Androstenedione synthesis

Testosterone, the principal male sex steroid hormone, is synthesized in five steps from cholesterol, as shown below. In the last step, five isozymes catalyze the 17/3-hydroxysteroid dehydrogenase reactions that interconvert 4-androstenedione and testosterone. Defects in the synthesis or action of testosterone can impair the development of the male phenotype during embryogenesis and cause the disorders of human sexuality termed male pseudohermaphroditism. Specifically, mutations in isozyme 3 of the 17/3-hydroxysteroid dehydrogenase in the fetal testis impair the for-... 

The follicular phase covers the development of the follicle, which involves an increase in its size due to an increase in follicular fluid, growth of the ovum (i.e. an increase in the contents of RNA and protein) and an increase in the number of cells that surround the ovum. These cells are of two types, the granulosa and the thecal cells. The role of these cells is to synthesise and secrete the steroid hormones oestrogens (mainly oestradiol). The precursor molecule for their synthesis is cholesterol. There is a division of labour between these cells the thecal cells convert cholesterol into the male sex hormones androstenedione and testosterone, which are released into the blood to be taken up by the granulosa cells where they are converted to the oestrogens (Figure 19.8). For details of pathways, see Appendix 19.1. 

Aminopyrine, 234 Aminotetradine, 265 2-Aminothiazole, 247 2-Aminothiazole synthesis, 126 Amisotetradine, 266 Amobarbital, 268 Amopyroquine, 342 Amoxycillin, 414 Amphetamine, 37, 70 Ampicillin, 413 Amprolium, 264 Amytriptylene, 141, 404 Anabolic effects, 169 Androgens, discovery, 155 Androstanolone, 173 Androstenedione, 158, 176 Anesthesia, parenteral, 56 Angst, 363 Anileridine, 300 Aniline, metabolism. 111 Anisindandione, 147 Anovlar , 186 Antagonists, 20, 65 Antazoline, 242 Antibodies, 41... 

Competitive AIs are chemical compounds that compete with the substrate androstenedione for non-covalent binding to the active site of the enzyme to decrease the amount of product formed. Initially, research and development of AIs started with the synthesis and biochemical characterisation of competitive inhibitors. 

Several sex-dependent differences have been observed in the action of cytochrome P450 isoenzymes on steroid hormones.290 2903 Thus, androstenedione is hydroxylated by rat liver enzymes specific for the 60, 7a, 16a, and 160 positions.291 Of these the 16 hydroxylase is synthesized only in males, and synthesis of the 6 hydroxylase is also largely suppressed in females. 

Formestane (Figure 5.138), the 4-hydroxy derivative of androstenedione, represents the first steroid aromatase inhibitor to be used clinically. It reduces the synthesis of oestrogens and is of value in treating advanced breast cancer in post-menopausal patients. 

Another issue is the dietary supplements commonly referred to as prohormones, which are touted as muscle builders and available legally at health food stores. In 1998 during the homerun race between baseball stars Mark McGuire and Sammy Sosa these supplements were propelled into the media spotlight. Mark McGuire announced he was quitting his use of the most popular prohormone, androstenedione (or andro ) to help boost his performance. DHEA is another popular one. Now under scrutiny by the DEA, FDA, and Federal Trade Commission, these prohormones are intermediates in the synthesis of testosterone, and can be converted to testosterone and other hormones in the body. 

Aminoglutethimide [ah me no glue TETH i mide] is useful in second line therapy for the treatment of metastatic breast cancer. It inhibits the adrenal synthesis of pregnenolone from cholesterol, and the extra-adrenal aromatase reaction responsible for the synthesis of estrogen from androstenedione. Aminoglutethimide is administered orally, and is metabolized by the hepatic cytochrome P-450 system to inactive products. Because of its ability to induce this system, its own metabolism is accelerated, and interactions that increase the metabolism of dexamethasone (see p. 275), theophylline (see p. 220) and digoxin (see p. 158) can occur. Aminoglutethimide causes transient CNS depression and a maculopapular rash. 

The answer is d. (Murray, pp 505-626. Scriver, pp 4029-4240. Sack, pp 121-138. Wilson, pp 287-320.) Both cortisol and aldosterone contain C-21-hydroxyl groups. Both are also derived from progesterone in the adrenal cortex. In contrast, the sex hormones are synthesized in the ovaries and testicular interstitial cells. In the synthesis of sex hormones, progesterone is converted to 17a-hydroxyprogesterone and then androstenedione, which may either become estrone or testosterone. Testosterone gives rise to estradiol in the ovaries. In the corpus luteum, progesterone is produced. 

Steroids are good substrates for microbiological reductions however, the reductions often lead to unwanted side reactions of desired transformations such as hydroxylations. The first report in 1937 291 dealt with baker s yeast reduction of the 3- and 17-groups and led to the synthesis of estradiol from estrone and testosterone from androstenedione. 

An eletrocyclization provides the key reaction in one total synthesis of an androstane. It takes approximately a dozen steps to prepare the substrate, 2-1 (shown in 3D in 2-2) (Scheme 5.2). Heating at 200 °C closes rings A and B to afford the steroid skeleton in a concerted process (2-3). Reaction of that product with singlet oxygen, formed for example by irradiation in the presence of a photosensitizer dye, leads to attack at C3 with concomitant shift of the double bond (2-4). Several more steps then give androstenedione (1-6). 

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