STEROID HORMONES:

SEX HORMONES
Of the various steroid hormones produced from cholesterol, the sex hormones are extremely important: The productive steroid hormones are divide into three classes: 1.Estrogens, which regulate ovulation and the development of the secondary female sex hormone. 2.Gestagens, or progestins, which maintain pregnancy 3.Anrogens, the male sex hormons.
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These three classes of sex hormones are of fundamental importance in medicinal chemistry, not only for their role in influencing reproductive susceptibilities, but also as potential therapeutics in a range of other conditions, including cancer.

1. ESTROGENS
Estrogens are produced mainly in the ovaries when the latter are stimulated by follicle-stimulating hormone (FSH) dihasilkan anterior pituitary. Under such stimulation, the estrogen levels rise until the middle of the menstrual cycle (when ovulation takes place), remain at a fairly constant concentration, and then decline if fertilization does not take place. The final result is menses, the shedding of the uterine endometrium (lining).

Naturally Occurring and Synthetic Steroidal Estrogens

O
HO

HO OH

HO
Estradiol

HO
Estrone

HO
Estriol

The major estrogens produced by women are estrone (E1) , estradiol (17-estradiol, E2), and estriol (E3). Estradiol is the major secretory product of the ovary. Estrone and estriol are formed either in the liver, from estradiol, or in peripheral tissues
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During the first part of the menstrual cycle, estrogens are produced in the ovarian follicles (80350 g/day estradiol); after ovulation, estrogens are synthesized (via a different biosynthetic pathway) in the corpus luteum, which is a proliferation of cells that replace clotted blood within the ruptured ovarian follicle.

large amounts of estrogen are synthesized by the fetoplacental unit (1000During pregnancy, fold increase when compared to the nonpregnant state). Estriol synthesized by the fetoplacental unit enters the maternal circulation and is excreted in the urine.
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Although estrogens are easily isolated from the urine of pregnant women, their most abundant (berlimpah)

source has historically been from the

urine of

horses,

especially pregnant mares. Somewhat surprisingly, however, the most prolific source of estrogen is stallions, in which urinary estrogens are produced as metabolites of androgens.

Horses excrete a variety of equine estrogens, including equilenin, a steroid containing the naphthalene ring system, and equilin; these equine estrogens are not synthesized in humans but readily bind to human estrogen receptors. All of these equine steroids have an aromatic A-ring and therefore lack a 19-methyl group. These estrogenic substances are excreted in very large quantities in equine urine and can be recovered and used for medicinal applications in human patients.

H HO HO

Equilenin

Equilin

Today, a variety of therapeutic estrogens are produced semisynthetically from estrogen intermediates

synthesized from diosgenin and other natural precursors. Two semisynthetic, orally active estrogens
are ethinyl

estradiol and its 3-methyl ether (mestranol). Both of these are used in

oral contraceptives. Quinestrol is another semisynthetic estrogen. The most important property of the semisynthetic estrogens is their increased oral effectiveness.

Two semisynthetic orally active estrogens are ethynil-estradiol dan its 3-methyl ether (mestranol). Both of these are used in oral contraceptives.

HO

CH

O H

H H HO
Ethynil-estradiol

H H3CO
Mestranol

All of these steroids have an aromatic A-ring and therefore lack a 19-methyl group.
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O H H O
Quinestrol

Quinestrol is another semisynthetic estrogen. The most important property of the semisynthetic estrogens is their increased oral effectiveness.
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Nonsteroidal estrogens
Nonsteroidal estrogens have also been synthesized. The first compounds were trans-diethylstilbestrol and reduced derivative hexestrol. OH

HO
Diethylstilbestrol

OH

HO
Hexestrol
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In addition to the geometric orientation of the two phenyl groups, the interatomic distance between the two phenolic OH groups in DES is also important. Indeed, as long ago as 1946, Schuler suggested that the distance between the two OH groups in DES matched the 3-OH to 17-OH distance in estradiol.
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Because their use may lead to cancer of the vulva in the daughters of their users, stilbestrol derivatives are obsolute and dangerous drugs. Estroges are used therapeutically to replace or augment hormone whose natural production is insufficient during menopause, in menstrual disorders, or as a result of insufficient development of the female reproductive tract. In androgen dependent prostate carcinoma, estrogens are used therapeutically to suppress androgen formation and thus tumor growth.

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Therapeutic Uses of Estrogens

a) The most common use of estrogens is in birth control pills. Since estrogen is combined with progestins in oral contraceptives, b) Estrogens are also used therapeutically to replace or augment hormones whose natural production is insufficient during menopause, in menstrual disorders, or as a result of insufficient development of the female reproductive tract. c) Estrogens are very useful in treating the hot flashes of early menopause and in helping menopausal conditions such as atrophic vaginitis. d) When used postmenopausally, estrogens may theoretically decrease the risk of heart disease by lowering the incidence of atherosclerosis; however, this is an extremely controversial area around which there is much debate. e) Another therapeutic role for estrogens is in the treatment of cancer. In androgendependent prostate carcinoma, estrogens are used therapeutically to suppress androgen formation and thus tumor growth. Estrogens are also used to treat inoperable breastcancer in men and postmenopausal women.
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Antiestrogens
Antiestrogens are used for two purposes: as fertility drugs and as antitumor agents. Two antiestrogens in use are clomiphene and tamoxafen, both of which are aminoether derivatives of stilbene.

OH

O H2C

Cl C2H5 H2 C N C2H5
Clomiphene
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The first application is based on the fact that estradiol, the natural hormone, inhibits the secretion of the gonadotrophic hormones LH and FSH by feedback inhibition. The result of this inhibition is the production of a single ovum in every menstrual period, thus preventing overlapping pregnancies. Antiestrogens, such as clomiphene, block this inhibition in women who are infertile because of anovulation resulting from excessive estradiol production. Antiestrogens are therefore useful in helping infertile women to become pregnant (Cuma ini yg penting kata bapak). As a complication of their use, multiple pregnancies are rather common in women treated with antiestrogens. This incidence of multiple births can rise up to 10% in women treated with antiestrogens for infertility, which is much higher than the normal rate.

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Both clomiphene and tamoxifen are aminoether derivatives of stilbene. They are both structurally related to the nonsteroidal estrogens such as diethylstilbestrol (DES) and chlorotrianisene. However, the latter two compounds are estrogen agonists,whereas the former two are estrogen antagonists.

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2. Gestagens (progestins)
These hormones are essential for

the maintenance of

pregnancy.

The only natural progestin hormone, progesterone, is produced by the corpus luteum, an endocrine gland formed in the ovary.

CH 2OH C O

O
Progesteron
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The main use of progestins is based on their antifertility effect. Since progesterone is poorly absorbed, it cannot be given orally; furthermore, it is not particularly potent and has an unacceptably short serum half-life of about 5 minutes. In early work, ethisterone (5.39), an acetylenic compound prepared from androsterone, was an orally activeprogestin, but also had male hormone action.

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In early work, ethisterone (5.39), an acetylenic compound prepared from androsterone, was an orally active progestin, but also had male hormone action.

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In subsequent work, a large semisynthetic progesterone (progestogens) were synthesized levonorgestrel (5.40), desogestrel (5.41), norethindrone (5.42), norgestrel (5.43), and ethynodiol(5.44)

number of derivatives

and found their principal use in oral contraceptive formulations.

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Combinations of Progestins and Estrogens (Oral Contraceptives)

The concept of oral contraception was pioneered by Pincus in the early 1950s. Modifications of the ethisterone moleculeremoval of the 19-methyl group or the introduction of additional methyl groups in position C-6 of 17 acetoxyprogesteroneled to a series of highly active progestins.

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Oral contraception based on hormonal manipulation may be achieved in three ways, as follows.

1) Ovulation Inhibitors To achieve inhibition of ovulation, a progestogen (e.g., levonorgestrel, norethindrone, norgestrel, norgestimate) and an oral estrogen (e.g., ethinyl estradiol, mestranol) are combined in varying amounts and/or at varying times during the menstrual cycle. The desired contraceptive effect is due to inhibition of ovulation through the hypothalamo-pituitary mechanism; administration of exogenous steroids during the first half of the menstrual cycle suppresses FSH production, there by inhibiting maturation of ovarian follicles and preventing ovulation. Adding a progestogen allows the secretory phase of the endometrium to be elicited, and when the exogenous steroids are temporarily withdrawn, menstruation occurs. These combination estrogen/progestogen agents exert a secondary contraceptive effect via alteration of the viscosity of the cervical mucus to physically impede the sperm. 29

These combination oral contraceptives are formulated in different phasic preparations. Phasic contraceptives vary the progestin dose during the cycle, mimicking its variation under physiological conditions. Monophasic and triphasic formulations are among the most popular. A typical monophasic oral contraceptive contains the same dose of estrogen and progestogen (e.g., ethinyl estradiol 30 g and levonorgestrel 150 g) given on 21 days of the menstrual cycle with 7 days off. A typical triphasic combination oral contraceptive varies the doses of the steroid hormones over the course of the cycle (e.g., ethinyl estradiol 30 g and levonorgestrel 50 g [days 16]; ethinyl estradiol 40 g and levonorgestrel 75 g [days 711]; and ethinyl estradiol 30 g and levonorgestrel 125 g [days 1221]; inert tablets [days 2228]).

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Of the various pharmacologic approaches to contraception, the combination pills are by far the most convenient and the most effective. In addition, several noncontraceptive benefits are recognized for combination oral contraceptives: 1. Reduced incidence of cancer of the endometrium 2. Reduced incidence of benign breast disease 3. Reduced likelihood of functional ovarian cysts 4. Less menstrual blood loss and more regular cycles 5. Decreased severity of premenstrual syndrome and improvement in acne and hirsutism (facial hair) These potential benefits are balanced by a slightly increased risk of gallbladder disease, hypertension, myocardial infarction, cerebral infarction, and pulmonary embolism. The increased risk of stroke and heart attack associated with the pill is accentuated when compounded by other risk factors, including smoking, migraine headaches, and advancing age. Indeed, convincing data support an upper age limit of 35 years for oral contraceptive use by women who smoke.

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2) Mini-Pill
A low dosage of progestin (mini-pill) is used, in the form of medroxyprogesterone acetate, which is active at a very low dose. The mini-pill does not inhibit ovulation, but rather interferes with the endometrium and the cervical mucus. The use of this pill prevents most of the side effects of oral contraception, specifically nausea, water retention, and in some cases thrombophlebitis. However, a lower success rate and other frequent side effects have reduced the widespread acceptance of this preparation. Nevertheless,the mini-pill has a role to play in certain specific situations. For example, in an uncommon form of epilepsy called catamenial epilepsy, female patients will experience seizures at particular times during their menstrual cycle, reflecting the fact that seizure focus is stimulated by estrogens but inhibited by progestins. In such women, the mini-pill may afford not only birth control but also improved seizure control.

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3) Morning After Pill This agent refers to the administration of a high dose of both an estrogen and a progestin.Preferably, this is given 1224 hr after coitus. The morning after pill induces menstrualbleeding which in turn prevents the fertilized ovum from implanting. Alternatively, implantation of the ovum can also be blocked with mifepristone, which is a progesterone and glucocorticoid receptor antagonist; this agent induces a noninvasive abortion in early pregnancy. It is to be expected that these extremely widely used oral methods of contraception will eventually be replaced by luteinizing hormone analogs as antiovulatory agents, or possibly by immunological methods directed against human chorionic gonadotrophin (hCG), which has both LH and FSH activity. Prostaglandins also show promise, and reliable male contraception is also a future possibility.

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B. STEROID HORMONES: SEX HORMONESANDROGENS

These steroids control the development of male characteristics: sperm production and growth of the sex organs (penis, testes), prostate, and seminal vesicles (their androgenic effect). Androgens also control metabolic effects during growth in adolescence and stimulate protein synthesis (causing nitrogen retention) (their anabolic effect).

OH
H

OH

H
H H

H O
Testoterone

O H
Dyhydrotestoterone

Testosterone is the prototypic androgen sex hormone. Testosterone is synthesized by the testes, and must be reduced to dihydrotestosterone (DHT) before it will bind 34 to the receptor.

Among highly active synthetic testosterone analogs, 7lfa-methyl-19nortestosterone and oxandrolone have about 100 times greater activity than testosterone as androgens. 17-Methyltestosterone is orally active.

OH CH 3 H H O
17 alfa methyl- 19- nor testoterone

OH H O

H H
O H H

Oxandrolone

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17lfa-Methyltestosterone is orally active

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Fluoxymesterone (5.50), the 9-fluoro-11-hydroxy-17-methyl derivative of methyltestosterone, has 10 times the androgenic and 20 times the anabolic activity of the parent compound, but is used mainly as an androgen in hormone-replacement therapy, hypogonadism, and some forms of breast cancer.

OH HO H F O
Fluoxymesterone

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Some other anabolic agents are methandrostenolone (5.51), and stanozolol (5.52), clostebol, and nandrolone. Use of anabolic steroids by athletes is a widespread but dangerous and banned misuse of these drugs. Nevertheless, their use does elicit protein anabolic effects and is thus associated with enhanced muscle bulk and more rapid recovery after injury. OH OH
H H N H O
Metandrostenolone

H N H
Stanazolol

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A nonvirilizing androgen that has been useful in the treatment of breast cancer in young women is the 2-methyl derivative of testosterone propionate.

O H H O
Testoterone Propionate
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Androgens: Molecular Action In the prostate, testosterone is reduced enzymatically to DHT, which then binds with high affinity (KD = 10-11 M) to a cytosol receptor. The binding of androgens to the cytosol receptor is a process requiring minutes to several hours. Molecular flatness, especially in the AB ring area, is a prerequisite for effective binding, and AB cis compounds are therefore inactive; accessory binding sites for a 7 alfa-methyl group seem to be present, which strengthens the binding; the 17 beta-hydroxyl group is essential for activity. The intracellular cytosol steroid receptor is bound to stabilizing proteins such as heat shock protein 90 (Hsp90); when the cytosol receptor binds to a molecule of steroid, the resulting steroidreceptor cytosol complex becomes unstable and releases the stabilizing proteins (Hsp90). The steroidreceptor complex then enters the nucleus, binding to a specific sequence of nucleotides (androgen response element) on a gene, thus regulating transcription by RNA polymerase II and associated transcription factors. The resulting mRNA is exported to the cytoplasm for the production of protein that enables the final androgen response.

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Antiandrogens
Antiandrogens, such as cyprosterone acetat or the nonsteroidal flutamide are competitive antagonist on the cytosol receptor. The do not prevent DHT formation, but inhibit the nuclear retention of DHT in the prostate. They cause feminization in male fetuses and decrease libido in males. Cyproterone is also an active progestogen.

O O C O
O2N CF 3 O C HN
Flutamide
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H O Cl

Cyprosterone acetate

In men, antiandrogens are used commonly in the treatment of prostatic cancer and uncommonly to inhibit sex drive in hypersexuality; in women, antiandrogens are used to treat virilization. Bicalutamide (5.56) and nilutamide (5.57) are potent, orally active antiandrogens that may be used in the treatment of metastatic prostate carcinoma.

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Androgens and Male Contraception Male contraception, involving the suppression of spermatogenesis, is an intensely investigated area, but there have been few positive results that could be used on a practical scale. Testosterone enantate injections produced azoospermia in only 65% of males in a pivotal multicentre study. Danazol (5.59), a gonadotropin inhibitor in females, is also only partially active in males, even if it is taken together with long-acting testosterone derivatives. Cyproterone acetate, the potent antiandrogen, likewise failed to yield reliable contraception. To date, no complete spermatozoan elimination has been achieved with male contraceptive agents, although arguably a total absence of sperm is probably not necessary for sterility.

OH

H N O
Danazol (5.59)
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Gossypol (5.60), a phenolic compound isolated from cottonseed oil, has direct antispermatogenic activity. Gossypol does not affect endocrine function but seems to act on the spermatid phase of spermatogenesis. In some studies it is 99% effective in reducing sperm counts. It has been most extensively studied in China. Unfortunately, it has considerable and only partly reversible side effects.

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