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Back LH Receptor Mutation

Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) stimulate a receptor called 'luteinizing hormone/choriogonadotropin receptor' (LHCGR) located on the surface of the Leydig cells of the testis. Specifically, the activity of this receptor is essential for proper androgen production by Leydig cells in the fetus with a typical male karyotype 46,XY. 
The clinical picture in individuals with karyotype 46,XY is characterised by scarcity/absence of Leydig cells and virilization deficits during intrauterine life and at puberty.
The complete form of this Variation of Sex Characteristic (VSC)/Difference of Sex Development (DSD) –caused by the absence of receptor activity– is characterised by the presence at birth of a typically female phenotype with small cryptorchid testes (outside the scrotal sac), in which the seminiferous tubules are preserved, but mature Leydig cells are absent. The structures derived from Wolff's ducts (from which the ejaculatory ducts, epididymis, vas deferens and seminal vesicles originate) are reduced in volume, and the structures derived from Müller's ducts (uterus, tubes and upper third of the vagina) are absent. At puberty, virilization does not occur.
In its partial form, receptor activity is reduced. In these cases, individuals with karyotype 46,XY present a male phenotype with virilization deficiency at birth. There is a micropenis and/or hypospadias (opening of the urethra anywhere on the penis, or around the scrotum or perineum, i.e., in the area between the scrotum and the anus). Cryptorchid testicles are often present. At puberty, only partial virilization is observed, and penis size is reduced. 

Genetic traits
This VSC/DSD is caused by mutations in the LHCGR gene, which is located on chromosome 2 (2p21). Transmission is autosomal recessive, which means that for the gene variation to occur it must be inherited from both parents. Individuals who have inherited the gene variation from only one parent will not exhibit it in any way, but they may still pass it on to their offspring. 

Identification 
Laboratory tests show extremely low levels of testosterone, if at all, and increased levels of LH. There will also be no response to the hCG stimulus test. Diagnostic confirmation is based on molecular analysis of the gene involved.  

Medical options
Most people with this variation in its complete form are assigned female at birth because of the presence of typically female external genitalia. There is little available data in the scientific literature, partly because this variation is extremely rare. However, gender assignment is recommended to be decided upon on a case-by-case basis, always bearing in mind the recommendation to postpone non-reversible medical and/or surgical interventions, when not urgent, to a time when the person can express their informed consent.
During puberty, hormone therapy with testosterone or oestrogen –depending on the person's gender identity– will still be needed to induce the development of secondary sexual characteristics.
At this time, if the person has chosen a female gender identity, orchiectomy may be contemplated to prevent the occurrence of testicular tumours, although data on their prevalence in individuals with this variation are not available. As long as a surgical approach is not opted for and in view of the oncological risk, adequate monitoring with imaging (ultrasound or MRI) is generally required on an annual basis. 

Bibliography 
Domenice S, et al. 46, XY Differences of Sexual Development. Last Update: 2022 Aug 21. In: Endotext [Internet]
Martens JW et al. A homozygous mutation in the luteinizing hormone receptor causes partial Leydig cell hypoplasia: correlation between receptor activity and phenotype. Molecular Endocrinology. 1998 Jun;12(6):775-84

Further Links
Orphanet. Leydig cell hypoplasia