Lec. 5Gonadal hormones

The ovaries and testis are exocrine (ova, sperm) as well as endocrine (hormonal) in function. They develop under the influence of anterior pituitary hormones, particularly:

1. The follicle-stimulating hormone (FSH) leads to the development of the ovarian follicles, to their formation of ova and of estrogen, and to the development of the testis and the maturation of the spermatozoa.

2. The luteinizing hormone (LH) is necessary to the development of the corpora lutea in the ovarian follicles after ovulation, to the formation of progesterone by the corpora lutea, and to the production of androgen in the matured testis.

Androgens (male hormones) and estrogens (female follicular hormones) act to:

1. Develop and maintain the secondary characters of sex.

2. Depress anterior pituitary function, leading in turn to the depression of the testis or the ovary.

Progesterone (corpus luteum hormone) similarly depresses anterior pituitary function and presents a mixed antagonism-synergism with estrogenic activity.

Testis• Following castration in the male, the sex organs atrophy,

and sexual desire and activity are diminished. These functions are restored by the administration of testis hormone.

• Hypogonadism is inadequate development of the testis owing to pituitary disorder, infection, or other disease. Therapy is still in the experimental stage.

• Hypergonadism is most frequently seen in young males, owing to testis tumors; this results in precocious development of sex organs and male characteristics. Therapy is usually surgical.

O

OH

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Testosterone

17

• Testosterone is the active male hormone.

• The quantities used for drug purposes are prepared synthetically.

• The 17-hydroxyl function of testosterone is readily oxidized and metabolized to the much less physiologically active keto compound. Thus, testosterone is not administered orally.

Male Sex Hormones(Androgens)

Physiological Effects

Development of the male Phenotype during embryonic life.

Development of the male sexual organs and male secondary sex characters.

Anabolic effect.

The hormone may be used buccally, implanted subcutaneously, or injected intramuscularly. However, many formulations for these purposes utilize derivatives of the hormone, such as the cypionate, enanthate, and propionate esters of the 17-hydroxyl group, which are characterized by delayed absorption and destruction.

The usual dose of testosterone, intramuscularly, is 25 mg as needed; implantation, 150 to 400 mg every 3 to 6 months.

cypionate enanthate propionate

PRESCRIPTION PRODUCTS. Delatestryl®,

Depo-testosterone®.

The introduction of a methyl substituent

at C-17 is another manipulation that has

been used to circumvent the chemical and

metabolic instability of testosterone.

Preparations of methyltestosterone

(Android®, Metandren®, Oreton®) are used

buccally and orally for androgenic

purposes.

Ovary Each is about the size and shape of an

unshelled almond and weighs about 4 to 8 g.

Ova develop within primitive ovarian follicles under the influence of the follicle-stimulating hormone (FSH) of anterior pituitary.

Ovulation with the extrusion of one ovum normally occurs each month during the childbearing period.

The ovary secretes 2 types of hormones: the estrogens, and the progestins.

EstrogensDeficiency in estrogenic activity is most

frequently experienced in the normal menopause or following surgical removal of the ovaries.

The estrogens are necessary to:1. Development of the female sexual organs.2. Development of the female secondary sex

characters.3. Control of the menstrual cycle.

4. Act as a growth hormone for uterine smooth muscle cells during pregnancy.

Uses Birth control pills. Failure of ovarian development. Menstrual disturbances. Suppress lactation after birth. Postmenopausal osteoporosis. Prostate cancer.

Side Effects Nausea, vomiting and diarrhea. Sodium and water retention. Inhibition of ovulation in large doses.

The 3 major estrogenic hormones are estradiol and its oxidation products, estriol, and estrone. These hormones can be isolated from urine during pregnancy and can be prepared synthetically.

Estrogens may be administered orally, parenterally, by implantation, or by injection for systemic activity.

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Estriol HO

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EstroneHO

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Estradiol

As much as 90% of parenterally administered

natural estrogens may be destroyed. This

factor, in addition to rapid absorption, tends

to diminish their efficiency and the effective

period of therapy. Pharmaceutic

manipulations, include the use of esters, such

as cypionate or valerate, and of formulations

involving sterile vegetable oils. These

manipulations slow absorption and

destruction of the hormones; they also lessen

the side effects of nausea and vomiting.

Orally administered natural estrogens

are destroyed in greater part.

Conjugated and esterified estrogens are

also used orally, and the introduction of

an ethinyl substituent at C-17 of

estradiol gives a potent, orally effective

compound.

Implantation of the estrogens or their

esters provides an even longer duration

of action than do preparations

administered intramuscularly.

EstradiolEstradiol is used orally, injected

intramuscularly, and implanted subcutaneously. The usual dose, orally, is 1 to 2 mg daily; implantation, 25 mg, as necessary.

HO

OHC CH

HO

OH

17-estradiol Ethinyl estradiol(Stertoidal Semisynthetic estrogen)

Nonsteroidal EstrogensDiethylstilbesterol:

The trans form is the active one.Advantages:

As active as Estradiol. Longer duration of action. Orally active Cheap.

Disadvantages: Increase the risk of uterine cancer.

Uses: Treatment of prostate cancer.

OH

HO

Xenoestrogens (Enviromental Estrogens)

Estrogenic compounds with weak activity present in food and drinks.

Isoflavones and comesterol derivatives present in family Leguminosae are examples of xenoestrogens.

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OH

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Genisten

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OHO

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Coumesterol

ProgesteroneProgesterone in the major natural progestin.Secretion: By the ovary mainly the corpus

luteum during the second half of the menstrual cycle.

Physiological Effects:Development of the endometrium.Development of the mammary

gland during pregnancy.Milk secretion stats when its

level decrease with birth.Thermogenic action.

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Progesterone

Progesterone is not formed during the first half of a normal menstrual cycle, but administration of it or of some other progestational agent during this part of the menstrual period offers an effective means of birth control.

Progesterone is also available in an intrauterine device (IUD). The hormone is dissolved in silicone oil, and the flexible polymer of the IUD acts as a membrane to allow for the slow release of progesterone (65 g daily) into the uterine cavity.

Progestrogenic Drugs• Lynestrenol :

•Semisynthetic progestin with pure progestrogenic activity.

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O

Progesterone(Natural)

OH

Lynesrenol(Synthetic)

C CH

UsesContraceptive pills.Uterine bleeding.Prevention of abortion.Amenorrhea, dysmenorrhea, endometriosis.Suppression of lactation.Endometrial, renal and breast carcinoma.Enhance respiration (for Hypoventilation).Side Effects:

Nausea, vomiting, irregular bleeding, edema, weight gain, breakthrough bleeding, breast disconfort.

Contraceptive agents

Contraceptive agents are drugs used for the prevention of pregnancy. The most effective and widely employed are the oral contraceptives (OCs), available only for women.

Oral contraceptives on the market belong to three different types: Sequential Ocs, combination OCs, minipills, and postcoital contraceptives.

Sequential Preparations:

Estrogens for 16 days then Estrogen and progesterone for 5- 6 days.

98- 99% successful.

Sequential OCs, used until 1975, have been removed from the market because they increase the incidence of endometrial cancer, due to their relatively high estrogen content.

Combination MethodIt is thus called because it consists of the

administration of a progestin combined with an estrogen from the fifth to the twenty-fifth day of the menstrual cycle, or 21 days of medication followed by 7 days in which inert tablets or iron (75 mg of ferrous fumarate, for example) are taken.

They prevent pregnancy by suppression of ovulation.

In this method natural steroids are not used because they are ineffective orally. Introduction of a 17-ethinyl group enhances oral activity by inhibiting hepatic degradation.

MinipillsMinipills contain progestin only and are

taken daily and continuously.They are slightly less effective than

combination OCs. They inhibit ovulation by rendering the

cervical mucus incompatible to sperm penetration.

Progestogens used in minipills include norethindrone (Norlutin®), norgestrel (Ovrette®), and quingestanol acetate.

• Postcoital ContraceptivesAlso called "morning after" pills, they

consist of:

1. large doses of estrogens administered daily for 5 days within 72 hours after coitus or

2. an estrogen-progestin mixture taken twice 12 hours apart.

Estrogens employed in this method are the following: estrone, or ethinyl estradiol. The mixture of estrogen with progestin is ethinyl estradiol-norgestrel.

Male ContraceptivesGossypol:

Is a phenolic compound present in cotton seed oil. Decrease number of sperms and impairs their

motility.It effect is reversible.

Side Effects:Hypokalemia, weakness, diarrhea and

edema.