An optimal endocrine replacement strategy for hypogonadotropic hypogonadal males aims at normalizing all aspects of deficient androgenic action. While testosterone replacement has been used in clinical practice to solely convey androgenic effects, gonadotropins have been employed for the purpose of additionally initiating testicular growth and spermatogenesis.13
The present study provides data on steroid hormone profiles of males with CHH, in which these two different replacement regimens were applied sequentially. The hormone concentrations in serum reflect the overall production of hormone that is contributed to the blood stream by each hormone-producing tissue. The naturally occurring ‘knock down condition’ of central hormonal stimulation of gonads, with uncompromised ACTH secretion that is present in CHH males, was used as a model, to enable delineation of gonadotropin effects on testicular and adrenal steroidogenic pathways involved in male androgen biosynthesis. Specifically, hCG/rFSH effects on serum steroid hormone concentrations of the classic Δ5 pathway of steroid biosynthesis, on concentrations of steroids of the Δ4 steroidogenic pathway, the alternative pathway of testosterone biosynthesis, the backdoor pathway of DHT synthesis and on concentrations of the 11-oxygenated C19 androgen pathway were investigated. In addition, the serum levels of testosterone metabolites were analyzed.
Our results indicate that treatment of CHH males with gonadotropins results in steroid hormone profiles similar to those of healthy men, with few exceptions (E2, progesterone). However, this is not the case using a regimen based on exogenous testosterone. If testosterone is applied, steroidogenic pathways in testicles of CHH males remain unstimulated. By contrast, if hCG + rFSH are used, the LHCG receptor in Leydig cells is activated.14 In response, multiple steroids of the classical steroidogenic cascade are synthesized by the gonads, including the classic potent androgens T and DHT. This explains the differences observed in serum steroid levels in CHH males on the two different replacement regimens.
4.5.6 Summarized results and conclusions
These biochemical studies of serum steroid hormone patterns in CHH males on two different androgenic replacement regimens contribute to our knowledge of human steroidogenesis, specifically androgen production and its regulation. Gonadotropins contribute to steroid production along the classic Δ4 pathway, by stimulation of 17-OHP production. In addition, gonadotropins co-activate an alternative pathway of T biosynthesis from DHEA via androstenediol.
However, Δ5 biosynthesis of 17-OH-pregnenolone, DHEA(S) seems fully gonadotropin-independent, and the production of androstenedione is largely gonadotropin-independent. Thus, an ‘adrenal-peripheral tissues-testicular collaboration’ regarding androgen synthesis by classic or alternative pathways seems possible.
The 11-oxygenated C19 androgen pathway is activated independently of gonadotropins. The activity of the three DHT backdoor pathways (converging in androstanediol biosynthesis) is not increased by gonadotropins.
A replacement regimen with combined hCG/rFSH mimics physiologic steroid hormone profiles better than a substitution with exogenous testosterone. The documented differences in steroid profiles on testosterone replacement in hypogonadal males with absent or severely reduced endogenous LH and FSH secretion may have long-term consequences for health and well-being. Specifically, body composition, bone health, glucose and lipid metabolism, salt and water balance, cognition, mood, sleep and sexual function could be affected. The steroidogenic differences could also be relevant for gonadotropin-suppressive treatments with long-acting testosterone preparations in males with primary hypogonadism. To what extent this hypothesis is true, should be addressed in future clinical studies.