Steroidogenesis

Extracellular calcium is required to give maximum LH stimulated steroidogenesis in isolated Leydig cells [15,18]. Using the intracellular fluorescent calcium indicator, Quin 2, it has been shown that lowering the extracellular calcium concentration from 2.5 mM to 1.1 xM lowered the LH stimulated intracellular calcium concentrations from 300-500 nM to only 52 nM. These studies showed that LH increases intracellular calcium and that this increase is dependent mainly on extracellular levels of calcium. Cyclic AMP analogues were also shown to increase intracellular calcium to the same concentrations as those obtained with LH, indicating that cyclic AMP is one of the mediators of LH action on calcium mobilization [15]. 

Studies with ovarian cells have also shown that extracellular calcium is required to give maximum steroidogenesis [29]. The calcium channel blockers, verapamil or diltiazem also suppressed LH-stimulated progesterone production. The calcium ionophore A23187 significantly enhanced the stimulatory effects of LH. Recently it was shown that FSH, prostaglandin E2 and F2 have distinct effects on steady state calcium exchange in ovarian cells [30]. 

In chicken granulosa cells, TMB-8, a putative antagonist of intracellular calcium mobilization, inhibited progesterone synthesis in calcium free medium and also inhibited LH stimulated 45Ca release from digitonin permeabilized cells [31]. The latter occurred in two phases after 1-2 min followed by a slower phase after 5 min. Forskolin and 8-Br-cyclic AMP stimulated only the slow phase of calcium mobilization. These studies indicate that LH may initially stimulate calcium mobilization in granulosa cells via a cyclic AMP-independent pathway followed by a slower cyclic AMP-dependent pathway. 

In testis Leydig cells the LH stimulated cyclic AMP production was unaffected by lowering the extracellular calcium concentration [15]. However, three inhibitors of calmodulin all inhibited LH stimulated cyclic AMP production, indicating that there may well be a requirement for calcium. In swine granulosa cells, calcium deprivation suppressed the LH dose-dependent accumulation of cyclic AMP by 50% [29]. 

The transport of cholesterol to, and its side-chain cleavage in, the mitochondria are the most important steps in the hormonal control of steroidogenesis. The enzymatic activities in the endoplasmic reticulum are also under hormonal control. However, expression of hormonal effects in this compartment requires several hours and is therefore part of the chronic, trophic effects of LH [3,4,32], 

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P and Pg, exist in foUicular fluid. Control of inhibin secretion involves a feedback relationship in which circulating FSH stimulates inhibin secretion, which in turn reduces the secretion of FSH (8). Both the homo- and the heterodimers of the P-subunits of inhibin promote the secretion of FSH and thus have been termed activins. Activin is secreted by the ovary and the testes into the circulation. In addition, both inhibin and activin have intragonadal autocrine and paracrine effects that influence gonadal steroidogenesis (9). 

The PBRis distinct from the central BZ receptor although both can be present in the same tissues in differing ratios. PBRs are predominately localized on the outer mitochondrial membrane and are thus intracellular BZ recognition sites. The PBR is composed of three subunits an 18,000 mol wt subunit that binds isoquinoline carboxamide derivatives a 30,000 mol wt subunit that binds BZs and a 32,000 mol wt voltage-dependent anion channel subunit. The porphyrins may be endogenous ligands for the PBR. PBRs are involved in the control of cell proliferation and differentiation and steroidogenesis. 

Anastrazole is a nonsteroidal, type H, aromatase inhibitor that is 200 times more potent than aminoglutethimide. It is eliminated primarily via hqDatic metabolism, has a terminal half life of 50 h with steady state concentrations achieved approximately 10 days with once daily dosing regimens. It is administered orally at a dose of 1 mg/day that achieves near maximal aromatase inhibition and hence estrogen suppression in breast cancer patients. No effect on adrenal steroidogenesis has been observed at up to ten times the daily recommended dose. When used in the metastatic setting, anastrozole has been shown... 

Spironolactone is an antiandrogen which blocks androgen-receptors, alters steroidogenesis by adrenals and gonads and inhibits 5-a reductase. In doses of 100-200 mg daily it reduces sebum production and improves inflammatory acne in women. During treatment, birth control measures are required due to the risk of male fetus feminization. 

Aluru, N. aud Vijayau, M.M. (2006). Aryl Hydrocarbou receptor activatiou impairs cortisol respouse to stress in Rainbow Trout by disrupting the rate-hmiting steps in steroidogenesis. ii rfocri o/ogy 147, 1895-1903. 

Crain, D.A., Guillette, L.J., and Rooney, A.A. et al. (1997). Alterations in steroidogenesis in aUigators (Alligator mississippiensis) exposed naturally and experimentally to environmental contaminants. Environmental Health Perspectives 105, 528-533. 

Gravel, A. and Vijayan, M.M. (2006). Sahcylate disrupts interrenal steroidogenesis and brain glucocorticoid receptor expression in rainbow trout. Toxicology Science 93, 41-49. 

Monteiro, P.R.R., Reis-Henriques, M.A., and Coimbra, J. (2000b). Polycyclic aromatic hydrocarbons inhibit in vitro ovarian steroidogenesis in the flounder Platichthys flesus L). Aquatic Toxicology 48, 549-559. 

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. 

Inhibitors of Adrenal Steroidogenesis Aminoglutethimide Inhibits conversion of 250 mg every High incidence of Used in ACTH-independent cases... 

Adrenolytic Agent Mitotane 11 P-hydroxylase. Inhibits steroidogenesis intermittently 2-6 g/day in 3-4 Gl intolerance (high Used primarily for adrenal... 

W5. Wade, C. E., Lindberg, J. S Cockrell, J. L Lamiell, J. M Hunt, M. M., Ducey, J., and Jumey, T. H., Upon-admission adrenal steroidogenesis is adapted to the degree of illness in intensive care unit patients. J. Clin. Endocrinol. Metab. 67,223-227 (1988). 

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). 

Figure 4.2 Steroidogenesis. Reproduced with permission from Essential Endocrinology, 4th edn, CGD Brook NJ Marshall (eds). John Wiley Sons, 2001...

Papadopouios V, Widmaier EP, Amri H, Ziiz A, Li H, Culty M, Castello R, Philip GH, Sridaran R, Drieu K. (1998). In vivo studies on the roie of the peripheral benzodiazepine receptor (PBR) in steroidogenesis. Endocr Res. 124(3-4) 479-87. 

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