Hormone profiling of adults with the KISS1 p.X139fs variant and its implications on fertility

Abstract

Idiopathic Hypogonadotropic hypogonadism (IHH) is characterised by the delayed or the lack of sexual development in an individual due to a lack or reduced secretions of sex steroid hormones. This problem arises due to abnormalities in the structure or the function of the Hypothalamic-pituitary-gonadal (HPG) axis. Such abnormalities include genetic variations in the KISS1 gene which encodes for the Kisspeptin ligand, crucial for the stimulation and activation of the GnRH neurons. Stimulations of the GnRH neurons is crucial for the secretion of GnRH from the hypothalamus, which in turn stimulates the pituitary gland to secret Follicle stimulating hormone (FSH) and Luteinizing hormone (LH). However, all genes and genetic variations that influence IHH are still not known due to the oligogenic nature of the disease, therefore, this study investigated the effect that the KISS1p.X139fs (rs71745629) stop loss and frameshift variant had on levels of: Sex Hormone Binding Globulin (SHBG), Dehydroepiandrosterone (DHEA) Sulphate, Oestradiol, Testosterone, FSH and LH. This was determined by analysing the 1000 whole genome sequencing (WGS) datasets of the MAMI study to identify individuals who were heterozygous, homozygous wildtype and homozygous alternative for KISS1p.X139fs. PCRs were designed and optimised to confirm the WGS data. Demographic analysis was used to determine the suitable subgroups for median hormone level analysis by genotype. Analysis by genotype showed a difference in the testosterone levels between heterozygous and homozygous alternative males aged 50 and over.