Comparison of the follicular output rate after controlled ovarian stimulation with daily recombinant follicle-stimulating hormone versus corifollitropin alfa.

OBJECTIVE: To compare the Follicular Output Rate (FORT) between corifollitropin alfa (CFA) and recombinant follicle-stimulating hormone (rFSH) during controlled ovarian stimulation (COS). STUDY DESIGN: This retrospective analysis compared FORT between women treated with CFA or rFSH from three clinical trials: ENGAGE (N = 1476; ages 18-36, >60 kg), ENSURE (N = 395; ages 18-36, ≤60 kg), and PURSUE (N = 1388; ages 35-42, ≥50 kg). Women underwent COS in a GnRH antagonist protocol followed by hCG trigger prior to IVF. Antral follicle count (AFC; <11 mm) and pre-ovulatory follicle count (>15 mm) were used for FORT, defined as [pre-ovulatory follicles/AFCx100]. RESULTS: For CFA and rFSH, respectively, mean FORT (adjusted for trial and age) was 85.0 versus 76.8 (p < 0.001) in the combined cohort, 86.0 versus 75.0 in ENGAGE (p < 0.001), 96.2 versus 79.2 in ENSURE (p = 0.070), and 74.1 versus 71.2 in PURSUE (p = 0.180); mean oocyte output (oocytes retrieved/AFCx100, adjusted for age) was 121.9 versus 107.3 in ENGAGE (p = 0.001), 133.5 versus 102.3 in ENSURE (p < 0.001), and 100.6 versus 98.1 in PURSUE (p = 0.463). FORT and oocyte output were consistent with the number of metaphase II oocytes retrieved for CFA and rFSH: 10.4 versus 8.8 in ENGAGE (p < 0.001), 10.3 versus 7.6 in ENSURE (p < 0.001), and 7.5 versus 7.2 in PURSUE (p = 0.37). No differences in pregnancy rates based on FORT were observed. CONCLUSIONS: FORT was significantly higher in CFA-stimulated cycles and accurately predicted oocyte output. No association of FORT with pregnancy likelihood was found.

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028.

OBJECTIVE: To evaluate safety, tolerability, and antitumor activity of pembrolizumab monotherapy in patients with programmed death ligand 1 (PD-L1)-expressing advanced ovarian cancer enrolled in the multicohort, phase Ib KEYNOTE-028 trial. METHODS: Key inclusion criteria were age ≥18 years; advanced ovarian epithelial, fallopian tube, or primary peritoneal carcinoma; failure of previous therapy; and tumor PD-L1 positivity. Patients received pembrolizumab (10 mg/kg every 2 weeks) for ≤24 months or until disease progression/intolerable toxicity. Tumor response was assessed per RECIST v1.1 (investigator review). Adverse events (AEs) were graded using CTCAE version 4.0. Primary end point was confirmed objective response rate (ORR) per RECIST v1.1 (investigator review); data cutoff date was February 20, 2017. RESULTS: Twenty-six patients (median age, 57.5 years) with PD-L1-positive advanced metastatic ovarian cancer received pembrolizumab; 38.5% had metastatic disease, and 73.1% previously received ≥3 lines of therapy. Treatment-related AEs (TRAEs) occurred in 19 (73.1%) patients, most commonly arthralgia (19.2%), nausea (15.4%), and pruritus (15.4%). One grade 3 TRAE (increased plasma transaminase level) occurred. No deaths and no treatment discontinuations due to TRAEs occurred. After a median follow-up duration of 15.4 months, ORR was 11.5% (1 complete response, 2 partial responses); 7 patients (26.9%) achieved stable disease. Median progression-free and overall survival were 1.9 (95% CI, 1.8-3.5) and 13.8 (95% CI, 6.7-18.8) months, respectively. CONCLUSION: Pembrolizumab conferred durable antitumor activity with manageable safety and toxicity in patients with advanced PD-L1-positive ovarian cancer and is under further investigation in an ongoing phase II trial, KEYNOTE-100.

Follicle-Stimulating Hormone: A Review of Form and Function in the Treatment of Infertility.

The use of gonadotropin therapy, including follicle-stimulating hormone (FSH), represents an indispensable part of fertility treatment. There are a number of FSH preparations commercially available or in development, including both urinary-derived products (urinary-derived FSH [uFSH]) and FSH produced through recombinant techniques (recombinant FSH [rFSH]). Differences in the glycosylation patterns of FSH give rise to a number of naturally occurring isoforms that may differ functionally. The relative concentrations of these isoforms vary over the course of the menstrual cycle and the lifetime, indicating that these differences in glycosylation may have physiologic relevance. Although both uFSH and rFSH contain human FSH, there are differences in the glycosylation patterns, which may give rise to differences in biologic activity between products. Current FSH products have been shown to have high purity and to exhibit consistent, favorable efficacy and safety profiles for the treatment of infertility, regardless of urinary or recombinant origin.

Assessing ovarian response: antral follicle count versus anti-Müllerian hormone.

Oocyte number and quality decline with age; however, fertility varies significantly even among women of the same age. Various measures have been developed to predict response to ovarian stimulation and reproductive potential. Evaluation of ovarian reserve can identify patients who may experience poor response or hyper-response to exogenous gonadotrophins and can aid in the personalization of treatment to achieve good response and minimize risks. In recent years, two key methods, antral follicle count (AFC), an ultrasound biomarker of follicle number, and the concentration of serum anti-Müllerian hormone (AMH), a hormone biomarker of follicle number, have emerged as preferred methods for assessing ovarian reserve. In this review, a live debate held at the American Society for Reproductive Medicine 2013 Annual Meeting is expanded upon to compare the predictive values, merits, and disadvantages of AFC and AMH level. An ovarian reserve measure without limitations has not yet been discovered, although both AFC and AMH have good predictive value. Published evidence, however, as well as the objectivity and potential standardization of AMH level and the convenience of testing any time throughout the menstrual cycle, leans towards AMH level becoming the gold-standard biomarker to evaluate ovarian reserve and predict ovarian response to stimulation.

Should ICSI be recommended routinely in patients with four or fewer oocytes retrieved?

PURPOSE: To determine if patients with a low response to controlled ovarian hyperstimulation during IVF benefit from intracytoplasmic sperm injection (ICSI) METHODS: Retrospective analysis of 350 IVF cycles in which four or fewer oocytes were retrieved. Severe male factor cases were excluded from analysis. Conventional insemination (CI) and ICSI were compared, with primary outcome measures of fertilization rate, implantation rate, clinical pregnancy rate per embryo transfer, and pregnancy loss rate. RESULT(S): Fertilization rates per oocyte retrieved for CI and ICSI were comparable (51.5% vs. 51.8%). Parallel implantation rates (22% vs. 25%), clinical pregnancy rates (32.8% vs. 33.3%), and loss rates (26.7% vs. 39.5%) were also noted. No difference in cancelled cycles was reported. CONCLUSION(S): Our results demonstrate that in the presence of normal semen parameters, low egg number is not an indication to perform ICSI.

The role of peripheral gonadotropin-releasing hormone receptors in female reproduction.

OBJECTIVE: To review the physiologic functions and clinical significance of peripheral GnRH receptors. DESIGN: Literature review. All peer-reviewed journal articles published before 2010 on peripheral GnRH receptors were searched for in the Pubmed database, and relevant findings were summarized. RESULT(S): Peripheral GnRH/GnRH receptor systems may serve as regulators of hCG synthesis and implantation, and play crucial roles in antiproliferation and apoptosis. Currently, GnRH agonists have been used in cancer treatment and ovary protection during chemotherapy, taking advantage of the local direct effect mediated by peripheral GnRH receptors. CONCLUSION(S): The ubiquitous GnRH/GnRH receptor system in human tissues has been shown to have some important physiologic functions. Further research to clarify functions of these peripheral GnRH receptors may lead to discovery of new therapeutic options.

A novel mutation of HOXA13 in a family with hand-foot-genital syndrome and the role of polyalanine expansions in the spectrum of Müllerian fusion anomalies.

OBJECTIVE: To report a novel mutation found in a family with hand-foot-genital syndrome (HFGS). To characterize the genetic basis of true HFGS versus presence of non-HFGS-related uterovaginal septa. DESIGN: Case-control study. SETTING: Academic medical center. PATIENT(S): The HFGS patients and family members; women with uterine or uterovaginal septa without other sequelae of HFGS. INTERVENTION(S): Sequence analysis of HOXA13 in members of a family with HFGS (3 affected, 1 unaffected); sequence analysis of HOXA13 in biopsy samples obtained from 17 non-HFGS patients with idiopathic uterine or uterovaginal septa and in 11 normal controls. MAIN OUTCOME MEASURE(S): Presence or absence of mutations of HOXA13. RESULT(S): Affected members of a family with HFGS showed a novel expansion of the third polyalanine tract of HOXA13, inserting 10 alanines in-frame. None of the patients with idiopathic uterovaginal septa displayed mutations of HOXA13. CONCLUSION(S): The cause of uterovaginal septa without hand and foot symptoms differs from true HFGS. When patients present with septa, it is not necessary to subject them to roentgenograms of the distal limbs or to sequence analysis of HOXA13 unless they show clear signs of the other sequelae characteristic of true HFGS.

Natural cycle cryo-thaw transfer may improve pregnancy outcome.

OBJECTIVE: To compare natural vs. hormone replacement treatment (HRT) for cryo-thaw embryo transfer cycles in patients with frozen embryos from previous ART. DESIGN AND SETTINGS: Retrospective chart review of 164 patients (242 cycles) who underwent natural or HRT cryo-thaw embryo transfer between January 2002 and April 2005. MAIN OUTCOME MEASURES: Pregnancy rates per transfer in natural and HRT cryo-thaw cycles. RESULTS: The pregnancy rate per transfer was higher with natural cycles (36.76% vs. 22.99%, P = 0.0298). There was no statistical difference in mean age, endometrial thickness, and average embryo quality in successful cycles. Mean endometrial thickness prior to transfer was greater in natural cycles (9.95 vs. 8.89 mm, P < 0.001). Mean serum estradiol levels were higher in the HRT group prior to transfer (526.1 vs. 103.8 pg/ml, P < 0.001), and were found to be lower in women who achieved pregnancy (337.1 vs. 433.3 pg/ml, P = 0.0136). CONCLUSION: Hormone replacement in preparation for cryo-thaw transfer of embryos was found to be associated with decreased pregnancy rates in comparison to natural cycle cryo-thaw transfer. Greater endometrial thickness was achieved with lower serum estradiol levels in patients undergoing natural cycles, suggesting that higher estradiol levels during HRT cycle may interfere with the window of implantation.

Effects of long-acting recombinant human follicle-stimulating hormone analogs containing N-linked glycosylation on murine folliculogenesis.

OBJECTIVE: To evaluate the efficacy of two novel long-acting rhFSH analogs, rhFSH-N2 and rhFSH-N4, in stimulating murine folliculogenesis. DESIGN: Experimental study. SETTING: Academic research environment. ANIMAL(S): Immature female mice. INTERVENTION(S): Recombinant hFSH-N2 and -N4 were administered via single IP injection to 3-week-old female mice (n = 10) who were killed 48 hours later for dissection and histologic examination of reproductive organs and serum inhibin A. Results were compared with other groups of mice who received either single or q 12 hour injections for 48 hours of commercial rhFSH, or a single injection of pregnant mare serum gonadotropin (PMSG). A subgroup of the mice receiving rhFSH-N4 was supplemented with daily injections of small doses of hCG to simulate LH add-back. MAIN OUTCOME MEASURE(S): Serum inhibin A levels, ovarian and uterine weights, and ovarian antral follicle counts. RESULTS(S): Recombinant human FSH-N2 and -N4 administration induced a statistically significant increase in ovarian weights, uterine weights, and inhibin A levels compared with single and twice-daily injection of rhFSH. PMSG induced the greatest increases in all three measured parameters. There was no statistical difference between rhFSH-N2 and rhFSH-N4 for any parameter analyzed. A single injection of rhFSH-N2 or -N4 induced a greater number of antral follicles than did either single or q 12 hour injections of rhFSH. The addition of small doses of hCG to rhFSH-N4 increased inhibin A levels and antral follicle number to reach statistical equivalence to PMSG treatment. CONCLUSION(S): Addition of a synthetic polypeptide containing two or four N-linked glycosylation sites to rhFSH increases in vivo bioactivity of the hormone compared to commercial rhFSH. After a single injection, both rhFSH-N2 and rhFSH-N4 effectively induced a greater follicular response in the mouse than did rhFSH.

Severe hypertriglyceridemia and pancreatitis following hormone replacement prior to cryothaw transfer.

PURPOSE: A case of acute pancreatitis with severe hypertriglyceridemia occurred following use of intramuscular estradiol valerate during endometrial preparation for cryopreserved embryos. METHODS: A 30-year-old woman with primary infertility and a past history of well-controlled hypothyroidism, underwent endometrial development with intramuscular estradiol valerate in preparation for the transfer of cryopreservred embryos. RESULTS: Initial hospitalization, discontinuation of all estrogens, aggressive intravenous fluid hydration, and initiation of low-fat diet with additional gemfibrozil treatment resulted in complete resolution of all symptoms related to the pancreatitis including the hyperlipidemia. A subsequent cryothaw cycle using oral estradiol resulted in a viable pregnancy with only mild increases in the patient's triglyceride and cholesterol levels noted throughout her 38-week gestation. CONCLUSION(S): Estradiol valerate, a commonly used form of estrogen for endometrial preparation during cryothaw cycles, may cause severe hypertriglyceridemia and acute pancreatitis in certain predisposed individuals. Oral and transdermal estrogens should be the preferred method of endometrial preparation in patients at high risk for lipid metabolism disorders, such as patients with polycystic ovarian syndrome and familial hypertriglyceridemia. These estrogens are more rapidly metabolized and have a shorter half life compared to that of estradiol valerate.