Oestradiol synthesis

In the human female, IGF-1 is expressed by follicular theca cells, while IGF-2 is synthesized by granulosa cells (Chapter 8). The IGF-1 and -2 receptors are widely expressed in ovarian tissue, and synthesis of both growth factors and their receptors are influenced by circulating gonadotrophin levels. IGF-1 exerts a direct mitogenic effect on human granulosa cells, and promotes increased androgen and oestradiol synthesis by these cells. IGF-1 also promotes increased expression of FSH and LH receptors in ovarian tissue. 

The follicular granulosa cells are the major site of synthesis of female steroid sex hormones the oestrogens. P-Oestradiol represents the principal female follicular oestrogen. Oestriol is produced by the placenta of pregnant females. Oestriol and oestrone are also produced in small quantities as products of P-oestradiol metabolism. 

Olsson, P.E., M. Zafarullah, and L. Gedamu. 1989. A role of metallothionein in zinc regulation after oestradiol induction of vitellogenin synthesis in rainbow trout, Salmo gairdneri. Biochem. Jour. 257 555-559. 

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. 

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.

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.

Compounds described as the 15 -carboxymethyl derivatives (32) of oestrone and oestradiol have been described as haptens, without any evidence as to their configurations at C-15, or their homogeneity. The method of synthesis (via Michael addition of malonic ester to the 15-en-17-one) normally gives 15/8-substituted compounds. Some 15/8-carboxyethylmercaptoandrostane derivatives (33), obtained by addition of methyl 3-mercaptopropionate to androst-15-en-... 

Starting with this hypothesis, several 6-sila-steroids were prepared127-129. As an example, the syntheses of 6,6-dimethyl-6-sila-oestradiol (197) and 6,6-dimethyl-6-sila-mestranol (198) are described in Scheme 25. Not only the synthesis of the key intermediate 4,4-dimethyl-4-sila-6-methoxy-l-tetralone (7 96) but also the well known organic reactions, leading from 196 to 197 and 198, are strongly influenced by the specific properties of the silicon atom. Although known reactions of steroid chemistry could be used for further transformations from 196 to 197 and 198, conditions were not directly transferable because of the chemical behaviour of the Si-Calkyi and Si-Qryl bond. Important differences in the pH- and solvent profile were neces-... 

This inability of fully functional receptor complexes to activate a given gene also occurs in normal cells. In new-born chicks, a single injection of oestradiol has a delayed effect on vitellogenin synthesis in liver. Having been exposed once to the hormone, second injections elicit an immediate response. It has been suggested that the first injection demethylates methyl cytosine residues within the hormone response element, thereby allowing receptor attachment [29]. 

Fig. 1. A model for the control of the luteinizing hormone receptor. LH interacts with a specific receptor (RLh) in Leydig cells which results in the activation of several transducing systems. This is followed by an uncoupling (desensitization) from one or more of the transducing systems. The latter may transiently remain active. The LH receptor complex is internalized and then dissociated in endocytic vesicles. LH is degraded in the lysosomes. The LH receptor synthesis can be controlled by several hormones including oestradiol, prolactin and growth hormone.

The role of oestrogens in controlling LH receptor synthesis in the testis is not known but oestradiol receptors are present in rat Leydig cells [39]. Glucocorticoids inhibit the induction of LH receptors corticosteroid receptors have been demonstrated in rat testis [40] and treatment of prepubertal rats [41] and immature hy-pophysectomized rats with corticosteroids decreased the numbers of LH receptors and steroid production. 

If as above we simply represent alicyclic rings sharing two Gs by a vertical line, then we can represent the basic tetracyclic structure of lanosterol as G61G61 G6 C5 (noting that there are two double bonds and various alkyl substituents and also a 3-hydroxyl on the first of the alicyclic rings). Many subsequent reactions yield cholesterol, a major triterpene membrane component that modifies the fluidity of animal cell membranes and is a precursor for synthesis of animal bile acids (fat solubilizing amphipathic detergents) plant triterpenes and steroid hormones such as the corticosteroids cortisol and cortisone, the mineralocorticoid aldosterone and the sex hormones testosterone and 17-(3-oestradiol. The structure and bioactivity of the plant terpenes is sketched below. 

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. 

El -Oestradiol ER - Oestrogeit receptor PR - Progesterone receptor Fig. 3 Progesterone receptor synthesis is dependent on the integrity of the oestrogen receptor pathway. 

An analogue is normally accepted as being that modification which brings about a carbon-skeletal transformation or substituent synthesis. Examples oxytetracycline, demclocycline, chlortetracycline, trans-diethylstilbesterol with regard to oestradiol. 

In the second synthesis, 8a-methyltestosterone (I48b) was prepared from the previously reported 8a-methyl-5a-pregn-9(l l)-ene-3)3.20-diol (149). Catalytic hydrogenation of (149) gave the saturated diol, which was successively oxidized to the diketone, selectively protected as the C-3 dimethyl ketal, reduced at C-20, and hydrolysed to the hydroxy-ketone (150). This in turn was transformed into the 8 -methylprogesterone (151), 8a-methyltestosterone (I48b), and 8a-methyl-oestradiol (152) analogues by conventional methods. ... 

In 1949, when Carl Djerassi took over the leadership of a research group at Syntex in Mexico City, nobody thought of hormonal contraceptives yet. In fact, meanwhile the biological function of progesterone had become known, but the hormone was not orally available and could be only administered by injection. Djerassi s aim was the synthesis of cortisone and possibly oestradiol. Cortisone had been discovered a few years earlier by Edward Calvin Kendall (1886-1972), and was at that time regarded as a miracle drug. Oestradiol was used for the treatment of problems during puberty and menopause. 

However, the remaining problem was the administration route of the drug. Shortly before the Second World War, Inhoffen had prepared 17a-ethynyl-oestradiol, and had noticed that this derivative is surprisingly stable in the stomach. The initial objective of Inhoffen s synthesis was actually oestradiol-17-car-boxylic acid, which ought to have been produced by ethynylation and ozonoly-sis. Fortunately, the intermediate was also checked for its oral bioavailability. In fact, the carboxylic acid was only synthesised 50 years later and proved to be completely inactive. [24]... 

The synthetically important intermediate (71) has been used by Saegusa to prepare oestrone [48] stereoselectively by an intramolecular Diels-Alder route and also employed in an non-racemic synthesis of oestradiol by Oppolzer [49],... 

In contrast, Michael additions of a,a-disubstituted lithium enolates proceed, apparently via the chelated form of enone sulfoxides (Figure 5.2), with almost complete jt-facial diastereoselectivity [104]. This methodology has been used in the asymmetric synthesis of the pheromone, (-)-methyl jasmonate (121), from cyclopentenone sulfoxide (98b) [105] via the intermediate (120), which was formed in at least 98% enantiomeric purity upon asymmetric Michael addition of bis a-silylated a-lithioacetate to (98b). Addition of the a-bromo enolate (122) to enantiomerically pure (98a) and oxidation gives the product sulfone (123), with almost complete asymmetric -induction with respect to the sulfoxide. Sulfone (123) was then converted into the steroidal sex hormone, (+)-oestradiol (124) (Scheme 5.42) [106]. 

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