Bruce R. Carr

OBJECTIVE: To evaluate elagolix, an oral gonadotropin-releasing hormone receptor antagonist, alone or with add-back therapy, in premenopausal women with heavy menstrual bleeding (greater than 80 mL per month) associated with uterine leiomyomas. METHODS: This double-blind, randomized, placebo-controlled, parallel-group study evaluated efficacy and safety of elagolix in cohorts 1 (300 mg twice daily) and 2 (600 mg daily) with four arms per cohort: placebo, elagolix alone, elagolix with 0.5 mg estradiol/0.1 norethindrone acetate, and elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate. A sample size of 65 per group was planned to compare elagolix with add-back to placebo on the primary end point: the percentage of women who had less than 80 mL menstrual blood loss and 50% or greater reduction in menstrual blood loss from baseline to the last 28 days of treatment. Safety assessments included changes in bone mineral density. RESULTS: From April 8, 2013, to December 8, 2015, 571 women were enrolled, 567 were randomized and treated (cohort 1=259; cohort 2=308), and 80% and 75% completed treatment, respectively. Participants had a mean±SD age of 43±5 years (cohort 2, 42±5 years), and 70% were black (cohort 2, 74%). Primary end point responder rates in cohort 1 (cohort 2) were 92% (90%) for elagolix alone, 85% (73%) for elagolix with 0.5 mg estradiol/0.1 mg norethindrone acetate, 79% (82%) for elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate, and 27% (32%) for placebo (all P <.001 vs placebo). Elagolix groups had significant decreases compared with placebo in lumbar spine bone mineral density, which was attenuated by adding 1.0 mg estradiol/0.5 mg norethindrone acetate. CONCLUSION: Elagolix with and without add-back significantly reduced menstrual blood loss in women with uterine leiomyomas. Add-back therapy reduced hypoestrogenic effects on bone mineral density. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01817530; EU Clinical Trial Register, 2013-000082-37.

Jones studied the luteal phase by evaluating basal body temperature charts, urinary pregnanediol excretion (48-hour urine collection at the peak of luteal phase by basal body temperature), cervical mucus, and most importantly, timed endometrial biopsies. In the initial study, Jones evaluated 255 cycles in 98 women with infertility that was not due to tubal, uterine, anovulation or male factor.

Background: There are limited evaluation and treatment options for low libido in premenopausal women. This review sought to evaluate the available evidence supporting the evaluation of testosterone serum levels and testosterone treatment of premenopausal women with low libido. Methods: MEDLINE, PubMed, and ClinicalTrials.gov were searched for articles that referenced the evaluation of testosterone serum level and/or testosterone treatment on premenopausal women with low libido from 1995 to 2015. Additional references were obtained from the reference sections of other papers and from peer review. Studies that included only postmenopausal women were excluded. A total of 13 studies were reviewed in detail. Nine studies examined the relationship between testosterone serum levels and sexuality, an additional three studies examined the effect of testosterone treatment on premenopausal women with low libido, and one study examined both the topics. Results: Six of the ten testosterone serum evaluation studies failed to show a significant association between testosterone serum level and libido. Only one out of four studies examining testosterone treatment in premenopausal women was able to show any clear improvement in libido; however, the effect was limited to only the intermediate dose of testosterone, with the low and high doses of testosterone not producing any effect. Conclusion: The currently available evidence does not support testosterone serum evaluation or treatment in premenopausal women with low libido. Hence, further studies are warranted.

Suppression of estrogen production and reduction of menstrual blood flow are the mainstays of medical treatment of endometriosis-related pain and have been traditionally achieved by methods such as combined hormonal contraception, progestins and GnRH analogs, all with comparable efficacies, though different side-effect profiles. Elagolix is the frontrunner among an emerging class of GnRH antagonists, which unlike their peptide predecessors has a nonpeptide structure resulting in its oral bioavailability. Phase I and II clinical trials have demonstrated safety of elagolix and its efficacy in partial and reversible suppression of ovarian estrogen production resulting in improvements in endometriosis-related pain. Phase III clinical trials are currently underway and elagolix may become a valuable addition to the armamentarium of pharmacological agents to treat endometriosis-related pain.

This randomized double-blind study, with 24-week treatment and 24-week posttreatment periods, evaluated the effects of elagolix (150 mg every day, 75 mg tw

In this issue of Seminars in Reproductive Medicine, I have recruited one of our hard working editorial board members, Dr. James Segars, and his colleague Dr. Kjersti Aagaard to guest edit an issue on The Microbiome and Reproduction. This is related to a new field of study which explains the relationship of the DNA of microorganisms that coexist and influence our bodies and in particularly the reproductive organs. Dr. Segars is head of the Unit of Reproductive Endocrinology within the Program of Reproductive and Adult Endocrinology in National Institute of Child Health and Human Development (NICHD) at National Institutes of Health (NIH) and professor of obstetrics and gynecology at the Uniformed Services University of the Health Sciences. Dr. Segars completed a residency in obstetrics and gynecology and a clinical fellowship in reproductive endocrinology at Vanderbilt University, followed by a 3-year postdoctoral fellowship in molecular biology in NIH as an RSDP scholar. Dr. Segars joined the intramural NICHD program where his laboratory pursues translational, clinical, and basic research relevant to reproduction with an emphasis on uterine fibroids and infertility. He has served as fellowship program director for the NICHD-sponsored Clinical Reproductive Endocrinology Training Program for 18 years and is keenly interested in graduate medical education and the training of the next generation of clinician-scientists. He is an author of more than 140 publications. Dr. Segars serves as editorial boards including Seminars in Reproductive Medicine, Reproductive Sciences, and Fertility and Sterility. His interest in molecular biology, genetics, and infertility kindled an interest in the microbiome and its possible relationship with disorders of infertility. Dr. Segars is board certified in obstetrics and gynecology and reproductive endocrinology. Dr. Aagaard is currently an associate professor at Baylor College of Medicine and holds numerous appointments in Maternal-Fetal Medicine, Molecular Physiology and Biophysics, Translational Biology and Biophysics, John M. Eisenberg Center for Clinical Decisions and Communication Sciences, HGSC Bioinformatics, and Research Laboratory, all at Baylor College of Medicine. She received her PhD in immunology at Mayo and her MD degree at the University of Minnesota. She completed a residency in obstetrics and gynecology at the same institution. She then completed a fellowship in Maternal-Fetal Medicine and a Masters in Clinical Investigation at the University of Utah. She holds numbers of honors in research and has or is holding numerous positions at the NIH, received a large number of NIH grants, and has an extensive and impressive publication record. Her primary interests presently include: (1) the effect of in utero exposure on the fetal epigenome, (2) birth and stillbirth, and (3) most importantly, related to this issue, the role of the microbiome in perinatal health.

Objective: The aim of this study was to estimate the efficacy of elagolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, for the treatment of endometriosis-associated pelvic pain. Methods: This was a phase II, randomized, placebo-controlled parallel group study conducted at 37 US centers, consisting of an 8-week double-blind period followed by a 16-week open-label period. Patients were 137 women aged 18 to 49, with laparoscopically confirmed endometriosis and moderate to severe nonmenstrual pelvic pain and dysmenorrhea, who were administered elagolix 150 mg daily or placebo. The primary outcomes of the study were the daily assessment of dysmenorrhea, nonmenstrual pelvic pain and dyspareunia using a modified Biberoglu-Behrman scale. Results: During the double-blind period, there were significantly greater mean reductions from baseline to week 8 in dysmenorrhea (-1.13 ± 0.11 vs. −0.37 ± 0.11, p<0.0001), nonmenstrual pelvic pain (-0.47 ± 0.07 vs. −0.19 ± 0.07, p = 0.0066), and dyspareunia scores (-0.61 ± 0.10 vs. −0.23 ± 0.10, p = 0.0070) in the elagolix group compared with placebo. Continued improvements were observed during the open-label treatment regardless of initial treatment allocation. Elagolix treatment was also associated with significant improvements in quality-of-life measures during the double-blind and open-label periods. The most common adverse events occurring with elagolix were nausea, headache and hot flush, each in 9.9% of patients. Conclusion: Elagolix effectively reduced endometriosis-associated pelvic pain over a 24-week period and was well-tolerated.