Steroidogenesis Inhibition

Inhibition of glial steroidogenesis Inhibition of ttj receptors Blocks sodium channels... 

Inhibition of steroidogenesis Inhibition of steroidogenesis Inhibition of key T3/ T4-producing enzymes thyroperoxidase, Na/I symporter... 

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. 

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. 

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... 

GnRH analogues (see Chapter 59) can induce chemical castration by suppressing the pulsatile release of LH and FSH, hence inhibiting testicular steroidogenesis. Administration of these compounds reduces circulating testosterone levels. These compounds are inhaled, injected subcutaneously, or implanted subcutaneously. They are used in males in the treatment of precocious puberty and carcinoma of the prostate. 

It is rapidly absorbed into the systemic circulation following intranasal delivery. It stimulates the release of LH and FSH from the anterior pituitary resulting in a temporary increase of ovarian steroidogenesis. After 2 to 3 days of daily administration, the pituitary becomes refractory to further stimulation. LH/ FSH release is inhibited within 10 days and is followed by a decrease in secretion of gonadal steroids within 2 to 6 weeks. 

The ovary also produces inhibin and activin. These peptides consist of several combinations of and 3 subunits and are described in greater detail later. The oc3 dimer (inhibin) inhibits FSH secretion while the 33 dimer (activin) increases FSH secretion. Studies in primates indicate that inhibin has no direct effect on ovarian steroidogenesis but that activin modulates the response to LH and FSH. For example, simultaneous treatment with activin and human FSH enhances FSH stimulation of progesterone synthesis and aromatase activity in granulosa cells. When combined with LH, activin suppressed the LH-induced progesterone response by 50% but markedly enhanced basal and LH-stimulated aromatase activity. Activin may also act as a growth factor in other tissues. The physiologic roles of these modulators are not fully understood. 

An alteration in the weight of the uterus can indicate reproductive toxicity. Compounds that inhibit steroidogenesis and cyclicity can dramatically reduce the weight of the uterus so that it appears atrophic and small. However, uterine weight fluctuates 3- to 4-fold during the... 

Lin T, Blaisdell J, Haskell JF (1987) Transforming growth factor-beta inhibits Leydig cell steroidogenesis in primary culture. Biochem Biophys Res Commun, 146 387-394. 

Etomidate inhibits adrenal function resulting in reduced steroidogenesis after administration of both single boluses and maintenance infusions (397). In a prospective cohort study of 62 critically ill patients who were mechanically ventilated for more than 24 hours, about half developed adrenal insufficiency on the day after intubation. Administration of a single intravenous dose of etomidate 0.2-0.4 mg/kg for intubation led to a 12-fold increased risk of adrenal insufficiency (398). Etomidate should therefore be avoided as an induction agent in critical illness, in particular in patients with septic shock, among whom the incidence of adrenal insufficiency is high (399,400,401). 

Wagner RL, White PF, Kan PB, Rosenthal MH, Feldman D. Inhibition of adrenal steroidogenesis by the anesthetic etomidate. N Engl J Med 1984 310 1415-21. 

Kleeman JM, Moore RW, Peterson RE. 1990. Inhibition of testicular steroidogenesis in... 

Moore RW, Jefcoate CR, Peterson RE. 1991. 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits steroidogenesis in the rat testis by inhibiting the mobilization of cholesterol to cytochrome P450scc. Toxicol Appl Pharmacol 109 85-97. 

The inhibitory GTP binding protein (G ) which has been demonstrated in many different cell types is also present in Leydig cells. Evidence for this was obtained from studies with cultured Leydig cells in which it was shown that the inhibitory effects of arginine vasotocin on steroidogenesis could be abolished by pertussis toxin, which inactivates Gj via ADP ribosylation [9]. However, effects of LH with or without vasotocin were not reported. Similar studies with forskolin [10] demonstrated that low concentrations of this compound inhibited hCG-stimulated cyclic AMP production and this inhibition was prevented by pertussis toxin. Recently, direct evidence for the presence of Gj in rat Leydig cells has been obtained by the demonstration of a 41000 protein (aj) after [32P]ADP ribosylation [11]. 

The level of cyclic AMP inside the cell is the balance between synthesis, breakdown and release. Increased intracellular levels of cyclic AMP can therefore also be obtained by inhibition of cyclic AMP metabolism with phosphodiesterase inhibitors. There are many reports of the use of these inhibitors to demonstrate increased steroidogenesis at submaximal (but not maximal) concentrations of LH, thus confirming the involvement of cyclic AMP. 

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-... 

Calcium, via calmodulin, also activates cyclic AMP phosphodiesterases which inactivate cyclic AMP by metabolism to AMP. Inhibition of phosphodiesterase yields a small increase in ACTH-stimulated steroidogenesis [2], This is relatively slight in the adrenocortical zona fasciculata-reticularis cell, which has a low phosphodiesterase level the zona glomerulosa cell has a higher activity [60,61], which may result from higher level of activation of the calcium/calmodulin intracellular messenger system in the zona glomerulosa. 

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