GONADONAL HORMONES AND INHIBITORS

Ovary

 At puberty, ovary begins a 30-40-year period of cyclic function called menstrual cycle
 It then fails to respond to gonadotropins secreted by the anterior pituitary gland, and cessation of
cyclic bleeding that are the major estradiol occurs is called menopause
Gonadotropin-releasing hormone is produced by the maturation of centers in the brain that may
withdraw a childhood-related inhibitory effect upon hypothalamic arcuate nucleus neurons. This
stimulates the release of follicle-stimulating hormone and luteinizing hormone.

 At first, small amounts of the latter two hormones are released during the night, and the limited
quantities of ovarian estrogen secreted in response start to cause breast development.
 FSH and LH are secreted day and night. Causing to release higher amounts of estrogen leading
to further breast enlargement
The change of ovarian function at puberty is called gonadarche.

The Estrogens
Estrogenic activity is shared by large number of chemical substances. In addition to the variety of
steroidal estrogens derived from animal sources, numerous nonsteroidal estrogens have been
synthesized. It has been proposed that these agents are associated with an increase breast cancer
incidence in both men and women in the industrialized world.
1. Natural Estrogens
Estradoil, Estriol, and Estrone-are the major estrogens produced. Estradiol is the
major secretory product of the ovary. During pregnancy, a large amount of estrogen is
synthesized by the fetoplacental unit-consisting of the fetal adrenal zone, secreting androgen
precursor, and the placenta, which aromatizes it into estrogen.
2. Synthetis Estrogens

The most important effect of these alterations has been to increase oral effectiveness.
Drugs: dienestrol, diethylstilbestrol, benzestrol, hexestrol, methestrol,
methallenestril, chlorothianisene
Pharmacokinetics
1. When released into circulation, estradiol binds strongly to alpha globulin and with lower affinity to
albumin
2. Estradiol is converted by the liver and other tissues to estrone and estriol and their 2-hydroxylated
derivatives and conjugated metabolites and excreted in the bile
3. However, conjugates may hydrolyzed in the intestine to active, reabsorbable compunds.
4. Estrogens are also excreted in small amounts in the breast milk of nursing mothers

A. Physiological Effect
Estrogens in the blood and interstitial fluid are bound to SHBG, from which they are dissociated to cross
the cell membrane, enter the nucleus, and bind to the receptor. Estrogens are found predominantly in the
nucleus bound to heat shock proteins that stabilize them. Estrogen response elements is where the
receptor-hormone complex form dimers will bind. The ERE is composed of two half-sites arranged as a
palindrome separated by a small group of nucleotides called the spacer.
B. Female Maturation
Estrogens stimulate the development of the vagina, uterus, and uterine tubes as well as the secondary
sex characteristics. They stimulate stromal development and ductal growth in breast and are responsible
for the accelerated growth phase and the closing of the epiphyses of the long bones that occur at puberty.
C. Endometrial Effects
Estrogens playa an important rolein the development of the endometrial lining. When estrogen production
is properly coordinated with the production of progesterone during the normal human menstrual cycle,
regular periodic bleeding and shedding of the endometrial lining occur.
D. Metabolic and Cardiovascular Effects
Estrogens decrease the rate of resorption of bone by promoting the apoptosis of osteoclasts and by
antagonizing the osteoclastogenic and pro-osteoclastic effects of parathyroid hormone and interleukin-6.
Alterations in the composition of the plasma lipids caused by estrogens are characterized by an increase
in the high-density lipoproteins, a slight reduction in the low density lipoproteins, and a reduction in total
plasma cholesterol levels. Plasma triglycerides levels are increased. Estrogens decrease hepatic
oxidation of adipose tissue lipid to ketones and increase synthesis of triglycerides.
E. Effects on Blood Coagulation
Estrogens enhance the coagulability of blood. Many changes in factors influencing coagulation have been
reported, including increased circulating levels of factors II, VII, IX, and X and decreased antithrombin III,
partially as a result of the hepatic effects mentioned.
Clinical Uses
a. Primary Hypogonadism
Treatment of primary hypogonadism is usually begun at 11-13 years of age in order to stimulate the
development of secondary sex characteristics and menses, to stimulate optimal growth, to prevent
osteoporosis, and to avoid the psychological consequences of delayed puberty and estrogen
deficiency.
b. Postmenopausal Hormonal Therapy
Optimal management of the menopausal patient requires careful assessment of her symptoms as
well as consideration of her age and the presence of cardiovascular disease, osteoporosis, breast
cancer, and endometrial cancer.
Adverse Effects
a. Uterine Bleeding
Estrogen therapy is a major cause of postmenopausal uterine bleeding. Unfortunately, vaginal
bleeding at this time of life may also due to carcinoma of the endometrium.
b. Cancer
A small risk in the incidence of tumor may occur with prolonged therapy. Although the risk factor is
small, the impact may be great since this tumor occurs in 10% of women, and addition of
progesterone does not confer a protective effect.
c. Other Effects
Nausea and breast tenderness are common and can be minimized by using the smallest effective
dose of estrogen. Hyperpigmentation also occurs. Estrogen therapy is associated with an increase in
frequency of migraine headaches as well as cholestasis, gallbladder disease, and hypertension.
Contraindications
Estrogens should not be used in patients with estrogen-dependent neoplasms such as carcinoma of the
endometrium or in those with-or at high risk for-carcinoma of the breast. They should be avoided in
patients with undiagnosed genital bleeding, liver disease, or a history, or a history of thromboembolic
disorder. In addition, the use of estrogens should be avoided by heavy smokers.

The Progesterone
Natural Progestins: Progesterone
Progesterone is the most important progestin in humans. It serves as a precursor to the estrogens,
androgens, and adrenocortical steroids. It is synthesized in the ovary, testis, and adrenal cortex from
circulating cholesterol.
Synthetic Progestins:
They are not a uniform group of compounds, and all of them differ from progesterone in one or more
respects. A new group of third-generation synthetic progestins has been introduced, principally as
components of oral contraceptives.
Pharmacokinetics
Progesterone is rapidly absorbed following administration by any route. Its half-life in the plasma is
approximately 5 minutes, and small amounts are stored temporarily in body fat. It is almost completely
metabolized in one passage through the liver, and for that reason it is quite ineffective when the usual
formulation is administered orally.
Physiologic Effects
A. Mechanism
Progestins enter the cell and bind to progesterone receptors that are distributed between the nucleus and
the cytoplasm. The ligand-receptor complex binds to a progesterone response element. To activate gene
transcription. The response element for progesterone appears to be similar to the cortocsteroid response
element, and the specificity of the response depends upon other cell-specific receptor coregulators and
interacting transcription factors.
B. Effects of Progesterone
It stimulates lipoprotein lipase activity and seems to favor fat deposition. The effects on carbohydrate
metabolism are more marked. Progesterone increases basal insulin levels and the insulin response to
glucose.
C. Synthetic Progestins
the 21-carbon progesterone analogs antagonize aldosterone-induced sodium retention. The remaining
compounds produce a decidual change in the endometrial stroma, do not support pregnancy in test
animals, are more effective gonadotropin inhibitors, and may have minimal estrogenic and androgenic or
anabolic activity.
Relaxin is another peptide that can be extracted from the ovary. The three-dimensional structure of
relaxin is related to that of growth-promoting peptides and is similar to that of insulin.
Hormonal Contraception
Two types of preparations are used for oral contraception: (1) combinations of estrogens and progestins
and (2) continuous progestin therapy without concomitant administration of estrogens.
1. Effects on the Ovary
Chronic use of combination agents depresses ovarian function. Follicular development is minimal,
and corpora lutea, larger follicles, stromal edema, and other orphologic features normally seen in
ovulating women are absent.
2. Effects on Uterus
After prolonged use, cervix may show some hypertrophy and polyp formation. There are also
important effects on the cervical mucus, making it more like postovulation mucus.
3. Effects on Breast
Stimulation of breasts occurs in most patients receiving estrogen-containing agents. Some
enlargement is generally noted. The administration of estrogens and progestins tends to suppress
lactation.
4. Other Effects
 CNS – estrogens tend to increase excitability in brain, whereas progestins decreases it. The
thermogenic action of progesterone and some of the synthetic progestins is also thought to
occur in the central nervous system.
 Endocrine function – estrogens also alter adrenal structure and function. Estrogens given
orally or at high doses increase the plasma concentration of the alpha2 globulin that binds
cortisol.
 Blood – the oral contraceptives do not consistently alter bleeding or clotting times. There is
an increase in factors VII, VIII, IX, and X and a decrease in antithrombin III.
 Liver – the effects on serum proteins results from the effects of the estrogens on the
synthesis on the various alpha2 globulins and fibrinogen.
 Lipid metabolism – estrogens increase serum triglycerides and free and esterifies
cholesterol. Phospholipids are also increased, as are HDL; levels of LDL usually decrease
 Carbohydrate metabolism – there is a reduction in the rate of absorption of carbohydrates
from the gastrointestinal tract
 Cardiovascular system – cause small increases in cardiac output associated with higher
systolic and diastolic blood pressure and heart rate. The pressure returns to normal when
treatment is terminated
 On skin – oral contraceptives have been noted to increase pigmentation of the skin. This
effect seems to be enhanced in women with dark complexions and by exposure to ultraviolet
light.
Adverse Effects
1. Nausea, nostalgia, breakthrough bleeding, and edema are related to the amount of estrogen in
the preparation.
2. Changes in serum proteins and other effects on endocrine function must be taken into account
when thyroid, adrenal, or pituitary function is being evaluated.
3. Headache is mild and often transient. Migraine is worse and has been reported to be associated
with an increased frequency of cerebrovascular accidents.
4. Withdrawal bleeding sometimes fails to occur-most often with combination preparations-and may
cause confusion with regard to pregnancy.
Estrogen & Progesterone Inhibitors & Antagonists
Tamoxifen, a competitive partial agonist inhibitor of estradiol at the estrogen receptor, was the first
selective estrogen receptor modulator. The mechanism of its mixed agonist/antagonist relations to the
estrogen receptor has been intensively studied but is still not completely understood.
Toremifene is a structurally similar compound with very similar properties, indications, and toxicities.
Raloxifene is another partial estrogen agonist-antagonist at some but not all target tissues. It has
estrogenic effects on lipids and bone but appears not to st8imulate the endosmetrium or breast.
Bazedoxifene is approved for treatment of menopausal symptoms and prophylaxis of postmenopausal
osteoporosis.
Clomiphene is an older partial agonist, a weak estrogen that acts as a competitive inhibitor of
endogenous estrogens
Mifepristone is a 19-norsteroid that binds strongly to the progesterone receptor and inhibits he activity of
progesterone.
Danazol is an isoxazole derivative of ethisterone with weak progestational, androgenic, and
glucocorticoid activities, is used to suppress ovarian function.

Receptor Inhibitors
Cyproterone and Cyproterone acetate are effective antiandrogens that inhibit the action of androgen at
the target organ.
Flutamide a substituted anilide, is a potent antoandrogenic that has been used in treatment of prostatic
carcinoma
Spironolactone is a competitive inhibitor of aldosterone, also competes with dihydrotestosterone for the
androgen receptors in target tissues.
Gossypol extensive trials of this cottonseed derivative have been conducted in China. This complund
destroys elements of the seminiferous epithelium but does not significantly alter the endocrine function of
the testis.