Hormone profiling of adults with the TACR3 p.K286R variant and its implications in fertility

Abstract

The HPG axis plays a key role in human sexual development and maturation, and reproductive function. A key component of this axis is a set of GnRH neurons, located in the hypothalamus. These neurons secrete GnRH-1, which acts on the pituitary gland in order to stimulate secretion of FSH and LH. LH and FSH act on the gonads, stimulating their function. Indeed, the axis is known to be active in the first few months of life, dormant throughout childhood, and is then reactivated in the early teen years, bringing about puberty. Following puberty, the axis remains active throughout most of adult life, with a decline in activity being observed in older individuals. Failure of the axis to form and function properly can thus lead to issues with sexual development and reproductive ability. In individuals where sexual maldevelopment can indeed be traced back to a dysfunctional HPG axis, the condition is termed IHH. IHH is oftentimes congenital in nature, caused by pathogenic variants in genes that regulate the development or function of the axis. Numerous pathogenic variants in each of these genes have been discovered. The disease is oligogenic, and thus, one pathogenic variant alone may not be enough to give rise to the IHH phenotype. Two categories of IHH exist: KS and nIHH. Each type of IHH has its own set of genes to which it has been linked, however several genes have been found to be associated with both types of IHH. Gonadotropin levels and sex hormone levels in individuals with IHH are known to differ significantly from levels in individuals without the condition, and can be decreased in individuals who carry variants that are pathogenic but are not causative of IHH on their own. Hence, measuring hormone levels can be used to identify which variants are pathogenic and which are not. In this study, the TACR3 p.K286R variant was the variant of interest. Individuals in the MAMI collection were divided based on sex, ten-year age groups, and case-control relative status, and median hormone data was analysed for each group, the results of which determined that males should be divided based on age, with 50 as the cutoff, and females should be divided based on menopausal status. Participants were further differentiated according to whether they were heterozygous or homozygous wild type for this allele and median hormone levels were compared statistically between the genotypes within the same age/menopause group. It was found that DHEAS levels showed a significant difference when comparing different genotypes within the same age/menopause group.