Clinical applications of gonadotropin-releasing hormone analogues: a broad impact on reproductive medicine.

Gonadotropin-releasing hormone (GnRH) is central to the control of the entire hypothalamic-pituitary-gonadal axis. Manipulation of GnRH, in turn, regulates pituitary response and ovarian hormone production. Gonadotropin-releasing hormone analogues have revolutionized assisted reproductive technology and gynecologic practice. The recent advent of oral GnRH antagonists with an inherent rapid onset of action continues to transform the treatment options available for several common gynecologic conditions, including endometriosis and fibroids. Herein, we review neuroendocrine GnRH activity and discuss modulation of the reproductive axis by GnRH analogues for diverse clinical applications.

Changes to reproductive endocrinology and infertility practice, research, and training as investor mergers increase.

Private equity investment in fertility clinics has rapidly increased and is leading to unprecedented changes in the field of reproductive endocrinology and infertility (REI). The goal of this paper was to review private equity's current integration in REI and discuss both benefits and challenges of investor involvement. We found that at least 25% of fellowship programs and medical schools were affiliated with private practice fertility clinics, not free-standing academic clinics. Approximately half of medical schools and nearly all REI fellowship programs that were affiliated with private practices were also backed by private investors. Research participation remains robust in private equity-affiliated REI clinics. With the changing infrastructure, we discuss the potential influence on trainee experience and research while also acknowledging the unique advantages that investor involvement may offer.

Hyperinsulinemia induces early and dyssynchronous puberty in lean female mice.

Girls with obesity are at increased risk of early puberty. Obesity is associated with insulin resistance and hyperinsulinemia. We hypothesized that insulin plays a physiological role in pubertal transition, and super-imposed hyperinsulinemia due to childhood obesity promotes early initiation of puberty in girls. To isolate the effect of hyperinsulinemia from adiposity, we compared pre-pubertal and pubertal states in hyperinsulinemic, lean muscle (M)-insulin-like growth factor 1 receptor (IGF-1R)-lysine (K)-arginine (R) (MKR) mice to normoinsulinemic WT, with puberty onset defined by vaginal opening (VO). Our results show MKR had greater insulin resistance and higher insulin levels (P < 0.05) than WT despite lower body weight (P < 0.0001) and similar IGF-1 levels (P = NS). Serum luteinizing hormone (LH) levels were higher in hyperinsulinemic MKR (P = 0.005), and insulin stimulation induced an increase in LH levels in WT. VO was earlier in hyperinsulinemic MKR vs WT (P < 0.0001). When compared on the day of VO, kisspeptin expression was higher in hyperinsulinemic MKR vs WT (P < 0.05), and gonadotropin-releasing hormone and insulin receptor isoform expression was similar (P = NS). Despite accelerated VO, MKR had delayed, disordered ovarian follicle and mammary gland development. In conclusion, we found that hyperinsulinemia alone without adiposity triggers earlier puberty. In our study, hyperinsulinemia also promoted dyssynchrony between pubertal initiation and progression, urging future studies in girls with obesity to assess alterations in transition to adulthood.

Differential Expression of IR-A, IR-B and IGF-1R in Endometrial Physiology and Distinct Signature in Adenocarcinoma.

CONTEXT: Type 2 diabetes and obesity are risk factors for endometrial hyperplasia and cancer, suggesting that hyperinsulinemia contributes to pathogenesis. Insulin action through insulin receptor (IR) splice variants IR-A and IR-B regulates cellular mitogenesis and metabolism, respectively. OBJECTIVE: We hypothesized that IR-A and IR-B are differentially regulated in normal endometrium, according to mitogenic and metabolic requirements through the menstrual cycle, as well as in endometrial hyperplasia and cancer. DESIGN: IR-A, IR-B, and IGF-1 receptor (IGF-1R) mRNA was quantified in endometrium, endometrial epithelial and stromal cells, and in vitro after hormone stimulation. SETTING: Academic center. PATIENTS: Endometrium was collected from women with regular cycles (n = 71), complex hyperplasia (n = 5), or endometrioid adenocarcinoma (n = 11). INTERVENTION(S): In vitro sex-steroid treatment. MAIN OUTCOME MEASURE(S): IR-A and IR-B expression Results: IR-A increased dramatically during the early proliferative phase, 20-fold more than IR-B. In early secretory phase, IR-B and IGF-1R expression increased, reaching maximal expression, whereas IR-A decreased. In adenocarcinoma, IR-B and IGF-1R expression was 5- to 6-fold higher than normal endometrium, whereas IR-A expression was similar to IR-B. Receptor expression was unrelated to body mass index. CONCLUSION: IR-A was elevated during the normal proliferative phase, and in endometrial hyperplasia and adenocarcinoma. The dramatic early rise of IR-A in normal endometrium indicates IR-A is the predominant isoform responsible for initial estrogen-independent endometrial proliferation as well as that of cancer. IR-B is elevated during the normal secretory phase when glucose uptake and glycogen synthesis support embryo development. Differing from other cancers, IR-B expression equals mitogenic IR-A in endometrial adenocarcinoma. Differential IR isoform expression suggests a distinct role for each in endometrial physiology and cancer.

Development of a Quantitative PCR Assay for Detection of Human Insulin-Like Growth Factor Receptor and Insulin Receptor Isoforms.

The biological activity of insulin and the insulin-like growth factor (IGF) ligands, IGF-I and IGF-II, is based in part on the relative abundance and distribution of their target receptors: the insulin receptor (IR) splice variants A (IR-A) and B (IR-B) and IGF 1 receptor (IGF-1R). However, the relative quantity of all three receptors in human tissues has never been measured together on the same scale. Due to the high homology between insulin receptor (IR)-A and IR-B proteins and lack of antibodies that discern the two IR splice variants, their mRNA sequence is the most reliable means of distinguishing between the receptors. Hence, highly specific primers for IR-A, IR-B, and IGF-1R mRNA were designed to accurately detect all three receptors by quantitative RT-PCR and enable direct quantification of relative receptor expression levels. A standard concentration curve of cDNA from each receptor was performed. Assay specificity was tested using competition assays and postamplification analysis by gel electrophoresis and cloning. Forward and reverse primer concentrations were optimized to ensure equal efficiencies across primer pairs. This assay enables a specific molecular signature of IGF/insulin signaling receptors to be assayed in different tissues, cell types, or cancers.