Androgens

The primary male sex hormone, or androgen, is testosterone (Figure 5.139). This is secreted by the testes and is responsible for development and maintenance of the male sex characteristics. Androgens* also have a secondary physiological effect, an anabolic activity which stimulates growth of bone and muscle, and promotes storage of protein. The biosynthetic pathway to testosterone is outlined in Figure 5.133, where it can feature as an intermediate in the pathway to oestrogens. Low levels of testosterone are also synthesized in females in the ovary. Testosterone

testosterone

Characteristic features of androgens:

• Ci9 androstane skeleton

• 17ß-hydroxyl testosterone

Characteristic features of androgens:

• Ci9 androstane skeleton

Figure 5.139

lacks any side-chain and has a 17ß-hydroxyl as in estradiol, but still contains the methyl C-19 and the A4-3-one system in ring A. This C19 skeleton is designated androstane.

It is particularly worthy of note that the routes to corticosteroids, progestogens, oestrogens, and androgens involve common precursors or partial pathways. This means that these processes need to be under very tight control if a person's normal physiological functions and characteristics are to be maintained. This balanced production is regulated primarily by gonadotrophic and hypothalamic proteins from the pituitary (see page 411).

Androgen Drugs

Testosterone can be produced from androstenolone (Figure 5.129) by chemical routes requiring reduction of the 17-carbonyl and oxidation of the 3-hydroxyl, and necessitating appropriate protecting groups. A simple high-yielding process (Figure 5.140) exploits yeast, in which fermentation firstly under aerobic conditions oxidizes the 3-hydroxyl, and then in the absence of air reduces the 17-keto group. Testosterone is not active orally since it is easily metabolized in the liver, and it has to be implanted, or injected in the form of esters. Transdermal administration from impregnated patches has also proved successful, and is now the method of choice for treating male sexual impotence caused by low levels of sex hormones (hypogonadism). Testosterone may also be prescribed for menopausal women as an adjunct to hormone replacement therapy (see page 279) to improve sex drive, and occasionally in the treatment of oestrogen-dependent breast cancer. The ester testosterone undecanoate is orally active, as is mesterolone (Figure 5.141), which features introduction of a 1a-methyl group and reduction of the A4 double bond. Oral activity may also be attained by adding a 17a-alkyl group to reduce metabolism, e.g. 17a-methyltestosterone (Figure 5.140), such groups being introduced using appropriate Grignard reagents. However, these types of 17a-alkyl derivative are being replaced since they can sometimes cause jaundice as a side-effect.

The ratio of androgenic to anabolic activity can vary in different molecules. There have been attempts to produce steroids with low androgenic but high anabolic activity to use for various

Pathway Androstenolone Mesterolone Derivatives

mesterolone nandrolone oxymetholone

(19-nortestosterone) cyproterone acetate mesterolone nandrolone oxymetholone

(19-nortestosterone) cyproterone acetate

stanozolol finasteride danazol gestrinone

Figure 5.141

stanozolol finasteride danazol gestrinone

Figure 5.141

metabolic and endocrine disorders. Methandrostenolone (methandienone) (Figure 5.140), oxymetholone, and nandrolone (19-nortestosterone) (Figure 5.141) are modifications used in this way. Treatment of oxymetholone with hydrazine leads to formation of a pyrazole ring fused to a saturated ring A as seen in stanozolol (Figure 5.141). However, it is difficult to completely remove the androgenic activity from anabolic steroids. These materials are frequently abused by athletes wishing to promote muscle development and strength. Androgenic activity can affect the sexual characteristics of women, making them more masculine, whilst prolonged use of these drugs can lower fertility in either sex and endanger long term health by increasing the risks of heart and liver disease or cancer.

The progestogen cyproterone acetate (Figure 5.141) is a competitive androgen antagonist or anti-androgen, that reduces male libido and fertility, and finds use in the treatment of severe hypersexuality and sexual deviation in the male, as well as in prostate cancer. Finasteride (Figure 5.141) is another anti-androgen, which is of value in prostate conditions. It is a 4-aza-steroid and a specific inhibitor of the 5a-reductase involved in testosterone metabolism. This enzyme converts testosterone into dihydrotestosterone, which is actually a more potent androgen, so that its inhibition helps to reduce prostate tissue growth. Finasteride has also been noted to prevent hair loss in men, and is marketed to treat male-pattern baldness.

Dehydroepiandrosterone (DHEA) (Figure 5.133) is a precursor of androgens and oestrogens, and is the most abundant steroid in the blood of young adult humans, with levels peaking at about 20 years of age, then declining as the person ages. Whilst this hormone has a number of demonstrated biological activities, its precise physiological functions remain to be clarified. This material has become popular in the hope that it will maintain youthful vigour and health, countering the normal symptoms of age. These claims are as yet unsubstantiated, but taking large amounts of this androgen and oestrogen precursor can lead to side-effects associated with high levels of these hormones, e.g. increased risk of prostate cancer in men, or of breast cancer in women, who may also develop acne and facial hair. DHEA is not a precursor of glucocorticoids, mineralocorticoids, or of progestogens.

Danazol and gestrinone (Figure 5.141) are inhibitors of pituitary gonadotrophin release, combining weak androgenic activity with antioestrogenic and antiprogestogenic activity. These highly modified structures bear one or more of the features we have already noted in discussions of androgens, progestogens and oestrogens, possibly accounting for their complex activity. These compounds are used particularly to treat endometriosis, where endometrial tissue grows outside the uterus.

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Responses

  • erling
    Is also use for good sex testosterone undecanoate?
    5 years ago

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