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.

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.

Objective: To evaluate the feasibility of percutaneous approach, we prospectively compared our experience in percutaneous-assisted hysterectomy (PSS-H) with that in a series of laparoscopic hysterectomies (LPS-Hs). Methods: In this multicentric cohort study, from May 2015 to October 2017, 160 patients affected by benign and malignant gynecological conditions were considered eligible for minimally invasive surgery (MIS): 80 patients received PSS-H and 80 LPS-H. In each group, 30 cases of low-/intermediate-risk endometrial cancer were enrolled. For both groups, we documented preoperative outcomes, postoperative pain, and cosmetic outcomes. Results: No statistically significant differences were noted in baseline characteristics or operative time. We observed significant differences in estimated blood loss: median of 50 cc (PSS-H) and 100 cc (LPS-H) (p = 0.0001). In LPS-H, we reported 4 (5.0%) intraoperative complications and 1 (1.3%) in PSS-H. Thirty-day complications were 4 (5%) in PSS-H and 11 (13.8%) in LPS-H (p = 0.058). No significative differences were found in visual analog scale score, despite a relevant disparity in cosmetic outcome (p = 0.0001). For oncological cases, the 2 techniques had comparable intraand postoperative outcomes and oncological accuracy. Conclusions: In this study, we reported that PSS-H is comparable to LPS-H for intra-and perioperative outcomes and postoperative pain, while PSS-H seems to be superior in cosmetic outcomes and patient satisfaction. PSS-H may represent a valid alternative in ultra-MIS for benign gynecological conditions and low-/intermediate-risk endometrial cancer.

Girls with obesity are at increased risk of early puberty. Obesity is associated with insulin resistance and hyperinsulinemia. We hypothesized 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)-IGF-1R-lysine (K)-arginine (R) (MKR) mice to normoinsulinemic wild-type (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 (pɘ.0001) and similar IGF-1 levels (p=NS). Serum 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 (pɘ.0001). When compared on the day of VO, kisspeptin expression was higher in hyperinsulinemic MKR vs WT (pɘ.05) and GnRH and IR 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.

Physiological insulin resistance and hyperinsulinemia occurs at the onset of puberty, and is thought to contribute to peri-pubertal growth and development. However, in contrast to IGF-1, little is known about how insulin affects the hypothalamic-pituitary-ovarian (HPO) axis in peri-pubertal girls. Insulin has mitogenic and metabolic activity through splice-variant isoform receptors IR-A and IR-B, respectively. We hypothesize that insulin signaling in HPO tissues contributes to the initiation of puberty, and sought to determine whether IR isoform expression is differentially regulated during puberty. We evaluated female, FVB/NJ mice: pre-pubertal, 3-4 week old mice (n=4) and peri-pubertal mice (n=7) identified within 24 hours of vaginal opening, an external marker of puberty. IR-A, IR-B, IGF-1R were quantified using a qRT-PCR assay previously validated for receptor comparison. Receptor expression was analyzed by Student’s t-test after log transformation. IR-A was the predominant IR isoform in the prepubertal hypothalamus, pituitary, and ovary, in a 20:1, 10:1, and 2:1 ratio with IR-B, respectively (p&lt;0.05, all). At puberty, IR-A did not change in the hypothalamus, whereas IR-A increased by 3.6-fold (p=0.059) in the pituitary. IR-B remained largely unchanged during puberty in both the hypothalamus and pituitary (p=NS, respectively). Interestingly, in the peripubertal ovary which has active folliculogenesis and steroid hormone synthesis, both IR-A and IR-B decreased by 33% and 68%, respectively (p&lt;0.03). As expected, IGF-1R levels were higher than IR isoforms in HPO tissues, at both developmental stages. Similar to mitogenic IR-A, IGF-1R increased in the pituitary (p&lt;0.059) during puberty. An increase in pituitary IR-A expression at the onset of puberty suggests a role for insulin signaling in regulating pituitary hormone production related to puberty. Obesity, a known risk factor for early puberty development in girls, may alter normal insulin signaling in the HPO axis. Disclosure F. Saleh: None. H.S. Taylor: None. C. Flannery: None.

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