Polycystic ovary syndrome as a plausible evolutionary outcome of metabolic adaptation.

As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. It is linked with insulin resistance through preferential abdominal fat accumulation that is worsened by obesity. Over the past two millennia, menstrual irregularity, male-type habitus and sub-infertility have been described in women and confirm that these clinical features of PCOS were common in antiquity. Recent findings in normal-weight hyperandrogenic PCOS women show that exaggerated lipid accumulation by subcutaneous (SC) abdominal stem cells during development to adipocytes in vitro occurs in combination with reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This PCOS phenotype may be an evolutionary metabolic adaptation to balance energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction. This review integrates fundamental endocrine-metabolic changes in healthy, normal-weight PCOS women with similar PCOS-like traits present in animal models in which tissue differentiation is completed during fetal life as in humans to support the evolutionary concept that PCOS has common ancestral and developmental origins.

Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques.

As in women with polycystic ovary syndrome (PCOS), hyperinsulinemia is associated with anovulation in PCOS-like female rhesus monkeys. Insulin sensitizers ameliorate hyperinsulinemia and stimulate ovulatory menstrual cycles in PCOS-like monkeys. To determine whether hyperinsulinemia (>694 pmol/L), alone, induces PCOS-like traits, five PCOS-like female rhesus monkeys with minimal PCOS-like traits, and four control females of similar mid-to-late reproductive years and body mass index, received daily subcutaneous injections of recombinant human insulin or diluent for 6−7 months. A cross-over experimental design enabled use of the same monkeys in each treatment phase. Insulin treatment unexpectedly normalized follicular phase duration in PCOS-like, but not control, females. In response to an intramuscular injection of 200 IU hCG, neither prenatally androgenized nor control females demonstrated ovarian hyperandrogenic responses while receiving insulin. An intravenous GnRH (100 ng/kg) injection also did not reveal evidence of hypergonadotropism. Taken together, these results suggest that experimentally induced adult hyperinsulinemia, alone, is insufficient to induce PCOS-like traits in female rhesus monkeys and to amplify intrinsic PCOS-like pathophysiology.

Loss of anti-Müllerian hormone (AMH) immunoactivity due to a homozygous AMH gene variant rs10417628 in a woman with classical polycystic ovary syndrome (PCOS).

Anti-Müllerian hormone (AMH) is produced by granulosa cells of pre-antral and small antral ovarian follicles. In polycystic ovary syndrome (PCOS), higher levels of serum AMH are usually encountered due to the ample presence of small antral follicles and a high AMH production per follicular unit which have led to the proposal of AMH as a serum diagnostic marker for PCOS or as a surrogate for polycystic ovarian morphology (PCOM). However, heterozygous coding mutations of the AMH gene with decreased in vitro bioactivity have been described in some women with PCOS. Such mutation carriers have a trend toward reduced serum AMH levels compared to noncarriers, although both types of women with PCOS have similar circulating gonadotropin and testosterone (T) levels. This report describes a normal-weight woman with PCOS by NIH criteria with severely reduced AMH levels (index woman with PCOS). Our objective was to examine the molecular basis for her reduced serum AMH levels and to compare her endocrine characteristics to similar-weight women with PCOS and detectable AMH levels. Twenty normoandrogenic ovulatory (control) and 13 age- and BMI-matched women with PCOS (19-35 years; 19-25 kg/m2) underwent transvaginal sonography and serum hormone measures including gonadotropins, sex hormone-binding globulin, total and free T, androstenedione, dehydroepiandrosterone sulfate, estrone, estradiol and AMH. The latter was measured by ELISA (Pico-AMH: Ansh Labs, Webster, TX, USA). Women with PCOS and detectable AMH had higher serum AMH (10.82 (6.74-13.40) ng/ml, median (interquartile range)), total and free T (total T: 55.5 (49.5-62.5) ng/dl; free T: 5.65 (4.75-6.6) pg/ml) levels and greater total antral follicle count (AFC) (46 (39-59) follicles) than controls (AMH: 4.03 (2.47-6.11) ng/ml; total T: 30 (24.5-34.5) ng/dl; free T: 2.2 (1.8-2.45) pg/ml; AFC 16 (14.5-21.5) follicles, P < 0.05, all values), along with a trend toward LH hypersecretion (P = 0.06). The index woman with PCOS had severely reduced serum AMH levels (∼0.1 ng/ml), although she also had a typical NIH-defined PCOS phenotype resembling that of the other women with PCOS and elevated AMH levels. All women with PCOS, including the index woman with PCOS, exhibited LH hypersecretion, hyperandrogenism, reduced serum estrogen/androgen ratios and PCOM. A homozygous Ala515Val variant (rs10417628) in the mature region of AMH was identified in the index woman with PCOS. Recombinant hAMH-515Val displayed normal processing and bioactivity, yet had severely reduced immunoactivity when measured by the commercial pico-AMH ELISA assay by Ansh Labs. In conclusion, homozygous AMH variant rs10417628 may severely impair serum AMH immunoactivity without affecting its bioactivity or PCOS phenotypic expression. Variants in AMH can interfere with serum AMH immunoactivity without affecting the phenotype in PCOS. This observation can be accompanied by discordance between AMH immunoactivity and bioactivity.

Mechanisms of intergenerational transmission of polycystic ovary syndrome.

Developmental origins of adult disease (DoHAD) refers to critical gestational ages during human fetal development and beyond when the endocrine metabolic status of the mother can permanently program the physiology and/or morphology of the fetus, modifying its susceptibility to disease after birth. The aim of this review is to address how DoHAD plays an important role in the phenotypic expression of polycystic ovary syndrome (PCOS), the most common endocrinopathy of women characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. Clinical studies of PCOS women are integrated with findings from relevant animal models to show how intergenerational transmission of these central components of PCOS are programmed through an altered maternal endocrine-metabolic environment that adversely affects the female fetus and long-term offspring health. Prenatal testosterone treatment in monkeys and sheep have been particularly crucial in our understanding of developmental programming of PCOS because organ system differentiation in these species, as in humans, occurs during fetal life. These animal models, along with altricial rodents, produce permanent PCOS-like phenotypes variably characterized by LH hypersecretion from reduced steroid-negative feedback, hyperandrogenism, ovulatory dysfunction, increased adiposity, impaired glucose-insulin homeostasis and other metabolic abnormalities. The review concludes that DoHAD underlies the phenotypic expression of PCOS through an altered maternal endocrine-metabolic environment that can induce epigenetic modifications of fetal genetic susceptibility to PCOS after birth. It calls for improved maternal endocrine-metabolic health of PCOS women to lower their risks of pregnancy-related complications and to potentially reduce intergenerational susceptibility to PCOS and its metabolic derangements in offspring.

A primate perspective on oocytes and transgenerational PCOS.

'Androgenized' rodent models are widely used to explore the pathophysiology underlying human polycystic ovary syndrome (PCOS), including reproductive and metabolic dysfunction. Based on a recent study using a dihydrotestosterone (DHT)-treated murine model, it has been proposed that prenatal androgen excess alone can predispose to transgenerational transmission of PCOS. From RNA sequencing analysis of metaphase II (MII) oocytes of androgenized lineages, the authors speculated that oocyte factors, including up-regulation of cytotoxic granulosa-associated RNA binding protein-like 1 (TiaL1), are sufficient to promote disease transfer across generations. Although this is an intriguing concept, it was not considered in the context of earlier publications in which the transcriptomes of human MII oocytes from PCOS women undergoing IVF were compared with women without PCOS. In one of these papers, a number of differentially expressed genes in PCOS MII oocytes (TIAL1 was not differentially expressed) were found to have putative response elements in their promoters for androgen receptors and peroxisome proliferating receptor gamma, providing a mechanism for how excess androgens and/or metabolic defects associated with PCOS might affect female germ cells.

Measures of Patient Dissatisfaction With Health Care in Polycystic Ovary Syndrome: Retrospective Analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder in women; however, many clinicians may not be well versed in scientific advances that aid understanding of the associated reproductive, metabolic, and psychological abnormalities. Women with PCOS are dissatisfied with health care providers, the diagnostic process, and the initial treatment of PCOS and seek information through alternative sources. This has affected the patient-physician relationship by allowing medical information acquired through the internet, whether correct or not, to become accessible to patients and reshape their health care perspective. Patient dissatisfaction with health care providers regarding PCOS raises questions about the responsibilities of academic institutions to adequately train and maintain the competence of clinicians and government agencies to sufficiently support scientific investigation in this field. OBJECTIVE: The primary aim was to examine internet searching behaviors of the public regarding PCOS vs another highly prevalent gynecologic disorder. The secondary aim was to explore satisfaction with health care among patients with PCOS and their internet use. The tertiary aim was to examine medical education in reproductive endocrinology and infertility (REI) during obstetrics and gynecology (Ob/Gyn) residency as a proxy for physician knowledge in this field. METHODS: Google search trends and StoryBase quantified monthly Google absolute search volumes for search terms related to PCOS and fibroids (January 2004 to December 2017; United States). The reproductive disorder, fibroids, was selected as a comparison group because of its high prevalence among women. Between female groups, monthly absolute search volumes and their trends were compared. A Web-based questionnaire (June 2015 to March 2018) explored health care experiences and the internet use of women with PCOS. REI rotation information during Ob/Gyn residency in the United States was obtained from the Association of Professors of Gynecology and Obstetrics website. RESULTS: For PCOS (R=0.89; P<.01), but not fibroids (R=0.09; P=.25), monthly absolute search volumes increased significantly. PCOS-related monthly absolute search volumes (mean 384,423 searches, SD 88,756) were significantly greater than fibroid-related monthly absolute search volumes (mean 348,502 searches, SD 37,317; P<.05). PCOS was diagnosed by an Ob/Gyn in 60.9% (462/759) of patients, and 57.3% (435/759) of patients were dissatisfied with overall care. Among patients with PCOS, 98.2% (716/729) searched for PCOS on the Web but only 18.8% (143/729) of patients joined an online PCOS support group or forum. On average, Ob/Gyn residencies dedicated only 4% (2/43) of total block time to REI, whereas 5.5% (11/200) of such residencies did not offer any REI rotations. CONCLUSIONS: Over time, PCOS has been increasingly searched on the Web compared with another highly prevalent gynecologic disorder. Patients with PCOS are dissatisfied with their health care providers, who would benefit from an improved understanding of PCOS during Ob/Gyn residency training.

Use of fertility medications and cancer risk: a review and update.

PURPOSE OF REVIEW: There is increasing use of fertility medications for ovulation induction and ovarian stimulation for in-vitro fertilization in the treatment of female infertility. In this review, recent literature regarding the association between fertility medication and cancer risk is reviewed. RECENT FINDINGS: Several important publications have recently addressed the relationship between use of fertility medications and cancer risk. There are methodological limitations to many of these studies, including unique challenges in studying rare cancers that often develop several years after the time of fertility medication exposure. Although infertility per se is a risk factor for some female cancers, including breast, endometrial and ovarian cancer, most studies do not show a significant risk of these cancers with the use of fertility medications. Some studies, however, have shown a possible increased relative risk of borderline ovarian cancer, although the increased absolute risk is small without a clear causal relationship. SUMMARY: The collective data regarding the risk of developing cancer from use of fertility medications are reassuring, although several methodological issues in these studies limit definitive conclusions.

Attributes That Fellowship Directors Value in the Selection of Reproductive Endocrinology and Infertility Fellows.

OBJECTIVE: To investigate which attributes of reproductive endocrinology and infertility (REI) fellowship applicants are most valued by fellowship program directors during the match process. STUDY DESIGN: An electronic survey was administered to determine characteristics most favored by program directors in the selection of REI fellows. A 5-point Likert scale was utilized to rank characteristics, with 1 being "most important" and 5 being" least important." The main outcome measures were factors desired by REI fellowship directors. RESULTS: The overall response rate was 61%. Objective factors that ranked highly were training at a competitive obstetrics and gynecology (OB/GYN) residency program, and clinical or basic science research experience. First authorship research ranked favorably regardless of whether it was in the form of a peer-reviewed paper, oral presentation, or poster abstract. Personal interview and perceived ability to work well with others were subjective factors considered favorably by REI fellowship directors. CONCLUSION: When selecting REI fellows for interviews, fellowship directors value candidates who have trained at competitive OB/GYN residency programs, who have clinical or basic science research experience, and who have contributed to scientific literature as first author. When subsequently ranking fellowship applicants, however, the most important factors are those found in the interview process, such as identification as a "team player".

Cost-Benefit Analysis of Hysteroscopic Polypectomy Before Controlled Ovarian Hyperstimulation and Intrauterine Insemination in Infertile Women.

Objective: To examine the cost benefit of performing hysteroscopic polypectomy (HP) in infertile women with endometrial polyp(s) before controlled ovarian hyperstimulation with intrauterine insemination (COH/IUI). Study Design: Decision analytic model comparing costs and clinical outcomes. Results: HP and COH/IUI costs ranged from $537­$12,530 and $800­$7,600, respectively. Performing an HP before COH/IUI lowered fertility cost by $7,652 per clinical pregnancy. When COH/IUI costs remained constant, HP was most cost beneficial when the cost of HP was below a threshold value of $9,452. When HP costs remained constant, the threshold value at which HP was no longer cost beneficial was at COH/IUI costs below $704. The cost benefit was greatest when an office-based HP is performed. Conclusion: HP before COH/IUI is more cost beneficial than fertility treatment alone, particularly when office-based hysteroscopy is performed.

Phospholipase C-zeta deficiency as a cause for repetitive oocyte fertilization failure during ovarian stimulation for in vitro fertilization with ICSI: a case report.

PURPOSE: The purpose of this study is to describe impaired oocyte fertilization from phospholipase C-zeta (PLC-ζ) deficiency in normal-appearing sperm that was successfully treated using calcium (Ca(2+)) ionophore with intracytoplasmic sperm injection (ICSI) of oocytes matured in vitro. METHODS: An infertile couple undergoing in vitro fertilization (IVF) experienced failed oocyte fertilization following ICSI with normal-appearing sperm. A semen sample collected from the patient was used to assess the expression of sperm PLC- ζ protein by Western blot analysis and immunofluorescence and PLC-ζ bioactivity by an in vitro model of Ca(2+) release. A second IVF cycle was performed using Ca(2+) ionophore with ICSI to enhance Ca(2+)-induced oocyte activation of oocytes matured in vitro. RESULTS: Sperm PLC-ζ protein deficiency was demonstrated by Western blot analysis and immunofluorescence and confirmed by reduced PLC-ζ bioactivity using an in vitro model of Ca(2+) release. Nevertheless, with this sperm and supplementation of Ca(2+) ionophore following ICSI, fertilization of four of six oocytes matured in vitro was obtained. In addition, four embryos underwent cleavage and two of them reached the blastocyst stage. Transfer of these blastocysts into the uterus led to a single pregnancy and live birth. CONCLUSIONS: Deficiency of PLC-ζ in normal-appearing human sperm is associated with impaired Ca(2+)-dependent oocyte activation during ICSI. Under this condition, use of Ca(2+) ionophore following ICSI of oocytes matured in vitro improves embryo developmental competence, possibly through the activation of Ca(2+)-dependent mechanisms governing fertilization and preimplantation embryogenesis.

Disparities and relative risk ratio of preterm birth in six Central and Eastern European centers.

AIM: To identify characteristic risk factors of preterm birth in Central and Eastern Europe and explore the differences from other developed countries. METHOD: Data on 33,794 term and 3867 preterm births (<37 wks.) were extracted in a retrospective study between January 1, 2007 and December 31, 2009. The study took place in 6 centers in 5 countries: Czech Republic, Hungary (two centers), Romania, Slovakia, and Ukraine. Data on historical risk factors, pregnancy complications, and special testing were gathered. Preterm birth frequencies and relevant risk factors were analyzed using Statistical Analysis System (SAS) software. RESULTS: All the factors selected for study (history of smoking, diabetes, chronic hypertension, current diabetes, preeclampsia, progesterone use, current smoking, body mass index, iron use and anemia during pregnancy), except the history of diabetes were predictive of preterm birth across all participating European centers. Preterm birth was at least 2.4 times more likely with smoking (history or current), three times more likely with preeclampsia, 2.9 times more likely with hypertension after adjusting for other covariates. It had inverse relationship with the significant predictor body mass index, with adjusted risk ratio of 0.8 to 1.0 in three sites. Iron use and anemia, though significant predictors of preterm birth, indicated mixed patterns for relative risk ratio. CONCLUSION: Smoking, preeclampsia, hypertension and body mass index seem to be the foremost risk factors of preterm birth. Implications of these factors could be beneficial for design and implementation of interventions and improve the birth outcome.

Exploring the potential association between brominated diphenyl ethers, polychlorinated biphenyls, organochlorine pesticides, perfluorinated compounds, phthalates, and bisphenol A in polycystic ovary syndrome: a case-control study.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is an endocrine-metabolic disorder that affects approximately 6-10% of women of child-bearing age. Although preliminary studies suggest that certain pollutants may act as endocrine disruptors in animals, little is known about their potential association with PCOS. The objective of this case-control pilot study is to determine whether women with PCOS have higher concentrations of specific environmental contaminants compared to women who have not developed PCOS. METHODS: Fifty-two PCOS case-patients (diagnosed using the National Institutes of Health 1990 definition) and 50 controls were recruited in 2007-2008, from an urban academic medical center in Los Angeles, CA. Brominated diphenyl ethers, polychlorinated biphenyls (PCBs), organochlorine pesticides, and perfluorinated compounds (PFCs) were measured in serum, and phthalates metabolites and bisphenol A (BPA) in urine. RESULTS: PCOS case-patients had significantly higher geometric mean (GM) serum concentrations of two PFCs: perfluorooctanoate (PFOA) (GMcases = 4.1 µg/L, GMcontrols = 2.3 µg/L; p = 0.001) and perfluorooctane sulfonate (PFOS) (GMcases = 8.2 µg/L, GMcontrols = 4.9 µg/L; p = 0.01), and lower urinary concentrations of monobenzyl phthalate (mBzP) (GMcases = 7.5 µg/g creatinine, GMcontrols = 11.7 µg/g creatinine; p = 0.02). Logistic regression, controlling for body mass index, age and race, identified an increased likelihood of PCOS in subjects with higher serum concentrations of PFOA and PFOS (adjusted-ORs = 5.8-6.9, p < 0.05), and with lower urine concentrations of mBzP and mono-n-butyl phthalate (mBP) (aORs = 0.14-0.25, p < 0.05). CONCLUSIONS: Our data suggest that PCOS case-patients may differ from controls in their environmental contaminant profile. PCOS subjects had higher serum concentrations of two PFCs, PFOA and PFOS, and lower urine concentrations of mBP and mBzP. Future studies are needed to confirm these preliminary findings and determine if these chemicals or their precursors may have a role in the pathogenesis of PCOS.

Protein phospholipase C Zeta1 expression in patients with failed ICSI but with normal sperm parameters.

PURPOSE: This study was conducted to determine if expression of the testis-specific phospholipase C Zeta1 (PLCZ1) correlated with low success or fertilization failure after ICSI in patients with normal parameters after standard semen analysis (SA). METHODS: Couples <43 years with one or two failed or low fertilization ICSI cycles. Standard Semen Analysis (SA) was performed to determine sperm parameters in male partners, whereas females were evaluated for antral follicle counts (AFC), day 3 FSH levels and peak Estradiol (E2) levels. The presence of PLCZ1 in sperm was ascertained using Western blotting and Immunofluorescence (IF) analysis. The ability of sperm to initiate changes in the intracellular concentrations of free calcium ([Ca(2+)]i), which is characteristic of mammalian sperm, was performed after injection of human sperm into mouse eggs loaded with the Ca(2+) sensitive dye fura-2 AM. RESULTS: Male partners of couples with failed or low success ICSI fertilization but with normal SA parameters showed low expression levels of PLCZ1 as determined by western blotting and reduced fluorescent signal during IF studies. In addition, fewer of these males' sperm showed PLCZ1 expression and were able to initiate robust [Ca(2+)]i oscillations upon injection into eggs. CONCLUSION: Our data suggest that in patients with normal SA parameters but with repeated low fertilization or outright failed fertilization results after ICSI, abnormal PLCZ1 function should be considered as the underlying mechanism responsible for the failure of fertilization.

Anti-Müllerian Hormone: A Molecular Key to Unlocking Polycystic Ovary Syndrome?

Anti-Müllerian hormone (AMH) is an important component within androgen receptor (AR)-regulated pathways governing the hyperandrogenic origin of polycystic ovary syndrome (PCOS). In women with PCOS, granulosa cell AMH overexpression in developing ovarian follicles contributes to elevated circulating AMH levels beginning at birth and continuing in adolescent daughters of PCOS women. A 6 to 7% incidence among PCOS women of gene variants coding for AMH or its receptor, AMHR2, suggests genetic contributions to AMH-related pathogenesis. Discrete gestational AMH administration to pregnant mice induces hypergonadotropic hyperandrogenic, PCOS-like female offspring with high circulating AMH levels that persist over three generations, suggesting epigenetic contributions to PCOS through developmental programming. Moreover, adult-onset, selective hyperactivation of hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH) induces hypergonadotropic hyperandrogenism and PCOS-like traits in female mice. Both gestational and adult AMH inductions of PCOS-like traits are prevented by GnRH antagonist coadministration, implicating luteinizing hormone-dependent ovarian theca cell testosterone (T) action, mediated through the AR in AMH-induced pathogenesis. Interestingly, gestational or peripubertal exogenous T or dihydrotestosterone induction of PCOS-like traits in female mice, rats, sheep, and monkeys fails to elicit ovarian AMH hypersecretion; thus, AMH excess per se may lead to a distinct pathogenic contribution to hyperandrogenic PCOS origins.

A novel approach to quantifying ovarian cell lipid content and lipid accumulation in vitro by confocal microscopy in lean women undergoing ovarian stimulation for in vitro fertilization (IVF).

PURPOSE: To quantify intracellular lipid levels in cumulus cells (CCs) and mural granulosa cells (MGCs) of lean women undergoing gonadotropin therapy for in vitro fertilization (IVF), based upon different cell preparation methods. METHODS: CCs and MGCs from 16 lean women undergoing ovarian stimulation for IVF were studied. Cells were pooled by cell type, with each type of cell separated into two groups for determination of initial lipid content (Method 1) and subsequent lipid accumulation in vitro (Method 2). Cells for initial lipid content were immediately fixed at the time of the oocyte retrieval with 4% paraformaldehyde in suspension, while those for subsequent lipid accumulation in vitro were cultured for 4 h with 5% fetal calf serum and then fixed. Cells were treated with lipid fluorescent dye BODIPY® FL C16 and nuclear marker DAPI. Intracellular lipid was quantified by confocal microscopy, using ImageJ software analysis. RESULTS: There was no significant effect of cell type (P = 0.2) or cell type-cell preparation method interaction (P = 0.8) on cell area (Method 1: CC 99.7 ± 5.1, MGC 132.8 ± 5.8; Method 2: CC 221.9 ± 30.4, MGC 265.1 ± 48.5 µm(2)). The mean area of all cells combined was significantly less for cells prepared by Method 1 (116.2 ± 4.9 µm(2)) vs. Method 2 (243.5 ± 22.5 µm(2), P < 0.00005). Intracellular lipid level, however, was significantly altered by cell preparation method (P < 0.05; cell preparation method-cell type interaction, P < 0.00001). Initial lipid content was significantly lower in CC (74.5 ± 9.3) than MGC (136.3 ± 16.7 fluorescence/cell area, P < 0.00005), while subsequent lipid accumulation in vitro was significantly higher in CC (154.0 ± 9.1) than MGC (104.6 ± 9.9 fluorescence/cell area, P < 0.00001). The relatively diminished initial CC lipid content compared to subsequent CC lipid accumulation in vitro (P < 0.00001), and the opposite pattern for MGC (P < 0.05), significantly lowered the CC/MGC lipid ratio in Method 1 (0.55 ± 0.04) vs. Method 2 (1.58 ± 0.10, P < 0.00001). CONCLUSIONS: Differential uptake or utilization of lipid by CC and MGC occurs during oocyte maturation and steroidogenesis, respectively, with the amount of lipid present in ovarian cells a function of both the follicular microenvironment at the time of the oocyte retrieval and the capacity of these cells to accumulate lipid in vitro over time.

An Evolutionary Model for the Ancient Origins of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-aged women, characterized by hyperandrogenism, oligo-anovulation and insulin resistance and closely linked with preferential abdominal fat accumulation. As an ancestral primate trait, PCOS was likely further selected in humans when scarcity of food in hunter-gatherers of the late Pleistocene additionally programmed for enhanced fat storage to meet the metabolic demands of reproduction in later life. As an evolutionary model for PCOS, healthy normal-weight women with hyperandrogenic PCOS have subcutaneous (SC) abdominal adipose stem cells that favor fat storage through exaggerated lipid accumulation during development to adipocytes in vitro. In turn, fat storage is counterbalanced by reduced insulin sensitivity and preferential accumulation of highly lipolytic intra-abdominal fat in vivo. This metabolic adaptation in PCOS balances energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction; its accompanying oligo-anovulation allowed PCOS women from antiquity sufficient time and strength for childrearing of fewer offspring with a greater likelihood of childhood survival. Heritable PCOS characteristics are affected by today's contemporary environment through epigenetic events that predispose women to lipotoxicity, with excess weight gain and pregnancy complications, calling for an emphasis on preventive healthcare to optimize the long-term, endocrine-metabolic health of PCOS women in today's obesogenic environment.

Interplay of Cortisol, Testosterone, and Abdominal Fat Mass in Normal-weight Women With Polycystic Ovary Syndrome.

Context: Ovarian and adrenal steroidogenesis underlie endocrine-metabolic dysfunction in polycystic ovary syndrome (PCOS). Adipocytes express aldo-keto reductase 1C3 and type 1 11ß-hydroxysteroid dehydrogenase, which modulate peripheral androgen and cortisol production. Objectives: To compare serum adrenal steroids, including 11-oxygenated androgens (11-oxyandrogens), cortisol, and cortisone between normal-weight women with PCOS and body mass index- and age-matched ovulatory women with normal-androgenic profiles (controls), and assess whether adrenal steroids associate with abdominal adipose deposition. Design: Prospective, cross-sectional, cohort study. Setting: Academic medical center. Patients: Twenty normal-weight women with PCOS and 20 body mass index-/age-matched controls. Interventions: Blood sampling, IV glucose tolerance testing, and total-body dual-energy x-ray absorptiometry. Main Outcome Measures: Clinical characteristics, hormonal concentrations, and body fat distribution. Results: Women with PCOS had higher serum total/free testosterone (T) and androstenedione (A4) levels and a greater android/gynoid fat mass than controls (androgens P < .001; android/gynoid fat mass ratio, P = .026). Serum total/free T and A4 levels correlated positively with android/gynoid fat mass ratio in all women combined (P < .025, all values). Serum 11ß-hydroxyA4, 11-ketoA4, 11ß-hydroxyT, 11-ketoT, cortisol, and cortisone levels were comparable between female types and unrelated to body fat distribution. Serum 11-oxyandrogens correlated negatively with % total body fat, but lost significance adjusting for cortisol. Serum cortisol levels, however, correlated inversely with android fat mass (P = .021), with a trend toward reduced serum cortisol to cortisone ratio in women with PCOS vs controls (P = .075), suggesting diminished 11ß-hydroxysteroid dehydrogenase activity. Conclusion: Reduced cortisol may protect against preferential abdominal fat mass in normal-weight PCOS women with normal serum 11-oxyandrogens.

Randomized clinical trial: effect of low-dose flutamide on abdominal adipogenic function in normal-weight women with polycystic ovary syndrome.

OBJECTIVE: To examine whether low-dose flutamide administration to normal-weight women with polycystic ovary syndrome (PCOS) reduces abdominal fat deposition, attenuates accelerated lipid accumulation in newly formed adipocytes derived from subcutaneous (SC) abdominal adipose stem cells (ASCs), and/or alters glucose-lipid metabolism. DESIGN: A double-blind, placebo-controlled randomized clinical trial. SETTING: An academic medical center. PATIENT(S): Twelve normal-weight women with PCOS and 12 age- and body mass index-matched controls. INTERVENTION(S): Women underwent circulating hormonal and metabolic determinations, intravenous glucose tolerance testing, total body dual-energy roentgenogram absorptiometry, and SC abdominal fat biopsy. Interventions were repeated in women with PCOS after 6-month administration of flutamide (125 mg orally daily) vs. placebo. MAIN OUTCOME MEASURE(S): Clinical parameters and lipid accumulation in newly formed adipocytes derived from SC abdominal ASCs in vitro were compared between controls and the women with PCOS receiving flutamide vs. placebo. RESULTS: Serum luteinizing hormone and androgen levels as well as lipid accumulation in newly formed SC abdominal adipocytes were greater in the women with PCOS than controls. Flutamide vs. placebo reduced percent android fat, lowered serum log low-density lipoprotein and log non-high-density lipoprotein levels, and increased fasting circulating glucose levels. In all women with PCOS, changes in percent android fat positively correlated with serum log non-high-density lipoprotein and log low-density lipoprotein levels, with correlations influenced by serum free testosterone levels. Flutamide vs. placebo also attenuated lipid accumulation in newly-formed PCOS SC abdominal adipocytes in vitro relative to controls, which was unrelated to serum lipid levels. CONCLUSION: Low-dose flutamide administration to normal-weight PCOS women reduces preferential abdominal fat deposition, attenuates accelerated lipid accumulation in newly-formed adipocytes derived from SC abdominal ASCs in vitro, and alters glucose-lipid homeostasis. CLINICAL TRIAL REGISTRATION NUMBER: NCT01889199 (URL, clinicaltrials.gov; date of registration, 6/28/2013; enrollment date of first subject, 6/28/2013).

Female Adult Acne and Androgen Excess: A Report From the Multidisciplinary Androgen Excess and PCOS Committee.

In endocrine and reproductive endocrine literature, adult female acne is considered as a possible clinical expression of hyperandrogenism, with most polycystic ovary syndrome (PCOS) guidelines considering acne as a condition of androgen excess. Adult female acne, however, in the dermatological literature is considered as an inflammatory skin disease and new guidelines on adult female acne have been produced by dermatological societies, with little perspective from any endocrine or reproductive endocrine points of view. An expert task force was appointed by the AE-PCOS society to determine the current state of knowledge and provide evidence-based recommendations that could be valid for all specialists taking care of female adult acne. The following are the recommendations (level of evidence A or B): (1) diagnosis of female adult acne is mainly clinical, but a grading tool is needed for optimizing the treatment; (2) measurement of serum androgen values (total testosterone, free testosterone, and dehydroepiandrosterone sulfate) by high-quality assays is recommended in all women with adult acne; (3) in women with adult acne and proven hyperandrogenism, oral combined estroprogestins should be added to the topical or systemic treatment of acne, independently of severity of acne; (4) all second- and third-generation estroprogestins may be used, independently of the estrogen dose and progestin component; (5) spironolactone may be added to estroprogestins in women with moderate or severe hyperandrogenic adult acne, not responding to usual treatments; (6) estroprogestins may be used in nonhyperandrogenic patients with adult acne as second-line therapy.

Passing on PCOS: new insights into its epigenetic transmission.

Polycystic ovary syndrome (PCOS) is a prevalent reproductive-metabolic disorder with poorly understood etiology. Mimouni et al. (2021) demonstrate global genomic DNA hypomethylation in women with PCOS and their daughters, and in F3 generation PCOS-like mice, together with substantial normalization of PCOS-like mice by methyl donor dietary supplementation.