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The Androgen Excess and Polycystic Ovary Syndrome Society (AEPCOS) has recommended an updated threshold for polycystic ovarian morphology (PCOM) of 25 follicles or more, 10 ml or more of ovarian volume, or both. We describe the effect of these guidelines on reproductive and metabolic characteristics in 404 women. These women were separated into four groups: group A: hyperandrogenism and oligo-amenorrhoea (n = 157); group B: hyperandrogenism or oligo-amenorrhoea and PCOM meeting AEPCOS 2014 criteria (n = 125); group C: hyperandrogenism or oligo-amenorrhoea and PCOM meeting Rotterdam 2003 but not AEPCOS 2014 criteria (n = 72); and group D: non-PCOS not meeting either criteria (n = 50). Groups B, C and D did not differ across any metabolic markers. The AEPCOS 2014 guidelines may have limited utility in distinguishing metabolic risk factors and result in the exclusion of a large group of oligo-anovulatory women., (Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objectives: Combined oral contraceptives (COCs) decrease testosterone (T) levels. This study investigated restoration of T and other androgen concentrations during COC use by 'co-administration' of dehydroepiandrosterone (DHEA)., Study Design: In this randomized, double-blind, placebo-controlled study in 99 new COC starters (18-35 years old with body mass index range 18-34 kg/m²), a COC containing 30mcg ethinylestradiol (EE) and 3 mg drospirenone (DRSP) was used for 3cycles, followed by 6cycles of the same COC combined with either 50 mg/day DHEA or placebo. Total T, albumin, sex hormone-binding globulin (SHBG), DHEA-sulfate (DHEA-S), Δ4-androstenedione (AD), 3α-androstanediol glucuronide (ADG) and estradiol (E₂) were measured, whereas free T and the free T index (FTI) were calculated. Assessments took place at baseline (no COC use), after the run-in period (COC use alone) and during the treatment period (DHEA or placebo)., Results: During COC use alone, androgen levels decreased, especially total T by 62% and free T by 86%, and SHBG increased by 243%. Total T increased with DHEA compared to placebo (change from end of run-in period to end of treatment period -- 1.3±1.2 nmol/L vs. 0.0±0.4 nmol/L; p<.0001) -- and was restored to baseline levels. Free T and the FTI increased significantly (p<.0001), but the free T level was still 53% below baseline levels. DHEA-S, AD and ADG increased significantly to levels above baseline (p<.0001 for each). DHEA had no effect on SHBG, albumin and E₂., Conclusions: An EE/DRSP containing COC strongly suppressed endogenous androgen concentrations in all users. The addition of 50 mg DHEA to a COC regimen containing EE/DRSP restored total T to baseline levels, but free T levels were restored by only 47% as most of the T remains bound to SHBG., Implications: When using a COC that increases SHBG considerably, a daily dose of 50 mg DHEA is insufficient to normalize free T levels completely., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Combined oral contraceptives (COCs) decrease androgen levels, including testosterone (T), which may be associated with sexual dysfunction and mood complaints in some women. We have shown that 'co-administration' of dehydroepiandrosterone (DHEA) to a drospirenone (DRSP)-containing COC restored total T levels to baseline and free T levels by 47%. Here we describe the effects on sexual function, mood and quality of life of such an intervention., Study Design: This was a randomized, double-blind, placebo-controlled study in 99 healthy COC starters. A COC containing 30 mcg ethinylestradiol (EE) and 3 mg DRSP was used for three cycles, followed by six cycles of the same COC combined with 50 mg/day DHEA or placebo. Subjects completed the Moos Menstrual Distress Questionnaire (MDQ), the McCoy Female Sexuality Questionnaire and the short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Safety and tolerability, including effects on skin, were evaluated., Results: The addition of DHEA induced small but significant improvements compared to placebo in the MDQ score for autonomic reactions during the menstrual (-2.0 vs. 0.71; p=0.05) and the premenstrual phase (-3.1 vs. 2.9; p=0.01) and for behavior during the intermenstrual phase (-1.4 vs. 3.6; p=0.02). A significant difference was found in the MDQ score for arousal during the premenstrual phase in favor of placebo (-5.0 vs. 1.0; p=0.01). There were no statistically significant differences between groups for the MSFQ and Q-LES-Q scores. DHEA 'co-administration' resulted in an acceptable safety profile. DHEA negated the beneficial effect of the COC on acne according to the subjects' self-assessment., Conclusions: 'Co-administration' with DHEA did not result in consistent improvements in sexual function, mood and quality of life indicators in women taking EE/DRSP. Retrospectively, the 50 mg dose of DHEA may be too low for this COC., Implications: A well-balanced judgment of the clinical consequences of normalizing androgens during COC use may require complete normalization of free T., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The Sixth Evian Annual Reproduction (EVAR) Workshop Group Meeting was held to evaluate the impact of IVF/intracytoplasmic sperm injection on the health of assisted-conception children. Epidemiologists, reproductive endocrinologists, embryologists and geneticists presented data from published literature and ongoing research on the incidence of genetic and epigenetic abnormalities and congenital malformations in assisted-conception versus naturally conceived children to reach a consensus on the reasons for potential differences in outcomes between these two groups. IVF-conceived children have lower birthweights and higher peripheral fat, blood pressure and fasting glucose concentrations than controls. Growth, development and cognitive function in assisted-conception children are similar to controls. The absolute risk of imprinting disorders after assisted reproduction is less than 1%. A direct link between assisted reproduction and health-related outcomes in assisted-conception children could not be established. Women undergoing assisted reproduction are often older, increasing the chances of obtaining abnormal gametes that may cause deviations in outcomes between assisted-conception and naturally conceived children. However, after taking into account these factors, it is not clear to what extent poorer outcomes are due to the assisted reproduction procedures themselves. Large-scale, multicentre, prospective epidemiological studies are needed to investigate this further and to confirm long-term health consequences in assisted-conception children. Assisted reproduction treatment is a general term used to describe methods of achieving pregnancy by artificial means and includes IVF and sperm implantation. The effect of assisted reproduction treatment on the health of children born using these artificial methods is not fully understood. In April 2011, fertility research experts met to give presentations based on research in this area and to look carefully at the evidence for the effects of assisted reproduction treatment on children's health. The purpose of this review was to reach an agreement on whether there are differences in the health of assisted-conception children with naturally conceived children. The researchers discovered no increased risk in birth defects in assisted-conception children compared with naturally conceived children. They found that IVF-conceived children have lower birth weights and higher fat under the skin, higher blood pressure and higher fasting glucose concentrations than naturally conceived children; however, growth, development and cognitive function are similar between groups. A very low risk of disorders of genetic control was observed in assisted-conception children. Overall, there did not appear to be a direct link between assisted reproduction treatment and children's health. The researchers concluded that the cause of some differences in the health of children conceived using assisted reproduction treatment may be due to the age of the woman receiving treatment. Large-scale, research studies are needed to study the long-term health of children conceived using assisted reproduction treatment., (Copyright © 2013 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The current proof of principle study explores the possibility that a genetic single-nucleotide polymorphism (SNP) profile is associated with ovarian response to standardized stimulation for IVF using exogenous FSH. Such a pharmacogenomic approach could aid in rendering ovarian stimulation for IVF more tailored to the patient, potentially improving the delicate balance between efficacy, side effects and chances for complications. Genome-wide association (GWA) analysis using Illumina Human 610-Quad BeadChips was used in a homogeneous group of 102 healthy, Caucasian, regularly cycling, non-smoking women aged 38 years or less with a body mass index <30 kg/m² with a regular indication for IVF in a tertiary referral University Hospital. Genetic profiles were associated with the number of oocytes obtained. Ovarian response varied widely, ranging from cancellation (less than three follicles) to more than 20 oocytes. After correction for multiple testing, no SNPs were observed to be significantly correlated to ovarian response, embryo quality or pregnancy. Restricting the information to SNPs involved in granulosa cell function, cell cycle regulation or apoptosis also did not yield significant associations for ovarian response. A study in a larger cohort is warranted, aiming to further explore subtle genetic variants with greater power., (Copyright © 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Fertility preservation is a key component of cancer management in young people. The Fourth Evian Annual Reproduction Workshop Meeting was held in April 2009 to discuss cancer and fertility in young adults. Specialists in oncology, assisted reproduction, embryology and clinical genetics presented published data and ongoing research on cancer and fertility, with particular focus on strategies to preserve fertility. This report is based on the expert presentations and group discussions, supplemented with publications from literature searches and the authors' knowledge. Fertility preservation should be considered for all young people undergoing potentially gonadotoxic cancer treatment. A variety of options are required to facilitate safe and effective fertility preservation for individual patients. Sperm banking is a simple and low-cost intervention. Embryo cryopreservation is the only established method of female fertility preservation. Oocyte cryopreservation offers a useful option for women without a male partner. Emergency ovarian stimulation and cryopreservation of ovarian tissue (followed by tissue transplantation or in-vitro maturation of oocytes) are experimental techniques for women who require urgent cancer treatment. Further prospective studies are required to validate cryopreservation of oocytes and ovarian tissue, in-vitro maturation of oocytes and new vitrification techniques and to identify any long-term sequelae of slow freezing of embryos., (Copyright © 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Polycystic ovary syndrome (PCOS) is strongly associated with metabolic abnormalities in Western women. However, data from other populations and geographical regions are scarce. This study evaluated cardiovascular and metabolic risk factors in Chinese infertile women diagnosed with PCOS using the 2003 Rotterdam consensus criteria. A total of 615 women representing the four PCOS phenotypes (oligo- or anovulation (AO)+hyperandrogenism (HA)+polycystic ovaries (PCO), AO+HA, AO+PCO and HA+PCO) underwent standardized metabolic screening including a 75g oral glucose tolerance test. All groups presented with similar reproductive characteristics, with the only difference being a significantly higher Ferriman-Gallwey score for hirsutism (P=0.01) in the subgroup characterized by HA+PCO. Overall, the prevalence of metabolic syndrome was 6.4%, with no difference among the four groups (range of 2.3-12.2%). Metabolic syndrome was associated with body mass index (P<0.001), waist/hip ratio (P=0.002), index of insulin resistance (P=0.005) and fasting insulin (P=0.009) in multivariate analysis. Compared with Caucasians and Chinese women in Westernized societies, mainland Chinese women with PCOS have a low risk of metabolic syndrome and its presence does not vary across the specific PCOS phenotypes., (Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.)

Investigation of human embryo implantation requires a non-disruptive means of studying the endometrium during the window of implantation. This study describes a novel approach of cytokine profiling in endometrial secretions. Endometrial secretions aspirated prior to embryo transfer from 210 women undergoing IVF or intracytoplasmic sperm injection were analysed by a multiplex immunoassay. Ten mediators [interleukin (IL)-1beta, IL-6, IL-12, IL-18, tumour necrosis factor-alpha, macrophage migration inhibitory factor, eotaxin, monocyte chemotactic protein-1, interferon-gamma inducible protein-10, vascular endothelial growth factor] were detectable in 90-100% of the samples. Heparin-binding epidermal growth factor, IL-5, IL-17, IL-10, Dickkopf homologue-1 and IL-15 were detected in 23-76%, whereas interferon-gamma was not detectable in any of the samples. To assess possible contamination of samples, cervical mucus was also aspirated for comparative analysis in 22 women. The endometrial cytokine profile differed significantly from cervical mucus. Pregnancy rates of the study participants who underwent endometrial secretion aspiration were compared with 210 controls matched for important prognostic variables; no significant differences were found. In conclusion, cytokine profiling in endometrial secretion offers an objective, non-disruptive means of analysing the in-vivo milieu encountered by the embryo and offers a new and potentially valuable approach to studying the endometrial factor in human embryo implantation.

The objective of this study was to investigate the effect of ovarian stimulation for IVF on endometrial secretion and tissue markers of receptivity in the mid-luteal phase. In 10 oocyte donors, endometrial secretions and biopsies were sampled 5 days after spontaneous ovulation and oocyte retrieval in consecutive cycles. Four subjects received progesterone in the luteal phase of the stimulated cycles. Mid-luteal endometrial maturation in the stimulated cycle was compared with the spontaneous cycle, by histological dating, Ki-67, oestrogen receptor (ER) and progesterone receptor (PR) expression, secretion levels of leukaemia inhibitory factor (LIF), glycodelin A (GdA) and progesterone, and protein profile. No significant differences in histological markers, expression of Ki-67, PR, ER, secretion protein profiles or concentrations of LIF, GdA, or progesterone were observed when comparing natural with stimulated cycles. Progesterone supplementation of stimulated cycles was associated with significantly lower Ki-67 (P = 0.03) and ER (P = 0.04) expression compared with the non-supplemented stimulated cycle. In this pilot study, ovarian stimulation was not demonstrated to alter the studied markers of endometrial maturation in the mid-luteal phase.

Serum anti-Müllerian hormone (AMH) concentrations decline with increasing age and constitute a sensitive marker for ovarian ageing. In addition, basal serum AMH concentrations predict ovarian response during IVF cycles. Concomitantly, oocyte quantity and embryo quality decrease with advancing age. Hence, it was postulated that AMH in serum constitutes a marker for embryo quality. Women aged 37 years and younger with regular menstrual cycles, normal body mass index and partners with normal semen parameters were randomly assigned to either a standard or mild stimulation protocol for IVF treatment. Blood samples were drawn at cycle day 3 and at the day of human chorionic gonadotrophin administration. Embryo quality was assessed using embryo morphology score and preimplantation genetic screening. Serum AMH concentrations on cycle day 3 were correlated with the number of oocytes retrieved in both groups. AMH and embryo morphology were correlated after mild stimulation, but not after conventional ovarian stimulation. AMH and the chromosomal competence of embryos were not correlated. Serum AMH is predictive for ovarian response to stimulation. However, the lack of a consistent correlation with embryo morphology and embryo aneuploidy rate is not in favour of a direct relationship between oocyte quantity and embryo quality.

For women aged 41-43 years old, success rates in IVF are generally poor. This study aimed to assess cumulative live birth rate related to treatment costs over a maximum of three IVF cycles in selected women who were considered to still have adequate ovarian reserve. Fifty-five patients (38% of the total cohort, n = 144) were excluded from IVF treatment based on low antral follicle count (<5 follicles) and/or elevated basal FSH (>15 IU/l). Of those admitted, 66 (74%) actually started and completed a total of 125 IVF/intracytoplasmic sperm injection cycles. Treatment resulted in 10 live births (8% per cycle). Kaplan-Meier survival analysis revealed a realistic cumulative live birth rate after three cycles of 17%. The direct medical costs per live birth were calculated to be approximately 44,000 euro. These results show that selection towards favourable ovarian reserve status in the female age group 41-43 years yielded disappointing results in terms of cumulative live birth rates after IVF. In view of the costs raised per live birth, improvement of selection parameters for treatment in this age group is warranted.

Assisted reproductive technologies (ART) are now widely accepted as effective treatment for most causes of infertility. With improving success rates, attention has turned to the problem of multiple pregnancies, which are associated with a poor perinatal outcome, maternal complications and significant financial consequences. The challenge is to reduce multigestational pregnancies while maintaining good treatment outcomes. Methods to prevent multiple pregnancy include restrictive use of ART in couples with a good chance of spontaneous pregnancy, cautious use of gonadotrophins, and increased use of natural-cycle intra-uterine insemination and elective single embryo transfer in in-vitro fertilization and intracytoplasmic sperm injection. The aim of this article is to review the contribution of fertility treatment to multiple pregnancies and strategies for reducing multiples in ART.

Ovarian stimulation in IVF allows selection of embryos for transfer, but may have detrimental effects on oocyte and embryo quality and endometrial receptivity. This study investigated the optimal response to ovarian stimulation in terms of number of oocytes for achieving pregnancy in a first IVF cycle. Data from 7422 women who underwent their first IVF cycle for standard indications were analysed. All had been treated with exogenous gonadotrophins and gonadotrophin releasing hormone (GnRH) agonist co-treatment in a long down-regulation protocol between 1990 and 1995. Pregnancy rates in relation to the number of obtained oocytes were adjusted for age, fecundity, subfertility cause, gonadotrophin dosage, type of luteal support, and number of transferred embryos by multivariate analysis. Of the 7422 women who underwent oocyte retrieval, overall 85% had an embryo transfer and 24% conceived. The highest pregnancy rates per embryo transfer and per started cycle were observed when 13 oocytes were obtained (31 and 28%, respectively). This study supports the concept of an optimal range of oocytes obtained in response to ovarian stimulation for IVF, below and above which outcomes are compromised.

Cell transplantation is being discussed as a potential therapy for multiple disorders caused by loss or malfunction of single or at most a few cell types. These include diabetes, Parkinson's disease and myocardial infarction or cardiac failure. However, it is not yet clear whether cells from adult tissues ('adult stem cells') or embryos ('embryonic stem cells') will prove to be the most appropriate replacement cells; most likely, each disease will have its own preferred source. This study presents the background to this discussion and the current state of research in replacement of cardiac tissue, with focus on recent developments using human embryonic stem cells. It also describes a new human embryonic stem cell (HESC) line, NL-HESC1, the first to be derived in the Netherlands, and shows that it forms cardiac cells in a manner comparable with that of hES2 and hES3 cells grown in the same laboratory.

Previous studies suggest that administration of follitropin-beta with a pen device (Puregon Pen(R)) is more convenient, less painful and 16-18% more efficient. The aim of this study was to perform an economic evaluation of the administration of follitropin-beta by this pen device against follitropin-alpha by multidose and highly purified (HP) HMG by conventional syringe in IVF treatment by comparing the process utilities and the costs for the Dutch setting. Conjoint analysis assessed the process utilities for the three administration modes on a scale from 0 to 1. A decision analytic model estimated the costs of an average IVF cycle from a societal perspective. Patients estimated the process utility at 0.96 for the pen, 0.53 for the multidose and 0.36 for the conventional syringe. Additional costs were estimated at 0 Euros and 194 Euros, comparing the pen with multidose or conventional methods respectively. Assuming a 16% efficiency gain of the pen, costs ranged from Euros-135 (savings) to 60 Euros (extra costs). In conclusion, patients perceive sufficient benefits to the pen device to choose it over other dosing methods. Dominance of the pen device over the multidose method was shown. Compared with the conventional administration method, the added value of the pen device was 2.7 (0.96/0.36) times higher.

For anovulatory women who fail to ovulate or conceive with clomiphene citrate, gonadotrophin ovulation induction has been the conventional second-line therapy. The aim of treatment is to achieve monofollicular development and ovulation. This differs fundamentally from the aim of ovarian stimulation for IVF, in which multiple follicular development is the goal. The small therapeutic window of ovulation induction requires a rigorous approach to monitoring, and willingness to cancel the cycle when multiple follicle development occurs. The two most widely used approaches are the low-dose step-up and the step-down protocols. While the latter more closely mimics the normo-ovulatory cycle, outcomes are similar. For safety reasons, the step-down protocol has not been widely adopted. The principle risks of ovulation induction are ovarian hyperstimulation syndrome and multiple pregnancy. There is a need to individualize treatment if outcomes are to be optimized. The role of adjuvant therapies remains unclear. However, prediction models based on initial screening parameters enable the optimal dose of FSH to be determined, and the identification of patients with a poor prognosis for successful treatment.

Analysis of protein patterns in endometrial secretion fluid may offer a relatively non-invasive means of assessing endometrial receptivity during fertility treatment cycles. In order to study the impact of the removal of endometrial secretions on embryo implantation, a prospective matched controlled study was performed. In 66 women undergoing IVF, endometrial fluid was obtained transcervically by aspiration just prior to embryo transfer (study group). Biochemical and ongoing pregnancy rates were compared with 66 control patients matched for stimulation treatment protocol, age, number of collected oocytes and number of high quality embryos. The protein content and uterine fluid protein profile in each sample was determined. Respective biochemical and ongoing pregnancy rates per embryo transfer were 36 and 33% in patients who underwent aspiration of endometrial secretion, compared with 33 and 30% respectively in matched control patients (P = 0.84 and P = 0.85). The protein content in endometrial fluid was sufficient for protein pattern analysis. Uterine fluid aspiration prior to IVF embryo transfer is a safe method for obtaining sufficient material for uterine secretion electrophoresis, thus allowing analysis of protein patterns serving as receptivity markers during treatment cycles. This technique may offer a novel tool for assessing endometrial receptivity during treatment cycles without affecting implantation rates.

Contribution of LH to ovarian stimulation, distinguishing treatment of anovulation and ovarian stimulation with the objective of IVF. LH and ovarian dysfunction LH furnishes the androgen substrate necessary for FSH for estrogen synthesis, but excess LH is a less reliable index than free androgen level to predict the absence of response to ovarian stimulation. LH and ovarian stimulation

The contemporary approach to ovarian stimulation for IVF treatment results in supraphysiological concentrations of steroids during the follicular and luteal phases of the menstrual cycle. These sex steroids act directly and indirectly to mature the endometrium, influencing receptivity for implantation. Corpus luteum function is distinctly abnormal in IVF cycles, and therefore luteal support is widely used. Various reasons may underlie the defective luteal phase, including (i) ovarian hyperstimulation per se, (ii) gonadotrophin-releasing hormone (GnRH) analogue co-treatment and (iii) the use of human chorionic gonadotrophin (HCG) to induce final oocyte maturation. The recent introduction of GnRH antagonist co-treatment for the prevention of a premature LH rise during the late follicular phase allows for different approaches to ovarian stimulation for IVF. However, a recent meta-analysis showed that implantation rates may be compromised by using GnRH antagonists in currently employed regimens. The development of endometrium receptive to embryo implantation is a complex process and may be altered by inappropriate exposure to sex steroids in terms of timing, duration and magnitude. New approaches to the assessment of endometrial receptivity are now required. Novel approaches to ovarian stimulation aimed at adjusted GnRH antagonist regimens and achieving a more physiological luteal phase endocrinology are now appearing in the literature and may represent an important step in the improvement of the overall health economics of IVF.

It is uncertain whether patients who do not ovulate but fail to conceive following CC therapy behave differently during gonadotropin therapy. However, if the infertile patient with PCOS is resistant to anti-estrogen therapy, gonatropin treatment administered through low dose protocols should be considered. As compared to conventional regimens, complication rates are reduced despite similar efficacy. It should be recognized that patients with PCOS constitute a very heterogeneous group. Therapy outcome may benefit from improved classification. The identification of clinical characteristics that identify those women with anovulation who are unlikely to respond to clomiphene would permit earlier use of gonadotropin therapy and potentially offer major health and economic benefits. Furthermore, if ovarian responsiveness to ovulation-induction therapy could be predicted for an individual patient, it might be possible to devise regimens that reduced the risk of ovarian hyperstimulation and multiple pregnancy.

This study was performed to evaluate pituitary-ovarian recovery in the pill-free interval during use of three low-dose combined oral contraceptives (COC). Either the estrogen component or the progestin component was comparable in the study groups, to evaluate their relative influence. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) levels were measured and follicle number and size estimated by transvaginal sonography daily during the 7-day pill-free interval in 44 healthy volunteers using three different low-dose oral contraceptives. Healthy volunteers were enrolled using 20 micrograms ethinyl estradiol (EE) + 75 micrograms gestodene (GSD) (Harmonet, Wyeth-Lederle; n = 15), 20 micrograms EE + 150 micrograms desogestrel (DSG) (Mercilon, Organon n = 17), or 30 micrograms EE + 150 micrograms DSG (Marvelon, Organon, n = 12) given according to the usual regimen of one tablet daily during 3 weeks and 1 week pill-free interval. No ovulations were observed. Pituitary hormones were not statistically significantly different at the beginning of the pill-free interval between the study groups. FSH concentrations were significantly higher at the end of the pill-free interval in the 30 micrograms EE group compared with both 20 micrograms EE groups (7.0 [0.6-12.4] IU/L vs 4.9 [1.4-6.1] IU/L and 4.5 [2.4-7.4] IU/L; p = 0.001). In both 20 micrograms EE groups, a single persistent follicle (24 and 28 mm) was present in one subject. Follicle diameters were statistically significantly smaller at the beginning and at the end of the pill-free period in the 30 micrograms EE group compared with both 20 micrograms EE study groups. Dominant follicles (defined as follicle diameter > or = 10 mm) were observed at the end of the pill-free interval in both 20 micrograms EE groups (in 27% and 18% of women, respectively) but not in the 30 micrograms EE group. Finally, the area-under-the-curve for E2 was statistically significantly lower in the 30 micrograms EE group compared with both 20 micrograms EE groups. In conclusion, the EE content rather than the progestin component in the studied COC determined the extent of residual ovarian activity at the beginning of the pill-free interval. Dominant follicles were encountered only in the 20 micrograms EE study groups.

The potential role of transforming growth factor-beta (TGF-beta) as an intragonadal regulator in the testis was investigated by studying the effect of TGF-beta on testosterone (T) production by neonatal rat testis cells in primary cultures. After 3 days of preincubation in serum-free medium, testis cells were treated with hormones for 3 additional days. Human chorionic gonadotropin (hCG) treatment (0.3-30 ng/ml) of testis cells elicited a dose-dependent increase of T levels with maximum values greater than 9-fold over baseline. Although TGF-beta alone did not affect T levels, a dose-dependent inhibition of hCG-stimulated T production was observed when cells were cotreated with TGF-beta. Maximal inhibition was greater than 85%, and the IC50 value was 5 ng/ml (2 x 10(-10) M; n = 5 experiments). This inhibitory effect was evident 48 h after the initiation of treatment and could be reversed 1 day after the cessation of TGF-beta exposure of cells. TGF-beta also reduced forskolin and (Bu)2cAMP-induced T production (greater than 85% decrease), indicating that TGF-beta can inhibit steroidogenesis distal to the formation of cAMP. The conversion of exogenously added androgen precursors (progesterone (P) and 17 alpha-hydroxyprogesterone) to T by hCG-stimulated cells was suppressed by the addition of TGF-beta. In contrast, endogenous P accumulation did not change in cultures treated with TGF-beta. Because TGF-beta-like activity has been found in the testis, the observed inhibitory effect of TGF-beta suggests a potential intratesticular regulatory role of this growth factor.