Progesterone aldosterone from

Congenital defects in the biosynthesis of steroid hormones can lead to severe developmental disturbances, in the adrenogenital syndrome (AGS), which is relatively common, there is usually a defect in 21-hydroxylase, which is needed for synthesis of cortisol and aldosterone from progesterone. Reduced synthesis of this hormone leads to increased formation of testosterone, resulting in masculin-ization of female fetuses. With early diagnosis, this condition can be avoided by providing the mother with hormone treatment before birth. 

FIGURE 25.43 The steroid hormones are synthesized from cholesterol, with intermediate formation of pregnenolone and progesterone. Testosterone, the principal male sex hormone steroid, is a precursor to /3-estradiol. Cortisol, a glucocorticoid, and aldosterone, a mineralocorticoid, are also derived from progesterone. 

In every case the information provided has been obtained by collating public domain sources of information, but unfortunately very often little data is available, particularly on commercial aspects, even for products that have proved to be big successes. Thus microbial biotransformations for steroid modification, particularly stereoselective hydroxylations, such as the use of Rhizopus arrhizus to convert progesterone into antiinflammatory and other dmgs via 11- -hydroxyprogestrone, have proved to be very successful. However, comparatively little useful information exists from public domain sources, despite (or perhaps because) a market of hundreds of millions /a exists for such microbially transformed steroids (cortisone, aldosterone, prednisolone and prednisone etc.) produced by microbial hydroxylation and dehydrogenation reactions coupled with complimentary chemical steps. 

The synthesis of adrenal steroids is illustrated in Fig. 5.3.1. Cortisol, corticosterone, and aldosterone are formed by sequential hydroxylations and oxidoreductions from pregnenolone and progesterone. 17a-Hydroxypregnenolone (17HP) is a branchpoint constituent because it can be converted to cortisol or adrenal androgens. All of the components of this pathway can be quantified by MS/MS. The steroids around the periphery are urinary metabolites and these are measured by GC-MS following hydrolysis of conjugates and derivatization. 

Severe consequences can occur from defective syn- thesis of a steroid hormone, as is the case in several metabolic diseases. Patients who have 21-hydroxylase deficiency are unable to convert progesterone to aldosterone and cortisol. Instead the progesterone is directed to an excess production of testosterone. In the female, this results in masculinization and hirsutism (growth of hair). In the male, premature masculinization occurs. If the disease is diagnosed before the first birthday, the patient can be treated with the missing steroid hormones, which in turn suppress the synthesis of excess progesterone and, as a consequence, testosterone via feedback mechanisms. 

The step-by-step synthesis of the steroid hormones pregnenolone and progesterone from cholesterol (C27) was presented in chapter 20 (see fig 20.22). Note that pregneno-lone (C2i) and progesterone (table 20.4) (C2 ) are intermediates in the biosynthesis of all of the major adrenal steroids, including cortisol (C2i), corticosterone (C21), and aldosterone (C21). The same two compounds are intermediates in the synthesis of the gonadal steroid hormones, testosterone (C,9) and 17/3-estradiol (CI8). Because the synthesis of all these hormones follows a common pathway, a defect in the activity or amount of an enzyme along that pathway can lead to both a deficiency in the hormones beyond the affected step and an excess of the hormones, or metabolites, prior to that step. 

Small quantities of progesterone, testosterone, and estradiol are also produced by the adrenal gland. However, they play a minor role compared to the testicular and ovarian hormones. Progesterone, which is the precursor of cortisol, aldosterone, testosterone, and estradiol, is synthesized from 5-pregnenolone by 3-P-ol-dehydrogenase. Deficiency of this enzyme results in cortisol and aldosterone deficiencies. Such patients require replacement therapy with both glucocorticoids and mineralocorticoids. 

Fig. 11.4 (a) Structure of vitamin D3. Vitamin D3 is derived from cholesterol by UV irradiation, (b) Structures of cortisol and aldosterone. Cortisol is a major glucocorticoid, and aldosterone is a major mineralocorticoid. Both are derived by a series of hydroxylation reactions from progesterone, from which androgens and oestrogens are also synthesized. 

In (hemid-l9.S()s. il was observed that progesterone inhibited the aniinalriurclic and kaliurelic effects of aldosterone, the primary mineralocorticoid in humans. An intensive effort was launched lo develop steroidal derivatives that pos-se.ssed only the antimincralocurticuid activity of progesterone. - " Spironolactone was. selected from a host of derivatives for further examination. ... 

B. Both pregnenolone and progesterone are intermediates in the synthesis of steroid hormones from cholesterol. 7-Hydroxycholesterol is an intermediate in bile salt synthesis, and aldosterone is a mineralocorticoid produced well beyond the branch point for the synthesis of the adrenal and gonadal steroids. Retinoic acid is derived from vitamin A. 

A generic depiction of the mechanism for steroid hormone activity at a target cell is shown in Figure 30-4. The first step consists of dissociation of the hormone from the plasma transport protein and entry into the cell by diffusion across the plasma membrane. In the second step the hormone binds with the receptors in the cytoplasm and nucleus. Receptors for glucocorticoid and aldosterone are found in the cytoplasm and receptors for estrogen and progesterone are found in the nucleus. Recall that receptors for... 

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. 

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