modification and bariatric surgery. The patient declines surgery and wishes to adopt a weight-reducing diet and exercise program, for which he is referred to a dietitian.

In addition, in view of the patient’s clinically and biochemically proven hypogonadism, his physician offers testosterone replacement therapy. He orders a serum prostate-specific antigen (PSA) level, which is 1.3 ng/dL (reference range < 4 ng/dL). The patient is prescribed 5 g of 1% testosterone gel daily.

TESTOSTERONE REPLACEMENT THERAPY

4. Which is the most common adverse effect of testosterone replacement therapy?

• Cardiovascular events
• Erythrocytosis
• Prostate cancer
• Infertility
• Obstructive sleep apnea

Clinicians should be very cautious in initiating testosterone replacement therapy in any patient with an unstable medical condition.

There are several formulations of testosterone replacement therapy, including intramuscular injections, transdermal gels or patches, buccal tablets, an intranasal gel, and oral tablets. Of note, there are 2 different forms of oral testosterone preparations: testosterone undecanoate and 17-alpha alkylated testosterone. The former is unavailable in the United States and the latter is not recommended for use due to its proven hepatic toxicity.⁴¹

Testosterone and erythrocytosis

Meta-analyses have concluded that the most frequent adverse event of testosterone replacement therapy is a significant rise in hematocrit.⁴² This rise was found to be dose-dependent and was more marked in older men.⁴³ Although all preparations can cause erythrocytosis, parenteral forms have been observed to raise it the most, particularly short-term injectables.^44,45

The mechanism behind this increase is attributed to increased erythropoietin levels and improved usage of iron for red blood cell synthesis.⁴⁶ In fact, testosterone replacement therapy has been shown to improve hemoglobin levels in patients with anemia.⁴⁷ On the other hand, increasing hematocrit levels may lead to thrombotic and vasoocclusive events.⁴⁴

Testosterone and prostate cancer

The relationship between testosterone treatment and prostate cancer has long been studied. Historically, testosterone replacement therapy was believed to increase the risk of prostate cancer; however, recent studies and meta-analyses have shown that this is not the case.^42,48 Nevertheless, clinical guidelines still recommend prostate monitoring for men on testosterone replacement therapy.^5,6

Testosterone and cardiovascular risk

The evidence regarding this issue has been contradictory and inconsistent. Meta-analyses have demonstrated that low testosterone is associated with higher risk of major adverse cardiovascular events.⁵⁰ These studies argue for the use of testosterone replacement therapy in hypogonadal men to decrease the risk. However, other studies and meta-analyses have found that testosterone replacement therapy is associated with increased cardiovascular risk and have concluded that major adverse cardiac events are in fact a risk of testosterone replacement therapy.⁵¹

Current recommendations advocate against the use of testosterone replacement therapy in men with uncontrolled heart failure or with cardiovascular events in the past 3 to 6 months.^5,6 Cardiovascular risk factors should be addressed and corrected, and patients should be educated on cardiovascular symptoms and the need to report them if they occur.

Testosterone and infertility

As described earlier, testosterone replacement therapy increases negative feedback on the pituitary and decreases LH and FSH production, leading to less spermatogenesis. Other treatment options should be sought for hypogonadal men wishing to preserve fertility.

Other adverse effects

Other adverse effects of testosterone replacement therapy include acne, oily skin, obstructive sleep apnea, gynecomastia, and balding.

Given all the adverse events that can be associated with testosterone replacement therapy, the risks and benefits of treating hypogonadism in each patient should be taken into consideration, and an individualized approach is required.

The patient presents 3 months later for follow-up. He reports significant improvement in his presenting symptoms including energy, libido, and erectile function. He also reports some improvement in his mood and concentration. He has lost 12 lb (5.4 kg) and is still trying to improve his diet and exercise program. He is compliant with his testosterone gel therapy.

His serum calculated free testosterone level is 7.8 ng/dL (4.5–17), and his hematocrit is 46%. The patient is instructed to continue his treatment and to return after 9 months for further follow-up.

TAKE-HOME POINTS

• Men with hypogonadism usually present with nonspecific manifestations, so clinicians should keep a high index of suspicion.
• Both clinical and biochemical evidence of hypogonadism should be present to diagnose and start treatment for it.
• Low levels of serum total testosterone do not necessarily reflect hypogonadism.
• The hormonal profile of central hypogonadism reveals low serum testosterone with low or inappropriately normal serum LH and FSH levels.

Obesity can cause central hypogonadism and should be suspected after pituitary and other systemic causes are excluded.

Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.

snyferok/ThinkStock

Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.

The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.

Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.

By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.

Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.

Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.

SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.

Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.

snyferok/ThinkStock

Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.

The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.

Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.

By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.

Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.

Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.

SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.

Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.

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Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.

The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.

Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.

By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.

Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.

Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.

SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.