Androgen Excess Polycystic Ovary Syndrome Research Articles

Unraveling PCOS: Exploring its causes and diagnostic challenges

Abstract Women in the reproductive age range are usually affected with Polycystic Ovary Syndrome (PCOS), a complex and multifaceted condition. Anovulation, hyperandrogenism, and metabolic difficulties like hyperglycemia, hypertension, and obesity in women are all manifestations of this condition, which also affects the reproductive system. The National Institutes of Health in the 1990s, Rotterdam in 2003, and Androgen Excess Polycystic Ovary Syndrome in 2009 all contributed to the evolution of the diagnostic criteria for PCOS. The 2003 Rotterdam criteria are currently the most generally used criteria. They call for at least two of the three criteria – irregular menstrual periods, polycystic ovary morphology on imaging, and hyperandrogenism – either clinically or biochemically – to be present in order to diagnose PCOS. It is currently being suggested that the anti-Müllerian hormone in serum be used instead of follicular count as an official indicator of polycystic ovarian morphology/PCOS. Hyperandrogenism and irregular periods are essential components in determining PCOS in adolescent patients. More recently, it has been shown that artificial intelligence, especially machine learning, holds great promise for detecting and predicting PCOS with high accuracy, potentially assisting in early management and treatment decisions. Examining the underlying mechanisms, clinical symptoms, and challenges involved in making a diagnosis of PCOS in females is the premise of this review article.

Testosterone-associated blood pressure dysregulation in women with androgen excess polycystic ovary syndrome.

We tested the hypothesis that hyperandrogenemia in androgen excess polycystic ovary syndrome (AE-PCOS) is a primary driver in blood pressure (BP) dysregulation via altered sympathetic nervous system activity (SNSA), reduced integrated baroreflex gain and increased renin-angiotensin system (RAS) activation. We measured resting SNSA (microneurography), integrated baroreflex gain, and RAS with lower body negative pressure in obese insulin-resistant (IR) women with AE-PCOS [n = 8, 23 ± 4 yr; body mass index (BMI) = 36.3 ± 6.4 kg/m2] and obese IR controls (n = 7, control, 29 ± 7 yr; BMI = 34.9 ± 6.8 kg/m2), at baseline (BSL), after 4 days of gonadotropin-releasing hormone antagonist (ANT, 250 μg/day) and 4 days of ANT + testosterone (ANT + T, 5 mg/day) administration. Resting BP was similar between groups for systolic blood pressure (SBP; 137 ± 14 vs. 135 ± 14 mmHg, AE-PCOS, control) and diastolic BP (89 ± 21 vs. 76 ± 10 mmHg, AE-PCOS, control). BSL integrated baroreflex gain was similar between groups [1.4 ± 0.9 vs. 1.0 ± 1.3 forearm vascular resistance (FVR) U/mmHg], but AE-PCOS had lower SNSA (10.3 ± 2.0 vs. 14.4 ± 4.4 burst/100 heartbeats, P = 0.04). In AE-PCOS, T suppression increased integrated baroreflex gain, which was restored to BSL with ANT + T (4.3 ± 6.5 vs. 1.5 ± 0.8 FVR U/mmHg, ANT, and ANT + T, P = 0.04), with no effect in control. ANT increased SNSA in AE-PCOS (11.2 ± 2.4, P = 0.04). Serum aldosterone was greater in AE-PCOS versus control (136.5 ± 60.2 vs. 75.7 ± 41.4 pg/mL, AE-PCOS, control, P = 0.04) at BSL but was unaffected by intervention. Serum angiotensin-converting enzyme was greater in AE-PCOS versus control (101.9 ± 93.4 vs. 38.2 ± 14.7 pg/mL, P = 0.04) and reduced by ANT in AE-PCOS (77.7 ± 76.5 vs. 43.4 ± 27.3 µg/L, ANT, and ANT + T, P = 0.04) with no impact on control. Obese, IR women with AE-PCOS showed decreased integrated baroreflex gain and increased RAS activation compared with control.NEW & NOTEWORTHY Here we present evidence for an important role of testosterone in baroreflex control of blood pressure and renal responses to baroreceptor unloading in women with a common, high-risk androgen excess polycystic ovary syndrome (AE-PCOS) phenotype. These data indicate a direct effect of testosterone on the vascular system of women with AE-PCOS independent of body mass index (BMI) and insulin-resistant (IR). Our study indicates that hyperandrogenemia is a central underlining mechanism of heightened cardiovascular risk in women with PCOS.

Testosterone effects on autonomic function in women with androgen excess polycystic ovary syndrome

Women with androgen excess-polycystic ovarian syndrome (AE-PCOS) present with increased blood pressure (BP) and impaired cardiovascular autonomic control. We tested the hypothesis that androgens play an obesity-independent role in impaired baroreflex (BR) sensitivity and renin-angiotensin system (RAS) control of BP in women with AE-PCOS. We measured the sympathetic baroreflex (sBR) and cardiovagal baroreflex (cvBR) with the modified Oxford procedure, and integrated baroreflex (iBR) and the RAS response to lower body negative pressure (LBNP) in obese, insulin resistant (IR) women with AE-PCOS (n=9; age=23±4 y; BMI=36.3±6.4 kg/m2) and obese, IR controls (CTL) (n=7; age=29±7 y; BMI=34.9±6.8 kg/m2). Studies were conducted at baseline (BSL), after 4 days of reproductive hormone suppression with a gonadotropin-releasing hormone antagonist (ANT, 250 μg/day), and after 4 days of ANT+testosterone (ANT+T, 5 mg/day). At BSL, AE-PCOS and CTL had similar systolic BP (137±14 vs.133±14 mmHg, respectively) and diastolic BP (76±8 vs.63±12 mmHg, respectively). Resting MSNA burst incidence was lower (10.3±3.1 vs. 14.3±4.4 bursts-1×100 hb, P=0.04), but total MSNA activity was greater in AE-PCOS compared to CTL (249±112 vs. 156±44 bursts/min, respectively, P=0.04). Hormone intervention did not impact resting MSNA or BP in either group. In the AE-PCOS group, sBR gain increased during modified Oxford with ANT suppression of T, but sBR gain was restored to BSL when T was reintroduced (-0.48±0.15, -0.63±0.19, and -0.50±0.15 bursts -1 ·100 hb·mmHg -1 for BSL, ANT and ANT+T, respectively, P=0.01). Hormone interventions did not impact sBR gain in CTL (-0.48±0.06, -0.47±0.10, and -0.46±0.09 bursts -1 ·100 hb·mmHg -1 for BSL, ANT and ANT+T, respectively). iBR gain for AE-PCOS and CTL was similar at BSL (1.4±0.9 vs. 1.0±1.3 FVR unit/mmHg, respectively). In AE-PCOS, T suppression increased iBR gain, which was restored to BSL with ANT+T (4.3±6.5 vs.1.5±0.8 FVR unit/mmHg for ANT and ANT+T respectively, P<0.04), with no effect in CTL (1.9 ± 3.0 vs. 0.7±0.9 FVR unit/mmHg for ANT and ANT+T, respectively). cvBR gain was unaffected by group or treatment. Serum aldosterone was greater in AE-PCOS vs CTL (136.5±60.2 vs. 75.7±41.4 pg/ml, respectively, P<0.04), but unaffected by hormone intervention. Serum angiotensin converting enzyme (S [ACE] ) in AE-PCOS was greater compared to CTL at BSL (101.9±93.4 vs. 38.2 ±14.7 pg/ml, respectively, P<0.04). In AE-PCOS, S [ACE] was reduced by ANT (77.7 ±76.5 and 40.6±10.6 μg/L for ANT vs. ANT+T, respectively, P<0.04), but hormone intervention did not impact CTL (43.4±27.3 and 40.6±1 μg/L for ANT vs. ANT+T, respectively, P<0.04). These data suggest the milieu of AE-PCOS increases susceptibility to T driven autonomic perturbations as T elevation had differential effects in AE-PCOS vs. CTL. Our data indicate a powerful relationship among elevated androgens, autonomic function, and the kidney.NIH HL135089/P20GM 121334 National Institutes of Health, NHLBI HL135089 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Polycystic Ovary Syndrome: Pathophysiology and Controversies in Diagnosis.

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous disorder that commonly affects women in the reproductive age group. The disorder has features that propose a blend of functional reproductive disorders, such as anovulation and hyperandrogenism, and metabolic disorders, such as hyperglycemia, hypertension, and obesity in women. Until today, the three implemented groups of criteria for the diagnosis of PCOS are from the National Institutes of Health (NIH) in the 1990s, Rotterdam 2003, and the Androgen Excess Polycystic Ovary Syndrome 2009 criteria. Currently, the most widely utilized criteria are the 2003 Rotterdam criteria, which validate the diagnosis of PCOS with the incidence of two out of the three criteria: hyperandrogenism (clinical and/or biochemical), irregular cycles, and polycystic ovary morphology. Currently, the anti-Müllerian hormone in serum is introduced as a substitute for the follicular count and is controversially emerging as an official polycystic ovarian morphology/PCOS marker. In adolescents, the two crucial factors for PCOS diagnosis are hyperandrogenism and irregular cycles. Recently, artificial intelligence, specifically machine learning, is being introduced as a promising diagnostic and predictive tool for PCOS with minimal to zero error that would help in clinical decisions regarding early management and treatment. Throughout this review, we focused on the pathophysiology, clinical features, and diagnostic challenges in females with PCOS.

Effects of androgen excess and body mass index on endothelial function in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction; whether this is attributable to comorbid hyperandrogenism and/or obesity remains to be established. Therefore, we 1) compared endothelial function between lean and overweight/obese (OW/OB) women with and without androgen excess (AE)-PCOS and 2) examined androgens as potential modulators of endothelial function in these women. The flow-mediated dilation (FMD) test was applied in 14 women with AE-PCOS (lean: n = 7; OW/OB: n = 7) and 14 controls (CTRL; lean: n = 7, OW/OB: n = 7) at baseline (BSL) and following 7 days of ethinyl estradiol supplementation (EE; 30 µg/day) to assess the effect of a vasodilatory therapeutic on endothelial function; at each time point we assessed peak increases in diameter during reactive hyperemia (%FMD), shear rate, and low flow-mediated constriction (%LFMC). BSL %FMD was attenuated in lean AE-PCOS versus both lean CTRL (5.2 ± 1.5 vs. 10.3 ± 2.6%, P < 0.01) and OW/OB AE-PCOS (5.2 ± 1.5 vs. 6.6 ± 0.9%, P = 0.048). A negative correlation between BSL %FMD and free testosterone was observed in lean AE-PCOS only (R2 = 0.68, P = 0.02). EE increased %FMD in both OW/OB groups (CTRL: 7.6 ± 0.6 vs. 10.4 ± 2.5%, AE-PCOS: 6.6 ± 0.9 vs. 9.6 ± 1.7%, P < 0.01), had no impact on %FMD in lean AE-PCOS (5.17 ± 1.5 vs. 5.17 ± 1.1%, P = 0.99), and reduced %FMD in lean CTRL (10.3 ± 2.6 vs. 7.6 ± 1.2%, P = 0.03). Collectively, these data indicate that lean women with AE-PCOS exhibit more severe endothelial dysfunction than their OW/OB counterparts. Furthermore, endothelial dysfunction appears to be mediated by circulating androgens in lean but not in OW/OB AE-PCOS, suggesting a difference in the endothelial pathophysiology of AE-PCOS between these phenotypes.NEW & NOTEWORTHY We present evidence for marked endothelial dysfunction in lean women with androgen excess polycystic ovary syndrome (AE-PCOS) that is 1) associated with free testosterone levels, 2) impaired relative to overweight/obese women with AE-PCOS, and 3) unchanged following short-term ethinyl estradiol supplementation. These data indicate an important direct effect of androgens on the vascular system in women with AE-PCOS. Our data also suggest that the relationship between androgens and vascular health differs between phenotypes of AE-PCOS.

Endothelial (Dys)function in Women With Androgen Excess Polycystic Ovary Syndrome: Effects of Body Composition and Ethinyl Estradiol Supplementation

Polycystic ovary syndrome (PCOS) has been associated with endothelial dysfunction. However, whether endothelial dysfunction occurs as a result of obesity in androgen excess PCOS (AE‐PCOS) remains unclear. The purpose of this study was to compare endothelial function between lean and overweight/obese (OW/OB) women with AE‐PCOS. We hypothesis that OW/OB women with AE‐PCOS would demonstrate impaired endothelial function relative to lean women with AE‐PCOS as well as both lean and OW/OB controls without any form of PCOS. We also tested the hypothesis that short‐term ethinyl estradiol (EE) supplementation improves endothelial function in both lean and OW/OB women with AE‐PCOS. We assessed conduit vessel endothelial function in 14 women with AE‐PCOS (lean: n=7; OW/OB: n=7) and 12 controls (CTRL; lean: n=6, OW/OB: n=6) using flow‐mediated dilation (FMD). FMD responses were assessed twice: before (baseline; BSL) and on the last day of 7‐day oral EE (post‐EE; 30mg/day) and quantified as the peak increase in diameter during reactive hyperemia (%FMD), shear rate, and low flow‐mediated vasoconstriction (LFMC). BSL %FMD was attenuated in lean AE‐PCOS relative to both lean CTRL (5.2 ± 1.5% vs10.3 ± 2.6%, P&lt;0.01) and OW/OB AE‐PCOS (5.2 ± 1.5% vs6.6 ± 0.9%, P=0.04). A negative correlation between BSL %FMD and free testosterone was observed in lean AE‐PCOS only (R2=0.68, P=0.02). %FMD was unchanged from BSL to post‐EE in lean AE‐PCOS (5.17±1.5 vs5.17±1.1, P=0.99). Post‐EE, %FMD was lower in lean CTRL (10.3±2.6% vs7.6±1.2%, P=0.03), but increased in both OW/OB CTRL (7.3±0.1.2% vs 10.4±2.5%) and OW/OB women with AE‐PCOS (6.6±0.92% vs 9.6±1.7%; main effect of EE, P&lt;0.01). Post‐EE %FMD changes from BSL were associated with EE‐induced changes in LFMC and shear rate. Our data indicate that lean women with AE‐PCOS exhibit more severe conduit vessel endothelial dysfunction than OW/OB women with AE‐PCOS. Our data also indicate that short‐term EE supplementation affects LFMC and shear rate (and therefore %FMD) differently across healthy lean women and OW/OB women with and without AE‐PCOS.

Androgen Effects on Baroreflex Sensitivity in Women with AE‐PCOS

Polycystic ovary syndrome (PCOS) is a reproductive endocrinopathy affecting approximately 10% of reproductive age women. Hyperandrogenism in women may be associated with increased sympathetic activity and impaired blood pressure (BP) regulation. Women with the Androgen-Excess PCOS (AE-PCOS) phenotype can have severe clinical metabolic and cardiovascular comorbidities, including elevated BP. We tested the hypothesis that androgen exposure in AE-PCOS increases BP and impairs BP regulation, as indexed by sympathetic baroreflex sensitivity (BRS). We measured BRS in 5 women with AE-PCOS (mean±SD, age=25±5 y; BMI=40±2 kg/m2) at Baseline (BSL), after 4 days of reproductive hormone suppression with a gonadotropin-releasing hormone (GnRH) antagonist (ANT, 250 μg/day) and 4 days of GnRH ant+testosterone (T, 5 mg/day). Before participating, subjects were screened to demonstrate insulin resistance using an oral glucose tolerance test (AUC=25949±11038 IU for insulin, AUC=23385±2561 mg/dl for glucose). Muscle sympathetic nerve activity (MSNA), expressed in bursts/100 heartbeat (Hb), and diastolic BP (DBP) were measured during the Modified Oxford technique, and sympathetic BR gain (MSNA/DBP) served as an index of sympathetic BRS. We also assessed integrated BR gain with forearm vascular resistance changes as a function of lower body negative pressure (LBNP). Reproductive hormone suppression decreased resting mean arterial pressure compared to BSL (114±10 mm Hg) under both ANT (107±2 mm Hg) and T conditions (106±9 mm Hg, P=0.04). Sympathetic BR gain during ANT was greater compared to BSL (-0.922±0.506 vs. -0.800±0.542 bursts/100 Hb/mm Hg, respectively), and gain was unaffected when androgens were reintroduced (T=-0.819±0.276 bursts/100 Hb, P=0.29). Integrated BRS during LBNP was unaffected by hormone treatment (BSL=0.911±0.653; ANT=0.794±0.967; T= 1.002±0.367 units/mm Hg). In obese, insulin resistant women with AE-PCOS, suppressing testosterone and estrogen (E2) improved arterial BR control of MSNA, while testosterone administration did not restore BR control. Thus, our initial hypothesis that T impairs baroreflex control of MSNA is not supported by these data but suggests that the continued suppression of E2 during ANT and ANT+T may play a more important role. The potential impact of E2 could be a promising clinical intervention and will be directly tested in our future studies.

Autonomic Dysfunction in Women with Androgen Excess PCOS

Polycystic ovary syndrome (PCOS) is the most common reproductive endocrinopathy, affecting approximately 10% of reproductive age women. Further, 75% of women with PCOS have the more severe phenotype, Androgen Excess‐PCOS (AE‐PCOS), that is dominated by clinical and biochemical manifestations of hyperandrogenism. AE‐PCOS is also associated with elevated blood pressure (BP), which we hypothesized is the result of androgen‐associated impairments in autonomic function. Thus, we tested the hypothesis that androgen excess is associated with impaired baroreflex sensitivity (BRS) in women with AE‐PCOS. We tested four obese women with AE‐PCOS (age 30±3 y; BMI 39±11 kg/m2) at 0, HDT, ‐20, ‐30 lower body negative pressure (LBNP) under three conditions: Baseline (BL), during hormone suppression with a GnRH antagonist (GnRH ant, 7 days, 250 μg/day), and with GnRH ant+testosterone (T, 4 days, 5 mg/day). Women were mildly hypertensive at rest at BL, but BP increased following hormone suppression with the GnRH ant and remained elevated with T (93±7, 105±5, 105±9 mm Hg for BL, GnRH ant, and T, respectively, P=0.02). Blood pressure was well maintained during LBNP under the three hormone conditions. Forearm vascular resistance (FVR) increased during LBNP under each condition, but the increase was greatest during GnRH ant and T (Δ54±19, Δ235±145, Δ104±64 units for BL, GnRH ant, and T, respectively, P=0.04). The resulting BRS slopes were greater in GnRH ant (−5.2 units/mm Hg) compared to BL (−1.6 units/mm Hg), demonstrating concomitant testosterone and estrogen suppression improved BRS in women with AE‐PCOS. When we restored androgens, the BRS slope was again attenuated (T= −1.7 units/mm Hg), suggesting an important role for androgens in autonomic function in AE‐PCOS. GnRH ant increased resting BP independent of T in AE‐PCOS, which is likely a function of the continued estrogen suppression. Thus, hypertension associated with AE‐PCOS appears closely associated with estrogen suppression and independent of testosterone‐induced changes in BRS. In summary, both estrogens and androgens contribute to BP regulation in women with AE‐PCOS. Women with AE‐PCOS frequently present with mild hypertension that is driven by altered estrogen and testosterone exposures. Treating hypertension is crucial for preventing cardiovascular disease in this vulnerable population.Support or Funding InformationR01 HL135089

Serum under-carboxylated osteocalcin levels in women with polycystic ovary syndrome: weight-dependent relationships with endocrine and metabolic traits

BackgroundUnder-carboxylated osteocalcin (ucOC), the precursor substrate of bone biomarker OC is a potent regulator of energy metabolism by promoting insulin production and adiponectin synthesis and decreasing fat stores. The aim of the present study was to point out the potential role of ucOC in the physiopathology of polycystic ovary syndrome (PCOS), a common disorder defined by the constellation of anovulation, insulinresistance, hyperinsulinemia, obesity and androgen excess.MethodsIn this prospective case–control investigation, 78 young premenopausal women, i.e. 52 PCOS patients and 26 age- and body mass index (BMI)-matched healthy controls, were successively enrolled. Recruitment of PCOS patients was performed according to Androgen Excess-Polycystic Ovary Syndrome (AE-PCOS) Society 2006 criteria. All study participants were subjected to clinical examination, whole-body composition assessment and measurements of serum ucOC, OC (1-49), glucose and lipids, insulin, total testosterone (TT), estradiol, sex-hormone binding globulin (SHBG), high-sensitivity C-reactive protein (Hs-CRP) and β-CrossLaps.ResultsBMI-stratified multivariate analysis revealed significantly higher ucOC levels in PCOS vs. controls in lean (p = 0.001) but not overweight and obese study participants (p = 0.456). Notably, a positive correlation between ucOC and TT (p = 0.018), calculated free testosterone (cFT, p = 0.028) and serum insulin (p = 0.036), respectively, was found to be confined to the lean analysis subgroup. Furthermore, in stepwise multiple regression models, β-CrossLaps and cFT were able to predict 46.71% of serum ucOC variability. (1-43/49)OC failed to be significantly associated to any PCOS trait.ConclusionsCirculating ucOC concentration is related to key endocrine PCOS characteristics in a weight-dependent manner. Within the bone-pancreas loop, high ucOC may favor insulin release in lean hyperandrogenic women to compensate for impaired insulin sensitivity.