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Variation of sex differentiation
Published in Joseph S. Sanfilippo, Eduardo Lara-Torre, Veronica Gomez-Lobo, Sanfilippo's Textbook of Pediatric and Adolescent GynecologySecond Edition, 2019
Anne-Marie Amies Oelschlager, Margarett Shnorhavorian
Luteinizing hormone receptor defect: HCG stimulates the Leydig cells to produce testosterone. Leydig cell hypoplasia is notable for absent or low levels of Leydig cells with high levels of LH and follicle-stimulating hormone (FSH), and low levels of testosterone. This has been associated with a LH receptor defect. The Sertoli cells will produce AMH; therefore, affected individuals do not have internal Müllerian structures. Clitorophallic enlargement will occur with testosterone supplementation.17
Hypospadias
Published in Brice Antao, S Irish Michael, Anthony Lander, S Rothenberg MD Steven, Succeeding in Paediatric Surgery Examinations, 2017
b) Partial loss of luteinising-hormone-receptor function, which is secondary to Leydig cell hypoplasia, has been found to be associated with hypospadias or even micropenis. It has also been found that defects in steroidogenic protein such as CYP11, p450 and 3β-hydroxysteroid dehydrogenase deficiency can cause salt-losing adrenal insufficiency and under-androgenisation and hypospadias. It has also been found that combined 17α-hydroxylase/17,20-hydroxylase deficiency can present with varying degrees of hypospadias or micropenis associated with hypertension or skeletal abnormalities.
Hypogonadism, erectile dysfunction, and infertility in men
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Pierre-Marc G. Bouloux, Shalender Bhasin
Inactivating mutations of the LH receptor gene are associated with hypogonadism and Leydig cell hypoplasia.92,93 Several families with resistance to LH action due to inactivating mutations of the LH receptor have been reported. Men with LH receptor mutations present with a spectrum of phenotypic abnormalities ranging from feminization of external genitalia in 46,XY males to Leydig cell hypoplasia, primary hypogonadism, and delayed sexual development. In a patient with Leydig cell hypoplasia and hypogonadism, a T-to-A mutation in position 1874 of the LH receptor gene was found.94 Testicular histology in this man revealed the absence of mature Leydig cells; the seminiferous tubules had thickened basal lamina and spermatogenic arrest at the elongated spermatid stage.95 Female members of the kindred with LH receptor mutation revealed normal development of secondary sex characteristics, increased LH levels, and amenorrhea.
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.
A novel variant in LCHGR gene in 3 siblings with type 1 Leydig cell hypoplasia
Published in Gynecological Endocrinology, 2020
Amine Aktar Karakaya, Edip Unal, Aslı Beştaş, Funda Taş, Hüseyin Onay, Yusuf Kenan Haspolat
Sex development disorders of 46, XY occurs due to gonadal dysgenesis, androgen synthesis disorders or insufficient androgen effect. Androgen synthesis deficiency is caused by an enzyme in steroid synthesis or a defect in Leydig cell differentiation [6]. Chorionic gonadotropin, released from the placenta in the fetal period, stimulates Leydig cell development and thus testosterone production. In the later weeks of pregnancy, CG is replaced by LH released from the pituitary gland. The common receptor of these hormones is LHCGR. Pituitary LH or placental hCG activates LHCGR, leading to increased testosterone biosynthesis. Increasing testosterone levels lead to the development of Wolfian structures, while dehydrotestosterone causes the formation of the external genitalia [4,7]. Inactivating mutations in LHCGR cause sexual differentiation disorders in 46 XY individuals. The patient’s phenotype is related to whether the mutation completely or partially inactivates LHCGR. If the mutation completely blocks testosterone synthesis, type 1 Leydig cell hypoplasia (type I LCH) develops and this is known as the most severe form. In partially inactive variants, type 2 Leydig cell hypoplasia (type II LCH) develops in different phenotypes [2,8–13]. In Leydig cell hypoplasia Type I, 46, XY individuals are born with completely female external genitalia and are raised as girls. They are generally not diagnosed in the newborn and childhood period. They apply to the clinic with the absence of breast development or primary amenorrhea during puberty. These patients do not have Mullerian structures because their Sertoli cells are normal and they can synthesize AMH. Wolfian is usually rudimentary, but may be improved in some cases [8,10,14]. All our three cases were in female phenotypes and were raised as female. The index patient had applied with the complaint of lack of breast development and primary amenorrhea during puberty. Therefore, our cases were clinically compatible with type 1 LCH. In our cases, since the Sertoli cell functions were normal, AMH levels were normal and Mullerian structures were not detected in pelvic USG. There are normal female external genital structures in 46 XX individuals with LHCGR mutation. Breast development, and pubic hair growth are known to be normal in the puberty, but primary amenorrhea, oligomenorrhea, polycystic ovaries or infertility may be seen [15–18]. In cases with type 2 LCH, the clinical picture is quite variable according to the degree of testosterone synthesis defect. They may present with inadequate virilization findings such as micropenis, hypospadias, undescended testis, or infertility only in adulthood. In these cases, there may be an increase in virilization findings during puberty. It is also shown that there may be a partial testosterone response to the hCG test [4,8,10,14,19,20]. In our cases, there was no testosterone response to the HCG test and no increase in virilization at puberty.