Endocrinology

Women eating a reduced-fat vegan diet combined with a daily serving of soybeans experienced a 78% reduction in frequency of menopausal hot flashes over 12 weeks, in a small, nonblinded, randomized-controlled trial.

“We do not fully understand yet why this combination works, but it seems that these three elements are key: avoiding animal products, reducing fat, and adding a serving of soybeans,” lead researcher Neal Barnard, MD, explained in a press release. “These new results suggest that a diet change should be considered as a first-line treatment for troublesome vasomotor symptoms, including night sweats and hot flashes,” added Dr. Barnard, who is president of the Physicians Committee for Responsible Medicine, and adjunct professor at George Washington University, Washington. 

Elliott O’Donovan Photography

But, while “the findings from this very small study complement everything we know about the benefits of an excellent diet and the health benefits of soy,” they should be interpreted with some caution, commented Susan Reed, MD, president of the North American Menopause Society, and associate program director of the women’s reproductive research program at the University of Washington, Seattle.

For the trial, called WAVS (Women’s Study for the Alleviation of Vasomotor Symptoms), the researchers randomized 84 postmenopausal women with at least two moderate to severe hot flashes daily to either the intervention or usual diet, with a total of 71 subjects completing the 12-week study, published in Menopause. Criteria for exclusion included any cause of vasomotor symptoms other than natural menopause, current use of a low-fat, vegan diet that includes daily soy products, soy allergy, and body mass index < 18.5 kg/m².

Participants in the intervention group were asked to avoid animal-derived foods, minimize their use of oils and fatty foods such as nuts and avocados, and include half a cup (86 g) of cooked soybeans daily in their diets. They were also offered 1-hour virtual group meetings each week, in which a registered dietitian or research staff provided information on food preparation and managing common dietary challenges.

Control group participants were asked to continue their usual diets and attend four 1-hour group sessions.

At baseline and then after the 12-week study period, dietary intake was self-recorded for 2 weekdays and 1 weekend day, hot flash frequency and severity was recorded for 1 week using a mobile app, and the effect of menopausal symptoms on quality of life was measured using the vasomotor, psychosocial, physical, and sexual domains of the Menopause-Specific Quality of Life (MENQOL) questionnaire.

Equol production was also assessed in a subset of 15 intervention and 12 control participants who had urinary isoflavone concentrations measured after eating half a cup (86 g) of soybeans twice daily for 3 days. This was based on the theory that diets such as the intervention in this study “seem to foster the growth of gut bacteria capable of converting daidzein to equol,” noted the authors. The ability to produce equol is detected more frequently in individuals following vegetarian diets than in omnivores and … has been proposed as a factor in soy’s apparent health benefits.”

The study found that total hot flash frequency decreased by 78% in the intervention group (P < .001) and 39% (P < .001) in the control group (between-group P = .003), and moderate to severe hot flashes decreased by 88% versus 34%, respectively (from 5.0 to 0.6 per day, P < .001 vs. from 4.4 to 2.9 per day, P < .001; between-group P < .001). Among participants with at least seven moderate to severe hot flashes per day at baseline, moderate to severe hot flashes decreased by 93% (from 10.6 to 0.7 per day) in the intervention group (P < .001) and 36% (from 9.0 to 5.8 per day) in the control group (P = .01, between-group P < .001). The changes in hot flashes were paralleled by changes in the MENQOL findings, with significant between-group differences in the vasomotor (P = 0.004), physical (P = 0.01), and sexual (P = 0.03) domains.

Changes in frequency of severe hot flashes correlated directly with changes in fat intake, and inversely with changes in carbohydrate and fiber intake, such that “the greater the reduction in fat intake and the greater the increases in carbohydrate and fiber consumption, the greater the reduction in severe hot flashes,” noted the researchers. Mean body weight also decreased by 3.6 kg in the intervention group and 0.2 kg in the control group (P < .001). “Equol-production status had no apparent effect on hot flashes,” they added.

The study is the second phase of WAVS, which comprises two parts, the first of which showed similar results, but was conducted in the fall, raising questions about whether cooler temperatures were partly responsible for the results. Phase 2 of WAVS enrolled participants in the spring “ruling out the effect of outside temperature,” noted the authors.

“Eating a healthy diet at midlife is so important for long-term health and a sense of well-being for peri- and postmenopausal women,” said Dr Reed, but she urged caution in interpreting the findings. “This was an unblinded study,” she told this news organization. “Women were recruited to this study anticipating that they would be in a study on a soy diet. Individuals who sign up for a study are hoping for benefit from the intervention. The controls who don’t get the soy diet are often disappointed, so there is no benefit from a nonblinded control arm for their hot flashes. And that is exactly what we saw here. Blinded studies can hide what you are getting, so everyone in the study (intervention and controls) has the same anticipated benefit.  But you cannot blind a soy diet.”

Dr. Reed also noted that, while the biologic mechanism of benefit should be equol production, this was not shown – given that both equol producers and nonproducers in the soy intervention reported marked symptom reduction.

“Only prior studies with estrogen interventions have observed reductions of hot flashes of the amount reported here,” she concluded. “Hopefully future large studies will clarify the role of soy diet for decreasing hot flashes.”

Dr. Barnard writes books and articles and gives lectures related to nutrition and health and has received royalties and honoraria from these sources. Dr. Reed has no relevant disclosures.

Women eating a reduced-fat vegan diet combined with a daily serving of soybeans experienced a 78% reduction in frequency of menopausal hot flashes over 12 weeks, in a small, nonblinded, randomized-controlled trial.

“We do not fully understand yet why this combination works, but it seems that these three elements are key: avoiding animal products, reducing fat, and adding a serving of soybeans,” lead researcher Neal Barnard, MD, explained in a press release. “These new results suggest that a diet change should be considered as a first-line treatment for troublesome vasomotor symptoms, including night sweats and hot flashes,” added Dr. Barnard, who is president of the Physicians Committee for Responsible Medicine, and adjunct professor at George Washington University, Washington. 

Elliott O’Donovan Photography

But, while “the findings from this very small study complement everything we know about the benefits of an excellent diet and the health benefits of soy,” they should be interpreted with some caution, commented Susan Reed, MD, president of the North American Menopause Society, and associate program director of the women’s reproductive research program at the University of Washington, Seattle.

For the trial, called WAVS (Women’s Study for the Alleviation of Vasomotor Symptoms), the researchers randomized 84 postmenopausal women with at least two moderate to severe hot flashes daily to either the intervention or usual diet, with a total of 71 subjects completing the 12-week study, published in Menopause. Criteria for exclusion included any cause of vasomotor symptoms other than natural menopause, current use of a low-fat, vegan diet that includes daily soy products, soy allergy, and body mass index < 18.5 kg/m².

Participants in the intervention group were asked to avoid animal-derived foods, minimize their use of oils and fatty foods such as nuts and avocados, and include half a cup (86 g) of cooked soybeans daily in their diets. They were also offered 1-hour virtual group meetings each week, in which a registered dietitian or research staff provided information on food preparation and managing common dietary challenges.

Control group participants were asked to continue their usual diets and attend four 1-hour group sessions.

At baseline and then after the 12-week study period, dietary intake was self-recorded for 2 weekdays and 1 weekend day, hot flash frequency and severity was recorded for 1 week using a mobile app, and the effect of menopausal symptoms on quality of life was measured using the vasomotor, psychosocial, physical, and sexual domains of the Menopause-Specific Quality of Life (MENQOL) questionnaire.

Equol production was also assessed in a subset of 15 intervention and 12 control participants who had urinary isoflavone concentrations measured after eating half a cup (86 g) of soybeans twice daily for 3 days. This was based on the theory that diets such as the intervention in this study “seem to foster the growth of gut bacteria capable of converting daidzein to equol,” noted the authors. The ability to produce equol is detected more frequently in individuals following vegetarian diets than in omnivores and … has been proposed as a factor in soy’s apparent health benefits.”

The study found that total hot flash frequency decreased by 78% in the intervention group (P < .001) and 39% (P < .001) in the control group (between-group P = .003), and moderate to severe hot flashes decreased by 88% versus 34%, respectively (from 5.0 to 0.6 per day, P < .001 vs. from 4.4 to 2.9 per day, P < .001; between-group P < .001). Among participants with at least seven moderate to severe hot flashes per day at baseline, moderate to severe hot flashes decreased by 93% (from 10.6 to 0.7 per day) in the intervention group (P < .001) and 36% (from 9.0 to 5.8 per day) in the control group (P = .01, between-group P < .001). The changes in hot flashes were paralleled by changes in the MENQOL findings, with significant between-group differences in the vasomotor (P = 0.004), physical (P = 0.01), and sexual (P = 0.03) domains.

Changes in frequency of severe hot flashes correlated directly with changes in fat intake, and inversely with changes in carbohydrate and fiber intake, such that “the greater the reduction in fat intake and the greater the increases in carbohydrate and fiber consumption, the greater the reduction in severe hot flashes,” noted the researchers. Mean body weight also decreased by 3.6 kg in the intervention group and 0.2 kg in the control group (P < .001). “Equol-production status had no apparent effect on hot flashes,” they added.

The study is the second phase of WAVS, which comprises two parts, the first of which showed similar results, but was conducted in the fall, raising questions about whether cooler temperatures were partly responsible for the results. Phase 2 of WAVS enrolled participants in the spring “ruling out the effect of outside temperature,” noted the authors.

“Eating a healthy diet at midlife is so important for long-term health and a sense of well-being for peri- and postmenopausal women,” said Dr Reed, but she urged caution in interpreting the findings. “This was an unblinded study,” she told this news organization. “Women were recruited to this study anticipating that they would be in a study on a soy diet. Individuals who sign up for a study are hoping for benefit from the intervention. The controls who don’t get the soy diet are often disappointed, so there is no benefit from a nonblinded control arm for their hot flashes. And that is exactly what we saw here. Blinded studies can hide what you are getting, so everyone in the study (intervention and controls) has the same anticipated benefit.  But you cannot blind a soy diet.”

Dr. Reed also noted that, while the biologic mechanism of benefit should be equol production, this was not shown – given that both equol producers and nonproducers in the soy intervention reported marked symptom reduction.

“Only prior studies with estrogen interventions have observed reductions of hot flashes of the amount reported here,” she concluded. “Hopefully future large studies will clarify the role of soy diet for decreasing hot flashes.”

Dr. Barnard writes books and articles and gives lectures related to nutrition and health and has received royalties and honoraria from these sources. Dr. Reed has no relevant disclosures.

Women eating a reduced-fat vegan diet combined with a daily serving of soybeans experienced a 78% reduction in frequency of menopausal hot flashes over 12 weeks, in a small, nonblinded, randomized-controlled trial.

“We do not fully understand yet why this combination works, but it seems that these three elements are key: avoiding animal products, reducing fat, and adding a serving of soybeans,” lead researcher Neal Barnard, MD, explained in a press release. “These new results suggest that a diet change should be considered as a first-line treatment for troublesome vasomotor symptoms, including night sweats and hot flashes,” added Dr. Barnard, who is president of the Physicians Committee for Responsible Medicine, and adjunct professor at George Washington University, Washington. 

Elliott O’Donovan Photography

But, while “the findings from this very small study complement everything we know about the benefits of an excellent diet and the health benefits of soy,” they should be interpreted with some caution, commented Susan Reed, MD, president of the North American Menopause Society, and associate program director of the women’s reproductive research program at the University of Washington, Seattle.

For the trial, called WAVS (Women’s Study for the Alleviation of Vasomotor Symptoms), the researchers randomized 84 postmenopausal women with at least two moderate to severe hot flashes daily to either the intervention or usual diet, with a total of 71 subjects completing the 12-week study, published in Menopause. Criteria for exclusion included any cause of vasomotor symptoms other than natural menopause, current use of a low-fat, vegan diet that includes daily soy products, soy allergy, and body mass index < 18.5 kg/m².

Participants in the intervention group were asked to avoid animal-derived foods, minimize their use of oils and fatty foods such as nuts and avocados, and include half a cup (86 g) of cooked soybeans daily in their diets. They were also offered 1-hour virtual group meetings each week, in which a registered dietitian or research staff provided information on food preparation and managing common dietary challenges.

Control group participants were asked to continue their usual diets and attend four 1-hour group sessions.

At baseline and then after the 12-week study period, dietary intake was self-recorded for 2 weekdays and 1 weekend day, hot flash frequency and severity was recorded for 1 week using a mobile app, and the effect of menopausal symptoms on quality of life was measured using the vasomotor, psychosocial, physical, and sexual domains of the Menopause-Specific Quality of Life (MENQOL) questionnaire.

Equol production was also assessed in a subset of 15 intervention and 12 control participants who had urinary isoflavone concentrations measured after eating half a cup (86 g) of soybeans twice daily for 3 days. This was based on the theory that diets such as the intervention in this study “seem to foster the growth of gut bacteria capable of converting daidzein to equol,” noted the authors. The ability to produce equol is detected more frequently in individuals following vegetarian diets than in omnivores and … has been proposed as a factor in soy’s apparent health benefits.”

The study found that total hot flash frequency decreased by 78% in the intervention group (P < .001) and 39% (P < .001) in the control group (between-group P = .003), and moderate to severe hot flashes decreased by 88% versus 34%, respectively (from 5.0 to 0.6 per day, P < .001 vs. from 4.4 to 2.9 per day, P < .001; between-group P < .001). Among participants with at least seven moderate to severe hot flashes per day at baseline, moderate to severe hot flashes decreased by 93% (from 10.6 to 0.7 per day) in the intervention group (P < .001) and 36% (from 9.0 to 5.8 per day) in the control group (P = .01, between-group P < .001). The changes in hot flashes were paralleled by changes in the MENQOL findings, with significant between-group differences in the vasomotor (P = 0.004), physical (P = 0.01), and sexual (P = 0.03) domains.

Changes in frequency of severe hot flashes correlated directly with changes in fat intake, and inversely with changes in carbohydrate and fiber intake, such that “the greater the reduction in fat intake and the greater the increases in carbohydrate and fiber consumption, the greater the reduction in severe hot flashes,” noted the researchers. Mean body weight also decreased by 3.6 kg in the intervention group and 0.2 kg in the control group (P < .001). “Equol-production status had no apparent effect on hot flashes,” they added.

The study is the second phase of WAVS, which comprises two parts, the first of which showed similar results, but was conducted in the fall, raising questions about whether cooler temperatures were partly responsible for the results. Phase 2 of WAVS enrolled participants in the spring “ruling out the effect of outside temperature,” noted the authors.

“Eating a healthy diet at midlife is so important for long-term health and a sense of well-being for peri- and postmenopausal women,” said Dr Reed, but she urged caution in interpreting the findings. “This was an unblinded study,” she told this news organization. “Women were recruited to this study anticipating that they would be in a study on a soy diet. Individuals who sign up for a study are hoping for benefit from the intervention. The controls who don’t get the soy diet are often disappointed, so there is no benefit from a nonblinded control arm for their hot flashes. And that is exactly what we saw here. Blinded studies can hide what you are getting, so everyone in the study (intervention and controls) has the same anticipated benefit.  But you cannot blind a soy diet.”

Dr. Reed also noted that, while the biologic mechanism of benefit should be equol production, this was not shown – given that both equol producers and nonproducers in the soy intervention reported marked symptom reduction.

“Only prior studies with estrogen interventions have observed reductions of hot flashes of the amount reported here,” she concluded. “Hopefully future large studies will clarify the role of soy diet for decreasing hot flashes.”

Dr. Barnard writes books and articles and gives lectures related to nutrition and health and has received royalties and honoraria from these sources. Dr. Reed has no relevant disclosures.

Vitamin D deficiency increases mortality risk and raising levels even slightly could decrease the risk, researchers examining data from the UK Biobank have found.

They used a Mendelian randomization approach, which uses genetic variants as “proxy indicators” for external factors that affect vitamin D levels, such as sun exposure or dietary intake. It allows for analysis of the relationship between deficiency and outcomes including mortality, which can’t be done in randomized clinical trials for ethical reasons.

Using this method, nutritionist Joshua P. Sutherland, PhD, of the Australian Centre for Precision Health, Adelaide, and colleagues found an association between genetically predicted vitamin D levels [25-(OH)D] and mortality from several major causes, with evidence of causality among people with measured concentrations below, but not above, 50 nmol/L. The findings were published online in Annals of Internal Medicine.

Genetic approach reveals causal relationship

The investigators analyzed data from 307,601 individuals in the UK Biobank, a prospective cohort of people recruited from England, Scotland, and Wales during March 2006 and July 2010. Most were of White European ancestry and were aged 37-73 years at baseline.

Genetically predicted vitamin D levels were estimated using 35 confirmed 25-(OH)D variants. Participants were followed for outcomes up to June 2020.

The average baseline measured 25-(OH)D concentration was 45.2 nmol/L, and 11.7% (n = 36,009) of participants had levels between 10.0  and 24.9 nmol/L. Higher levels were seen in people living in southern areas and nonsmokers as well as those with a higher level of physical activity, less socioeconomic deprivation, and lower body mass index.

During follow-up, 6.1% of participants died (n = 18,700). After adjustment for variables, odds ratios for all causes of mortality were highest among people with 25-(OH)D levels below 25 nmol/L and appeared to plateau between 50 and 75 nmol/L, with no further reduction in mortality at values of 75-125 nmol/L.
 

Mortality 36% higher in those deficient in vitamin D

The risk for mortality was a significant 36% higher for participants with 25-(OH)D 25 nmol/L compared with 50 nmol/L.

With the Mendelian randomization, there was an L-shaped association between genetically predicted 25-(OH)D level and all-cause mortality (P for nonlinearity < .001) and for mortality because of cancer and cardiovascular disease (P for nonlinearity ≤ .033).

Again, the strongest association with those outcomes and genetically predicted 25-(OH)D was found at levels below 25 nmol/L and a plateau was seen by 50 nmol/L.

Compared with a measured 25-(OH)D concentration of 50 nmol/L, investigators estimated that the genetically predicted odds of all-cause mortality would increase sixfold (odds ratio, 6.00) for participants at 10 nmol/L and by 25% (OR, 1.25) for those at 25 nmol/L.

And, compared with a measured 25-(OH)D concentration of 50 nmol/L, those with 10 nmol/L had genetically predicted odds ratios of 5.98 for cardiovascular mortality, 3.37 for cancer mortality, and 12.44 for respiratory mortality.

Comparing measured 25-(OH)D concentrations of 25 nmol/L versus 50 nmol/L, odds ratios for those outcomes were 1.25, 1.16, and 1.96 (95% confidence interval, 1.88-4.67), respectively. All were statistically significant.

Consistent results supportive of a causal effect of genetically predicted 25-(OH)D on all-cause mortality in those with low measured vitamin D concentrations were also found in a sensitivity analysis of 20,837 people of non-White ethnic origin.

The study was funded by the Australian National Health and Medical Research Council. Dr. Sutherland’s studentship is funded by an Australian Research Training Program Scholarship.

A version of this article first appeared on Medscape.com.  

Vitamin D deficiency increases mortality risk and raising levels even slightly could decrease the risk, researchers examining data from the UK Biobank have found.

They used a Mendelian randomization approach, which uses genetic variants as “proxy indicators” for external factors that affect vitamin D levels, such as sun exposure or dietary intake. It allows for analysis of the relationship between deficiency and outcomes including mortality, which can’t be done in randomized clinical trials for ethical reasons.

Using this method, nutritionist Joshua P. Sutherland, PhD, of the Australian Centre for Precision Health, Adelaide, and colleagues found an association between genetically predicted vitamin D levels [25-(OH)D] and mortality from several major causes, with evidence of causality among people with measured concentrations below, but not above, 50 nmol/L. The findings were published online in Annals of Internal Medicine.

Genetic approach reveals causal relationship

The investigators analyzed data from 307,601 individuals in the UK Biobank, a prospective cohort of people recruited from England, Scotland, and Wales during March 2006 and July 2010. Most were of White European ancestry and were aged 37-73 years at baseline.

Genetically predicted vitamin D levels were estimated using 35 confirmed 25-(OH)D variants. Participants were followed for outcomes up to June 2020.

The average baseline measured 25-(OH)D concentration was 45.2 nmol/L, and 11.7% (n = 36,009) of participants had levels between 10.0  and 24.9 nmol/L. Higher levels were seen in people living in southern areas and nonsmokers as well as those with a higher level of physical activity, less socioeconomic deprivation, and lower body mass index.

During follow-up, 6.1% of participants died (n = 18,700). After adjustment for variables, odds ratios for all causes of mortality were highest among people with 25-(OH)D levels below 25 nmol/L and appeared to plateau between 50 and 75 nmol/L, with no further reduction in mortality at values of 75-125 nmol/L.
 

Mortality 36% higher in those deficient in vitamin D

The risk for mortality was a significant 36% higher for participants with 25-(OH)D 25 nmol/L compared with 50 nmol/L.

With the Mendelian randomization, there was an L-shaped association between genetically predicted 25-(OH)D level and all-cause mortality (P for nonlinearity < .001) and for mortality because of cancer and cardiovascular disease (P for nonlinearity ≤ .033).

Again, the strongest association with those outcomes and genetically predicted 25-(OH)D was found at levels below 25 nmol/L and a plateau was seen by 50 nmol/L.

Compared with a measured 25-(OH)D concentration of 50 nmol/L, investigators estimated that the genetically predicted odds of all-cause mortality would increase sixfold (odds ratio, 6.00) for participants at 10 nmol/L and by 25% (OR, 1.25) for those at 25 nmol/L.

And, compared with a measured 25-(OH)D concentration of 50 nmol/L, those with 10 nmol/L had genetically predicted odds ratios of 5.98 for cardiovascular mortality, 3.37 for cancer mortality, and 12.44 for respiratory mortality.

Comparing measured 25-(OH)D concentrations of 25 nmol/L versus 50 nmol/L, odds ratios for those outcomes were 1.25, 1.16, and 1.96 (95% confidence interval, 1.88-4.67), respectively. All were statistically significant.

Consistent results supportive of a causal effect of genetically predicted 25-(OH)D on all-cause mortality in those with low measured vitamin D concentrations were also found in a sensitivity analysis of 20,837 people of non-White ethnic origin.

The study was funded by the Australian National Health and Medical Research Council. Dr. Sutherland’s studentship is funded by an Australian Research Training Program Scholarship.

A version of this article first appeared on Medscape.com.  

Vitamin D deficiency increases mortality risk and raising levels even slightly could decrease the risk, researchers examining data from the UK Biobank have found.

They used a Mendelian randomization approach, which uses genetic variants as “proxy indicators” for external factors that affect vitamin D levels, such as sun exposure or dietary intake. It allows for analysis of the relationship between deficiency and outcomes including mortality, which can’t be done in randomized clinical trials for ethical reasons.

Using this method, nutritionist Joshua P. Sutherland, PhD, of the Australian Centre for Precision Health, Adelaide, and colleagues found an association between genetically predicted vitamin D levels [25-(OH)D] and mortality from several major causes, with evidence of causality among people with measured concentrations below, but not above, 50 nmol/L. The findings were published online in Annals of Internal Medicine.

Genetic approach reveals causal relationship

The investigators analyzed data from 307,601 individuals in the UK Biobank, a prospective cohort of people recruited from England, Scotland, and Wales during March 2006 and July 2010. Most were of White European ancestry and were aged 37-73 years at baseline.

Genetically predicted vitamin D levels were estimated using 35 confirmed 25-(OH)D variants. Participants were followed for outcomes up to June 2020.

The average baseline measured 25-(OH)D concentration was 45.2 nmol/L, and 11.7% (n = 36,009) of participants had levels between 10.0  and 24.9 nmol/L. Higher levels were seen in people living in southern areas and nonsmokers as well as those with a higher level of physical activity, less socioeconomic deprivation, and lower body mass index.

During follow-up, 6.1% of participants died (n = 18,700). After adjustment for variables, odds ratios for all causes of mortality were highest among people with 25-(OH)D levels below 25 nmol/L and appeared to plateau between 50 and 75 nmol/L, with no further reduction in mortality at values of 75-125 nmol/L.
 

Mortality 36% higher in those deficient in vitamin D

The risk for mortality was a significant 36% higher for participants with 25-(OH)D 25 nmol/L compared with 50 nmol/L.

With the Mendelian randomization, there was an L-shaped association between genetically predicted 25-(OH)D level and all-cause mortality (P for nonlinearity < .001) and for mortality because of cancer and cardiovascular disease (P for nonlinearity ≤ .033).

Again, the strongest association with those outcomes and genetically predicted 25-(OH)D was found at levels below 25 nmol/L and a plateau was seen by 50 nmol/L.

Compared with a measured 25-(OH)D concentration of 50 nmol/L, investigators estimated that the genetically predicted odds of all-cause mortality would increase sixfold (odds ratio, 6.00) for participants at 10 nmol/L and by 25% (OR, 1.25) for those at 25 nmol/L.

And, compared with a measured 25-(OH)D concentration of 50 nmol/L, those with 10 nmol/L had genetically predicted odds ratios of 5.98 for cardiovascular mortality, 3.37 for cancer mortality, and 12.44 for respiratory mortality.

Comparing measured 25-(OH)D concentrations of 25 nmol/L versus 50 nmol/L, odds ratios for those outcomes were 1.25, 1.16, and 1.96 (95% confidence interval, 1.88-4.67), respectively. All were statistically significant.

Consistent results supportive of a causal effect of genetically predicted 25-(OH)D on all-cause mortality in those with low measured vitamin D concentrations were also found in a sensitivity analysis of 20,837 people of non-White ethnic origin.

The study was funded by the Australian National Health and Medical Research Council. Dr. Sutherland’s studentship is funded by an Australian Research Training Program Scholarship.

A version of this article first appeared on Medscape.com.  

MONTREAL – Patients who discontinue levothyroxine for subclinical hypothyroidism may gravitate towards becoming mildly hypothyroid again, but they importantly show no differences in terms of symptoms and quality of life – and sometimes show even improvement – compared with those who continue treatment, new research shows.

“Our results show feasibility of patient enrollment and safety of discontinuing levothyroxine in patients with subclinical hypothyroidism,” said first author Spyridoula Maraka, MD, when presenting the findings at the American Thyroid Association annual meeting.

Recommendations against levothyroxine for subclinical hypothyroidism

Subclinical hypothyroidism is commonly over-diagnosed, and treatment with thyroid hormone replacement, levothyroxine, has been shown to provide little, if any, benefit in terms of quality of life or relief of thyroid-related symptoms for these patients.

The treatment is meanwhile associated with burdens including cost and lifestyle adjustments, and one guideline panel recently issued a strong recommendation against routine levothyroxine use in most adults with subclinical hypothyroidism.

Nevertheless, levothyroxine treatment has soared in popularity and become one of the most commonly prescribed drugs in the United States.

With research lacking on one key solution of discontinuation of the therapy, Dr. Maraka, who is part of the Division of Endocrinology and Metabolism at the University of Arkansas for Medical Sciences, Little Rock, and colleagues conducted a double-blind, placebo-controlled trial at the Central Arkansas Veterans Healthcare System. In total, 50 patients treated for subclinical hypothyroidism were randomized 1:1 to continue receiving levothyroxine (25-75 mcg daily) or to discontinue treatment and receive a placebo instead, with a planned 6-month follow-up.

In the current interim analysis, Dr. Maraka reported results for the first 40 patients, including 20 randomized to levothyroxine and 20 to discontinuation.

There were no significant differences between the discontinuation and levothyroxine groups at baseline, which were of a similar age (66.2 vs. 70.8 years) and gender (75% women vs. 85% men).

The groups had similar baseline thyroid-stimulating hormone (TSH) levels (3.0 vs. 2.6 mIU/L), free T4 (both 0.9 ng/dL), thyroid peroxidase antibody positivity (17% vs. 11%), and similar clinical symptoms. All patients had at least one elevated TSH reading prior to starting levothyroxine.

With a follow-up of 6-8 weeks, 36.8% of patients in the discontinuation group had subclinical hypothyroidism, compared with 10% of patients who remained on levothyroxine (P = .0648), TSH levels were 5.5 versus 2.7 mIU/L (P = .001) and free T4 levels were 0.8 versus 0.9 ng/dL (P = .011).
 

No differences in symptoms, quality of life between groups

Importantly, there were no significant differences between the discontinuation versus levothyroxine groups in terms of symptoms, and even some improvements with discontinuation, including Thyroid-Specific Quality of Life Patient-Reported Outcome (ThyPRO)-Hypothyroid Symptoms score (4.6 reduction vs. 2.2 increase), tiredness (2.6 reduction vs. 1.1 increase), and EuroQoL 5-Dimension Self-Report Questionnaire (EQ-5D) quality of life score, for which there were no differences between groups.

There were no reports of overt hypothyroidism; hyperthyroidism; cardiovascular events including atrial fibrillation, stroke, or heart failure; osteoporotic fractures; or deaths.

One patient in the discontinuation group had a TSH level of 11 mIU/L at 6-8 weeks and switched to open-label levothyroxine 75 mcg daily. Another patient in the discontinuation group switched to open-label levothyroxine 75 mcg daily at 10 weeks due to fatigue; however, the patient was diagnosed with metastatic colon cancer 1 month later.

The finding that only about a third of patients who discontinued levothyroxine developed subclinical hypothyroidism was lower than expected, Dr. Maraka noted.

“This was ... unexpected ... for us,” she said. “We were expecting a larger number of patients to develop hypothyroidism, but to our surprise, that was not the case.”

“But what is more important is that there was no difference in the quality of life measures,” she added. “If anything, the placebo group was a little better, though the [differences] were not statistically significant.”

Dr. Maraka also noted that in further research and a final 6-month analysis, the authors will look at factors associated with developing subclinical hypothyroidism after treatment discontinuation, among other issues.
 

Discontinuation of levothyroxine is manageable

The results are encouraging, as they provide assurance that discontinuation of levothyroxine is manageable.

“This research will pave the way for initiatives to promote levothyroxine deprescription and implementation of evidence-based care for patients with subclinical hypothyroidism,” she said.

In further comments, Dr. Hennessey noted that the dilemma of having patients on levothyroxine who may not be benefitting from treatment is “significant,” with patients sometimes reluctant to discontinue treatment due to concerns of developing hypothyroidism-associated symptoms such as brain fog and weight gain.

He noted, however, that “many with mildly elevated TSH actually go on to normalize with time, so they are not really hypothyroid, [and] if we remove thyroxine from people with normal thyroid function, they will remain normal.”

Dr. Maraka has reported no relevant financial relationships. Dr. Hennessey has reported consulting for pharmaceutical companies to design clinical studies for thyroid medications.

A version of this article first appeared on Medscape.com.

MONTREAL – Patients who discontinue levothyroxine for subclinical hypothyroidism may gravitate towards becoming mildly hypothyroid again, but they importantly show no differences in terms of symptoms and quality of life – and sometimes show even improvement – compared with those who continue treatment, new research shows.

“Our results show feasibility of patient enrollment and safety of discontinuing levothyroxine in patients with subclinical hypothyroidism,” said first author Spyridoula Maraka, MD, when presenting the findings at the American Thyroid Association annual meeting.

Recommendations against levothyroxine for subclinical hypothyroidism

Subclinical hypothyroidism is commonly over-diagnosed, and treatment with thyroid hormone replacement, levothyroxine, has been shown to provide little, if any, benefit in terms of quality of life or relief of thyroid-related symptoms for these patients.

The treatment is meanwhile associated with burdens including cost and lifestyle adjustments, and one guideline panel recently issued a strong recommendation against routine levothyroxine use in most adults with subclinical hypothyroidism.

Nevertheless, levothyroxine treatment has soared in popularity and become one of the most commonly prescribed drugs in the United States.

With research lacking on one key solution of discontinuation of the therapy, Dr. Maraka, who is part of the Division of Endocrinology and Metabolism at the University of Arkansas for Medical Sciences, Little Rock, and colleagues conducted a double-blind, placebo-controlled trial at the Central Arkansas Veterans Healthcare System. In total, 50 patients treated for subclinical hypothyroidism were randomized 1:1 to continue receiving levothyroxine (25-75 mcg daily) or to discontinue treatment and receive a placebo instead, with a planned 6-month follow-up.

In the current interim analysis, Dr. Maraka reported results for the first 40 patients, including 20 randomized to levothyroxine and 20 to discontinuation.

There were no significant differences between the discontinuation and levothyroxine groups at baseline, which were of a similar age (66.2 vs. 70.8 years) and gender (75% women vs. 85% men).

The groups had similar baseline thyroid-stimulating hormone (TSH) levels (3.0 vs. 2.6 mIU/L), free T4 (both 0.9 ng/dL), thyroid peroxidase antibody positivity (17% vs. 11%), and similar clinical symptoms. All patients had at least one elevated TSH reading prior to starting levothyroxine.

With a follow-up of 6-8 weeks, 36.8% of patients in the discontinuation group had subclinical hypothyroidism, compared with 10% of patients who remained on levothyroxine (P = .0648), TSH levels were 5.5 versus 2.7 mIU/L (P = .001) and free T4 levels were 0.8 versus 0.9 ng/dL (P = .011).
 

No differences in symptoms, quality of life between groups

Importantly, there were no significant differences between the discontinuation versus levothyroxine groups in terms of symptoms, and even some improvements with discontinuation, including Thyroid-Specific Quality of Life Patient-Reported Outcome (ThyPRO)-Hypothyroid Symptoms score (4.6 reduction vs. 2.2 increase), tiredness (2.6 reduction vs. 1.1 increase), and EuroQoL 5-Dimension Self-Report Questionnaire (EQ-5D) quality of life score, for which there were no differences between groups.

There were no reports of overt hypothyroidism; hyperthyroidism; cardiovascular events including atrial fibrillation, stroke, or heart failure; osteoporotic fractures; or deaths.

One patient in the discontinuation group had a TSH level of 11 mIU/L at 6-8 weeks and switched to open-label levothyroxine 75 mcg daily. Another patient in the discontinuation group switched to open-label levothyroxine 75 mcg daily at 10 weeks due to fatigue; however, the patient was diagnosed with metastatic colon cancer 1 month later.

The finding that only about a third of patients who discontinued levothyroxine developed subclinical hypothyroidism was lower than expected, Dr. Maraka noted.

“This was ... unexpected ... for us,” she said. “We were expecting a larger number of patients to develop hypothyroidism, but to our surprise, that was not the case.”

“But what is more important is that there was no difference in the quality of life measures,” she added. “If anything, the placebo group was a little better, though the [differences] were not statistically significant.”

Dr. Maraka also noted that in further research and a final 6-month analysis, the authors will look at factors associated with developing subclinical hypothyroidism after treatment discontinuation, among other issues.
 

Discontinuation of levothyroxine is manageable

The results are encouraging, as they provide assurance that discontinuation of levothyroxine is manageable.

“This research will pave the way for initiatives to promote levothyroxine deprescription and implementation of evidence-based care for patients with subclinical hypothyroidism,” she said.

In further comments, Dr. Hennessey noted that the dilemma of having patients on levothyroxine who may not be benefitting from treatment is “significant,” with patients sometimes reluctant to discontinue treatment due to concerns of developing hypothyroidism-associated symptoms such as brain fog and weight gain.

He noted, however, that “many with mildly elevated TSH actually go on to normalize with time, so they are not really hypothyroid, [and] if we remove thyroxine from people with normal thyroid function, they will remain normal.”

Dr. Maraka has reported no relevant financial relationships. Dr. Hennessey has reported consulting for pharmaceutical companies to design clinical studies for thyroid medications.

A version of this article first appeared on Medscape.com.

MONTREAL – Patients who discontinue levothyroxine for subclinical hypothyroidism may gravitate towards becoming mildly hypothyroid again, but they importantly show no differences in terms of symptoms and quality of life – and sometimes show even improvement – compared with those who continue treatment, new research shows.

“Our results show feasibility of patient enrollment and safety of discontinuing levothyroxine in patients with subclinical hypothyroidism,” said first author Spyridoula Maraka, MD, when presenting the findings at the American Thyroid Association annual meeting.

Recommendations against levothyroxine for subclinical hypothyroidism

Subclinical hypothyroidism is commonly over-diagnosed, and treatment with thyroid hormone replacement, levothyroxine, has been shown to provide little, if any, benefit in terms of quality of life or relief of thyroid-related symptoms for these patients.

The treatment is meanwhile associated with burdens including cost and lifestyle adjustments, and one guideline panel recently issued a strong recommendation against routine levothyroxine use in most adults with subclinical hypothyroidism.

Nevertheless, levothyroxine treatment has soared in popularity and become one of the most commonly prescribed drugs in the United States.

With research lacking on one key solution of discontinuation of the therapy, Dr. Maraka, who is part of the Division of Endocrinology and Metabolism at the University of Arkansas for Medical Sciences, Little Rock, and colleagues conducted a double-blind, placebo-controlled trial at the Central Arkansas Veterans Healthcare System. In total, 50 patients treated for subclinical hypothyroidism were randomized 1:1 to continue receiving levothyroxine (25-75 mcg daily) or to discontinue treatment and receive a placebo instead, with a planned 6-month follow-up.

In the current interim analysis, Dr. Maraka reported results for the first 40 patients, including 20 randomized to levothyroxine and 20 to discontinuation.

There were no significant differences between the discontinuation and levothyroxine groups at baseline, which were of a similar age (66.2 vs. 70.8 years) and gender (75% women vs. 85% men).

The groups had similar baseline thyroid-stimulating hormone (TSH) levels (3.0 vs. 2.6 mIU/L), free T4 (both 0.9 ng/dL), thyroid peroxidase antibody positivity (17% vs. 11%), and similar clinical symptoms. All patients had at least one elevated TSH reading prior to starting levothyroxine.

With a follow-up of 6-8 weeks, 36.8% of patients in the discontinuation group had subclinical hypothyroidism, compared with 10% of patients who remained on levothyroxine (P = .0648), TSH levels were 5.5 versus 2.7 mIU/L (P = .001) and free T4 levels were 0.8 versus 0.9 ng/dL (P = .011).
 

No differences in symptoms, quality of life between groups

Importantly, there were no significant differences between the discontinuation versus levothyroxine groups in terms of symptoms, and even some improvements with discontinuation, including Thyroid-Specific Quality of Life Patient-Reported Outcome (ThyPRO)-Hypothyroid Symptoms score (4.6 reduction vs. 2.2 increase), tiredness (2.6 reduction vs. 1.1 increase), and EuroQoL 5-Dimension Self-Report Questionnaire (EQ-5D) quality of life score, for which there were no differences between groups.

There were no reports of overt hypothyroidism; hyperthyroidism; cardiovascular events including atrial fibrillation, stroke, or heart failure; osteoporotic fractures; or deaths.

One patient in the discontinuation group had a TSH level of 11 mIU/L at 6-8 weeks and switched to open-label levothyroxine 75 mcg daily. Another patient in the discontinuation group switched to open-label levothyroxine 75 mcg daily at 10 weeks due to fatigue; however, the patient was diagnosed with metastatic colon cancer 1 month later.

The finding that only about a third of patients who discontinued levothyroxine developed subclinical hypothyroidism was lower than expected, Dr. Maraka noted.

“This was ... unexpected ... for us,” she said. “We were expecting a larger number of patients to develop hypothyroidism, but to our surprise, that was not the case.”

“But what is more important is that there was no difference in the quality of life measures,” she added. “If anything, the placebo group was a little better, though the [differences] were not statistically significant.”

Dr. Maraka also noted that in further research and a final 6-month analysis, the authors will look at factors associated with developing subclinical hypothyroidism after treatment discontinuation, among other issues.
 

Discontinuation of levothyroxine is manageable

The results are encouraging, as they provide assurance that discontinuation of levothyroxine is manageable.

“This research will pave the way for initiatives to promote levothyroxine deprescription and implementation of evidence-based care for patients with subclinical hypothyroidism,” she said.

In further comments, Dr. Hennessey noted that the dilemma of having patients on levothyroxine who may not be benefitting from treatment is “significant,” with patients sometimes reluctant to discontinue treatment due to concerns of developing hypothyroidism-associated symptoms such as brain fog and weight gain.

He noted, however, that “many with mildly elevated TSH actually go on to normalize with time, so they are not really hypothyroid, [and] if we remove thyroxine from people with normal thyroid function, they will remain normal.”

Dr. Maraka has reported no relevant financial relationships. Dr. Hennessey has reported consulting for pharmaceutical companies to design clinical studies for thyroid medications.

A version of this article first appeared on Medscape.com.

An international group representing leading endocrinology associations has recommended that the name “diabetes insipidus” – which in some cases has led to harm – be changed to eliminate confusion with “diabetes mellitus” and to reflect the former condition’s pathophysiology.

The new proposed names are arginine vasopressin deficiency (AVP-D) for central (also called “cranial”) etiologies and arginine vasopressin resistance (AVP-R) for nephrogenic (kidney) etiologies.

“What we’re proposing is to rename the disease according to the pathophysiology that defines it,” statement co-author Joseph G. Verbalis, MD, professor of medicine and chief of endocrinology and metabolism at Georgetown University Medical Center, Washington, told this news organization.

The statement advises that henceforth the new names be used in manuscripts and the medical literature while keeping the old names in parentheses during a transition period, as in “AVP-deficiency (cranial diabetes insipidus)” and “AVP-resistance (nephrogenic diabetes insipidus).”

The condition formerly known as diabetes insipidus is relatively rare, occurring in about 1 person per 10-15,000 population. It is caused by either deficient production or resistance in the kidney to the hormone AVP, normally produced by the hypothalamus and stored in the pituitary gland. AVP, also called antidiuretic hormone, regulates the body’s water level and urine production by the kidney.

Both etiologies lead to extreme thirst and excessive production of urine. Common causes of the deficiency include head trauma or brain tumor, while resistance in the kidney is often congenital. It is currently treated with a synthetic form of AVP called desmopressin and fluid replacement.
 

What’s in a name?

The proposal to change the name by the Working Group for Renaming Diabetes Insipidus is endorsed by The Endocrine Society, European Society of Endocrinology, Pituitary Society, Society for Endocrinology, European Society for Paediatric Endocrinology, Endocrine Society of Australia, Brazilian Endocrine Society, and Japanese Endocrine Society and is under review by several other societies. It was published as a position statement in several of those society’s journals, with more to follow.

Historically, the word “diabetes,” a Greek word meaning “siphon,” was used in the 1st and 2nd century BC to describe excess flow of urine. The Latin word “mellitus” or “honey” was added in the late 17th century to describe the sweetness of the urine in the dysglycemic condition.

A century later, the Latin word “insipidus,” meaning insipid or tasteless, was coined to distinguish between the two types of polyuria, the position statement details.

In the late 19th to early 20th century, the vasopressor and antidiuretic actions of posterior pituitary extracts were discovered and used to treat people with both the central and nephrogenic etiologies, which were also recognized around that time, yet the name “diabetes insipidus” has persisted.

“From a historical perspective, the name is perfectly appropriate. At the time it was identified, and it was realized that it was different from diabetes mellitus, that was a perfectly appropriate terminology based on what was known in the late 19th century – but not now. It has persisted through the years simply because in medicine there’s a lot of inertia for change ... It’s just always been called that. If there’s not a compelling reason to change a name, generally there’s no move to change it,” Dr. Verbalis observed.  
 

‘Dramatic cases of patient mismanagement’ due to name confusion

Unfortunately, the urgency for the change arose from tragedy. In 2009, a 22-year-old man was admitted to the orthopedics department of a London teaching hospital for a hip replacement. Despite his known panhypopituitarism and diabetes insipidus, the nurses continually checked his blood glucose but didn’t give him desmopressin or sufficient fluids. Laboratory testing showed normal glucose, but his serum sodium was 149 mmol/L. The morning after his operation, he had a fatal cardiac arrest with a serum sodium of 169 mmol/L. 

“The nurses thought he had diabetes mellitus ... So that was death due to failure to recognize that diabetes insipidus is not diabetes mellitus,” Dr. Verbalis said. “If he had been admitted to endocrinology, this wouldn’t have happened. But he was admitted to orthopedics. Non-endocrinologists are not so aware of diabetes insipidus, because it is a rare disease.”

In 2016, National Health Service England issued a patient safety alert about the “risk of severe harm or death when desmopressin is omitted or delayed in patients with cranial diabetes insipidus,” citing at least four incidents within the prior 7 years where omission of desmopressin had resulted in severe dehydration and death, with another 76 cases of omission or delay that were acted on before the patients became critically ill.

Further impetus for the name change came from the results of an anonymous web-based survey of 1,034 adult and pediatric patients with central diabetes insipidus conducted between August 2021 and February 2022. Overall, 80% reported encountering situations in which their condition had been confused with diabetes mellitus by health care professionals, and 85% supported renaming the disease.

There was some divergence in opinion as to what the new name(s) should be, but clear agreement that the term “diabetes” should not be part of it.  

“We’ve only become recently aware that there are dramatic cases of patient mismanagement due to the confusion caused by the word ‘diabetes.’ We think patients should have a voice. If a legitimate patient survey says over 80% think this name should be changed, then I think we as endocrinologists need to pay attention to that,” Dr. Verbalis said.

But while endocrinologists are the ones who see these patients the most often, Dr. Verbalis said a main aim of the position statement “is really to change the mindset of non-endocrinologist doctors and nurses and other health care professionals that this is not diabetes mellitus. It’s a totally different disease. And if we give it a totally different name, then I think they will better recognize that.”

As to how long Dr. Verbalis thinks it will take for the new names to catch on, he pointed out that it’s taken about a decade for the rheumatology field to fully adopt the name “granulomatosis with polyangiitis” as a replacement for “Wegener’s granulomatosis” after the eponymous physician’s Nazi ties were revealed.

“So we’re not anticipating that this is going to change terminology tomorrow. It’s a long process. We just wanted to get the process started,” he said.

Dr. Verbalis has reported consulting for Otsuka.

A version of this article first appeared on Medscape.com.

An international group representing leading endocrinology associations has recommended that the name “diabetes insipidus” – which in some cases has led to harm – be changed to eliminate confusion with “diabetes mellitus” and to reflect the former condition’s pathophysiology.

The new proposed names are arginine vasopressin deficiency (AVP-D) for central (also called “cranial”) etiologies and arginine vasopressin resistance (AVP-R) for nephrogenic (kidney) etiologies.

“What we’re proposing is to rename the disease according to the pathophysiology that defines it,” statement co-author Joseph G. Verbalis, MD, professor of medicine and chief of endocrinology and metabolism at Georgetown University Medical Center, Washington, told this news organization.

The statement advises that henceforth the new names be used in manuscripts and the medical literature while keeping the old names in parentheses during a transition period, as in “AVP-deficiency (cranial diabetes insipidus)” and “AVP-resistance (nephrogenic diabetes insipidus).”

The condition formerly known as diabetes insipidus is relatively rare, occurring in about 1 person per 10-15,000 population. It is caused by either deficient production or resistance in the kidney to the hormone AVP, normally produced by the hypothalamus and stored in the pituitary gland. AVP, also called antidiuretic hormone, regulates the body’s water level and urine production by the kidney.

Both etiologies lead to extreme thirst and excessive production of urine. Common causes of the deficiency include head trauma or brain tumor, while resistance in the kidney is often congenital. It is currently treated with a synthetic form of AVP called desmopressin and fluid replacement.
 

What’s in a name?

The proposal to change the name by the Working Group for Renaming Diabetes Insipidus is endorsed by The Endocrine Society, European Society of Endocrinology, Pituitary Society, Society for Endocrinology, European Society for Paediatric Endocrinology, Endocrine Society of Australia, Brazilian Endocrine Society, and Japanese Endocrine Society and is under review by several other societies. It was published as a position statement in several of those society’s journals, with more to follow.

Historically, the word “diabetes,” a Greek word meaning “siphon,” was used in the 1st and 2nd century BC to describe excess flow of urine. The Latin word “mellitus” or “honey” was added in the late 17th century to describe the sweetness of the urine in the dysglycemic condition.

A century later, the Latin word “insipidus,” meaning insipid or tasteless, was coined to distinguish between the two types of polyuria, the position statement details.

In the late 19th to early 20th century, the vasopressor and antidiuretic actions of posterior pituitary extracts were discovered and used to treat people with both the central and nephrogenic etiologies, which were also recognized around that time, yet the name “diabetes insipidus” has persisted.

“From a historical perspective, the name is perfectly appropriate. At the time it was identified, and it was realized that it was different from diabetes mellitus, that was a perfectly appropriate terminology based on what was known in the late 19th century – but not now. It has persisted through the years simply because in medicine there’s a lot of inertia for change ... It’s just always been called that. If there’s not a compelling reason to change a name, generally there’s no move to change it,” Dr. Verbalis observed.  
 

‘Dramatic cases of patient mismanagement’ due to name confusion

Unfortunately, the urgency for the change arose from tragedy. In 2009, a 22-year-old man was admitted to the orthopedics department of a London teaching hospital for a hip replacement. Despite his known panhypopituitarism and diabetes insipidus, the nurses continually checked his blood glucose but didn’t give him desmopressin or sufficient fluids. Laboratory testing showed normal glucose, but his serum sodium was 149 mmol/L. The morning after his operation, he had a fatal cardiac arrest with a serum sodium of 169 mmol/L. 

“The nurses thought he had diabetes mellitus ... So that was death due to failure to recognize that diabetes insipidus is not diabetes mellitus,” Dr. Verbalis said. “If he had been admitted to endocrinology, this wouldn’t have happened. But he was admitted to orthopedics. Non-endocrinologists are not so aware of diabetes insipidus, because it is a rare disease.”

In 2016, National Health Service England issued a patient safety alert about the “risk of severe harm or death when desmopressin is omitted or delayed in patients with cranial diabetes insipidus,” citing at least four incidents within the prior 7 years where omission of desmopressin had resulted in severe dehydration and death, with another 76 cases of omission or delay that were acted on before the patients became critically ill.

Further impetus for the name change came from the results of an anonymous web-based survey of 1,034 adult and pediatric patients with central diabetes insipidus conducted between August 2021 and February 2022. Overall, 80% reported encountering situations in which their condition had been confused with diabetes mellitus by health care professionals, and 85% supported renaming the disease.

There was some divergence in opinion as to what the new name(s) should be, but clear agreement that the term “diabetes” should not be part of it.  

“We’ve only become recently aware that there are dramatic cases of patient mismanagement due to the confusion caused by the word ‘diabetes.’ We think patients should have a voice. If a legitimate patient survey says over 80% think this name should be changed, then I think we as endocrinologists need to pay attention to that,” Dr. Verbalis said.

But while endocrinologists are the ones who see these patients the most often, Dr. Verbalis said a main aim of the position statement “is really to change the mindset of non-endocrinologist doctors and nurses and other health care professionals that this is not diabetes mellitus. It’s a totally different disease. And if we give it a totally different name, then I think they will better recognize that.”

As to how long Dr. Verbalis thinks it will take for the new names to catch on, he pointed out that it’s taken about a decade for the rheumatology field to fully adopt the name “granulomatosis with polyangiitis” as a replacement for “Wegener’s granulomatosis” after the eponymous physician’s Nazi ties were revealed.

“So we’re not anticipating that this is going to change terminology tomorrow. It’s a long process. We just wanted to get the process started,” he said.

Dr. Verbalis has reported consulting for Otsuka.

A version of this article first appeared on Medscape.com.

An international group representing leading endocrinology associations has recommended that the name “diabetes insipidus” – which in some cases has led to harm – be changed to eliminate confusion with “diabetes mellitus” and to reflect the former condition’s pathophysiology.

The new proposed names are arginine vasopressin deficiency (AVP-D) for central (also called “cranial”) etiologies and arginine vasopressin resistance (AVP-R) for nephrogenic (kidney) etiologies.

“What we’re proposing is to rename the disease according to the pathophysiology that defines it,” statement co-author Joseph G. Verbalis, MD, professor of medicine and chief of endocrinology and metabolism at Georgetown University Medical Center, Washington, told this news organization.

The statement advises that henceforth the new names be used in manuscripts and the medical literature while keeping the old names in parentheses during a transition period, as in “AVP-deficiency (cranial diabetes insipidus)” and “AVP-resistance (nephrogenic diabetes insipidus).”

The condition formerly known as diabetes insipidus is relatively rare, occurring in about 1 person per 10-15,000 population. It is caused by either deficient production or resistance in the kidney to the hormone AVP, normally produced by the hypothalamus and stored in the pituitary gland. AVP, also called antidiuretic hormone, regulates the body’s water level and urine production by the kidney.

Both etiologies lead to extreme thirst and excessive production of urine. Common causes of the deficiency include head trauma or brain tumor, while resistance in the kidney is often congenital. It is currently treated with a synthetic form of AVP called desmopressin and fluid replacement.
 

What’s in a name?

The proposal to change the name by the Working Group for Renaming Diabetes Insipidus is endorsed by The Endocrine Society, European Society of Endocrinology, Pituitary Society, Society for Endocrinology, European Society for Paediatric Endocrinology, Endocrine Society of Australia, Brazilian Endocrine Society, and Japanese Endocrine Society and is under review by several other societies. It was published as a position statement in several of those society’s journals, with more to follow.

Historically, the word “diabetes,” a Greek word meaning “siphon,” was used in the 1st and 2nd century BC to describe excess flow of urine. The Latin word “mellitus” or “honey” was added in the late 17th century to describe the sweetness of the urine in the dysglycemic condition.

A century later, the Latin word “insipidus,” meaning insipid or tasteless, was coined to distinguish between the two types of polyuria, the position statement details.

In the late 19th to early 20th century, the vasopressor and antidiuretic actions of posterior pituitary extracts were discovered and used to treat people with both the central and nephrogenic etiologies, which were also recognized around that time, yet the name “diabetes insipidus” has persisted.

“From a historical perspective, the name is perfectly appropriate. At the time it was identified, and it was realized that it was different from diabetes mellitus, that was a perfectly appropriate terminology based on what was known in the late 19th century – but not now. It has persisted through the years simply because in medicine there’s a lot of inertia for change ... It’s just always been called that. If there’s not a compelling reason to change a name, generally there’s no move to change it,” Dr. Verbalis observed.  
 

‘Dramatic cases of patient mismanagement’ due to name confusion

Unfortunately, the urgency for the change arose from tragedy. In 2009, a 22-year-old man was admitted to the orthopedics department of a London teaching hospital for a hip replacement. Despite his known panhypopituitarism and diabetes insipidus, the nurses continually checked his blood glucose but didn’t give him desmopressin or sufficient fluids. Laboratory testing showed normal glucose, but his serum sodium was 149 mmol/L. The morning after his operation, he had a fatal cardiac arrest with a serum sodium of 169 mmol/L. 

“The nurses thought he had diabetes mellitus ... So that was death due to failure to recognize that diabetes insipidus is not diabetes mellitus,” Dr. Verbalis said. “If he had been admitted to endocrinology, this wouldn’t have happened. But he was admitted to orthopedics. Non-endocrinologists are not so aware of diabetes insipidus, because it is a rare disease.”

In 2016, National Health Service England issued a patient safety alert about the “risk of severe harm or death when desmopressin is omitted or delayed in patients with cranial diabetes insipidus,” citing at least four incidents within the prior 7 years where omission of desmopressin had resulted in severe dehydration and death, with another 76 cases of omission or delay that were acted on before the patients became critically ill.

Further impetus for the name change came from the results of an anonymous web-based survey of 1,034 adult and pediatric patients with central diabetes insipidus conducted between August 2021 and February 2022. Overall, 80% reported encountering situations in which their condition had been confused with diabetes mellitus by health care professionals, and 85% supported renaming the disease.

There was some divergence in opinion as to what the new name(s) should be, but clear agreement that the term “diabetes” should not be part of it.  

“We’ve only become recently aware that there are dramatic cases of patient mismanagement due to the confusion caused by the word ‘diabetes.’ We think patients should have a voice. If a legitimate patient survey says over 80% think this name should be changed, then I think we as endocrinologists need to pay attention to that,” Dr. Verbalis said.

But while endocrinologists are the ones who see these patients the most often, Dr. Verbalis said a main aim of the position statement “is really to change the mindset of non-endocrinologist doctors and nurses and other health care professionals that this is not diabetes mellitus. It’s a totally different disease. And if we give it a totally different name, then I think they will better recognize that.”

As to how long Dr. Verbalis thinks it will take for the new names to catch on, he pointed out that it’s taken about a decade for the rheumatology field to fully adopt the name “granulomatosis with polyangiitis” as a replacement for “Wegener’s granulomatosis” after the eponymous physician’s Nazi ties were revealed.

“So we’re not anticipating that this is going to change terminology tomorrow. It’s a long process. We just wanted to get the process started,” he said.

Dr. Verbalis has reported consulting for Otsuka.

A version of this article first appeared on Medscape.com.

Most adolescents with gender dysphoria who took puberty-blocking drugs for at least 3 months and then progressed to cross-sex hormone treatment were still taking hormones as they entered adulthood, new research of patients at a pioneering Dutch clinic shows.

The study negates past findings that large numbers of youth regret transitioning, say Maria Anna Theodora Catharina van der Loos, MD, and colleagues from the Centre of Expertise on Gender Dysphoria, Amsterdam, in their article published online in The Lancet Child & Adolescent Health. They believe the difference between their findings and those of other studies lies in proper diagnostic evaluation.

“The study aims to demonstrate, with a methodology that is more than adequate, that transgender people who begin their transition in childhood-adolescence do not give up,” Adrián Carrasco Munera, MD, a specialist in family and community medicine and member of the LGTBIQ+ Health Group of the Madrid Society of Family and Community Medicine told the UK Science Media Centre.

The cohort included 720 youth: 220 (31%) were assigned male at birth (AMAB) and 500 (69%) were assigned female at birth (AFAB). At the start of puberty-blocking treatment with a gonadotrophin-releasing hormone agonist, the median age of patients was 14.1 years for AMAB and 16.0 years for AFAB.

Of that cohort, 704 (98%) continued hormone therapy to the end of data collection (Dec. 31, 2018), at which point the median age of patients was 20 years for AMAB and 19 years for AFAB.

Careful consideration of patient needs

All the patients received care at the “Dutch Clinic,” which more than 20 years ago pioneered the approach of giving puberty-blocking drugs to children looking to transition, followed by cross-sex hormones. The study includes the “complete adolescent population” at the facility who met the inclusion criteria.

A similar U.S. study published earlier this year found that 74.4% of individuals who had started gender-affirming hormones before age 18 were still on them 4 years after starting medical treatment.

“However, it is unclear how many of these adolescents [in the U.S. study] used puberty-suppressing treatment before gender-affirming hormone treatment and to what extent they underwent diagnostic evaluation before initiation of medical treatment,” say Dr. van der Loos and colleagues.

She told this news organization that her clinic provides “a thorough diagnostic and mental health assessment” and discussion of fertility preservation prior to any youth being prescribed puberty blockers or cross-sex hormones.

About 40% of adolescents assessed by the gender clinic in Amsterdam go on to receive hormonal treatment.

“The gender identity unit of the Amsterdam UMC is a world leader in all aspects of transgender medicine and is governed by protocolized actions. This is reflected in the quality of the data and methodology of the study, and therefore of its conclusions,” endocrinologist Gilberto Pérez López, MD, Gregorio Marañón General University Hospital, Madrid, told the UK Science Media Centre.

“These findings can and should help and guide the current public and legal debate on the initiation of medical treatment in transgender minors.”

However, he cautioned the study is limited by the fact that the data come from a registry and they looked at only prescriptions issued and not compliance.

Another interesting thing to note in the research is that almost 70% of patients were born girls and they presented at the gender clinics later in adolescence than the natal boys.

“We don’t have a sound reason for this,” Dr. van der Loos noted.

Study limitations

She also acknowledges that the short follow-up data in some individuals make it difficult to draw conclusions about regret, to some extent.

The average use of cross-sex hormones in their study was 3.5 years for males transitioning to females and 2.3 years for females transitioning to males, so on average, this wouldn’t be long enough to see regret, she acknowledged.

Prior research shows that if youth decide to detransition to their natal sex, this can take, on average, 5 years from the start of medical therapy among born females and 7 years among born males.

However, some born males in the study had been taking hormones for 20 years and some natal females for 15 years, said Dr. van der Loos.

Another limitation is that the research only followed individuals until the end of 2018 while some government data estimate that the number of teens identifying as transgender has nearly doubled over the past 5 years.

The authors, Dr. Munera, and Dr. Lopez have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Most adolescents with gender dysphoria who took puberty-blocking drugs for at least 3 months and then progressed to cross-sex hormone treatment were still taking hormones as they entered adulthood, new research of patients at a pioneering Dutch clinic shows.

The study negates past findings that large numbers of youth regret transitioning, say Maria Anna Theodora Catharina van der Loos, MD, and colleagues from the Centre of Expertise on Gender Dysphoria, Amsterdam, in their article published online in The Lancet Child & Adolescent Health. They believe the difference between their findings and those of other studies lies in proper diagnostic evaluation.

“The study aims to demonstrate, with a methodology that is more than adequate, that transgender people who begin their transition in childhood-adolescence do not give up,” Adrián Carrasco Munera, MD, a specialist in family and community medicine and member of the LGTBIQ+ Health Group of the Madrid Society of Family and Community Medicine told the UK Science Media Centre.

The cohort included 720 youth: 220 (31%) were assigned male at birth (AMAB) and 500 (69%) were assigned female at birth (AFAB). At the start of puberty-blocking treatment with a gonadotrophin-releasing hormone agonist, the median age of patients was 14.1 years for AMAB and 16.0 years for AFAB.

Of that cohort, 704 (98%) continued hormone therapy to the end of data collection (Dec. 31, 2018), at which point the median age of patients was 20 years for AMAB and 19 years for AFAB.

Careful consideration of patient needs

All the patients received care at the “Dutch Clinic,” which more than 20 years ago pioneered the approach of giving puberty-blocking drugs to children looking to transition, followed by cross-sex hormones. The study includes the “complete adolescent population” at the facility who met the inclusion criteria.

A similar U.S. study published earlier this year found that 74.4% of individuals who had started gender-affirming hormones before age 18 were still on them 4 years after starting medical treatment.

“However, it is unclear how many of these adolescents [in the U.S. study] used puberty-suppressing treatment before gender-affirming hormone treatment and to what extent they underwent diagnostic evaluation before initiation of medical treatment,” say Dr. van der Loos and colleagues.

She told this news organization that her clinic provides “a thorough diagnostic and mental health assessment” and discussion of fertility preservation prior to any youth being prescribed puberty blockers or cross-sex hormones.

About 40% of adolescents assessed by the gender clinic in Amsterdam go on to receive hormonal treatment.

“The gender identity unit of the Amsterdam UMC is a world leader in all aspects of transgender medicine and is governed by protocolized actions. This is reflected in the quality of the data and methodology of the study, and therefore of its conclusions,” endocrinologist Gilberto Pérez López, MD, Gregorio Marañón General University Hospital, Madrid, told the UK Science Media Centre.

“These findings can and should help and guide the current public and legal debate on the initiation of medical treatment in transgender minors.”

However, he cautioned the study is limited by the fact that the data come from a registry and they looked at only prescriptions issued and not compliance.

Another interesting thing to note in the research is that almost 70% of patients were born girls and they presented at the gender clinics later in adolescence than the natal boys.

“We don’t have a sound reason for this,” Dr. van der Loos noted.

Study limitations

She also acknowledges that the short follow-up data in some individuals make it difficult to draw conclusions about regret, to some extent.

The average use of cross-sex hormones in their study was 3.5 years for males transitioning to females and 2.3 years for females transitioning to males, so on average, this wouldn’t be long enough to see regret, she acknowledged.

Prior research shows that if youth decide to detransition to their natal sex, this can take, on average, 5 years from the start of medical therapy among born females and 7 years among born males.

However, some born males in the study had been taking hormones for 20 years and some natal females for 15 years, said Dr. van der Loos.

Another limitation is that the research only followed individuals until the end of 2018 while some government data estimate that the number of teens identifying as transgender has nearly doubled over the past 5 years.

The authors, Dr. Munera, and Dr. Lopez have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Most adolescents with gender dysphoria who took puberty-blocking drugs for at least 3 months and then progressed to cross-sex hormone treatment were still taking hormones as they entered adulthood, new research of patients at a pioneering Dutch clinic shows.

The study negates past findings that large numbers of youth regret transitioning, say Maria Anna Theodora Catharina van der Loos, MD, and colleagues from the Centre of Expertise on Gender Dysphoria, Amsterdam, in their article published online in The Lancet Child & Adolescent Health. They believe the difference between their findings and those of other studies lies in proper diagnostic evaluation.

“The study aims to demonstrate, with a methodology that is more than adequate, that transgender people who begin their transition in childhood-adolescence do not give up,” Adrián Carrasco Munera, MD, a specialist in family and community medicine and member of the LGTBIQ+ Health Group of the Madrid Society of Family and Community Medicine told the UK Science Media Centre.

The cohort included 720 youth: 220 (31%) were assigned male at birth (AMAB) and 500 (69%) were assigned female at birth (AFAB). At the start of puberty-blocking treatment with a gonadotrophin-releasing hormone agonist, the median age of patients was 14.1 years for AMAB and 16.0 years for AFAB.

Of that cohort, 704 (98%) continued hormone therapy to the end of data collection (Dec. 31, 2018), at which point the median age of patients was 20 years for AMAB and 19 years for AFAB.

Careful consideration of patient needs

All the patients received care at the “Dutch Clinic,” which more than 20 years ago pioneered the approach of giving puberty-blocking drugs to children looking to transition, followed by cross-sex hormones. The study includes the “complete adolescent population” at the facility who met the inclusion criteria.

A similar U.S. study published earlier this year found that 74.4% of individuals who had started gender-affirming hormones before age 18 were still on them 4 years after starting medical treatment.

“However, it is unclear how many of these adolescents [in the U.S. study] used puberty-suppressing treatment before gender-affirming hormone treatment and to what extent they underwent diagnostic evaluation before initiation of medical treatment,” say Dr. van der Loos and colleagues.

She told this news organization that her clinic provides “a thorough diagnostic and mental health assessment” and discussion of fertility preservation prior to any youth being prescribed puberty blockers or cross-sex hormones.

About 40% of adolescents assessed by the gender clinic in Amsterdam go on to receive hormonal treatment.

“The gender identity unit of the Amsterdam UMC is a world leader in all aspects of transgender medicine and is governed by protocolized actions. This is reflected in the quality of the data and methodology of the study, and therefore of its conclusions,” endocrinologist Gilberto Pérez López, MD, Gregorio Marañón General University Hospital, Madrid, told the UK Science Media Centre.

“These findings can and should help and guide the current public and legal debate on the initiation of medical treatment in transgender minors.”

However, he cautioned the study is limited by the fact that the data come from a registry and they looked at only prescriptions issued and not compliance.

Another interesting thing to note in the research is that almost 70% of patients were born girls and they presented at the gender clinics later in adolescence than the natal boys.

“We don’t have a sound reason for this,” Dr. van der Loos noted.

Study limitations

She also acknowledges that the short follow-up data in some individuals make it difficult to draw conclusions about regret, to some extent.

The average use of cross-sex hormones in their study was 3.5 years for males transitioning to females and 2.3 years for females transitioning to males, so on average, this wouldn’t be long enough to see regret, she acknowledged.

Prior research shows that if youth decide to detransition to their natal sex, this can take, on average, 5 years from the start of medical therapy among born females and 7 years among born males.

However, some born males in the study had been taking hormones for 20 years and some natal females for 15 years, said Dr. van der Loos.

Another limitation is that the research only followed individuals until the end of 2018 while some government data estimate that the number of teens identifying as transgender has nearly doubled over the past 5 years.

The authors, Dr. Munera, and Dr. Lopez have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MONTREAL – Amid common patient concerns about weight gain in the treatment of hyperthyroidism, findings from a large study suggest the therapy with the most favorable survival rate – radioiodine – is not associated with an increased risk of weight gain or obesity.

“EGRET is the first large study using population-based linked community and hospital data to elucidate the long-term consequences of treatment modalities for hyperthyroidism,” said co-author Kristien Boelaert, MD, PhD, while presenting the research at the American Thyroid Association annual meeting.

“The administration of [radioiodine] for hyperthyroidism is associated with a survival benefit for patients with hyperthyroidism and is not associated with increased risks of becoming obese,” Dr. Boelaert, a professor of endocrinology and consultant endocrinologist with the Institute of Applied Health Research, University of Birmingham, England, told this news organization.

However, “overall, there was a nearly 10% risk of major adverse cardiac events [MACE] in patients with hyperthyroidism regardless of the treatment modality used,” she noted.

Commenting on the findings, Jonathon O. Russell, MD, said the study offers surprising – but encouraging – results.

The discovery that radioiodine shows no increase in weight gain “contradicts numerous previous studies which have consistently demonstrated weight gain following definitive radioiodine,” Dr. Russell told this news organization.

Overall, however, “these findings reinforce our knowledge that definitive treatment of an overactive thyroid leads to a longer life – even if there is some weight gain,” added Dr. Russell, who is chief of the Division of Head and Neck Endocrine Surgery at Johns Hopkins, Baltimore.
 

Hyperthyroidism associated with serious long-term cardiometabolic issues

Hyperthyroidism is associated with serious long-term cardiovascular and metabolic morbidity and mortality, and treatment is therefore essential. However, the swing to hypothyroidism that often occurs afterward commonly results in regaining the weight lost due to the hyperthyroidism, if not more, potentially leading to obesity and its attendant health risks.

To investigate those risks in relation to the three key hyperthyroidism treatments, the authors conducted the EGRET trial. They identified 62,474 patients in the United Kingdom population-based electronic health record database who had newly diagnosed hyperthyroidism and were treated with antithyroid drugs (73.4%), radioiodine (19.5%), or thyroidectomy (7.1%) between April 1997 and December 2015.

Exclusion criteria included those with less than 6 months of antithyroid drugs as the only form of treatment, thyroid cancer, or pregnancy during the first episode.

With a median follow-up of about 8 years, those who were treated with thyroidectomy had a significantly increased risk of gaining weight, compared with the general population (P < .001), and of developing obesity (body mass index > 30 kg/m2; P = .003), while the corresponding increases with antithyroid drugs and radioiodine were not significantly different, compared with the general population over the same period.

In terms of survival, with an average follow-up of about 11 years per person, about 14% of the cohort died, with rates of 14.4% in the antithyroid drug group, 15.8% in the radioiodine group, and 9.2% in the thyroidectomy group.

Mortality rates were further assessed based on an average treatment effects analysis in which the average change was estimated, compared with the index of antithyroid drugs – for instance, if all were treated instead with radioiodine. In that extension of life analysis, those treated with radioiodine could be expected to die, on average, 1.2 years later than those taking antithyroid drugs (P < .001), while those treated with thyroidectomy would be expected to die 0.6 years later, which was not statistically significant.

Using the same average treatment effects analysis, Dr. Boelaert noted, “we found a slightly increased risk of major adverse cardiovascular events following radioiodine, compared with antithyroid drugs; [however], the risk was very small and may not be clinically relevant.”

“Previous data from our and other groups have shown reduced risks of mortality and cardiovascular death following radioiodine-induced hypothyroidism, although this is not confirmed in all studies.”
 

Weight gain after hyperthyroid treatment drives concerns

The findings are important because weight gain associated with hyperthyroidism treatment is no small matter for many patients, even prompting a lack of adherence to therapy for some, despite its importance, Dr. Boelaert noted.

“Since the majority of patients lose weight as a consequence of being hyperthyroid, it can be expected that they will at least regain the lost weight and possibly even have a weight overshoot,” she explained. “Indeed, many patients are reluctant to accept definitive treatment with surgery or radioiodine out of fear of weight gain.”

“This may cause difficulties to some patients who occasionally may even stop taking antithyroid drugs to prevent this weight regain. Such lack of adherence may have dire consequences and is likely a contributing factor to the increased mortality in these patients,” she observed.

In a previous study of 1,373 patients, Dr. Boelaert and colleagues found that men treated for hyperthyroidism gained an average of 8.0 kg (17.6 lb), and women gained an average of 5.5 kg (12.1 lb).

Compared with the background population, men were significantly more likely to gain weight over the study period (odds ratio, 1.7; P < .001) as were women (OR, 1.3; P < .001). Also in that study, radioiodine was associated with greater weight gain (0.6 kg; P < .001), compared with antithyroid drug treatment alone.

Dr. Russell added that even when weight gain does occur, the payoff of having treated the potentially serious state of hyperthyroidism is a highly beneficial trade-off.

Ultimately, “the goal of treating any patient with Graves’ should be to get them to become hypothyroid as quickly as possible,” he said. “Patients have options, and all of these options can be safe in the right situation.”

“It is unrealistic to think that going from a hyperthyroid state to a low thyroid state will not result in weight gain for many patients,” Dr. Russell added. “But the key point is that overall health is better despite this weight gain.”

Dr. Boelaert has disclosed consulting fees paid to the University of Birmingham by Lilly and Eisai. Dr. Russell has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MONTREAL – Amid common patient concerns about weight gain in the treatment of hyperthyroidism, findings from a large study suggest the therapy with the most favorable survival rate – radioiodine – is not associated with an increased risk of weight gain or obesity.

“EGRET is the first large study using population-based linked community and hospital data to elucidate the long-term consequences of treatment modalities for hyperthyroidism,” said co-author Kristien Boelaert, MD, PhD, while presenting the research at the American Thyroid Association annual meeting.

“The administration of [radioiodine] for hyperthyroidism is associated with a survival benefit for patients with hyperthyroidism and is not associated with increased risks of becoming obese,” Dr. Boelaert, a professor of endocrinology and consultant endocrinologist with the Institute of Applied Health Research, University of Birmingham, England, told this news organization.

However, “overall, there was a nearly 10% risk of major adverse cardiac events [MACE] in patients with hyperthyroidism regardless of the treatment modality used,” she noted.

Commenting on the findings, Jonathon O. Russell, MD, said the study offers surprising – but encouraging – results.

The discovery that radioiodine shows no increase in weight gain “contradicts numerous previous studies which have consistently demonstrated weight gain following definitive radioiodine,” Dr. Russell told this news organization.

Overall, however, “these findings reinforce our knowledge that definitive treatment of an overactive thyroid leads to a longer life – even if there is some weight gain,” added Dr. Russell, who is chief of the Division of Head and Neck Endocrine Surgery at Johns Hopkins, Baltimore.
 

Hyperthyroidism associated with serious long-term cardiometabolic issues

Hyperthyroidism is associated with serious long-term cardiovascular and metabolic morbidity and mortality, and treatment is therefore essential. However, the swing to hypothyroidism that often occurs afterward commonly results in regaining the weight lost due to the hyperthyroidism, if not more, potentially leading to obesity and its attendant health risks.

To investigate those risks in relation to the three key hyperthyroidism treatments, the authors conducted the EGRET trial. They identified 62,474 patients in the United Kingdom population-based electronic health record database who had newly diagnosed hyperthyroidism and were treated with antithyroid drugs (73.4%), radioiodine (19.5%), or thyroidectomy (7.1%) between April 1997 and December 2015.

Exclusion criteria included those with less than 6 months of antithyroid drugs as the only form of treatment, thyroid cancer, or pregnancy during the first episode.

With a median follow-up of about 8 years, those who were treated with thyroidectomy had a significantly increased risk of gaining weight, compared with the general population (P < .001), and of developing obesity (body mass index > 30 kg/m2; P = .003), while the corresponding increases with antithyroid drugs and radioiodine were not significantly different, compared with the general population over the same period.

In terms of survival, with an average follow-up of about 11 years per person, about 14% of the cohort died, with rates of 14.4% in the antithyroid drug group, 15.8% in the radioiodine group, and 9.2% in the thyroidectomy group.

Mortality rates were further assessed based on an average treatment effects analysis in which the average change was estimated, compared with the index of antithyroid drugs – for instance, if all were treated instead with radioiodine. In that extension of life analysis, those treated with radioiodine could be expected to die, on average, 1.2 years later than those taking antithyroid drugs (P < .001), while those treated with thyroidectomy would be expected to die 0.6 years later, which was not statistically significant.

Using the same average treatment effects analysis, Dr. Boelaert noted, “we found a slightly increased risk of major adverse cardiovascular events following radioiodine, compared with antithyroid drugs; [however], the risk was very small and may not be clinically relevant.”

“Previous data from our and other groups have shown reduced risks of mortality and cardiovascular death following radioiodine-induced hypothyroidism, although this is not confirmed in all studies.”
 

Weight gain after hyperthyroid treatment drives concerns

The findings are important because weight gain associated with hyperthyroidism treatment is no small matter for many patients, even prompting a lack of adherence to therapy for some, despite its importance, Dr. Boelaert noted.

“Since the majority of patients lose weight as a consequence of being hyperthyroid, it can be expected that they will at least regain the lost weight and possibly even have a weight overshoot,” she explained. “Indeed, many patients are reluctant to accept definitive treatment with surgery or radioiodine out of fear of weight gain.”

“This may cause difficulties to some patients who occasionally may even stop taking antithyroid drugs to prevent this weight regain. Such lack of adherence may have dire consequences and is likely a contributing factor to the increased mortality in these patients,” she observed.

In a previous study of 1,373 patients, Dr. Boelaert and colleagues found that men treated for hyperthyroidism gained an average of 8.0 kg (17.6 lb), and women gained an average of 5.5 kg (12.1 lb).

Compared with the background population, men were significantly more likely to gain weight over the study period (odds ratio, 1.7; P < .001) as were women (OR, 1.3; P < .001). Also in that study, radioiodine was associated with greater weight gain (0.6 kg; P < .001), compared with antithyroid drug treatment alone.

Dr. Russell added that even when weight gain does occur, the payoff of having treated the potentially serious state of hyperthyroidism is a highly beneficial trade-off.

Ultimately, “the goal of treating any patient with Graves’ should be to get them to become hypothyroid as quickly as possible,” he said. “Patients have options, and all of these options can be safe in the right situation.”

“It is unrealistic to think that going from a hyperthyroid state to a low thyroid state will not result in weight gain for many patients,” Dr. Russell added. “But the key point is that overall health is better despite this weight gain.”

Dr. Boelaert has disclosed consulting fees paid to the University of Birmingham by Lilly and Eisai. Dr. Russell has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MONTREAL – Amid common patient concerns about weight gain in the treatment of hyperthyroidism, findings from a large study suggest the therapy with the most favorable survival rate – radioiodine – is not associated with an increased risk of weight gain or obesity.

“EGRET is the first large study using population-based linked community and hospital data to elucidate the long-term consequences of treatment modalities for hyperthyroidism,” said co-author Kristien Boelaert, MD, PhD, while presenting the research at the American Thyroid Association annual meeting.

“The administration of [radioiodine] for hyperthyroidism is associated with a survival benefit for patients with hyperthyroidism and is not associated with increased risks of becoming obese,” Dr. Boelaert, a professor of endocrinology and consultant endocrinologist with the Institute of Applied Health Research, University of Birmingham, England, told this news organization.

However, “overall, there was a nearly 10% risk of major adverse cardiac events [MACE] in patients with hyperthyroidism regardless of the treatment modality used,” she noted.

Commenting on the findings, Jonathon O. Russell, MD, said the study offers surprising – but encouraging – results.

The discovery that radioiodine shows no increase in weight gain “contradicts numerous previous studies which have consistently demonstrated weight gain following definitive radioiodine,” Dr. Russell told this news organization.

Overall, however, “these findings reinforce our knowledge that definitive treatment of an overactive thyroid leads to a longer life – even if there is some weight gain,” added Dr. Russell, who is chief of the Division of Head and Neck Endocrine Surgery at Johns Hopkins, Baltimore.
 

Hyperthyroidism associated with serious long-term cardiometabolic issues

Hyperthyroidism is associated with serious long-term cardiovascular and metabolic morbidity and mortality, and treatment is therefore essential. However, the swing to hypothyroidism that often occurs afterward commonly results in regaining the weight lost due to the hyperthyroidism, if not more, potentially leading to obesity and its attendant health risks.

To investigate those risks in relation to the three key hyperthyroidism treatments, the authors conducted the EGRET trial. They identified 62,474 patients in the United Kingdom population-based electronic health record database who had newly diagnosed hyperthyroidism and were treated with antithyroid drugs (73.4%), radioiodine (19.5%), or thyroidectomy (7.1%) between April 1997 and December 2015.

Exclusion criteria included those with less than 6 months of antithyroid drugs as the only form of treatment, thyroid cancer, or pregnancy during the first episode.

With a median follow-up of about 8 years, those who were treated with thyroidectomy had a significantly increased risk of gaining weight, compared with the general population (P < .001), and of developing obesity (body mass index > 30 kg/m2; P = .003), while the corresponding increases with antithyroid drugs and radioiodine were not significantly different, compared with the general population over the same period.

In terms of survival, with an average follow-up of about 11 years per person, about 14% of the cohort died, with rates of 14.4% in the antithyroid drug group, 15.8% in the radioiodine group, and 9.2% in the thyroidectomy group.

Mortality rates were further assessed based on an average treatment effects analysis in which the average change was estimated, compared with the index of antithyroid drugs – for instance, if all were treated instead with radioiodine. In that extension of life analysis, those treated with radioiodine could be expected to die, on average, 1.2 years later than those taking antithyroid drugs (P < .001), while those treated with thyroidectomy would be expected to die 0.6 years later, which was not statistically significant.

Using the same average treatment effects analysis, Dr. Boelaert noted, “we found a slightly increased risk of major adverse cardiovascular events following radioiodine, compared with antithyroid drugs; [however], the risk was very small and may not be clinically relevant.”

“Previous data from our and other groups have shown reduced risks of mortality and cardiovascular death following radioiodine-induced hypothyroidism, although this is not confirmed in all studies.”
 

Weight gain after hyperthyroid treatment drives concerns

The findings are important because weight gain associated with hyperthyroidism treatment is no small matter for many patients, even prompting a lack of adherence to therapy for some, despite its importance, Dr. Boelaert noted.

“Since the majority of patients lose weight as a consequence of being hyperthyroid, it can be expected that they will at least regain the lost weight and possibly even have a weight overshoot,” she explained. “Indeed, many patients are reluctant to accept definitive treatment with surgery or radioiodine out of fear of weight gain.”

“This may cause difficulties to some patients who occasionally may even stop taking antithyroid drugs to prevent this weight regain. Such lack of adherence may have dire consequences and is likely a contributing factor to the increased mortality in these patients,” she observed.

In a previous study of 1,373 patients, Dr. Boelaert and colleagues found that men treated for hyperthyroidism gained an average of 8.0 kg (17.6 lb), and women gained an average of 5.5 kg (12.1 lb).

Compared with the background population, men were significantly more likely to gain weight over the study period (odds ratio, 1.7; P < .001) as were women (OR, 1.3; P < .001). Also in that study, radioiodine was associated with greater weight gain (0.6 kg; P < .001), compared with antithyroid drug treatment alone.

Dr. Russell added that even when weight gain does occur, the payoff of having treated the potentially serious state of hyperthyroidism is a highly beneficial trade-off.

Ultimately, “the goal of treating any patient with Graves’ should be to get them to become hypothyroid as quickly as possible,” he said. “Patients have options, and all of these options can be safe in the right situation.”

“It is unrealistic to think that going from a hyperthyroid state to a low thyroid state will not result in weight gain for many patients,” Dr. Russell added. “But the key point is that overall health is better despite this weight gain.”

Dr. Boelaert has disclosed consulting fees paid to the University of Birmingham by Lilly and Eisai. Dr. Russell has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Diabetes persists as a risk factor for cardiovascular events, but where it once meant the same risk of heart attack or stroke as cardiovascular disease itself, a large Canadian population study reports that’s no longer the case. Thanks to advances in diabetes management over the past quarter century, diabetes is no longer considered equivalent to CVD as a risk factor for cardiovascular events, researchers from the University of Toronto reported.

The retrospective, population-based study used administrative data from Ontario’s provincial universal health care system. The researchers created five population-based cohorts of adults at 5-year intervals from 1994 to 2014, consisting of 1.87 million adults in the first cohort and 1.5 million in the last. In that 20-year span, the prevalence of diabetes in this population tripled, from 3.1% to 9%.

“In the last 25 years we’ve seen wholesale changes in the way people approach diabetes,” lead study author Calvin Ke, MD, PhD, an endocrinologist and assistant professor at the University of Toronto, said in an interview. “Part of the findings show that diabetes and cardiovascular disease were equivalent for risk of cardiovascular events in 1994, but by 2014 that was not the case.”

However, Dr. Ke added, “Diabetes is still a very strong cardiovascular risk factor.”

The investigators for the study, reported as a research letter in JAMA, analyzed the risk of cardiovascular events in four subgroups: those who had both diabetes and CVD, CVD only, diabetes only, and no CVD or diabetes.

Between 1994 and 2014, the cardiovascular event rates declined significantly among people with diabetes alone, compared with people with no disease: from 28.4 to 12.7 per 1,000 person-years, or an absolute risk increase (ARI) of 4.4% and a relative risk (RR) more than double (2.06), in 1994 to 14 vs. 8 per 1,000 person-years, and an ARI of 2% and RR less than double (1.58) 20 years later.

Among people with CVD only, those values shifted from 36.1 per 1,000 person-years, ARI of 5.1% and RR of 2.16 in 1994 to 23.9, ARI of 3.7% and RR still more than double (2.06) in 2014.

People with both CVD and diabetes had the highest CVD event rates across all 5-year cohorts: 74 per 1,000 person-years, ARI of 12% and RR almost four times greater (3.81) in 1994 than people with no disease. By 2014, the ARI in this group was 7.6% and the RR 3.10.

The investigators calculated that event rates from 1994 to 2014 declined across all four subgroups, with rate ratios of 0.49 for diabetes only, 0.66 for CVD only, 0.60 for both diabetes and CVD, and 0.63 for neither disease.

Shift in practice

The study noted that the shift in diabetes as a risk factor for heart attack and stroke is “a change that likely reflects the use of modern, multifactorial approaches to diabetes.”

“A number of changes have occurred in practice that really focus on this idea of a multifactorial approach to diabetes: more aggressive management of blood sugar, blood pressure, and lipids,” Dr. Ke said. “We know from the statin trials that statins can reduce the risk of heart disease significantly, and the use of statins increased from 28.4% in 1999 to 56.3% in 2018 in the United States,” Dr. Ke said. He added that statin use in Canada in adults ages 40 and older went from 1.2% in 1994 to 58.4% in 2010-2015. Use of ACE inhibitors and angiotensin receptor blockers for hypertension followed similar trends, contributing further to reducing risks for heart attack and stroke, Dr. Ke said.

Dr. Ke also noted that the evolution of guidelines and advances in treatments for both CVD and diabetes since 1994 have contributed to improving risks for people with diabetes. SGLT2 inhibitors have been linked to a 2%-6% reduction in hemoglobin A1c, he said. “All of these factors combined have had a major effect on the reduced risk of cardiovascular events.”

Prakash Deedwania, MD, professor at the University of California, San Francisco, Fresno, said that this study confirms a trend that others have reported regarding the risk of CVD in diabetes. The large database covering millions of adults is a study strength, he said.

And the findings, Dr. Deedwania added, underscore what’s been published in clinical guidelines, notably the American Heart Association scientific statement for managing CVD risk in patients with diabetes. “This means that, from observations made 20-plus years ago, when most people were not being treated for diabetes or heart disease, the pendulum has swung,” he said.

However, he added, “The authors state clearly that it does not mean that diabetes is not associated with a higher risk of cardiovascular events; it just means it is no longer equivalent to CVD.”

Managing diabetes continues to be “particularly important,” Dr. Deedwania said, because the prevalence of diabetes continues to rise. “This is a phenomenal risk, and it emphasizes that, to really conquer or control diabetes, we should make every effort to prevent diabetes,” he said.

Dr. Ke and Dr. Deedwania have no relevant financial relationships to disclose.

Diabetes persists as a risk factor for cardiovascular events, but where it once meant the same risk of heart attack or stroke as cardiovascular disease itself, a large Canadian population study reports that’s no longer the case. Thanks to advances in diabetes management over the past quarter century, diabetes is no longer considered equivalent to CVD as a risk factor for cardiovascular events, researchers from the University of Toronto reported.

The retrospective, population-based study used administrative data from Ontario’s provincial universal health care system. The researchers created five population-based cohorts of adults at 5-year intervals from 1994 to 2014, consisting of 1.87 million adults in the first cohort and 1.5 million in the last. In that 20-year span, the prevalence of diabetes in this population tripled, from 3.1% to 9%.

“In the last 25 years we’ve seen wholesale changes in the way people approach diabetes,” lead study author Calvin Ke, MD, PhD, an endocrinologist and assistant professor at the University of Toronto, said in an interview. “Part of the findings show that diabetes and cardiovascular disease were equivalent for risk of cardiovascular events in 1994, but by 2014 that was not the case.”

However, Dr. Ke added, “Diabetes is still a very strong cardiovascular risk factor.”

The investigators for the study, reported as a research letter in JAMA, analyzed the risk of cardiovascular events in four subgroups: those who had both diabetes and CVD, CVD only, diabetes only, and no CVD or diabetes.

Between 1994 and 2014, the cardiovascular event rates declined significantly among people with diabetes alone, compared with people with no disease: from 28.4 to 12.7 per 1,000 person-years, or an absolute risk increase (ARI) of 4.4% and a relative risk (RR) more than double (2.06), in 1994 to 14 vs. 8 per 1,000 person-years, and an ARI of 2% and RR less than double (1.58) 20 years later.

Among people with CVD only, those values shifted from 36.1 per 1,000 person-years, ARI of 5.1% and RR of 2.16 in 1994 to 23.9, ARI of 3.7% and RR still more than double (2.06) in 2014.

People with both CVD and diabetes had the highest CVD event rates across all 5-year cohorts: 74 per 1,000 person-years, ARI of 12% and RR almost four times greater (3.81) in 1994 than people with no disease. By 2014, the ARI in this group was 7.6% and the RR 3.10.

The investigators calculated that event rates from 1994 to 2014 declined across all four subgroups, with rate ratios of 0.49 for diabetes only, 0.66 for CVD only, 0.60 for both diabetes and CVD, and 0.63 for neither disease.

Shift in practice

The study noted that the shift in diabetes as a risk factor for heart attack and stroke is “a change that likely reflects the use of modern, multifactorial approaches to diabetes.”

“A number of changes have occurred in practice that really focus on this idea of a multifactorial approach to diabetes: more aggressive management of blood sugar, blood pressure, and lipids,” Dr. Ke said. “We know from the statin trials that statins can reduce the risk of heart disease significantly, and the use of statins increased from 28.4% in 1999 to 56.3% in 2018 in the United States,” Dr. Ke said. He added that statin use in Canada in adults ages 40 and older went from 1.2% in 1994 to 58.4% in 2010-2015. Use of ACE inhibitors and angiotensin receptor blockers for hypertension followed similar trends, contributing further to reducing risks for heart attack and stroke, Dr. Ke said.

Dr. Ke also noted that the evolution of guidelines and advances in treatments for both CVD and diabetes since 1994 have contributed to improving risks for people with diabetes. SGLT2 inhibitors have been linked to a 2%-6% reduction in hemoglobin A1c, he said. “All of these factors combined have had a major effect on the reduced risk of cardiovascular events.”

Prakash Deedwania, MD, professor at the University of California, San Francisco, Fresno, said that this study confirms a trend that others have reported regarding the risk of CVD in diabetes. The large database covering millions of adults is a study strength, he said.

And the findings, Dr. Deedwania added, underscore what’s been published in clinical guidelines, notably the American Heart Association scientific statement for managing CVD risk in patients with diabetes. “This means that, from observations made 20-plus years ago, when most people were not being treated for diabetes or heart disease, the pendulum has swung,” he said.

However, he added, “The authors state clearly that it does not mean that diabetes is not associated with a higher risk of cardiovascular events; it just means it is no longer equivalent to CVD.”

Managing diabetes continues to be “particularly important,” Dr. Deedwania said, because the prevalence of diabetes continues to rise. “This is a phenomenal risk, and it emphasizes that, to really conquer or control diabetes, we should make every effort to prevent diabetes,” he said.

Dr. Ke and Dr. Deedwania have no relevant financial relationships to disclose.

Diabetes persists as a risk factor for cardiovascular events, but where it once meant the same risk of heart attack or stroke as cardiovascular disease itself, a large Canadian population study reports that’s no longer the case. Thanks to advances in diabetes management over the past quarter century, diabetes is no longer considered equivalent to CVD as a risk factor for cardiovascular events, researchers from the University of Toronto reported.

The retrospective, population-based study used administrative data from Ontario’s provincial universal health care system. The researchers created five population-based cohorts of adults at 5-year intervals from 1994 to 2014, consisting of 1.87 million adults in the first cohort and 1.5 million in the last. In that 20-year span, the prevalence of diabetes in this population tripled, from 3.1% to 9%.

“In the last 25 years we’ve seen wholesale changes in the way people approach diabetes,” lead study author Calvin Ke, MD, PhD, an endocrinologist and assistant professor at the University of Toronto, said in an interview. “Part of the findings show that diabetes and cardiovascular disease were equivalent for risk of cardiovascular events in 1994, but by 2014 that was not the case.”

However, Dr. Ke added, “Diabetes is still a very strong cardiovascular risk factor.”

The investigators for the study, reported as a research letter in JAMA, analyzed the risk of cardiovascular events in four subgroups: those who had both diabetes and CVD, CVD only, diabetes only, and no CVD or diabetes.

Between 1994 and 2014, the cardiovascular event rates declined significantly among people with diabetes alone, compared with people with no disease: from 28.4 to 12.7 per 1,000 person-years, or an absolute risk increase (ARI) of 4.4% and a relative risk (RR) more than double (2.06), in 1994 to 14 vs. 8 per 1,000 person-years, and an ARI of 2% and RR less than double (1.58) 20 years later.

Among people with CVD only, those values shifted from 36.1 per 1,000 person-years, ARI of 5.1% and RR of 2.16 in 1994 to 23.9, ARI of 3.7% and RR still more than double (2.06) in 2014.

People with both CVD and diabetes had the highest CVD event rates across all 5-year cohorts: 74 per 1,000 person-years, ARI of 12% and RR almost four times greater (3.81) in 1994 than people with no disease. By 2014, the ARI in this group was 7.6% and the RR 3.10.

The investigators calculated that event rates from 1994 to 2014 declined across all four subgroups, with rate ratios of 0.49 for diabetes only, 0.66 for CVD only, 0.60 for both diabetes and CVD, and 0.63 for neither disease.

Shift in practice

The study noted that the shift in diabetes as a risk factor for heart attack and stroke is “a change that likely reflects the use of modern, multifactorial approaches to diabetes.”

“A number of changes have occurred in practice that really focus on this idea of a multifactorial approach to diabetes: more aggressive management of blood sugar, blood pressure, and lipids,” Dr. Ke said. “We know from the statin trials that statins can reduce the risk of heart disease significantly, and the use of statins increased from 28.4% in 1999 to 56.3% in 2018 in the United States,” Dr. Ke said. He added that statin use in Canada in adults ages 40 and older went from 1.2% in 1994 to 58.4% in 2010-2015. Use of ACE inhibitors and angiotensin receptor blockers for hypertension followed similar trends, contributing further to reducing risks for heart attack and stroke, Dr. Ke said.

Dr. Ke also noted that the evolution of guidelines and advances in treatments for both CVD and diabetes since 1994 have contributed to improving risks for people with diabetes. SGLT2 inhibitors have been linked to a 2%-6% reduction in hemoglobin A1c, he said. “All of these factors combined have had a major effect on the reduced risk of cardiovascular events.”

Prakash Deedwania, MD, professor at the University of California, San Francisco, Fresno, said that this study confirms a trend that others have reported regarding the risk of CVD in diabetes. The large database covering millions of adults is a study strength, he said.

And the findings, Dr. Deedwania added, underscore what’s been published in clinical guidelines, notably the American Heart Association scientific statement for managing CVD risk in patients with diabetes. “This means that, from observations made 20-plus years ago, when most people were not being treated for diabetes or heart disease, the pendulum has swung,” he said.

However, he added, “The authors state clearly that it does not mean that diabetes is not associated with a higher risk of cardiovascular events; it just means it is no longer equivalent to CVD.”

Managing diabetes continues to be “particularly important,” Dr. Deedwania said, because the prevalence of diabetes continues to rise. “This is a phenomenal risk, and it emphasizes that, to really conquer or control diabetes, we should make every effort to prevent diabetes,” he said.

Dr. Ke and Dr. Deedwania have no relevant financial relationships to disclose.

Geographic location within the United States appears to have an impact on the specific symptoms of polycystic ovary syndrome (PCOS) that any one particular woman will develop, according to a new prospective cohort study.

Women in California were more likely to exhibit high levels of testosterone (hyperandrogenism), while women in Alabama with PCOS had more metabolic dysfunction and hirsutism.

And although the women in Alabama were younger and had a higher body mass index (BMI), even after adjusting for these factors, the clinical differences were still present between the geographic locations, the authors said.

“This study suggests there are regional differences in hormonal and metabolic parameters in women with PCOS in California and Alabama, highlighting the impact of differing genetic and environmental modulators on PCOS development,” Katherine VanHise, MD, of Cedars-Sinai Medical Center, Los Angeles, and colleagues wrote in their article, published online in the Journal of Clinical Endocrinology and Metabolism.
 

Genetic and environmental factors play a role

Prior research has looked at variations in symptoms of PCOS across countries and identified differences in hirsutism and its prevalence, which is greater in Middle Eastern, Mediterranean, and Indian women, noted senior author Margareta D. Pisarska, MD.

And women of some other backgrounds “are at increased risk of developing metabolic syndrome and insulin resistance, including South Asian, African, and Hispanic women, so they are at a greater risk trajectory of developing manifestations later on in life that can ultimately lead to adverse outcomes in overall health,” Dr. Pisarska, director of the division of reproductive endocrinology and infertility in obstetrics and gynecology at Cedars-Sinai, told this news organization.

“We do see regional differences in the diagnosis of PCOS [in the United States] as well as the manifestations of PCOS including high andrenoemia, hirsutism, and metabolic parameters ... and we need to better understand it because, at least in the entire population, weight was not the entire factor contributing to these differences,” she explained.

“So there are definitely environmental factors and possibly genetic factors that we need to take into consideration as we try to study these women and try to help them decrease their risk of metabolic syndrome later in life,” she noted.
 

Differences not attributable to race either

PCOS is a common endocrine disorder affecting women and female adolescents worldwide. Diagnosis usually requires at least two of the following to be present: ovulatory dysfunction, hyperandrogenism, and/or polycystic ovarian morphology.

Because of the prior work that had identified differences in symptoms among women with PCOS in different countries, the investigators set out to determine if women of the same race would have distinct hormonal and metabolic traits of PCOS in two geographical locations in the United States, suggesting geo-epidemiologic contributors of the disease

They evaluated 889 women at the University of Alabama at Birmingham and 721 at Cedars-Sinai Medical Center. Participants in Birmingham were a mean age of 28 years, had a mean BMI of 33.1 kg/m2, a mean waist-to-hip ratio of 0.8, and a mean hirsute rate of 84.6%. Participants in California were a mean age of 29.5 years, had an average BMI of 30.1 kg/m2, a mean waist-to-hip ratio of 0.9, and a mean hirsute rate of 72.8%.

The study team gathered data on menstrual cycle history, metabolic and hormonal parameters, and demographic data for each participant. They assessed hirsutism based on modified Ferriman-Gallwey scores of four or more. Patients were classified as having hyperandrogenemia if they had elevated androgen values greater than the 95th percentile of all values or androgen values that exceeded laboratory reference ranges.

The findings showed that Alabama women with PCOS had elevated homeostatic model assessment for insulin resistance scores (adjusted beta coefficient, 3.6; P < .001) and were more likely to be hirsute (adjusted odds ratio, 1.8; P < .001) after adjustment for BMI and age than those in California.

In contrast, women with PCOS in California were more likely to have elevated free testosterone and total testosterone values than women in Alabama (both P < .001). These findings persisted after adjusting for age and BMI.

When stratified by White race, these findings were similar. Notably, BMI and waist-to-hip ratio did not vary between regions in Black women with PCOS, although variations in metabolic dysfunction and androgen profiles persisted.

“This study supports regional differences in hormonal and metabolic parameters in women with PCOS in the United States, highlighting the impact of the environment on PCOS phenotype. Individuals of the same race in different geographical locations of the United States may have differing genetic predispositions for developing diseases such as PCOS,” the researchers said.

“Ongoing research is needed to identify modifiable environmental risk factors for PCOS that may be race and ethnic specific to bring precision medicine to the management of PCOS,” they conclude.

This work was supported in part by grants from the National Institutes of Health and an endowment of the Helping Hand of Los Angeles. Dr. VanHise reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Geographic location within the United States appears to have an impact on the specific symptoms of polycystic ovary syndrome (PCOS) that any one particular woman will develop, according to a new prospective cohort study.

Women in California were more likely to exhibit high levels of testosterone (hyperandrogenism), while women in Alabama with PCOS had more metabolic dysfunction and hirsutism.

And although the women in Alabama were younger and had a higher body mass index (BMI), even after adjusting for these factors, the clinical differences were still present between the geographic locations, the authors said.

“This study suggests there are regional differences in hormonal and metabolic parameters in women with PCOS in California and Alabama, highlighting the impact of differing genetic and environmental modulators on PCOS development,” Katherine VanHise, MD, of Cedars-Sinai Medical Center, Los Angeles, and colleagues wrote in their article, published online in the Journal of Clinical Endocrinology and Metabolism.
 

Genetic and environmental factors play a role

Prior research has looked at variations in symptoms of PCOS across countries and identified differences in hirsutism and its prevalence, which is greater in Middle Eastern, Mediterranean, and Indian women, noted senior author Margareta D. Pisarska, MD.

And women of some other backgrounds “are at increased risk of developing metabolic syndrome and insulin resistance, including South Asian, African, and Hispanic women, so they are at a greater risk trajectory of developing manifestations later on in life that can ultimately lead to adverse outcomes in overall health,” Dr. Pisarska, director of the division of reproductive endocrinology and infertility in obstetrics and gynecology at Cedars-Sinai, told this news organization.

“We do see regional differences in the diagnosis of PCOS [in the United States] as well as the manifestations of PCOS including high andrenoemia, hirsutism, and metabolic parameters ... and we need to better understand it because, at least in the entire population, weight was not the entire factor contributing to these differences,” she explained.

“So there are definitely environmental factors and possibly genetic factors that we need to take into consideration as we try to study these women and try to help them decrease their risk of metabolic syndrome later in life,” she noted.
 

Differences not attributable to race either

PCOS is a common endocrine disorder affecting women and female adolescents worldwide. Diagnosis usually requires at least two of the following to be present: ovulatory dysfunction, hyperandrogenism, and/or polycystic ovarian morphology.

Because of the prior work that had identified differences in symptoms among women with PCOS in different countries, the investigators set out to determine if women of the same race would have distinct hormonal and metabolic traits of PCOS in two geographical locations in the United States, suggesting geo-epidemiologic contributors of the disease

They evaluated 889 women at the University of Alabama at Birmingham and 721 at Cedars-Sinai Medical Center. Participants in Birmingham were a mean age of 28 years, had a mean BMI of 33.1 kg/m2, a mean waist-to-hip ratio of 0.8, and a mean hirsute rate of 84.6%. Participants in California were a mean age of 29.5 years, had an average BMI of 30.1 kg/m2, a mean waist-to-hip ratio of 0.9, and a mean hirsute rate of 72.8%.

The study team gathered data on menstrual cycle history, metabolic and hormonal parameters, and demographic data for each participant. They assessed hirsutism based on modified Ferriman-Gallwey scores of four or more. Patients were classified as having hyperandrogenemia if they had elevated androgen values greater than the 95th percentile of all values or androgen values that exceeded laboratory reference ranges.

The findings showed that Alabama women with PCOS had elevated homeostatic model assessment for insulin resistance scores (adjusted beta coefficient, 3.6; P < .001) and were more likely to be hirsute (adjusted odds ratio, 1.8; P < .001) after adjustment for BMI and age than those in California.

In contrast, women with PCOS in California were more likely to have elevated free testosterone and total testosterone values than women in Alabama (both P < .001). These findings persisted after adjusting for age and BMI.

When stratified by White race, these findings were similar. Notably, BMI and waist-to-hip ratio did not vary between regions in Black women with PCOS, although variations in metabolic dysfunction and androgen profiles persisted.

“This study supports regional differences in hormonal and metabolic parameters in women with PCOS in the United States, highlighting the impact of the environment on PCOS phenotype. Individuals of the same race in different geographical locations of the United States may have differing genetic predispositions for developing diseases such as PCOS,” the researchers said.

“Ongoing research is needed to identify modifiable environmental risk factors for PCOS that may be race and ethnic specific to bring precision medicine to the management of PCOS,” they conclude.

This work was supported in part by grants from the National Institutes of Health and an endowment of the Helping Hand of Los Angeles. Dr. VanHise reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Geographic location within the United States appears to have an impact on the specific symptoms of polycystic ovary syndrome (PCOS) that any one particular woman will develop, according to a new prospective cohort study.

Women in California were more likely to exhibit high levels of testosterone (hyperandrogenism), while women in Alabama with PCOS had more metabolic dysfunction and hirsutism.

And although the women in Alabama were younger and had a higher body mass index (BMI), even after adjusting for these factors, the clinical differences were still present between the geographic locations, the authors said.

“This study suggests there are regional differences in hormonal and metabolic parameters in women with PCOS in California and Alabama, highlighting the impact of differing genetic and environmental modulators on PCOS development,” Katherine VanHise, MD, of Cedars-Sinai Medical Center, Los Angeles, and colleagues wrote in their article, published online in the Journal of Clinical Endocrinology and Metabolism.
 

Genetic and environmental factors play a role

Prior research has looked at variations in symptoms of PCOS across countries and identified differences in hirsutism and its prevalence, which is greater in Middle Eastern, Mediterranean, and Indian women, noted senior author Margareta D. Pisarska, MD.

And women of some other backgrounds “are at increased risk of developing metabolic syndrome and insulin resistance, including South Asian, African, and Hispanic women, so they are at a greater risk trajectory of developing manifestations later on in life that can ultimately lead to adverse outcomes in overall health,” Dr. Pisarska, director of the division of reproductive endocrinology and infertility in obstetrics and gynecology at Cedars-Sinai, told this news organization.

“We do see regional differences in the diagnosis of PCOS [in the United States] as well as the manifestations of PCOS including high andrenoemia, hirsutism, and metabolic parameters ... and we need to better understand it because, at least in the entire population, weight was not the entire factor contributing to these differences,” she explained.

“So there are definitely environmental factors and possibly genetic factors that we need to take into consideration as we try to study these women and try to help them decrease their risk of metabolic syndrome later in life,” she noted.
 

Differences not attributable to race either

PCOS is a common endocrine disorder affecting women and female adolescents worldwide. Diagnosis usually requires at least two of the following to be present: ovulatory dysfunction, hyperandrogenism, and/or polycystic ovarian morphology.

Because of the prior work that had identified differences in symptoms among women with PCOS in different countries, the investigators set out to determine if women of the same race would have distinct hormonal and metabolic traits of PCOS in two geographical locations in the United States, suggesting geo-epidemiologic contributors of the disease

They evaluated 889 women at the University of Alabama at Birmingham and 721 at Cedars-Sinai Medical Center. Participants in Birmingham were a mean age of 28 years, had a mean BMI of 33.1 kg/m2, a mean waist-to-hip ratio of 0.8, and a mean hirsute rate of 84.6%. Participants in California were a mean age of 29.5 years, had an average BMI of 30.1 kg/m2, a mean waist-to-hip ratio of 0.9, and a mean hirsute rate of 72.8%.

The study team gathered data on menstrual cycle history, metabolic and hormonal parameters, and demographic data for each participant. They assessed hirsutism based on modified Ferriman-Gallwey scores of four or more. Patients were classified as having hyperandrogenemia if they had elevated androgen values greater than the 95th percentile of all values or androgen values that exceeded laboratory reference ranges.

The findings showed that Alabama women with PCOS had elevated homeostatic model assessment for insulin resistance scores (adjusted beta coefficient, 3.6; P < .001) and were more likely to be hirsute (adjusted odds ratio, 1.8; P < .001) after adjustment for BMI and age than those in California.

In contrast, women with PCOS in California were more likely to have elevated free testosterone and total testosterone values than women in Alabama (both P < .001). These findings persisted after adjusting for age and BMI.

When stratified by White race, these findings were similar. Notably, BMI and waist-to-hip ratio did not vary between regions in Black women with PCOS, although variations in metabolic dysfunction and androgen profiles persisted.

“This study supports regional differences in hormonal and metabolic parameters in women with PCOS in the United States, highlighting the impact of the environment on PCOS phenotype. Individuals of the same race in different geographical locations of the United States may have differing genetic predispositions for developing diseases such as PCOS,” the researchers said.

“Ongoing research is needed to identify modifiable environmental risk factors for PCOS that may be race and ethnic specific to bring precision medicine to the management of PCOS,” they conclude.

This work was supported in part by grants from the National Institutes of Health and an endowment of the Helping Hand of Los Angeles. Dr. VanHise reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

A version of this article first appeared on Medscape.com.

Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

A version of this article first appeared on Medscape.com.

Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

A version of this article first appeared on Medscape.com.

Google the word “dopamine” and you will learn that its nicknames are the “happy hormone” and the “pleasure molecule” and that it is among the most important chemicals in our brains. With The Guardian branding it “the Kim Kardashian of neurotransmitters,” dopamine has become a true pop-science darling – people across the globe have attempted to boost their mood with dopamine fasts and dopamine dressing.

A century ago, however, newly discovered dopamine was seen as an uninspiring chemical, nothing more than a precursor of noradrenaline. It took several stubborn and hardworking scientists to change that view.
 

Levodopa: An indifferent precursor

When Casimir Funk, PhD, a Polish biochemist and the discoverer of vitamins, first synthesized the dopamine precursor levodopa in 1911, he had no idea how important the molecule would prove to be in pharmacology and neurobiology. Nor did Markus Guggenheim, PhD, a Swiss biochemist, who isolated levodopa in 1913 from the seeds of a broad bean, Vicia faba. Dr. Guggenheim administered 1 g of levodopa to a rabbit, with no apparent negative consequences. He then prepared a larger dose (2.5 g) and tested it on himself. “Ten minutes after taking it, I felt very nauseous, I had to vomit twice,” he wrote in his paper. In the body, levodopa is converted into dopamine, which may act as an emetic – an effect Dr. Guggenheim didn’t understand. He simply abandoned his human study, erroneously concluding, on the basis of his animal research, that levodopa is “pharmacologically fairly indifferent.”

Around the same time, several scientists across Europe successfully synthesized dopamine, but those discoveries were shelved without much fanfare. For the next 3 decades, dopamine and levodopa were pushed into academic obscurity. Just before World War II, a group of German scientists showed that levodopa is metabolized to dopamine in the body, while another German researcher, Hermann Blaschko, MD, discovered that dopamine is an intermediary in the synthesis of noradrenaline. Even these findings, however, were not immediately accepted.

The dopamine story picked up pace in the post-war years with the observation that the hormone was present in various tissues and body fluids, although nowhere as abundantly as in the central nervous system. Intrigued, Dr. Blaschko, who (after escaping Nazi Germany, changing his name to Hugh, and starting work at Oxford [England] University) hypothesized that dopamine couldn’t be an unremarkable precursor of noradrenaline – it had to have some physiologic functions of its own. He asked his postdoctoral fellow, Oheh Hornykiewicz, MD, to test a few ideas. Dr. Hornykiewicz soon confirmed that dopamine lowered blood pressure in guinea pigs, proving that dopamine indeed had physiologic activity that was independent of other catecholamines.
 

Reserpine and rabbit ears

While Dr. Blaschko and Dr. Hornykiewicz were puzzling over dopamine’s physiologic role in the body, across the ocean at the National Heart Institute in Maryland, pharmacologist Bernard Brodie, PhD and colleagues were laying the groundwork for the discovery of dopamine’s starring role in the brain.

Spoiler alert: Dr. Brodie’s work showed that a new psychiatric drug known as reserpine was capable of fully depleting the brain’s stores of serotonin and – of greatest significance, as it turned out – mimicking the neuromuscular symptoms typical of Parkinson’s disease. The connection to dopamine would be made by new lab colleague Arvid Carlsson, MD, PhD, who would go on to win a Nobel Prize.

Derived from Rauwolfia serpentina (a plant that for centuries has been used in India for the treatment of mental illness, insomnia, and snake bites), reserpine was introduced in the West as a treatment for schizophrenia.

It worked marvels. In 1954, the press lauded the “dramatic” and seemingly “incredible”: results in treating “hopelessly insane patients.” Reserpine had a downside, however. Reports soon changed in tone regarding the drug’s severe side effects, including headaches, dizziness, vomiting, and, far more disturbingly, symptoms mimicking Parkinson’s disease, from muscular rigidity to tremors.

Dr. Brodie observed that, when reserpine was injected, animals became completely immobile. Serotonin nearly vanished from their brains, but bizarrely, drugs that spur serotonin production did not reverse the rabbits’ immobility.

Dr. Carlsson realized that other catecholamines must be involved in reserpine’s side effects, and he began to search for the culprits. He moved back to his native Sweden and ordered a spectrophotofluorimeter. In one of his experiments, Carlsson injected a pair of rabbits with reserpine, which caused the animals to become catatonic with flattened ears. After the researchers injected the animals with levodopa, within 15 minutes, the rabbits were hopping around, ears proudly vertical. “We were just as excited as the rabbits,” Dr. Carlsson later recalled in a 2016 interview. Dr. Carlsson realized that, because there was no noradrenaline in the rabbits’ brains, dopamine depletion must have been directly responsible for producing reserpine’s motor inhibitory effects.
 

Skeptics are silenced

In 1960, however, the medical community was not yet ready to accept that dopamine was anything but a boring intermediate between levodopa and noradrenaline. At a prestigious London symposium, Dr. Carlsson and his two colleagues presented their hypothesis that dopamine may be a neurotransmitter, thus implicating it in Parkinson’s disease. They were met with harsh criticism. Some of the experts said levodopa was nothing more than a poison. Dr. Carlsson later recalled facing “a profound and nearly unanimous skepticism regarding our points of view.”

That would soon change. Dr. Hornykiewicz, the biochemist who had earlier discovered dopamine’s BP-lowering effects, tested Dr. Carlsson’s ideas using the postmortem brains of Parkinson’s disease patients. It appeared Dr. Carlsson was right: Unlike in healthy brains, the striatum of patients with Parkinson’s disease contained almost no dopamine whatsoever. Beginning in 1961, in collaboration with neurologist Walther Birkmayer, MD, Hornykiewicz injected levodopa into 20 patients with Parkinson’s disease and observed a “miraculous” (albeit temporary) amelioration of rigidity, motionlessness, and speechlessness.

By the late 1960s, levodopa and dopamine were making headlines. A 1969 New York Times article described similar stunning improvements in patients with Parkinson’s disease who were treated with levodopa. A patient who had arrived at a hospital unable to speak, with hands clenched and rigid expression, was suddenly able to stride into his doctor’s office and even jog around. “I might say I’m a human being,” he told reporters. Although the treatment was expensive – equivalent to $210 in 2022 – physicians were deluged with requests for “dopa.” To this day, levodopa remains a gold standard in the treatment of Parkinson’s disease.
 

Still misunderstood

The history of dopamine, however, is not only about Parkinson’s disease but extends to the treatment of schizophrenia and addiction. When in the1940s a French military surgeon started giving a new antihistamine drug, promethazine, to prevent shock in soldiers undergoing surgery, he noticed a bizarre side effect: the soldiers would become euphoric yet oddly calm at the same time.

After the drug was modified by adding a chlorine atom and renamed chlorpromazine, it fast became a go-to treatment for psychosis. At the time, no one made the connection to dopamine. Contemporary doctors believed that it calmed people by lowering body temperature (common treatments for mental illness back in the day included swaddling patients in cold, wet sheets). Yet just like reserpine, chlorpromazine produced range of nasty side effects that closely mimicked Parkinson’s disease. This led a Dutch pharmacologist, Jacques van Rossum, to hypothesize that dopamine receptor blockade could explain chlorpromazine’s antipsychotic effects – an idea that remains widely accepted today.

In the 1970s, dopamine was linked with addiction through research on rodents, and this novel idea caught people’s imagination over the coming decades. A story on dopamine titled, “How We Get Addicted,” made the cover of Time in 1997.

Yet as the dopamine/addiction connection became widespread, it also became oversimplified. According to a 2015 article in Nature Reviews Neuroscience, a wave of low-quality research followed – nonreplicated, insufficient – which led the authors to conclude that we are “addicted to the dopamine theory of addiction.” Just about every pleasure under the sun was being attributed to dopamine, from eating delicious foods and playing computer games to sex, music, and hot showers. As recent science shows, however, dopamine is not simply about pleasure – it’s about reward prediction, response to stress, memory, learning, and even the functioning of the immune system. Since its first synthesis in the early 20th century, dopamine has often been misunderstood and oversimplified – and it seems the story is repeating itself now.

In one of his final interviews, Dr. Carlsson, who passed away in 2018 at the age of 95, warned about playing around with dopamine and, in particular, prescribing drugs that have an inhibitory action on this neurotransmitter. “Dopamine is involved in everything that happens in our brains – all its important functions,” he said.

We should be careful how we handle such a delicate and still little-known system.

A version of this article first appeared on Medscape.com.

Google the word “dopamine” and you will learn that its nicknames are the “happy hormone” and the “pleasure molecule” and that it is among the most important chemicals in our brains. With The Guardian branding it “the Kim Kardashian of neurotransmitters,” dopamine has become a true pop-science darling – people across the globe have attempted to boost their mood with dopamine fasts and dopamine dressing.

A century ago, however, newly discovered dopamine was seen as an uninspiring chemical, nothing more than a precursor of noradrenaline. It took several stubborn and hardworking scientists to change that view.
 

Levodopa: An indifferent precursor

When Casimir Funk, PhD, a Polish biochemist and the discoverer of vitamins, first synthesized the dopamine precursor levodopa in 1911, he had no idea how important the molecule would prove to be in pharmacology and neurobiology. Nor did Markus Guggenheim, PhD, a Swiss biochemist, who isolated levodopa in 1913 from the seeds of a broad bean, Vicia faba. Dr. Guggenheim administered 1 g of levodopa to a rabbit, with no apparent negative consequences. He then prepared a larger dose (2.5 g) and tested it on himself. “Ten minutes after taking it, I felt very nauseous, I had to vomit twice,” he wrote in his paper. In the body, levodopa is converted into dopamine, which may act as an emetic – an effect Dr. Guggenheim didn’t understand. He simply abandoned his human study, erroneously concluding, on the basis of his animal research, that levodopa is “pharmacologically fairly indifferent.”

Around the same time, several scientists across Europe successfully synthesized dopamine, but those discoveries were shelved without much fanfare. For the next 3 decades, dopamine and levodopa were pushed into academic obscurity. Just before World War II, a group of German scientists showed that levodopa is metabolized to dopamine in the body, while another German researcher, Hermann Blaschko, MD, discovered that dopamine is an intermediary in the synthesis of noradrenaline. Even these findings, however, were not immediately accepted.

The dopamine story picked up pace in the post-war years with the observation that the hormone was present in various tissues and body fluids, although nowhere as abundantly as in the central nervous system. Intrigued, Dr. Blaschko, who (after escaping Nazi Germany, changing his name to Hugh, and starting work at Oxford [England] University) hypothesized that dopamine couldn’t be an unremarkable precursor of noradrenaline – it had to have some physiologic functions of its own. He asked his postdoctoral fellow, Oheh Hornykiewicz, MD, to test a few ideas. Dr. Hornykiewicz soon confirmed that dopamine lowered blood pressure in guinea pigs, proving that dopamine indeed had physiologic activity that was independent of other catecholamines.
 

Reserpine and rabbit ears

While Dr. Blaschko and Dr. Hornykiewicz were puzzling over dopamine’s physiologic role in the body, across the ocean at the National Heart Institute in Maryland, pharmacologist Bernard Brodie, PhD and colleagues were laying the groundwork for the discovery of dopamine’s starring role in the brain.

Spoiler alert: Dr. Brodie’s work showed that a new psychiatric drug known as reserpine was capable of fully depleting the brain’s stores of serotonin and – of greatest significance, as it turned out – mimicking the neuromuscular symptoms typical of Parkinson’s disease. The connection to dopamine would be made by new lab colleague Arvid Carlsson, MD, PhD, who would go on to win a Nobel Prize.

Derived from Rauwolfia serpentina (a plant that for centuries has been used in India for the treatment of mental illness, insomnia, and snake bites), reserpine was introduced in the West as a treatment for schizophrenia.

It worked marvels. In 1954, the press lauded the “dramatic” and seemingly “incredible”: results in treating “hopelessly insane patients.” Reserpine had a downside, however. Reports soon changed in tone regarding the drug’s severe side effects, including headaches, dizziness, vomiting, and, far more disturbingly, symptoms mimicking Parkinson’s disease, from muscular rigidity to tremors.

Dr. Brodie observed that, when reserpine was injected, animals became completely immobile. Serotonin nearly vanished from their brains, but bizarrely, drugs that spur serotonin production did not reverse the rabbits’ immobility.

Dr. Carlsson realized that other catecholamines must be involved in reserpine’s side effects, and he began to search for the culprits. He moved back to his native Sweden and ordered a spectrophotofluorimeter. In one of his experiments, Carlsson injected a pair of rabbits with reserpine, which caused the animals to become catatonic with flattened ears. After the researchers injected the animals with levodopa, within 15 minutes, the rabbits were hopping around, ears proudly vertical. “We were just as excited as the rabbits,” Dr. Carlsson later recalled in a 2016 interview. Dr. Carlsson realized that, because there was no noradrenaline in the rabbits’ brains, dopamine depletion must have been directly responsible for producing reserpine’s motor inhibitory effects.
 

Skeptics are silenced

In 1960, however, the medical community was not yet ready to accept that dopamine was anything but a boring intermediate between levodopa and noradrenaline. At a prestigious London symposium, Dr. Carlsson and his two colleagues presented their hypothesis that dopamine may be a neurotransmitter, thus implicating it in Parkinson’s disease. They were met with harsh criticism. Some of the experts said levodopa was nothing more than a poison. Dr. Carlsson later recalled facing “a profound and nearly unanimous skepticism regarding our points of view.”

That would soon change. Dr. Hornykiewicz, the biochemist who had earlier discovered dopamine’s BP-lowering effects, tested Dr. Carlsson’s ideas using the postmortem brains of Parkinson’s disease patients. It appeared Dr. Carlsson was right: Unlike in healthy brains, the striatum of patients with Parkinson’s disease contained almost no dopamine whatsoever. Beginning in 1961, in collaboration with neurologist Walther Birkmayer, MD, Hornykiewicz injected levodopa into 20 patients with Parkinson’s disease and observed a “miraculous” (albeit temporary) amelioration of rigidity, motionlessness, and speechlessness.

By the late 1960s, levodopa and dopamine were making headlines. A 1969 New York Times article described similar stunning improvements in patients with Parkinson’s disease who were treated with levodopa. A patient who had arrived at a hospital unable to speak, with hands clenched and rigid expression, was suddenly able to stride into his doctor’s office and even jog around. “I might say I’m a human being,” he told reporters. Although the treatment was expensive – equivalent to $210 in 2022 – physicians were deluged with requests for “dopa.” To this day, levodopa remains a gold standard in the treatment of Parkinson’s disease.
 

Still misunderstood

The history of dopamine, however, is not only about Parkinson’s disease but extends to the treatment of schizophrenia and addiction. When in the1940s a French military surgeon started giving a new antihistamine drug, promethazine, to prevent shock in soldiers undergoing surgery, he noticed a bizarre side effect: the soldiers would become euphoric yet oddly calm at the same time.

After the drug was modified by adding a chlorine atom and renamed chlorpromazine, it fast became a go-to treatment for psychosis. At the time, no one made the connection to dopamine. Contemporary doctors believed that it calmed people by lowering body temperature (common treatments for mental illness back in the day included swaddling patients in cold, wet sheets). Yet just like reserpine, chlorpromazine produced range of nasty side effects that closely mimicked Parkinson’s disease. This led a Dutch pharmacologist, Jacques van Rossum, to hypothesize that dopamine receptor blockade could explain chlorpromazine’s antipsychotic effects – an idea that remains widely accepted today.

In the 1970s, dopamine was linked with addiction through research on rodents, and this novel idea caught people’s imagination over the coming decades. A story on dopamine titled, “How We Get Addicted,” made the cover of Time in 1997.

Yet as the dopamine/addiction connection became widespread, it also became oversimplified. According to a 2015 article in Nature Reviews Neuroscience, a wave of low-quality research followed – nonreplicated, insufficient – which led the authors to conclude that we are “addicted to the dopamine theory of addiction.” Just about every pleasure under the sun was being attributed to dopamine, from eating delicious foods and playing computer games to sex, music, and hot showers. As recent science shows, however, dopamine is not simply about pleasure – it’s about reward prediction, response to stress, memory, learning, and even the functioning of the immune system. Since its first synthesis in the early 20th century, dopamine has often been misunderstood and oversimplified – and it seems the story is repeating itself now.

In one of his final interviews, Dr. Carlsson, who passed away in 2018 at the age of 95, warned about playing around with dopamine and, in particular, prescribing drugs that have an inhibitory action on this neurotransmitter. “Dopamine is involved in everything that happens in our brains – all its important functions,” he said.

We should be careful how we handle such a delicate and still little-known system.

A version of this article first appeared on Medscape.com.

Google the word “dopamine” and you will learn that its nicknames are the “happy hormone” and the “pleasure molecule” and that it is among the most important chemicals in our brains. With The Guardian branding it “the Kim Kardashian of neurotransmitters,” dopamine has become a true pop-science darling – people across the globe have attempted to boost their mood with dopamine fasts and dopamine dressing.

A century ago, however, newly discovered dopamine was seen as an uninspiring chemical, nothing more than a precursor of noradrenaline. It took several stubborn and hardworking scientists to change that view.
 

Levodopa: An indifferent precursor

When Casimir Funk, PhD, a Polish biochemist and the discoverer of vitamins, first synthesized the dopamine precursor levodopa in 1911, he had no idea how important the molecule would prove to be in pharmacology and neurobiology. Nor did Markus Guggenheim, PhD, a Swiss biochemist, who isolated levodopa in 1913 from the seeds of a broad bean, Vicia faba. Dr. Guggenheim administered 1 g of levodopa to a rabbit, with no apparent negative consequences. He then prepared a larger dose (2.5 g) and tested it on himself. “Ten minutes after taking it, I felt very nauseous, I had to vomit twice,” he wrote in his paper. In the body, levodopa is converted into dopamine, which may act as an emetic – an effect Dr. Guggenheim didn’t understand. He simply abandoned his human study, erroneously concluding, on the basis of his animal research, that levodopa is “pharmacologically fairly indifferent.”

Around the same time, several scientists across Europe successfully synthesized dopamine, but those discoveries were shelved without much fanfare. For the next 3 decades, dopamine and levodopa were pushed into academic obscurity. Just before World War II, a group of German scientists showed that levodopa is metabolized to dopamine in the body, while another German researcher, Hermann Blaschko, MD, discovered that dopamine is an intermediary in the synthesis of noradrenaline. Even these findings, however, were not immediately accepted.

The dopamine story picked up pace in the post-war years with the observation that the hormone was present in various tissues and body fluids, although nowhere as abundantly as in the central nervous system. Intrigued, Dr. Blaschko, who (after escaping Nazi Germany, changing his name to Hugh, and starting work at Oxford [England] University) hypothesized that dopamine couldn’t be an unremarkable precursor of noradrenaline – it had to have some physiologic functions of its own. He asked his postdoctoral fellow, Oheh Hornykiewicz, MD, to test a few ideas. Dr. Hornykiewicz soon confirmed that dopamine lowered blood pressure in guinea pigs, proving that dopamine indeed had physiologic activity that was independent of other catecholamines.
 

Reserpine and rabbit ears

While Dr. Blaschko and Dr. Hornykiewicz were puzzling over dopamine’s physiologic role in the body, across the ocean at the National Heart Institute in Maryland, pharmacologist Bernard Brodie, PhD and colleagues were laying the groundwork for the discovery of dopamine’s starring role in the brain.

Spoiler alert: Dr. Brodie’s work showed that a new psychiatric drug known as reserpine was capable of fully depleting the brain’s stores of serotonin and – of greatest significance, as it turned out – mimicking the neuromuscular symptoms typical of Parkinson’s disease. The connection to dopamine would be made by new lab colleague Arvid Carlsson, MD, PhD, who would go on to win a Nobel Prize.

Derived from Rauwolfia serpentina (a plant that for centuries has been used in India for the treatment of mental illness, insomnia, and snake bites), reserpine was introduced in the West as a treatment for schizophrenia.

It worked marvels. In 1954, the press lauded the “dramatic” and seemingly “incredible”: results in treating “hopelessly insane patients.” Reserpine had a downside, however. Reports soon changed in tone regarding the drug’s severe side effects, including headaches, dizziness, vomiting, and, far more disturbingly, symptoms mimicking Parkinson’s disease, from muscular rigidity to tremors.

Dr. Brodie observed that, when reserpine was injected, animals became completely immobile. Serotonin nearly vanished from their brains, but bizarrely, drugs that spur serotonin production did not reverse the rabbits’ immobility.

Dr. Carlsson realized that other catecholamines must be involved in reserpine’s side effects, and he began to search for the culprits. He moved back to his native Sweden and ordered a spectrophotofluorimeter. In one of his experiments, Carlsson injected a pair of rabbits with reserpine, which caused the animals to become catatonic with flattened ears. After the researchers injected the animals with levodopa, within 15 minutes, the rabbits were hopping around, ears proudly vertical. “We were just as excited as the rabbits,” Dr. Carlsson later recalled in a 2016 interview. Dr. Carlsson realized that, because there was no noradrenaline in the rabbits’ brains, dopamine depletion must have been directly responsible for producing reserpine’s motor inhibitory effects.
 

Skeptics are silenced

In 1960, however, the medical community was not yet ready to accept that dopamine was anything but a boring intermediate between levodopa and noradrenaline. At a prestigious London symposium, Dr. Carlsson and his two colleagues presented their hypothesis that dopamine may be a neurotransmitter, thus implicating it in Parkinson’s disease. They were met with harsh criticism. Some of the experts said levodopa was nothing more than a poison. Dr. Carlsson later recalled facing “a profound and nearly unanimous skepticism regarding our points of view.”

That would soon change. Dr. Hornykiewicz, the biochemist who had earlier discovered dopamine’s BP-lowering effects, tested Dr. Carlsson’s ideas using the postmortem brains of Parkinson’s disease patients. It appeared Dr. Carlsson was right: Unlike in healthy brains, the striatum of patients with Parkinson’s disease contained almost no dopamine whatsoever. Beginning in 1961, in collaboration with neurologist Walther Birkmayer, MD, Hornykiewicz injected levodopa into 20 patients with Parkinson’s disease and observed a “miraculous” (albeit temporary) amelioration of rigidity, motionlessness, and speechlessness.

By the late 1960s, levodopa and dopamine were making headlines. A 1969 New York Times article described similar stunning improvements in patients with Parkinson’s disease who were treated with levodopa. A patient who had arrived at a hospital unable to speak, with hands clenched and rigid expression, was suddenly able to stride into his doctor’s office and even jog around. “I might say I’m a human being,” he told reporters. Although the treatment was expensive – equivalent to $210 in 2022 – physicians were deluged with requests for “dopa.” To this day, levodopa remains a gold standard in the treatment of Parkinson’s disease.
 

Still misunderstood

The history of dopamine, however, is not only about Parkinson’s disease but extends to the treatment of schizophrenia and addiction. When in the1940s a French military surgeon started giving a new antihistamine drug, promethazine, to prevent shock in soldiers undergoing surgery, he noticed a bizarre side effect: the soldiers would become euphoric yet oddly calm at the same time.

After the drug was modified by adding a chlorine atom and renamed chlorpromazine, it fast became a go-to treatment for psychosis. At the time, no one made the connection to dopamine. Contemporary doctors believed that it calmed people by lowering body temperature (common treatments for mental illness back in the day included swaddling patients in cold, wet sheets). Yet just like reserpine, chlorpromazine produced range of nasty side effects that closely mimicked Parkinson’s disease. This led a Dutch pharmacologist, Jacques van Rossum, to hypothesize that dopamine receptor blockade could explain chlorpromazine’s antipsychotic effects – an idea that remains widely accepted today.

In the 1970s, dopamine was linked with addiction through research on rodents, and this novel idea caught people’s imagination over the coming decades. A story on dopamine titled, “How We Get Addicted,” made the cover of Time in 1997.

Yet as the dopamine/addiction connection became widespread, it also became oversimplified. According to a 2015 article in Nature Reviews Neuroscience, a wave of low-quality research followed – nonreplicated, insufficient – which led the authors to conclude that we are “addicted to the dopamine theory of addiction.” Just about every pleasure under the sun was being attributed to dopamine, from eating delicious foods and playing computer games to sex, music, and hot showers. As recent science shows, however, dopamine is not simply about pleasure – it’s about reward prediction, response to stress, memory, learning, and even the functioning of the immune system. Since its first synthesis in the early 20th century, dopamine has often been misunderstood and oversimplified – and it seems the story is repeating itself now.

In one of his final interviews, Dr. Carlsson, who passed away in 2018 at the age of 95, warned about playing around with dopamine and, in particular, prescribing drugs that have an inhibitory action on this neurotransmitter. “Dopamine is involved in everything that happens in our brains – all its important functions,” he said.

We should be careful how we handle such a delicate and still little-known system.

A version of this article first appeared on Medscape.com.