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STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference?SUMMARY ANSWER: International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS.WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist.STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength.PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels.MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management.LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided.WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program.STUDY FUNDING/COMPETING INTEREST(S): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.

OBJECTIVE: To study the presence of several maternal and neonatal complications in a cohort of women with hyperandrogenic as well as normoandrogenic polycystic ovary syndrome (PCOS) and women with PCOS who received different fertility treatments.DESIGN: Prospective multicenter cohort study.SETTING: Hospitals and midwifery practices.PATIENT(S): One hundred and eighty-eight women with PCOS and singleton pregnancies (study group) and 2,889 women with a naturally conceived singleton pregnancy (reference group).INTERVENTION(S): Observational study.MAIN OUTCOME MEASURE(S): Maternal and neonatal pregnancy complications.RESULT(S): Women with PCOS had a statistically significantly increased risk of developing gestational diabetes (adjusted odds ratio [AOR] 4.15; 95% confidence interval [CI], 2.07-8.33) compared with the reference group, and their infants were more often born small for gestational age (AOR 3.76; 95% CI, 1.69-8.35). In a subgroup analysis, maternal complications were statistically significantly more often present in women with hyperandrogenic (defined as a free androgen index >4.5) PCOS (n = 76; 40% of all PCOS women) compared with those with normoandrogenic PCOS (n = 97; 52% of all PCOS women) (45% vs. 24%; P=.003); no statistically significant differences were observed between these groups regarding neonatal complications.CONCLUSION(S): Women with PCOS have an increased risk of maternal and neonatal pregnancy complications, especially women with the hyperandrogenic phenotype.CLINICAL TRIAL REGISTRATION NUMBER: NCT00821379.

One of the barriers to access to fertility care is the relative complexity of fertility treatments. If these can be simplified, more patients may be able to take advantage of these treatments. In this overview, we review the potential benefits of simplifying ovarian stimulation by the means of four distinct methods: 1) using mild stimulation for IVF cycles; 2) using in vitro maturation to allow for the retrieval of oocytes that are not yet fully mature yet have the potential to result in live births; 3) conducting IVF in modified natural cycles which use no exogenous FSH stimulation; and 4) allowing embryo culture to take place in a novel intravaginal incubation system. These methods are considered to be somewhat unconventional, yet they have all been shown to lead to live births. In the era of individualized patient care, these techniques present viable alternatives to standard treatment. As experience and outcome data accumulate, they may prove to be not just alternatives to standard treatment, but potentially first-line treatment choices.

Objective To compare the endocrine and cardiometabolic cord blood characteristics of offspring of mothers with polycystic ovary syndrome (PCOS) with those of healthy controls. Design Cross-sectional case control study. Setting University medical centers. Patient(s) Offspring from mothers with PCOS (n = 61) and healthy controls (n = 82). Intervention(s) Cord blood withdrawal from neonates. Main Outcome Measure(s) Cord blood estradiol, androstenedione, dehydroepiandrosterone sulfate (DHEAS), testosterone, sex hormone-binding globulin, free androgen index (FAI), insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, c-reactive protein, adiponectin, and leptin. Result(s) Androstenedione and leptin concentrations were increased in the offspring of women with PCOS compared with the controls: androstenedione median 2.9 (interquartile range [IQR] 2.3–3.9) nmol/L vs. 2.2 [IQR 1.6–2.7] nmol/L; and leptin median 13.6 [IQR 8.3–22.9] μg/L vs. 9.8 [IQR 6.0–16.5] μg/L. After adjusting for maternal and pregnancy-related confounders (such as maternal age, gestational age, birth weight), androstenedione appeared associated with PCOS in both male (relative change 1.36 [1.04; 1.78]) and female offspring (relative change 1.40 [1.08; 1.82]). Similarly, in male offspring the leptin concentrations appeared associated with PCOS after correction for confounders (relative change 1.55 [1.12; 2.14]). After correction for multiple testing, these associations attenuated. Conclusion(s) Observed results suggest that androstenedione concentrations are increased in the cord blood of male and female offspring of women with PCOS, although this requires confirmation. This finding would support the hypothesis that a maternal hyperandrogenic environment during pregnancy in women with PCOS may predispose their offspring to fetal hyperandrogenism. The potential associations between fetal hyperandrogenism and long-term health effects remain to be elucidated. Clinical Trial Registration Number NCT00821379.

Objective To discuss the mechanism of action of selective progesterone receptor modulators (SPRMs) and summarize the preclinical and clinical efficacy and safety data supporting the potential use of these compounds for gynecologic indications. Design Relevant publications from 2005 onward were identified using a PubMed search. Additional relevant articles were identified from citations within these publications. Setting None. Patient(s) None. Intervention(s) None. Main Outcome Measure(s) None. Result(s) Mifepristone was first developed as a progesterone receptor antagonist and licensed for pregnancy termination because of the unique property of this compound to terminate pregnancy when associated with prostaglandins. Then SPRMs were developed, and among those ulipristal acetate, an efficient emergency contraceptive. Because SPRMs effectively inhibit endometrial proliferation and reduce endometriotic lesions in animal models, this suggests a possible role in the treatment of endometriosis in humans. Finally, a number of double-blind, randomized, placebo-controlled trials have demonstrated the efficacy of asoprisnil, mifepristone, telapristone acetate, and ulipristal acetate in reducing leiomyoma and uterine volume, and suppressing bleeding in women with uterine fibroids. Conclusion(s) Mifepristone in combination with prostaglandins has been licensed for pregnancy termination because of its unique ability is this area. Ulipristal acetate is available for emergency contraception. Several SPRMs hold further promise as an effective medical therapy for patients suffering from endometriosis and leiomyoma.

Objective To evaluate the association between estrogen (E) exposure and deficiency and cardiovascular disease (CVD) risk among women with primary ovarian insufficiency (POI). Design Cross-sectional study conducted between 1996 and 2016. Setting Tertiary referral centers. Patient(s) A total of 385 women with POI, defined by amenorrhea and FSH levels ≥40 IU/L before 40 years of age, were recruited. Intervention(s) None. Main Outcome Measure(s) Women underwent a standardized intake questionnaire including data on menstrual cyclicity. Lifetime E exposure and E-free period were assessed. Serum was analyzed for endocrine and CVD profiles. The Framingham 30-year risk of CVD was calculated. Result(s) Lifetime E exposure (mean ± SD) was 19.3 ± 7.0 years, E-free period was 3.1 ± 4.1 years, and age at screening was 34.8 ± 7.4 years. In multivariate models E-free interval associated positively with estimated risk of hard and general CVD events (β 0.18 [95% confidence interval 0.08, 0.29]; 0.20 [0.05, 0.35], respectively), and lifetime E exposure associated negatively with estimated risk of hard and general CVD events (−0.15 [−0.24, −0.05]; −0.16 [−0.29, −0.03], respectively), as well as low density lipoprotein cholesterol (−0.03 [−0.06, 0.00]) and non–high density lipoprotein cholesterol (−0.04 [−0.07, 0.00]). Conclusion(s) Prolonged E deprivation is associated with an increased estimated risk of CVD, whereas prolonged E exposure is associated with a reduced estimated risk. These results support the policy of early and continued use of E replacement therapy in women with POI. Clinical Trial Registration Number NCT0230904.

Objective: To elucidate the impact of ovarian stimulation on the intrauterine milieu represented by the cytokine, chemokine, and growth factor profile in endometrial secretions aspirated before embryo transfer. Design: Prospective cohort study. Setting: Fertility center in tertiary referral university hospital. Patient(s): Forty-two patients undergoing ovarian stimulation with GnRH analogues were recruited. They participated in both a natural and an ovarian-stimulated cycle for within patient comparisons. Intervention(s): Endometrial secretion aspiration was performed immediately before embryo transfer. Main Outcome Measure(s): The concentrations of 17 mediators known to be involved in human embryo implantation were assessed by multiplex immunoassay. Result(s): After correction for multiple testing, significantly higher concentrations of interleukin (IL)-1 beta, IL-5, IL-10, IL-12, IL-17, tumor necrosis factor (TNF)-alpha, heparin-binding epidermal growth factor (HbEGF), eotaxin, and dickkopf homologue-1 were present in endometrial secretions obtained in stimulated compared with natural cycles. Conclusion(s): Endometrial secretion analysis provides a novel means of investigating the effect of ovarian stimulation on the intrauterine milieu. The in vivo milieu encountered by the embryo after transfer is significantly altered by ovarian stimulation. (Fertil Steril (R) 2010;94:1764-8. (C)2010 by American Society for Reproductive Medicine.)

Objective To develop a prognostic model for the prediction of ongoing pregnancy after single-embryo transfer (SET) following mild stimulation for IVF in women less than 38 years of age. Design Prospective cohort study. Setting Two fertility centers in tertiary referral university hospitals. Patient(s) A total of 152 women with an elective SET following mild ovarian stimulation (cycle day 5 start of 150 IU/day recombinant FSH and late follicular phase GnRH antagonist cotreatment). Intervention(s) Database analysis. Main outcome measure(s) Ongoing pregnancy. Result(s) The ongoing pregnancy rate per elective SET was 28% (42 of 152). In a multivariate logistic regression analysis, body mass index, the total gonadotrophin dose needed, and number of oocytes retrieved were negatively correlated whereas the availability of a top-quality embryo was positively correlated with ongoing pregnancy. The predictive ability of the model assessed by the area under the receiver operating characteristic curve was 0.68. At a probability cut-off level of 0.20 the model showed a sensitivity of 37% and a specificity of 90%. Conclusion(s) The developed prediction model for ongoing pregnancy provides an evidence-based strategy for guidance under which conditions SET may be performed. After external validation, application of the model may help to improve overall singleton pregnancy rates.

Objective To assess the accuracy of antimullerian hormone (AMH) in predicting cumulative live birth rate (CLBR) within 1 year after treatment initiation in GnRH antagonist treatment cycles for in vitro fertilization (IVF). Design Observational (retrospective) substudy as part of an ongoing prospective cohort study. Setting University medical center. Patient(s) A total of 487 patients scheduled for IVF/intracytoplasmic sperm injection (ICSI). Intervention(s) Patients starting their first IVF/ICSI cycle with 150 or 225 IU recombinant FSH and GnRH antagonist cotreatment were included. Serum samples collected before the first IVF treatment were used to determine AMH. Treatment data after treatment initiation for a maximum of 1 year were recorded. Main Outcome Measure(s) Prediction of CLBR with the use of AMH. Result(s) The model for predicting CLBR within 1 year included age at first treatment, AMH, type of infertility, and previous assisted reproductive technology treatment leading to live birth. The accuracy in discriminating between women who did or did not achieve a live birth was only 59%. AMH had intermediate added value in the prediction of CLBR as demonstrated by the net reclassification improvement (total 29.8). A nomogram based on age and AMH was developed by which a subgroup of patients could be identified with the poorest pregnancy prospects. Conclusion(s) The predictive accuracy of AMH for 1-year CLBR in GnRH antagonist treatment cycles was limited and did not yield much additional value on top of age. Withholding treatment based on predictors such as age and AMH, or a combination, remains problematic. Clinical Trial Registration Number www.clinicaltrials.gov, NCT02309073.

Objective: To assess the incidence of different FSH receptor genotypes in normogonadotropic anovulatory infertile women (World Health Organization class II) and normo-ovulatory controls and to correlate these genotypes with baseline characteristics and ovarian responsiveness during ovulation induction. Design: Cross-sectional study. Setting: University hospital. Patient(s): Thirty normo-ovulatory controls and 148 normogonadotropic anovulatory infertile women. Intervention(s): All participants underwent a standardized evaluation that included cycle history, body mass index measurement, and transvaginal ultrasonography of ovaries. Fasting blood samples were obtained for endocrine evaluation. Ovarian responsiveness to FSH in normogonadotropic anovulatory infertile women was assessed during ovulation induction, and DNA was analyzed to determine the FSH receptor genotype. Main Outcome Measure(s): Prevalence of FSH receptor polymorphisms, baseline serum FSH levels, amount of FSH administered, duration of stimulation, and ovarian response dose. Result(s): The Thr/Thr 307 genotype was significantly less prevalent (52% vs. 23%) and the Ser/Ser 680 polymorphism was significantly more prevalent (40% vs. 16%) in patients compared with controls. Normogonadotropic anovulatory infertile women with the Ser/Ser 680 polymorphism presented with higher median FSH serum levels (5.2 IU/L [range, 2.4-9.7 IU/L]) than did those with the Asn/Asn 680 (4.6 IU/L [range, 1.4-5.8 IU/L) and Asn/Ser 680 (4.5 IU/L [range, 1.8-9.7 IU/L) variants. However, ovarian responsiveness to FSH was similar among anovulatory women with the various polymorphisms. Conclusion(s): Normogonadotropic anovulatory infertile patients have a different FSH receptor genotype than do normo-ovulatory controls. Although this characteristic is associated with increased baseline FSH serum levels, altered ovarian sensitivity to exogenous FSH during ovulation induction could not be established.

Objective: To investigate whether serum concentrations of antimullerian hormone may be used as a marker for ovarian aging. Design: Longitudinal observational study. Setting: Academic research center. Patient(s): Forty-one normo-ovulatory premenopausal women and 13 healthy postmenopausal women. Main Outcome Measure(s): Concentrations of serum antimullerian 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 antimullerian hormone decreased significantly over time (median value, 2.1 μg/L [range, 0.1–7.4 μg/L] at visit 1 vs. 1.3 μg/L [range, 0.0–5.0 μg/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 antimullerian hormone correlated with age (r = −.40, P=.01 and r = −.57, P

Objective: To establish whether initial screening characteristics of normogonadotropic anovulatory infertile women can aid in predicting live birth after induction of ovulation with clomiphene citrate (CC). Design: Prospective longitudinal single-center study. Setting: Specialist academic fertility unit. Patient(s): Two hundred fifty-nine couples with a history of infertility, oligoamenorrhea, and normal follicle-stimulating hormone (FSH) concentrations who have not been previously treated with any ovulation-induction medication. Intervention(s): 50, 100, or 150 mg of oral CC per day, for 5 subsequent days per cycle. Main Outcome Measure(s): Conception leading to live birth after CC administration. Result(s): After receiving CC, 98 (38%) women conceived, leading to live birth. The cumulative live birth rate within 12 months was 42% for the total study population and 56% for the ovulatory women who had received CC. Factors predicting the chances for live birth included free androgen index (testosterone/sex hormone–binding globulin ratio), body mass index, cycle history (oligomenorrhea versus amenorrhea), and the woman's age. Conclusion(s): It is possible to predict the individual chances of live birth after CC administration using two distinct prediction models combined in a nomogram. Applying this nomogram in the clinic may be a step forward in optimizing the decision-making process in the treatment of normogonadotropic anovulatory infertility. Alternative first line of treatment options could be considered for some women who have limited chances for success.

At present, much attention in medicine is being directed toward individualized or patient-tailored care with the use of novel tools such as biomarkers or genomics. Research tools different from randomized controlled trials, focusing on the heterogeneity of patients rather than the intervention per se, are required to develop this concept further. In infertility care, few examples of individualized approaches with the use of multivariate prediction models can be found, such as the prediction of spontaneous conception chances in infertile patients or regarding the medical treatment of anovulatory infertility. Few prospective studies have been published in recent years concerning individualized dosing based on response prediction for ovarian stimulation in IVF. Potentially much may be gained by such methods because at present ovarian response to stimulation varies greatly, with distinct implications for both efficacy and safety of IVF treatment.

Objective To assess the prevalence of infectious complications and the protective effect of prophylactic antibiotic treatment after diagnostic office hysteroscopy in asymptomatic, infertile patients with normal results from transvaginal sonography. Design Recording of infectious complications after routine hysteroscopy in the context of a randomized controlled trial; pseudorandomized, center-specific application of antibiotic prophylaxis. Setting Two tertiary infertility care units. Patient(s) Six hundred thirty-one unselected, asymptomatic, infertile women who underwent routine, diagnostic hysteroscopy prior to a first in vitro fertilization (IVF) or intracytoplasmic sperm injection treatment. Intervention(s) Depending on the hospital and according to local protocols, hysteroscopy was performed with or without antibiotic prophylaxis. Main Outcome Measure(s) The prevalence of infectious complications after routine hysteroscopy. Result(s) Of the 631 women who underwent routine, diagnostic hysteroscopy, antibiotic prophylaxis was prescribed to 266 women, whereas 365 women underwent the procedure without prophylaxis. Only one infectious complication occurred (0.4%) in a patient who had not undergone therapeutic interventions and had taken antibiotic prophylaxis. This complication was successfully treated with antibiotics on an outpatient basis. Conclusion(s) Considering the extremely low risk of infectious complications and the lack of evidence, suggesting a beneficial effect of antibiotic prophylaxis, its use for routine, diagnostic office hysteroscopy should not be recommended.

Item does not contain fulltext OBJECTIVE: To assess the impact of elevated early follicular progesterone (P) levels in gonadotropin-releasing hormone (GnRH) antagonist cycles on clinical outcome using prospective data in combination with a systematic review and meta-analysis. DESIGN: Nested study within a multicenter randomized controlled trial and a systematic review and meta-analysis. SETTING: Reproductive medicine center in an university hospital. PATIENT(S): 158 in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) patients. INTERVENTION(S): Recombinant follicle-stimulating hormone (FSH) (150-225 IU) administered daily from cycle day 2 onward; GnRH antagonist treatment randomly started on cycle day 2 or 6; assignment into two groups according to P level on cycle day 2: normal or elevated (>4.77 nmol/L or >1.5 ng/mL, respectively). MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate (OPR) per started cycle. RESULT(S): The incidence of elevated P was 13.3%. A non-statistically-significant difference in OPR was present between the normal and elevated P groups (27.0% vs. 19.0%). No differential impact of early or late GnRH antagonist initiation on the effect of elevated or normal P on OPR was observed. A systematic search of Medline and EMBASE from 1972-2013 was performed to identify studies analyzing elevated early P levels in GnRH antagonists. The meta-analysis (n=1,052) demonstrated that elevated P levels statistically significantly decreased the OPR with 15% (95% CI -23, -7 %). Heterogeneity across the studies, presumably based on varying protocols, may have modulated the effect of elevated P. CONCLUSION(S): From the present meta-analysis it appears that early elevated P levels are associated with a lower OPR in GnRH antagonists. The incidence of such a condition, however, is low. CLINICAL TRIAL REGISTRATION NUMBER: NCT00866034.

Objective: To investigate relations between dose of GnRH antagonist and follicular phase characteristics. Design: Randomized controlled multicenter trial. Setting: Tertiary referral fertility centers. Patient(s): Three hundred and twenty-nine IVF patients. Intervention(s): Ovarian stimulation for IVF with recombinant FSH starting on cycle day 2. From cycle day 7 onwards, cotreatment was provided with 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0 mg/d GnRH antagonist. Main Outcome Measure(s): Number of follicles, total follicular surface area, gonadotropin, and serum steroid concentrations. Result(s): In 311 patients, similar follicular growth was observed in all treatment groups. FSH levels increased during the follicular phase. Late follicular phase LH, androstenedione (AD), and E 2 levels showed a GnRH antagonist dose-related decrease ( P 2 levels correlated with total follicular surface area, AD, LH, and FSH (all P 2 levels. Conclusion(s): Follicular growth was unaffected by the dose of GnRH antagonist. A rise in follicular phase FSH serum concentrations during the follicular phase, largely related to exogenous FSH, enabled ongoing follicular growth in all treatment groups. The effect of GnRH antagonist on late follicular phase E 2 levels could not be exclusively attributed to suppression of LH.

Objective: To evaluate implantation and pregnancy rates in patients undergoing IVF after the transfer of a maximum of two embryos that had been cultured for 3–5 days. Design: Prospective study. Setting: An IVF laboratory at a tertiary referral university hospital. Patient(s): One thousand seven hundred eighty-seven couples who underwent their first IVF cycle between January 1995 and December 1997. Intervention(s): In vitro fertilization and transfer of embryos after 3, 4, or 5 days of culture using a single medium without coculture. Main Outcome Measure(s): Implantation and pregnancy rates. Result(s): Overall implantation and pregnancy rates were not significantly different with different culture periods. Forty-one percent of all available embryos developed into blastocysts on day 5. The transfer of at least one good-quality blastocyst could be performed in 62% of patients. Blastocysts had an implantation rate of 26% per embryo, whereas the implantation rate of eight-cell embryos on day 3 was 18%. Implantation rates for retarded, normal, and advanced embryos were not significantly different with an extended culture period. Conclusion(s): Under the study conditions, the transfer of embryos after 5 days rather than 3 days of embryo culture did not change the overall implantation and pregnancy rates. The implantation potential of embryos available for transfer can be assessed better after an extended culture period. Five days of culture allows the transfer of a reduced number of embryos without decreasing overall pregnancy rates.

Objective: To evaluate the influence of oral contraceptive pills (OCPs) on anthromorphometric, endocrine, and metabolic parameters in women with polycystic ovary syndrome (PCOS). Design: Retrospective cross-sectional cohort study for the period 1993-2011. Setting: Tertiary university hospital. Patient(s): PCOS patients, who never, ever, or at time of screening were using OCPs were included. A total of 1,297 patients, of whom 827 were white, were included. All PCOS patients diagnosed according to the Rotterdam 2003 consensus criteria were divided into three groups: current users, (n = 76; 6% of total), ever users (n = 1,018; 78%), and never users (n = 203; 16%). Ever users were subdivided based on the OCP-free interval. Intervention(s): None. Main Outcome Measure(s): Anthromorphometric (blood pressure, cycle duration) and ultrasound (follicle count, mean ovarian volume) parameters, endocrine (SHBG, testosterone, free androgen index, antimullerian hormone [AMH]) and lipid profiles. Result(s): Current users and ever users were compared with never users. In current users, SHBG was increased and androgen levels decreased. Patients with an OCP-free interval of < 1 year had a higher mean follicle count, higher AMH level, and increased serum androgen level compared with never users. SHBG levels remained increased until 5-10 years after cessation of OCP use. Conclusion(s): OCP use causes a milder phenotypic presentation of PCOS regarding hyperandrogenism. However, it does not alter parameters associated with increased health risks. (C) 2014 by American Society for Reproductive Medicine.

Objective To study ovarian stimulation and response patterns during a gonadotropin step-down dose regimen for induction of ovulation by applying a decremental dose regimen in polycystic ovary syndrome (PCOS) patients. Design The present prospective study involves 28 infertile clomiphene citrate-resistant PCOS patients during gonadotropin-induced cycles using a modified step-down dose regimen (and adjuvant GnRH agonist medication). Applied gonadotropin doses included initial daily doses of 150IU IM followed by two reducing steps (37.5IU each) based on sonographic criteria to a final daily dose of 75IU IM. Setting Anovulatory infertile women in an academic referral center. Intervention Daily blood withdrawal and transvaginal pelvic ultrasound. Main Outcome Measures Serum FSH and E 2 concentration and follicle growth were investigated daily during gonadotropin administration. Results An initial 2.1-fold increase in serum FSH levels was observed followed by a subsequent decrease of 10% (median) per day for 4 days. Growth of ovarian follicles was sustained and ovulation achieved (midluteal P, 11.7 ± 1.3 ng/mL; conversion factor to SI unit, 3.180; mean ± SD) in 22 patients. Major variability in day 3 E 2 increase (range, 67 to 866 pg/mL; conversion factor to SI unit, 3.671)—not related to differences in FSH serum concentrations and without changes in follicle number and size—suggests differences in ovarian sensitivity for FSH stimulation. A strong correlation ( r = 0.82) was found between day 3 E 2 increase and the chance of ovulation. Moreover, E 2 levels on the day of gonadotropin dose reduction predict ( r = 0.68) chances of late follicular phase E 2 levels exceeding 871 pg/mL (conversion factor to SI value, 3.671). Conclusions These findings provide the endocrine basis for the concept of gonadotropin induction of ovulation using a step-down dose regimen. Initial E 2 increase (before initiation of follicle growth) represent differences in ovarian sensitivity to gonadotropins and predict treatment outcome.

Objective To study the relationship between decreasing serum FSH levels in the follicular phase of the normal menstrual cycle and follicle development by means of transvaginal sonography and E 2 production. Design Daily blood samples were taken and transvaginal sonography was performed every other day in 16 normal regularly cycling female volunteers. Main Outcome Measure Serum levels of FSH, LH, E 2 , and P and follicle diameter by transvaginal sonography. Results A distinct variability in individual maximal early follicular phase FSH plasma levels was observed (range 4.4 to 11.2 mIU/mL [conversion factor to SI unit, 1.000]). Differences in maximum FSH levels did not correlate with other endocrine or sonographic follicular phase characteristics. The follicular phase FSH decrease (from median 6.6 to 2.9 mIU/mL [conversion factor to SI unit, 1.000]) took place between cycle day 5 and 13 and was linear (0.5 ± 0.05 mIU/mL per day; mean ± SD). A significant correlation was found between serum FSH decrease and E 2 increase. The day of sonographic appearance of a dominant follicle (median cycle day 8) did correlate with the first rise of the E 2 plasma concentration. Conclusions The present study suggests that even in women exhibiting normal ovarian function a 2.5-fold difference in FSH threshold concentrations for follicle recruitment does occur. Moreover, the magnitude of decrease in serum FSH concentrations during the follicular phase affects dominant follicle E 2 production. The sonographic appearance of the dominant follicle is associated with a rise in serum E 2 levels.

Objective To investigate the efficacy and safety of repeated 12-week courses of 5 or 10 mg daily ulipristal acetate for intermittent treatment of symptomatic uterine fibroids. Design Double-blind, randomized administration of four 12-week courses of ulipristal acetate. Setting Gynecology centers. Patient(s) Four hundred fifty-one subjects with symptomatic uterine fibroid(s) and heavy menstrual bleeding. Intervention(s) Four repeated 12-week treatment courses of daily 5 or 10 mg ulipristal acetate. Main Outcome Measure(s) Endometrial safety and general safety, laboratory parameters, amenorrhea, controlled bleeding, fibroid volume, quality of life (QoL), and pain. Result(s) Efficacy results, such as bleeding control and fibroid volume reduction, were in line with previously published data. Pain and QoL showed marked improvements from screening, even during the off-treatment intervals. The safety profile of ulipristal acetate was confirmed, and repeated treatment courses did not increase the occurrence of adverse reactions. There were no significant changes in laboratory parameters during the study. The percentage of subjects with endometrial thickness ≥16 mm was 7.4% (all subjects) after the first treatment course and returned to below screening levels (4.9%) in subsequent treatment courses. As in previous studies, ulipristal acetate did not increase the occurrence of endometrial features of concern. The frequency of nonphysiological changes did not increase with repeated treatment. They were observed in 17.8% and 13.3% of biopsies after treatment courses 2 and 4, respectively, and were reversible after treatment cessation. Conclusion(s) The results of this study demonstrate the efficacy and further support the safety profile of repeated intermittent treatment of symptomatic fibroids with ulipristal acetate. Clinical Trial Registration Number NCT01629563.

Objective To assess the prevalence of chronic endometritis and the impact on the fertility of asymptomatic patients indicated for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. Design In the context of a randomized controlled trial, a hysteroscopy-guided endometrial biopsy was obtained and histologically examined. The live birth rate (including spontaneous pregnancies) after initiation of IVF/ICSI treatment of patients diagnosed with chronic endometritis was compared with the live birth rate of a randomly selected matched control group of patients without endometritis. Setting Two tertiary infertility care units. Patient(s) A total of 678 asymptomatic infertile women with a normal transvaginal ultrasound (TVS) who underwent diagnostic hysteroscopy before a first IVF/ICSI treatment cycle. Intervention(s) Hysteroscopy guided endometrial biopsy. Main outcome measure(s) The prevalence of chronic endometritis and the live birth rate (including spontaneous pregnancies) within 3 years after initiation of the randomized controlled trial. Result(s) The prevalence of chronic endometritis in the 606 patients with an adequate biopsy was 2.8%. The cumulative live birth rate (including spontaneous pregnancies) did not significantly differ between patients with or without endometritis: 76% versus 54%. Also, the clinical pregnancy rate per embryo transfer was not significantly different (hazard ratio 1.456, 95% confidence interval 0.770-2.750). Conclusion(s) Chronic endometritis can be rarely diagnosed in a population of asymptomatic infertile patients with a normal TVS before a first IVF/ICSI treatment. Moreover, the reproductive outcome after initiation of IVF/ICSI was not found to be negatively affected by chronic endometritis. In conclusion, the clinical implication of chronic endometritis seems minimal.

Data presented in this study indicate that ovulation can be induced in patients with PCOS using a GnRH analogue combined with hMG in a decreasing dose regimen. Based on the observed decline in functional, medium sized follicles in the late follicular phase, it may be speculated that the risk of ovarian hyperstimulation during gonadotropin induction of ovulation in patients with PCOS can be reduced.

Objective To investigate the efficacy and safety of repeated 12-week courses of 5 or 10 mg daily of ulipristal acetate for intermittent treatment of symptomatic uterine fibroids. Design Double-blind, randomized administration of two 12-week courses of ulipristal acetate. Setting Gynecology centers. Patient(s) A total of 451 patients with symptomatic uterine fibroid(s) and heavy bleeding. Intervention(s) Two repeated 12-week treatment courses of daily 5 or 10 mg of ulipristal acetate. Main Outcome Measure(s) Amenorrhea, controlled bleeding, fibroid volume, quality of life (QoL), pain. Result(s) In the 5- and 10-mg treatment groups (62% and 73% of patients, respectively) achieved amenorrhea during both treatment courses. Proportions of patients achieving controlled bleeding during two treatment courses were >80%. Menstruation resumed after each treatment course and was diminished compared with baseline. After the second treatment course, median reductions from baseline in fibroid volume were 54% and 58% for the patients receiving 5-and 10 mg of ulipristal acetate, respectively. Pain and QoL improved in both groups. Ulipristal acetate was well tolerated with less than 5% of patients discontinuing treatment due to adverse events. Conclusion(s) Repeated 12-week courses of daily oral ulipristal acetate (5-and 10 mg) effectively control bleeding and pain, reduce fibroid volume, and restore QoL in patients with symptomatic fibroids. Clinical Trial Registration Number NCT01629563 (PEARL IV).

OBJECTIVE: To validate a published model for the prediction of the individual FSH response dose for gonadotropin induction of ovulation in polycystic ovary syndrome (PCOS). DESIGN: Structured, complete, and carefully monitored patient-based data collection to test the external validity of the prediction model. SETTING: Twenty-nine hospitals in The Netherlands. PATIENT(S): Eighty-five clomiphene citrate (CC)-resistant women with PCOS. INTERVENTION(S): Ovulation induction in a chronic low-dose step-up FSH regimen. MAIN OUTCOME MEASURE(S): Predicted individual FSH response dose, defined as follicle growth >10 mm in diameter on ultrasound. RESULT(S): The model, using the women's body mass index, CC response, initial serum FSH level, and initial serum insulin-to-glucose ratio was studied in the validation sample. Overall, the FSH response dose predicted by the model was higher than the observed response dose. The predictive performance of the model was poor, with an R(2) of 0.11, and the average prediction error was 35 IU. CONCLUSION(S): The external validity of the model predicting the individual FSH response dose was inadequate in women with CC-resistant PCOS undergoing ovulation induction with recombinant FSH in a low-dose step-up regimen

This Views and Reviews series concerning future developments in in vitro fertilization will highlight various aspects of in vitro fertilization from the global perspective.

The use of GnRH antagonist rather than agonist cotreatment during ovarian hyperstimulation for IVF is not widely accepted. Possible benefits, current shortcomings, and avenues for future development are discussed.

Objective: To investigate whether follicular phase characteristics associated with ovarian aging can be observed in women of normal reproductive age, who had previously shown a poor response to ovarian hyperstimulation for IVF. Design: Observational, prospective study. Setting: Tertiary fertility center. Patient(s): Eleven regularly cycling, ovulatory women, aged 29–40 years who previously presented with fewer than four dominant follicles after ovarian hyperstimulation for IVF. Intervention(s): Frequent serum hormone assessments and transvaginal ultrasound during the follicular phase of a spontaneous, unstimulated cycle. Main Outcome Measure(s): Duration of the follicular phase; serum LH, FSH, E 2 , P, inhibin A, and inhibin B levels; and number of antral follicles observed by ultrasound. Results were compared with the cycle characteristics of a reference population of 38 healthy normo-ovulatory women aged 20–36 years (as published elsewhere). Result(s): Poor responders had significantly fewer antral follicles than controls. Median FSH concentrations were significantly higher compared with controls, but the majority had FSH levels within the normal range. Follicular phase P levels were significantly higher in poor responders. Duration of the follicular phase, E 2 , and inhibin A and inhibin B serum levels did not differ between poor responders and controls. Conclusion(s): Normo-ovulatory regularly cycling women with a previous poor response to ovarian hyperstimulation for IVF show follicular phase characteristics suggestive of ovarian aging.

Objective: To study the cardiometabolic profile characteristics and compare the prevalence of cardiovascular (CV) risk factors between women with different polycystic ovary syndrome (PCOS) phenotypes. Design: A cross-sectional multicenter study analyzing 2,288 well phenotyped women with PCOS. Setting: Specialized reproductive outpatient clinic. Patient(s): Women of reproductive age (18-45 years) diagnosed with PCOS. Intervention(s): Women suspected of oligo- or anovulation underwent a standardized screening consisting of a systematic medical and reproductive history taking, anthropometric measurements, and transvaginal ultrasonography followed by an extensive endocrinologic/metabolic evaluation. Main Outcome Measure(s): Differences in cardiometabolic profile characteristics and CV risk factor prevalence between women with different PCOS phenotypes, i.e., obesity/overweight, hypertension, insulin resistance, dyslipidemia, and metabolic syndrome. Result(s): Women with hyperandrogenic PCOS (n = 1,219; 53.3% of total) presented with a worse cardiometabolic profile and a higher prevalence of CV risk factors, such as obesity and overweight, insulin resistance, and metabolic syndrome, compared with women with nonhyperandrogenic PCOS. In women with nonhyperandrogenic PCOS overweight/obesity (28.5%) and dyslipidemia (low-density lipoprotein cholesterol >= 3.0 mmol/L; 52.2%) were highly prevalent. Conclusion(s): Women with hyperandrogenic PCOS have a worse cardiometabolic profile and higher prevalence of CV risk factors compared with women with nonhyperandrogenic PCOS. However, all women with PCOS should be screened for the presence of CV risk factors, since the frequently found derangements at a young age imply an elevated risk for the development of CV disease later in life. ((C)2014 by American Society for Reproductive Medicine.)

Objective: To study whether minimal interference in the process of selection of the single dominant follicle may serve as the basis for a simplified ovarian stimulation regimen for IVF. Design: Single-center randomized pilot study. Setting: Tertiary referral fertility center. Patient(s): Fifteen normo-ovulatory patients with a regular indication for IVF. Intervention(s): Ovarian stimulation for IVF was begun with 100 or 150 IU/d recombinant FSH starting on cycle day 5. From cycle day 8 or later, cotreatment was begun with 0.25 mg/d GnRH antagonist. No luteal support was provided. Main Outcome Measure(s): Total number of dominant follicles and characteristics of the endocrine cycle. Result(s): Multiple follicle development occurred in five of eight patients in the 100-IU group and in all seven women in the 150-IU group. Follicular phase and luteal phase lengths were normal, but the endocrine profile was abnormal. Conclusion(s): A fixed daily dose of 150 IU recombinant FSH starting in the midfollicular phase resulted in ongoing growth of a restricted number of dominant follicles and sufficient oocytes retrieved to lead to ET. A marked reduction in the total amount of gonadotropins administered compared with standard treatment was achieved. Withholding luteal support did not exclude pregnancies.

Until recently, the only GnRH analogues available were GnRH agonists. Their range of indications is now well established and includes the suppression of gonadotropin-dependent disorders. The first antagonist analogue is now available in Europe (cetrorelix), and its use is thus far limited to the suppression of the LH surge in ovarian stimulation protocols for assisted reproductive techniques (IVF).

To study increases of serum FSH and gonadal response in gonadotropin-deficient men treated with recombinant FSH (Puregon; NV Organon, Oss, The Netherlands).An open, prospective, multiple rising dose study in which volunteers received single daily IM doses of recombinant FSH for 3 weeks. The dose administered was increased at weekly intervals: the first 7 days, 75 IU/d; the subsequent 7 days, 150 IU/d; and the last 7 days, 225 IU/d.Nine men suffering from isolated gonadotropin deficiency or panhypopituitarism.Immunoreactive FSH, LH, inhibin, T, and androstenedione.Serum immunoreactive FSH (median) rose in accordance with the recombinant FSH doses administered from 0.5 mIU/mL (range0.05 to 1.9 mIU/mL) at baseline to 4.3 mIU/mL (range 2.0 to 8.5 mIU/mL), 8.4 mIU/mL (range 4.9 to 17.8 mIU/mL), and 13.6 mIU/mL (5.6 to 28.4 mIU/mL) after 1, 2, and 3 weeks of medication, respectively. The elimination half-life of recombinant FSH was 48 +/- 5 hours (mean +/- SD), which was slightly longer than that reported after single dose administration of recombinant FSH (32 +/- 12 hours). The bioactivity of recombinant FSH was reflected by serum inhibin levels, which rose from 116 U/L (range 34 to 356 U/L) at baseline to 350 U/L (range 63 to 1,109 U/L) at day 22. However, serum FSH and inhibin levels did not correlate when compared after 1, 2, and 3 weeks of recombinant FSH administration. Serum immunoreactive LH, T, androstenedione, and E2 were 0.2 mIU/mL (range0.05 to 0.7 mIU/mL [conversion factor to SI unit, 1.0]), 58 ng/dL (range12 to 222 ng/dL [conversion factor to SI unit, 0.0347]), 14 ng/dL (range 6 to 115 ng/dL [conversion factor to SI unit, 0.0349]), and 14 pg/mL (range14 to 16 pg/mL [conversion factor to SI unit, 3.67]), respectively, at baseline and remained unchanged during the entire treatment period.These data indicate that recombinant FSH treatment increases serum FSH in a dose-proportional fashion, increases inhibin secretion, and lacks intrinsic LH activity.

Objective To determine whether ovarian polycystic changes estimated by transvaginal sonography correlate with clinical and endocrine findings associated with the polycystic ovarian syndrome. Design Prospective study. Setting Reproductive Endocrinology Unit in the Department of Obstetrics and Gynecology at a teaching hospital. Participants Ninety-five consecutive patients suffering from oligoamenorrhea entering an infertility treatment program. Interventions All women were examined by transvaginal sonography, assessed for body mass index and hirsutism. Blood withdrawal was performed for hormone estimates. Main Outcome Measures Ovarian follicle number, volume, and stroma echogenicity. Estimates of immunoreactive and bioactive luteinizing hormone (LH), testosterone (T), free T, insulin levels, and insulin resistance index were performed. Results Hirsutism was present in 63% of the patients and correlated with the number of follicles, ovarian volume, and stroma echogenicity. Follicle number, ovarian volume, and stroma echogenicity values were significantly correlated with immunoreactive LH, bioactive LH, and T levels. Both T and immunoreactive LH were independently correlated with ovarian structure sonography parameters. Insulin and insulin resistance correlated with ovarian volume and stroma echogenicity. Insulin resistance was of significant additional predictive value of ovarian volume and amount of stroma. Evaluating the predictive value of immunoreactive LH and T together in regard to all sonography parameters, only T levels were statistically significant predictors of increase in follicle number, ovarian volume, and stroma amount. Conclusions Although immunoreactive LH and bioactive LH correlated with all ovarian parameters, the effect of androgens on ovarian changes appeared to be independent from LH. This further substantiates the apparent cardinal role of androgens in the genesis of polycystic ovaries. Besides, transvaginal sonography assessment of ovaries is a valuable additional tool for the diagnosis of PCOS. In this regard, insulin resistance is of additional predictive value for ovarian volume and stroma echogenicity.

Objective: To assess safety, pharmacokinetic, and pharmacodynamic properties of recombinant human follicle-stimulating hormone (FSH; Org 32489, Organon International, Oss, the Netherlands) after a single intramuscular injection in the buttock. Design: In a prospective study, safety variables, serum FSH, luteinizing hormone, inhibin, estradiol (females only), and testosterone (males only) were evaluated up to a maximum of 11 days after injection of 300 IU recombinant FSH. Setting: Four specialist Reproductive Endocrinology and Infertility units. Volunteers: Fifteen men and women exhibiting all pituitary gonadotropin deficiency. Result(s): A single bolus of 300 IU recombinant FSH was well tolerated, and no drug-related adverse effects were noted. Comparison of before and after treatment safety variables, including serum antirecombinant FSH antibodies, showed no changes of clinical relevance. Analysis of serum FSH levels revealed comparable elimination half-lives of 44 ± 14 (mean ± SD) and 32 ± 12 hours in women and men volunteers, respectively. In contrast, peak FSH concentrations were significantly lower in women than in men volunteers (4.3 ± 1.7 versus 7.4 ± 2.8 IU/L), and the time required to reach peak levels of FSH was significantly longer in women than in men (27 ± 5 versus 14 ± 8 hours). The area under the serum level versus time curve tended to be smaller in women than in men volunteers (339 ± 105 versus 452 ± 183 IU/L × hours), but the difference did not reach statistical significance. Together these data suggest that recombinant FSH is absorbed from its intramuscular depot to a lower rate and extent in women than in men. In both sexes a relationship between serum FSH levels and body weight was apparent. During the experimental period, other hormones remained low at baseline levels or were only slightly increased. Conclusion(s): Our findings indicate that recombinant FSH is well tolerated and that it is absorbed from its intramuscular depot to a higher rate and extent in men than in women. After intramuscular administration, its half-life is in good agreement with that previously reported for natural FSH.

Objective: To report an in vitro fertilization (IVF) pregnancy in a patient with histologically confirmed chronic endometritis before the IVF treatment without prior antibiotherapy. Design: Case report. Setting: Academic reproductive medicine unit. Patient(s): A30-year-oldwoman with primary infertility due to mild oligoasthenoteratospermia of the male partner. Intervention(s): Diagnostic hysteroscopy and endometrial biopsy. Main Outcome Measure(s): Delivery after the first IVF. Result(s): Histologic examination of the endometrium revealed chronic endometritis. The patient delivered a healthy boy at 40 weeks' gestation after the first IVF treatment. Conclusion(s): Our findings suggest that the impact of chronic endometritis on infertility and IVF outcome should be further investigated in prospective randomized studies. (Fertil Steril (R) 2009;91:1293.e9-e11. (C) 2009 by American Society for Reproductive Medicine.)

Transvaginal ultrasound examinations were performed in seven normally cycling women to characterize growth of nondominant follicles in both ovaries. Mean follicle number showed little variation throughout the menstrual cycle with no differences between dominant and nondominant ovaries. Up to 11 follicles (greater than or equal to 2 mm) were observed in any one ovary. From observations of the first appearance of the dominant follicle (mean size 9.9 +/- 3.0 [SD] mm), selection was assumed to take place on cycle day 6.3 +/- 2.3. The diameter of nondominant follicles always remained less than 11 mm. Growth of small follicles was established in both dominant and nondominant ovaries up to the time of selection. The late follicular and luteal phases were characterized by a decrease in mean growth slopes of nondominant follicles in the dominant ovary only. These observations may provide in vivo evidence for the concept of intraovarian paracrine mechanisms and may have implications for the sonographic diagnosis of anovulation and monitoring of ovulation induction.

Basal serum gonadotropin levels in 11 oligospermic men were significantly higher than in 9 euspermic control subjects, although most were still in the normal range. Basal serum testosterone (T), 17-hydroxyprogesterone (17-OHP), and estradiol levels and their ratios did not differ significantly. Continuous luteinizing hormone-releasing hormone (LH-RH) infusion (1 microgram/minute for 180 minutes) during integrated blood sampling evoked similar gonadotropin responses in both groups but had a differential effect on T: in the control subjects T increased (P less than 0.01) within 15 minutes to 1.5 times baseline, whereas in the oligospermic men T decreased (P less than 0.01). From 60 minutes on, however, T also significantly rose in the oligospermic men, but the maximum increment was about half lower (P less than 0.01) than in the euspermic men, despite virtually similar rises in 17-OHP. Only in the oligospermic men did the 17-OHP/T ratio increase (P less than 0.02) during LH-RH, which is compatible with the occurrence of a 17,20-lyase block. Serum estradiol did not increase in either group. In conclusion, continuous LH-RH infusion uncovers an intrinsic difference in acute Leydig cell stimulation between euspermic and oligospermic men.

Exogenous luteinizing hormone-releasing hormone (LH-RH) was intravenously administered as a single-bolus injection to 26 healthy normal men. LH-RH doses were selected at 1, 2.5, 5, and 20 micrograms for exploration of the optimum LH-RH dose to obtain adequate pituitary stimulation. Blood samples (for LH-RH and LH determinations) were collected at frequent intervals from 10 minutes before to 60 or 90 minutes after injection. LH-RH peak levels varied, in a dose-dependent way, between 119 +/- 16 and 517 +/- 70 ng/l. Peak values were all reached between 1 and 3 minutes after injection, and elimination occurred rapidly, with half-lives between 2.6 +/- 0.4 and 5.2 +/- 1.0 minutes. The area under the curves increased significantly (P less than 0.01) if the doses of LH-RH had been augmented from 1 to 20 micrograms. Maximum LH values were reached more rapidly in the low-dose (1 and 2.5 micrograms) experiments (between 13.5 and 16.3 minutes), with an obvious decline afterwards. The area under the LH curves increased (P less than 0.01) if the doses of LH-RH had been elevated from 1 to 2.5 micrograms, but no further increase of LH release occurred (P greater than or equal to 0.21) if LH-RH doses were further elevated from 2.5 to 20 micrograms. The current study demonstrates that a 2.5-micrograms intravenous LH-RH dose is best suited for an adequate pituitary stimulation in normal men.

Objective: To assess the effects of aging on the features of polycystic ovary syndrome (PCOS).Design: Retrospective longitudinal follow-up study.Setting: Tertiary care center.Patient(s): Patients with PCOS, diagnosed according to the 2003 Rotterdam criteria, who visited the outpatient clinic on consecutive occasions with a minimum interval of 6 months.Intervention(s): Comparisons were made between the first visit and the consecutive visit grouped by intervals.Main Outcome Measure(s): Changes in clinical and endocrine characteristics.Result(s): A total of 254 women visited the outpatient clinic on 2 occasions each. Consecutive visits were grouped into 0.5 to 3.9 years (n = 172; mean follow-up, 2.6 years) and 4.0 to 7.0 years (n = 82; mean follow-up, 5.5 years). At their second visit, significantly more women had regained a regular cycle. The total antral follicle count was similar. Serum levels of testosterone, androstenedione, and dehydroepiandrosterone sulfate had decreased significantly. Plasma glucose levels had increased, whereas serum insulin levels and homeostasis model assessment score had significantly decreased.Conclusion(s): The PCOS phenotype changed with aging, suggesting an amelioration of the phenotype and ovarian dysfunction as indicated by the increase in number of regular menstrual cycles, decrease in serum androgen levels, and decrease in insulin resistance. (Fertil Steril (R) 2011; 96: 1259-65. (C) 2011 by American Society for Reproductive Medicine.)

Serum levels of luteinizing hormone-releasing hormone (LH-RH), LH, and follicle-stimulating hormone (FSH) were measured for 60 minutes after 5- and 20-micrograms bolus doses of LH-RH given either intravenously or subcutaneously to 20 healthy men, for the study of LH-RH pharmacokinetics and the corresponding pituitary gonadotropin release. Intravenous (5- and 20-micrograms) LH-RH administration revealed much sharper LH-RH pulses, with significantly higher levels between 1 and 5 minutes (P less than 0.001) but lower levels between 30 and 60 minutes (P less than 0.05), compared with the subcutaneous route. No statistically significant differences were observed in the magnitude and time occurrence of maximum LH release or in the area under the LH response curves between intravenous and subcutaneous LH-RH administration, either in the 5-micrograms or in the 20-micrograms group. FSH responses were small and insignificant in all the performed tests. The intravenous route of administration seems preferential in therapeutic regimens that use pulsatile exogenous LH-RH, because the conditions of intermittent pituitary stimulation are more adequately fulfilled and the risk of dose accumulation is reduced. Furthermore, LH-RH doses of 5 micrograms are capable of producing adequate pituitary LH release, whereas increases in the pulse dose up to 20 micrograms seem to have no additional effects.

In 22 potentially fertile men, pituitary gonadotropin secretion was investigated by intravenous luteinizing hormone-releasing hormone (LH-RH) administration. LH-RH was administered continuously (1 microgram/minute) and in a pulsatile fashion (20 micrograms at 20-minute intervals, 20 micrograms at 60-minute intervals, and 60 micrograms at 60-minute intervals), for 3 hours, under standardized conditions. Blood was collected continuously by means of an integrated sampling technique. The mean serum luteinizing hormone (LH) concentration after any type of pulsatile administration rose significantly more than after continuous LH-RH administration. The mean increase in LH after pulsatile LH-RH administration with a 60-micrograms dose and 60-minute intervals was significantly greater than after pulsatile administration with a 20-micrograms dose and 20- or 60-minute intervals. No differences were observed in follicle-stimulating hormone responses after any type of LH-RH administration. These data confirm the existence of a self-priming effect for LH in the men; and maximum pituitary stimulation, within the dosage range tested, is reached after pulsatile LH-RH stimulation with an interval of 60 minutes.