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Environmental toxicants on Leydig cell function
Published in C. Yan Cheng, Spermatogenesis, 2018
Leping Ye, Xiaoheng Li, Xiaomin Chen, Qingquan Lian, Ren-Shan Ge
Steroidogenesis in Leydig cells is regulated by luteinizing hormone (LH), which is secreted by the pituitary. LH reaches Leydig cells via circulation and it binds to the LH receptor (LHCGR, encoded by human LHCGR or rat Lhcgr) on the surface of Leydig cells. This receptor is mainly coupled to adenylate cyclase pathways.47 After the LHCGR is bound by LH, the receptor causes a rapid increase of intracellular cAMP level. The increased cAMP level induces a series of downstream signaling to increase the expression levels of cholesterol-transporting proteins and steroidogenic enzymes (Figure 20.1).
The endometrium in polycystic ovary syndrome
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
PCOS is known to have a genetic component, and so far genome-wide association studies (GWASs) have revealed 11 susceptibility loci (77,78). Of these rs2479106 (DENND1A) and rs13405728 (LHCGR) have been associated with endometrial cancer, although ethnicity-related differences also play a role (29,79). Subsequent to these GWASs, causal Mendelian randomization analyses have revealed causality between certain genetic variations and PCOS, with EGF receptor (EGFR) genes (ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4) being among the most interesting in the context of endometrial cancer (79). EGFRs are present in endometrial cancers, and as the mitogenic effects of E2 require priming with insulin or insulin growth factor (IGF) and EGF, EGFR variants can modulate the estrogen effect and thus affect the endometrial hormonal milieu (80). Further studies are needed to delineate the association between genetic predisposition and endometrial health in women with PCOS.
Normal and abnormal development of the genitalia
Published in David M. Luesley, Mark D. Kilby, Obstetrics & Gynaecology, 2016
Rebecca Deans, Sarah M Creighton
At around weeks 8–10, Leydig cells appear in the testis and start to secrete testosterone. The control of testosterone production may be independent initially, then under the control of placental human chorionic gonadotrophin (hCG) through the shared leutinizing hormone/hCG receptor (LHCGR), and subsequently by 20 weeks the hypothalamic pituitary (gon-adotrope) axis becomes active and fetal leutinizing hormone (LH) production controls steroidogenesis. Testosterone acts through the androgen receptor and causes development of the Wolffian ducts into the vasa deferentia, and later the seminal vesicles and epididymides. Testosterone is also released into the circulation and undergoes peripheral conversion to its more active metabolite DHT by the enzyme 5α-reductase type 2, and acts on the target tissues of the perineum resulting in development and growth of the genital tubercle, urogenital sinus, urogenital folds and labioscrotal swellings into the glans penis, penile shaft, urethral tube and scrotum, respectively. The penis is similar in size to the clitoris at 14 weeks and, under the influence of DHT, continues growing until birth. Testicular descent is mediated by the Leydig cells under the influence of the hypothalamic pituitary (gonadotrope) axis, commences at 12 weeks, and is usually complete by week 34.
Updates in diagnosing polycystic ovary syndrome-related infertility
Published in Expert Review of Molecular Diagnostics, 2023
Hélio Haddad-Filho, Jéssica A. G. Tosatti, Fernanda M. Vale, Karina B. Gomes, Fernando M. Reis
The luteinizing hormone/choriogonadotropin receptor (LHCGR) gene is present on chromosome 2 with 11 exons. Polymorphisms that have been implicated in infertility and subfertility as well as in the response to fertility treatments have been detected in the LHCGR gene. Rama Raju et al. investigated the SNP rs2293275 (c.935A>G on exon-10) in women under controlled ovarian stimulation after pituitary gonadotropin down-regulation with GnRH agonist. Homozygous G allele was associated with higher requirements exogenous LH, while the numbers of oocytes and good quality embryos were significantly higher in women homozygous for the A allele [114]. One study showed that the frequency of the G allele was similar in PCOS patients and controls. However, as in this study multiple polymorphisms were genotyped within the LHCGR gene, there is a possibility that specific combinations of allelic variants may have a more pronounced influence on phenotype [112]. Almawi et al. observed lower frequency of heterozygous LHCGR rs7371084 (T > C) and increased frequency of homozygous LHCGR rs4953616 (T > C) genotype in women with PCOS compared to controls [115], suggesting that other LHCGR SNPs should be investigated and correlated with ovarian stimulation.
Molecular study and genotype–phenotype in Chinese female patients with 46, XY disorders of sex development
Published in Gynecological Endocrinology, 2021
Junke Xia, Jing Wu, Chen Chen, Zhenhua Zhao, Yanchuan Xie, Zhouxian Bai, Xiangdong Kong
The LHCGR gene (OMIM #152790) encodes a shared receptor for human chorionic gonadotropin (CG) and luteinizing hormone (LH), which plays a critical role in sexual differentiation [28]. During early embryogenesis, placental CG stimulates the production of testosterone and maturation of fetal Leydig cells via binding to LHCGR [29]. Loss-of-function mutations of LHCGR could result in Leydig cell hypoplasia (LCH) and hypergonadotropic hypogonadism [30]. LCH is a rare autosomal recessive disorder, characterized by varying degrees of pseudo-hermaphroditism [9]. LHCGR protein comprises extracellular, trans-membrane, and intracellular domains [31]. Here, two novel heterozygous variants (Ile89Leu/Val141Ala) were identified in a patient with male pseudo-hermaphroditism. The 3D protein model of the extracellular domain showed that the two variants may be located in the β-folding domain and affect ligand recognition and binding affinity (Figure 4). Further studies are required to determine the clear molecular mechanism. Additionally, DNA sequencing showed that the two variants of the proband were inherited from the mother and father. Based on Mendel's law of inheritance, there was a possibility of 25% that the family would have a child with LCH at next pregnancy. An effective way to prevent the birth of a child with LCH is prenatal diagnosis by chorion villus sampling during early pregnancy or amniocentesis after the second trimester. Prenatal diagnosis was successfully performed, and the proband’ mother gave birth to a healthy child.
Expression of LHCG receptors in the human penis
Published in The Aging Male, 2020
Helen Zirnask, Pasi Pöllanen, Siim Suutre, Marianne Kuuslahti, Andres Kotsar, Tomi Pakarainen, Kersti Kokk
The luteinizing hormone/choriogonadotropin receptor (LHCGR) belongs to the group of glycoprotein hormone receptors (GpHRs) [1,2]. LH and hCG bind both to the LHCGR [3]. Similar to other G-protein coupled receptors, LHCGR is anchored within the cell membrane by seven transmembrane domains [4,5]. Locating on the short arm of chromosome 2 (2p21), the human LHCGR gene consists of 11 exons and 10 introns, complemented by the primate-specific exon 6A [6,7]. Inactivating and disease-causing mutations of the LHCGR gene have been described [8,9]. Besides Leydig cells [10,11] the LHCGR is expressed by many cell types, including the corpus luteal cells of the ovary [12], the decidua [13], the myometrium [14], the uterine vasculature [15], the smooth muscle and endothelial cells of umbilical arteries and vein [16], the embryonic stem cells [17], the trophoblasts [18], and some of the brain cells [12,19]. In the testis, LHGCRs are expressed during the fetal life, postnatally, at puberty, and also throughout adult life [20]. This makes it possible for the pituitary LH to stimulate testosterone production in Leydig cells during the normal male embryogenesis and also after puberty, leading to induction and maintenance of secondary sexual features, including penile growth.