Joop S.E. Laven

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder.Polycystic ovary syndrome (PCOS) affects 5–20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) — with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder.

Antimüllerian hormone serum levels: a putative marker for ovarian aging

OBJECTIVE To investigate whether serum concentrations of antimüllerian hormone may be used as a marker for ovarian aging. DESIGN Longitudinal observational study. SETTING Academic research center. PATIENTS Forty-one normo-ovulatory premenopausal women and 13 healthy postmenopausal women. MAIN OUTCOME MEASURE(S) Concentrations of serum antimüllerian hormone (assessed on two occasions 2.6 +/- 1.7 years apart), FSH, inhibin B, and estradiol and number of ovarian follicles on ultrasonography. RESULT(S) Concentrations of antimüllerian hormone decreased significantly over time (median value, 2.1 microg/L [range, 0.1-7.4 microg/L] at visit 1 vs. 1.3 microg/L [range, 0.0-5.0 microg/L] at visit 2), whereas the number of antral follicles and levels of FSH and inhibin B did not change. During visits 1 and 2, concentrations of antimüllerian hormone correlated with age (r = -.40, P=.01 and r = -.57, P<.001, respectively); number of antral follicles (r =.66, P<.001 and r =.71, P<.001); and, to a lesser extent, with FSH level (r = -.29, P=.07 and r = -.37, P<.05) but not with inhibin B levels. CONCLUSION(S) Serum concentrations of antimüllerian hormone decreased over time in young normo-ovulatory women, whereas other markers associated with ovarian aging did not change. Concentrations of antimüllerian hormone correlate with the number of antral follicles and age and less strongly with FSH level. Concentrations of antimüllerian hormone may be a novel marker for ovarian aging.

Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females, with a high prevalence. The etiology of this heterogeneous condition remains obscure, and its phenotype expression varies. Two widely cited previous ESHRE/ASRM sponsored PCOS consensus workshops focused on diagnosis (published in 2004) and infertility management (published in 2008), respectively. The present third PCOS consensus report summarizes current knowledge and identifies knowledge gaps regarding various womens health aspects of PCOS. Relevant topics addressed-all dealt with in a systematic fashion-include adolescence, hirsutism and acne, contraception, menstrual cycle abnormalities, quality of life, ethnicity, pregnancy complications, long-term metabolic and cardiovascular health, and finally cancer risk. Additional, comprehensive background information is provided separately in an extended online publication.

Anti-mullerian hormone predicts menopause: a long-term follow-up study in normoovulatory women

CONTEXT It has been hypothesized that a fixed interval exists between age at natural sterility and age at menopause. Both events show considerable individual variability, with a range of 20 yr. Correct prediction of age at menopause could open avenues of individualized prevention of age-related infertility and other menopause-related conditions, like cardiovascular disease and breast carcinoma. OBJECTIVE The aim of this study was to explore the ability of ovarian reserve tests to predict age at menopause. DESIGN AND SETTING We conducted a long-term follow-up study at an academic hospital. PARTICIPANTS A total of 257 normoovulatory women (age, 21-46 yr) were derived from three cohorts with highly comparable selection criteria. INTERVENTIONS Anti-Müllerian hormone (AMH), antral follicle count, and FSH were assessed at time 1 (T1). At time 2 (T2), approximately 11 yr later, cycle status (strictly regular, menopausal transition, or postmenopause) and age at menopause were inventoried. MAIN OUTCOME MEASURES Accuracy of the ovarian reserve tests in predicting time to menopause was assessed by Cox regression, and a nomogram was constructed for the relationship between age-specific AMH concentrations at T1 and age at menopause. RESULTS A total of 48 (19%) women had reached postmenopause at T2. Age, AMH, and antral follicle count at T1 were significantly related with time to menopause (P < 0.001) and showed a good percentage of correct predictions (C-statistic, 0.87, 0.86, and 0.84, respectively). After adjusting for age, only AMH added to this prediction (C-statistic, 0.90). From the constructed nomogram, it appeared that the normal distribution of age at menopause will shift considerably, depending on the individual age-specific AMH level. CONCLUSIONS AMH is highly predictive for timing of menopause. Using age and AMH, the age range in which menopause will subsequently occur can be individually calculated.

Anti-Mullerian hormone: ovarian reserve testing and its potential clinical implications

BACKGROUND In women, anti-Müllerian hormone (AMH) is exclusively produced by granulosa cells of ovarian follicles during the early stages of follicle development. After an initial increase until early adulthood, AMH concentrations slowly decrease with increasing age until becoming undetectable ∼5 years before menopause when the stock of primordial follicles is exhausted. However, major individual variability exists in the pace of follicle pool depletion and the initial size of the follicle pool, reflected by a wide range of age at menopause. Individual AMH serum concentration does accurately reflect the size of the pool of antral follicles, representing the quantity of the remaining primordial follicles. Accordingly, AMH levels may vary significantly in women of the same chronological age, allowing AMH to predict the remaining length of a womans reproductive lifespan. METHODS Following 10 years of intense clinical research in this area (with over 300 papers published in core clinical journals every year), the level of evidence justifying use of AMH in ovarian reserve testing is rapidly increasing. We have conducted a summarizing review regarding all evidence published. RESULTS Many studies have convincingly demonstrated that AMH is the best currently available measure of ovarian reserve under a variety of clinical situations, such as infertility treatment (especially IVF), the forecasting of reproductive lifespan, ovarian dysfunction (especially polycystic ovary syndrome) and gonadotoxic cancer treatment or ovarian surgery. Moreover, AMH may help to individualize dosing for ovarian stimulation thereby improving the efficiency and safety of IVF. However, there are concerns about the performance of the AMH assay under different conditions regarding storage of samples and handling techniques. Therefore an international guideline for laboratories and a reference preparation are needed to make test results between laboratories truly comparable. CONCLUSIONS AMH is the best current available measure of ovarian reserve for different clinical conditions. However, prospective well powered studies comparing different infertility treatment strategies based on initial AMH levels using appropriate end-points, such as live birth and cost-effectiveness, are urgently awaited. Such studies could represent a true step forward in rendering counseling and infertility care more patient tailored.

Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society

BACKGROUND The diagnosis of polycystic ovary syndrome (PCOS) relies on clinical, biological and morphological criteria. With the advent of ultrasonography, follicle excess has become the main aspect of polycystic ovarian morphology (PCOM). Since 2003, most investigators have used a threshold of 12 follicles (measuring 2-9 mm in diameter) per whole ovary, but that now seems obsolete. An increase in ovarian volume (OV) and/or area may also be considered accurate markers of PCOM, yet their utility compared with follicle excess remains unclear. METHODS Published peer-reviewed medical literature about PCOM was searched using PubMed.gov online facilities and was submitted to critical assessment by a panel of experts. Studies reporting antral follicle counts (AFC) or follicle number per ovary (FNPO) using transvaginal ultrasonography in healthy women of reproductive age were also included. Only studies that reported the mean or median AFC or FNPO of follicles measuring 2-9 mm, 2-10 mm or <10 mm in diameter, or visualized all follicles, were included. RESULTS Studies addressing women recruited from the general population and studies comparing control and PCOS populations with appropriate statistics were convergent towards setting the threshold for increased FNPO at ≥25 follicles, in women aged 18-35 years. These studies suggested maintaining the threshold for increased OV at ≥10 ml. Critical analysis of the literature showed that OV had less diagnostic potential for PCOM compared with FNPO. The review did not identify any additional diagnostic advantage for other ultrasound metrics such as specific measurements of ovarian stroma or blood flow. Even though serum concentrations of anti-Müllerian hormone (AMH) showed a diagnostic performance for PCOM that was equal to or better than that of FNPO in some series, the accuracy and reproducibility issues of currently available AMH assays preclude the establishment of a threshold value for its use as a surrogate marker of PCOM. PCOM does not associate with significant consequences for health in the absence of other symptoms of PCOS but, because of the use of inconsistent definitions of PCOM among studies, this question cannot be answered with absolute certainty. CONCLUSIONS The Task Force recommends using FNPO for the definition of PCOM setting the threshold at ≥25, but only when using newer technology that affords maximal resolution of ovarian follicles (i.e. transducer frequency ≥8 MHz). If such technology is not available, we recommend using OV rather than FNPO for the diagnosis of PCOM for routine daily practice but not for research studies that require the precise full characterization of patients. The Task Force recognizes the still unmet need for standardization of the follicle counting technique and the need for regularly updating the thresholds used to define follicle excess, particularly in diverse populations. Serum AMH concentration generated great expectations as a surrogate marker for the follicle excess of PCOM, but full standardization of AMH assays is needed before they can be routinely used for clinical practice and research. Finally, the finding of PCOM in ovulatory women not showing clinical or biochemical androgen excess may be inconsequential, even though some studies suggest that isolated PCOM may represent the milder end of the PCOS spectrum.

Effects of varicocele treatment in adolescents: a randomized study

OBJECTIVE To study the effects of varicocele treatment on testicular function in adolescents. DESIGN A prospective controlled study in 88 randomly selected adolescents. SETTING All participants were referred to the fertility outpatient clinic of our university hospital. PARTICIPANTS All participants with a varicocele were randomly assigned into two groups. Group 1 (n = 33) was not treated, whereas group 2 (n = 34) was treated. A similar group of healthy volunteers without a varicocele served as a control group (group 3, n = 21). INTERVENTIONS Testes volumes were measured at intake and during follow-up using an orchiometer. Semen analysis was performed according to standard procedures both at intake and after 1 year of follow-up. Serum hormone levels were determined at intake using a radioimmunoassay. Treatment was performed by means of transcatheter embolization of the left testicular vein. MAIN OUTCOME MEASURES Testes volumes and semen quality at intake and after 1 year of follow-up were compared within and between the three groups. Hormonal parameters were determined at intake only. RESULTS Before treatment, the mean left testis volume in groups 1 (n = 26) and 2 (n = 27) (20.0 mL; 95% confidence interval [CI]: 18.2 to 21.8 and 21.6 mL; 95% CI: 19.4 to 23.8, respectively) were significantly smaller than those in the control group (n = 19) (24.5 mL; 95% CI: 22.7 to 26.4). During follow-up, left testis volumes of the treated group were comparable with those in the control group (24.2 mL; 95% CI: 22.2 to 26.1 and 24.8 mL; 95% CI: 23.0 to 26.7 respectively) and significantly (P < 0.001) different from the untreated group (20.3 mL; 95% CI: 18.8 to 21.8). A significant increase in left (P < 0.01) as well as right (P < 0.05) testis volume was observed after treatment. Semen parameters before treatment were not significantly different between the three groups. Sperm concentration increased significantly (P < 0.01) from 47.4 x 10(6)/mL (95% CI: 42.5 to 53.3) to 68.9 x 10(6)/mL (95% CI: 50.6 to 87.2) in the treated group, whereas semen quality in the untreated and control groups did not change. Although both testes volumes and sperm concentration improved in the treated group, these phenomena were not consistently correlated to each other. CONCLUSIONS Although not apparent in all adolescents, varicocele correction resulted in an increase in left testis volume and sperm concentration. At this moment, it is not clear if early preventive treatment of varicocele in adolescents, in time, will have a positive effect on testicular function.

Consensus on women's health aspects of polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females with a high prevalence. The etiology of this heterogeneous condition remains obscure and its phenotype expression varies. Two, widely cited, previous ESHRE/ASRM-sponsored PCOS consensus workshops focused on diagnosis (published in 2004) and infertility management (published in 2008). The present third PCOS consensus paper summarizes current knowledge and identifies knowledge gaps regarding various womens health aspects of PCOS. Relevant topics addressed-all dealt with in a systematic fashion-include adolescence, hirsutism and acne, contraception, menstrual cycle abnormalities, quality of life, ethnicity, pregnancy complications, long-term metabolic and cardiovascular health and finally cancer risk. Additional, comprehensive background information is provided separately in an extended online publication.

Anti-Müllerian Hormone, Inhibin B, and Antral Follicle Count in Young Women with Ovarian Failure

CONTEXT Ovarian dysfunction is classically categorized on the basis of cycle history, FSH, and estradiol levels. Novel ovarian markers may provide a more direct insight into follicular quantity in hypergonadotropic women. OBJECTIVE The objective of the study was to investigate the distribution of novel ovarian markers in young hypergonadotropic women as compared with normogonadotropic regularly menstruating women. DESIGN This was a nationwide prospective cohort study. SETTING The study was conducted at 10 hospitals in The Netherlands. PATIENTS Women below age 40 yr with regular menses and normal FSH (controls; n = 83), regular menstrual cycles and elevated FSH [incipient ovarian failure (IOF); n = 68]; oligomenorrhea and elevated FSH [referred to as transitional ovarian failure (TOF); n = 79]; or at least 4 months amenorrhea together with FSH levels exceeding 40 IU/liter [premature ovarian failure (POF); n = 112]. MAIN OUTCOME MEASURES Serum levels of anti-Müllerian hormone (AMH), inhibin B, and antral follicle count (AFC) was measured. RESULTS All POF patients showed AMH levels below the fifth percentile (p(5)) of normoovulatory women. Normal AMH levels (>p(5)) could be identified in 75% of IOF, 33% of TOF patients, and 98% of controls. AFC and AMH levels changed with increasing age (P < 0.0001), whereas inhibin B did not (P = 0.26). AMH levels were significantly different between TOF and IOF over the entire age range, whereas AFC became similar for TOF and IOF at higher ages. CONCLUSIONS Compared with inhibin B and AFC, AMH was more consistently correlated with the clinical degree of follicle pool depletion in young women presenting with elevated FSH levels. AMH may provide a more accurate assessment of the follicle pool in young hypergonadotropic patients, especially in the clinically challenging subgroups of patients with elevated FSH and regular menses (i.e. IOF) and in hypergonadotropic women with cycle disturbances not fulfilling the POF diagnostic criteria (i.e. TOF).

Anti-Müllerian hormone and ovarian dysfunction

Anti-Müllerian hormone (AMH) has important roles in postnatal ovarian function. Produced by ovarian granulosa cells, AMH is involved in initial follicle development. In fact, serum AMH level correlates with ovarian follicle number. In patients with polycystic ovary syndrome (PCOS), AMH levels are elevated, which indicates its potential relevance in PCOS diagnosis and management. AMH represents a useful clinical marker for the assessment of ovarian reserve in cases of subfertility caused by advanced age in women. A potential role for AMH in dominant follicle selection has also been suggested. Future challenges comprise the availability of a well-standardized assay and the development of AMH agonists and antagonists as possible tools to manipulate ovarian function for contraception or ovarian longevity.