Summary
The clinical sequelae of oestrogen deficiency during menopause are undoubted. However, the pathophysiological role of testosterone during the menopause is less clear. Several randomized, ...placebo‐controlled clinical trials suggest that testosterone therapy improves sexual function in postmenopausal women. Some studies suggest that testosterone therapy has additional effects, which include increased bone mineral density and decreased serum high‐density lipoprotein (HDL) cholesterol. Furthermore, the long‐term safety profile of testosterone therapy in postmenopausal women is not clear. This article will provide a concise and critical summary of the literature, to guide clinicians treating postmenopausal women.
Primordial follicles, consisting of granulosa cell (GC)-enveloped oocytes are maintained in a state of developmental arrest until activated to grow. The mechanism that operates to maintain this ...arrested state in GCs is currently unknown. Here, we show the TGFβ-activated transcription factor SMAD3 is expressed in primordial GC nuclei alongside the cell cycle proteins, cyclin D2 (CCND2) and P27. Using neonatal C57/Bl6 mouse ovaries densely populated with primordial follicles, CCND2 protein co-localised and was detected in complex with P27 by immunofluorescence and co-immunoprecipitation, respectively. In the same tissue, SMAD3 co-precipitated with DNA sequences upstream of Ccnd2 and Myc transcription start sites implicating both as direct SMAD3 targets. In older ovaries follicle growth was associated with nuclear exclusion of SMAD3 and reduced P27 and CCND2 in GCs, alongside elevated Myc expression. Brief (2 H) exposure of neonatal ovaries to TGFβ1 (10 ng/ml) in vitro led to immediate dissociation of SMAD3 from the Ccnd2 and Myc promoters. This coincided with elevated Myc and phospho-S6, an indicator of mTOR signalling, followed by a small increase in mean primordial GC number after 48 H. These findings highlight a concentration-dependent role for TGFβ signalling in the maintenance and activation of primordial follicles, through SMAD-dependent and independent signalling pathways, respectively.
Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in adolescents, with potentially significant lifelong consequences. This prospective study set out to determine if the investigators ...could derive a threshold value of antimullerian hormone (AMH) that would predict its presence according to two internationally recognized definitions using a simple measurement, avoiding more extensive and potentially more invasive investigations. The study failed to demonstrate, in a general adolescent population, that serum AMH is a reliable predictor of PCO morphology or for the presence of PCOS.
The second trimester human fetal ovary possesses the machinery to synthesize and detect key members of the steroid signaling pathway, especially estrogenic signaling, with elevated expression during ...the onset of primordial follicle formation.
Context:
Ovarian primordial follicle formation is critical for subsequent human female fertility. It is likely that steroid, and especially estrogen, signaling is required for this process, but details of the pathways involved are currently lacking.
Objective:
The aim was to identify and characterize key members of the steroid-signaling pathway expressed in the second trimester human fetal ovary.
Design:
We conducted an observational study of the female fetus, quantifying and localizing steroid-signaling pathway members.
Setting:
The study was conducted at the Universities of Aberdeen, Edinburgh, and Glasgow.
Patients/Participants:
Ovaries were collected from 43 morphologically normal human female fetuses from women undergoing elective termination of second trimester pregnancies.
Main Outcome Measures:
We measured mRNA transcript levels and immunolocalized key steroidogenic enzymes and steroid receptors, including those encoded by ESR2, AR, and CYP19A1.
Results:
Levels of mRNA encoding the steroidogenic apparatus and steroid receptors increased across the second trimester. CYP19A1 transcript increased 4.7-fold during this period with intense immunostaining for CYP19A detected in pregranulosa cells around primordial follicles and somatic cells around oocyte nests. ESR2 was localized primarily to germ cells, but androgen receptor was exclusively expressed in somatic cells. CYP17A1 and HSD3B2 were also localized to oocytes, whereas CYP11A1 was detected in oocytes and some pregranulosa cells.
Conclusions:
The human fetal ovary expresses the machinery to produce and detect multiple steroid signaling pathways, including estrogenic signaling, with the oocyte acting as a key component. This study provides a step-change in our understanding of local dynamics of steroid hormone signaling during the key period of human primordial follicle formation.
Follicle-stimulating hormone (FSH) and its G protein-coupled receptor, FSHR, represents a paradigm for receptor signaling systems that activate multiple and complex pathways. Classically, FSHR ...activates Gαs to increase intracellular levels of cAMP, but its ability to activate other G proteins, and β-arrestin-mediated signaling is well documented in many different cell systems. The pleiotropic signal capacity of FSHR offers a mechanism for how FSH drives multiple and dynamic downstream functions in both gonadal and non-gonadal cell types, including distinct diseases, and how signal bias may be achieved at a pharmacological and cell system-specific manner. In this study, we identify an additional mechanism of FSH-mediated signaling and downstream function in the endometrial adenocarcinoma Ishikawa cell line. While FSH did not induce increases in cAMP levels, this hormone potently activated pertussis toxin sensitive Gαi/o signaling. A selective allosteric FSHR ligand, B3, also activated Gαi/o signaling in these cells, supporting a role for receptor-mediated activation despite the low levels of
mRNA. The low expression levels may attribute to the lack of Gαs/cAMP signaling as increasing FSHR expression resulted in FSH-mediated activation of the Gαs pathway. Unlike prior reports for FSH-mediated Gαs/cAMP signaling, FSH-mediated Gαi/o signaling was not affected by inhibition of dynamin-dependent receptor internalization. While chronic FSH did not alter cell viability, FSH was able to increase lipid droplet size. The β-arrestins are key adaptor proteins known to regulate FSHR signaling. Indeed, a rapid, FSH-dependent increase in interactions between β-arrestin1 and Gαi1 was observed
NanoBiT complementation in Ishikawa cells. Furthermore, both inhibition of Gαi/o signaling and siRNA knockdown of β-arrestin 1/2 significantly reduced FSH-induced lipid droplet accumulation, implying a role for a Gαi/o/β-arrestin complex in FSH functions in this cell type. As FSH/FSHR has been implicated in distinct hormone-dependent cancers, including endometrial cancer, analysis of the cancer genome database from 575 human endometrial adenocarcinoma tumors revealed that a subpopulation of samples expressed FSHR. Overall, this study highlights a novel mechanism for FSHR signal pleiotropy that may be exploited for future personalized therapeutic approaches.
Context:
Polycystic ovary syndrome (PCOS), the commonest cause of anovulatory infertility, is characterized by disordered follicle development including increased activation and accelerated growth of ...preantral follicles. Data from experimental animals and preliminary results from studies of human ovarian tissue suggest that IGFs affect preantral follicle development.
Objective:
Our objectives were to investigate the expression of the type-1 IGF receptor (IGFR-1) in the human ovary and to determine whether IGFs are involved in stimulating the transition of follicles from primordial to primary stage in normal and polycystic ovaries.
Design:
We used archived ovarian tissue for protein expression studies and small cortical biopsies for follicle isolation and for tissue culture.
Setting:
This was a laboratory-based study, using clinical tissue samples.
Patients:
A total of 54 women, 33 with normal ovaries and 21 with polycystic ovaries, were classified by reference to menstrual cycle history and ultrasonography.
Main Outcome Measures:
We evaluated expression of IGFR-1 mRNA in isolated preantral follicles and of IGFR-1 protein in archived ovarian tissue samples from normal and polycystic ovaries and effects of exogenous IGF-1 on preantral follicle development and survival in cultured fragments of normal and polycystic ovaries.
Results:
IGFR-1 mRNA and protein was expressed in preantral follicles at all stages of development and enhanced expression was noted in PCOS follicles during early preantral development. IGF-1 stimulated initiation of follicle growth in normal tissue but had little effect on preantral follicle growth in polycystic ovaries in which, characteristically, there was a higher proportion of follicles that had entered the growing phase even before culture.
Conclusions:
IGFs are plausible candidates in regulation of initiation of human follicle growth, and accelerated preantral follicle growth in PCOS may be due to increased activity of endogenous IGFs.
Objective To determine prevalence of metabolic syndrome in adolescents with polycystic ovary syndrome (PCOS) and derive features suggestive of propensity for development of metabolic syndrome. Design ...Prospective cohort study. Setting Population-based cohort of adolescents in Western Australia. Participant(s) Metabolic data from 1,377 children aged 14 years, features of PCOS obtained from 244 girls aged 14 to 17 years. Intervention(s) Assessment for features of PCOS and subsequent fasting blood samples. Main Outcome Measure(s) Relationship between features of PCOS and features of metabolic syndrome. Result(s) With use of five definitions of metabolic syndrome the maximal prevalence of metabolic syndrome recorded was 11.8% in girls with PCOS (National Institutes of Health NIH) and 6.6% (Rotterdam) (non-PCOS 0.6% and 0.7%, respectively). With use of cluster analysis of metabolic risk (a technique to cluster the adolescents according to multidimensional relationships of established cardiovascular risk factors), 35.3% with PCOS-NIH were at risk for metabolic syndrome and 26.2% with PCOS-Rotterdam (non-PCOS 15.4% and 15.4%, respectively). Menstrual irregularity and high free T (PCOS-NIH) were associated with high metabolic syndrome risk (odds ratio 3.00, confidence interval 1.3–6.4), not after controlling for body mass index. Of PCOS features, an elevated free T level was most predictive of insulin resistance. Menstrual irregularity and polycystic ovary morphology were not associated with insulin resistance (56.3% vs. 52.9% and 60.0% vs. 34.4%, respectively). Conclusion(s) Despite the low prevalence of metabolic syndrome in girls with PCOS, one third have features putting them at high risk for development of metabolic syndrome.
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