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Department of Surgery, Division of Urology, University of Missouri, Columbia, Missouri, USA
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In brief
Female hypospadias is a little-known and poorly studied birth defect. This research establishes an anatomical and molecular foundation for future research to investigate the origins of this defect.
Abstract
Hypospadias is a congenital anomaly of the external genitalia where the urethra does not properly close. In humans, hypospadias is mostly reported in male newborns, whereas in females hypospadias is rare, although it is generally considered to be under-reported. Improper urethra closure in the female genitalia can cause recurrent genitourinary tract infections and infertility. In mice, female hypospadias was induced by exposure to exogenous estrogenic compounds. Aside from the link between estrogen exposure and female hypospadias, the process of female urethra closure is largely unstudied, with the precise timing of urethra closure and associated molecular mechanisms remaining poorly understood. To address this gap, we determined when urethra closure occurs and identified gene expression patterns during the process of urethra closure in female neonatal mice from postnatal day (PND) 5 to 10. Using whole mount imaging and histology, we discovered that the initiation of urethra closure begins at PND7, and urethra closure is fully completed by PND10. To identify the genes associated with urethra closure, we conducted bulk RNA sequencing on female external genitalia prior to and after urethra closure. Gene ontology analyses revealed an increase in steroidogenic gene expression (Star, Hsd3b6, and Cyp17a1) during urethra closure, suggesting that the female genitalia locally produce steroids which could facilitate steroid signaling within the genitalia. With this study, we establish an anatomical timeline of female urethra closure and hypothesize a paracrine steroid signaling mechanism of urethra closure. These observations provide entry points to aid in further understanding external genital abnormalities, like hypospadias, in females.
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In brief
Cordycepin (COR), a compound derived from Cordyceps, is recognized as an adenosine analog with numerous beneficial effects on human health. However, its impact on steroidogenic acute regulatory protein (STAR) expression in ovarian granulosa cells is not well understood. This study demonstrates that COR downregulates STAR expression by reducing the expression of the SP1 transcription factor.
Abstract
Cordycepin (COR), a pure compound of Cordyceps, is known as an adenosine analog that exerts many beneficial effects on human health. The steroidogenesis mediated by ovarian granulosa cells is pivotal in maintaining normal female reproductive function. The steroidogenic acute regulatory protein (STAR) regulates the rate-limiting step in steroidogenesis. COR has been shown to stimulate STAR expression in mouse Leydig cells, the steroidogenic cells in the testes. However, the effect of COR on STAR expression in ovarian granulosa cells remains undetermined. In the present study, we show that treatment with COR downregulates STAR expression in a steroidogenic human granulosa-like tumor cell line, KGN, and primary culture of human granulosa-lutein (hGL) cells obtained from patients undergoing in vitro fertilization. We used specific adenosine receptor (AR) antagonists, and our results reveal that the inhibitory effect of COR on STAR expression is mediated by AR–A1, AR–A2A, and AR–A3. In both KGN and primary hGL cells, COR activates ERK1/2 and AKT signaling pathways, but only activation of ERK1/2 is required for the COR-induced downregulation of STAR expression. In addition, our results demonstrate that COR downregulates STAR expression by reducing the expression of the SP1 transcription factor. These results provide a better understanding of the biological function of COR on STAR expression in the ovary, which may lead to the development of alternative therapeutic approaches for female reproductive disorders.
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Department of Pathology, College of Medicine, University of Illinois at Chicago (UIC), Chicago, Illinois, USA
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In brief
The hypoglycemic drug metformin has shown reproductive effects in women, although its mechanism of action is not fully understood. In this study, we demonstrate the direct effects of metformin on the ovary of healthy mice, with no alterations in fertility.
Abstract
Metformin is a hypoglycemic drug widely used in type-2 diabetes (T2D) patients. In recent years, this drug has been suggested as a treatment for gestational diabetes and recommended to women with ovarian hyperstimulation syndrome (PCOS) to increase the chances of pregnancy or avoid early miscarriages. However, the exact effects of metformin on the female reproductive tract in general, and on the ovary in particular, are still not completely understood. In this study, we analyzed the effect of metformin on fertility and ovarian physiology in healthy female mice. We found that this drug altered the estrous cycle, early follicular development, serum estradiol and progesterone levels, and ovarian steroidogenic enzyme expression. Moreover, ovarian angiogenesis was lower in metformin-treated animals compared with untreated ones, whereas natural or gonadotropin-induced fertilization rates remained unchanged. However, offspring of metformin-treated animals displayed decreased body weight at birth. In this work, we unraveled the main effects of metformin on the ovary, isolated from other conditions such as hyperglycemia and hyperandrogenism, which is essential for a better understanding of metformin’s mechanisms of action on reproduction and fertility.
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In brief
Melatonin plays a crucial role in enhancing reproductive performance in small ruminants. This paper reveals the effects of exogenous melatonin on the placental and endometrial rearrangement in early pregnancy in sheep.
Abstract
Early pregnancy losses cause 25% of pregnancy failures in small ruminants because of asynchrony between conceptus and uterine signals. In this context, melatonin plays a crucial role in sheep reproductive dynamics, but little is known about its effects during the peri-implantation period. We hypothesized that melatonin supports embryo implantation by modulating the uterine microenvironment. This study aimed to assess the effects of exogenous melatonin on the endometrial and early placental rearrangement. Ten multiparous ewes either did (MEL, n = 5) or did not (CTR, n = 5) receive a subcutaneous melatonin implant (18 mg) 50 days before a synchronized mating. On day 21 of pregnancy, the sheep were euthanized. MEL ewes exhibited a higher prolificity rate (2.8 vs 2.0 embryos/ewe) and plasma progesterone levels (3.84 vs 2.96 ng/mL, P < 0.05) than did CTR ewes. Groups did not differ significantly in embryo crown-rump length. MEL placentas had significantly (P < 0.001) more binucleated trophoblast cells in the chorion region, and ovine placental lactogen expression was significantly (P < 0.05) more strongly upregulated than in CTR. Exogenous melatonin increased significantly (P < 0.05) gene expression of angiogenic factors (VEGFA, VEGFR1, IGF1R), IFNAR2, and PR in the caruncular endometrium. Expression of the MT2 receptor in the endometrium and placenta was significantly (P < 0.05) higher in the MEL group. These results indicate that melatonin implants acted differentially on uterine and placental rearrangement. Melatonin increases differentiation in the placenta and induces changes that could promote vessel maturation in the endometrium, suggesting that it enhances the uterine microenvironment in the early stage of pregnancy in sheep.
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In brief
This review article highlights the associations between endocrine-disrupting chemicals, reproductive aging, and menopause. Collectively, the current literature indicates that phthalates, bisphenols, parabens, per- and poly-fluoroalkyl substances, polychlorinated biphenyls, dioxins, and pesticides are associated with reproductive aging in women and animal models.
Abstract
Menopause marks the end of a woman’s reproductive lifetime and can have a significant effect on a woman’s quality of life. Menopause naturally occurs at 51 years of age on average, but recent literature suggests that endocrine-disrupting chemicals (EDCs) in our environment can accelerate reproductive aging, causing women to reach menopause at earlier ages. This is concerning as menopause can significantly alter a woman’s quality of life and is associated with increased risks of conditions such as depression, osteoporosis, and cardiovascular disease. EDC exposures have also been associated with more intense menopausal symptoms, making the menopausal transition more difficult for some women. This review highlights the associations between EDC exposure, early menopause, and reproductive aging, using both epidemiological and experimental studies.
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In Brief
This point of view article focuses on the potential contribution of defects in protein synthesis (translation) to the incidence of oocyte meiotic failure. We discuss the potential cause of diminished oocyte translation during aging and the impact of these deficits on the function of the meiotic spindle.
Abstract
Errors during female meiosis lead to embryonic aneuploidy and miscarriage and occur with increasing frequency during aging. The underlying molecular changes that drive female meiotic instability remain a subject of debate. Developing oocytes undergo a tremendous increase in cytoplasmic volume over several months of follicle development and rely on long-lived mRNAs and ribosomes accumulated during this growth phase for subsequent meiotic maturation. In this point of view article, we discuss how the unique reliance on stores of long-lived mRNAs and ribosomes may represent an Achilles' heel for oocyte function and how alterations that reduce the translational capacity of oocytes could be a factor significantly contributing to female infertility. Understanding these mechanisms could lead to new therapeutic strategies to improve fertility outcomes.
Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA
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Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
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Department of Urology, University of Michigan, Ann Arbor, Michigan, USA
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA
Department of Women's Heath, Henry Ford Health, Rochester Hills, Michigan, USA
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Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA
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In brief
Animal studies are needed to inform clinical guidance on the effects of testosterone gender-affirming hormone therapy (T-GAHT) on fertility. This review summarizes current animal models of T-GAHT and identifies gaps in knowledge for future study.
Abstract
Testosterone gender affirming hormone therapy (T-GAHT) is frequently used by transgender and gender-diverse individuals assigned female at birth to establish masculinizing characteristics. Although many seek parenthood, particularly as a gestational parent or through surrogacy, the current standard guidance of fertility counseling for individuals on testosterone (T) lacks clarity. At this time, individuals are typically recommended to undergo fertility preservation or stop treatment, associating T-therapy with a loss of fertility; however, there is an absence of consistent information regarding the true fertility potential for transgender and gender-diverse adults and adolescents. This review evaluates recent studies that utilize animal models of T-GAHT to relate to findings from clinical studies, with a more specific focus on fertility. Relevant literature based on murine models in post- and pre-pubertal populations has suggested reversibility of the impacts of T-GAHT, alone or following gonadotropin-releasing hormone agonist (GnRHa), on reproduction. These studies reported changes in clitoral area and ovarian morphology, including corpora lutea, follicle counts, and ovarian weights from T-treated mice. Future studies should aim to determine the impact of the duration of T-treatment and cessation on fertility outcomes, as well as establish animal models that are clinically representative of these outcomes with respect to gender diverse populations.
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In brief
Transgender and gender-diverse (TGD) people have similar desires for parenting as cisgender individuals but are likely to face greater barriers in accessing fertility treatment than their cisgender peers. Mental health professionals are well-positioned to advocate for and support TGD individuals seeking fertility care through pre-fertility treatment implications counseling regarding the psychosocial aspects of fertility treatment and family building.
Abstract
Transgender and gender-diverse (TGD) individuals experience significantly greater all-cause mortality and mental health disparities compared to their cisgender peers. Gender-affirming hormone therapy (GAHT) is a safe and effective treatment option for gender dysphoria that dramatically improves psychosocial health outcomes but may adversely impact fertility. Medical society guidelines recommend medical fertility preservation (FP) counseling and pre-fertility treatment psychoeducational implications consultation from qualified, reproductive mental health professionals (MHPs) for TGD individuals pursuing FP or third-party reproductive treatment. However, sparse literature exists specific to the structure of mental health psychoeducational consultation for TGD individuals pursuing FP. This narrative review highlights important areas for discussion in pre-fertility treatment mental health consultations. Results indicate that implications counseling should be conducted by an MHP with specialized training in reproductive mental health with TGD populations to reduce the risk of harm and promote successful emotional navigation of fertility treatment. Such counseling should be psychoeducational and not gatekeeping in nature and may include consideration of the psychosocial (e.g. emotional, relational, ethical, spiritual, social) risks and benefits of various family-building options. During these consultations, TGD individuals can explore their hopes and fears related to fertility and future family-building plans and discuss realistic treatment expectations, individual strengths, coping and communication strategies, and identify key support network members who may aid in navigating the fertility treatment process. MHPs can provide referrals to appropriate resources if necessary to help TGD individuals navigate treatment while coping with psychological symptoms and promoting behavior change.
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In brief
This manuscript aims to promote an understanding of the special needs of transgender and gender-diverse people by putting trans gynecology into context. By definition, medical interventions for transgender people are not different from the treatment of cisgender people but cannot be singled out as gender-affirmative treatment. Treatment is dedicated to an overarching goal beyond medicine, namely to enable and maintain social functioning under the signs of the social gender. It is therefore that this narrative overview intensively deals with the requirements of trans gynecology. Also, various gynecological disorders are touched upon, provided they are relevant to trans people. The different significance of gynecological symptoms for either trans men or trans women, and the effects of supraphysiological androgen treatment on hormone-sensitive tissue, are stressed.
Abstract
Transgender health care is not just gender-affirmative transitional care but is committed to a superior objective, often beyond a medical perspective: to create and maintain physical conditions for social functioning under the signs of the individually appropriate sex and to contribute to significantly reducing gender dysphoria. For these purposes, it is a prerequisite to have a distinct contextual understanding of the complex reality of transpeople and knowledge about the numerous facets of transgender healthcare. Gynecology for transgender and gender-diverse people does not differ greatly from gynecology for cisgender female patients except in goals and context. Relief from complaints derived from genital organs is, of course important, but for transpeople there always is an overarching gender dimension that sometimes complicates treatment and might give rise to misunderstandings. Also, minority stress caused by societal factors frequently impacts the mental and physical state of health negatively and needs to be considered. This paper focuses on the context of trans gynecology and addresses various contentual aspects for both transmale patients having left genital organs in situ and transfemale patients with gynecological demands. Gynecological topics are addressed, highlighting their relevance for transgender and gender-diverse people (TGD), including the effects of supra-physiological androgen exposure on ovaries and uterus, vaginal bleeding, pelvic pain under testosterone treatment, screening policies, and benign gynecological disorders as clinical manifestations may appear differently and treatment may be more burdensome.
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In brief
FSH leads to glutamine dependence, which is required for mTORC1 activation and in consequence Sertoli cell proliferation.
Abstract
The spermatogenic capacity of adult individuals depends on, among other factors, the number of Sertoli cells (SCs) that result from the proliferative waves during development. FSH upregulates SC proliferation at least partly, through the activation of the PI3K/Akt/mTORC1 pathway, among other mechanisms. It is widely known that mTORC1 is a sensor of amino acids. Among amino acids, glutamine acquires relevance since it might contribute to cell cycle progression through the modulation of mTORC1 activity. It has not been studied yet whether glutamine intervenes in FSH-mediated regulation of SC proliferation and cell cycle progression, or if FSH has any effect on glutamine metabolism. Eight-day-old rat SCs were incubated in culture media without glutamine or with glutamine in the absence or presence of a glutamine transporter inhibitor or a glutaminase activity inhibitor under basal conditions or stimulated with FSH. The results obtained show that FSH does not promote SC proliferation and mTORC1 activation in the absence of glutamine. Also, FSH modulates glutamine metabolism increasing glutaminase isoform 2 and reducing glutamine synthetaseexpression. FSH did not promote SC proliferation and mTORC1 activation when glutaminase activity was inhibited. The results suggest that glutamine or its metabolites might cooperate with FSH in the upregulation of SC proliferation through mTORC1. In addition, as FSH modulates glutamine metabolism through the induction of glutaminase isoform 2, the hormonal control of glutamine metabolism might be part of the intricate signaling network triggered by FSH, which is crucial to establish the population of mature SCs that supports the reproductive function.
