Regulation of sex hormones (testosterone)

Male sex hormones such as testosterone help develop and maintain male sexual characteristics and are involved in the production of sperm in the testes.

Testosterone is an androgen synthesized by the Leydig cells of the testes and is the predominant sex hormone in men. Testosterone production in men declines with aging.

In the general circulation, total testosterone is currently classified into four major fractions: testosterone bound to SHBG (∼44%), testosterone bound to albumin (∼50%), testosterone bound to cortisol-binding globulin (∼4%), and unbound or free testosterone (∼2%).

It is also the main male hormone responsible for regulating sexual differentiation, producing male sexual characteristics, spermatogenesis and fertility. The effects of testosterone are first observed in the fetus. During the first 6 weeks of development, the reproductive tissues of males and females are identical. Around the seventh week in utero, SRY (sex-related gene on the Y chromosome) initiates the development of the testes.

Testosterone is also involved in the regulation of secondary male characteristics, which are responsible for masculinity. These secondary sex characteristics include male hair patterns, vocal changes and deepening of the voice, anabolic effects, which include growth spurts at puberty and skeletal muscle growth (testosterone stimulates protein synthesis).

Testosterone levels tend to decline with increasing age; thus, men tend to experience decreased testicular size, decreased libido, decreased bone density, decreased muscle mass, increased fat production, and decreased erythropoiesis, leading to possible anemia.

Changes in sex hormone levels such as SHBG or testosterone are subject to various environmental factors such as age as well as genetic factors. One of the latest GWAS studies to date has used nearly 370,000 participants of European ancestry to identify 203 markers associated with testosterone levels.

The role of genetics in the inheritance of testosterone levels has been shown to be strongly influenced by the gender of the individual and that genetically higher testosterone is detrimental for metabolic diseases in women, but beneficial in men.

Some of the most significant markers found to be related to testosterone levels in the study pertain to genes such as REEP3 which is believed to be involved in hormone-dependent transcriptional activation of testosterone.Some of the most significant markers that have been found to be related to testosterone levels in the study pertain to genes such as REEP3 which is believed to be involved in hormone-dependent transcriptional activation, the FAM9A gene related to hormone regulation and sperm production, and the SAT2 gene, which produces the diamine acetyltransferase 2 enzyme involved in spermine and putrescine degradation.

Number of observed variants

13.5 million variants

Number of loci analyzed in the study

203 loci

Bibliography

Ruth K.S., Day F.R., et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nature Medicine, 10 Feb 2020, 26(2):252-258.

Nassar G.N. et Leslie S.W. Physiology, Testosterone. StatPearls.

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