Reproductive Functions of the Mitochondrial Progesterone Receptor (PR-M).

Classic transcriptional regulation by progesterone via the nuclear progesterone receptors A and B (PR-A, PR-B) has been recognized for decades. Less attention has been given to a mitochondrial progesterone receptor (PR-M) responsible for non-nuclear activities. PR-M is derived from the progesterone receptor (PR) gene from an alternate promoter with the cDNA encoding a unique 5' membrane binding domain followed by the same hinge and hormone-binding domain of the nPR. The protein binds to the mitochondrial outer membrane and functions to increase cellular respiration via increased beta-oxidation and oxidative phosphorylation with resulting adenosine triphosphate (ATP) production. Physiologic activities of PR-M have been studied in cardiac function, spermatozoa activation, and myometrial growth, all known to respond to progesterone. Progesterone via PR-M increases cardiomyocyte cellular respiration to meet the metabolic demands of pregnancy with increased contractility. Consequential gene changes associated with PR-M activation include production of proteins for sarcomere development and for fatty acid oxidation. Regarding spermatozoa function, progesterone via PR-M increases cellular energy production necessary for progesterone-dependent hyperactivation. A role of progesterone in myometrial and leiomyomata growth may also be explained by the increase in necessary cellular energy for proliferation. Lastly, the multi-organ increase in cellular respiration may contribute to the progesterone-dependent increase in metabolic rate reflected by an increase in body temperature through compensatory non-shivering thermogenesis. An evolutionary comparison shows PR-M expressed in humans, apes, and Old World monkeys, but the necessary gene sequence is absent in New World monkeys and lower species. The evolutionary advantage to PR-M remains to be defined, but its presence may enhance catabolism to support the extended gestation and brain development found in these primates.

Total follicle stimulating hormone dose is negatively correlated with live births in a donor/recipient model with fresh transfer: an analysis of 8,627 cycles from the Society for Assisted Reproductive Technology Registry.

OBJECTIVE: Oocyte donation has optimized our understanding of ovarian stimulation. Increasing the follicle-stimulating hormone (FSH) dose has been shown to adversely affect live birth rates in autologous cycles. Our objective is to assess whether this relationship holds true within the donor/recipient population. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENTS: Data from 2014-2016 included 8,627 fresh donor cycles. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Live birth, clinical pregnancy, and miscarriage rates. RESULTS: The mean donor age ± standard deviation (SD) was 25.8 ± 2.8 years. Donors underwent a median of 16 days (interquartile range [IQR] 12, 19) of stimulation with a median (IQR) total FSH dose and daily dose of 2,350.0 (1,800.0, 3,025.0) and 153.8 (113.2, 205.0) IU, respectively. The live birth rate was 56.7% per transfer. For every 500-unit increase in FSH dose, there was a 3% reduction in the odds of a live birth (odds ratio [OR] 0.97; 95% confidence interval 0.95, 0.99), and a 3% reduction in the odds of a clinical pregnancy (OR 0.97; 95% confidence interval 0.95, 0.99). Days of stimulation and average daily dose were not significantly associated with live birth or clinical pregnancy. No significant association was found between miscarriage rates and total FSH dose, days of stimulation, or average daily dose. CONCLUSION: This is a novel report of a negative association of total FSH dosage on fresh IVF live births, performed in the donor population to control for oocyte source and endometrial receptivity.

Pre-implantation genetic testing alters the sex ratio: an analysis of 91,805 embryo transfer cycles.

PURPOSE: To determine if pre-implantation genetic testing (PGT) shifts the sex ratio (SER), the ratio of male to female births in a population normalized to 100 and typically stable at 105, following in vitro fertilization (IVF). METHODS: Data from 2014 to 2016 was requested from the Society for Assisted Reproductive Technologies (SART) database including fresh and frozen transfer cycles. Women with a singleton live birth following a fresh or frozen autologous embryo transfer of a PGT blastocyst, non-PGT blastocyst, or non-PGT cleavage stage embryo were included. The SER between groups was compared using chi-square tests. Modified Poisson regression modeled the relative risk (RR) of having a male compared to a female among PGT blastocyst transfers versus non-PGT cleavage and blastocyst transfers adjusting for age, BMI, smoking status, race, parity, number of oocytes retrieved, and clinic region. RESULTS: The SER was 110 among PGT blastocyst offspring, 107 among non-PGT blastocyst offspring (p = 0.005), and 99 among non-PGT cleavage offspring (p < 0.001). The risk of having a male infant was 2% higher among PGT blastocyst transfers compared to non-PGT blastocyst transfers (RR 1.02; 95% CI: 1.01, 1.04). The risk was 5% higher among PGT blastocyst transfers compared to non-PGT cleavage transfers (RR 1.05; 95% CI: 1.02, 1.07). The association between PGT and infant gender did not significantly differ by region (p = 0.57) or parity (p = 0.59). CONCLUSION: Utilizing PGT shifts the SER in the IVF population from the standard of 105 to 110, increasing the probability of a male offspring.

Surrogacy Laws in the United States: What Obstetrician-Gynecologists Need to Know.

The first child carried by a surrogate after in vitro fertilization in the United States was born in 1985. Since then, the number of such births has steadily grown. According to the Centers for Disease Control and Prevention, the number of gestational carrier cycles increased from 727 in 1999 to 3,432 in 2013, encompassing more than 18,000 children born over this period. Surrogacy offers an alternative to adoption. However, it also disrupts traditional notions of parentage and gestation and complicates the role of obstetrician-gynecologists (ob-gyns) in helping their patients navigate difficult ethical issues. Surrogacy legislation falls under the jurisdiction of each individual state, which results in a variety of approaches. In this article, we review the legal aspects of surrogacy important for specialist ob-gyns, including select landmark court cases, states' approaches to surrogacy legislation, and unique components of informed consent. We also provide clinical recommendations specific to the United States for working with gestational surrogates and intended parents, spanning preconception, prenatal care, and delivery.

Cervical Cancer Screening in HIV-Positive Farmers in South Africa: Mixed-Method Assessment.

BACKGROUND: In 2015, a See and Treat cervical cancer screening program was implemented at a local HIV clinic in Limpopo, South Africa, where infrastructure limited adequate Pap smear usability. OBJECTIVE: The purpose of this evaluation was to determine the quality and sustainability of the implemented program. METHODS: A mixed-methods program analysis was conducted at 18-months post implementation. Data collection techniques included in-depth interviews of staff and patients, observation of healthcare workers delivering screening, and review of charts and patient logs. FINDINGS: Eighteen in-depth interviews revealed improved cervical cancer screening understanding and awareness. Privacy concerns and negative perceptions of medical care were barriers to screening. Informal observations revealed continued clinical competence among healthcare workers who had been previously trained. Review of charts demonstrated positive correlation between VIA and Pap smear results. In evaluating loss to attrition, about half of the first cohort of patients were lost to follow-up. VIAs and Pap smears were offered on an ongoing basis, and month-over-month change for overlapping four months of programming between 2015 and 2016 showed a 4.4% negative change in number of Pap smears and a 57% negative change in VIAs. CONCLUSION: Our evaluation reveals successful integration of See and Treat into current clinic services in rural South Africa and increased awareness of cervical cancer among health workers and participants. Program sustainability was challenging to assess as many patients were lost to follow-up, given the migrant and transient population attending this clinic. Acceptance by health workers and patients alike is vital for the long-term impact on cervical cancer incidence in this region.

The cumulative dose of gonadotropins used for controlled ovarian stimulation does not influence the odds of embryonic aneuploidy in patients with normal ovarian response.

OBJECTIVE: Controlled ovarian hyperstimulation (COH) promotes multifollicular growth, increasing the chance of obtaining euploid embryos that will successfully implant. Whether aneuploidy is increased from COH with exogenous gonadotropins interfering with natural selection of dominant follicles is a concern. This study evaluates the association between gonadotropin exposure and aneuploidy. METHODS: This is a retrospective cohort study of 828 patients that underwent 1122 IVF cycles involving controlled ovarian stimulation and trophectoderm biopsy for preimplantation genetic screening (PGS), from 2010 to 2015. Polymerase chain reaction (PCR) was used to assess aneuploidy. Kruskal-Wallis tests and logistic regression with generalized estimating equations (GEEs) were used for data analysis. RESULTS: Overall, after controlling for patient age, ovarian reserve, stimulation protocol, days of stimulation, and diagnoses, there was no significant association between cumulative gonadotropin (GND) dose and the odds of aneuploidy (adjusted OR = 1.049, p = 0.232). Similarly, in cycles where patients did not require COH beyond cycle day 12, there was no significant association between cumulative gonadotropin dose and the odds of aneuploidy (adjusted OR = 0.909, p = 0.148). However, in cases where patients were stimulated past cycle day 12, there was a significant increase in the odds of aneuploidy (adjusted OR = 1.20, 95% CI 1.125-1.282, p < 0.0001) with increasing cumulative gonadotropin dose, with a small effect size (Cohen's d = 0.10, 95% CI 0.08-0.12). In this cohort, there was a 16.4% increase in the odds of aneuploidy for each 1000-u increase in cumulative GND exposure (adjusted OR = 1.164, p = 0.002). When the analysis was restricted to low responders (peak estradiol <500 pg/mL or <4 mature follicles achieved; there was no significant association between gonadotropin dose and aneuploidy (adjusted OR = 1.12, 95% CI 0.982-1.28, p = 0.09), regardless of the duration of COH required to reach vaginal oocyte retrieval. CONCLUSION: The degree of exposure to exogenous gonadotropins did not significantly modify the likelihood of aneuploidy in patients with a normal ovarian response to stimulation (not requiring COH beyond cycle day 12). Patients requiring prolonged COH were demonstrated to have elevated odds of aneuploidy with increasing cumulative gonadotropin dose. This finding may reflect an increased tendency towards oocyte and embryonic aneuploidy in patients with a diminished response to gonadotropin stimulation.

An Evaluation of Mobile Applications for Reproductive Endocrinology and Infertility Providers.

OBJECTIVE: To identify and rate reproductive endocrinology and infertility (REI) mobile applications (apps) targeted toward REI providers. DESIGN: A list of REI apps was found in both the Apple iTunes and Google Play stores using the following seven MeSH terms: reproductive endocrinology, REI, infertility, fertility, In Vitro Fertilization, IVF, and embryology. Patient-centered apps were excluded. The remaining apps were then evaluated for accuracy using reliable references. SETTING: Mobile technology. PATIENTS/INTERVENTIONS: None. MAIN OUTCOME MEASURES: Accurate apps were evaluated for comprehensiveness (the extent of the ability to aid in clinical decision-making) and rated with objective and subjective components using the APPLICATIONS scoring system. RESULTS: Using the seven REI-related MeSH terms, 985 apps and 1,194 apps were identified in the Apple iTunes and Google Play stores, respectively. Of these unique apps, only 20 remained after excluding patient-centered apps. Upon further review for applicability to REI specifically and content accuracy, only seven apps remained. These seven apps were then rated using the APPLICATIONS scoring system. CONCLUSION: Only 0.32% of 2,179 apps reviewed for this study were useful to REI providers. There is potential for further mobile resource development in the area of REI, given the limited number and varying comprehensiveness and quality of available apps.