Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we ...identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.
STUDY QUESTION
What is the reported overall prevalence of polycystic ovary syndrome (PCOS) according to the criteria of the National Institutes of Health (NIH), Rotterdam or the Androgen Excess and ...PCOS Society (AE-PCOS Society)?
SUMMARY ANSWER
The reported overall prevalence of PCOS (95% CI) according to diagnostic criteria of the NIH, Rotterdam and the AE-PCOS Society is 6% (5–8%, n = 18 trials), 10% (8–13%, n = 15 trials) and 10% (7–13%, n = 10 trials), respectively.
WHAT IS ALREADY KNOWN
PCOS is the most common endocrine disorder among women of reproductive age. Although many studies have investigated the prevalence of PCOS, there are discrepancies in their results, in part due to the use of various definitions of the syndrome and its subphenotypes, differences between study cohorts, ethnicities, and types of recruitment and sampling.
STUDY DESIGN, SIZE, DURATION
A systematic review and meta-analysis were performed on all published studies that have reported the prevalence of PCOS according to at least one subset of diagnostic criteria.
PARTICIPANTS/MATERIALS, SETTING, METHODS
To identify relevant studies based on the PRISMA statement, PubMed and Ovid databases were searched up to September 2015 by two blind investigators using the terms ‘PCOS’, ‘polycystic ovarian disease’, ‘Stein Leventhal syndrome’, ‘Androgen Excess Society’, ‘National Institute of Health’, ‘Rotterdam’, ‘ESHRE/ASRM’, ‘criteria’ and ‘prevalence’. Articles that represented the prevalence of PCOS according to at least one subset of diagnostic criteria were included. Exclusion criteria were a focus on adolescent subjects, an absence of data on prevalence, inappropriate design or non-English reporting. An appraisal tool to evaluate the methodological quality of the available studies was generated by the authors.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 55 reports remained following screening of the abstracts and text for the subject of the study. Of these, 24 articles were eligible and evaluated for qualitative and quantitative synthesis. Since heterogeneity was observed among studies, a random-effects model was used to estimate the prevalence and its 95% CI. The proportions of PCOS prevalence (95% CI) according to the diagnostic criteria of NIH, Rotterdam and AE-PCOS Society were 6% (5–8%, n = 18 trials), 10% (8–13%, n = 15 trials) and 10% (7–13%, n = 10 trials), respectively. When only unselected population studies were included, the given rates were 6% (5–8%, n = 3 trials), 9% (7–12%, n = 6 trials) and 10% (7–14%, n = 3 trials). The respective proportions for hirsutism, hyperandrogenaemia, polycystic ovaries (PCO) and oligo-anovulation were 13% (8–20%, n = 14 trials), 11% (8–15%, n = 9 trials), 28% (22–35%, n = 12 trials) and 15% (12–18%, n = 19 trials), respectively.
LIMITATIONS, REASONS FOR CAUTION
The effects of ethnic differences, particularly, on the presence or severity of hirsutism cannot be ruled out in any way. In addition, there was a lack of standardization in defining phenotypes of the syndrome and selection bias was evident in most of the studies regarding recruitment of the cohorts.
WIDER IMPLICATIONS OF THE FINDINGS
Geographical differences in frequencies of the components of the syndrome, such as oligo-anovulation and clinical/biochemical androgen excess, must be taken into account in the development and implementation of regional diagnostic and precision treatment strategies. Further efforts and resources are required to increase standardization of the methods and comparability of the study results on prevalence and phenotypic characterization of PCOS around the globe.
STUDY FUNDING/COMPETING INTEREST(S)
No funding to declare. The authors have no conflicts of interest to declare.
REGISTRATION NUMBER
None.
The polycystic ovary syndrome (PCOS) is recognized as one of the most common endocrine abnormalities of humans, with global prevalences so far generally 5%-15%. Overall, the disorder appears to be an ...ancient complex genetic trait, perhaps dating at least 50,000 years ago. The phenotype of PCOS can be subdivided into four different types. Phenotype A and B (hyperandrogenism + ovulatory dysfunction, with A and without B polycystic ovarian morphology PCOM, respectively) can be considered to represent the "classic" form of the disorder. Phenotype C is the so-called "ovulatory" PCOS (hyperandrogenism + PCOM only). And phenotype D is often referred to as "nonhyperandrogenic" PCOS (ovulatory dysfunction + PCOM only). The different phenotypes vary in the degree to which they are associated with an increased risk for metabolic dysfunction and reproductive complications. There are a number of determinants of the epidemiology (prevalence) and presentation (phenotype) of PCOS, including environmental (e.g., socioeconomic, geographic, toxicologic, life-style, and dietary) and genetic (e.g., gene variants, epigenetic, and race/ethnicity) factors. Finally a better understanding of the evolutionary determinants of PCOS has the potential for providing additional insight into those factors determining the etiology, prevalence, and persistence of a disorder that appears to be, superficially at least, an evolutionary paradox.
This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming ...to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents.
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism, oligo/anovulation, and/or polycystic ...ovarian morphology, PCOS women often display also notable metabolic comorbidities. An array of pathogenic mechanisms have been implicated in the etiology of this heterogeneous endocrine disorder; hyperandrogenism at various developmental periods is proposed as a major driver of the metabolic and reproductive perturbations associated with PCOS. However, the current understanding of the pathophysiology of PCOS-associated metabolic disease is incomplete, and therapeutic strategies used to manage this syndrome's metabolic complications remain limited.
This study is a systematic review of the potential etiopathogenic mechanisms of metabolic dysfunction frequently associated with PCOS, with special emphasis on the metabolic impact of androgen excess on different metabolic tissues and the brain. We also briefly summarize the therapeutic approaches currently available to manage metabolic perturbations linked to PCOS, highlighting current weaknesses and future directions.
Androgen excess plays a prominent role in the development of metabolic disturbances associated with PCOS, with a discernible impact on key peripheral metabolic tissues, including the adipose, liver, pancreas, and muscle, and very prominently the brain, contributing to the constellation of metabolic complications of PCOS, from obesity to insulin resistance. However, the current understanding of the pathogenic roles of hyperandrogenism in metabolic dysfunction of PCOS and the underlying mechanisms remain largely incomplete. In addition, the development of more efficient, even personalized therapeutic strategies for the metabolic management of PCOS patients persists as an unmet need that will certainly benefit from a better comprehension of the molecular basis of this heterogeneous syndrome.
Polycystic ovary syndrome (PCOS) is the most common, heterogeneous, and multifactorial endocrine disorder in premenopausal women. The pathophysiology of this endocrinopathy is still unclear; however, ...the heterogeneity of its features within ethnic races, geographic location, and families suggests that environment and lifestyle are of prime importance. This work is mainly focused on the possible role of the most common and studied environmental toxins for this syndrome in the pathogenesis of PCOS. Plasticizers, such as bisphenol A (BPA) or phthalates, which belong to the categories of endocrine disrupting chemicals (EDCs) and advanced glycation end products (AGEs), affect humans' health in everyday, industrialized life; therefore special attention should be paid to such exposure. Timing of exposure to EDCs is crucial for the intensity of adverse health effects. It is now evident that fetuses, infants, and/or young children are the most susceptible groups, especially in the early development periods. Prenatal exposure to EDCs that mimic endogenous hormones may contribute to the altered fetal programming and in consequence lead to PCOS and other adverse health effects, potentially transgenerationally. Acute or prolonged exposure to EDCs and AGEs through different life cycle stages may result in destabilization of the hormonal homeostasis and lead to disruption of reproductive functions. They may also interfere with metabolic alterations such as obesity, insulin resistance, and compensatory hyperinsulinemia that can exacerbate the PCOS phenotype and contribute to PCOS consequences such as type 2 diabetes and cardiovascular disease. Since wide exposure to environmental toxins and their role in the pathophysiology of PCOS are supported by extensive data derived from diverse scientific models, protective strategies and strong recommendations should be considered to reduce human exposure to protect present and future generations from their adverse health effects.
Since the 1990 NIH‐sponsored conference on polycystic ovary syndrome (PCOS), it has become appreciated that the syndrome encompasses a broader spectrum of signs and symptoms of ovarian dysfunction ...than those defined by the original diagnostic criteria. The 2003 Rotterdam consensus workshop concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology. PCOS remains a syndrome and, as such, no single diagnostic criterion (such as hyperandrogenism or PCO) is sufficient for clinical diagnosis. Its clinical manifestations may include: menstrual irregularities, signs of androgen excess, and obesity. Insulin resistance and elevated serum LH levels are also common features in PCOS. PCOS is associated with an increased risk of type 2 diabetes and cardiovascular events.
Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation ...to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.
Polycystic Ovary Syndrome (PCOS), the most common endocrinological problem among women in the reproductive age, is characterized by chronic ovulatory dysfunction, hyperandrogenism, and raised ...Luteinizing hormone : Follicle Stimulating Hormone (LH:FSH) ratio. Obesity and insulin resistance have been linked to PCOS. However, there is recently a growing population of thin, lean women who are diagnosed with PCOS.
This study aimed to compare normal and high Body mass index (BMI) women with PCOS and to investigate the correlation between BMI and LH/FSH ratio.
It was a case -control study at the Department of Obstetrics and Gynaecology, Qassim University clinic, Saudi Arabia. Women with PCOS were included in the study and were classified according to their BMI. Their computerized records were retrieved for the demographic, clinical, and laboratory data. The study groups were compared by the t-test and the Spearman correlation between BMI and LH/FSH ratio was calculated.
A total of 63 women were included in this study (normal BMI group: n=30, and high BMI group: n=33). There was no difference between the two groups in terms of the LH/FSH ratio (2.76 vs. 2.79, P=0.48). There was no significant correlation between BMI and LH/FSH ratio, prolactin, or Thyroid stimulating hormone (TSH ) levels (Spearman correlation with
>0.05).
The data suggests that the body mass index was not correlated with increased LH/FSH ratio. Since LH/FSH ratio was the same in normal BMI women, healthcare professionals need to think about ways to normalize this ratio beyond weight reduction.
STUDY QUESTION
What is the prevalence of insulin resistance (IR) and the contributions of intrinsic and extrinsic IR in women diagnosed with polycystic ovary syndrome (PCOS) according to the ...Rotterdam criteria?
SUMMARY ANSWER
We report novel clamp data in Rotterdam diagnosed PCOS women, using World Health Organization criteria for IR showing that women with PCOS have a high prevalence of IR, strengthening the evidence for an aetiological role of IR in both National Institutes of Health (NIH) and Rotterdam diagnosed PCOS in lean and overweight women.
WHAT IS KNOWN ALREADY
PCOS is a complex endocrine condition with a significant increased risk of gestational diabetes and type 2 diabetes.
STUDY DESIGN, SIZE, DURATION
Using a cross-sectional study design, 20 overweight and 20 lean PCOS (Rotterdam criteria), 14 overweight and 19 lean body mass index (BMI)-matched control non-PCOS women underwent clinical measures of IR after a 3-month withdrawal of insulin sensitizers and the oral contraceptive pill.
MATERIALS, SETTING, METHODS
In an academic clinic setting, glucose infusion rate (GIR) on euglycaemic–hyperinsulinaemic clamp was investigated as a marker of insulin sensitivity.
MAIN RESULTS AND THE ROLE OF CHANCE
PCOS women were more IR than BMI-matched controls (main effect for BMI and PCOS; P < 0.001). IR was present in 75% of lean PCOS, 62% of overweight controls and 95% of overweight PCOS. Lean controls (mean ± SD; GIR 339 ± 76 mg min−1 m–2) were less IR than lean PCOS (270 ± 66 mg min−1 m−2), overweight controls (264 ± 66 mg min−1 m−2) and overweight PCOS (175 ± 96 mg min−1 m−2). The negative relationship between BMI and IR reflected by GIR was more marked in PCOS (y = 445.1 – 7.7x, R2 = 0.42 (P < 0.0001) than controls (y = 435.5 – 4.6x, R2 = 0.04 (P < 0.01)).
LIMITATIONS, REASONS FOR CAUTION
The study did not use glucose tracer techniques to completely characterize the IR, as well as the lack of matching for body composition and age.
WIDER IMPLICATIONS OF THE FINDINGS
IR is exacerbated by increased BMI, supporting intrinsic IR in PCOS. BMI impact on IR is greater in PCOS, than in controls, irrespective of visceral fat, prioritizing lifestyle intervention and the need for effective therapeutic interventions to address intrinsic IR and prevent diabetes in this high-risk population.
STUDY FUNDING/COMPETING INTEREST(S)
This investigator-initiated trial was supported by grants from the National Health & Medical Research Council (NHMRC) Grant number 606553 (H.J.T., N.K.S. and S.K.H.) as well as Monash University and The Jean Hailes Foundation. H.J.T. is an NHMRC Research Fellow. N.K.S. is supported through the Australian Government's Collaborative Research Networks (CRN) programme. A.E.J. is a Jean Hailes and NHMRC scholarship holder. The authors declare that there is no conflict of interest associated with this manuscript.
CLINICAL TRIAL REGISTRATION
ISRCTN84763265.
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