Steroidogenesis pathway

The pathway has an oxidative phase, which is irreversible and generates NADPH and a nonoxidative phase, which is reversible and provides ribose precursors for nucleotide synthesis. The complete pathway is present only in those tissues having a requirement for NADPH for reductive syntheses, eg, lipogenesis or steroidogenesis, whereas the nonoxidative phase is present in all cells requiring ribose. 

Occurrence in molluscs of steroidogenesis along a pathway very similar to that found in vertebrates has been claimed. Testosterone (64) - androstenedione (65) interconversion has been demonstrated in gonads of the male and female bivalve - Mytilus edulis [117] and of the gastropod Crepidula fornicata [118], by using labelled testosterone and androstenedione. Moreover, several steroids have been identified in the gonads and hepatopancreas of the opisthobranch... 

Similarly, five closely related melanocortin receptors that respond to various peptides derived from the POMC precursor have been identified (Fig. 18-7) [24]. As expected, the receptor on adrenal cortical cells responds best to ACTH, which normally stimulates adrenal steroidogenesis, and the receptor on melano cytes responds best to aMSH, which causes skin darkening. However, the pattern of melanocortin receptor expression in the brain is not simply explained by the known patterns of peptide expression in the brain or by the known effects of POMC-derived peptides when applied to various brain regions. With this number of peptide receptors, it is obvious that production of final peptide products must be precisely controlled and that different biosynthetic processing pathways can dramatically affect the biological activity observed (Figs 18-5,18-7). 

In addition to the stimulatory actions of LH and hCG on steroidogenesis in Leydig cells and ovarian cells, these hormones also cause a refractoriness or desensitization of that same steroidogenic response. This may involve a loss of LH receptors (down regulation), an uncoupling of the LH receptor from the adenylate cyclase, an increase in the metabolism of cyclic AMP due to an increased phosphodiesterase activity and a decrease in the activities in some of the enzymes in the pathways of steroidogenesis (see Ref. 69 for other references). 

The pathway of biosynthesis of steroids in the adrenal cortex 1.5.1. The enzymes of steroidogenesis... 

Fig. 2. Pathway of biosynthesis of the glucocorticoid, cortisol, in the adrenal cortex. Cholesterol, from stores in cholesteryl esters or from other sources (see text) is converted via mitochondrial cytochrome P-450SCC (cholesterol side-chain cleavage enzyme) to pregnenolone, which then is successively converted by the microsomal enzymes cytochrome P-450,7 (17a-hydroxylase), 3 j8-hydroxysteroid dehydrogenase/ isomerase and cytochrome P-450c2, (21-hydroxylase) to 11-deoxycortisol, followed by conversion by the mitochondrial cytochrome P-450ll(3 (11/3-hydroxylase) to cortisol. The short-term action of ACTH in stimulation of steroidogenesis is to increase the availability of cholesterol for conversion by cytochrome P-450scc. From Ref. 9.

The rate of total steroidogenesis is determined by the rate of supply of cholesterol to cytochrome P-450scc. The rate of flux through this step determines the rate of synthesis of the sum of the steroid products, but does not determine the rate of synthesis of any individual steroid. The pattern of steroidogenesis, i.e. which steroids are produced and in what ratio, is determined by the relative activities of the enzymes of the steroidogenic pathway beyond the formation of pregnenolone. 

Fig. 3. The rate-limiting step of steroidogenesis under ACTH regulation. The transfer of cholesterol (C) from the outer to the inner mitochondrial membrane under ACTH regulation (step 3) makes cholesterol available to cytochrome /M50scc for conversion to pregnenolone (step 4), which diffuses out of the mitochondrion (step 5). Because of its insolubility in aqueous media, cholesterol must be transported to mitochondria, probably by SCP2, from a precursor pool (step 2). Here, cholesterol in the precursor pool is shown as being formed from cholesterol esters (CE) by cholesterol ester hydrolase (CEH) (step 1) other possible pathways are shown in Figs. 4 and 6. From Ref. 14.

Steroidogenesis synthesis of steroid hormones from cholesterol. Interactions of Fat Metabolism Pathways ... 

Lieberman S, Prasad V. Heterodox notions on pathways of steroidogenesis. Endocr Rev I990 ll 469-93. 

The biochemical pathway illustrating the aromatization of testosterone to estradiol and androstenedione to estrone is shown in Figure 53-10, Steroidogenesis and its regulation during the menstrual cycle have been discussed in detail by... 

Conley, A.J. and I.M. Bird. The role of cytochrome P450 17a-hydroxylase and 3/3-hydroxylase and 3(3-hydroxysteroid dehydrogenase in the integration of gonadal and adrenal steroidogenesis via the A5 and A4 pathways of steroidogenesis in mammals. Biol. Reprod. 56 789-799, 1997. 

Ahsan, S.,Lacey, M. and Whitehead, S.A. (1997). Interactions between interleukin-113, nitric oxide, and prostaglandin Ej in the rat ovary effects on steroidogenesis. Eur. J. Endocrinol. /J7 293-300. Anteby, E.Y., Hurwitz, A. Korach, O., Revel, A., Simon, A., Finci-Yeheskel, Z., Mayer, M., and Laufer, N. (1996). Human follicular nitric oxide pathway Relationship to follicular size, oestradiol, concentrations and ovarian blood flow. Human Reproduction 77 1947-1951. 

---