Steroidogenesis regulation

DiBartolomeis MJ, Moore RW, Peterson RE, et al. 1986. Hypercholesterolemia and the regulation of adrenal steroidogenesis in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats. Toxicol Appl Pharmacol 85 313-323. 

In addition to calcium, the products of phospholipid metabolism, especially the leukotrienes, could also be regulators of steroidogenesis. The roles of calcium and the leukotrienes is supported by the observed correlations of the inhibitions of calmodulin action [35], leukotriene formation [16] and steroidogenesis. However, it remains difficult to prove the specificity of the inhibitors. Positive correlations be-... 

With regard to the possible roles of the detected phosphoproteins in steroidogenesis, the phosphorylation of the nuclear 17 kDa protein occurs too slowly for it to be directly involved. It may be involved in regulation of gene expression and consequently the trophic effects of LH. It has been shown that RNA synthesis is not required in the acute stimulation of steroidogenesis [43,41]. 

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). 

Fig. 1. A model for the pleiotropic effects of LH on functions of Leydig cells. LH interacts with its specific receptor in the plasma membrane of the Leydig cell which results in the activation of several transducing systems and the formation of several second messengers (cyclic AMP, Ca2+, diacylglycerol and arachidonic acid metabolites). Protein kinases (A, C and calmodulin dependent) are activated resulting in the phosphorylation of specific proteins and the synthesis of specific proteins. The (phospho)proteins are involved in the transport of cholesterol to, and the control of, cholesterol metabolism in the inner mitochondrial membrane. Arachidonic acid metabolites (prostaglandins, leukotrienes) may also control steroidogenesis. LH can also regulate the secretion of proteins. The trophic effects of LH are manifested in the growth and differentiation of the Leydig cells.

The regulation by ACTH of the rate-limiting step of steroidogenesis, the conversion of cholesterol to 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.

Fig. 9. The interaction of ACTH with the cyclic AMP and calcium intracellular messenger systems in the regulation of steroidogenesis in the adrenocortical zona glomerulosa cell comparison with angiotensin II and potassium. ACTH activates both adenylate cyclase and calcium influx, here shown as involving two receptor subtypes (R, and R2) although such receptor subtypes have not been identified. The A-kinase and calmodulin systems produce individual responses of characteristic amplitudes and time-courses, which combine to give the observed response of the intact cell. The sequence of events for ACTH is compared to those for the other two major stimuli of steroidogenesis in the zona glomerulosa cell, angiotensin II and potassium. From Ref. 41.

Fig. 10. Hypothesis for the interaction of the A-kinase (A-K) system activated by ACTH with the C-kinase system (C-K) in the long-term regulation of the enzymes of steroidogenesis throughout the adrenal cortex. The primary determinant of zonation of A-kinase and C-kinase activities, via zonation of cell surface receptors or other mechanisms, is hypothesized to be a gradient (e.g., of steroids) created by the pattern of blood flow in the adrenal cortex. The resultant levels of induction of steroidogenic enzymes are indicated by to show particular elevation and by to show particular lack of induction or suppression of induction. Other enzymes involved in steroidogenesis are shown in parentheses. SCC=cholesterol side-chain cleavage enzyme 3/3=3/3-hydroxysteroid dehydrogenase 17a=17a-hy-droxylase 21 =21-hydroxylase 11/3= 11/3-hydroxylase CMO= corticosterone methyl oxidase activity of 11/3-hydroxylase. Secreted steroids are indicated as B=corticosterone Aldo=aldosterone F=cortisol DHEA(S)= dehydroepiandrosterone (sulfate).

Catt KH, Harwood JP, Clayton RN, Davies TE, Chan V, Kaiti-neni M, Nozu K, Dufau M (1980) Regulation of peptide hormone receptors and gonadal steroidogenesis. Rec Progr Horm Res 36 557-622... 

Figure 2. Hypothalamic-anterior pituitary regulation of mammalian steroidogenesis (see text for explanation).

The initial rate limiting step in the transport of intracellular cholesterol to sites of steroidogenesis is mediated by a steroidogenic acute regulatory protein (StAR) that is regulated by adrenocorticotropic hormone (ACTH). 

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... 

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