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Objective: We conducted a systematic review and meta-analysis to comprehensively compare cardiometabolic and reproductive health risk between Hispanic and White women with polycystic ovary syndrome in the United States in response to the call by the international guideline for polycystic ovary syndrome to delineate health disparities., Data Sources: Databases of MEDLINE, Web of Science, and Scopus were initially searched through October 25, 2020, and confirmed on February 1, 2021., Study Eligibility Criteria: Observational studies comparing glucoregulatory, lipid profile, anthropometric, blood pressure, androgen, ovarian morphology, oligoanovulation, and infertility status between Hispanic and White women with polycystic ovary syndrome were included. The primary outcome was metabolic syndrome risk. Furthermore, major cardiovascular events (stroke, coronary heart disease, and heart failure) and mortality rate (cardiovascular death and total mortality) data were evaluated. Studies on adolescents (<2 years after menarche), pregnant, or menopausal-aged women (>50 years) were excluded., Methods: Data were pooled by random-effects models and expressed as mean differences and 95% confidence intervals. Risk of bias was assessed by the Newcastle-Ottawa Scale., Results: A total of 11 studies (n=2267; 589 Hispanic and 1678 White women) were eligible. All studies, including both White and Hispanic women, had high-quality assessment (Newcastle-Ottawa Scale score of ≥8). Hispanic women exhibited comparable metabolic syndrome prevalence (7% [95% confidence interval, -1 to 14]; P=.06; I 2 =0%); however, Hispanic women exhibited higher modified Ferriman-Gallwey score (0.60 [95% confidence interval, -0.01 to 1.21]; P=.05; I 2 =0%), fasting insulin (5.48 μIU/mL [95% confidence interval, 3.11-7.85]; P≤.01; I 2 =40.0%), and homeostatic model assessment of insulin resistance (1.20 [95% confidence interval, 0.50-1.89]; P≤.01; I 2 =43.0%) than White women. The 2 groups had comparable glucose, lipid profile, waist circumference, blood pressure, and androgen status (all P≥.08). Findings about group differences in certain reproductive outcomes (ie, ovarian dysmorphology and infertility) were contradictory and described only narratively as inclusion in the meta-analyses was not possible. No study reported on cardiovascular events or mortality., Conclusion: Hispanic women with polycystic ovary syndrome exhibited greater impairments in glucoregulatory status than White women. Disparities in reproductive risks could not be concluded. The degree to which glucoregulatory aberrations translate into patient-pressing diseases (diabetes mellitus and infertility) remains a major roadblock given the paucity of available evidence. Our observations have supported the consideration of these disparities in the diagnostic, monitoring, and management practices for polycystic ovary syndrome and reinforced the need to elucidate mechanisms that account for the observed disparities to foster equity in polycystic ovary syndrome care., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: We conducted a systematic review and meta-analysis to summarize and quantitatively pool evidence on cardiometabolic health disparities between Black and White women with polycystic ovary syndrome in the United States in response to the call for further delineation of these disparities in the international evidence-based guideline for the assessment and management of polycystic ovary syndrome., Data Sources: Databases of MEDLINE, Web of Science, and Scopus were searched initially through March 05, 2020, and confirmed on September 11, 2020., Study Eligibility Criteria: Observational studies documenting cardiometabolic risk profile (glucoregulatory, lipid profile, anthropometric, and blood pressure status) in Black and White women with polycystic ovary syndrome were included. Studies on children (<17 years old) and pregnant or menopausal-aged women (>50 years) were excluded. The primary outcome was fasting glucose. Furthermore, data on major cardiovascular events (stroke, coronary heart disease, heart failure) and mortality rate (cardiovascular death, total mortality) were evaluated., Methods: Data were pooled by random-effects models and expressed as mean differences and 95% confidence intervals. Studies were weighted based on the inverse of the variance. Heterogeneity was evaluated by Cochran Q and I 2 statistics. Study methodologic quality was assessed by the Newcastle-Ottawa scale., Results: A total of 11 studies (N=2851 [652 Black and 2199 White]) evaluated cardiometabolic risk profile and all had high quality (Newcastle-Ottawa scale score of ≥8). No studies reported on cardiovascular events and mortality rate. Black women had comparable fasting glucose (-0.61 [-1.69 to 2.92] mg/dL; I 2 =62.5%), yet exhibited increased fasting insulin (6.76 [4.97-8.56] μIU/mL; I 2 =59.0%); homeostatic model assessment of insulin resistance (1.47 [0.86-2.08]; I 2 =83.2%); systolic blood pressure (3.32 [0.34-6.30] mm Hg; I 2 =52.0%); and decreased triglyceride (-32.56 [-54.69 to -10.42] mg/dL; I 2 =68.0%) compared with White women (all, P≤.03). Groups exhibited comparable total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and diastolic blood pressure (all, P≥.06)., Conclusions: Black women with polycystic ovary syndrome have a greater tendency for an adverse cardiometabolic risk profile (increased insulin, homeostatic model assessment of insulin resistance, and systolic blood pressure) despite lower triglycerides than White women. Our observations support the consideration of these disparities for diagnostic, monitoring, and management practices in Black women and for future guideline recommendations. Given the heterogeneity among studies, future research should address the relative contributions of biologic, environmental, socioeconomic, and healthcare factors to the observed disparities. Furthermore, longitudinal research is required to address patient-pressing complications, including cardiovascular events and mortality rate in Black women with polycystic ovary syndrome as a high-risk yet understudied population., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Eighty years ago a publication in the Journal proved to be seminal and transformative. The report by Irving Freiler Stein and Michael Leventhal titled, "Amenorrhea associated with polycystic ovaries," has proven to be a remarkably lasting and influential publication. The growth in related literature has been increasing exponentially: the 50 years between 1950 and 2000 saw a little more than 8000 publications on the topic, whereas the 15 year period between 2001 and 2015 (so far) has seen more than 20,000 related publications, a greater than 8-fold increase in the publication rate after 2000. As we commemorate the 80th anniversary year of the publication of the report by Stein and Leventhal, it is important to ask ourselves, "Was this publication truly as seminal as it is generally assumed to be? And why did it gain such a strong foothold on the medical psyche?" To the first question, a review of the antecedent medical literature makes it clear that the report of Drs Stein and Leventhal in 1935, although not flawless, was both seminal and transformative. In fact, it was the first report to describe a series of patients, rather than isolated cases, who demonstrated the triad of polycystic ovaries, hirsutism, and oligo/amenorrhea, connecting what had previously been disparate features of polycystic ovaries and menorrhagia, and hirsutism and oligo/amenorrhea. Second, the facts that Dr Stein and his collaborators were relatively prolific writers, consistent and clear in their message and descriptions; that a possible therapy (bilateral ovarian wedge resection) had been conveniently included in the report; and that the disorder was (is) relatively prevalent, permitted what would eventually be called the Stein-Leventhal syndrome to gain a strong foothold in contemporary medical practice. Overall, we in the field of medicine have much to celebrate, as we commemorate the 80th anniversary of the publication of the report by Stein and Leventhal in 1935, for a new disorder was described, one that we know today affects, in its various forms, 1 in every 7-17 women worldwide., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Women with polycystic ovary syndrome (PCOS) have a myriad of phenotypic and clinical features that may guide therapeutic options for metabolic protection and ovulation induction. The use of metformin may prove beneficial in a subset of the population of women with PCOS. Hyperinsulinemia, as demonstrated by elevated insulin levels on a 2-hour 75-g load glucose tolerance test, is an important parameter in deciding whether or not to initiate metformin therapy to women with PCOS with the hope of preventing or delaying the onset of type 2 diabetes mellitus (DM). Cardiovascular risk factors including markers of subclinical inflammation, and dyslipidemia may also be improved by metformin therapy. For ovulation induction, metformin is not as effective as clomiphene citrate as first-line therapy for women with PCOS. There are no clear data to suggest that metformin reduces pregnancy loss or improves pregnancy outcome in PCOS, and it is currently recommended that metformin be discontinued with the first positive pregnancy test result, unless there are other medical indications (eg, type 2 DM). This review addresses practical management guidelines for the uses of metformin in women with PCOS.

Objective: The purpose of this study was to assess the sibling correlation of adrenocorticotropic hormone-stimulated steroid hormone levels between probands with polycystic ovary syndrome and their sisters., Study Design: Twenty-seven women with polycystic ovary syndrome and 28 of their sisters underwent an adrenocorticotropic hormone stimulation test with measurement of the steroids dehydroepiandrosterone, androstenedione, and cortisol 60 minutes later. The 60-minute values were used to calculate sister-sister correlations by regression analyses., Results: The adrenocorticotropic hormone-stimulated (60-minute) log-transformed dehydroepiandrosterone and cortisol values were significantly correlated between siblings (r = 0.47, P = .01 and r = 0.57, P = .01, respectively); a similar trend was observed for the 60-minute A4 values (r = 0.29, P = .06)., Conclusion: Women with polycystic ovary syndrome and their sisters have significantly correlated levels of adrenocorticotropic hormone-stimulated steroids, supporting a genetic basis of the adrenal androgen excess observed in polycystic ovary syndrome.

Objective: The prevalence of androgen excess (AE) and the value of preemptive endocrine evaluation in women with minimal unwanted hair growth are unclear., Subjects: A total of 228 patients presented with minimal unwanted hair growth and a mF-G score of 5 or less. Total and free testosterone, dehydroepiandrosterone sulfate, 17-hydroxy-progesterone, sex hormone-binding globulin, and basal insulin and glucose levels were measured., Results: Of the patients, 54% demonstrated an AE disorder (50%: polycystic ovary syndrome, 2%: hyperandrogenic insulin-resistant acanthosis nigricans syndrome, 2%: nonclassic adrenal hyperplasia), 29% isolated oligoovulation, 6% isolated hyperandrogenemia, and 10% had a normal evaluation. Of the patients with menstrual irregularities, 65% had an underlying AE disorder compared with 22% of those with normal menstrual function ( P < .001). Of eumenorrheic patients, 11% had oligo-ovulation and an AE disorder., Conclusion: Patients with minimal unwanted hair growth should be evaluated endocrinologically because approximately 50% of subjects demonstrate an AE disorder. Eumenorrhea does not preclude an underlying AE disorder, and ovulatory function should be assessed in these women.

Objective: Polycystic ovary syndrome is the most common cause of oligo-ovulation, affecting approximately 4% of women. A primary defect of steroidogenesis resulting in increased ovarian and adrenal androgen production may be responsible for polycystic ovary syndrome, at least in some patients. Because the action of the steroidogenic acute regulatory protein (StAR) initiates the process of steroidogenesis, we proceeded to test the hypothesis that increased production or concentration of StAR may result in the abnormality of steroidogenesis found in polycystic ovary syndrome., Study Design: We examined the ovaries from 10 healthy women and 7 women with polycystic ovary syndrome, determining the relative concentration of StAR in total protein extracts by use of Western blotting, and the overall distribution and staining intensity of StAR in prepared tissue sections., Results: Overall the ovaries of healthy women and women with polycystic ovary syndrome demonstrated a similar prevalence and size of follicular cysts, although the ovaries of women with polycystic ovary syndrome had a greater mean number of follicular cysts. In general, the distribution of StAR immunoreactivity within most of the ovarian structures was not different in the ovaries of women with polycystic ovary syndrome compared to those of the healthy ovaries. However, the ovaries from the cases demonstrated a significantly greater number of follicular cysts with staining for StAR immunoreactivity in the thecal cells than did the ovaries from healthy women (100% vs 38%, P <.05)., Conclusion: These data suggest that the exaggeration in androgen biosynthesis in the ovaries of patients with polycystic ovary syndrome may be occurring at its earliest step (ie, that involving StAR), such that an increased amount of cholesterol is made available for androgen biosynthesis in the polycystic ovary.

Objective: Our aim was to determine whether the clinical features of 21-hydroxylase-deficient nonclassic adrenal hyperplasia are correlated with either age at symptom onset or age at presentation, or both, and with the degree of adrenocortical abnormality., Study Design: In a multicenter cohort design 220 women with nonclassic adrenal hyperplasia, with a basal or adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone level >30.3 nmol/L, were studied, either prospectively (n = 39) or retrospectively (n = 181). Patients were stratified by age of presentation into 5 groups: (1) <10 years (n = 25), (2) 10 to 19 years (n = 64), (3) 20 to 29 years (n = 83), (4) 30 to 39 years (n = 30), and (5) 40 to 49 years (n = 16). Two patients >50 years old were excluded from the analysis because of age., Results: Ninety-two percent of patients <10 years old had premature pubarche at presentation, whereas clitoromegaly and acne were each present in only 20% of these younger subjects. With only patients > or =10 years old considered, presenting clinical features included hirsutism (59%), oligomenorrhea (54%), acne (33%), infertility (13%), clitoromegaly (10%), alopecia (8%), primary amenorrhea (4%), and premature pubarche (4%). Among the patients >/=10 years old, the prevalence but not the degree of hirsutism increased significantly with age. Basal levels of 17-hydroxyprogesterone in adolescents were significantly higher than the levels found either in children (<10 years old) or women 40 to 49 years old (P <.01 and P <.03, respectively), although no difference was noted in the stimulated 17-hydroxyprogesterone levels between age groups. The adrenocorticotropic hormone-stimulated levels but not the basal levels of 17-hydroxyprogesterone were significantly higher in patients with clitoromegaly than in women without clitoromegaly. Alternatively, there were no differences in either basal or stimulated 17-hydroxyprogesterone levels between patients with and those without hirsutism, acne, or alopecia., Conclusion: In children <10 years old the most common presenting complaint was premature pubarche, whereas hirsutism and oligomenorrhea were more common in older patients. The prevalence of hirsutism increased with age, suggesting the progressive nature of nonclassic adrenal hyperplasia. Furthermore, the adrenocorticotropic hormone-stimulated levels of 17-hydroxyprogesterone were higher in patients with clitoromegaly, which suggests that the degree of adrenocortical dysfunction in nonclassic adrenal hyperplasia determines, at least in part, the clinical presentation.

Objective: We sought to determine the prevalence of 3beta-hydroxysteroid dehydrogenase-deficient nonclassic adrenal hyperplasia among adult hyperandrogenic women with dehydroepiandrosterone sulfate excess., Study Design: Thirty consecutive hyperandrogenic women with hirsutism, oligomenorrhea, or both and dehydroepiandrosterone sulfate levels of >8.5 micromol/L and 24 control subjects were studied. Basal sex hormone binding globulin, total and free testosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, and basal and 60-minute corticotropin-stimulated 17-hydroxypregnenolone and dehydroepiandrosterone were measured, and the increment (change from basal to 60-minute value) was calculated., Results: Twenty-six (87%) and 25 (83%) of the 30 hyperandrogenic patients studied had 60-minute dehydroepiandrosterone and change in 0- to 60-minute dehydroepiandrosterone levels greater than the mean + 2 SD of control subjects, respectively. Six (20%) and 6 (20%) of the 30 hyperandrogenic patients had 60-minute 17-hydroxypregnenolone and 0- to 60-minute change in 17-hydroxypregnenolone levels greater than the mean + 2 SD of control subjects, respectively. However, none of the subjects had either 60-minute 17-hydroxypregnenolone levels or 60-minute dehydroepiandrosterone levels or both associated with the diagnosis of genetically proved 3beta-hydroxysteroid dehydrogenase deficiency (>5-fold of the control mean value)., Conclusion: 3beta-Hydroxysteroid dehydrogenase-deficient nonclassic adrenal hyperplasia is rare even among adult hyperandrogenic patients with adrenal androgen excess.

Objective: Many women with androgen excess demonstrate elevated circulating insulin levels independent of obesity. In addition, in these women some investigators have demonstrated a negative correlation between the circulating levels of the adrenal androgens, dehydroepiandrosterone or dehydroepiandrosterone sulfate and insulin. The mechanism by which insulin decreases adrenal androgens is unclear. The objective of this study was to determine whether chronic hyperinsulinemia in hyperandrogenic women results in an alteration in the adrenocortical response to corticotropin, resulting in decreased androgen secretion., Study Design: We studied seven hyperandrogenic women with severe chronic hyperinsulinemia and eight hyperandrogenic normoinsulinemic patients. Nine healthy women served as controls for the basal hormonal levels and the response to a 3-hour, 100 gm oral glucose tolerance test. In all subjects insulin and glucose were measured hourly during the oral glucose tolerance test and the baseline sample was assayed for total testosterone, dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, sex hormone-binding globulin, and free testosterone. In hyperandrogenic women cortisol, dehydroepiandrosterone, and androstenedione were also measured, before and 60 minutes, after acute intravenous administration of 0.25 mg corticotropin (1-24)., Results: There was no difference in the response of cortisol, dehydroepiandrosterone, or androstenedione to corticotropin-(1-24) stimulation between normoinsulinemic and hyperinsulinemic hyperandrogenic patients. As defined, the hyperinsulinemic patients had higher basal and peak insulin levels and areas under the insulin response curve compared with the normoinsulinemic patients or controls. Total testosterone and dehydroepiandrosterone did not differ among study groups. As expected, hyperandrogenic patients demonstrated lower sex hormone-binding globulin activity and higher free testosterone, androstenedione, and dehydroepiandrosterone sulfate basal levels compared with controls., Conclusions: The results of this study do not support the hypothesis that chronic hyperinsulinemia in hyperandrogenic patients significantly inhibits the andrenocortical secretion of dehydroepiandrosterone or androstenedione in response to corticotropin stimulation or the basal circulating adrenal androgen levels. Additional studies, including a greater number of patients, may be needed to fully establish these conclusions.

Objective: Our purpose was to establish the incidence of point mutations of the 21-hydroxylase gene (CYP21) in hyperandrogenic women with and without a 17-hydroxyprogesterone response to corticotropin stimulation above normal but below those levels associated with nonclassic adrenal hyperplasia., Study Design: We studied 22 patients with hirsutism or hyperandrogenic oligoovulation: eight with an exaggerated net increase in 17-hydroxyprogesterone (i.e., change in 17-hydroxyprogesterone between 8.8 and 36 nmol/L) and 14 with a normal change in 17-hydroxyprogesterone. Large deletions of the 21-hydroxylase gene were evaluated by laser densitometry. Point mutations were detected with the polymerase chain reaction and dot blot hybridization analysis and included 30 Leu, intron-2 (G), 8 bp deletion exon-3, 172 Asn, 236-237-239 exon-6, 281 Leu, 318 stop, 339 His, 341 Trp, 356 Trp, and 453 Ser., Results: Four patients with an increase in 17-hydroxyprogesterone carried a 281 Leu mutation, one patient had an intron-2 (G) mutation, and one had a complete deletion of CYP21. Only two of these patients demonstrated no obvious abnormality of CYP21. In contrast, only one of the control patients demonstrated a CYP21 abnormality, a significant difference (p < 0.001)., Conclusions: These findings suggest that the majority of hyperandrogenic women with an exaggerated 17-hydroxyprogesterone response to corticotropin stimulation are heterozygotes (carriers) for inherited defects of CYP21. Whether these mutations are incidental to the androgen excess or predispose to the development of this disorder remains to be determined.

Objective: Deficient adrenocortical 3 beta-hydroxysteroid dehydrogenase activity has been reported in 5% to 30% of hyperandrogenic women. Our objective was to determine the incidence and degree of 3 beta-hydroxysteroid dehydrogenase deficiencies in hyperandrogenism., Study Design: A prospective study of adrenal function in patients with hyperandrogenism was performed in a tertiary care university medical center. Eighty-six consecutive patients with hirsutism or hyperandrogenic oligomenorrhea were studied; 26 healthy eumenorrheic women served as controls. All subjects underwent serum sampling at rest and a 1-hour adrenal stimulation test with 1 mg of intravenously corticotropin-(1-24). Dehydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin, total and free testosterone, and luteinizing and follicle-stimulating hormones were measured in basal serum; dehydroepiandrosterone, 17-hydroxyprogesterone, and 17-hydroxypregnenolone were measured in basal and corticotropin-stimulated serum. On the basis of experience with genetically defined 21-hydroxylase late-onset adrenal hyperplasia, patients were presumed to suffer from 3 beta-hydroxysteroid-deficient late-onset adrenal hyperplasia if they demonstrated a dehydroepiandrosterone or 17-hydroxypregnenolone response to corticotropin-(1-24) stimulation (absolute poststimulation level or net increment) greater than threefold the upper 95th percentile of controls., Results: Three women of two families (2.3%) had a 17-hydroxyprogesterone response consistent with 21-hydroxylase-deficient late-onset adrenal hyperplasia and were excluded from further study. Eighteen (21%) of the remaining patients had a 17-hydroxypregnenolone poststimulation increment above the upper 95th percentile of controls (13.9 nmol/L), and two had an elevated dehydroepiandrosterone increment (> 19.5 nmol/L). However, no patient exceeded threefold the upper control limit for either steroid response. Patients with an exaggerated dehydroepiandrosterone or 17-hydroxypregnenolone increment had higher circulating dehydroepiandrosterone sulfate levels but similar basal total and free testosterone, sex hormone-binding globulin, luteinizing and follicle-stimulating hormone concentrations, basal or stimulated androstenedione, dehydroepiandrosterone/androstenedione, and 17-hydroxypregnenolone/17-hydroxyprogesterone than their less responsive counterparts., Conclusions: Although an exaggerated response of 17-hydroxypregnenolone to adrenal stimulation is common in hyperandrogenism, a response severe enough to merit consideration as 3 beta-hydroxysteroid dehydrogenase-deficient late-onset adrenal hyperplasia was not encountered in this unselected patient population, suggestive of the rarity of this disorder.

Late-onset adrenal hyperplasia caused by 21-hydroxylase deficiency leads to hyperandrogenic symptoms in 1% to 6% of hyperandrogenic women. Normally there are two 21-hydroxylase genes present in a 1:1 ratio. Gene CYP21A is a nonfunctional pseudogene, whereas CYP21B is an active gene. Abnormalities of the CYP21A/CYP21B gene ratio may serve as a marker for late-onset adrenal hyperplasia. Eight hyperandrogenic patients with late-onset adrenal hyperplasia and five control subjects were studied by evaluation of autoradiograms of Taq I and Kpn I digests by means of laser densitometry. Seven of eight (87%) patients with late-onset adrenal hyperplasia had an abnormal CYP21A/CYP21B gene ratio on laser densitometry, suggestive of CYP21A gene duplication, CYP21B gene deletion, or the conversion of a CYP21B gene to a CYP21A gene. One of the five control subjects had a heterozygous deletion of the CYP21A gene. The CYP21A/CYP21B gene ratio may serve as a useful genetic marker for late-onset adrenal hyperplasia in a non-high-risk population.

Postoperative endomyometritis develops in as many as 85% of women undergoing cesarean section, which is 10- to 30-fold higher than after vaginal delivery. The timing and mechanism by which the infecting organisms gain access to the uterine cavity are unclear. One possibility is that the infection may occur postpartum by ascending colonization of the wound. Alternatively, myometritis may be already present at the time the cesarean section is performed in asymptomatic patients. With tissue necrosis, the stage is then set for puerperal endomyometritis. To study this second alternative mechanism, myometrial and placental biopsy specimens were obtained in 91 asymptomatic patients at the time of cesarean section. Histologic evidence of chorioamnionitis was identified in 10% (9/91) of patients. Acute myometritis was present in 11% (10/91) of the myometrial biopsy specimens. Seven of the nine women (77%) with subclinical acute chorioamnionitis demonstrated extension of the inflammation into the myometrium. Thirty-two percent (8/25) of women in labor and 31% (5/16) of those with rupture of membranes for greater than 6 hours had acute chorioamnionitis or myometritis, which is significantly higher (p less than 0.01) than in women without these risk factors. These findings suggest that approximately one third of asymptomatic women with rupture of the membranes for more than 6 hours or who are in labor at the time of cesarean section demonstrate histologic evidence of subclinical chorioamnionitis. In most of these patients the myometrium is also involved. The uterine incision is then performed through infected myometrium, possibly setting the stage for puerperal endomyometritis.