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Toshiyuki Yamada Department of Microbiology and Molecular Cell Biology, Nihon Pharmaceutical University, Ina-machi, Kitaadachi-gun, Saitama, Japan

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Aya Ando Department of Microbiology and Molecular Cell Biology, Nihon Pharmaceutical University, Ina-machi, Kitaadachi-gun, Saitama, Japan

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Ryusuke Morita Department of Microbiology and Molecular Cell Biology, Nihon Pharmaceutical University, Ina-machi, Kitaadachi-gun, Saitama, Japan

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Ken-Ichi Sako Department of Clinical Pharmacology, Nihon Pharmaceutical University, Ina-machi, Kitaadachi-gun, Saitama, Japan

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Shigeki Tsuchida Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan

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Hiroyuki Yamamoto Department of Health and Nutritional Sciences, Faculty of Health and Medical Sciences, Aichi Shukutoku University, Nagakute-city, Aichi, Japan

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In brief

Social and reproductive behaviors in mammals are regulated by pheromones. This study shows the possibility that male extraorbital lacrimal gland-derived pheromones are involved in reproductive efficiency in rats.

Abstract

In rodents, male-derived pheromones play fundamental roles in reproduction. The Hirosaki hairless rat (HHR) is a mutant strain derived from the Sprague–Dawley rat (SDR). While investigating the natural mating between single males and females, (SDR♂ × SDR♀) or (HHR♂ × HHR♀), the HHRs showed higher fecundity than the SDRs; the mean period between mating and delivery was shorter, and every HHR pair gave birth, whereas approximately half of the SDR pairs gave birth in the 3 months of experimental testing. By changing partners between the HHRs and SDRs, (SDR♂ × HHR♀) or (HHR♂ × SDR♀), we attributed the fecundity difference to the males. However, no significant difference was observed in the litter size, the concentration, morphology, or motility of sperm in the cauda epididymis, or the testosterone concentration in the serum between the SDR and HHR males. When an SDR and HHR male were simultaneously mated with a single female, the HHR males always succeeded in leaving progeny. Therefore, we assumed that the reason for the fecundity difference was the difference in copulation efficiency and focused on male-derived pheromones that may induce reproductive behaviors in females. Whereas Darcin (MUP20), one of the pheromones produced in the liver, did not appear to be involved, the extraorbital lacrimal gland (ELG) was heavier in the HHR males and showed larger amounts of pheromones, namely exocrine gland-secreting peptide 1 (ESP1) and cystatin-related protein 1 (CRP1). These results suggest that the fecundity difference is due to the difference in amounts of ELG-derived pheromones.

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Xingxing Wang Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
NHC Key Laboratory of the Study of Abnormal Gametes and the Reproductive Tract, Anhui Medical University, Hefei, Anhui Province, China.
Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei, Anhui, China

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Huihui Yu Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
NHC Key Laboratory of the Study of Abnormal Gametes and the Reproductive Tract, Anhui Medical University, Hefei, Anhui Province, China.
Anhui Province Key Laboratory of Reproductive Disorders and Obstetrics and Gynaecology Diseases, Hefei, Anhui, China

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Xuan Li Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
NHC Key Laboratory of the Study of Abnormal Gametes and the Reproductive Tract, Anhui Medical University, Hefei, Anhui Province, China.
Anhui Province Key Laboratory of Reproductive Disorders and Obstetrics and Gynaecology Diseases, Hefei, Anhui, China

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Ruixian Tian Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, Hefei, Anhui, China

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Chenyi Xu Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei, Anhui, China
Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, Hefei, Anhui, China

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Tengteng Li Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
Center for Big Data and Population Health of IHM, Hefei, Anhui, China

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Jiajia Fei Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China

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Xue Du Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
Center for Big Data and Population Health of IHM, Hefei, Anhui, China

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Zongzhi Yin Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
NHC Key Laboratory of the Study of Abnormal Gametes and the Reproductive Tract, Anhui Medical University, Hefei, Anhui Province, China.
Anhui Province Key Laboratory of Reproductive Disorders and Obstetrics and Gynaecology Diseases, Hefei, Anhui, China
Center for Big Data and Population Health of IHM, Hefei, Anhui, China

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In brief

During pregnancy and delivery, the myometrium was affected by hypoxia stress, which acts as a regulator of cell proliferation. The proliferation of uterine smooth muscle cells in pregnant mice was inhibited under hypoxia, which was related to the up-regulated autophagy through the mTOR pathway.

Abstract

Hypoxia is closely associated with physiological and pathological conditions in the human body, and the myometrium is affected by hypoxic stress during pregnancy and delivery. Autophagy is a catabolic pathway involved in the regulation of apoptosis, proliferation, and migration of a variety of cells, which can be activated under hypoxia. However, the mechanism and function of autophagy in uterine smooth muscle cells remained unclear. The aim of this study was to investigate the changes in autophagy in pregnant uterine smooth muscle cells (pUSMCs) under hypoxia and the effect of autophagy on myometrial cellscell proliferation during pregnancy. In this study, primary uterine smooth muscle cells were isolated from mice in late pregnancy and cultured under normoxic and hypoxic conditions, respectively. Western blotting and immunofluorescence were used to detect the expression levels of autophagy-related proteins LC3B, P62, mTOR, and p-mTOR under different culture conditions. Cell proliferation was assessed by CCK-8 assay. In addition, 3-methyladenine (3-MA) was used to inhibit autophagy in hypoxia-treated pUSMCs, and MHY1485 was used to activate mTOR. Studies have confirmed that under hypoxic conditions, autophagy is enhanced and cell proliferative viability is reduced in pUSMCs. The autophagy inhibitor 3-MA restored cell proliferation inhibited by hypoxia. Furthermore, hypoxia in pUSMCs led to a downregulation of p-mTOR/mTOR levels. The mTOR activator MHY1485 inhibited autophagy by preventing the binding of autophagosomes to lysosomes and reversed the hypoxia-induced inhibition of cell proliferation. Collectively, our results indicate that hypoxia upregulates autophagy through the mTOR pathway in pUSMCs, thereby inhibiting cell proliferation during pregnancy.

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Xiyu Ge Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA

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Karen Weis Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA

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Lori Raetzman Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA

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In brief

Endocrine-disrupting chemicals can impact reproduction by affecting the hypothalamic–pituitary–gonadal axis. This review emphasizes the impact of endocrine-disrupting chemicals on pituitary development and function.

Abstract

The pituitary gland is crucial for regulating many physiological systems, including reproduction. Clear evidence suggests that pituitary function can be impaired by exposure to endocrine-disrupting chemicals (EDCs). Humans and animals are exposed to EDCs throughout life, but exposure during critical periods when the pituitary is developing could have more damaging consequences. In this review, we summarize the development of the pituitary gland, including the impact of hormone signals, and describe how in vivo EDC exposure during development might alter pituitary function. These include changes in pituitary hormone, mRNA, and protein expression levels, as well as pituitary cell number and population balance. We focus on reproductive hormone-producing cells as well as other endocrine and pituitary stem/progenitor cells. We reveal the current gaps in knowledge and suggest future directions in terms of understanding the effects of developmental EDC exposure directly on the pituitary gland.

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Malia D Berg Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA

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Matthew Dean Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA

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In livestock, the amount of glucose needed by the endometrium and embryo increases during early pregnancy. Yet, how glucose concentrations in the endometrium are regulated remains unclear. The bovine uterine epithelium can store glucose as glycogen, and glycogen content decreases in the luteal phase. Our objective was to elucidate the role of progesterone in glycogen breakdown in immortalized bovine uterine epithelial (BUTE) cells. After 48 h of treatment, progesterone decreased glycogen abundance in BUTE cells (P < 0.001) but did not alter glycogen phosphorylase levels. RU486, a nuclear progesterone receptor (nPR; part of the PAQR family) antagonist, did not block progesterone’s effect, suggesting that progesterone acted through membrane progesterone receptors (mPRs). RT-PCR confirmed that BUTE cells express all five mPRs, and immunohistochemistry showed that the bovine uterine epithelium expresses mPRs in vivo. An mPRα agonist (Org OD 02-0) reduced glycogen abundance in BUTE cells (P < 0.001). Progesterone nor Org OD 02-0 affected cAMP concentrations. Progesterone increased phosphorylated AMP-activated protein kinase (pAMPK) levels (P < 0.001), indicating that progesterone increases intracellular AMP concentrations. However, AMPK did not mediate the effect of progesterone. AMP allosterically activates glycogen phosphorylase, and D942 (which increases intracellular AMP concentrations) decreased glycogen abundance in BUTE cells. A glycogen phosphorylase inhibitor partially blocked the effect of progesterone (P < 0.05). Progesterone and Org OD 02-0 had similar effects in Ishikawa cells (P < 0.01), a human cell line that lacks nPRs. In conclusion, progesterone stimulates glycogen breakdown in the uterine epithelium via mPR/AMP signaling. Glucose released from glycogen could support embryonic development or be metabolized by the uterine epithelium.

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Tengteng Xu Department of Gynecology, Clinical Transformation and Application Key Lab for Obstetrics and Gynecology, Pediatrics, and Reproductive Medicine of Jiangmen, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, China
MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
Clinical Experimental Center, Jiangmen Engineering Technology Research Center of Clinical Biobank and Translational Research, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, China

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Min Gao Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Hainan Provincial Clinical Research Center for Thalassemia, Reproductive Medical Center, International Technology Cooperation Base “China-Myanmar Joint Research Center for Prevention and Treatment of Regional Major Disease” By the Ministry of Science and Technology of China, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China
Key Laboratory of Reproductive Health Diseases Research and Translation of Ministry of Education, The First Affiliated Hospital, Hainan Medical University, Haikou, China

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Ling Zhang GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, Guangdong, China

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Tianqi Cao MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

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Yanling Qiu MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

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Simiao Liu MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

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Wenlian Wu MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

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Yitong Zhou MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

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Haiying Liu MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

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Rui Zhang MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

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Xiaohong Ruan Department of Gynecology, Clinical Transformation and Application Key Lab for Obstetrics and Gynecology, Pediatrics, and Reproductive Medicine of Jiangmen, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, China
Clinical Experimental Center, Jiangmen Engineering Technology Research Center of Clinical Biobank and Translational Research, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, China

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Junjiu Huang Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
Key Laboratory of Reproductive Medicine of Guangdong Province, the First Affiliated Hospital and School of Life Sciences, Sun Yat-sen University, Guangzhou, China

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In brief

The mechanism by which the NSUN2 mutation causes female infertility is still unclear. This study reveals the role and potential mechanism of NSUN2 in mouse oocyte maturation and early embryonic development, and provides a resource for elucidating female infertility with NSUN2 mutations.

Abstract

Biallelic variants in the NSUN2 gene cause a rare intellectual disability and female infertility in humans. However, the function and mechanism of NSUN2 during mouse oocyte meiotic maturation and early embryonic development are unknown. Here, we show that NSUN2 is important for mouse oocyte meiotic maturation and early embryonic development. Specifically, NSUN2 is required for ovarian development and oocyte meiosis, and deletion of Nsun2 reduces oocyte maturation and increases the rates of misaligned chromosomes and aberrant spindles. In addition, Nsun2 deficiency results in a low blastocyst rate and impaired blastocyst quality. Strikingly, loss of Nsun2 leads to approximately 35% of embryos being blocked at the 2-cell stage, and Nsun2 knockdown impairs zygotic genome activation at the 2-cell stage. Taken together, these findings suggest that NSUN2 plays a critical role in mouse oocyte meiotic maturation and early embryonic development, and provide key resources for elucidating female infertility with NSUN2 mutations.

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Chloe He Wellcome/EPSRC Centre for Interventional and Surgical Sciences, University College London, London, United Kingdom
Research Team, Sapphic Bison, London, United Kingdom

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Nour Al-Ma’ani Research Team, Sapphic Bison, London, United Kingdom

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Mei Francis Department of Philosophy, University of Warwick, Coventry, United Kingdom

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Jules Sales Product Team, Apricity, Paris, France

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Isabella Marson Acquisition Team, Apricity, London, United Kingdom

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Neringa Karpaviciute Department of Life Sciences, Manchester Metropolitan University, Manchester, United Kingdom

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Rishabh Hariharan Research Team, Apricity, London, United Kingdom

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Ranya Derrick Wonersh Surgery, NHS, Guildford, United Kingdom

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Sotirios Saravelos Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom

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Luca Sabatini Centre for Reproductive Medicine, Barts Health NHS Trust, London, United Kingdom

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Sofia Tzouganatou Embryology, Centre for Reproductive and Genetic Health, London, United Kingdom

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Devika Nair Embryology, Centre for Reproductive and Genetic Health, London, United Kingdom

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Danielle Ellis Care Team, Apricity, London, United Kingdom

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Céline Jacques Research Team, Apricity, Paris, France

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Timothy Ferrand Research Team, Apricity, Paris, France

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Tash Oakes-Monger Trans Learning Partnership, Spectra, London, United Kingdom

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Teodora Popa EGA Institute for Women’s Health, University College London, London, United Kingdom

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Francisco Vasconcelos Wellcome/EPSRC Centre for Interventional and Surgical Sciences, University College London, London, United Kingdom

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Cristina Hickman Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom

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In brief

We describe a first-of-its-kind audit of LGBTQ+ inclusivity in fertility care providers across the United Kingdom. Despite efforts being made to improve LGBTQ+ inclusion in fertility care, our results paint a picture of widespread gaps in clinical and cultural expertise alongside significant barriers to LGBTQ+ inclusion.

Abstract

LGBTQ+ patients comprise one of the fastest-growing user demographics in fertility care, yet they remain under-represented in fertility research, practice, and discourse. Existing studies have revealed significant systemic barriers, including cisheteronormativity, discrimination, and gaps in clinical expertise. In this article, we present a checklist of measures that clinics can take to improve LGBTQ+ inclusion in fertility care, co-created with members of the LGBTQ+ community. This checklist focuses on three key areas: cultural competence, clinical considerations, and online presence. The cultural competence criteria encompass inclusive communication practices, a broad understanding of LGBTQ+ healthcare needs, and knowledge of treatment options suitable for LGBTQ+ individuals. Clinical considerations include awareness of alternative examination and gamete collection techniques for transgender and gender diverse patients, the existence of specific clinical pathways for LGBTQ+ patients, and sensitivity to the psychological aspects of fertility care unique to this demographic. The online presence criteria evaluate provider websites for the use of inclusive language and the availability of LGBTQ+-relevant information. The checklist was used as the foundation for an audit of fertility care providers across the UK in early 2024. Our audit identified a widespread lack of LGBTQ+ inclusion, particularly for transgender and gender diverse patients, highlighting deficiencies in clinical knowledge and cultural competence. Our work calls attention to the need for further efforts to understand the barriers to inclusive and competent LGBTQ+ fertility care from both healthcare provider and patient perspectives.

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Abigail S Kitakule Reproductive Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA

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Ciro M Amato Reproductive Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA
Department of Surgery, Division of Urology, University of Missouri, Columbia, Missouri, USA

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Humphrey Hung-Chang Yao Reproductive Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, 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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Lingling Zhang Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

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Shenghui Zhou Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

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Beibei Bi Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

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Hailong Wang Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

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Bingxin Fu Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

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Manman Guo Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

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Siwei Luo Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

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Jung-Chien Cheng Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

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Lanlan Fang Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

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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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Candela Velazquez Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina

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Mayra Bordaquievich Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina

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Yamila Herrero Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina

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Débora Juana Cohen Molecular Mechanisms of Fertilization Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina.

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María Silvia Bianchi Neuroendocrine Biochemistry Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina.

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Patricia Cuasnicu Molecular Mechanisms of Fertilization Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina.

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Katherine Prost Pedro Fiorito Hospital, Endocrinology area, Buenos Aires Province, Argentina.

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Natalia Pascuali Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina
Department of Pathology, College of Medicine, University of Illinois at Chicago (UIC), Chicago, Illinois, USA

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Fernanda Parborell Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina

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Dalhia Abramovich Studies of the Physiopathology of the Ovary Laboratory, Institute of Biology and Experimental Medicine (IBYME) - National Scientific and Technical Research Council (CONICET), Autonomous City of Buenos Aires, Argentina

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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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Irene Viola Department of Veterinary Sciences, University of Turin, Grugliasco, Torino, Italy

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Cecilia Sosa Department of Biochemistry and Cell and Molecular Biology, Faculty of Veterinary Medicine, University of Zaragoza, Zaragoza, Spain

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Paolo Accornero Department of Veterinary Sciences, University of Turin, Grugliasco, Torino, Italy

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Isabella Manenti Department of Veterinary Sciences, University of Turin, Grugliasco, Torino, Italy

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Francisco Canto Environmental Science Research Institute (IUCA), Faculty of Veterinary Medicine, University of Zaragoza, Zaragoza, Spain

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Silvia Miretti Department of Veterinary Sciences, University of Turin, Grugliasco, Torino, Italy

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José Alfonso Abecia Environmental Science Research Institute (IUCA), Faculty of Veterinary Medicine, University of Zaragoza, Zaragoza, Spain

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Paola Toschi Department of Veterinary Sciences, University of Turin, Grugliasco, Torino, Italy

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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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