Testosterone synthesis

Lehmann, K.P., Phillips, S., and Sar, M. et al. (2004). Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl) phthalate. Toxicological Sciences 81, 60-68. 

The critical period for the induction of hypospadias by finasteride in rats is Days 16 to 17 of gestation (Clark et al., 1990a). It is unlikely that other agents would have a much earlier critical period since testosterone synthesis, which is required for the development of the penile urethra, begins in the rat on Day 15 of gestation (Habert and Picon, 1984). Thus, if treatment in the embryo-fetal development study... 

Bloch, E., Lew, M. and Klein, M. (1971). Studies on the inhibition of fetal androgen formation. Inhibition of testosterone synthesis in rat and rabbit fetal testes with observations on reproductive tract development. Endocrinology 89 16-31. 

Alomary AA, Vallee M, O Dell LE, Koob GF, Purdy RH, et al. 2003. Acutely administered ethanol participates in testosterone synthesis and increases testosterone in rat brain. Alcohol Chn Exp Res 27 38-43. 

The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol Sci 58 339-349... 

At high doses, ketoconazole causes a clinically significant reduction in testosterone synthesis and blocks the adrenal response to corticotropin. Gynecomastia, impotence, reduced sperm counts, and dimiiushed libido can occur in men, and prolonged drug use can result in irregular menses in women. These hormonal effects have led to the use of ketoconazole as a potential adjunctive treatment for prostatic carcinoma. 

Testosterone synthesis from pregnenolone can occur along two distinct metabolic pathways (Fig. 63.1). The names given to these two routes of metabolism refer to the position in the steroid molecule where an unsaturated bond is maintained. Thus, in the delta-4 pathway an unsaturated position is between C4 and C5 of ring A, whereas in the delta-5 pathway, the unsaturated position is between C5 and C6 of ring B. In the human testis, the delta-5 pathway is the predominant (but not exclusive) one used for the biosynthesis of testosterone. 

A. In the Leydig cell the rate-limiting step in testosterone synthesis is the enzymatic cleavage of side chains from cholesterol to form pregnenolone. 

B. Finasteride is a 5a-reductase inhibitor, which essentially makes dihydrotestosterone unavailable to the prostate but does not reduce serum testosterone levels. The decreased prostatic levels of dihydrotestosterone frequently result in a size regression of the prostate, while the relatively normal testosterone levels minimize a depressed libido. Flutamide and spironolactone exhibit antiandrogen effects by competing for the androgen receptor ketoconazole inhibits testosterone synthesis and stanozolol is an oral anabolic androgen preparation. 

Induces testosterone synthesis in Leydig cells of the testis. 

Androgen synthesis in the human male fetus begins at the age of about 70 days when the testes enlarge and go through an important period of activity that begins the conversion of the infant body to a male type. Other bursts of testosterone synthesis occur during infancy, but there is little further synthesis until the onset of puberty.268 272... 

Luteinizing hormone (LH] Female T ovulation T estrogen and progesterone synthesis from corpus luteum Male t testosterone synthesis... 

Therefore, both pituitary gonadotropins are required for optimal androgen function. LH acts on the Leydig cells to stimulate testosterone synthesis,... 

Spironolactone competes for the mineralocorticoid receptor and thus inhibits sodium reabsorption in the kidney (see p. 232). It can also antagonize aldosterone and testosterone synthesis. It is effective against hyperaldosteronism. The drug is also useful in the treatment of hirsutism in women, probably due to interference at the androgen receptor of the hair follicle. 

CYP enzymes are a large and diverse superfamily of haemoproteins. Primarily membrane-associated proteins, they are located in the inner membrane of mitochondria and the endoplasmic reticulum of cells, and metabolise thousands of endogenous and exogenous compounds. Most of these enzymes can metabolise multiple substrates, and many can catalyse multiple reactions. While prevalent in the liver, CYP enzymes are also present in most other tissues of the body, and play an important role in hormone synthesis and breakdown (including oestrogen and testosterone synthesis and metabolism), cholesterol synthesis and vitamin D metabolism. Hepatic CYPs are the most widely smdied. 

ORIGIN Anterior pituitary gland (basophil cells) STRUCTURE Both are glycoproteins FUNCTION In males, LH stimulates testosterone synthesis in the testes, whereas FSH stimulates spermato-... 

Ketoconazole is well absorbed from the gut (poorly where there is gastric hypoacidity, see below) it is widely distributed in tissues but concentrations in CSF and urine are low its action is terminated by metabolism by cytochrome P450 3A (CYP 3A) (t) 8 h). Ketoconazole is effective by mouth for systemic mycoses (see Table 14.2) but has been superseded by fluconazole and itraconazole for many indications largely on groimds of improved pharmacokinetics, imwanted effect profile and efficacy. Impairment of steroid synthesis by ketoconazole has been put to other uses, e.g. inhibition of testosterone synthesis lessens bone pain in patients with advanced androgen-dependent prostatic cancer. 

Adverse reactions include nausea, giddiness, headache, pruritus and photophobia. Impairment of testosterone synthesis may cause gynaecomastia and decreased libido in men. Of particular concern is impairment of liver function, ranging from transient elevation of hepatic transaminases and alkaline phosphatase to severe injury and death. 

In males (Fig. 2. -IO). LH stimulates testosterone synthesis by the testes, and together, testosterone and LH promote spermatogenesis (spenii pnxluction) and development of the testes. Testosterone is also essential for development of secondary sex characteristics in males. FSH stimulates production of proteins and nutrients required for sperm maturation. 

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