Successful testicular sperm recovery and IVF treatment in a man with Leydig cell hypoplasia.

Abstract

Fetal sex differentiation of the male involves complex processes and is dependent on the androgen production from fetal Leydig cells triggered by placental human chorionic gonadotropin (hCG) [1, 2]. It is later replaced by luteinizing hormone (LH) that is secreted by the fetal pituitary gland during gestation [3]. The hormones, such as antimullerian hormone (AMH) synthesized by Sertoli cells of the testes, testosterone produced by the Leydig cells and dihydrotestosterone, are also essential for the formation of male genitalia [4–6]. Because the action of both hCG and LH is through the luteinizing hormone/chorionic gonadotropin receptor (LHCGR), its presence and smooth function is crucial for male sex differentiation and characteristics in fetal and adult life. Any changes in the DNA or gene expression levels of LHCGR are associated with a variety of phenotypic as well as clinical symptoms and pathologies. Human LHCGR gene is located on chromosome 2 and encodes 11 exons (NCBI GeneID 3,973; http://www.ncbi.nlm.nih.gov/). Exons 1–10 and a part of exon 11 encode the extracellular domain which is responsible for ligand binding, and the remaining of exon 11 encodes a transmembrane domain and intracellular C-terminal domain which is responsible for signal transduction [7]. Leydig cell hypoplasia (LCH) or Leydig cell agenesis is a very rare disease with an approximate incidence of 1:1,000,000 occurring with inactivating mutations in the LHCGR gene (6). These mutations mainly affect the amino acid sequence, leading to the alterations of receptor protein structure and function. Depending on the severity of the functional incompetence, a spectrum of phenotypes has been described [8]. The phenotype of males with LCH varies from micropenis, ambiguous genitalia, hypospadias to pseudohermaphroditism. In females, LH insensitivity is also presented with irregular menstrual cycles, infertility, recurrent miscarriage loss, polycystic ovarian syndrome (PCOS), and genital malformations [9–13]. The most severe form of LCH, type I, occurs due to luteinizing hormone/human chorionic gonadotropin receptor (LHCGR) mutations that completely prevent hCG/LH signal transduction [10, 14, 15]. On the other hand, patients with LCH type II have milder symptoms caused by LHCGR mutations that partially affect the responsiveness of hCG [9, 10, 16]. In the last decade, several mutations including homozygous and compound heterozygous mutations in the LHCGR gene have been reported in both familial and sporadic cases of LCH. A number of these studies showed an impaired or absent ligand binding and cAMP production in response to hCG stimulation, suggesting that some of these mutations have inactivating roles [11–13, 16]. In such cases, the basal hormone status, usually with normal FSH, elevated LH, and low testosterone, provides an initial diagnostic hint of the underlying defect. Diagnosis confirmed by testicular biopsy showed LCH and by techniques of molecular biology revealed mutations of the LH receptor gene [17]. To date, no standard treatment approaches have been suggested or developed in LCH. Here, we report our experience with a man with LCH that resulted in successful sperm recovery and live birth with IVF treatment.