Impact of gonadotropin type on progesterone elevation during ovarian stimulation in GnRH antagonist cycles.

STUDY QUESTION: Does hormonal stimulation with corifollitropin alpha (CFA) only, mimicking a step down protocol, result in lower incidence of progesterone elevation on the day of hCGtrigger as compared to sustained stimulation with recombinant FSH (rFSH)? SUMMARY ANSWER: The current findings support the concept that sustained FSH stimulus contributes to premature progesterone elevation in stimulated IVF cycles. WHAT IS KNOWN ALREADY: Serum progesterone rise during the follicular phase of ovarian stimulation for IVF treatment seems to be related to a poorer reproductive outcome. However, the mechanism by which the rise in progesterone is caused is not yet fully understood. STUDY DESIGN, SIZE, DURATION: This study was a post hoc analysis of data from two multi-center, randomized, double-blind, double-dummy, active-controlled, non-inferiority trials, ENGAGE and PURSUE, conducted from June 2006 to January 2008 and from July 2010 to October 2012 respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the ENGAGE-study, 1506 women, aged 18-36 years, were allocated to either a single injection of 150 mg CFA or daily injections of 200 IU rFSH in the first week of stimulation, using a standard GnRH antagonist protocol. In the PURSUE-study, a total of 1390 women, aged 35-42 years, were allocated to either a single injection of 150 mg of CFA or daily 300 IU of rFSH for the first week, again using a standard GnRH antagonist protocol. In both trials, daily rFSH was continued until three follicles reached >17 mm in size. All women had a body weight of between 50 and 90 kg, regular menstrual cycles and an indication for ovarian stimulation before IVF. The incidence of progesterone elevation on day of hCG-trigger in patients with CFA only or rFSH stimulation, and triggered on Day 8 of stimulation, was analyzed. MAIN RESULTS AND THE ROLE OF CHANCE: Of patients with CFA only stimulation, 5.4% (13/239 patients) showed a progesterone elevation above 1.5 ng/ml on day of hCG-trigger, whereas patients with rFSH stimulation had a significant higher incidence of progesterone elevation (18.3%; 62/339 patients) (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Post hoc analysis of data from previously published trials could be considered as a reason for caution. WIDER IMPLICATIONS OF THE FINDINGS: Future studies should evaluate whether it would be possible to prevent a premature progesterone rise in cycles stimulated with daily FSH by using a step down protocol towards the end of the follicular phase. STUDY FUNDING/COMPETING INTERESTS: Financial/Material Support was provided by Merck & Co., Inc., Kenilworth, NJ, USA. Davis Gates is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may own stock and/or hold stock options in the company. Fabiola Beligotti is an employee of MSD, Italy, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may own stock and/or hold stock options in the company. Barbara Lawrenz, Nils Engelmann and Human M. Fatemi have no conflict of interest. TRIAL REGISTRATION NUMBER: ENGAGE study: ClinicalTrials.gov identifier NTC00696800. PURSUE-study: NCT01144416.

Endothelin-1 stimulates deoxyribonucleic acid synthesis and contraction in testicular peritubular myoid cells.

In the testis, endothelin-1 (ET-1) is produced by Sertoli cells, and it has been proposed to be a paracrine factor participating in the regulation of tubular and interstitial function. The response of purified testicular peritubular myoid cells (TPMC) to ET-1 was investigated in the present study. TPMC expressed a single class of high-affinity receptors that were shown by competitive binding experiments with sarafotoxin-6c to belong to the ETA subtype. The binding of ET-1 to TPMC was followed by rapid internalization of the receptor-ligand complex. ET-1 induced a prompt rise in intracellular Ca2+ concentration that was blunted in Ca(2+)-free medium and in the presence of Mn2+ or of voltage-operated-calcium-channel (VOC) blockers, indicating that both Ca2+ mobilization from intracellular stores and extracellular Ca2+ influx were involved. Thymidine uptake was promoted by ET-1 in a time-dependent manner, and the use of cyclo[D-Asp-L-Pro-D-Val-L-Leu-D-Trp] (BQ123) reduced the incorporation of thymidine. Protein kinase C (PKC) inhibition (100 nM calphostin C) abolished the ET-1 mitogenic effect. ET-1 also promoted TPMC contraction, as evaluated in collagen lattices, in a dose-related manner, with the half-maximal response observed at 1 nM. As in the case of mitogenesis, BQ123 blunted ET-1-induced contraction. PKC inhibition abolished ET-1-induced contraction. These findings indicate that ET-1 promotes DNA synthesis and contraction of TPMC and that both effects are mediated by PKC; they suggest as well that ET-1 may have a physiological role in the interaction between Sertoli cells and TPMC.

[Alteration of luteinizing hormone pulsatility in patients with arterial hypertension]. / Alterazione della pulsatilità dell'ormone luteinizzante in pazienti affetti da ipertensione arteriosa.

The pattern of luteinizing hormone (LH) secretion in men with mild and moderate hypertension was studied. LH pulsatility was evaluated for eight hours in 14 male patients, who were subdivided into two groups: group A, consisting of 8 patients, whose systolic blood pressure ranged between 180-160 mmHg and the diastolic between 104-95 mmHg; group B, 6 patients whose systolic blood pressure ranged between 220 and 180 mmHg and the diastolic between 115-105 mmHg. Seven healthy adult males were evaluated as a control. The major changes of LH pulsatility in group A included an increased peak width (p < 0.05), increased peak amplitude (p < 0.001) and increased peak area (p < 0.001). In group B the changes followed the same pattern as in group A, but were more pronounced. The number of LH peaks was reduced (p < 0.01), the peak width was increased (p < 0.05), and both peak amplitude and peak area were increased as compared to the control group (p < 0.001). Our study demonstrates that the pattern of LH pulsatility is altered in essential hypertension and the main feature is represented by the prolonged duration of LH peaks and their greater amplitude. The altered pattern of LH secretion is likely to reflect a primary hypothalamic derangement with the gonadotropin releasing hormone (Gn-RH) secreting neurons remaining synchronized for longer times and secreting larger Gn-RH masses than in normal subjects.

Luteinizing hormone pulsatility and computer-assisted analysis of sperm features in patients with Hodgkin's disease.

The aim of this work was to characterize further the impairment of the reproductive function reported in untreated male patients with Hodgkin's disease. We evaluated the pattern of luteinizing hormone pulsatility and unconventional sperm features by computer-assisted sperm analysis (CASA) in 20 adult patients affected by biopsy-proven Hodgkin's disease before they were submitted to any therapeutic approach. Changes of luteinizing hormone pulsatility were documented and consisted mainly in an increase in pulse number in comparison with control subjects (P < 0.05). On CASA, 1/3 of the patients showed a reduction in the sperm number but, when motility, velocity and linearity of progression were evaluated, the number of patients with seminal alterations rose to 2/3. Sperm velocity and linearity were already impaired in stages I and II, whereas sperm number was reduced only in stage III. Symptomatic patients, regardless of the stage, showed a significant deterioration of all parameters. Our study supports the view that in Hodgkin's disease, before any treatment, a disorder of the reproductive system is present, both at hypothalamic/hypophysial and the gonadal level, having a pathogenesis that deserves to be elucidated by further study.

Human Sertoli cells in vitro: morphological features and androgen-binding protein secretion.

Sertoli cells play a pivotal role in the regulation of spermatogenesis as they provide the anatomical basis of the blood-testis barrier. In the present paper we report some results of our studies on the ultrastructural features, the responsiveness to FSH, and the ability to secrete androgen-binding protein (ABP) of human Sertoli cells in vitro. The nucleus showed the characteristic foldings of the nuclear membrane, scattered chromatin, and a fibrillar nucleolus. In the cytoplasm Charcot-Boettcher crystals were present and active phagocytic activity was documented by the presence of vacuoles containing lipids and cellular debris. Human Sertoli cells in culture responded to FSH with a maximal rise in cAMP that was approx. 3-fold. This response to FSH is comparable to that reported for the adult rat but lower than that of the immature rat, and suggests that human as well as rat Sertoli cells could have a reduced response to FSH since sexual maturation was achieved. As no evidence has been reported on ABP secretion by human Sertoli cells in culture we evaluated the concentration of this protein in the Sertoli cell spent media. Human Sertoli cells in culture produced ABP and the response to FSH was dose-related. The Kd value of human ABP (hABP) was approx. 7.5 nM, being slightly higher than that of the rat ABP and an order of magnitude different from that of sex hormone-binding globulin (SHBG) present in human plasma. We also measured the association and dissociation rates of dihydrotestosterone-hABP complexes and the Kd/Ka ratio was very close to the value of Kd of the Scatchard analysis. The differences between hABP and SHBG may open the way to the selective measurement of ABP in many conditions of male infertility.