AKAP13 Enhances CREB1 Activation by FSH in Granulosa Cells.

Granulosa cells (GCs) must respond appropriately to follicle-stimulating hormone (FSH) for proper follicle maturation. FSH activates protein kinase A (PKA) leading to phosphorylation of the cyclic AMP response element binding protein-1 (CREB1). We identified a unique A-kinase anchoring protein (AKAP13) containing a Rho guanine nucleotide exchange factor (RhoGEF) region that was induced in GCs during folliculogenesis. AKAPs are known to coordinate signaling cascades, and we sought to evaluate the role of AKAP13 in GCs in response to FSH. Aromatase reporter activity was increased in COV434 human GCs overexpressing AKAP13. Addition of FSH, or the PKA activator forskolin, significantly enhanced this activity by 1.5- to 2.5-fold, respectively (p < 0.001). Treatment with the PKA inhibitor H89 significantly reduced AKAP13-dependent activation of an aromatase reporter (p = 0.0067). AKAP13 physically interacted with CREB1 in co-immunoprecipitation experiments and increased the phosphorylation of CREB1. CREB1 phosphorylation increased after FSH treatment in a time-specific manner, and this effect was reduced by siRNA directed against AKAP13 (p = 0.05). CREB1 activation increased by 18.5-fold with co-expression of AKAP13 in the presence of FSH (p < 0.001). Aromatase reporter activity was reduced by inhibitors of the RhoGEF region, C3 transferase and A13, and greatly enhanced by the RhoGEF activator, A02. In primary murine and COV43 GCs, siRNA knockdown of Akap13/AKAP13 decreased aromatase and luteinizing hormone receptor transcripts in cells treated with FSH, compared with controls. Collectively, these findings suggest that AKAP13 may function as a scaffolding protein in FSH signal transduction via an interaction with CREB, resulting in phosphorylation of CREB.

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.

Racial and ethnic differences in reproductive knowledge and awareness among women in the United States.

Objective: To evaluate if knowledge and awareness of concepts and concerns pertaining to reproductive health and fertility vary by race/ethnicity among reproductive-aged women in the United States. Methods: A 2013 cross-sectional web-based survey assessed reproductive health-related knowledge, awareness, and perceptions of 1,000 women (18-40 years). Multivariable logistic regression analyses, adjusting for age, education, income, marital status, employment, region, and pregnancy history, examined the association between race/ethnicity and subfertility-related risk factor awareness; knowledge of factors that may affect pregnancy susceptibility; and future fertility-related concerns. Results: Knowledge and awareness related to reproductive wellness and fertility differed by race/ethnicity in US women. Compared with Caucasians, Hispanic women were less likely to be aware of smoking-related harm to fertility (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.38-0.86); African American women were more aware of the implications of sexually transmitted infections on fertility (OR, 2.13; 95% CI, 1.15-3.94); and Asian women demonstrated greater awareness of a possible relationship between dysmenorrhea and subfertility (OR, 2.05; 95% CI, 1.09-3.86). Asian women consider fertility socially taboo to talk about and a private affair that is difficult to discuss (OR, 2.63; 95% CI, 1.32-5.29 and OR, 1.99; 95% CI, 1.05-3.75, respectively), were more concerned about their future fertility (OR, 2.36; 95% CI, 1.24-4.52), and more likely to perceive a need for future fertility treatment (OR, 2.36; 95% CI, 1.18-4.71). Conclusion: Among reproductive-aged women in the United States, knowledge, awareness, and perceptions relating to reproductive health vary by race/ethnicity. Our findings suggest race/ethnicity as potential modulators of population perceptions regarding reproductive health and infertility. Clinical Trial Registration Number: NIH ZIA# HD008985.

Fertility and CAR T-cells: Current practice and future directions.

Chimeric antigen receptor (CAR) T-cells serve to overcome chemotherapeutic resistance and have been proven to be highly effective in B-cell hematologic malignancies. Although initial use has been in patients with multiply relapsed/refractory disease, as CAR T-cells are used earlier in the treatment paradigm, it will be important to explore implications of this novel therapy on cancer late-effects. We sought to assess the current framework for considerations of fertility surrounding CAR T-cell use and identify opportunities for education and future research. To assess current practice patterns regarding post-CAR T-cell fertility, peri-CAR T-cell fertility guidance, utilization of fertility preservation surrounding CAR T-cell administration and identify future areas of research, a cross-sectional survey assessing practice patterns regarding fertility counseling and outcomes surrounding CAR T-cell therapy was distributed electronically to approximately 300 Center for International Blood and Marrow Transplant Research medical centers treating patients with CAR T-cell therapy in the United States and internationally between October 12 and November 2, 2021. One medical provider was asked to complete the study survey on behalf of their institution. We received 96 survey responses, of which 66 centers utilized CAR T-cells and provided at least partial responses that were used for the primary analysis. Centers were varied in demographics, experience in administering CAR T-cells, and aspects of patients receiving CAR T-cells. Eighteen centers exclusively treated pediatric patients, and patients at these centers were more likely to be treated for B-cell acute lymphoblastic leukemia. Seven pregnancies and 5 live births after CAR T-cells were reported from 6 centers (1 pediatric-only). Most centers had no established guidelines in place regarding fertility preservation in the peri-CAR T-cell period or regarding recommendations for avoiding pregnancy/fathering a child after receiving CAR T-cells. Areas for future research were elicited from responding centers and categorized into 3 broad themes, including: standardized peri-CAR T-cell fertility guidelines; long-term fertility outcomes after CAR T-cell therapy; impact of CAR T-cells on a developing fetus; and determining the relevance of studying fertility in patients who receive CAR T-cells. We identified a high degree of variability in peri-CAR T-cell guidance on avoidance of pregnancy/fathering a child, as well as a wide-range of practices surrounding referral for fertility preservation, the latter of which may be likely due to the fact that patients receiving CAR T-cells in the present era are likely multiply relapsed/refractory. In summary, this is the first report of several live-births following CAR T-cells, which highlights the important need for further research in CAR T-cell therapy and fertility, with a host of novel research questions identified.

Fertility after Curative Therapy for Sickle Cell Disease: A Comprehensive Review to Guide Care.

Curative therapy for sickle cell disease (SCD) currently requires gonadotoxic conditioning that can impair future fertility. Fertility outcomes after curative therapy are likely affected by pre-transplant ovarian reserve or semen analysis parameters that may already be abnormal from SCD-related damage or hydroxyurea treatment. Outcomes are also likely affected by the conditioning regimen. Conditioning with myeloablative busulfan and cyclophosphamide causes serious gonadotoxicity particularly among post-pubertal females. Reduced-intensity and non-myeloablative conditioning may be acutely less gonadotoxic, but more short and long-term fertility outcome data after these approaches is needed. Fertility preservation including oocyte/embryo, ovarian tissue, sperm, and experimental testicular tissue cryopreservation should be offered to patients with SCD pursing curative therapy. Regardless of HSCT outcome, longitudinal post-HSCT fertility care is required.

An intersectional analysis of contraceptive types chosen among sexual minority women: A nationally representative study.

OBJECTIVE: The purpose of this study is to use an intersectional approach in which race, insurance, care setting, and disclosure of sexual orientation to a provider are used to assess patterns of contraceptive use in sexual minority women. STUDY DESIGN: This study analyzes cross-sectional data from the 2011-2019 National Survey of Family Growth (NSFG). Sexual orientation of 21,075 respondents' data was used to investigate contraceptive use in sexual minority women, specifically lesbian and bisexual women, as compared to heterosexual women, controlling for variables such as race, age, and socioeconomic factors. RESULTS: Black and Hispanic lesbian women (adjusted odds ratio [aOR] = 0.39 confidence interval [CI] 0.20-0.76 and aOR = 0.44 CI 0.23-0.82, respectively) and Hispanic and Other Race bisexual women use hormonal contraceptive methods less than their White lesbian and bisexual peers (aOR = 0.45 CI 0.29-0.69 and aOR = 0.43 CI 0.20-0.94). Care setting was not correlated with long-acting reversible contraceptive methods (LARC; such as intra-uterine device, hormonal implants) or prescription-based hormonal methods (such as oral contraceptive pills, injectables, vaginal rings, and patches) in lesbian women (aOR = 2.92 CI 0.60-14.2 and aOR = 1.43 CI 0.47-4.38, respectively) or bisexual women (aOR = 0.90 CI 0.48-1.58 and aOR = 0.83 CI 0.37-1.86), but it was for straight women (aOR = 1.28 CI 1.03-1.59 and aOR = 0.68 CI 0.53-0.86). Similarly, insurance status did not correlate with contraceptive patterns in sexual minority women. Importantly, adjusting for nationally representative data did not impact the results; in other words, the odds ratios after adjusting yielded the same results as before adjustment. CONCLUSIONS: Insurance and care setting are important determinants of straight women's contraceptive use patterns with fewer effects seen among sexual minority women. These findings support previous work and indicate that known advantages of insurance coverage or use of public clinics may not positively impact sexual minority women as much as they do straight women. Provider awareness of sexual identity and sexual orientation is important for adequate contraceptive care. IMPLICATIONS: While prior research has presented findings on sexual minority women contraceptive use, to our knowledge there are limited studies that address the social and demographic implications for contraceptive use in this population.

Case report: two cases of mature oocytes found in prepubertal girls during ovarian tissue cryopreservation.

OBJECTIVE: To report two cases of mature oocytes found in prepubertal girls undergoing ovarian tissue cryopreservation (OTC). DESIGN: Case report. SETTING: Large tertiary care children's hospital and a private fertility clinic. PATIENTS: An 8-year-old prepubertal girl with ß-thalassemia and a 2-year-old girl with sickle cell disease who both underwent OTC before bone marrow transplantations. INTERVENTIONS: Laparoscopic right oophorectomy was performed in each patient. The ovarian cortical tissue was processed for slow freezing and long-term storage, and all oocytes were subsequently vitrified. MAIN OUTCOME MEASURES: Oocytes found at the time of OTC processing for fertility preservation. RESULTS: After a complete right oophorectomy, one mature metaphase II oocyte was discovered on tissue processing for OTC in each patient. Neither patient has yet returned for use of tissue or oocytes. CONCLUSIONS: To our knowledge, this is the first report of mature oocytes found during prepubertal OTC processing. These findings may indicate the need for increased research regarding prepubertal oocyte development and suggest that the technique of examining the media for both mature and immature oocytes at the time of OTC should become more widespread and perhaps recommended in prepubertal patients to optimize fertility preservation methods.

Predictive factors for fertility preservation in pediatric and adolescent girls with planned gonadotoxic treatment.

PURPOSE: To characterize female pediatric and adolescent patients seen for fertility preservation consultation at an academic medical center and to describe the association between demographic or clinical factors and the use of fertility preservation treatment (FPT). METHODS: This is a retrospective chart analysis of female pediatric and adolescent patients seen for fertility preservation consultation at an academic fertility center over a 14-year period from 2005 to 2019. RESULTS: One hundred six females aged 3-21 years were seen for fertility preservation consultation with a mean age of 16.6 years. Diagnoses included hematologic malignancies (41.5%), gynecologic malignancies (9.4%), other malignancies (31.1%), non-malignant hematologic disease (14.2%), and non-malignant conditions (3.8%). Overall, 64.2% of subjects pursued fertility preservation, including oocyte cryopreservation (35.8%) and ovarian tissue cryopreservation (23.6%). Overall, age, minority race, diagnosis, time since diagnosis, and median household income were not significantly associated with odds of completing an FPT procedure. Among all patients, those who underwent gonadotoxic therapy prior to consultation had a lower odds of receiving FPT (OR= 0.24, 95% CI 0.10-0.55). Among patients without chemotherapy exposure, no factors were associated with FPT. CONCLUSIONS: Among pediatric and adolescent patients at an academic center undergoing a fertility preservation consultation, there were no socioeconomic or clinical barriers to FPT use in those who had not yet undergone gonadotoxic therapy. The only factor that was negatively associated with odds of pursuing FPT was prior chemotherapy exposure.

Conservatively treated endometrial intraepithelial neoplasia/cancer: Risk of intrauterine synechiae.

INTRODUCTION: To determine whether progestin type or number of dilation and curettage procedures (D&Cs) were associated with intrauterine synechiae (IS) or pregnancy outcomes in patients conservatively treated for endometrial intraepithelial neoplasia (EIN) or endometrial cancer (EC). MATERIALS AND METHODS: We evaluated patients conservatively treated for EIN or EC from 2000 to 2017 at an academic center. IS were identified hysteroscopically. We calculated proportions for categorical variables and tested associations between D&C number, progestin, and pregnancy outcomes using Pearson chi-squared and Fisher's exact tests. A post-hoc power analysis indicated sufficient power to detect livebirth. RESULTS: We analyzed 54 patients, 15 with EIN (28 %) and 39 with EC (72 %), with a mean age of 34 ± 1.2 years. Progestin treatment types included megestrol acetate (MA) (n = 24), MA with levonorgestrel intrauterine device (LngIUD) (n = 10), MA followed by LngIUD (n = 3), and LngIUD alone (n = 6). Mean number of D&Cs was 3.9 ± 0.9. Overall, 53 subjects underwent hysteroscopy; 10 (19 %) had IS. When D&Cs were grouped into 0-2, 3-4 and ≥5, each increase in D&C group had a 2.9 higher odds of IS (OR: 2.91, p = 0.04, CI: 1.05-10.02). LngIUD was associated with a nonsignificant 46 % decrease in the odds of IS (OR: 0.54, p = 0.66, CI: 0.08-2.87). Twenty-two women attempted pregnancy; 14 women achieved a total of 20 pregnancies and 9 women had total of 15 livebirths (41 % livebirth rate). The number of D&Cs and progestin treatment type were not associated with pregnancy outcomes. DISCUSSION: Among 54 patients conservatively treated for EC/EIN, nearly 20 % developed IS. However, hysteroscopic and/or fertility treatments may improve pregnancy outcomes.

Does theFMR1 gene affect IVF success?

FMR1 CGG trinucleotide repeat expansions are associated with Fragile X syndrome (full mutations) and primary ovarian insufficiency (premutation range); the effect of FMR1 on the success of fertility treatment is unclear. The effect of FMR1 CGG repeat lengths on IVF outcomes after ovarian stimulation was reviewed. PubMed was searched for studies on IVF-related outcomes reported by FMR1 trinucleotide repeat length published between 2002 and December 2017. For women with CGG repeats in the normal (<45 CGG), intermediate range (45-54 CGG), or both, research supports a minimal effect on IVF outcomes, including pregnancy rates; although one study reported lower oocyte yields after IVF stimulation in women with lower CGG repeat lengths and normal ovarian reserve. Meta-analysis revealed no association within subcategories of normal repeat length (<45 CGG) and IVF pregnancy rates (summary OR 1.0, 95% CI 0.87 to 1.15). Premutation carriers (CGG 55-200) may have reduced success with IVF treatment (lower oocyte yield) than women with a normal CGG repeat length or a full mutation, although findings are inconsistent. Direct implications of the repeat length on inheritance and the risk of Fragile X syndrome have been observed. Patients may require clinical and psychological counselling, and further preimplantation genetic testing options should be considered. Thus, there are clinical and psychological counseling implications for patients and potential further patient decisions regarding preimplantation genetic testing options.

Risks associated with fertility preservation for women with sickle cell anemia.

OBJECTIVE: To highlight the risk of complications among women with sickle cell anemia (SCA) receiving fertility preservation treatment (FPT) before hematopoietic stem cell transplant (HSCT). DESIGN: Single-center case series. SETTING: Academic fertility center. PATIENT(S): Women aged 15-32 years with SCA undergoing FPT before HSCT. INTERVENTION(S): Retrospective, systematic review. MAIN OUTCOME MEASURE(S): FPT modality, SCA complications during FPT. RESULT(S): Over an 8-year period (2009-2017), seven women with SCA ages 15-32 years (mean 28.5 years) underwent FPT with embryo cryopreservation (n = 1), oocyte cryopreservation (n = 4), and ovarian tissue cryopreservation (n = 2). The five women subjects who underwent oocyte or embryo cryopreservation were treated with an antagonist controlled ovarian hyperstimulation protocol and individualized gonadotropin dosing. The trigger medications included leuprolide acetate (n = 2), and human chorionic gonadotropin (n = 3). Most patients (n = 5) received a disease-modifying therapy for SCA (hydroxyurea or chronic transfusions) before FPT. Three patients experienced periprocedural SCA complications that included life-threatening respiratory failure, painful crisis requiring interruption of a stimulation cycle, and severe postharvest painful crisis. CONCLUSION(S): Women with SCA may choose to undergo diverse FPT strategies before HSCT and are at risk for serious SCA-related complications. Evidence-based strategies to mitigate SCA-related morbidity and to optimize fertility preservation outcomes are needed.

Controlled ovarian stimulation and triggers in in vitro fertilization: protocol personalization key to optimize outcomes.

The past four decades have delivered many advancements to improve in vitro fertilization (IVF) outcomes. These include a delicate balance of controlled ovarian hyperstimulation (COH) without causing ovarian hyperstimulation syndrome (OHSS), a safe oocyte retrieval, fertilization and embryo culture, endometrial growth and receptivity to promote implantation, and luteal support to maintain the pregnancy. Contemporary IVF practice includes both the classic COH protocols as well as protocols for poor responders and those for specific patient populations. An assortment of agents have been developed and utilized in various combinations to improve COH outcomes and promote oocyte maturation while decreasing the risk of OHSS. Various protocols have evolved over time. Ideal practices involve selecting the optimal protocol for a personalized, patient-specific stimulation and trigger.