Δ4 pathway
Progesterone, 17-OH-progesterone (17 OHP)
One major finding of this study is that hCG/rFSH replacement stimulates and thus normalizes some important steroid hormones belonging to the Δ4 pathway of steroidogenesis in hypogonadotropic hypogonadal males. 17-OHP levels were significantly decreased on treatment with testosterone, but not while the males were on gonadotropin replacement, indicating that a major proportion of this precursor steroid is produced in the gonads and requires gonadotropin stimulation for secretion, while a minor part of it stems from other sources. It is likely that ACTH- stimulated production in the adrenal gland contributes to it.
17-OHP is recognized to have anti-mineralocorticoid 15 and glucocorticoid potency 16,17, without direct androgenic properties. Since cross-reactivity among steroids is a recognized phenomenon, due to the high degree of homology at the DNA-binding domains of nuclear receptors within the steroid hormone receptor superfamily 18, the measured differences in serum 17-OHP concentrations may have clinical implications. Surprisingly, progesterone serum levels in CHH males were decreased on both hCG+rFSH and testosterone substitution, when compared to controls, but the decrease was more pronounced on testosterone replacement. This indicates that the gonadotropins used for replacement do enhance progesterone serum production in males, albeit to a lower extent than in healthy subjects. The use of hCG instead of LH for CHH replacement may explain this phenomenon. Progesterone acts via intracellular progesterone receptors (PRs) A and B, thereby exerting classical genomic action. In addition, it has non-genomic effects. In males, progesterone is involved in sperm capacitation/acrosome reaction, it influences LH receptor expression and subsequent testosterone biosynthesis in Leydig cells; it interacts with the GABAA receptor complex in the CNS, thereby eliciting effects on sleep, mood, and cognition, and also exert effects in adipose tissue and kidneys 19. Progesterone is a high-affinity antagonist of the mineralocorticoid receptor (NR3C2; MR)15, thus eliciting anti-mineralocorticoid effects 20-23. Progesterone is able to transactivate the glucocorticoid receptor (NR3C1; GR) 16. A lack of progesterone and 17-OHP in men could therefore have an impact on water and electrolyte balance and systemic blood pressure regulation.
Figure 1
Pathways of human androgen biosynthesis
-The classic pathways, proceeding parallel for Δ5 and Δ4, convert steroidogenic precursors and lead to the formation of T, which can be further converted to DHT.
-The alternative pathway of T formation proceeds via androstenediol.
-The backdoor pathway proceeds via androstanediol to generate DHT.
-The 11-oxygenated C19 androgen pathway generates 11K T and 11 K DHT. The steroids measured in the present study are indicated in bold.
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