Gonadal Hormones and Estrogens

Gonadal Hormones

• Follicle-stimulating hormone (FSH) stimulates follicle development in the ovaries
• Luteinizing hormone (LH) stimulates androgen production in the ovaries
• LH stimulates progesterone and estrogen production in the ovaries
• In pregnancy, placental hormone beta human chorionic gonadotropin (beta HCG) takes over estrogen and progesterone production
• FSH regulates spermatogenesis in the testes
• LH is the primary stimulus for testosterone synthesis in the testes

The Estrogens

• Major estrogens produced by humans are estradiol, estrone, and estriol
• Estradiol is the primary estrogen produced by the ovary
• In the first part of the menstrual cycle, estrogens are produced by the ovarian follicle
• After ovulation, estrogens and progesterone are produced in the corpus luteum
• Synthetic estrogens have improved oral effectiveness
• Mechanism of Action: Estrogens enter the cell freely (steroids), bind to receptors in the nucleus, and initiate protein transcription
• Estrogens facilitate female maturation and female characteristics
• Estrogen with progesterone plays an important role in the development of the endometrial lining
• Estrogens help maintain vascular flow in females
• Estrogens decrease the rate of bone resorption, helping to prevent osteoporosis
• Estrogens enhance blood coagulation

Clinical Uses of Estrogens (Other Than for Birth Control)

• Estrogen replacement is used to treat estrogen-deficient patients
• Estrogen replacement is used to treat postmenopausal women
• Major ADRs of estrogen include uterine bleeding and breast cancer after prolonged use

Progesterone

• It is a precursor to estrogens, androgens, and adrenocortical steroids
• Progesterone is synthesized from cholesterol in the ovaries, testis, and adrenal cortex

Synthetic Progesterone

• Progesterone is poorly absorbed after oral administration

Physiological Effects of Progesterone

• Progesterone enters cells and binds to receptors in the cytoplasm and the nucleus
• Progesterone results in gene transcription
• Gene transcription causes stimulation of lipoprotein lipase, which favors fat deposition, increased insulin and glucose levels, and promotes glycogen storage in the liver

Hormonal Contraception

• Daily injections of estrogen and progesterone can prevent ovulation
• Orally available progesterone did not exist, which was a problem
• Two types of contraceptives are now used
• Estrogen and progesterone combinations come in monophasic pills which have a constant dosage of both hormones during the dosing cycle
• Multiphasic pills contain a variable dosage of one or both hormones, which is changed once or more during the dosing cycle
• Continuous progesterone therapy with no estrogen is another form of contraceptive

Pharmacological Effects of Birth Control Pills

• Mechanism of Action includes the inhibition of anterior pituitary function, which prevents ovulation
• Changes to the endometrium cervical mucus, and changes in motility and secretion in the uterine tubes contribute to a reduced likelihood of conception and implantation
• Ovaries functions are depressed, and ovaries become smaller
• Prolonged use may induce hypertrophy of the cervix and polyp formation in the uterus
• Some breast enlargement is noted due to estrogen
• The estrogen-progesterone combination suppresses lactation
• The transport of oral contraceptives into the mother’s milk is small and not considered important

ADRs of Birth Control Pills

• Mild ADRs include nausea, mastalgia (breast pain), and breakthrough bleeding due to estrogen content
• Increased levels of some proteins that are important for binding hormones (like thyroid) can alter normal function
• Headache is mild, but migraines are made worse
• Withdrawal bleeding fails to occur and can cause confusion with regard to pregnancy
• Moderate ADRs require discontinuance of oral contraceptives
• Breakthrough bleeding is mostly found with progesterone agents alone
• Other ADRs include weight gain, increased skin pigmentation, and acne exacerbated with androgen-like progesterone, but acne is improved by estrogen in combination pills
• Vaginal infections are more common in those taking birth control pills
• Severe adverse effects include thromboembolic disease, including venous thrombosis and pulmonary embolism
• Oral contraceptives lower the level of antithrombin III, the major inhibitor of thrombin
• Myocardial infarction occurs with a slightly higher risk

Contraception With Progesterone Alone

• Often used as an implant capsule placed under the skin
• Contraception lasts 2-4 years

Estrogen & Progesterone Inhibitors & Antagonists

• Raloxifene is a newer SERM that blocks (antagonist) estrogen receptors in the breast
• SERMs are used to treat breast cancers that require estrogen for growth
• These drugs allow estrogen produced by the patient to bind to estrogen receptors in bone, providing beneficial effects
• Prior to SERM drugs, a patient with estrogen-positive breast cancer had ovaries and a uterus removed to stop estrogen production

Morning After Pills

• Mifepristone (RU-486) binds to progesterone and glucocorticoid receptors as an antagonist drug to block progesterone, preventing pregnancy
• A dose of 400-600 mg/day for 4 days or 800 mg/day for 2 days will terminate pregnancy in > 85% of cases
• Mifepristone followed by misoprostol 24-48 h later will be 95% effective for up to 12 weeks of pregnancy.
• Misoprostol is a prostaglandin (PGE1) that induces contractions and will expel the pregnancy tissue
• CVS and Walgreens will provide mifepristone
• The rollout will cover New York, Pennsylvania, Massachusetts, California, Illinois, Rhode Island
• A total of 21 states have banned the sale of this drug
• Prior to the FDA ruling that allowed pharmacies to dispense this drug with a prescription, only clinics and doctor’s offices could dispense it
• the only exception was a telemedicine website that was FDA approved which dispensed a prescription after a patient interview

Ovulation-Inducing Agents

• Clomiphene is a partial agonist at estrogen receptors
• It stimulates ovulation in women who wish to become pregnant

Testosterone

• The testis produces testosterone
• Testosterone is converted to the active form dihydrotestosterone by the enzyme 5-alpha reductase
• The actions of testosterone in its active form are varied and include all male characteristics
• Mechanism of Action: The active agent dihydroxytestosterone acts at the DNA level to synthesize a variety of enzymes and proteins along with effects of growth and differentiation

Androgen Suppression & Antiandrogens

• Ketoconazole inhibits adrenal and gonadal steroid synthesis