The role of inhibin in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder which, in its severest manifestations, is associated with anovulation, hyperandrogenism and metabolic imbalance. The biochemical markers for the condition can include a significantly raised LH:FSH ratio and a raised testosterone concentration, indicating a derangement of the hypothalamo--pituitary--ovarian axis which may be primary or secondary to a primary ovarian pathology. The bioactive inhibins are heterodimeric glycoproteins consisting of alpha-betaA (inhibin A) and alpha-betaB (inhibin B) subunits. They play an endocrine role in co-regulating (with oestradiol) the suppression of FSH during the late follicular and luteal phases of the ovarian cycle and they are implicated in intraovarian paracrine signalling. Inhibin B, which is the predominant form in small pre-ovulatory follicles, increases in concentration from early in the follicular phase to reach a peak coincident with the onset of the decrease in FSH which forms the basis of the pattern of mono-ovulation seen in normo-ovulatory women. Several unique features of the dysovulation of women with PCOS, namely their failure to recruit and develop a dominant follicle despite having 'normal' concentrations of endogenous FHS, the raised LH:FSH ratio and their exquisite sensitivity to exogenous FSH injections, may be explained by their significantly higher inhibin B concentrations. Studies into inhibin B parameters in women with PCOS demonstrate that women with anovular PCOS have significantly higher concentrations of circulating inhibin B and that they lack the pulsatile pattern of secretion that can be detected in normo-ovulatory women during the mid-follicular phase. The inhibin B response to ovulation induction with clomiphene citrate in women with PCOS differs from that in normo-ovulatory women taking the antioestrogen. Women with PCOS who over-respond to ovulation induction with injected FSH in a 'low-dose' step-up protocol' and recruit multiple follicles have significantly higher concentrations of pre-treatment inhibin B than PCOS subjects who do not.     

The role of ovarian surgery in polycystic ovary syndrome

Problems in inducing ovulation in women with polycystic ovary syndrome (PCOS) and anovulation are well recognized. In 1935, Stein and Leventhal first described surgical treatment by ovarian wedge resection at laparotomy for women with anovulation and PCOS. Ovarian wedge resection was eventually abandoned because of the significant risk of postsurgical adhesion formation, which resulted in tubal adhesions, and because of the advent of medical ovulation induction with clomiphene and gonadotrophins. However, since the arrival of minimally invasive surgical techniques, laparoscopic ovarian surgery has become feasible. The potential advantages of laparoscopic ovarian surgery include repeated single ovulations and less adhesion formation. Lowered costs make ovarian surgery an attractive alternative to gonadotrophins. However, although many case series have suggested that ovarian surgery is an effective strategy, few randomized, controlled trials have been undertaken comparing the success rates of surgery with gonadotrophins. The long-term concerns with surgery include adhesion formation and premature ovarian failure.     

The role of the adrenal cortex in polycystic ovary syndrome

Adrenal androgen excess affects approximately 25% of PCOS patients. The exact etiology of this excess in PCOS patients is unclear. Some evidence that adrenal androgen excess may be a genetic trait. The adrenal androgen response to ACTH is highly individualized, and the relative response seems to be constant over time. In addition, there is a strong familial component to adrenal androgen levels in normal individuals and PCOS patients. It is possible that the tendency to overproduce adrenal androgens is an inherited risk factor for the development of PCOS. Overall, few hyperandrogenic patients actually have isolated deficiencies of 3 beta-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11-hydroxylase. The ovarian hormonal secretion in PCOS can affect adrenal androgen secretion and metabolism, although this factor accounts for only part of this abnormality. More likely, the adrenal androgen excess results from a generalized hyperresponsiveness of the adrenal cortex to ACTH, but without an increase in CRH or ACTH sensitivity. Although glucocorticoid administration may improve the ovulatory function of these patients, the results are modest and cannot be predicted by the circulating androgen levels.     

The polycystic ovary syndrome

Much is known about the pathophysiology and pathogenesis of the polycystic ovary syndrome (PCO). The key clinical features are inappropriate gonadotropin secretion, altered production rates, binding and metabolism of steroids and androgen excess, all resulting in defeminization, anovulatory infertility, obesity and endometrial hyperplasia. Management should be based on the patient's reproductive goals. Adjunct measures can control hirsutism.     

The role of metformin in the management of polycystic ovary syndrome

PURPOSE OF REVIEW: The purpose of this review is to provide a critical summary of recent studies on the clinical effects of metformin in polycystic ovary syndrome. RECENT FINDINGS: After the recognition that hyperinsulinaemia is a fundamental disturbance in polycystic ovary syndrome, a novel and promising form of therapy in the form of insulin-sensitizing drugs has been introduced. Among these, metformin is the most widely used. This therapeutic intervention has been shown to exert beneficial effects on the endocrine and metabolic disturbances that characterize the syndrome and, more recently, to improve the reproductive outcome in women with polycystic ovary syndrome. With rapid progress in this area, metformin use has also been extended to the management of lean polycystic ovary syndrome patients. SUMMARY: Although most studies are nonrandomized trials, current data provide a rationale for metformin as first-line management for women with polycystic ovary syndrome, alone or in combination with conventional treatments. Controversy still exists, however, regarding the mechanisms by which metformin exerts its beneficial effects in polycystic ovary syndrome.     

The metabolic syndrome in polycystic ovary syndrome

Approximately one-third to one-half of all women and adolescent girls with polycystic ovary syndrome (PCOS) has the metabolic syndrome, associated with increased risk for cardiovascular disease and type 2 diabetes. Evidence suggests that insulin resistance is the likely link between PCOS and the metabolic syndrome. Early screening for impaired glucose tolerance, even in adolescents, is recommended. Lifestyle modification with increased physical activity and weight reduction remains first-line therapy. Insulin-sensitizing drugs may also ameliorate features of the metabolic syndrome in PCOS but long-term prospective studies are needed to determine the role of these drugs in the prevention of the metabolic syndrome.     

The role of miRNAs in polycystic ovary syndrome with insulin resistance

PurposeThis review aims to summarize the key findings of several miRNAs and their roles in polycystic ovary syndrome with insulin resistance, characterize the disease pathogenesis, and establish a new theoretical basis for diagnosing, treating, and preventing polycystic ovary syndrome.MethodsRelevant scientific literature was covered from 1992 to 2020 by searching the PubMed database with search terms: insulin/insulin resistance, polycystic ovary syndrome, microRNAs, and metabolic diseases. References of relevant studies were cross-checked.ResultsThe related miRNAs (including differentially expressed miRNAs) and their roles in pathogenesis, and possible therapeutic targets and pathways, are discussed, highlighting controversies and offering thoughts for future directions.ConclusionWe found abundant evidence on the role of differentially expressed miRNAs with its related phenotypes in PCOS. Considering the essential role of insulin resistance in the pathogenesis of PCOS, the alterations of associated miRNAs need more research attention. We speculate that race/ethnicity or PCOS phenotype and differences in methodological differences might lead to inconsistencies in research findings; thus, several miRNA profiles need to be investigated further to qualify for the potential therapeutic targets for PCOS-IR.     

Do basal inhibin A and inhibin B levels have value in the diagnosis of polycystic ovary syndrome?

In the present study we aimed to investigate whether basal inhibin A and B levels in women with polycystic ovary syndrome (PCOS) would be used in diagnosis of the condition. Forty women with PCOS and 40 women with normal cycles (control group) were evaluated. There was no statistically significant difference in mean age and mean body mass index between the two groups (p > 0.05). Serum levels of inhibin A and B, follicle-stimulating hormone (FSH), luteinizing hormone and total testosterone, and total ovarian volume, were determined in the PCOS group and the control group on day 3. In the PCOS group, total follicle number was obtained by counting follicles of diameter > or =2 mm in both ovaries. Results were evaluated using Student's t test, Pearson correlation and regression tests. There was no significant difference in mean basal inhibin A or inhibin B levels between the two groups. Basal inhibin B levels showed a statistically significant negative correlation with basal FSH levels and a positive correlation with total follicle number in the PCOS group (p < 0.05 and p < 0.01, respectively). We conclude that basal inhibin A or B levels cannot be used in the diagnosis of PCOS.     

The treatment of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women in reproductive age. As for the treatment of this disease the lack of a clear etiology for PCOS has led to a symptom-orientated treatment. However, the overall aims of treatment are to induce ovulation for women desiring conception, to reduce androgen levels, to reduce body weight and to reduce long-term health risks of diabetes mellitus and cardiovascular disease. Clomiphene citrate (CC) is recommended as first line treatment for induction of ovulation in patients with PCOS by virtue of its efficacy, safety, and ease of administration. Alternatives for CC-resistant patients include gonadotrophin therapy (better with low-dose step-up protocol) and laparoscopic ovarian diathermy. Recently, recombinant FSH (rFSH) has been introduced in clinical practice and it seems more effective than urinary FSH as demonstrated by a significantly higher number of follicles recruited and embryos obtained with a shorter treatment period. The addition of GnRH-agonist to the stimulation protocol for women affected by PCOS could reduce premature luteinization and increase cycle fecundity. Other drugs under investigation are metformin and cabergoline. Hirsutism is the manifestation of hyperandrogenemia in PCOS. The primary goal of the treatment of hirsutim is central or peripheral androgen suppression using 3 groups of drugs: inhibitors of androgen production (oral contraceptives, GnRH analogues), peripheral androgen blockers (cyproterone acetate, flutamide, finasteride and spironolactone), and insulin-sensitizing agents (metformin). Weight reduction and exercise could also improve not only menstrual disturbances and infertility, but also insulin resistance and its adverse metabolic con-sequences.     

The genetics of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder. There is evidence for a genetic component in PCOS based on familial clustering of cases. The majority of the evidence supports an autosomal dominant form of inheritance. Steroidogenesis has been shown to be upregulated in PCOS theca cells, suggesting that the genetic abnormality in PCOS affects signal transduction pathways controlling the expression of a family of genes. Although a number of candidate genes have been proposed, the putative PCOS gene(s) has yet to be identified. Linkage and association studies implicate a region near the insulin receptor gene at chr 19p13.3. New genetic approaches, such as microarray technology, hold promise for elucidation of the pathophysiology underlying PCOS.     

Role of inhibin in polycystic ovarian syndrome

The possible role of inhibin in the etiology of polycystic ovarian syndrome (PCO) was studied. In rats PCO was induced by thiouracil and human chorionic gonadotropin (hCG). These animals were grouped under different treatment schedules: inhibin; antibodies to inhibin; ovine follicle stimulating hormone (FSH). In rats treated with antibodies to inhibin, there was a decrease in ovarian weight concomitant with specific increase in serum FSH levels. No changes in serum luteinizing hormone (LH) and prolactin levels were observed. However, testosterone levels were significantly decreased. Histological examination of the ovaries showed a marked arrest in the cyst formation with new growing follicles. In animals treated with inhibin, testosterone levels increased without any accompanying changes in ovarian weight. The circulating levels of prolactin and LH were unaffected. A decrease in serum FSH levels was accompanied by an increase in the number of cysts. The study corroborates the hypothesis that inhibin is involved in the development of PCO syndrome. Hence, an antagonist to inhibin may prove useful for the treatment of women with this condition.     

Serum inhibin levels in polycystic ovary syndrome: effect of insulin resistance and insulin secretion

Insulin resistance is common in women with the polycystic ovary syndrome. We investigated the relationship between insulin resistance and the serum inhibin concentration in a group of 19 women with polycystic ovary syndrome and eight control subjects at different phases of the menstrual cycle. Insulin resistance was measured by the frequently sampled intravenous glucose tolerance test, and inhibin was measured by a specific radioimmunoassay. Insulin sensitivity (mean +/- SE) was significantly reduced in the polycystic ovary syndrome group compared with controls: reduced insulin sensitivity 46.7 +/- 5.0 min-1/(nmol/mL), normally insulin-sensitive 106.6 +/- 11.7 min-1/(nmol/mL) (P less than .01). The women with polycystic ovary syndrome had inhibin levels (126 +/- 15.2 microLEq/mL) comparable to those found during the early follicular phase of the control group (117 +/- 22.1 microLEq/mL), but significantly lower than late follicular phase (259 +/- 25.6 microLEq/mL) or luteal phase (448 +/- 91.8 microLEq/mL) levels in the control group. No association was found between the degree of insulin resistance and the inhibin concentration, which remained unaltered over a 3-hour period despite maximal stimulation of endogenous insulin secretion. The inhibin concentrations in polycystic ovary syndrome may reflect impaired follicular maturation. Inhibin secretion is not acutely affected by insulin secretion in normal or in hyperandrogenic women.     

Metabolic syndrome in polycystic ovary syndrome

Because insulin resistance and visceral obesity are important features of polycystic ovary syndrome (PCOS), metabolic syndrome is much more common in women with PCOS than in the general female population of similar age. It has been reported that in the USA almost 50% of women with PCOS present the metabolic syndrome. In Italy, where women with PCOS have a lower mean body weight and less frequently increased serum triglycerides than US PCOS, metabolic syndrome is less common but still 4 times more frequent in PCOS patients than in the general female population of similar age. Patients with mild PCOS phenotype (ovulatory PCOS) have a lower prevalence of metabolic syndrome but, in these patients too, metabolic syndrome is 2 times more frequent than in the normal population. These data suggest that PCOS is the most common cause of increased cardiovascular risk in young adult women. All obese and overweight women with PCOS should be screened for metabolic syndrome and, when the syndrome is not found, the screening should be repeated every 2 or 3 years. Treatment consists in lifestyle intervention. Pharmacological therapies should be used only when lifestyle fails to normalize cardiovascular risk factors.     

The role of genes in the polycystic ovary syndrome: Predisposition and mechanisms

The polycystic ovary syndrome (PCOS), mainly characterized by clinical and/or biochemical hyperandrogenism, ovarian dysfunction and/or polycystic morphology as well as associated metabolic disorders, is the most common endocrine disorder in women of reproductive age. The familial clustering of PCOS cases and the accumulating evidence that the interaction between multiple genetic and environmental factors is necessary for the development of the syndrome, has triggered the conduct of genetic studies on PCOS. These studies have focused on many genetic polymorphisms, investigating their possible positive or negative correlation with the syndrome. The related genes can be grouped in four categories: those related with insulin resistance, those that interfere with the biosynthesis and the action of androgens, those that encode inflammatory cytokines and other candidate genes. Despite the progress that has been made in the elucidation of the genetic mechanisms of the PCOS, the genetic studies on the syndrome still face many obstacles and challenges. Further studies are needed, in order to shed new light in the pathogenesis of the syndrome, which will allow for new approaches in the diagnostics and therapeutics of PCOS.     

Characterization of unilateral polycystic ovary compared with polycystic ovary syndrome

Twelve patients with unilateral polycystic ovarian morphology demonstrated milder degrees of ovarian and other endocrine dysfunction than polycystic ovary syndrome patients and had fewer incidences of hyperprolactinemia and hyperandrogenism.