Do ovulatory hormone profiles among healthy premenopausal women differ between women with and without sporadic anovulation? SUMMARY ANSWER: Women with one anovulatory cycle tended to have lower estradiol, progesterone and LH peak levels during their ovulatory cycle. WHAT IS KNOWN ALREADY: Anovulation occurs sporadically in healthy premenopausal women, but the influence of hormones in a preceding cycle and the impact on a subsequent cycle's hormone levels is unknown. STUDY DESIGN, SIZE, DURATION: The BioCycle Study was a prospective cohort including 250 healthy regularly menstruating women, 18-44 years of age, from Western New York with no history of menstrual or ovulation disorders. The women were followed with up to eight study visits per cycle for two cycles, most of which were consecutive. PARTICIPANTS/MATERIALS, SETTING AND METHODS: All study visits were timed to menstrual cycle phase using fertility monitors and located at the University at Buffalo women's health research center from 2005 to 2007. The main outcomes measured were estradiol, progesterone, LH and follicle-stimulating hormone levels in serum at up to 16 visits over two cycles. Anovulation was defined as peak serum progesterone concentrations ≤5 ng/ml and no serum LH peak detected during the mid- or late-luteal phase visit. MAIN RESULTS AND THE ROLE OF CHANCE: Reproductive hormone concentrations were lower during anovulatory cycles, but significant reductions were also observed in estradiol (-25%, P = 0.003) and progesterone (-22%, P = 0.001) during the ovulatory cycles of women with one anovulatory cycle compared with women with two ovulatory cycles. LH peak concentrations were decreased in the ovulatory cycle of women with an anovulatory cycle (significant amplitude effect, P = 0.004; geometric mean levels 38% lower, P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Follow-up was limited to two menstrual cycles, and no ultrasound assessment of ovulation was available. Data were missing for a total of 168 of a possible 4072 cycle visits (4.1%), though all women had at least five visits per cycle (94% had seven or more per cycle). WIDER IMPLICATIONS OF THE FINDINGS: These results suggest a possible underlying cause of anovulation, such as a longer-term subclinical follicular, ovarian or hypothalamic/pituitary dysfunction, even among healthy, regularly menstruating women. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (Contract no. HHSN275200403394C). The authors have no potential competing interests.

Do uric acid levels across the menstrual cycle show associations with endogenous estradiol (E2) and reproductive hormone concentrations in regularly menstruating women? SUMMARY ANSWER: Mean uric acid concentrations were highest during the follicular phase, and were inversely associated with E2 and progesterone, and positively associated with FSH. WHAT IS KNOWN ALREADY: E2 may decrease serum levels of uric acid in post-menopausal women; however, the interplay between endogenous reproductive hormones and uric acid levels among regularly menstruating women has not been elucidated. STUDY DESIGN, SIZE, DURATION: The BioCycle study was a prospective cohort study conducted at the University at Buffalo research centre from 2005 to 2007, which followed healthy women for one (n = 9) or 2 (n = 250) menstrual cycle(s). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were healthy women aged 18-44 years. Hormones and uric acid were measured in serum eight times each cycle for up to two cycles. Marginal structural models with inverse probability of exposure weights were used to evaluate the associations between endogenous hormones and uric acid concentrations. MAIN RESULTS AND THE ROLE OF CHANCE: Uric acid levels were observed to vary across the menstrual cycle, with the lowest levels observed during the luteal phase. Every log-unit increase in E2 was associated with a decrease in uric acid of 1.1% (β = -0.011; 95% confidence interval (CI): -0.019, -0.004; persistent-effects model), and for every log-unit increase in progesterone, uric acid decreased by ∼0.8% (β = -0.008; 95% CI: -0.012, -0.004; persistent-effects model). FSH was positively associated with uric acid concentrations, such that each log-unit increase was associated with a 1.6% increase in uric acid (β = 0.016; 95% CI: 0.005, 0.026; persistent-effects model). Progesterone and FSH were also associated with uric acid levels in acute-effects models. Of 509 cycles, 42 were anovulatory (8.3%). Higher uric acid levels were associated with increased odds of anovulation (odds ratio 2.39, 95% CI: 1.25, 4.56). LIMITATIONS, REASONS FOR CAUTION: The change in uric acid levels among this cohort of healthy women was modest, and analysis was limited to two menstrual cycles. The women in this study were healthy and regularly menstruating, and as such there were few women with high uric acid levels and anovulatory cycles. WIDER IMPLICATIONS OF THE FINDINGS: These findings demonstrate the importance of taking menstrual cycle phase into account when measuring uric acid in premenopausal women, and confirm the hypothesized beneficial lowering effects of endogenous E2 on uric acid levels. These findings suggest that there could be an underlying association affecting both sporadic anovulation and high uric acid levels among young, regularly menstruating women. Further studies are needed to confirm these findings and elucidate the connection between uric acid and reproductive and later cardiovascular health. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract # HHSN275200403394C). No competing interests declared.

Polycystic ovary syndrome (PCOS) is a common endocrine condition affecting women of reproductive age. There are many typical signs and symptoms that allow for the diagnosis of PCOS depending on the criteria used. Interestingly, ethnicity influences the extent of these signs and symptoms; therefore, the frequency of symptoms varies between different countries and ethnic groups. The prevalence of this syndrome in Croatia is unknown, and it's clinical and biochemical characteristics have not yet been reported. During this study, we used the Rotterdam criteria to evaluate 365 Croatian women with PCOS, and compared them to 304 age matched controls to assess the clinical and biochemical abnormalities that occur in PCOS patients. The mean age of PCOS patients at presentation was 26.1 +/- 5.9 years and of controls were 28.0 +/- 4.2 years. Women with PCOS has significantly higher body mass index (BMI) than the control group, although in both groups most patients had normal weight (76.2% vs. 87.8%). Abdominal distribution of fat tissue was similar in both groups. Menstrual cycle abnormalities were observed in 90.7% of PCOS patients, and ultrasonographic appearance of polycystic ovaries was reported in 97.3% of PCOS cases. Nearly 75% of patients with PCOS had hirsutism and 49.6% had acne. We recorded significantly higher serum levels of luteinizing hormone (LH), total testosterone (TT), free testosterone (fT) and insulin, while the serum levels of sex hormone binding globuline (SHBG) and follicular stimulating hormone (FSH) were significantly lower than in the control group. Serum glucose values were not significantly different between the groups. In conclusion, chronic anovulation, hirsutism and ultrasound appearance of polycystic ovaries are the dominant features of PCOS in Croatian population. The majority of patients with PCOS had normal body weight. The incidence of insulin resistance in this group of patients is less than the previously described frequency in other populations of patients with PCOS and normal weight.

Polycystic ovary syndrome is a heterogeneous disorder characterized by chronic ovulatory dysfunction and hyperandrogenism. It occurs in 6-8% of the female population in the reproductive age. The syndrome may be associated with various metabolic disorders which may impair the quality of life and life expectancy of patients. The diagnosis in adults is usually established by the presence of three criteria. Polycystic ovary syndrome can be also identified in adolescent girls. Although the clinical, hormonal and metabolic features are similar to those found in adult women, it may be difficult to distinguish normal adolescents from those with polycystic ovary syndrome. Irregular menstruation, anovulatory cycles, and acne are not uncommon in adolescents, and polycystic ovary syndrome may mimic physiological anovulation in adolescents. There is a high probability of polycystic ovary syndrome if anovulatory cycles persist for more than 2 years. The diagnosis of polycystic ovary syndrome in adolescents may require a unique set of criteria, however, there are no generally accepted recommendations for the diagnostic work-up. The authors propose that hyperandrogenemia is often the most reliable finding in this age group, and it may be prudent to define adolescent polycystic ovary syndrome according to the Rotterdam consensus criteria. Obesity in adolescent girls may increase the severity of symptoms of polycystic ovary syndrome and this underlines the importance of early diagnosis and treatment.

The long-term effects and tolerability of flutamide (Flu) on the menstrual cycle and the ovulatory function of hyperandrogenic women with or without polycystic ovary syndrome (PCOS) were investigated. The study included 118 white women with the diagnosis of various forms of hyperandrogenism (80 PCOS and 38 non-PCOS patients). Patients received Flu for three years at dosages that declined each of the three years (250, 125 and 62.5 mg/day). Sex steroid, ovulatory function and menstrual profile at baseline and during each year of Flu treatment were evaluated. Flu therapy showed a significant increase in the percentage of cycles that were ovulatory (with progesterone concentrations greater than 4 ng/ml in mid-luteal phase) and concomitant regularization of the menstrual profile in PCOS patients. A luteinizing hormone decrease and an estrone, estradiol and 17-hydroxyprogesterone increase are also observed during treatment. Regular cycles persisted in non-PCOS patients. The results were maintained during the three years of treatment. The study suggests that Flu is a satisfactory therapeutic regimen of the chronic anovulation and the irregularities of the menstrual cycle in hyperandrogenic PCOS patients in the long run.

Polycystic ovary syndrome (PCOS) is associated with chronic oligo-anovulation and high circulating sex hormone levels. Women with PCOS have an increased risk of developing endometrial cancer. In anovulatory women with PCOS a positive relationship between endometrial thickness and endometrial hyperplasia has been observed. Uterine peristalsis, which has been suggested to be of importance for female fertility, has not previously been studied in PCOS.To assess whether women with PCOS have altered endometrial thickness, uterine wall morphology, and peristalsis.In this prospective case-control study 55 women with PCOS (mean age, 29.5 years ± 4.5 SD) and 28 controls (27.6 ± 3.2) were examined using magnetic resonance imaging (MRI), assessing thickness of endometrium, junctional zone (JZ), and myometrium, and evaluating the occurrence, frequency (waves/min), strength (amplitude), pattern, and direction of peristalsis. Uterine morphology was also assessed by transvaginal ultrasonography (TVUS).The endometrium was thinner in PCOS with oligo-amenorrhea compared to controls, also after adjustments for age and BMI (adjusted P = 0.043). There was no difference in thickness of the JZ or the myometrium in cases versus controls. Uterine peristalsis was less commonly observed in women with PCOS than in controls (adjusted P = 0.014).There were no differences in myometrial morphology between PCOS and controls, but the endometrium was thinner in PCOS with oligo-amenorrhea. Based on cine MRI, uterine peristalsis was less common in PCOS than in controls.

Mayer-Rokitansky-Küster-Hauser Syndrome (MRKHS) is characterized by complete or partial absence of the vagina, uterus and proximal fallopian tubes and diagnosis is usually made in late adolescence, when primary amenorrhea appears as the major symptom. Polycystic Ovary Syndrome (PCOS), which is the most common endocrine disorder among women of reproductive age, includes a variety of clinical manifestations (menstrual irregularities, hirsuitism, acne, alopecia, obesity and infertility), due to androgen hypersecretion, insulin resistance and chronic anovulation. Both MRKHS and PCOS have been studied concerning the psychological aspects and have been associated with emotional distress as well as self-esteem, body image, identity and femininity impairment. The purpose of this study was to assess psychological functioning in adolescents with uterovaginal agenesis and primary amenorrhea due to MRKHS and those with hyperandrogenism and oligomenorrhea due to PCOS, compared with healthy adolescents. The participants were 70 adolescent girls, of whom 24 with MRKHS, 22 with PCOS and 24 healthy eumenorrheic adolescents (control group) matched by age and school grade. Psychological assessment included self report questionnaires, standardized in Greek population sample. Particularly, the "Beck Depression Inventory" (BDI), the "State-Trait Anxiety Inventory" (STAI-Gr) and the "Youth Self Report" (YSR) were used to measure depression, anxiety and psychopathology respectively, while the "Symptom Checklist-90-R" was used to measure psychopathology for the patients >18 years old. The results showed significantly higher scores on the state - anxiety scale for the MRKHS group compared with the control group. The MRKHS patients in late adolescence (18-20 years old) presented also significantly higher scores in depression and psychopathology scales (symptoms of anxiety, aggressive behavior and phobic disorder) than PCOS patients of the same age. On the contrary, regarding PCOS patients, age was negative correlated with attention problems and PCOS patients >18 reported significantly more somatic complaints compared with age-mate MRKHS patients and controls. PCO syndrome's clinical manifastations, including menstrual disorders, hirsuitism, acne, alopecia, obesity and infertility, may cause significant emotional distress. Nevertheless, they appear in great variety and our sample is characterized by mild features of hyperandrogenism and oligomenorrhea. This may explain findings of milder psychological disturbance associated with PCOS in this sample in comparison to other studies. As far as MRKHS is concerned, diagnosis and loss of reproductive ability, especially in late adolescence, obstruct emotional stability, physical maturity and sexual identity development ending that are expected in this period of life. Undoubtedly, the management of MRKHS in adolescence constitutes a complex multidisciplinary issue and psychological support of patients is needed in order to prevent possible psychological consequences and to achieve a normal transition to adulthood. Among the limitations of this study is the small sample size, which limits the generalisability of the reported results, especially in "Youth Self Report" and in "Symptom Checklist-90-R" questionnaires, where the sample was divided according to the age. Nevertheless, the very low incidence of MRKHS (1/5000) emphasize the value of the present results, which support the need for further investigation.

Folic acid is recommended to reproductive-aged women to prevent birth defects, though little is known about the effects of dietary intake on other reproductive outcomes. Improved pregnancy rates have been documented after folic acid supplement use, suggesting a possible link with ovulation, however research is limited. Our objective was to evaluate the association between dietary folate intake, hormone levels, and sporadic anovulation in healthy, regularly menstruating women.The BioCycle study (2005-2007) prospectively followed 259 healthy women aged 18-44 years from the western New York region for up to 2 menstrual cycles. Total folate and specific sources of folate were assessed up to 4 times per cycle by 24-hour recall. Estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured in serum up to 8 times per cycle, timed using fertility monitors. Anovulation was defined as a cycle with peak progesterone concentration ≤ 5 ng/mL and no LH peak in the mid/late luteal phase. Higher intake of dietary folate (in dietary equivalents) across tertiles had a marginally significant association with greater luteal progesterone levels (P trend 0.08). Higher intake of synthetic folate was significantly associated with higher luteal progesterone levels (P trend 0.05). Specifically, women in the 3(rd) tertile of synthetic folate intake had, on average, 16.0% (95% CI, 0.5-33.8%) higher luteal progesterone levels compared to women in the 1(st) tertile. Moreover, consumption of synthetic folate was significantly and inversely associated with anovulation such that women in the 3(rd) tertile had a 64% (95% CI, 8-86%) decreased odds of anovulation compared to the women in the 1(st) tertile (P trend 0.03).These findings suggest that a diet high in synthetic folate may be associated with increased progesterone levels and lower risk of sporadic anovulation. Further study of the effect of dietary folate and folic acid supplement use on reproductive health is warranted.

Laparoscopic electrocautery of the ovaries and ovulation induction with gonadotrophins are both second line treatments for women with clomiphene citrate-resistant polycystic ovary syndrome (PCOS). Long-term follow-up after electrocautery versus ovulation induction with gonadotrophins has demonstrated at least comparable chances for a first live born child with a reduced need for ovulation induction or assisted reproduction treatment and increased chances for a second live born child. In this study, we report on the long-term economic consequences of both treatment modalities.Between February 1998 and October 2001, we performed a multi-centre randomized controlled trial (RCT) comparing a strategy of laparoscopic electrocautery of the ovaries, followed by clomiphene citrate and gonadotrophins when anovulation persisted, and a strategy of ovulation induction with gonadotrophins in women with clomiphene citrate-resistant PCOS. Eight to twelve years after randomization we performed a follow-up study on reproductive outcome in these women and the fertility treatments they had needed including data on direct medical costs of pregnancy and delivery. Clinical data included number of treatment cycles, live births, miscarriages, ectopic pregnancies and multiple pregnancies. We calculated mean costs per woman after randomization until the first live birth. Confidence intervals (CIs) were estimated by bootstrapping.We obtained data for an economic analysis on 159 of the 168 randomized women (95%). In total, 71 of 83 women (86%) allocated to the electrocautery strategy and 69 of 85 women (81%) allocated to the gonadotrophin strategy had at least one live birth. Given the equivalence between the two treatment strategies in terms of a first live birth-the primary outcome measure-our analysis focused on the cost difference between the two strategies within a mean follow-up time of 8-12 years. The mean costs per first live birth after randomization were €11 176 (95% CI: €9689-€12 549) for the electrocautery group and €14 423 (95% CI: €12 239-€16 606) for the recombinant FSH group, resulting in significantly lower costs (P < 0.05) per first live birth for women allocated to the electrocautery group (mean difference €3247; 95% CI: €650-€5814).In women with clomiphene-resistant PCOS, laparoscopic electrocautery of the ovaries results in significantly lower costs per live birth than ovulation induction with gonadotrophins for an at least equal effectiveness.

Women with classical congenital adrenal hyperplasia (CAH) exhibit reduced fertility due to several factors including anovulation. This has been attributed to a disturbed gonadotropic axis as in polycystic ovary syndrome (PCOS), but there is no precise evaluation. Our aim was to evaluate the gonadotropic axis and LH pulsatility patterns and to determine factor(s) that could account for the potential abnormality of LH pulsatility.Case/control study.Sixteen CAH women (11 with the salt-wasting form and five with the simple virilizing form), aged from 18 to 40 years, and 16 age-matched women, with regular menstrual cycles (28 ± 3 days), were included. LH pulse patterns over 6 h were determined in patients and controls.No differences were observed between patients and controls in terms of mean LH levels, LH pulse amplitude, or LH frequency. In CAH patients, LH pulsatility patterns were heterogeneous, leading us to perform a clustering analysis of LH data, resulting in a two-cluster partition. Patients in cluster 1 had similar LH pulsatility patterns to the controls. Patients in cluster 2 had: lower LH pulse amplitude and frequency and presented menstrual cycle disturbances more frequently; higher 17-OH progesterone, testosterone, progesterone, and androstenedione levels; and lower FSH levels.LH pulsatility may be normal in CAH women well controlled by hormonal treatment. Undertreatment is responsible for hypogonadotropic hypogonadism, with low LH pulse levels and frequency, but not PCOS. Suppression of progesterone and androgen concentrations during the follicular phase of the menstrual cycle should be a major objective in these patients.