W. Chang

Adipocytes from women with polycystic ovary syndrome demonstrate altered phosphorylation and activity of glycogen synthase kinase 3

OBJECTIVE To test the hypothesis that an abnormality in glycogen synthase kinase-3 (GSK3) is a pathogenic factor in polycystic ovary syndrome (PCOS). DESIGN Prospective experimental study (adipocytes). SETTING Tertiary-care academic medical center and teaching hospital. PATIENT(S) Twenty patients with PCOS and 21 healthy control women. INTERVENTION(S) Blood sampling, physical exam, biopsy of SC lower abdominal fat. MAIN OUTCOME MEASURE(S) Glucose transport and protein levels and phosphorylation state of glycogen synthase kinase (GSK)-3alpha and GSK3beta in adipocytes; assessment of GSK3beta activity. RESULT(S) Basal protein levels of glycogen synthase kinase (GSK3alpha and GSK3beta) did not differ between control women and women with PCOS, nor did basal or insulin-stimulated levels of serine phosphorylated GSK3alpha. However, in adipocytes of women with PCOS, insulin stimulation was not associated with increased serine phosphorylation of GSK3beta, in contrast to the case of control women. Tyrosine phosphorylation of GSK3beta also was higher in women with PCOS, compared with in control women. Consistent with the phosphorylation data, GSK3beta activity was elevated in PCOS adipocytes. CONCLUSION(S) These data suggest that GSK3beta is hyperactivated and resistant to down-regulation by insulin in PCOS. By using physiologic approaches, we demonstrated that abnormal GSK3beta regulation is a potential mechanism for the insulin resistance that is seen in some women with PCOS, which may contribute to their development of the syndrome.

Effect of bilateral oophorectomy on adrenocortical function in women with polycystic ovary syndrome

OBJECTIVE To determine the impact of ovary-secreted products on adrenocortical function in women with PCOS by studying the adrenocortical response to acute adrenocorticotropic-stimulating hormone (ACTH) stimulation before and after bilateral oophorectomy. DESIGN Prospective study. SETTING Tertiary care medical center. PATIENT(S) Fourteen women with PCOS, scheduled for bilateral oophorectomy for benign indications, on postoperative transdermal estradiol (E(2)). INTERVENTION(S) Physical examination, blood sampling before and after oophorectomy, measurement of hormone levels; assessment of basal (Steroid(0)), maximum stimulated (Steroid(60)), and net increment (ΔSteroid) levels of androstenedione (A4), dehydroepiandrosterone (DHEA), and cortisol (F) before and after ACTH 1-24 stimulation. MAIN OUTCOME MEASURE(S) Preoperative and postoperative basal and ACTH (1-24) stimulated hormone levels. RESULT(S) Total testosterone, free testosterone, and estrone levels decreased, and follicle-stimulating hormone levels statistically significantly increased after oophorectomy. No statistically significant differences in E(2), DHEA sulfate (DHEAS), or sex hormone-binding globulin levels were detected. Basal and ACTH-stimulated A4 levels statistically significantly decreased after oophorectomy, and ΔA4 was statistically significantly increased. No statistically significant differences in DHEA(0), DHEA(60), or F(0) levels were detected. The F(60) and ΔF levels tended to increase after oophorectomy, but the differences did not reach statistical significance. CONCLUSION(S) Ovarian factors do not appear to contribute significantly to the adrenocortical dysfunction of PCOS.

Pathogenesis of Hyperandrogenism in Polycystic Ovary Syndrome

Androgen excess (AE) is an important, even essential feature of the polycystic ovary syndrome (PCOS), and arises primarily from ovarian AE, although a hyperactivity of adrenocortical function and adrenal androgen (AA) excess are present in a significant number of patients. Increased ovarian theca cell function, and possibly number, and augmented expression of steroidogenic enzymes have been demonstrated in PCOS. Increased LH stimulation of thecal androgen biosynthesis also appears to be an important, early event in PCOS. Abnormalities in other intrinsic ovarian factors such as inhibin, activin, and follistatin appear to modulate ovarian LH response. Granulosa cell dysfunction may also contribute, with PCOS women demonstrating arrested granulose development and increased 5α-reductase expression. Adrenal AE, possibly arising from generalized adrenocortical hyper-responsivity, is a relatively common feature of PCOS. Finally, the metabolic consequences of obesity and insulin resistance appear to potentiate excess androgen production in adolescent and adult PCOS patients. In short, the hyperandrogenism of PCOS appears to be aptly multifactorial, consistent with the complex nature of the syndrome itself.

The Day of Blastocyst Vitrification Significantly Effects Implantation in Subsequent Frozen Embryo Transfers

Icsi vs. Insemination for Trophectoderm Biopsy PGS Cycles: Is There Any Difference in Chromosomal Abnormalities or Pregnancy Rates? J. Barritt, PhD, D. L. Hill, PhD, H. Danzer, MD, M. Surrey, MD, S. Ghadir, MD, W. Chang, MD, S. Munne, PhD. ART Reproductive Center, 450 N. Roxbury Dr, Ste 520, Beverly Hills, CA 90210; Southern California Reproductive Center, 450 N. Roxbury Dr, Ste 500, Beverly Hills, CA 90210; Reprogenetics, 3 Regent Street, Suite 301, Livingston, NJ 07039.

The proximity of warmed embryo transfer of “intentional freeze” embryos from vitrification impacts implantation rates

OBJECTIVE: There is mounting evidence that performing blastocyst transfer at least one menstrual cycle from that in which the patient’s eggs were retrieved improves implantation, presumably due to a more receptive uterine environment. Doing this requires vitrification of blastocysts, warming and transferring them in a subsequent cycle that is 1, 2 or more menstrual cycles from that in which the embryos were created. We wanted to exam if implantation rates were affected by this proximity. DESIGN: Retrospective data analysis from a private laboratory for assisted reproductive technology. MATERIALS AND METHODS: From 2011 to 2013, 216 transfers (excluding donors and surrogates) did not have a fresh blastocyst transfer, electing to have all embryos intentionally vitrified. In 104 of these transfers the patient also had PGD by array comparative genomic hybridization (aCGH). Transfers of warmed blastocysts were performed anywhere from within 40 days of the vitrification cycle, 41-70 days or>70 days and beyond, representing endometrial lining recreation from 1–3 cycles. Based on the idea that it would take somewhere 70 days post-vitrification. RESULTS: Non-PGD defined embryo transfers occurring 70 day group (P 70 day group. Noticeably 11/112 (10%) of the cases in the ‘‘no PGD’’ group were >37, whereas 61/104 (59%) of the ‘‘PGD’’ group were >37. This outcome is therefore reflective of a elimination of the ‘‘age effect’’ in patients 37–41 years old when aCGH-defined blastocysts are used for transfer. CONCLUSION: Our data demonstrates that performing a warmed embryo transfer soon after the vitrification cycle does not allow themost optimal uterine receptivity. Most dramatically demonstrated in warmed cycles after PGD in which at least 2 endometrial lining recreations increased pregnancy rates so significantly that the ‘‘age effect’’ in older patients was overcome by doing intentional freezes with PGD. We strongly recommend not performing warmed ETs of blastocysts <40 days from vitrification.