Search

BackgroundThere is evidence for differences between endocrinologists and other specialists in their approach to diagnosis and management of the polycystic ovary syndrome (PCOS).ObjectiveA mailed survey consisting of a simple questionnaire aiming to understand current practice for diagnosis and management of the PCOS by specialists across Europe.MethodsThe questionnaire consisted of 23 questions grouped to achieve information on i) the general characteristics of the respondents, ii) patients with PCOS seen by endocrinologists, iii) the main diagnostic criteria, iv) biochemical parameters used in the differential diagnosis of hyperandrogenism, v) long-term concerns, and, finally vi) treatment choices. A total of 357 questionnaires representing 13.3% of the members of European Society of Endocrinology (ESE) were available for final analysis; 93% of the respondents were endocrinologistsResultsIn relation to the diagnostic criteria, respondents were most likely to select menstrual irregularity as the most frequent criteria used for the diagnosis of PCOS although very high rates were achieved for the use of hirsutism and biochemical hyperandrogenism. It therefore appears that the NIH criteria were followed by the majority of respondents. The most frequent biochemical parameters in the differential diagnosis of hyperandrogenism were total testosterone or free androgen index. Obesity and type 2 diabetes were regarded as the principal long-term concerns for PCOS. The most common treatments for patients with PCOS were metformin (33%), lifestyle modification (25%), and oral contraceptives (22%). More direct treatments of infertility include clomiphene citrate alone or in combination with metformin, prescribed by 9 and 23%, respectively, whereas only 6% used other methods for induction of ovulation.ConclusionThe survey produced by ESE is a good start for evaluating the perspective in the diagnosis and treatment of PCOS by endocrinologists in Europe.

Polycystic ovary syndrome (PCOS) is a frequent endocrine disease affecting 10 to 15% of women. Menstrual disorders, hyperandrogenism and ultrasonographic aspect of ovaries are typical of the disease and are established diagnostic criteria. But PCOS has also long term complications frequently forgotten and underestimated. During pregnancy, gestational diabetes and gestational hypertensive disorders can occur. At an older age, metabolic disease such as glucose intolerance, type 2 diabetes or dyslipidaemia are frequently described. Women with PCOS have increased classical cardiovascular risks and increased subclinical cardio-vascular disease without proven increase of cardiovascular morbidity and mortality. Finally, endometrial cancer seems to be more frequent in women with PCOS. Therefore, PCOS have numerous long-term health risks and a life-long follow-up is necessary for these women "at-risk" to detect and prevent complications as soon as possible.

Does surgery for deep infiltrating endometriosis (DIE) before in vitro fertilization (IVF) improve pregnancy and birth rate?Cohort study of 177 consecutive patients with DIE related infertility and receiving IVF. Patients were divided into 3 groups according to surgical management decided during multidisciplinary team meeting. Group no surgery (NS) (n=65), group complete surgery (CS) with complete resection of all lesions (n=49) and group incomplete surgery (IS) with gestures improving ovaries accessibility for IVF and/or facilitating embryonic implantation (n=63). Pre-surgery clinical, MRI lesion locations, and history of IVF characteristics were analyzed with logistic regression.There was no significant difference in general and IVF characteristics and in the severity of endometriosis among the three groups (P=0.43). Overall pregnancy and birth rates after IVF were 45.8% and 33.3%, respectively and were not different among the 3 groups (P=0.59 and P=0.49). Four major complications during oocytes retrievals were observed in NS group, one in IS group and none in CS group. Presence of an inter-utero-rectal lesion at MRI decreased the rate of pregnancy (OR=0.49 [0.25, 0.97]).Surgery for deep infiltrating endometriosis does not improve pregnancy and birth rates before IVF. This inter-utero-rectal extensive lesion might explain IVF failures by ovarian difficult access and difficulties in embryonic transfers. Further studies should explore the impact of surgical excision of inter-utero-rectal lesion on oocyte retrieval and embryonic transfer.

Objective To evaluate the utility of a hypersensitive assay for measuring low antimullerian hormone (AMH) levels in young cancer patients during the ovarian recovery phase of their chemotherapy. Design Retrospective study. Setting Academic medical center. Patient(s) Fifty-eight samples drawn at least 3 months after the end of chemotherapy in 30 women having either breast cancer (n = 13) or hematologic malignancies (n = 17) were selected to constitute two equally size groups: amenorrhea (n = 30 samples) or spontaneous cycle (n = 28 samples). Intervention(s) None. Main Outcome Measure(s) Serum AMH levels were measured by a conventional AMH ELISA (EIA AMH/MIS) and a hypersensitive ELISA (PicoAMH, AnshLabs) on the same sample. Result(s) Using a conventional assay, serum AMH was detectable (≥3 pmol/L) in 6.7% and in 10.7% of the samples corresponding to amenorrheic or cycling patients, respectively (nonsignificant). By contrast, with PicoAMH, serum AMH was detectable (≥0.07 pmol/L) in 71.4% of the samples from cycling women vs. 16.7% of the samples from amenorrheic patients. Multivariate regression analysis showed that among putative contributors, only the menstrual status ( r = 0.307) and serum FSH level ( r = −0.546) were independently correlated to a detectable serum AMH with the picoAMH assay exclusively. Conclusion(s) The picoAMH assay, allowing measurement of very low AMH concentrations in human serum, should refine postchemotherapy ovarian follow-up in young women.

Resume Objectifs Evaluer les resultats de la fertiloscopie et redefinir sa place au sein du bilan d’infertilite feminine. Patientes et methodes Etude retrospective portant sur 262 fertiloscopies realisees chez 260 patientes presentant une infertilite primaire ou secondaire, idiopathique. Analyse des resultats du bilan d’infertilite (hysterosalpingographie), des donnees perioperatoires (technique operatoire, cœlioconversion, echecs et complications). Etude de la concordance des resultats de l’hysterosalpingographie avec les constatations peroperatoires ; confrontation des constatations hydropelviscopiques et cœlioscopiques. Resultats L’acces a la cavite peritoneale a ete possible pour 248 fertiloscopies (95 %) et l’exploration du pelvis jugee complete pour 226 d’entre elles (86 %). Une cœlioconversion a ete necessaire dans 54 cas (21 %) et indiquee par une pathologie chirurgicale dans plus du tiers des cas (n = 20). Notre taux d’echec a ete limite a 5,3 % (n = 14), en partie grâce a la realisation d’une colpotomie posterieure (70 % d’echecs evites). Nous avons deplore 8 complications (3,05 %) peu severes (aucune perforation rectale), dont la moitie etait liee a l’hysteroscopie (perforation uterine). Dans les cas de cœlioconversion, les resultats de la cœlioscopie ont confirme les constatations per-fertiloscopiques, en termes d’adherences et de permeabilite tubaire. La sensibilite et la valeur predictive positive de l’hysterosalpingographie se sont revelees peu probantes. Discussion et conclusion La fertiloscopie est une intervention peu invasive, sure et reproductible. Elle peut se substituer a la cœlioscopie dans le bilan d’infertilite lorsqu’il n’existe pas d’indication chirurgicale patente. Plus encore, elle pourrait devenir l’examen morphologique de premiere intention en remplacement de l’hysterosalpingographie, dont la sensibilite et la valeur predictive positive semblent peu probantes.

This paper is a summary of the presentations at the ESHRE campus workshop on AMH in Lille, France, on 10–11 May 2012, with literature update until September 2013. We are grateful to Ronnie Grant for assistance with the figures. BACKGROUND The measurement of circulating anti-Müllerian hormone (AMH) has been applied to a wide array of clinical applications, mainly based on its ability to reflect the number of antral and pre-antral follicles present in the ovaries. AMH has been suggested to predict the ovarian response to hyperstimulation of the ovaries for IVF and the timing of menopause, and to indicate iatrogenic damage to the ovarian follicle reserve. It has also been proposed as a surrogate for antral follicle count (AFC) in the diagnosis of polycystic ovary syndrome (PCOS). METHODS This paper is a summary of presentations at a European Society of Human Reproduction and Embryology campus workshop on AMH, with literature cited until September 2013. Published peer-reviewed medical literature about AMH was searched through MEDLINE and was subjected to systematic review and critical assessment by the panel of authors. RESULTS Physiologically, recent data confirm that AMH is a follicular gatekeeper limiting follicle growth initiation, and subsequently estradiol production from small antral follicles prior to selection. AMH assays continue to evolve and technical issues remain; the absence of an international standard is a key issue. The dynamics of circulating AMH levels throughout life can be split into several distinct phases, with a peak in the early 20s before a decline to the menopause, with a strong and positive correlation with non-growing follicle recruitment. There is a more complex rise during childhood and adolescence, which is likely to be more reflective of different stages of follicle development. AMH shows limited short-term variability, but the influence of states such as prolonged oral contraceptive use need to be considered in clinical assessment. There are only very limited data on relationships between AMH and natural fertility at different stages of reproductive life, and while it has a relationship to age at menopause the marked variability in this needs further exploration. AMH may be useful in assessing the need for fertility preservation strategies and detecting post-chemotherapy or surgical damage to the ovarian reserve. Long-term follow-up of patients to ascertain fully the value of post-cancer serum AMH in predicting long-term ovarian function is required. There is a linear relationship between AMH and oocyte yield after ovarian stimulation, which is of value in predicting ovarian hyperstimulation. AMH can also identify 'poor responders', but it seems inappropriate at present to withhold IVF purely on this basis. Women with PCOS show markedly raised AMH levels, due to both the increased number of small antral follicles and intrinsic characteristics of those granulosa cells, and this may contribute to anovulation. The value of AMH in the diagnosis of PCOS remains controversial, but it may replace AFC in the future. CONCLUSIONS For the first time in female reproductive biology, it is possible to measure the submerged part of the iceberg of follicle growth, i.e. the intrinsic, so-called 'acyclic' ovarian activity. An international standard for AMH and improved assay validity are urgently needed to maximize the clinical utility of this very promising biomarker of ovarian function in a large array of clinical situations, both in childhood and adulthood. Postprint

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

International audience; CONTEXT: Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown. OBJECTIVE: The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients. DESIGN: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7. RESULTS: We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families. CONCLUSION: Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.

Quantitative ultrasound (QUS) of bone is a valuable tool in the assessment of postmenopausal osteoporosis. QUS and new markers of bone turnover have been poorly assessed in Cushing's syndrome, however. Twenty-five patients with Cushing's syndrome (20 women, 3 men; mean age +/- SEM: 38+/-2 years) were studied and compared with 35 age- and sex-matched control patients (mean age +/- SEM: 38+/-2 years). The following variables were measured in both groups: QUS parameters at the heel (BUA; SOS; Stiffness Index, SI); bone mineral density (BMD) at both the lumbar spine (LS) and femoral neck (FN) by dual-energy X-ray absorptiometry; and serum markers of bone turnover (osteocalcin, procollagen type I N- and C-terminal propeptides (PINP and PICP), bone alkaline phosphatase (BAP), procollagen type I C-terminal telopeptide (ICTP) and urinary type I collagen C-telopepetide breakdown products (CTX)). Both BUA and SI were decreased in patients with Cushing's syndrome (p0.01) but not SOS (p=0.08). BMD was also strongly decreased in Cushing's syndrome, at both the LS and FN (p0.005). The two markers of bone turnover statistically significantly different between the two groups were osteocalcin (mean + SEM: 3.5 + 0.7 ng/ml (Cushing's syndrome) vs 6.4+/-0.5 ng/ml (controls, p0.01)) and CTX (mean +/- SEM: 148.7+/-17.1 microg/mmol Cr (Cushing's syndrome) vs 220.8+/-22.9 microg/mmol Cr (controls), p0.05). The areas under the receiver operating characteristic curve (AUC) were 0.72 (BUA), 0.73 (SI), 0.90 (BMD(LS)), 0.81 (BMD(FN)), 0.83 (osteocalcin) and 0.64 (CTX) respectively. AUC was significantly higher for BMD(LS) than for both BUA and SI (p0.05). Conversely AUC was not statistically significantly different for BMDFN as compared with either BUA or SI. AUC was also higher for osteocalcin than for other markers of bone turnover. In conclusion, QUS of bone seems to be a relevant tool for assessing bone involvement in Cushing's syndrome. QUS does have a lower sensitivity compared with DXA, however, and the relevance of QUS cannot be ascertained until some longitudinal data are forthcoming. Except for CTX, the other new markers of bone turnover assessed in this study (PINP, PICP, BAP and ICTP) do not seem of interest in Cushing's syndrome.

Characteristic presentation of nonclassical adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency was compared between women carrying a severe and a mild CYP21 mutation (Group 1, N = 26) versus homozygotes for mild mutations (Group 2, N = 8). The diagnosis was based on elevated ACTH-stimulated 17OH-progesterone (17OHP). Genotyping for 10 mutations was performed by PCR-based techniques. Jewish patients predominated among Group 2 (25% vs 11.5% in Group 1); however, 85% of all patients were non-Jewish Caucasians. Average age of presentation was 23-25 years, and did not differ between groups. Hirsutism, and to a lesser extent oligomenorrhea and acne, were more prevalent among Group 1 women. There was a trend to higher basal 17OHP among Group 1 patients (mean +/- SEM; 1354+/-323 vs 714+/-129 ng/dl, P< or =0.25). The lack of significant difference was perhaps due to the relatively few homozygotes for 2 mild mutations (24%). V281L was carried on approximately 48% of all alleles, and about 16% carried either P30L or P453S. Approximately 38% of alleles and 77% of patients carried a classic mutation. These data have important implications for genetic counseling. In summary, we describe differences in clinical, hormonal, and genetic characteristics among a multiethnic group of females with NCAH.

Objective: To test the hypothesis that patients with nonclassic adrenal hyperplasia (NCAH) exhibit a generalized exaggeration in their response to ACTH stimulation that favors the normal production of F. Patients with 21-hydroxylase (21-OH)-deficient NCAH do not demonstrate cortisol (F) deficiency. Design: Prospective controlled study. Setting: Tertiary university clinic. Patient(s): Twenty-four untreated patients with NCAH diagnosed by a 17α-hydroxyprogesterone (17-HP) level of >30.3 nmol/L (>10 ng/mL), and 37 age- and body mass-matched healthy eumenorrheic nonhirsute controls. Intervention(s): All study subjects underwent a 60 minute acute stimulation using 0.25 mg of ACTH-(1-24) i.v. Main Outcome Measure(s): Basal and stimulated serum levels of pregnenolone (PREG), 17-hydroxypregnenolone (17-HPREG), dehydroepiandrosterone (DHA), progesterone (P4), 17-HP, androstenedione (A4), 11-deoxycortisol (S), and cortisol (F). Result(s): The median basal (i.e., Steroid 0 ) or ACTH-stimulated (i.e., Steroid 60 ) serum levels of PREG, 17-HPREG, DHA, P4, 17-HP, A4 and, most importantly, S were higher in NCAH patients than in controls. In contrast, the levels of F at either 0 minute or 60 minutes of stimulation were similar between NCAH and control women. The proportion of NCAH patients with stimulated steroids levels of >the 95th percentile of controls were as follows: 84.21% for PREG 60 , 87.5% for 17-HPREG 60 , 95.8% for DHA 60 , 89.5% for P4 60 , 100% for 17-HP 60 , 91.7% for A4 60 , 29.2% for S 60 , and 4.1% for F 60 . Conclusion(s): A generalized adrenocortical hyperresponsivity to ACTH stimulation seems to be present in patients with 21-OH-deficient NCAH, with an exaggerated production of S evident in approximately 30%. The excess production of S in these NCAH patients may, in part, account for their normal F production.

This article aims to answer two questions in defining polycystic ovary syndrome (PCOS): what is PCOS and how should the syndrome be recognized in clinical practice? Whether PCOS is a primary or a secondary ovarian disease remains controversial. It has been suggested for many years that the main pathophysiological factor in PCOS is dysregulation of the relationship between the hypothalamus, the pituitary and the ovary. However, PCOS also involves intraovarian morphological and functional abnormalities. With respect to clinical practice, many reports have questioned the sensitivity as well as the specificity of a high LH concentration. Similarly, the biological hyperandrogenism of PCOS cannot define the syndrome. GnRH agonist or hCG tests are not convenient for the diagnosis of PCOS in practice. Stromal hyperplasia is considered to be indicative of PCOS but it is highly dependent on the settings of the ultrasound machine, thus use of the total ovarian area, the upper normal limit of which is 5.5 cm(2), is recommended. The need for diagnostic markers of PCOS depends on the clinical presentation. In the full-blown syndrome (classic PCOS), the clinical symptoms provide the most powerful indication and the association of the three components (hyperandrogenism, anovulatory dysfunction and metabolic abnormalities) has a strong diagnostic potency. In non-classic PCOS, a cost-effective and safe work-up should be applied, which includes ultrasonography and hormonal assays (basal serum concentrations of testosterone, sex hormone binding globulin, 17-hydroxyprogesterone, LH, FSH and prolactin). Asymptomatic PCOS may be discovered incidentally during ultrasonography, and it is important to take this finding into account when designing an ovulation induction protocol. In most cases of PCOS, the diagnosis may remain presumptive providing other diagnoses have been ruled out and the follow-up does not disclose any atypical development of the condition.

Quantitative ultrasound (QUS) of bone and new markers of bone remodeling have been poorly investigated in mild primary hyperparathyroidism (PHPT). In this study 26 patients (20 females and 6 males) were evaluated. BUA and SOS were measured by QUS at the heel. Markers of bone remodeling assessed were bone alkaline phosphatase (BAP), osteocalcin (OC), procollagen type I N- and C-terminal propeptides (PINP et PICP), and procollagen type I C-terminal telopeptide in blood and urine (ICTP and CTX). Bone mineral density (BMD) was measured at the lumbar spine (LS), femoral neck (FN), and Ward's triangle (WT). The control group comprised 35 sex- and age-matched subjects. The statistically significant variables between the two groups were (P0.05) BUA, BMD(LS), BMD(FN), BMD(WT), BAP, and OC. Corresponding z-scores were -0.55 +/- 0.75, -0.66 +/- 0.77, -0.66 +/- 0.71, -0.67 +/- 0.52, 1.87 +/- 3.87, and 1.93 +/- 3.53, respectively. Although PICP and PINP levels were higher in PHPT patients as compared with controls, the difference was not significant. Several markers of bone turnover were moderately correlated with both QUS (r = -0.39 to -0.55) and BMD (r = -0.48 to 0.63). In conclusion QUS seems to be a relevant tool in the assessment of bone status for patients with mild PHPT.

Objective: To determine the sensitivity of 11β-hydroxyandrostenedione (11-OHA4) and Δ 5 -androstenediol (ADIOL) as markers of excessive adrenal androgen production. Design: Prospective study. Setting: Academic medical centers. Patient(s): Thirteen women with untreated 21-hydroxylase–deficient nonclassic adrenal hyperplasia (NCAH) and 18 healthy, eumenorrheic, nonhirsute controls matched for age and body mass index. Intervention(s): All subjects were studied before and after acute adrenal stimulation with 0.25 mg of IV ACTH-(1–24). Main Outcome Measure(s): Basal levels of total testosterone, sex hormone-binding globulin, DHEAS, and free testosterone were measured. Levels of androstenedione (A4), DHEA, 11-OHA4, and ADIOL were determined before (Steroid 0 ) and 60 minutes after (Steroid 60 ) acute ACTH-(1–24) stimulation. Result(s): Patients with NCAH had higher median basal levels of DHEAS and total and free testosterone than controls. Patients with NCAH had higher median A4 0 , A4 60 , DHEA 0 , DHEA 60 , 11-OHA4 0 , ADIOL 0 , and ADIOL 60 levels but similar 11-OHA4 60 levels compared with controls. Among patients with NCAH, 30%, 54%, 15%, and 85% had 11-OHA4 0 , ADIOL 0 , 11-OHA4 60 , and ADIOL 60 levels, respectively, above the 95th percentile of controls. Conclusion(s): Overall, serum levels of 11-OHA4 did not appear to be a very sensitive marker of excessive adrenal androgen production, at least in patients with NCAH. Although ACTH-stimulated ADIOL levels were elevated in 85% of the patients studied, they did not appear to have any advantage over the measurement of A4 or DHEA levels.

OBJECTIVE Multiple endocrine neoplasia type 1 (MEN1) is an autosomal genetic disorder, the clinical phenotype of which includes tumours of the parathyroids and/or anterior pituitary and/or endocrine pancreas. The genetic defect has been mapped to the chromosome 11q13 and the MEN1 gene has been recently identified, thus allowing genetic screening in affected kindreds. The aim of this study was to establish the usefulness of genetic screening in the follow-up of a large MEN1 kindred. PATIENTS We describe a large kindred of 91 members, of whom 56 had clinical, biochemical and genetic screening. Twenty eight of them have been tested annually for the last 5 years. RESULTS Although the precise mutation is still undetermined in this kindred, genotypic determination confirmed linkage with the MEN1 gene in affected members and excluded 28 members from annual testing. By drawing our attention to susceptible subjects, genetic screening improved the evaluation of age-related penetrance of the disease in the 3 generations from this kindred. For instance, annual screening showed conversion from unaffected to affected phenotype in 4 subjects aged 14, 14, 15, and 17 years. Moreover, genetics helped us to evaluate the specificity of clinical or biochemical markers, and thus to discard useless investigations. So far however, the genetics have not helped to explain the phenotypic heterogeneity and particularly low incidence of pancreatic tumours in this kindred. CONCLUSION Genetic screening is very useful in detecting high risk individuals for MEN 1, since it avoids time-consuming and expensive investigations in non-affected subjects. By providing better understanding of the age-related penetrance of this syndrome, it improves the efficiency of screening. Genetic studies allow differentiation between clinical and biochemical features that are useful in follow-up and other confusing or unhelpful parameters.

To date, only one study has demonstrated increased serum inhibin levels in women with polycystic ovary syndrome (PCOS). Moreover, no relationship between serum inhibin and either FSH or androgen levels has been noted. This lack of data could be due to 1) the heterogeneity of PCOS and the small sample size of previous studies, and/or 2) the complexity of circulating inhibin molecular forms, which hinders the precise evaluation of bioactive inhibin. In the present study,α -inhibin levels were assayed in the serum of 61 healthy women and 72 PCOS patients by means of an α-α enzyme-linked immunosorbent assay. Serum α-inhibin levels together with LH and androstenedione (A) levels were significantly increased in PCOS women (mean ± sd, 1.45 ± 0.55 vs. 0.94 ± 0.36 U/mL in controls; P < 0.001). Moreover, simple and partial regression analysis demonstrated that serum A levels were positively and independently correlated to serum α-inhibin (r = 0.32; P < 0.01) and LH levels (r = 0.48; P < 0.001) in PCOS. The respective influences of α-inhibin and LH on A variability were 20% and 80%, as determined by multiple regression analysis. In conclusion, in agreement with recent in vitro data, our in vivo results argue for a role of inhibin in the hyperandrogenism of PCOS together with, but independently from, that of LH. Further studies are needed to determine whether this effect is produced by inhibin A and/or B.

Defining the polycystic ovarian syndrome (PCOS) has challenged clinicians for many years. The clinical, hormonal and morphological definitions of PCOS have their own limitations and do not correspond exactly. Clinically, PCOS can be schematically divided into three components, i.e. hyperandrogenic, anovulatory and dysmetabolic. No one is specific for the syndrome. Hormonally, PCOS has recently been defined by the GnRH agonist test as a functional abnormality in ovarian androgen synthesis. This functional ovarian hyperandrogenism seems closely linked to hyperinsulinism secondary to an insulin resistance. Morphologically, ovarian ultrasonography has emerged in the last decade or so as a new diagnostic tool. However, the sonographic definition of the polycystic ovary (PCO) is controversial, mainly because of a lack of consensus about normative data. The aim of this review is to present the diagnostic dilemma in the diagnosis of PCOS and to discuss the prognostic significance of the PCO.

The cardinal features of polycystic ovary syndrome (PCOS) are hyperandrogenism and oligoanovulation. The increase in ovarian androgen production is a fundamental characteristic of PCOS and, although enigmatic, it is at the heart of one of the major issues about the pathophysiology of PCOS, i.e. whether it has developmental origins or not. Intraovarian androgens are designated as primarily responsible for the follicle excess. The defective selection of a dominant follicle in anovulatory patients results from both an insufficient secretion of FSH and a local inhibition of FSH action. Anti-müllerian hormone (AMH) seems to be involved in the latter by repressing the FSH-dependent aromatase activity. AMH level is increased in PCOS because of the follicle excess and increased production per follicle. Therefore, in anovulatory patients, serum FSH, although at low to normal plasma concentrations, would not be able to induce a decrease in AMH sufficient to allow the expression of aromatase. In conclusion, the fundamental anomaly of PCOS is still unknown, but it can be hypothesized that any genetic, epigenetic or environmental factor leading to intraovarian hyperandrogenism can result in PCOS.

STUDY QUESTION Are anti-Mullerian hormone (AMH) and AMH type II receptor (AMHR-II) mRNAs similarly regulated by gonadotrophins in lutein granulosa cells (GCs) from control, normo-ovulatory and oligo/anovulatory women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER AMH mRNA expression was induced by LH only in lutein GC of oligo/anovulatory PCOS women; down-regulation of AMHR-II, induced by LH in control and normo-ovulatory PCOS women, was absent in oligo/anovulatory women. WHAT IS KNOWN ALREADY It was suggested that AMH could be responsible for the blockade of follicles at the small antral stage in PCOS women. In keeping with this hypothesis, both AMH and AMHR-II are overexpressed in lutein GCs from oligo/anovulatory PCOS women. STUDY DESIGN, SIZE, DURATION Women undergoing IVF were included in this prospective study, either in the control group (30 women) or in the PCOS group (21 normo-ovulatory and 19 oligo/anovulatory patients) between January 2010 and July 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Human lutein GCs were isolated from follicular fluid during IVF protocols. Twenty-four hours after seeding, lutein GCs from each woman were serum starved and cultured for 48 h ± FSH, LH or cAMP. Then AMH and AMHR-II mRNAs were quantified by quantitative RT-PCR and AMH protein concentration was measured in the culture medium by ELISA. Experimental results were analyzed, within each group of women, by the non-parametric Wilcoxon test for paired comparisons between cells cultured in control medium and FSH, LH or cAMP treated cells. Clinical comparisons between the three groups of women were performed on log values using the ANOVA test with Bonferroni correction. MAIN RESULTS AND THE ROLE OF CHANCE FSH up-regulated both AMH expression and secretion by lutein GCs from the three groups of women (P < 0.05). LH had no effect on AMH mRNAs levels in lutein GCs from controls and normo-ovulatory PCOS women, but increased AMH expression in oligo/anovulatory PCOS women (P < 0.05). Interestingly, LH and cAMP treatments reduced AMHR-II expression by lutein GCs from controls and normo-ovulatory PCOS women (P < 0.05), but had no effect on AMHR-II mRNA levels in oligo/anovulatory PCOS women. LIMITATIONS, REASONS FOR CAUTION The lutein GCs are not the best model to study AMH and AMHR-II regulation by gonadotrophins. Indeed, AMH and AMHR-II are down-regulated in luteinized cells. Furthermore, these cells have been exposed to non-physiological levels of gonadotrophins and hCG. However, AMH and AMHR-II mRNAs are quantifiable by real-time RT-PCR, and the cells are still responsive to FSH and LH. The age of patients is significantly different between control and oligo/anovulatory PCOS women: this may be a bias in the interpretation of results but older women in the control group had a good ovarian reserve. WIDER IMPLICATIONS OF THE FINDINGS The overexpression of AMH and AMHR-II in oligo/anovulatory PCOS women could be due to increased LH levels and/or inhibition of its repressive action. The fact that this dysregulation is observed in oligo/anovulatory, but not in normo-ovulatory, PCOS women emphasizes the role of LH in the follicular arrest of PCOS women and suggests that this involves the AMH/AMHR-II system. STUDY FUNDING/COMPETING INTEREST(S) The Assistance-Publique Hopitaux de Paris provided a Contrat d'Interface and the Agence de Biomedecine provided a grant to Nathalie di Clemente. Schering-Plough provided an FARO grant to Alice Pierre. The authors have nothing to disclose.

The study was performed to validate the threshold for anti-Müllerian hormone (AMH) that suggests the presence of polycystic ovaries in women with polycystic ovary syndrome (PCOS).This prospective observational study included 59 infertile women: (A) 22 PCOS with hyperandrogenism (HA) and oligo-anovulation, (B) 15 suspected PCOS with either HA or oligo-anovulation and (C) 22 asymptomatic control women. The diagnosis of PCOS was made according to the NIH classification.For serum AMH and follicle number, respectively, the areas under the receiver operating characteristic curve (A versus C) were 0.97 and 0.93. The best compromise between specificity (95% and 91%) and sensitivity (95% and 82%) was obtained with threshold values of 33 pmol/l and 13 follicles, respectively. Using a serum AMH33 pmol/l as a surrogate for either HA or oligo-anovulation in group B would lead to the diagnosis of PCOS in seven (46.6%) patients from this group.Our data confirms that the AMH assay has a high diagnostic potential, providing that an appropriate threshold is used. AMH measurement may be included as an ultimate diagnostic criterion for the diagnosis of PCOS when either HA or anovulation is missing and/or when no reliable antral follicle count can be obtained.

Objective To extend our previous findings on the diagnostic validity of ovarian stroma hypertrophy in women with hyperandrogenic and/or menstrual disorders. Design Transvaginal ultrasonography was performed in 69 patients complaining of hyperandrogenism and/or menstrual disorders and in 48 normal ovulatory women in early follicular phase. To check the validity of stroma assessment by visual analysis, we used computer-assisted analysis, which allowed selective measurement of the stromal area on a longitudinal ovarian cut. Sensitivity and specificity of each method were estimated by using the normative data from the control group. Results Stromal area was considered to be increased using visual analysis and computer-assisted analysis in 74% and 61% patients, respectively. Specificity of this sign was 84% and 96% by visual analysis and computer-assisted analysis, respectively. In patients, the increase in stromal area correlated very significantly with the one of total ovarian area, whose upper normal limit was 5.5 cm 2 per ovary. Conclusion Visual assessment of stroma may be misleading in some cases, with the risk of overestimating its hypertrophy. An increased total ovarian area >5.5 cm 2 (which can easily be detected by carefully shaping a strict longitudinal ovarian cut) has the same diagnostic value as an increased stromal area by computerized measurement.

The cardinal features of polycystic ovary syndrome (PCOS) are hyperandrogenism and oligoanovulation. The increase in ovarian androgen production is a fundamental characteristic of PCOS and, although enigmatic, it is at the heart of one of the major issues about the pathophysiology of PCOS, i.e. whether it has developmental origins or not. Intraovarian androgens are designated as primarily responsible for the follicle excess. The defective selection of a dominant follicle in anovulatory patients results from both an insufficient secretion of FSH and a local inhibition of FSH action. Anti-mullerian hormone (AMH) seems to be involved in the latter by repressing the FSH-dependent aromatase activity. AMH level is increased in PCOS because of the follicle excess and increased production per follicle. Therefore, in anovulatory patients, serum FSH, although at low to normal plasma concentrations, would not be able to induce a decrease in AMH sufficient to allow the expression of aromatase. In conclusion, the fundamental anomaly of PCOS is still unknown, but it can be hypothesized that any genetic, epigenetic or environmental factor leading to intraovarian hyperandrogenism can result in PCOS.

Clinical signs of hyperandrogenism include hirsutism, acne and/or seborrhea, androgenic alopecia, menstrual disorders and at maximum virilization. Hirsutism is defined by the presence of a coarse and pigmented hair in male territory. In the Caucasian populations, a Ferriman Gallwey score ≥ 6 means hirsutism. Polycystic ovary syndrome is the most common cause of hyerandrogenism in women (70 % of cases) but must remain a diagnosis of exclusion. A neoplasm origin is suspected in case of recent onset of hyperandrogenism, which is rapidly progressive and with signs of virilization. The serum level of total testosterone and 17-hydroxyprogesterone and pelvic ultrasonography are the first line tests in case of clinical hyperandrogenism. Combined oral contraceptive pill can be the first line treatment in case of moderate hyperandrogenia, associated, if needed, with a specific acne treatment. Cyproterone acetate is the best-known and most effective antiandrogenic treatment. It decreases the hair density, speed of regrowth and pigmentation. It is indicated in severe hirsutism and must be combined with cosmetic cares.

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1 sema/sema mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS–like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder., Author Summary Kallmann syndrome is a hereditary developmental disease that affects both the hormonal reproductive axis and the sense of smell. There is a developmental link between the reproductive and olfactory disorders: neuroendocrine cells producing the gonadotropin-releasing hormone that is deficient in the patients normally migrate from the nose to the forebrain along olfactory nerve fibers during embryonic life, and they fail to do so in the patients. Affected individuals usually do not undergo spontaneous puberty. Hormone replacement therapy is the treatment to initiate virilization in males or breast development in females and later to develop fertility in both sexes. This is a genetically heterogeneous disease. Mutations in any of eight causative genes identified so far have been found in approximately 30% of the affected individuals, thus indicating that other genes remain to be discovered. We report on the identification, in 6% of the KS patients, of various loss-of-function mutations in the gene coding for semaphorin-3A, a secreted protein involved in the navigation of olfactory nerve fibers during embryogenesis. The fact that many of these mutations were also detected in clinically unaffected individuals indicates that they must combine with other genetic defects to produce the disease phenotype.

TSH assay is the best parameter of the thyroid function. For adults, the normal interval of TSH concentrations range from 0.4 to 4 mUI/L. At the first trimester of pregnancy, TSH levels must be2.5 mUI/L. Normal TSH levels increase with aging and obesity. The biological diagnosis relies on the identification of excessive secretion of the metanephrines which are more sensitive and specific than those of catecholamines. The concentrations of the free plasmatic metanephrines reflect the ongoing production of tumor. Plasma methoxytyramine is a novel biomarker of metastatic pheochromocytomas and paragangliomas. Serum IGF1 is a reliable measure of integrated GH concentrations in patients with acromegaly. Accurate assessment of IGF1 concentrations requires age and sex-matched control values. IGF1 is a sensitive tool for the diagnosis of acromegaly and efficacy of therapies. Serum AMH assay is more sensitive, more specific and more reproducible that counting of ovarian follicles by ultrasound. AMH level above 5 ng/mL (35 pmol/L) could be chosen as one of the diagnostic criteria for the polycystic ovary syndrome. In early or "incipiens" ovarian failure, the decrease in serum AMH is far ahead of the increase in FSH. Thyroglobulin (TG) and calcitonin (CT) are the sensitive and specific markers of respectively well-differentiated thyroid cancers of follicular origin and of the medullary thyroid cancers. The same tumour marker assay should be used to monitor a given patient. Chromogranin A (CgA) is a highly efficient biomarker for diagnosis and follow-up of various endocrine tumours. Despite the lack of international standardisation, some CgA assays are reliable.

Objective It is not known whether polycystic ovaries (PCO) are an ovarian appearance without pathological meaning or whether they share with polycystic ovary syndrome (PCOS) the same ovarian follicle abnormality. There are few studies including strictly selected women with PCO but without other criteria of PCOS. In order to address these issues, we compared hormonal, metabolic and ultrasound parameters obtained from patients with PCO only, patients with PCOS and controls. Methods This was a comparative analysis including three age-matched groups of 95 patients, who were included consecutively in a database: controls, patients with sonographic PCO but no symptoms (PCO group) and patients with PCOS. A clinical examination, fasting serum sampling and pelvic ultrasound examination were performed between cycle days 2 and 5 and results were compared between groups. Results The median serum anti-Mullerian hormone (AMH) level in the PCO group was intermediate between that in controls and that in the PCOS group (33.6 pmol/L, 19.8 pmol/L and 63.3 pmol/L, respectively), the differences being significant after adjustment for follicle number (P < 0.05), while the mean androgen serum level in the PCO group was similar to that in the control group and significantly lower than that in the PCOS group (P < 0.05) (median serum testosterone levels: 0.90 nmol/L, 0.79 nmol/L and 1.39 nmol/L; median androstenedione levels: 5.25 nmol/L, 4.37 nmol/L and 6.09 nmol/L, respectively). Body mass index, waist circumference and insulin levels had no effect on these differences. Conclusion PCO is an abnormal condition, affected women showing no evidence of hyperandrogenism but having higher AMH serum levels compared with controls, suggesting a granulosa cell abnormality in PCO similar to that observed in PCOS. The absence of hyperandrogenism in PCO does not seem linked to the metabolic status. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

Le syndrome des ovaires polymicrokystiques (SOPMK) represente l'endocrinopathie la plus frequente de la femme en âge de procreer. L'hyperandrogenie, l'anovulation, et le syndrome metabolique constituent les trois piliers du SOPMK. L'hyperandrogenie du SOPMK resulte d'une hyperactivite enzymatique diffuse au niveau des cellules theco-interstitielles. L'anovulation traduit un trouble de la selection du follicule dominant alors que les follicules plus petits, des stades primaires aux tertiaires, sont en nombre exagere. Le mecanisme moleculaire d'insulinoresistance pourrait etre une augmentation de l'auto-phosphorylation basale du recepteur de l'insuline. La classification clinique actuelle du SOPMK distingue trois grands types de presentation le syndrome « classique », associant les 3 composantes sus-citees, les formes incompletes ou « non-classiques », et le SOPMK asymptomatique, decouvert par l'echographie. Seule l'hypertrophie ovarienne (au moins une surface > 5,5 cm 2 ou un volume > 11 ml), bilaterale et symetrique, doit etre consideree comme un signe echographique specifique. Le traitement de l'hyperandrogenie liee au SOPMK reste base sur l'utilisation de l'acetate de cyproterone. Le traitement de l'anovulation et de l'infecondite liee au SOPMK suit maintenant une strategie bien codifiee. Le traitement insulinosensibilisant permet d'obtenir une diminution de l'hyperandrogenie, une regularisation du cycle et l'obtention de grossesses spontanees ou induites.

Several clinical studies reported the efficacy of the long-acting SRIH analog, octreotide (Octreotide, Sandoz) in the treatment of acromegaly. Recently, another SRIH analog (BIM 23014, Ipsen Biotech) was shown to decrease plasma GH levels in acromegalic patients. The recent availability of a long-acting formulation of BIM 23014 [slow release (SR) lanreotide] could avoid the inconveniences associated with either repeated sc injections or continuous sc infusions. In this study, we compared the clinical and biochemical efficacies of both drugs in a cohort of 19 acromegalic patients, considered initially as responsive to octreotide and sequentially treated with octreotide (3 sc injections of 100-200 micrograms/day) for 12 months and with SR lanreotide (30 mg, im, every 10 or 14 days) for 6 months. Before octreotide treatment, baseline plasma GH (mean +/- SE of 8 hourly samplings) was 29.0 +/- 10.0 micrograms/L and was lowered to 3.2 +/- .2 micrograms/L during the first 7 h after the first 100-micrograms sc octreotide administration. After 12 months of treatment with octreotide, 14 of 19 patients (74%) were considered normalized, as their mean individual GH profiles and insulin-like growth factor-I (IGF-I) values were within the normal range. After octreotide withdrawal for 1 week, plasma GH and IGF-I levels rose to 18.3 +/- 4.8 and 4.1 +/- 0.4 U/mL, respectively. The first 30-mg SR lanreotide im injection produced an acute suppression of plasma GH levels (mean GH value during the 7 h after the injection, 3.0 +/- 0.4 micrograms/L), not different from results previously observed after the first octreotide injection. After 3 months of treatment with 30 mg SR lanreotide every 14 days, normalization of baseline GH and IGF1 levels was achieved in 6 of 19 patients. Ten patients, who did not achieve normal GH levels, subsequently received a 30-mg SR lanreotide injection every 10 days. Among them, normalization of GH and IGF-I levels occurred in 7 of 10 patients after 3 months of such a regimen. After 6 months of SR lanreotide treatment, 13 of 19 patients (68%) were considered normalized, with mean GH and IGF-I values, respectively, of 3.1 +/- 0.4 micrograms/L and 1.5 +/- 0.1 U/mL. The overall tolerance of both drugs (glucose homeostasis and gallstone formation) was similar.(ABSTRACT TRUNCATED AT 400 WORDS)

Bromocriptine or other dopamine agonists are usually effective for the treatment of prolactin-secreting adenomas. Five to 18% of prolactinomas, however, do not respond to such therapy. We have shown previously that such resistance to bromocriptine correlates with reduced binding to the D2 receptor subtype of dopamine, the major PRL inhibiting factor. In the present work, we demonstrated that reduced binding actually corresponds to decreased expression of the gene coding for the D2 receptor in the pituitary from bromocriptine-resistant patients, as shown by 4-fold lower levels of the corresponding mRNAs compared to those coding for actin. The existence of two D2 receptor isoforms, D2S and D2L generated by alternative splicing, has been described in several tissues, including the pituitary. Both are negatively coupled to adenylyl cyclase and inhibit prolactin secretion, but, in addition, the shortest one (D2S) is more efficiently coupled to phospholipase C. Consequently, we also investigated whether expression of a particular D2 receptor isoform was preferentially affected in resistant adenomas. The proportion of messengers corresponding to the short receptor isoform (D2S) was lower in resistant compared to responsive adenomas: D2S/D2L = 0.74 ± 0.08 and 1.00 ± 0.07, respectively. In parallel, much lower levels of D2 receptor mRNAs were found in growth hormone-secreting adenomas, with a D2S/D2L ratio comparable to those of both normal human pituitary and bromocriptine-sensitive prolactinomas (1.05 ± 0.11). Thus, resistance to bromocriptine therapy seems to involve defects in D2 dopamine receptor expression and possibly in posttranscriptional splicing.

Recently cerebrospinal fluid CRF was found to be significantly elevated in patients with OCD compared with controls. These data are compatible with the hypothesis that CRF is hypersecreted in OCD. To explore this hypothesis, we studied plasma cortisol and ACTH responses to ovine CRF (o-CRF) in patients with OCD

Background Hirsutism, defined by the presence of excessive terminal hair in androgen-sensitive areas of the female body, is one of the most common disorders in women during reproductive age. Methods We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of hirsutism. Results The prevalence of hirsutism is ~10% in most populations, with the important exception of Far-East Asian women who present hirsutism less frequently. Although usually caused by relatively benign functional conditions, with the polycystic ovary syndrome leading the list of the most frequent etiologies, hirsutism may be the presenting symptom of a life-threatening tumor requiring immediate intervention. Conclusions Following evidence-based diagnostic and treatment strategies that address not only the amelioration of hirsutism but also the treatment of the underlying etiology is essential for the proper management of affected women, especially considering that hirsutism is, in most cases, a chronic disorder needing long-term follow-up. Accordingly, we provide evidence-based guidelines for the etiological diagnosis and for the management of this frequent medical complaint.

Polycystic ovarian morphology (PCOM) at ultrasound is currently used in the diagnosis of polycystic ovary syndrome (PCOS). We hypothesized that the previously proposed threshold value of 12 as an excessive number of follicles per ovary (FN) is no longer appropriate because of current technological developments. In this study, we have revisited the thresholds for FN and for the serum Anti-Müllerian hormone (AMH) level (a possible surrogate for FN) for the definition of PCOM.Clinical, hormonal and ultrasound data were consecutively recorded in 240 patients referred to our department between 2008 and 2010 for exploration of hyperandrogenism (HA), menstrual disorders and/or infertility.According to only their symptoms, patients were grouped as: non-PCOS without HA and with ovulatory cycles (group 1, n = 105), presumption of PCOS with only HA or only oligo-anovulation (group 2, n = 73) and PCOS with HA and oligo-anovulation (group 3, n = 62). By cluster analysis using androgens, LH, FSH, AMH, FN and ovarian volume, group 1 appeared to be constituted of two homogeneous clusters, most likely a non-PCOM non-PCOS subgroup (n = 66) and a PCOM, non-PCOS (i.e. asymptomatic) subgroup (n = 39). Receiver operating characteristic curve analysis was applied to distinguish the non-PCOM non-PCO members of group 1 and to group 3. For FN and serum AMH respectively, the areas under the curve were 0.949 and 0.973 and the best compromise between sensitivity (81 and 92%) and specificity (92 and 97%) was obtained with a threshold values of 19 follicles and 35 pmol/l (5 ng/ml).For the definition of PCOM, the former threshold of12 for FN is no longer valid. A serum AMH35 pmol/l (or5 ng/ml) appears to be more sensitive and specific than a FN19 and should be therefore included in the current diagnostic classifications for PCOS.

In order to compare the diagnostic significance of hormonal and ultrasonic criteria of polycystic ovarian syndrome (PCOS), the presence or the absence of ultrasonographic and hormonal features of PCOS were recorded in a heterogeneous population of 90 women presenting with hyperandrogenism and/or menstrual disorders. On clinical and hormonal grounds exclusively, these patients could be separated into five diagnostic subgroups: presumed cases of PCOS (n = 21), idiopathic hirsutism (IH) (n = 26), hypothalamic anovulation (HA) (n = 11), hyperprolactinemia (HPRL) (n = 9), and miscellaneous or undetermined diagnosis (n = 23). By the means of a computed automatic classification of patients (cluster analysis) using five hormonal and ultrasonic criteria of PCOS, four homogeneous clusters of patients were obtained. Cluster #1 (25 patients) had the most characteristic profile of PCOS. It included 15 cases of PCOS and 7 cases of IH. Cluster #4 (47 patients) had the less characteristic profile of PCOS. It included the majority of patients with HA and HPRL and the half of the patients with IH. Cluster #2 included only two hyperandrogenic patients, who were massively obese and in whom ultrasonography may have failed to detect PCOS. Cluster #3 (16 patients) included patients from each diagnostic group, who were gathered together because ultrasonographic and hormonal features were, respectively, present and absent in nearly all of them. With the same analysis, the criteria of PCOS could be graded according to their grouping potential. The presence of an abnormal ovarian stroma by ultrasonography appeared as the most potent criterion. Elevated serum testosterone and androstenedione levels and the polyfollicular pattern of ovaries gave intermediate results, while elevated basal LH level was a much weaker grouping parameter. In conclusion, the automatic classification of patients by cluster analysis using both hormonal and ultrasonographic criteria revealed that the classical diagnostic classification, relying upon hormonal data exclusively, may arbitrarily separate patients having the same disease; and that ultrasonography affords pertinent information that should help provide a better diagnostic definition of PCOS.

To evaluate by the birth rate the impact of the number of days of estrogens continued beyond the menses in a four days estradiol IVF antagonist programming cycles.Retrospective study from September 2004 to January 2009 among women of age ranging between 25 and 38 years. Four milligrams of provames is prescribed 3 to 5 days before the theorical menses and continued until the beginning day of stimulation, which is distributed equitably between Thursday and Sunday. The birth rate is evaluated according to the number of days of estrogen continued beyond the menses within a limit from 1 to 8.No significant difference appears neither in the duration of stimulation, in the quantity of gonadotrophin, the oocytes pick up, nor in the rate of birth between the groups.The programming by estrogens of the antagonist IVF cycles implies a variable number of days of estrogens continued beyond the menses, which does not seem to affect the birth rate.

This introduction presents an overview of the concepts discussed in this book. This book provides a comprehensive approach to each of the possible factors that act as a barrier to conception. The probability of conception depends on the success rate of the particular treatment, and the number of cycles of treatment that a couple undertake. This has been applied to the lifetable analysis of repeated treatment cycles by donor insemination, ovulation induction, and in vitro fertilization (IVF). There are the three main fertility parameters (eggs, sperm, and tubes), and if these are found to be relatively normal and the couple still does not conceive, then it is termed as unexplained or idiopathic subfertility. The most effective option to proceed to next if unexplained subfertility is diagnosed is IVF. The chapter presents an overview of how other chapters of the book are organised.

Polycystic ovary syndrome (PCOS) and hyperprolactinemia are the two most common etiologies of disorders of the cycle in women. In clinical practice, it is not unusual to find hyperprolactinemia associated with clinical, hormonal and ultrasound features of PCOS. However, currently, there is no evidence of a pathophysiological link between these two entities. Thus, this association seems to be fortuitous. Therefore, hyperprolactinemia in women with PCOS must lead to etiological investigations, including eliminating macroprolactinemia (excess of "big prolactin" and/or "big-big prolactin"). Finally, symptomatic hyperprolactinemias (excluding macroprolactinemia) can "mask" an underlying PCOS through a gonadotropic inhibition. Moreover, symptomatic hyperprolactinemias can provide clinical and ultrasound features of a "moderate" PCOS. Therefore, in agreement with the consensus of Rotterdam, PCOS must remain a diagnosis of exclusion, after eliminating symptomatic hyperprolactinemias (excluded macroprolactinemia) and all other etiologies of hyperandrogenism.

Polycystic ovary syndrome (PCOS) is the most common etiology of menstrual disorders and hyperandrogenism. It is characterized by an excess of ovarian follicles. The mechanisms that underlie folliculogenesis disorder in PCOS appear to arise from primitive ovarian hyperandrogenism. This can be modulated by hormonal factors, such as LH or insulin. Ovarian hyperandrogenism results from a real theca cells dysfunction, whose origin is still poorly understood. It seems that complex genetic factors may be involved, but these have not yet been clearly identified. PCOS also results from granulosa cells dysfunction. For example, intra-ovarian factors, such as anti-mullerian hormone, are possibly involved in ovulation's disorders by blocking the physiological process of follicular recruitment. In turn, the oocyte could also be one of the actors possibly involved in the follicular excess in PCOS.