Anatomic nomenclature and 3-dimensional regional model of the human ovary: call for a new paradigm.

The ovaries are the female gonads that are crucial for reproduction, steroid production, and overall health. Historically, the ovary was broadly divided into regions defined as the cortex, medulla, and hilum. This current nomenclature lacks specificity and fails to consider the significant anatomic variations in the ovary. Recent technological advances in imaging modalities and high-resolution omic analyses have brought about the need for revision of the existing definitions, which will facilitate the integration of generated data and enable the characterization of organ subanatomy and function at the cellular level. The creation of these high-resolution multimodal maps of the ovary will enhance collaboration and communication among disciplines and between clinicians and researchers. Beginning in March 2021, the Pediatric and Adolescent Gynecology Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development invited subject-matter experts to participate in a series of workshops and meetings to standardize ovarian nomenclature and define the organ's features. The goal was to develop a spatially defined and semantically consistent terminology of the ovary to support collaborative, team science-based endeavors aimed at generating reference atlases of the human ovary. The group recommended a standardized, 3-dimensional description of the ovary and an ontological approach to the subanatomy of the ovary and definition of follicles. This new greater precision in nomenclature and mapping will better reflect the ovary's heterogeneous composition and function, support the standardization of tissue collection, facilitate functional analyses, and enable clinical and research collaborations. The conceptualization process and outcomes of the effort, which spanned the better part of 2021 and early 2022, are introduced in this article. The institute and the workshop participants encourage researchers and clinicians to adopt the new systems in their everyday work to advance the overarching goal of improving human reproductive health.

Uterine Artery Embolization for Symptomatic Adenomyosis: Proceedings from a Society of Interventional Radiology Foundation Research Consensus Panel.

Adenomyosis poses an important diagnostic and therapeutic challenge in women's health because of a variety of clinical/imaging presentations and frequent coexistence with other benign gynecologic conditions. In recent years, uterine artery embolization (UAE) for the treatment of adenomyosis has shown encouraging and favorable outcomes and long-term symptom improvement. To expand the current understanding of adenomyosis pathophysiology, imaging diagnostic criteria, and treatment outcomes, the Society of Interventional Radiology Foundation gathered a multidisciplinary Research Consensus Panel with experts from diverse backgrounds. The topics addressed were centered around the following: (i) the clinical presentation and imaging findings to diagnose adenomyosis; (ii) the currently available medical, interventional, and surgical treatment options; and (iii) existing literature for and experiences with UAE in symptomatic disease. The panel acknowledged that before the pursuit of a clinical trial, it would be necessary to first evaluate the imaging criteria for adenomyosis and correlate them with pathology and symptoms to establish a noninvasive imaging classification system. Second priority was given to the development of a quality of life questionnaire to assess patient outcomes following treatment. The third priority was the performance of a prospective clinical trial comparing UAE with medical therapy, which would help establish UAE in the treatment algorithm and societal guidelines for symptomatic adenomyosis.

Eye to the Future in Adenomyosis Research.

Adenomyosis is a poorly understood and clinically underappreciated gynecologic disorder associated with substantial morbidity including dysmenorrhea, pelvic pain, heavy menstrual bleeding, infertility, and poor pregnancy outcomes. Substantial gaps persist in our understanding of essentially all aspects of this disorder - epidemiology, risk factors, pathogenesis, pathophysiology, diagnosis, and treatment. In this article, we summarize current thoughts on future directions in basic, translational, and clinical adenomyosis research.

Report of the National Cancer Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development-sponsored workshop: gynecology and women's health-benign conditions and cancer.

The Division of Cancer Prevention and the Division of Cancer Biology at the National Cancer Institute and the Gynecologic Health and Disease Branch in the National Institute of Child Health and Human Development organized a workshop in April 2019 to explore current insights into the progression of gynecologic cancers from benign conditions. Working groups were formed based on 3 gynecologic disease types: (1) Endometriosis or Endometrial Cancer and Endometrial-Associated Ovarian Cancer, (2) Uterine Fibroids (Leiomyoma) or Leiomyosarcoma, and (3) Adenomyosis or Adenocarcinoma. In this report, we highlight the key questions and current challenges that emerged from the working group discussions and present potential research opportunities that may advance our understanding of the progression of gynecologic benign conditions to cancer.

Effect of preconception low dose aspirin on pregnancy and live birth according to socioeconomic status: A secondary analysis of a randomized clinical trial.

Low socioeconomic status (SES) is associated with adverse pregnancy outcomes and infertility. Low-dose aspirin (LDA) was shown to improve livebirth rates in certain subsets of women, and therefore, may impact pregnancy rates differentially by SES status. Therefore, the aim of the current study was to examine whether daily preconception-initiated LDA affects rates of pregnancy, livebirth, and pregnancy loss differently across strata of socioeconomic status (SES). This is a secondary analysis of The Effects of Aspirin in Gestation and Reproduction (EAGeR) Trial, a multisite, block- randomized, placebo-controlled trial conducted at four U.S. medical centers (n = 1,228, 2007-2012). Women attempting spontaneous conception with a history of pregnancy loss were randomly allocated preconception to 81mg of aspirin + 400mcg of folic acid (n = 615) or placebo + 400mcg of folic acid (n = 613). Study medication was administered for six menstrual cycles or until 36 weeks' gestation if pregnancy was achieved. For this analysis, women were stratified by SES, which included income (low, mid, high) and a combined grouping of education and income (low-low, low-high, high-low, high-high). Log binomial models with robust variance estimated risks of pregnancy, livebirth, and pregnancy loss for LDA versus placebo. LDA increased pregnancy and livebirth rates (RR 1.23, 95% CI: 1.03, 1.45) in the high-income, but not mid- or low-income groups. LDA increased pregnancy rates in both the low education-low income group (RR 1.22, 95% CI: 1.02, 1.46) and the high education-high income group (RR 1.23, 95%CI: 1.06, 1.42), with no effect observed in mid-SES groupings. LDA, a low-cost and widely available treatment, may be particularly beneficial to women at the highest and lowest ends of the socioeconomic spectrum, though underlying mechanisms of this disparity are unclear. Confirming these findings and identifying factors which may modulate the effectiveness of LDA will ultimately facilitate personalized clinical care and improvements in population-level reproductive health. Trial registration number: ClinicalTrials.gov, NCT00467363.

Gynecologic Health and Disease Research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development: A Scientific Vision.

In May 2016, the newly formed Gynecologic Health and Disease Branch in the Eunice Kennedy Shriver National Institute of Child Health and Human Development invited experts to a 2-day meeting aimed at identification of emerging opportunities in gynecologic investigation. Four primary disorders were chosen for emphasis because they represent the majority of the current Gynecologic Health and Disease Branch portfolio: uterine leiomyomas, endometriosis, pelvic floor disorders, and gynecologic pain conditions. Discussions generated a set of seven cross-cutting themes, which encompass both gaps in our current knowledge and potential directions for further research. These themes formed a continuum for understanding these disorders beginning with the need for classification systems, improved understanding of the natural history and etiology of these disorders, development of novel diagnostics, identification of opportunities for prevention, and the generation of new treatments using cutting-edge approaches. Along with these themes, three broad strategies were proposed to facilitate future research. First, investigators should improve utilization of existing research resources and focus on developing new resources to include databases, biospecimen repositories, animal models, and patient cohorts. Second, multidisciplinary scientific partnerships should be strengthened to bring new insights and approaches to gynecologic research. Third, patient and health care provider education must be promoted to ensure timely and accurate diagnosis and optimize treatment of gynecologic disorders. This article provides a summary of the workshop themes and suggestions, several of which have already been implemented through the development of program priorities and funding opportunity announcements aimed at improving women's reproductive health.

Gonadotropin-releasing hormone and gonadal steroids regulate transcription factor mRNA expression in primary pituitary and immortalized gonadotrope cells.

Hormonal regulation of pituitary gonadotropin gene expression has been attributed to gonadotropin-releasing hormone (GnRH)-mediated stimulation of immediate early gene expression and gonadal steroid interactions with their respective nuclear receptors. A number of orphan nuclear receptors including steroidogenic factor 1, liver receptor homologue 1, dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1, and chicken ovalbumin upstream promoter-transcription factors I/II as well as the GATA family members, GATA2 and GATA4, have also been implicated in transcriptional regulation of the gonadotropin genes. We hypothesized that hormonally mediated changes in these latter transcription factors may provide an additional mechanism for mediating hormonal effects beyond the more classically appreciated pathways. In these studies, we demonstrate significant regulation of orphan nuclear receptor and GATA messenger RNA levels by GnRH, dihydrotestosterone, estradiol, and progesterone in both cultured primary pituitary cells and gonadotrope-derived cell line, LßT2. These results advance our understanding of the complex mechanisms by which GnRH and steroid hormones achieve precise regulation of anterior pituitary function.

Interaction of gonadal steroids and gonadotropin-releasing hormone on pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP receptor expression in cultured rat anterior pituitary cells.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are expressed in the hypothalamus, the gonadotrope cells of the anterior pituitary gland, and the gonads, forming an autocrine-paracrine system in these tissues. Within the pituitary, PACAP functions either alone or synergistically with gonadotropin-releasing hormone (GnRH) to stimulate gonadotropin gene expression and secretion. Our goal was to define the hormonal regulation of pituitary PACAP and PACAP receptor (PAC1) gene expression by dihydrotestosterone (DHT), estradiol, and progesterone alone or in conjunction with GnRH. Treatment of adult male rat pituitary cell cultures with DHT or progesterone augmented GnRH-mediated increase in PACAP messenger RNA (mRNA) levels, but neither had an effect when present alone. Conversely, estradiol treatment blunted PACAP gene expression but did not alter GnRH effects on PACAP expression. Expression of PACAP receptor mRNA was decreased by GnRH treatment, minimally increased by DHT treatment, but not altered by the addition of estradiol or progesterone. DHT and GnRH together blunted PACAP receptor gene expression. Taken together, these results suggest that the activity of the intrapituitary PACAP-PAC1 system is regulated via the complex interaction of gonadal steroids and hypothalamic GnRH.

PACAP modulates GnRH signaling in gonadotropes.

Hypothalamic gonadotropin-releasing hormone is known to be critical for normal gonadotropin biosynthesis and secretion by the gonadotrope cells of the anterior pituitary gland. Additional regulation is provided by gonadal steroid feedback as well as by intrapituitary factors, such as activin and follistatin. Less well-appreciated is the role of pituitary adenylate-cyclase activating polypeptide (PACAP) as both a hypothalamic-pituitary releasing factor as well as an autocrine-paracrine factor within the pituitary. PACAP regulates gonadotropin expression alone and through modulation of GnRH responsiveness achieved by increases in GnRH receptor expression and interactions at the level of intracellular signaling pathways. In addition to direct effects on the gonadotrope, PACAP stimulates follistatin secretion by the folliculostellate cells and thereby contributes to differential expression of the gonadotropin subunits. Conversely, GnRH augments the ability of PACAP to regulate gonadotrope function by increasing pituitary PACAP and PACAP receptor expression. This review will summarize the current understanding of the mechanisms by which PACAP modulates gonadotrope function, with a focus on interactions with GnRH.

GATA augments GNRH-mediated increases in Adcyap1 gene expression in pituitary gonadotrope cells.

Pituitary adenylate cyclase-activating polypeptide 1 (PACAP or ADCYAP1) regulates gonadotropin biosynthesis and secretion, both alone and in conjunction with GNRH. Initially identified as a hypothalamic-releasing factor, ADCYAP1 subsequently has been identified in pituitary gonadotropes, suggesting it may act as an autocrine-paracrine factor in this tissue. GNRH has been shown to increase pituitary Adcyap1 gene expression through the interaction of CREB and jun/fos with CRE/AP1 cis-elements in the proximal promoter. In these studies, we were interested in identifying additional transcription factors and cognate cis-elements which regulate Adcyap1 gene promoter activity and chose to focus on the GATA family of transcription factors known to be critical for both pituitary cell differentiation and gonadotropin subunit expression. By transient transfection and electrophoretic mobility shift assay analysis, we demonstrate that GATA2 and GATA4 stimulate Adcyap1 promoter activity via a GATA cis-element located at position -191 in the rat Adcyap1 gene promoter. Furthermore, we show that addition of GATA2 or GATA4 significantly augments GNRH-mediated stimulation of Adcyap1 gene promoter activity in the gonadotrope LßT2 cell line. Conversely, blunting GATA expression with specific siRNA inhibits the ability of GNRH to stimulate ADCYAP1 mRNA levels in these cells. These data demonstrate a complex interaction between GNRH and GATA on ADCYAP1 expression, providing important new insights into the regulation of gonadotrope function.

Androgen receptor drives transcription of rat PACAP in gonadotrope cells.

Gonadotropin expression is precisely regulated within the hypothalamic-pituitary-gonadal axis through the complex interaction of neuropeptides, gonadal steroids. and both gonadal- and pituitary-derived peptides. In the anterior pituitary gland, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) modulates gonadotropin biosynthesis and secretion, acting both alone and in conjunction with GnRH. Steroid hormone feedback also influences gonadotropin expression via both direct and indirect mechanisms. Evidence from nonpituitary tissues suggests that PACAP may be a target for gonadal steroid regulation. In the present study, we show that androgen markedly stimulates rat (r) PACAP promoter-reporter activity in the LßT2 mature mouse gonadotrope cell line. 5'-Serial deletion analysis of reporter constructs identifies 2 regions of androgen responsiveness located at (-915 to -818) and (-308 to -242) of the rPACAP promoter. Androgen receptor (AR) binds directly to DNA cis-elements in each of these regions in vitro. Site-directed mutagenesis of 3 conserved hormone response element half-sites straddling the (-308 to -242) region dramatically blunts androgen-dependent PACAP promoter activity and prevents AR binding at the mutated promoter element. Chromatin immunoprecipitation demonstrates that endogenous AR binds the homologous region on mouse chromatin in LßT2 cells in both the presence and absence of androgen. These data demonstrate that androgen stimulates PACAP gene expression in the pituitary gonadotrope via direct binding of AR to a specific cluster of evolutionarily conserved hormone response elements in the proximal rPACAP gene promoter. Thus, androgen regulation of pituitary PACAP expression may provide an additional layer of control over gonadotropin expression within the hypothalamic-pituitary-gonadal axis.

Identification of HESX1 mutations in Kallmann syndrome.

OBJECTIVE: To determine whether HESX1 mutations are present in patients with idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS). DESIGN: Polymerase chain reaction-based DNA sequencing was performed on 217 well-characterized IHH/KS patients. Putative missense mutations were analyzed by sorting intolerant from tolerant (SIFT) and Clustal Ω. SETTING: Academic medical center. PATIENT(S): Two hundred seventeen patients with IHH/KS and 192 controls. INTERVENTION(S): Deoxyribonucleic acid was extracted from patients and controls; genotype/phenotype comparisons were made. MAIN OUTCOME MEASURE(S): Deoxyribonucleic acid sequence of HESX1, SIFT analysis, and ortholog alignment. RESULT(S): Two novel heterozygous missense mutations (p.H42Y and p.V75L) and previously reported heterozygous missense mutation p.Q6H in HESX1 were identified in 3 of 217 patients (1.4%). All were males with KS. Both p.Q6H and p.H42Y were predicted to be deleterious by SIFT, whereas p.V75L was conserved in 8 of 9 species. No other IHH/KS gene mutations were present. CONCLUSION(S): HESX1 mutations may cause KS in addition to more severe phenotypes. Our findings expand the phenotypic spectrum of HESX1 mutations in humans, thereby broadening its role in development.

Pituitary adenylate cyclase-activating polypeptide (PACAP) in the hypothalamic-pituitary-gonadal axis: a review of the literature.

Pituitary adenylate cyclase-activating polypeptide (PACAP), an ancient molecule highly preserved across species, has been classified as a member of the secretin/glucagon/vasoactive intestinal peptide/growth hormone-releasing hormone polypeptide family. PACAP was first identified as a hypothalamic-releasing factor; nevertheless, it has subsequently been determined to have widespread distribution and function, including expression in the pituitary, gonads, placenta, central and peripheral nervous systems, intestinal tract, and adrenal gland. Consistent with its widespread distribution, PACAP has been found to exert pleiotropic effects. Although first described over 20 years ago, only relatively recently has substantial attention turned to evaluating PACAP's role in the reproductive system. This review will focus on our current understanding of the expression pattern and function of PACAP in the hypothalamic-pituitary-gonadal axis.

GnRH decreases adiponectin expression in pituitary gonadotropes via the calcium and PKA pathways.

As endocrinologically active cells, adipocytes are capable of secreting various adipocytokines such as leptin, resistin, and adiponectin to impact metabolic function. Although adipocytes remain to be the primary site of synthesis and secretion, there is now growing evidence that supports the presence of adiponectin and its receptors within the hypothalamic-pituitary-gonadal axis, providing a possible link between obesity and abnormal reproductive physiology. It has been demonstrated that adiponectin may reduce gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus as well as modulate gonadal steroid hormone production. Furthermore, prior data indicate that adiponectin may play a role in decreasing luteinizing hormone secretion from pituitary gonadotropes. We aimed to identify the hormonal regulators of adiponectin and its receptors, AdipoR1 and AdipoR2, in pituitary gonadotropes using immortalized gonadotropic LßT2 cells and primary rat pituitary cells. Our study shows significant alterations in adiponectin expression across the estrous cycle. In addition, we present a novel finding that GnRH suppresses pituitary adiponectin expression via the calcium and protein kinase A intracellular pathways in both cultured rat primary pituitary cells and the LßT2 gonadotrope cell line. The GnRH did not alter expression of the adiponectin receptors, AdipoR1 and AdipoR2, in cultured gonadotropes. Expression of the adiponectin receptors, AdipoR1 and AdipoR2, was not altered by GnRH in cell culture but in vivo or in vitro. Our data suggest that gonadotrope function may be modulated by GnRH-mediated changes in adiponectin expression.

Subclinical thyroid disease and the incidence of hypertension in pregnancy.

OBJECTIVE: To estimate the possibility of long-term effects of subclinical thyroid dysfunction on hypertension and other cardiovascular-related conditions during pregnancy. METHODS: This is a secondary analysis of a prospective prenatal population-based study in which serum thyroid-function analytes were measured from November 2000 through April 2003. Women with evidence of overt thyroid disease were excluded. The remaining women were classified as being euthyroid, having subclinical hyperthyroid, or having subclinical hypothyroid, and the frequency of pregnancy-associated hypertensive disorders was compared between these groups. RESULTS: Pregnancy outcomes in 24,883 women were analyzed for pregnancy hypertension, classified as gestational hypertension, mild preeclampsia, or severe preeclampsia. The incidence of hypertensive disorders were compared between the three cohorts. The overall incidences of hypertension in pregnancy were 6.2%, 8.5%, and 10.9% in the subclinical hyperthyroid, euthyroid, and subclinical hypothyroid groups, respectively, and were found to be significant when unadjusted (P=.016). After adjusting for confounding factors, there was a significant association between subclinical hypothyroidism and severe preeclampsia (adjusted odds ratio 1.6, 95% confidence interval 1.1-2.4; P=.03). CONCLUSION: Women with subclinical hypothyroidism identified during pregnancy have an increased risk for severe preeclampsia when compared with euthyroid women. LEVEL OF EVIDENCE: II.

Antithyroid antibodies and parity: further evidence for microchimerism in autoimmune thyroid disease.

OBJECTIVE: Fetal microchimerism may have a role in development of autoimmune thyroid disorders. Using parity as a surrogate for increasing fetal cell exposure, we analyzed its association with thyroid peroxidase antibody levels. STUDY DESIGN: Secondary analysis of serum thyroid analytes determined in 17,298 women from a population-based prospective study between 2001 and 2003. Sera were assayed for thyrotropin, free thyroxine, and antithyroid peroxidase antibodies. We analyzed the relationship between thyroid peroxidase antibodies and increasing parity. RESULTS: The incidence of abnormally elevated thyroid peroxidase antibody levels (>50 IU/mL) increased with advancing parity, but was not significant after adjustment for maternal characteristics. However, at higher thyroid peroxidase antibody levels (>500 IU/mL), a significant relationship with advancing parity persisted after adjustments (P = .002). CONCLUSION: Advancing parity is associated with an increased risk for high serum concentrations of antithyroid peroxidase antibodies. This suggests fetal microchimerism may play a role in development of autoimmune thyroid disorders.