Testosterone, from oestradiol

Figure 19.11 Hormones secreted by the hypothalamus, anterior pituitary, ovary and testis and feedback regulation. GnRH is gonadotrophin-releasing hormone the gonadotrophins are follicle-stimulating hormone (FSH) and luteinising hormone (LH). The effect of these hormones on activities in the ovary and testes is shown. FSH stimulates synthesis and secretion of oestradiol from follicle, and spermatogenesis in testis. LH stimulates synthesis and secretion of progesterone from corpus luteum and synthesis and secretion of testosterone by the Leydig cells.

Cholesterol is an extremely important biological molecule that modulates the fluidity of animal cell membranes and is the precursor of steroid hormones (such as progesterone, testosterone, oestradiol and cortisol) and bile acids. Cholesterol is either derived from the diet or synthesised de novo. Regardless of the source, cholesterol is transported through the circulation in lipoprotein particles, as are cholesterol esters, the cellular storage form of cholesterol. The amount of cholesterol synthesised daily in the liver of a normal person is usually double that obtained from dietary sources. Other sites of cholesterol synthesis include the intestine, and the degree of production is highly responsive to cellular levels of cholesterol. Over 1.2 g of cholesterol is lost in the faeces daily in the form of free sterol or as bile acids. 

The formation of oestradiol from testosterone and its physiological significance... 

Figure 19.8 A brief summary of the pathways for formation and secretion of oestradiol and progesterone within the cells of the follicle. Cholesterol is taken up by thecal cells in a complex with low density lipoprotein. In the thecal cells, cholesterol is converted to testosterone which is released to be taken up by granulosa cells where it is converted into oestradiol. For synthesis of progesterone in the granulosa cells, cholesterol is synthesised de novo within the cells from acetyl-CoA. In the follicle the enzyme aromatase, which produces the aromab c ring in the female sex hormones, is restricted to the granulosa cells. The reacrions that are stimulated by LH and FSH increase synthesis and, therefore, secretion of testosterone and increased synthesis of oestrogens and progesterone.

The first step in the conversion of 4-androstenedione to oestrone is the hydrox-ylation at C-19, a reaction associated with the ER and which requires NADPH and 02. It was thought earlier that the 19-hydroxy derivative was then converted to the 19-aldehyde, which gave rise to oestrone or oestradiol-17/3 (from 4-androstenedi-one or testosterone, respectively) as rupture of the bond between C-10 and the angular methyl group at C-19 occurred through C-10,19-lyase action (Fig. 12). More recent studies [42,52] have resulted in the proposal of at least three mechanisms, which all involve a second stereospecific hydroxylation at C-19 (requiring a second... 

Two types of human hormone are steroidal—the sex hormones such as oestradiol and testosterone and the adrenal hormones such as cortisone. Cholesterol is a steroid too, as is vitamin D, derived from ergosterol. 

The application of the twin ion technique [257] is also of importance in metabolism studies. The doubly labelled steroids [4- C+ 7-l- Ho.44]-androstenedione and [4- C + 7/3- Ho.42]-testosterone, were incubated with human placental microsomes and the resulting metabolites quantitated by counting C and identified by GC-MS [258]. The identified metabolites 17/8,19-dihydroxyandrost-4-en-3-one, 19-hydroxyandrost-4-en-3,17-dione, 17/8-hydroxy-3-oxo-androst-4-en-3-one, 3,17-dioxoandrost-4-en-19-al, oestradiol-17/3 and oestrone were easily recognisable from the double sets of relevant ions in their spectra due to the mixture of hydrogen and deuterium substitution at C-7. Hence the presence of the aromatizing enzymes in the placental preparation and the intermediates in oestrogen biosynthesis were confirmed. 

In h)rpopituitarism there is a partial or complete deficiency of hormones secreted by the anterior lobe of the pituitary. The posterior lobe hormones (see below) may also be deficient in a few cases, e.g. when a tumour has destroyed the pituitary. Patients suffering from hypopituitarism may present in coma, in which case treatment is as for a severe acute adrenal insufficiency. Maintenance therapy is required, using hydrocortisone, th5Toxine, oestradiol and progesterone (in women) and testosterone (in men). For growth hormone see above. 

In Japan mortality from cancer of the prostate is lower than in Western countries. A number of other groups and nationahties also have a low risk of developing this type of cancer, e.g. Seventh Day Adventists who eat a lot of pulses (peas, beans, lentils) had plasma levels of testosterone and 17 j -oestradiol which were significantly lower than those who did not consume diets rich in these compounds as well as having a significantly decreased incidence of prostate cancer. Hawaiians of Japanese ancestry who eat rice and tofu (a soybean product) also have a lower risk of developing this cancer. 

Testosterone and oestradiol are known as the sex steroid hormones. Testosterone is the principal androgen and is synthesized by the testes in the male. Oestradiol. which is secreted by the ovaries, varies w idely in concentration in plasma throughout the female menstrual cycle. Steroids with oestradiol-like action arecalledoestrogens. Progesterone is a product ofthe ovary and is secreted when a corpus lutcum forms after ovulation. Normal female plasma also contains testosterone, about half of which comes from the ovary and half from peripheral conversion of androstenedione and dehydroepiandrosterone (DHA) sulphate which are secreted by the adrenal cortex. Some oestradiol is present in low concentration in normal male plasma. 

The accepted pathway for the biosynthesis of the oestrogens from the appropriate androgen substrate is shown in Scheme 2.1. The conversion of either testosterone (16) or androstenedione (17) to their respective oestrogens, oestradiol and oestrone, is catalysed by a E-450-NADPH-flavoprotein-reduc-tase-dependent enzyme complex, aromatase (AR) [143, 144]. The overall... 

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