High testosterone, dihydrotestosterone linked to adverse metabolic phenotype in patients with PCOS


Patients with polycystic ovary syndrome who have a high testosterone to dihydrotestosterone ratio appear to be more likely to have an adverse metabolic phenotype, according to recent findings.

In the study, researchers evaluated 275 premenopausal women aged 16 to 48 years with PCOS and 35 BMI-matched, premenopausal, health women aged 21 to 50 years as controls. The researchers recorded anthropometric data for all participants, including height, weight, waist circumference and hip circumference.

Researchers recorded systolic and diastolic blood pressure measurements and calculated BMI. Fasting blood samples were taken to evaluate basal hormone serum levels. Additionally, an oral glucose tolerance test was performed, and blood samples were collected at 30, 60 and 120 minutes to determine glucose and insulin concentrations.

A routine method for liquid chromatography/mass spectrometry was used to determine total testosterone (T), total dihydrotestosterone (DHT), androstenedione and dehydroepiandrosterone (DHEA).

The researchers found that patients with PCOS had significantly higher levels of total T (P<.001), free testosterone (P<.001) and free DHT (P<.001) vs. healthy controls. Additionally, patients with PCOS had a significantly higher total T/DHT ratio (P<.001). No difference was found between PCOS and control participants in terms of total DHT levels (P=.072).

An analysis of just patients with PCOS revealed a significantly higher total T/DHT ratio in patients with obesity (P<.001) as well as those with metabolic syndrome (P<.001), impaired glucose tolerance (P<.001) or insulin resistance (P<.001).

The researchers also found significant association between total T/DHT ratio and various adverse anthropometric, hormonal, lipid and liver measures, and measures of glucose tolerance.

“This correlation was only found in PCOS patients, suggesting the [total] T/DHT ratio is a new biomarker for an adverse metabolic phenotype in PCOS patients,” the researchers wrote. “Nevertheless, future studies and larger trials are needed for the evaluation of results.”

PCOS increased risk for CVD, obesity.


In a case-control study, researchers found that young women with polycystic ovary syndrome have a higher prevalence of cardiovascular disease risk factors, including hypertension, obesity and metabolic syndrome, compared with controls. The researchers also found significantly lower levels of lipoprotein apolipoprotein A-I and observed a significant reduction in efflux capacity.

  • “Given the available data, there is evidence to suggest that women with PCOS are at an increased risk for developing CV-related outcomes,” Andrea Roe, MD, of the department of obstetrics and gynecology in the division of reproductive endocrinology at the University of Pennsylvania, and colleagues wrote. “These data strongly support educating all PCOS patients about the associated risk of dyslipidemia and need for frequent lipid screening.”

The researchers evaluated women aged 18 to 50 years with PCOS (n=124) and geographically matched controls (n=67). The patients with PCOSdemonstrated higher BMI and blood pressure, but similar HDL and LDL levels compared with controls, according to data.

The mean ApoA-I levels were lower and ApoB to ApoA-I ratio was greater among patients with PCOS compared with controls (P<.01), researchers wrote.

In addition, women with PCOS displayed an 11% decrease in normalized cholesterol efflux capacity compared with controls (P<.05). The cholesterolefflux capacity was correlated with BMI, ApoA-I, HDL and presence of metabolic syndrome, researchers wrote.

Multivariable regression model data indicated that PCOS was significantly associated with less cholesterol efflux (beta level, –0.05; 95% CI, –0.1 to –0.009).

After adjustments for age and BMI, PCOS was also significantly associated with an atherogenic profile, including an increase in large VLDL particles, size and small LDL particles (P<.01).

BMI may be most vital determinant of basal metabolic rate in PCOS.


The BMI of patients with polycystic ovary syndrome appeared to be the most important factor in basal metabolic rate, independent of the polycystic ovary syndrome phenotype and insulin resistance, according to Margareta D. Pisarska, MD, who presented the data at the conjoint meeting of the International Federation of Fertility Societies and the American Society for Reproductive Medicine.

“Based on our study — since we do think obesity does play a significant role — we believe it is important for endocrinologists to help counsel these women in a fashion similar to those who are obese by emphasizing that weight loss and lowering BMI are important,” Pisarska, director of the division of reproductive endocrinology and infertility; director of the Fertility and Reproductive Medicine Center at Cedars-Sinai Medical Center; associate professor at Cedars-Sinai Medical Center and the David Geffen School of Medicine at UCLA, told Endocrine Today.

 

The researchers conducted the case-control study examining the metabolic changes (ie, lean body mass, body fat mass, body fat percentage, skeletal muscle mass, BMI and basal metabolic rate) in 128 patients with PCOS (mean age, 28.1 years) and 72 eumenorrheic, non-hirsute controls (mean age, 32.9 years).

In terms of hormonal profile, patients with PCOS had greater testosterone, dehydroepiandrosterone sulfate (DHEA-sulfate), fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) levels compared with controls.

After controlling for age and BMI differences, there was no difference in body composition parameters between patients with PCOS and controls. There were no significant results regarding changes to the basal metabolic rate (P=.0162), lean body mass (P=.0153) or skeletal muscle mass (P=.0169), she said.

However, differences in fasting insulin and HOMA-IR remained significant. When looking at insulin resistance in women with PCOS as a potential factor affecting body composition and metabolic rates, there was also no difference between these groups.

“It is not necessarily PCOS; BMI and age are probably the more important determinants of basal metabolic rate, regardless of PCOS phenotype and insulin resistance,” Pisarska said.

Two-state solution’ proposed for renaming PCOS.


New terminology is warranted for improved diagnosis and treatment of polycystic ovary syndrome phenotypes, according to researchers.

 “We would like to propose a nosological ‘two-state solution’ to the conflict. The endocrine syndrome of hyperandrogenism and chronic anovulation, eg, the National Institutes of Health (NIH) phenotype, should have a new name that acknowledges both its reproductive features as well as its long-term metabolic risks. The phenotypes diagnosed by ovarian morphology, eg, the remaining Rotterdam phenotypes, should continue to be known as PCOS,” wroteAndrea Dunaif, MD, vice chair for research in the department of medicine at Northwestern University Feinberg School of Medicine, and Bart Fauser, MD, of the department of reproductive medicine and gynecology at the University Medical Center in Utrecht, the Netherlands.

 

The researchers cited recommendations from the NIH Office for Disease Prevention’s Evidence-based Methodology Workshop on PCOS held last year, which suggested clarifying benefits and drawbacks from diagnostic criteria; causes, predictors and long-term consequences; and treatment and prevention strategies. They added that the syndrome is often overlooked outside of obstetrics and gynecology visits.

Currently, the diagnostic criteria for PCOS by the NIH include hyperandrogenism and chronic anovulation; Rotterdam includes two of the following: hyperandrogenism, chronic anovulation and polycystic ovaries. Finally, the Androgen Excess Society criteria state that PCOS is marked by hyperandrogenism plus ovarian dysfunction indicated by oligo/amenorrhea and/or polycystic ovaries, according to the researchers.

“Specifically, we want to ensure that this recommendation does not lead to Balkanization of the field, which will clearly undermine the broad interdisciplinary efforts required for meaningful scientific advances in our understanding of PCOS,” they wrote.

Source: Endocrine Today

Spironolactone/metformin superior to either treatment alone for PCOS.


Low-dose spironolactone and metformin combination therapy compared with either drug alone appeared to be an effective treatment for the management of polycystic ovary syndrome, according to results from an open-label, randomized study conducted in India.

“The key findings suggest superior efficacy (menstrual cyclicity, Ferriman–Gallwey [FG] score, serum total testosterone, insulin sensitivity and compliance) of low-dose spironolactone and metformin over either drug alone in the management of PCOS, without increasing the adverse event rate,”Mohd Ashraf Ganie, MD, of the department of endocrinology and metabolism at All India Institute of Medical Sciences in Ansari Nagar, New Delhi, India, and colleagues wrote.

Women who fell under the Androgen Excess-PCOS (AE-PCOS) 2006 criteria for PCOS were randomly assigned to one of three groups: metformin 1,000 mg per day (n=56), low-dose spironolactone 50 mg per day (n=51) or a combination of both drugs (n=62) for 6 months.

Before randomization, women were given dietary counseling (30 kcal/kg to 35 kcal/kg composed of 50% to 55% carbohydrates, 20% to 25% protein and 15% to 20% fat with high fiber content) besides lifestyle advice (ie, 25 to 35 minutes of brisk walking per day).

Menstrual cycle patterns, FG score, BMI, waist-hip ratio, blood pressure, luteinizing hormone, follicle-stimulating hormone, total testosterone, glucose and insulin sensitivity indices were measured at baseline, 3 and 6 months after the intervention. Data indicate all groups had comparable mean age and BMI at baseline.

At 6 months, menstrual cycles per year increased, whereas FG scores, serum total testosterone, AUC-glucose and AUC-insulin decreased significantly (P<.05) in the combination group compared with either therapy alone, according to data.

The adverse events associated with combination therapy were not significantly high. However, some of the clinical benefits could be the result of lifestyle modifications due to the lack of a placebo arm, researchers wrote. Yet, the efficacy and compliance were apparent without an increase in adverse events.

PERSPECTIVE

 

  • This study confirms what we have suspected for some time: that combination therapy is better for women with PCOS than single-agent treatment. In this case, combination therapy included an insulin sensitizer (metformin) and an androgen blocker (spironolactone). It is important to understand that combination therapy works best if the medications being used have differing mechanisms of action. For example, there are a number of drugs that decrease the production of androgens (i.e., metformin or oral contraceptives) while other drugs will block the action of androgens (i.e., spironolactone, finasteride, etc.). Medications may also improve metabolic function (e.g. metformin) if needed. In a disorder as complex and multifactorial as PCOS, optimum therapy will be one that combines currently available therapies to affect maximum benefit while minimizing side-effects. This study suggests that the combination of metformin 1000 mg and spironolactone 50 mg daily is one of these therapies.
  • Ricardo Azziz, MD
  • Professor of obstetrics and gynecology, medicine, and medical humanities
    President of Georgia Regents University
    CEO of Georgia Regents Health System

Source: Endocrine Today

 

Risk for PCOS in women with European ancestry linked to genetic variants.


After discovering three loci that present a risk for polycystic ovary syndrome in Han Chinese women in a genome-wide association study, researchers replicated risk variants and found that women with European ancestry were also at risk for the disorder.

“Previous studies have demonstrated association between variants in more than 70 candidate genes and risk for PCOS, although the majority of these have not been replicated,” the researchers wrote.

Corrine K. Welt, MD, a researcher in the reproductive endocrine unit at Massachusetts General Hospital, and colleagues conducted a case-control study at deCODE Genetics in Iceland and two academic medical centers in the United States.

They examined 376 Icelandic women, 565 women in Boston and 203 women in Chicago, all of whom were diagnosed with PCOS according to NIH criteria. Control groups were 16,947 women in Iceland, 483 women in Boston (aged 18-45 years with regular menses between 21 and 35 days and no hyperandrogenism) and 189 (healthy reproductive-aged women, aged at least 18 years) in Chicago.

Researchers replicated two strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3: rs10986105[C] (OR=1.68; P=.00033) and rs10818854[A] (OR=1.53; P=.0019) in samples of European ancestry.

Other risk variants at alternate chromosomes were not related to PCOS, the researchers wrote. Additionally, the same allele of rs10986105[C], which increased the risk for PCOS, also put women without PCOS from Iceland at risk for hyperandrogenism and displayed a heightened risk for PCOS according to NIH criteria rather than Rotterdam criteria, the researchers wrote.

They said the variants found may be involved in the hyperandrogenism and irregular menses associated with PCOS. Despite impressive findings linking women with European ancestry to risk for PCOS based on variants found in this study, further studies should be considered to determine the role of the variant in the pathogenesis of PCOS.

Disclosure: Four of the 12 researchers are employed by deCODE Genetics. All other researchers report no relevant financial disclosures.

Perspective

 

Andrea Dunaif

  • This is the second study that has replicated findings in a genome-wide association study done in Chinese women with polycystic ovary syndrome. What’s exciting is that the Chinese study confirmed what’s been hypothesized now since the early ‘90s; that there is a genetic susceptibility to PCOS by mapping a couple of gene regions. To then replicate it in a distinct ethnic population in European women suggests that some of the same susceptibility variants are contributing to the disease in two very different populations.

It was suggested many years ago, in 1998, in a landmark paper by Rick Legro and colleagues (Legro RS. Proc Natl Acad Sci USA. 1998;95:14956-14960), that elevated testosterone levels were the underlying trait in PCOS families that most likely had a genetic basis. In this current study, they find that the gene variants are associated with testosterone levels in these populations.

The syndrome has been a disorder that we still don’t know the etiology of. We know that there’s a genetic component, and this is showing how genetic analyses can focus on what is causing all the other features, and again suggesting maybe it’s the testosterone and elevated androgen levels rather than the way the ovaries look.

Could we now do a genotype in a girl and predict whether or not she was going to have PCOS? Could it be used for personalized medicine? Unfortunately, none of these genes in these common, yet complex diseases have enough of the effect. Even if you had these variants that were associated with a 50% to 60% increased risk, that’s still not really enough to say that you’re going to have a disease or not. So, we really can’t use these gene variants for prediction. However, they’re very helpful in beginning to understand causality.

The strength of these studies is that they’re using rigorous new technology, the appropriate statistics, and these are meaningful findings, and hopefully, we’ll be seeing more of these related to other endocrine diseases of interest. This has certainly been the approach that’s been used in type 1 and 2 diabetes, where a number of genetic variants have been discovered.

    • Andrea Dunaif, MD
    • Professor of Endocrinology and Metabolism
      Vice Chair for Research in the Department of Medicine
      Northwestern University, Feinberg School of Medicine
  • Source: Endocrine Today