The Gonadal Hormones & Inhibitors

Hypothalamus Adenohypophysis Testes or Ovaries Target tissues Control of Sex Hormones Indirect Loop Short Loop Direct Loop GnRH LH, FSH Testosterone or Estrogen & Progesterone neural inputs

Sex hormon Sex hormones produced by the gonads are necessary for Conception embryonic maturation development of primary and secondary sexual characteristics at puberty. Their activity in target cells is modulated by receptors.

Sex hormon The gonadal hormones are used therapeutically in replacement therapy, for contraception, Management of menopausal symptoms. Several antagonists are effective in cancer chemotherapy. All gonadal hormones are synthesized from the precursor, cholesterol, in a series of steps

Estrogen The gonadal hormones are used therapeutically in replacement therapy, for contraception, Management of menopausal symptoms. Several antagonists are effective in cancer chemotherapy. All gonadal hormones are synthesized from the precursor, cholesterol, in a series of steps

Estrogens Natural estrogens The major estrogens produced by women are Estradiol is the most potent estrogen produced and secreted by the ovary. It is the principle estrogen in the premenopausal woman. Estrone is a metabolite of estradiol. Estrone is the primary circulating estrogen after menopause. Estriol another metabolite of estradiol, is significantly less potent than estradiol. It is present in significant amounts during pregnancy, because it is the principal estrogen produced by the placenta.

Estrogens Natural estrogens during the first part of the menstrual cycle estrogens are produced in the ovarian follicle by the theca and granulosa cells. After ovulation, the estrogens as well as progesterone are synthesized by the luteinized granulosa and theca cells of the corpus luteum. During pregnancy, a large amount of estrogen is synthesized by the fetoplacental unit

Estrogens Synthetic estrogens variety of chemical alterations have been applied to the natural estrogens. The most important effect of these alterations has been to increase their oral effectiveness.

Estrogens Synthetic estrogens In addition to the steroidal estrogens, a variety of nonsteroidal compounds with estrogenic activity have been synthesized and used clinically. These include dienestrol, diethylstilbestrol, benzestrol, hexestrol, methestrol, and methallenestril.

Estrogens Pharmacokinetics These agents and their esterified or conjugated derivatives are readily absorbed through the gastrointestinal tract, skin, and mucous membranes. bioavailability of estrogen taken orally is low due to firstpass metabolism. To reduce first-pass metabolism, the drugs may be administered via the transdermal route (patch, topical gel, topical emulsion, or spray), intravaginally (tablet, cream, or ring), or by injection. When released into the circulation, estradiol binds strongly to an α2 globulin (sex hormone-binding globulin [SHBG]) and with lower affinity to albumin Estradiol is converted by the liver and other tissues to estrone and estriol

Estrogens Pharmacokinetics They are hydroxylated in the liver to derivatives thatare subsequently glucuronidated or sulfated. The parent drugs and their metabolites undergo excretion into bile and are then reabsorbed through the enterohepatic circulation. Inactive products are excreted in urine.

Estrogens MECHANISM Plasma estrogens in the blood and interstitial fluid are bound to SHBG, from which they dissociate to enter the cell and bind to their receptor. Two estrogen-receptor subtypes hormone a and b mediate the effects of the hormone. The estrogen receptors bound to heat shock proteins that stabilize them. Binding of the hormone to its receptor alters its conformation and releases it from the stabilizing proteins (predominantly Hsp90). The receptor-hormone complex forms homodimers. The steroid- receptor complex is able to enter the nucleus and bind to a specific sequence of nucleotides called estrogen response elements (EREs) in the promoters of various genes and regulate their transcription. This results in the synthesis of specific proteins that mediate a number of physiologic functions

Estrogens Physiologic Effects FEMALE MATURATION Estrogens are required for the normal sexual maturation and growth of the female. They stimulate the development of the vagina, uterus, and uterine tubes as well as the secondary sex characteristics. ENDOMETRIAL EFFECTS In addition to its growth effects on uterine muscle, estrogen also plays an important role in the development of the endometrial lining.

EstrogensPhysiologic Effects METABOLIC AND CARDIOVASCULAR EFFECTS   Estrogens seem to be partially responsible for maintenance of the normal structure and function of the skin and blood vessels in women. Estrogens also decrease the rate of resorption of bone.   Metabolic alterations in the liver are especially important, so that there is a higher circulating level of proteins such as transcortin (corticosteroidbinding globulin [CBG]), thyroxine-binding globulin (TBG), SHBG, transferrin, renin substrate, and fibrinogen. This leads to increased circulating levels of thyroxine, estrogen, testosterone, iron, copper, and other substances   Estrogens effect on plasma lipids characterized by an increase in the highdensity lipoproteins (HDL), a slight reduction in the low-density lipoproteins (LDL), and a reduction in total plasmacholesterol levels

EstrogensPhysiologic Effects 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.

Clinical Uses Primary Hypogonadism Estrogens have been used extensively for replacement therapy in estrogen-deficient patients. The estrogen deficiency may be due to primary failure of development of the ovaries, premature menopause, castration, or menopause. 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

Clinical Uses Postmenopausal Hormonal Therapy The primary indication for estrogen therapy is menopausal symptoms such as vasomotor instability (for example, hot flashes‌ or hot flushes‌) and vaginal atrophy, therapy with the lowest dose of estrogen required for symptomatic relief is recommended. Treatment may be required for only a limited period of time and the possible increased risk for breast cancer avoided. In women who have undergone hysterectomy, estrogens alone can be given 5 days per week or continuously, since progestins are not required to reduce the risk for endometrial hyperplasia and cancer. Hot flushes, sweating, insomnia, and atrophic vaginitis are generally relieved by estrogens. For women who have not undergone a hysterectomy, a progestin is always included with the estrogen therapy

Estrogen Therapeutic uses of estrogens Osteoporosis is effectively treated with estrogen; however, other drugs, such as alendronate, should be considered first-line therapy over estrogen. Use of estrogen in contraceptive will discus later

Estrogen Adverse effects: Postmenopausal uterine bleeding. Breast tenderness & increased risk of breast cancer. Endometrial hyperplasia & increased risk of endometrial cancer (if not given with a progestin). Thromboembolic disorders. Hypertension.Cholestasis.Nausia.Migrains. Vaginal adenocarcinoma in young women whose mothers were treated with diethylstilbestrol in an effort to prevent miscarriage.

Selective Estrogen Receptor Modulators (SERM) (clomiphene, tamoxifen, raloxifene) In the past, a number of these agents had been categorized as antiestrogen. SERM bind estrogen receptors, but have different effects on different tissues i.e. they display selective agonism or antagonism according to the tissue type for example: tamoxifen is an estrogen antagonist in breast cancer, but acts as a particular agonist on the uterus giving rise to endometrial hyperplesia

SERM Side effects UsesDrug Hot flushes, menstrual irregularities, Increased risk of endometrial cancer. palliative treatment of metastatic breast cancer in postmenopausal women. It may also be used as adjuvant therapy following mastectomy or radiation and to reduce the risk of breast cancer in high-risk patients.Tamoxifen DVT & pulmonary embolism. postmenopausal osteoporosis. postmenopausal osteoporosis. reduce the incidence of invasive breast cancer in postmenopausal women.Raloxifene are dose related and include headache, nausea, vasomotor flushes, visual disturbances, and ovarian enlargement. Male & female infertility Clomiphene

Progesterone Source Corpus luteum under the control of luteinizing hormone. Placenta.Actions: Prepares the uterus for implantation of the fertilized ovum. Inhibit uterine contraction that would expel the fetus. alveolobular development of the secretory apparatus in the breast.. -ve feed back effect on luteinizing hormone so, block ovulation. Thick cervical secretion, so block sperm penetration. Thermogenic i.e. it increases body temperature. Compete aldosterone on mineralocorticoid receptor so induced sodium retention. Decreases the plasma levels of many amino acids.

Progestine Progesterone and progestins (progestogens): Progesterone is the natural hormone. It is not effective orally due to the extensive 1 st pass metabolism so, it must be given by i.m injection. It has a short duration of action. Progesterone is the natural hormone. It is not effective orally due to the extensive 1 st pass metabolism so, it must be given by i.m injection. It has a short duration of action. Progestins are synthetic derivatives of progesterone, effective orally, and have a long duration of action. Progestins are synthetic derivatives of progesterone, effective orally, and have a long duration of action. Some of progestins have androgenic, estrogenic, and even glucocorticoid-like effects.

progestin progestin Uses of progestins: Oral contraception. Dysfunctional uterine bleeding. HRTDysmenorrhea.Endometriosis. Suppression of postpartum lactation. Infertility if due to deficiency of progesterone. Maintenance of pregnancy.

Progestine Adverse effects 1. Increase blood pressure in some patients. 2. The more androgenic progestins also reduce plasma HDL levels in women. 3. Combined progestin plus estrogen replacement therapy in postmenopausal women may increase breast cancer risk significantly compared with the risk in women taking estrogen alone.

Antiprogestogens Mifepristone: It is an orally active steroid antagonist of progesterone & glucocorticoid receptors. It is used for induction of abortion in the 1 st trimester (abortifaciant). It is used as a single oral dose followed by PGE1 (gemeprost) or PGF2α (dinoprost) analogue to produce uterine contraction. The major adverse effects are significant uterine bleeding and the possibility of an incomplete abortion