Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome?

Animal and human studies suggest that leptin modulates hypothalamic-pituitary-gonadal axis functions. Leptin may stimulate gonadotrophin-releasing hormone (GnRH) release from the hypothalamus and luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion from the pituitary. A synchronicity of LH and leptin pulses has been described in healthy women, suggesting that leptin probably also regulates the episodic secretion of LH. In some pathological conditions, such as polycystic ovarian syndrome (PCOS), LH-leptin interactions are not known. The aim of the present investigation was to assess the episodic fluctuations of circulating LH and leptin in PCOS patients compared to regularly menstruating women. Six PCOS patients and six normal cycling (NC) women of similar age and body mass index (BMI) were studied. To assess episodic hormone secretion, blood samples were collected at 10-min intervals for 6 h. LH and leptin concentrations were measured in all samples. For pulse analysis the cluster algorithm was used. To detect an interaction between LH and leptin pulses, an analysis of copulsatility was employed. LH concentrations were significantly higher in the PCOS group in comparison to NC women, however serum leptin concentrations and leptin pulse characteristics for PCOS patients did not differ from NC women. A strong synchronicity between LH and leptin pulses was observed in NC women; 11 coincident leptin pulses were counted with a phase shift of 0 min (P = 0.027), 18 pulses with a phase shift of -1 (P = 0.025) and 24 pulses with a phase shift of -2 (P = 0.028). PCOS patients also exhibited a synchronicity between LH and leptin pulses but weaker (only 20 of 39 pulses) and with a phase shift greater than in normal women, leptin pulses preceding LH pulses by 20 min (P = 0.0163). These results demonstrate that circulating leptin and LH are synchronized in normal women and patients with PCOS. The real significance of the apparent copulsatility between LH and leptin must be elucidated, as well as the mechanisms that account for the ultradian leptin release.     

Surrogate end-points or primary outcomes in clinical trials in women with polycystic ovary syndrome?

There are multiple surrogate variables in polycystic ovary syndrome (PCOS), including biometric and biochemical parameters. The number of surrogate variables and their poor validity in relationship to primary clinical end-points pose major problems to conducting a trial in women with PCOS. The aim of this review is to discuss the use of surrogate variables compared with primary clinical end-points in women with PCOS. Arguably the best documented correlation between a surrogate variable and a primary clinical end-point is that between ovulation and pregnancy in women with PCOS. Good correlation has been noted between the increase in ovulation frequency with clomiphene citrate and the chance of pregnancy in women with PCOS. However, ovulation cannot be equated with pregnancy, as a host of other factors may affect the true outcome of interest: a healthy liveborn child. Pregnancy and an improvement in hirsutism are clinical end-points that have been successfully studied in past and ongoing clinical trials in women with PCOS. Many other clinical end-points, such as endometrial cancer and cardiovascular disease, are rare in premenopausal women with PCOS, and may not be suitable as the primary outcome of clinical studies. Future multicentre trials in women with PCOS should focus on primary clinical end-points.     

Do young women with polycystic ovary syndrome show early evidence of preclinical coronary artery disease?

BACKGROUND: It is thought that women with polycystic ovary syndrome (PCOS) are at increased risk of developing cardiovascular diseases. METHODS: In this study, we used transthoracic echocardiography to measure coronary flow reserve (CFR) in 28 women with PCOS and in 26 healthy women. RESULTS: The PCOS and the control groups were similar in terms of age (27.1 +/- 4.5 versus 28.8 +/- 4.4 years) and BMI (26.6 +/- 5.7 versus 24.7 +/- 4.4 kg/m2). Fasting insulin levels and homeostasis model assessment insulin resistance index were higher in the PCOS group. LH, the LH/FSH ratio, total testosterone, free testosterone and androstenedione were higher in the PCOS group. FSH, estradiol, prolactin, progesterone, cholesterol, triglyceride and high-sensitive C-reactive protein were similar between the two groups, but homocysteine levels were higher in the PCOS group. Baseline diastolic peak f low velocity (DPFV) (25.0 +/- 4.6 versus 23.3 +/- 2.7 cm/s, P > 0.05), hyperaemic DPFV (71.2 +/- 12.8 versus 73.0 +/- 12.9 cm/s, P > 0.05) and CFR (2.8 +/- 0.8 versus 3.2 +/- 0.8 cm/s, P > 0.05) of the left anterior descending coronary artery were similar between the two groups. CONCLUSION: We conclude that in young women with PCOS and without cardiovascular risk factors, CFR is preserved.     

Proinsulin serum concentrations in women with polycystic ovary syndrome: a marker of beta-cell dysfunction?

BACKGROUND: The aim of this study was to establish the effect of polycystic ovary syndrome (PCOS) adjusted for adiposity on proinsulin concentrations. METHODS: Ninety-one women with PCOS and 72 normal cycling (NC) women were recruited. A 2 h, 75 g oral glucose tolerance test was performed. Glucose and insulin were measured in each sample. Proinsulin and C-peptide were determined at 0 and 30 min and the fasting proinsulin/insulin ratio (PI/I) was calculated. Insulin sensitivity was estimated by insulin sensitivity index (ISI) composite, and beta-cell function was estimated by insulinogenic index. RESULTS: Insulin, proinsulin and C-peptide concentrations were higher in women with PCOS than in NC women (P < 0.05). PI/I and insulinogenic index were similar in both groups. Proinsulin concentrations increased with body mass index (P < 0.05) only in women with PCOS; therefore, proinsulin concentrations were higher in obese PCOS patients compared with obese control women (P < 0.05). Moreover, a positive association between proinsulin concentrations and waist diameter adjusted for C-peptide (P < 0.05) and a negative association between proinsulin concentrations and ISI composite values were observed in PCOS patients (P < 0.05). CONCLUSIONS: Data suggest that in PCOS patients an elevated proinsulin concentration could reflect insulin resistance more than beta-cell dysfunction. However, the elevated concentration of proinsulin in these patients could also result from impaired beta-cell function resulting from intra-abdominal obesity independently of insulin resistance.     

What is polycystic ovary syndrome? Are national views important?

Polycystic ovary syndrome (PCOS) is a true syndrome, being a heterogeneous collection of signs and symptoms that gathered together form a spectrum of a disorder with a mild presentation in some, whilst in others there is a severe disturbance of reproductive, endocrine and metabolic function. There has been much debate about phenotype and, more recently, genotype. There has also been scepticism in some quarters, with a feeling that we may be looking at one end of a spectrum that is in reality 'normal', or perhaps a consequence of the modern disease of obesity. Whilst the polycystic ovary is at the centre of the syndrome, it is external effects such as hyperinsulinism, that influence its expression. There is no consensus on the definition of PCOS and so studies that compare epidemiology and treatments often have very different starting points, and so cannot be compared. In this debate we wish to re-explore our current thinking on PCOS, with a particular emphasis on the British and European perspective and invite others to contribute to the discussion which could form the basis for an international consensus.     

Is there a dose-response relationship of metformin treatment in patients with polycystic ovary syndrome? Results from a multicentric study

STUDY QUESTION: Do different dosages of metformin account for different clinical and biochemical outcomes in women with polycystic ovary syndrome (PCOS) and do basal anthropometric and metabolic characteristics of the patients provide any indications regarding the dose required to reach the target effect? SUMMARY ANSWER: Different doses of metformin exerted the same effects on clinical, biochemical and metabolic parameters in patients affected by PCOS. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Since the insulin-sensitizing agents came into use in the management of PCOS, metformin has shown a positive benefits-risks ratio. Nonetheless, therapeutic schedules are not well standardized. This is the first study which systematically analyses the effect of different doses of metformin on clinical, hormonal and metabolic features of PCOS. On the basis of our results, higher doses are no more effective than lower doses. DESIGN: A multicentric cohort prospective study. A total of 250 PCOS women were enrolled, 49 lost to follow-up. Menstrual cyclicity, hormonal assays, oral glucose tolerance test, lipid profile and ultrasonographic pelvic examination were evaluated at the baseline and after 6 months of metformin treatment at different doses (1000, 1500 and 1700 mg). PARTICIPANTS AND SETTING: A total of 201 PCOS patients completed the study without protocol violations in three university hospitals: seventy-three patients from Centre A (treated with metformin 500 mg twice a day), 60 patients from Centre B (treated with metformin 500 mg three times a day) and 68 patients from Centre C (treated with metformin 850 mg twice a day). MAIN RESULTS AND THE ROLE OF CHANCE: Metformin exerted an overall positive effect on the clinical and endocrine-metabolic features of PCOS. The degree of these effects was independent of the administered dosage in every range of basal body mass index (BMI). When patients were stratified according to their insulinaemic status, scattered inter-doses differences were found in some of the outcome measures. Patients who exhibited an increase of >2 menstrual cycles/year were considered as responders to treatment. Responders had a higher basal BMI than non-responders and showed a greater reduction in plasma testosterone levels after metformin treatment, but other outcome measures did not differ significantly. Total insulin secretion in the 180 min following the glucose tolerance test before metformin treatment (basal AUC-I) was significantly correlated with the decrease in insulin secretion induced by metformin in both the whole group and in responders, but only correlated with the variation in the number of cycles in responders. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: The different doses were administered in different centres, and between-centre variation is a potential confounding factor. GENERALIZABILITY TO OTHER POPULATIONS: The paradigm of using the minimum effective dose of metformin could be pursued in other pathological conditions characterized by insulin resistance. STUDY FUNDING/COMPETING INTEREST(S): No funding or competing interests to declare.     

Should patients with polycystic ovarian syndrome be treated with metformin?

The recognition of insulin resistance as a principal factor in the pathogenesis of polycystic ovarian syndrome (PCOS) has led to the use of insulin-lowering agents, also called 'insulin-sensitizing drugs', for its treatment. The most extensively studied insulin-lowering agent in the treatment of PCOS is metformin: an oral antihyperglycaemic agent used initially in the treatment of type 2 diabetes mellitus. Metformin is effective in the treatment of PCOS-related anovulation and infertility. Moreover, preliminary evidence indicates that metformin may also be effective in decreasing the risk of early spontaneous miscarriage in women with PCOS. Metformin also appears to induce cardioprotective effects on serum lipids as well as plasminogen activator inhibitor (PAI)-1 and may decrease the risk of development of type 2 diabetes. The highly promising therapeutic profile of metformin is related to the role of this agent in controlling an important aetiologic factor in the pathogenesis of PCOS: hyperinsulinaemia.     

Association of IL-1β, IL-1Ra and FABP1 gene polymorphisms with the metabolic features of polycystic ovary syndrome

Background

Polycystic ovary syndrome (PCOS), a highly prevalent endocrinopathy is currently being designated as chronic low grade inflammatory state. IL-1β, IL-1Ra and FABP1 are critical mediators of inflammatory processes and are speculated to play a role in the pathogenesis of PCOS. The aim of this study was to study the association of IL-β, IL-1Ra and FABP1 gene polymorphisms with PCOS and related metabolic features.

Subjects

95 PCOS and 45 age matched healthy control subjects were enrolled in this study.

Methods

Polymorphism in genes IL-1β, IL-1Ra and FABP1 was studied by PCR, PCR–RFLP and sequencing methods, respectively. Hormonal and lipid profiles were evaluated for all the subjects.

Results

Hormonal and lipid profiles showed significant differences between PCOS and control subjects. Allele and genotype frequencies of IL-1β, IL-1Ra and FABP1 gene polymorphisms did not vary between the control and PCOS group. However, T allele of C[-511]T variant of IL-1β, allele II in intron 2 of IL-1Ra and A allele of A/G variant of FABP1 (rs2197076) showed significant association with many metabolic features associated with PCOS.

Conclusions

Polymorphism in genes encoding cytokines and proteins involved in lipid metabolism can provide insights into the genetics of the disease and may contribute to assess the associated risk of cardiovascular diseases (CVD), dyslipidemia and metabolic syndrome (MetS) associated with PCOS.

     

Reply to: Are laparoscopic ovarian diathermy and gonadotropin administration the only therapeutic second-steps in clomiphene-citrate resistant women with polycystic ovary syndrome?

Sir, We would like to thank Dr Palomba and colleagues for their interestin our paper (van Wely et al., 2004). In Western Europe, recombinantFSH is most commonly used for ovulation induction in women withpolycystic ovary syndrome (PCOS) that     

Serum anti-Müllerian hormone levels remain high until late reproductive age and decrease during metformin therapy in women with polycystic ovary syndrome

BACKGROUND: Anti-Müllerian hormone (AMH) is secreted by granulosa cells of ovarian early developing follicles and its serum levels have been shown to correlate with small antral follicle number. Since the pronounced androgen secretion from follicles/stroma in women with polycystic ovary syndrome (PCOS) remains until late reproductive age, and since AMH reflects the number of antral follicles, it was of interest to study the possible age-related relationship between AMH, androgens and follicle number in women with PCOS and in control women. Moreover, the possible effect of metformin on serum AMH levels and the relationship to follicle count and volume were studied. METHODS: Forty-four healthy women (aged 21-44 years) and 65 women with previously diagnosed PCOS (aged 16-44 years) participated in the study. Serum basal AMH levels were correlated with those of serum androstenedione, testosterone, estradiol (E2), LH, FSH and inhibin B, and with follicle number. The effect of metformin on serum AMH concentrations, follicle number and ovarian volume was studied in 26 women (aged 20-41 years) with PCOS after 6 months of treatment. RESULTS: Serum AMH levels were 2- to 3- fold higher in PCOS women than in healthy women. In control women, serum AMH levels correlated positively with those of serum androstenedione (r = 0.564, P < 0.001) and testosterone (r = 0.328, P = 0.036) and negatively with serum FSH concentrations (r = -0.374, P = 0.012) and age (r = -0.691, P<0.001). In women with PCOS, serum AMH levels correlated positively with those of androstenedione (r = 0.311, P = 0.011) and testosterone (r = 0.310, P = 0.011) and with follicle count (r = 0.352, P = 0.012), and negatively with age (r = -0.300, P = 0.014). Serum AMH levels, the number of antral follicles and ovarian volume decreased significantly during metfromin treatment. CONCLUSIONS: Serum AMH levels decreased with age both in healthy women and in women with PCOS, although they were always 2- to 3-fold higher and remained elevated until 40 years of age in PCOS subjects. Thus, since serum AMH levels correlate well with antral follicle count and serum androgen levels, the measurement of AMH could be used as a tool to assess ovarian ageing, to diagnose polycystic ovaries/PCOS and to evaluate treatment efficacy.     

Women with polycystic ovary syndrome (PCOS) often undergo protracted treatment with metformin and are disinclined to stop: indications for a change in licensing arrangements?

Women with polycystic ovary syndrome (PCOS) are increasingly being treated with metformin as an insulin sensitizing agent to reduce symptoms of hyperandrogenism and promote fertility. Indications such as hirsutism and cycle regulation require long term treatment. The drug is also being used through pregnancy. It is not licensed for any indication specific to PCOS, which means that much of this prescribing is taking place in an environment short of reliable information concerning safety. We describe the failure of recruitment to a study undertaken to explore the effects of metformin treatment discontinuation in women with PCOS, to provide both clinical and aetiological information. The study failed because the patients did not wish to stop treatment, and it illustrates the problems facing doctors working in this area. To achieve a safer prescribing environment, we recommend that action be taken by the manufacturer of metformin to work with regulatory agencies on a European base to extend prescribing indications for metformin to women with PCOS.     

Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?

The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.     

Do women with polycystic ovary syndrome (PCOS) report differences in sex-typed behavior as children and adolescents?: Results of a pilot study

Background: The etiology of polycystic ovary syndrome (PCOS) is poorly understood, as is the impact of female hyperandrogenism on psychosocial and psychosexual behavior.

Aim: The present study sought to test whether women with PCOS self-report more masculine sex-typed behavior in childhood, at adolescence, and as adults.

Subjects and methods: Sixty-one women (34 women self-reporting a clinical diagnosis of PCOS and 27 control women not reporting a PCOS diagnosis) completed a questionnaire containing items on childhood sex-typed behavior, adolescent behavior, and present masculinity, femininity and mood.

Results: Results revealed significant differences (p<0.05) in retrospective self-reports of childhood sex-typed behavior and gender conformity according to PCOS status, with women in the PCOS group reporting less feminine childhood behavior, and less gender-typical behavior. A composite of sex-typed behaviors did not differ according to PCOS status at adolescence, although several individual items did. As adults, we found no differences between the groups in masculinity and femininity, although PCOS women reported lower happiness than controls (p<0.05), and trends toward a bisexual orientation and having changed sex orientation more often than controls (p<0.10).

Conclusion: Results of this pilot study provide evidence of PCOS women self-reporting discrete psychosocial developmental patterns compared to non-PCOS women. These differences in retrospective self-reported accounts may be factual or biased by current psychosocial differences, such as depression.