Impact of Oral Ovulatory Induction Medications Among Female Military Members and Military Beneficiaries.

INTRODUCTION: Twelve percent of reproductive aged females in the United States have utilized fertility services, and it is estimated that 25% of infertility patients have ovulatory dysfunction. Clomiphene and letrozole are currently first-line treatment options for ovulatory dysfunction. These are both disqualifying medications in the U.S. Navy and Air Force for duties that involve flying. These medication restrictions could reduce the likelihood of female aviators seeking infertility treatment. This pilot study seeks to evaluate the severity of common side effects in order to provide recommendations to the current aeromedical guidelines. MATERIALS AND METHODS: An anonymous survey was provided to all active duty and dependent patients who presented to the infertility clinic at a single military medical center for a mid-cycle scan from February 2021 to February 2022. The survey included demographic, treatment cycle, medication type, medication dose, and the presence and severity of common adverse reactions. The provider additionally recorded the number of dominant follicles that were noted at the time of ultrasound. The Kruskal-Wallis test was used to analyze the severity of adverse effects, and chi-square analysis was used to compare the difference in symptoms from previous cycles. RESULTS: A total of 569 surveys were collected. Of the participants, 45.4% were military members and 3.5% worked in the field of aviation. Letrozole was prescribed to 88.7% of the patients. Less than 3% reported severe or debilitating side effects. There was no difference in presence or severity when comparing the cycle number. CONCLUSIONS: The majority of side effects for oral ovulation induction medications were described as slight or mild. Therefore, this study provides evidence-based data of severity side effects that could be used to guide the waiver process and improve readiness for female aviators in the military.

Female Genital Fibroblasts Diminish the In Vitro Efficacy of PrEP against HIV.

The efficacy of HIV pre-exposure prophylaxis (PrEP) is high in men who have sex with men, but much more variable in women, in a manner largely attributed to low adherence. This reduced efficacy, however, could also reflect biological factors. Transmission to women is typically via the female reproductive tract (FRT), and vaginal dysbiosis, genital inflammation, and other factors specific to the FRT mucosa can all increase transmission risk. We have demonstrated that mucosal fibroblasts from the lower and upper FRT can markedly enhance HIV infection of CD4+ T cells. Given the current testing of tenofovir disoproxil fumarate, cabotegravir, and dapivirine regimens as candidate PrEP agents for women, we set out to determine using in vitro assays whether endometrial stromal fibroblasts (eSF) isolated from the FRT can affect the anti-HIV activity of these PrEP drugs. We found that PrEP drugs exhibit significantly reduced antiviral efficacy in the presence of eSFs, not because of decreased PrEP drug availability, but rather of eSF-mediated enhancement of HIV infection. These findings suggest that drug combinations that target both the virus and infection-promoting factors in the FRT-such as mucosal fibroblasts-may be more effective than PrEP alone at preventing sexual transmission of HIV to women.

Biomarkers of Stress and Male Fertility.

To study if stress, as measured by salivary alpha-amylase and cortisol, negatively impacts male fertility, as measured by semen parameters, pregnancy, and live birth rates. Prospective, cohort study of men enrolled in the Males, Antioxidants, and Infertility (MOXI) trial. One-hundred twelve infertile men provided first-morning salivary and semen samples at baseline. Salivary samples were analyzed for alpha-amylase and cortisol. Couples attempted to conceive naturally (months 1-3) and with clomiphene citrate/intrauterine insemination (months 4-6). The association between stress-related biomarkers and semen parameters including DNA fragmentation was assessed using linear regression models adjusting for male age. Salivary levels were dichotomized at the 80th percentile. Pregnancy/live birth rates in couples in the upper quintile were compared to remaining subjects using chi-square testing. Salivary levels of alpha-amylase were not associated with semen parameters or DNA fragmentation. Salivary cortisol levels were not correlated with DNA fragmentation or normal morphology. For every 1-unit increase in salivary cortisol, total sperm count increased by 13.9 million (95% CI: 2.5, 25.3) and total motile sperm count increased by 9.9 million (95% CI: 3.2-16.6). Couple pregnancy rates and live birth rates did not differ for males in the highest quintile of alpha-amylase (27% and 28%, p = 0.96; 23% and 21%, p = 0.87) or cortisol (40% and 26%, p = 0.22; 35% and 19%, p = 0.12), compared to males with lower values. Physiologic measures of high stress may not harm but actually improve semen parameters among men with male-factor infertility.

Establishing the Most Accurate Due Date in Dichorionic Twin Gestations by First and Second Trimester Ultrasound.

OBJECTIVE: To determine the optimal sonographic dating of dichorionic gestations. MATERIALS AND METHODS: We reviewed dichorionic pregnancies conceived with assisted reproductive technologies (ART) at 2 institutions between 2006-2016, excluding fetuses with major anomalies. Gestational age was calculated with smaller, larger, and mean of the crown-rump lengths (CRL) and biometry midgestation and compared to the ART age. The mean and mean absolute deviation of the observed gestational age from the ART age was calculated to assess accuracy, precision, and presence of bias. The incidence of small for gestational age using the smaller and larger CRLs was compared to the ART age via McNemar's test. RESULTS: Based on 140 ultrasounds, the CRL from the smaller twin best approximates the true gestational age with least bias compared to the larger twin or average (mean absolute deviation: 2.8, mean deviation: -0.1 [95% CI: -0.4, 0.2] versus 2.7, -0.9 [-1.1, -0.6] and 2.9, -1.5 [-1.8, -1.3], in days, respectively). Based on 165 ultrasounds, biometry from the smaller fetus is least accurate compared to the larger or mean (11.8, 2.5 [1.5, 3.6] versus 11.7, 0.8 [-0.3, 1.8] and 11.9, -1.0 [-2.0, 0.04], respectively). The incidence of small for gestational age neonates did not differ from the true rate using either the CRL from the larger or smaller twin (p > .05). CONCLUSION: In ART dichorionic gestations, ultrasound of the smaller fetus is most accurate in establishing gestational age in the first trimester but least accurate in the second, though all methods performed well with little clinical difference.

HIV efficiently infects T cells from the endometrium and remodels them to promote systemic viral spread.

The female reproductive tract (FRT) is the most common site of infection during HIV transmission to women, but viral remodeling complicates characterization of cells targeted for infection. Here, we report extensive phenotypic analyses of HIV-infected endometrial cells by CyTOF, and use a 'nearest neighbor' bioinformatics approach to trace cells to their original pre-infection phenotypes. Like in blood, HIV preferentially targets memory CD4+ T cells in the endometrium, but these cells exhibit unique phenotypes and sustain much higher levels of infection. Genital cell remodeling by HIV includes downregulating TCR complex components and modulating chemokine receptor expression to promote dissemination of infected cells to lymphoid follicles. HIV also upregulates the anti-apoptotic protein BIRC5, which when blocked promotes death of infected endometrial cells. These results suggest that HIV remodels genital T cells to prolong viability and promote viral dissemination and that interfering with these processes might reduce the likelihood of systemic viral spread.

Seminal plasma promotes decidualization of endometrial stromal fibroblasts in vitro from women with and without inflammatory disorders in a manner dependent on interleukin-11 signaling.

STUDY QUESTION: Do seminal plasma (SP) and its constituents affect the decidualization capacity and transcriptome of human primary endometrial stromal fibroblasts (eSFs)? SUMMARY ANSWER: SP promotes decidualization of eSFs from women with and without inflammatory disorders (polycystic ovary syndrome (PCOS), endometriosis) in a manner that is not mediated through semen amyloids and that is associated with a potent transcriptional response, including the induction of interleukin (IL)-11, a cytokine important for SP-induced decidualization. WHAT IS KNOWN ALREADY: Clinical studies have suggested that SP can promote implantation, and studies in vitro have demonstrated that SP can promote decidualization, a steroid hormone-driven program of eSF differentiation that is essential for embryo implantation and that is compromised in women with the inflammatory disorders PCOS and endometriosis. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional study involving samples treated with vehicle alone versus treatment with SP or SP constituents. SP was tested for the ability to promote decidualization in vitro in eSFs from women with or without PCOS or endometriosis (n = 9). The role of semen amyloids and fractionated SP in mediating this effect and in eliciting transcriptional changes in eSFs was then studied. Finally, the role of IL-11, a cytokine with a key role in implantation and decidualization, was assessed as a mediator of the SP-facilitated decidualization. PARTICIPANTS/MATERIALS, SETTING, METHODS: eSFs and endometrial epithelial cells (eECs) were isolated from endometrial biopsies from women of reproductive age undergoing benign gynecologic procedures and maintained in vitro. Assays were conducted to assess whether the treatment of eSFs with SP or SP constituents affects the rate and extent of decidualization in women with and without inflammatory disorders. To characterize the response of the endometrium to SP and SP constituents, RNA was isolated from treated eSFs or eECs and analyzed by RNA sequencing (RNAseq). Secreted factors in conditioned media from treated cells were analyzed by Luminex and ELISA. The role of IL-11 in SP-induced decidualization was assessed through Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas-9-mediated knockout experiments in primary eSFs. MAIN RESULTS AND THE ROLE OF CHANCE: SP promoted decidualization both in the absence and presence of steroid hormones (P < 0.05 versus vehicle) in a manner that required seminal proteins. Semen amyloids did not promote decidualization and induced weak transcriptomic and secretomic responses in eSFs. In contrast, fractionated SP enriched for seminal microvesicles (MVs) promoted decidualization. IL-11 was one of the most potently SP-induced genes in eSFs and was important for SP-facilitated decidualization. LARGE SCALE DATA: RNAseq data were deposited in the Gene Expression Omnibus repository under series accession number GSE135640. LIMITATIONS, REASONS FOR CAUTION: This study is limited to in vitro analyses. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the notion that SP promotes decidualization, including within eSFs from women with inflammatory disorders. Despite the general ability of amyloids to induce cytokines known to be important for implantation, semen amyloids poorly signaled to eSFs and did not promote their decidualization. In contrast, fractionated SP enriched for MVs promoted decidualization and induced a transcriptional response in eSFs that overlapped with that of SP. Our results suggest that SP constituents, possibly those associated with MVs, can promote decidualization of eSFs in an IL-11-dependent manner in preparation for implantation. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by NIH (R21AI116252, R21AI122821 and R01AI127219) to N.R.R. and (P50HD055764) to L.C.G. The authors declare no conflict of interest.

Fibroepithelial Vaginal Polyps in a Newborn Female.

Discussion, diagnosis, and management of fibroepithelial polyps in a newborn female.

Offspring gender rates in active duty fighter pilots and flight officers.

INTRODUCTION: It has been reported in small studies that fighter pilots have a higher likelihood of producing female offspring secondary to job-related exposures. No large-scale study has investigated this potential gender disparity. METHODS: This retrospective study utilized electronic medical record systems to identify men with flight-related occupations within the U.S. military from September 2012 to January 2018. The gender of offspring born to those men at least one year after entry into the flight community were compared to gender rates of children born to the U.S. general population during the same time period. RESULTS: 10,879 and 62,624 children born to fighter pilots and pilots of non-fighter type aircraft respectively were compared. The gender distribution of children born to both communities was similar to U.S. general population trends. CONCLUSIONS: This large-scale study provides social reassurances that the degree of risk imposed on our nation's air defense force does not influence the gender balance of the subsequent generation.

Human Endometrial Fibroblasts Derived from Mesenchymal Progenitors Inherit Progesterone Resistance and Acquire an Inflammatory Phenotype in the Endometrial Niche in Endometriosis.

Human endometrium undergoes cyclic regeneration involving stem/progenitor cells, but the role of resident endometrial mesenchymal stem cells (eMSC) as progenitors of endometrial stromal fibroblasts (eSF) has not been definitively demonstrated. In endometriosis, eSF display progesterone (P4) resistance with impaired decidualization in vivo and in vitro. To investigate eMSC as precursors of eSF and whether endometriosis P4 resistance is inherited from eMSC, we analyzed transcriptomes of eutopic endometrium eMSC and eSF isolated by fluorescence-activated cell sorting (FACS) from endometriosis (eMSCendo, eSFendo) and controls (eMSCcontrol, eSFcontrol) and their derived primary cultures. Differentially expressed lineage-associated genes (LG) of FACS-isolated eMSC and eSF were largely conserved in endometriosis. In culture, eSFcontrol maintained in vitro expression of a subset of eSF LG and decidualized in vitro with P4 The eMSCcontrol cultures differentiated in vitro to eSF lineage, down-regulating eMSC LG and up-regulating eSF LG, showing minimal transcriptome differences versus eSFcontrol cultures and decidualizing in vitro. Cultured eSFendo displayed less in vitro LG stability and did not decidualize in vitro. In vitro, eMSCendo differentiated to eSF lineage but showed more differentially expressed genes versus eSFendo cultures, and did not decidualize in vitro, demonstrating P4 resistance inherited from eMSCendo Compared to controls, cultures from tissue-derived eSFendo uniquely had a pro-inflammatory phenotype not present in eMSCendo differentiated to eSF in vitro, suggesting divergent niche effects for in vivo versus in vitro lineage differentiation. These findings substantiate eMSC as progenitors of eSF and reveal eSF in endometriosis as having P4 resistance inherited from eMSC and a pro-inflammatory phenotype acquired within the endometrial niche.

Perivascular human endometrial mesenchymal stem cells express pathways relevant to self-renewal, lineage specification, and functional phenotype.

Human endometrium regenerates on a cyclic basis from candidate stem/progenitors whose genetic programs are yet to be determined. A subpopulation of endometrial stromal cells, displaying key properties of mesenchymal stem cells (MSCs), has been characterized. The endometrial MSC (eMSC) is likely the precursor of the endometrial stromal fibroblast. The goal of this study was to determine the transcriptome and signaling pathways in the eMSC to understand its functional phenotype. Endometrial stromal cells from oocyte donors (n = 20) and patients undergoing benign gynecologic surgery (n = 7) were fluorescence-activated cell sorted into MCAM (CD146)(+)/PDGFRB(+) (eMSC), MCAM (CD146)(-)/PDGFRB(+) (fibroblast), and MCAM (CD146)(+)/PDGFRB(-) (endothelial) populations. The eMSC population contained clonogenic cells with a mesenchymal phenotype differentiating into adipocytes when cultured in adipogenic medium. Gene expression profiling using Affymetrix Human Gene 1.0 ST arrays revealed 762 and 1518 significantly differentially expressed genes in eMSCs vs. stromal fibroblasts and eMSCs vs. endothelial cells, respectively. By principal component and hierarchical clustering analyses, eMSCs clustered with fibroblasts and distinctly from endothelial cells. Endometrial MSCs expressed pericyte markers and were localized by immunofluorescence to the perivascular space of endometrial small vessels. Endometrial MSCs also expressed genes involved in angiogenesis/vasculogenesis, steroid hormone/hypoxia responses, inflammation, immunomodulation, cell communication, and proteolysis/inhibition, and exhibited increased Notch, TGFB, IGF, Hedgehog, and G-protein-coupled receptor signaling pathways, characteristic of adult tissue MSC self-renewal and multipotency. Overall, the data support the eMSC as a clonogenic, multipotent pericyte that displays pathways of self-renewal and lineage specification, the potential to respond to conditions during endometrial desquamation and regeneration, and a genetic program predictive of its differentiated lineage, the stromal fibroblast.

What the obstetrician/gynecologist should know about thyroid disorders.

UNLABELLED: Thyroid disease is a common disorder faced by women of all ages. Because of its high incidence in women, recognizing and treating thyroid dysfunction often becomes the responsibility of the obstetrician/gynecologist. It is important that women's healthcare providers understand how the thyroid's function changes as a woman enters her reproductive years, as well as during pregnancy and menopause. Current guidelines for diagnosing and managing thyroid dysfunction and recommended treatment strategies are discussed in this review. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this educational activity, the obstetrician/gynecologist should be better able to evaluate normal thyroid physiology and pathophysiology of thyroid dysfunction; assess appropriate screening options for their patients; and diagnose and manage thyroid disorders common among reproductive-aged women.

Does ethnicity influence in vitro fertilization (IVF) birth outcomes?

OBJECTIVE: To determine if ethnicity influences IVF birth outcome. DESIGN: Retrospective cohort study. SETTING: University-based IVF program. PATIENT(S): All African American women (n = 71) and Caucasian women (n = 180) who underwent initial fresh, nondonor IVF/embryo transfer (ET) cycles between January 1, 2004 and December 31, 2005. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Gonadotropin dose, duration of stimulation, peak estradiol levels, oocyte yield, implantation, clinical pregnancy, and live birth rates. RESULT(S): African American women generated significantly fewer embryos than Caucasian women (5.3 +/- 3.7 vs. 6.6 +/- 4.8) despite having similar ages, day 3 FSH, peak estradiol levels, length of stimulation, and number of oocytes retrieved. In addition, compared with Caucasian women, African American had significantly greater body mass indices (26.5 +/- 5.2 vs. 23.7 +/- 4.8) and required significantly more total gonadotropin (IU) (4,791 +/- 2,161 vs. 3,725 +/- 2,005) for ovarian stimulation. African American women were more likely to have uterine fibroids (21% vs. 3%) and tubal factor infertility (23% vs. 9%). Caucasian women were more likely to have unexplained infertility (53% vs. 32%). Differences in embryo yield between patient groups persisted after accounting for differences in infertility diagnosis and prevalence of fibroids. Biochemical, clinical pregnancy, and live birth rates as well as implantation rates (number of sacs visualized/number of embryos transferred) did not significantly differ between groups. CONCLUSION(S): Although African Americans yield fewer embryos than Caucasian women with IVF, these ethnic groups do not seem to differ with regard to IVF pregnancy outcomes.