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It is increasingly recognized that crucial gender differences exist in heart disease, with men being at higher cardiovascular (CV) risk, especially at a young age. It is generally accepted that women often suffer most from the burden of CV disease after menopause (1), which has been attributed to a safer hormonal environment before menopause. However, as elegantly suggested recently, in women the CV risk increases exponentially with age with no specific increase after natural menopause (2). This further emphasizes the need for the early recognition of risk factors and for developing secondary prevention strategies in women. It has recently become apparent that multiple disease conditions in obstetrics and gynecology [such as pregnancyinduced hypertension (PIH), polycystic ovary syndrome (PCOS), but also hypothalamic amenorrhea, primary ovarian insufficiency, and early menopause] are associated with increased CV risk. Moreover, increased CV disease has been convincingly demonstrated for both PIH and primary ovarian insufficiency (3, 4). Much controversy remains regarding the many clinical issues associated with the enigmatic PCOS. Ongoing debate as to whether hyperandrogenemia should remain the hallmark for diagnosis has rendered the 2003 Rotterdam consensus criteria for PCOS diagnosis one of the most frequently cited papers in the (short) history of clinical reproductive medicine (5). Until recently, interest has focused mainly on infertility treatment of anovulatory PCOS (6). In more recent years, however, overall attention has shifted toward the more frequent occurrence of pregnancy complications in PCOS, such as gestational diabetes and PIH (7). Moreover, a wealth of literature—mostly published in this journal—has established the presence of metabolic abnormalities in the daughters of women with PCOS (8–10), with increasing claims for the need to treat such adolescent girls with multiple drugs such as flutamide, metformin, and pioglitazone (11). The diagnosis of the notoriously heterogeneous PCOS is based on three features, i.e. menstrual cycle abnormalities, polycystic ovaries, and hyperandrogenemia. In addition, many of these women are obese and present with impaired glucose tolerance (even in lean PCOS). Numerous studies have now established beyond any doubt that women with PCOS exhibit multiple CV risk factors such as impaired glucose tolerance, type 2 diabetes and the metabolic syndrome (12), dyslipidemia (13), and other CV risk markers such as C-reactive protein, homocysteine, TNF, and many others (14). Relatively few and small sample size studies have suggested subclinical arterial disease in women with PCOS, such as abnormal carotid intima media thickness or coronary artery calcification (15). The metabolic syndrome is associated with a 2-fold increase in CV disease and a 1.5-fold higher all-cause mortality, as demonstrated by a recent systematic review involving 87 studies and a total of almost 1 million patients (16). Based on the above-mentioned observations, firm position statements have been generated by the Androgen Excess Society—again published in JCEM—recommending that every woman with PCOS should undergo a 2-h

Premature ovarian failure (POF) is defined by amenorrhea of at least 4- to 6-month duration, occurring before 40 yr of age, with two FSH levels in the postmenopausal range. Its etiology remains unknown in more than 80% of cases. Standard karyotypes, having a resolution of 5-10 Mb, have identified critical chromosomal regions, mainly located on the long arm of the X chromosome. Array comparative genomic hybridization (a-CGH) analysis is able to detect submicroscopic chromosomal rearrangements with a higher genomic resolution. We searched for copy number variations (CNVs), using a-CGH analysis with a resolution of approximately 0.7 Mb, in a cohort of patients with POF.We prospectively included 99 women. Our study included a conventional karyotype and DNA microarrays comprising 4500 bacterial artificial chromosome clones spread on the entire genome.Thirty-one CNVs have been observed, three on the X chromosome and 28 on autosomal chromosomes. Data have been compared to control populations obtained from the Database of Genomic Variants (http://projects.tcag.ca/variation). Eight statistically significantly different CNVs have been identified in chromosomal regions 1p21.1, 5p14.3, 5q13.2, 6p25.3, 14q32.33, 16p11.2, 17q12, and Xq28.We report the first study of CNV analysis in a large cohort of Caucasian POF patients. In the eight statistically significant CNVs we report, we found five genes involved in reproduction, thus representing potential candidate genes in POF. The current study along with emerging information regarding CNVs, as well as data on their potential association with human diseases, emphasizes the importance of assessing CNVs in cohorts of POF women.

Anti-Müllerian hormone (AMH) concentrations correlate with the number of antral follicles as well as age and constitute an endocrine marker for ovarian aging. In normogonadotropic anovulatory infertile women [World Health Organization (WHO) class 2], the number of early antral follicles is usually increased. To investigate whether AMH concentrations are increased, serum levels in 128 WHO 2 women were compared with those in 41 normoovulatory premenopausal women of similar age.Serum AMH concentrations are significantly (P < 0.001) elevated in WHO 2 patients [median, 7.6 μg/liter (range, 0.1–40.0)], compared with controls [median, 2.1 μg/liter (0.1–7.4)]. In 106 patients presenting with polycystic ovaries (PCOs) (≥12 follicles/ovary measuring 2–9 mm and/or an ovarian volume > 10 ml), AMH levels were elevated [9.3 μg/liter (1.8–40.0)], compared with 22 patients without PCOs [6.4 μg/liter (0.1–22.1)] (P < 0.0001). In WHO 2 patients, AMH concentrations correlated with features characteristic for polycystic ovary syndrome such as LH concentrations (r = 0.331; P = 0.0001), testosterone levels (r = 0.477, P = 0.0001), mean ovarian volume (r = 0.421; P = 0.0001), and the number of ovarian follicles (r = 0.308; P = 0.0001). AMH levels correlated well with age in WHO 2 patients (r = −0.248; P = 0.002) as well as in controls (r = −0.465; P = 0.005). However, the relative decline in AMH with age is less pronounced in WHO 2 patients. In a subset of patients no significant correlation was found between AMH serum concentrations and the FSH response dose, the duration of stimulation, and the total number of ampoules of FSH used.In conclusion, serum AMH concentrations are elevated in WHO 2 women, especially in those patients exhibiting PCOs. Because AMH concentrations correlated well with other clinical, endocrine, and ultrasound markers associated with polycystic ovary syndrome, AMH may be used as a marker for the extent of the disease. A less pronounced AMH decrease over time in these women may suggest retarded ovarian aging. The latter hypothesis, however, should be confirmed by longitudinal studies.

Extending the FSH window for multifollicular development by administering FSH from the midfollicular phase onward constitutes a novel mild protocol for ovarian stimulation for in vitro fertilization (IVF) based on the physiology of single dominant follicle selection in normo-ovulatory women. We compared outcomes from this protocol with two other stimulation protocols. One hundred and forty-two normo-ovulatory patients with an indication for IVF (or IVF/ICSI) were randomized to a GnRH agonist long protocol (group A; n = 45) or one of two GnRH antagonist protocols commencing recombinant FSH on cycle d 2 (group B; n = 48) or cycle d 5 (group C; n = 49). A fixed dose (150 IU/d) of rFSH was used for ovarian stimulation, and GnRH antagonist cotreatment was initiated on the day when the leading follicle reached 14 mm diameter. Group C showed a shorter duration of stimulation (median duration, 11, 9, and 8 d for groups A, B, and C, respectively; P < 0.001), reflected in a significantly lower total dose of rFSH used (median amount of rFSH, 1650, 1350, and 1200 IU for groups A, B, and C, respectively; P < 0.001). In group C more cycles were cancelled during the stimulation phase due to insufficient response, resulting in a lower percentage of oocyte retrievals (84%, 73%, and 63% for groups A, B, and C; P = 0.02). However, women in group C obtained better quality embryos (percentage of embryo score of 1 for best embryo, 29%, 37%, and 61% for groups A, B, and C, respectively; P = 0.008), resulting in more transfers per oocyte retrieval (68%, 71%, and 90% for groups A, B, and C, respectively; P = 0.04). After profound ovarian stimulation (groups A and B) only 7% of the patients who retrieved four oocytes or less conceived, whereas after mild stimulation (group C) 67% of these patients conceived (P < 0.01). Overall, no differences were found among the three groups comparing pregnancy rate per started IVF cycle. In conclusion, application of the described mild ovarian stimulation protocol resulted in pregnancy rates per started IVF cycle similar to those observed after profound stimulation with GnRH agonist cotreatment despite shorter stimulation and a 27% reduction in exogenous FSH. A higher cancellation rate before oocyte retrieval was compensated by improved embryo quality concomitant with a higher chance of undergoing embryo transfer. A relatively low number of oocytes retrieved after mild ovarian stimulation distinctly differs from the pathological reduction in the number of oocytes retrieved after profound ovarian stimulation (poor response) associated with poor IVF outcome. The relatively small number of oocytes obtained after mild ovarian stimulation may represent the best of the cohort in a given cycle.

In a randomized multicenter study, the efficacies of two different GnRH agonists were compared with that of hCG for triggering final stages of oocyte maturation after ovarian hyperstimulation for in vitro fertilization. Ovarian stimulation was conducted by recombinant FSH (Puregon), and the GnRH antagonist ganirelix (Orgalutran) was coadministered for the prevention of a premature LH rise. Luteal support was provided by daily progestin administration. Frequent blood sampling was performed at midcycle in the first 47 eligible subjects included in the current study, who were randomized for a single dose of 0.2 mg triptorelin (n 17), 0.5 mg leuprorelin (n 15), or 10,000 IU hCG (n 15). Serum concentrations of LH, FSH, E2, and progesterone (P) were assessed at variable intervals. LH peaked at 4 h after both triptorelin and leuprorelin administration, with median LH levels of 130 and 107 IU/liter (P < 0.001), respectively. LH levels returned to baseline after 24 h. Subjects receiving hCG showed peak levels of 240 IU/liter hCG 24 h after administration. A rise in FSH to 19 IU/liter (P < 0.001) was noted in both GnRH agonist groups 8 h after injection. Within 24 h the areas under the curve for LH and FSH were significantly higher (P < 0.001) in both GnRH agonist groups compared with that for hCG. E2 and P levels were similar for all groups up to the day of oocyte retrieval. Luteal phase areas under the curve for P and E2 were significantly elevated (P < 0.001) in the hCG group. The mean (SD) numbers of oocytes retrieved were 9.8 5.4, 8.7 4.5, and 8.3 3.3; the percentages of metaphase II oocytes were 72%, 85%, and 86%; and fertilization rates were 61%, 62%, and 56% in the triptorelin, leuprorelin, and hCG group, respectively (P NS for all three comparisons). These findings support the effective induction of final oocyte maturation in both GnRH agonist groups. In summary, after treatment with the GnRH antagonist ganirelix for the prevention of premature LH surges, triggering of final stages of oocyte maturation can be induced effectively by a single bolus injection of GnRH agonist, as demonstrated by the induced endogenous LH and FSH surge and the quality and fertilization rate of recovered oocytes. Moreover, corpus luteum formation is induced by GnRH agonists with luteal phase steroid levels closer to the physiological range compared with hCG. This more physiological approach for inducing oocyte maturation may represent a successful and safer alternative for in vitro fertilization patients undergoing ovarian hyperstimulation. (J Clin Endocrinol Metab 87: 709 –715, 2002)