Neuroendocrinology and ovarian aging

The ovarian aging, a dynamic process that precedes the clinical manifestations of menopause, can be assessed using ovarian reserve biomarkers. It is well-known that reproduction during the later years of reproductive life has known limitations that challenge the success of assisted reproduction. Therefore, a review of the neuroendocrine modifications during this critical period of reproductive life may help to elucidate the ovarian aging process and its impact on reproduction. In this review, we aim to further the discussion of neuroendocrine changes taking place during the ovarian aging process that may impact reproductive function. Copyright © 2012 Informa UK, Ltd

A single midcycle dose of levonorgestrel similar to emergency contraceptive does not alter the expression of the L-selectin ligand or molecular markers of endometrial receptivity

Objective: To examine the effects of a single-dose of 1.5 mg of levonorgestrel (commonly used as emergency contraceptive) on endometrial receptivity biomarkers through the oral or vaginal route. Design: Prospective randomized single-blinded trial. Setting: Affiliated Hospital and University Research Center. Patient(s): Fertile normal women previously sterilized by tubal ligation. Intervention(s): Levonorgestrel (1.5 mg) was administered on the day of LH surge either orally (n ¼ 14) or vaginally (n ¼ 13). Main Outcome Measure(s): Molecular assessment of endometrial progesterone receptors, L-selectin ligand, glicodelin-A and avb3 integrin by Immunohistochemistry and reverse transcriptase-polymerase chain reaction. Result(s): Plasma progesterone concentration and endometrial dating were not different. The pattern of progesterone receptors and glycodelin-A expression was not affected during the early and midsecretory phase. Some endometrial biopsies from the group in which levonorgetrel was orally administered showed areas of glandular atrophy and stromal decidualization. However, the expression of the progesterone receptor, L-selectin ligand, avb3 integrin, and glycodelin-A were not different between the groups. Conclusion(s): Levonorgestrel, given as emergency contraceptive on the day of LH surge, does not disrupt either ovulation or progesterone production by the corpus luteum. The contraceptive mechanism of levonorgestrel at the time of LH surge does not include changes in the progesterone receptors or the endometrial receptivity biomarkers.Chilean Research Council CONICYT-FONDAP 150160000; Programa latinoamericano de Investigacion en Salud Sexual y Reproductiva (PLISSER), Mexico 213-9

Effect of the aromatase inhibitor 4-hydroxyandrostene-3,17-dione progesterone synthesis by human luteal cells

The authors studied the effects of 4-hydroxyandrostene-3,17-dione (4-OHA) on progesterone (P), 17β-estradiol (E2), and 20α-hydroxy-4-pregnen-3-one synthesis and pregnenolone accumulation in cultured human midluteal cells. A dose-dependent inhibition with and without human chorionic gonadotropin (hCG) of E2 and P production was observed. The accumulation of pregnenolone was significantly enhanced three to fourfold by 4-OHA in this culture system, as compared with control values. In addition, a sevenfold increase on pregnenolone accumulation was observed in the presence of 4-OHA plus 10 IU of hCG as compared with control values and 2.2-fold as compared with the 4-OHA treatments. These in vitro findings indicate a direct effect of 4-OHA on luteal steroidogenesis. Nevertheless, the suppressive effect of 4-OHA on P and E2 production is located at different sites of the steroidogenic pathway. In addition, the results demonstrate that hCG in the presence of 4-OHA stimulated pregnenolone accu

The significance of estradiol metabolites in human corpus luteum physiology

The human corpus luteum (CL) is a temporary endocrine gland derived from the ovulated follicle. Its formation and limited lifespan is critical for steroid hormone production required to support menstrual cyclicity, endometrial receptivity for successful implantation, and the maintenance of early pregnancy. Endocrine and paracrine-autocrine molecular mechanisms associated with progesterone production throughout the luteal phase are critical for the development, maintenance, regression, and rescue by hCG which sustains CL function into early pregnancy. However, the signaling systems driving the regression of the primate corpus luteum in non conception cycles are not well understood. Recently, there has been interest in the functional roles of estradiol metabolites (EMs), mostly in estrogen-producing tissues. The human CL produces a number of EMs, and it has been postulated that the EMs acting via paracrine-autocrine pathways affect angiogenesis or LH-mediated events. The present review describes advances in understanding the role of EMs in the functional lifespan and regression of the human CL in non-conception cycles.CONICYT/FONDECYT, 1140693 / University of Chile, School of Medicine, Santiago, Chil

Progesterone synthesis by human luteal cells: Modulation by estradiol

To assess the role of estradiol (E2) upon progesterone (P4) synthesis, a well defined human midluteal cell system was used. A dose-dependent inhibition of P4 synthesis with and without hCG was induced by E2. In addition, E2 had a dose related cumulative effect on pregnenolone as compared with control experiments (2-fold, P < 0.05) as well as in hCG- stimulated conditions (3-fold, P < 0.005). On the other hand, the concentrations of 20α-hydroxyprogesterone obtained in all experimental conditions were similar to control values, indicating that the catabolism of P4 was not modified. 3β-Hydroxysteroid dehydrogenase activity was significantly diminished (P < 0.05) in the presence of E2. Finally, the kinetic studies on P4 synthesis from pregnenolone showed a competitive type of inhibition with a K1 of 2.22 x 10-6 mol/L. These data indicate an inhibition of 3β-hydroxysteroid dehydrogenase on human corpus luteum by E2

Human corpus luteum physiology and the luteal-phase dysfunction associated with ovarian stimulation

The human corpus luteum is a temporary endocrine gland that develops after ovulation from the ruptured follicle during the luteal phase. It is an important contributor of steroid hormones, particularly progesterone, and is critical for the maintenance of early pregnancy. Luteal-phase dysfunction can result in premature regression of the gland, with a subsequent shift to an infertile cycle. Understanding the mechanism of steroidogenesis during corpus luteum growth and regression is crucial for evaluating the normal physiology and pathophysiology of reproductive cycles. The rate-limiting step in corpus luteum steroidogenesis is the transport of cholesterol to the site of steroid production. Steroidogenic acute regulatory protein is a key player in this process and is positively correlated with progesterone concentrations troughout the early an dmid-luteal phase. Changes in the endocrine environment brought on by the gonadotrophins used for ovarian stimulation are thought to underlie th

Complement C3 and Decay-Accelerating Factor Expression Levels Are Modulated by Human Chorionic Gonadotropin in Endometrial Compartments During the Implantation Window

Artículo de publicación ISIThe control of complement activation in the embryo–maternal environment has been demonstrated to be critical for embryo survival. Complement proteins are expressed in the human endometrium; however, the modulation of this expression by embryo signals has not been explored. To assess the expression of complement proteins in response to human chorionic gonadotropin (hCG), we designed an experimental study using in vivo and in vitro models. Twelve fertile women were treated with hCG or left untreated during the mid-luteal phase, and an endometrial biopsy was performed 24 hours later. The localizations of C3, membrane cofactor protein (MCP; CD46), decay-accelerating factor (DAF; CD55), and protectin (CD59) were assessed by immunohistochemistry, and the messenger RNA (mRNA) levels of these proteins were quantified by real-time reverse transcriptase–polymerase chain reaction (RT-PCR) in cells harvested from endometrial compartments using laser capture microdissection. Endometrial explants were cultured with or without hCG for 24 hours, and the C3 and DAF protein levels were measured byWestern blotting. Elevated C3 mRNA levels in stromal cells and elevated DAF levels in epithelial luminal cells were detected after hCG treatment. In the endometrial explant model, the progesterone receptor antagonist RU486 inhibited the increases in the levels of C3 and DAF in response to hCG. The findings of this study indicate that hCG plays a role in embryo–endometrium communication and affects the expression of complement proteins in endometrial compartments during the implantation window

In vitro net progesterone production by human corpora lutea: Effects of human chorionic gonadotropin, dibutyryl adenosine 3′,5′-monophosphate, cholera toxin, and forskolin

Slices of human corpora lutea (CL) obtained at varying stages of the luteal phase from 21 women were used to study the effect of hCG on progesterone (P4) production. Slices obtained from mid- and late CL incubated with 10 IU/mL hCG exhibited a significant increase in net P4 production (P < 0.001), whereas slices from early CL did not. Mid-CL slices were the most sensitive to hCG (4.2-fold increase in P4 production compared to 1.2-fold for early CL and 2.7-fold for late CL). To investigate the unresponsiveness of early CL to hCG, [125I]hCG binding was studied. All early CL had LH/hCG-specific receptors, and the apparent Kd for this binding was 1.95 × 10−10 M. Dibutyryl cAMP (1 mM), cholera toxin (0.84 mM), and forskolin (50 μM) stimulated net P4 production (P < 0.05) in slices of early CL tissue incubated in the presence of methylisobutylxanthine (0.1 mM). Cholera toxin and forskolin stimulated cAMP formation by the early CL, but hCG failed to do so. These results confirm that hCG has

Assessment of diagnostic competence of plasmatic androgens on polycystic ovary syndrome based on receiver operator characteristic curves

Objective.This study was designed to assess the diagnostic potency of different androgens in hyperandrogenaemia criterion on polycystic ovary syndrome (PCOS) based on receiver operator characteristic (ROC) curves analysis. Methods.We evaluated 55 PCOS patients and 27 healthy fertile women (control). Androgen evaluation included bio-available testosterone (BAT) by ammonium sulphate precipitation, Free Testosterone Index (FTI), androstenedione (A), total testosterone and dehydroepiandrosterone sulphate (DHEA-S). Results.The androgen tests with the best diagnostic capacities were FTI and BAT. Although T and A had similar diagnostic potencies, A detected 5 of PCOS patients that could not be recognised by FTI, BAT (), or T. The association of FTI, BAT () and A identified 96.36 of the hyperandrogenaemic patients. DHEA-S showed a wide dispersion of values and therefore poor discriminatory competence. Discussion.This study suggests that routine androgen evaluation in PCOS should include FTI,

The acrosome reaction-inducing activity of individual human follicular fluid samples is highly variable and is related to the steroid content

In this study, we have evaluated the relationship between the acrosome reaction-inducing activity of individual human follicular fluid samples and their steroid content. Eighteen samples of follicular fluid were obtained during egg retrieval in six patients undergoing assisted fertilization. Motile spermatozoa were incubated in modified Tyrode's medium (26 mg/ml bovine serum albumin) for 20 h at 1 x 107 cells/ml. In a single experiment, aliquots of a semen specimen were simultaneously treated with an aliquot of each follicular fluid sample. The percentage of acrosome reacted spermatozoa was determined using fluorescein isothiocyanate-conjugated Pisum sativum agglutinin (FTTC-PSA) lectin. The fluids were also analysed by radioimmunoassay to determine the levels of progesterone, 17α-hydroxy-progesterone, testosterone and oestradioh The results showed that there was a positive, highly significant correlation between the acrosome reaction-inducing activity and the progesterone level of ea