Pharmacology of Breast Cancer Medications

Lesson 34: Gonadal Hormones

• Gonadal hormones are primarily produced by the testes and ovaries, but a small amount is also produced by the adrenal glands' zona reticularis (DHEA and androstenedione).
• These adrenal hormones can be converted into testosterone or estrogen in peripheral tissues.
• Gonadal hormones play significant roles in sexual development, reproduction, and maintaining secondary sexual characteristics.

Types of Gonadal Hormones

• Estrogens
• Progesterone
• Testosterone
• Luteinizing Hormone (LH)
• Follicle-stimulating Hormone (FSH)

Neurohormonal Control of the Female Reproductive System

• Gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the anterior pituitary to release FSH and LH.
• FSH and LH stimulate follicle development in the ovaries, which leads to estrogen release.
• LH also triggers ovulation at mid-cycle and controls progesterone secretion from the corpus luteum.
• Estrogen controls the proliferative phase of the endometrium and provides negative feedback on the anterior pituitary.
• Progesterone controls the secretory phase and provides negative feedback to both the hypothalamus and anterior pituitary.

Hormonal Changes and Phases of the Menstrual Cycle

• The diagram and graphs represent hormonal fluctuations (FSH, LH, estrogen, progesterone) throughout the menstrual cycle.
• Different phases are clearly marked (follicular, ovulation, luteal).
• Correspondingly, ovarian histology and endometrial histology are illustrated.

Neurohormonal Control of the Male Reproductive System

• GnRH controls gonadotropin secretion in both sexes.
• FSH is essential for seminiferous tubule integrity and gametogenesis.
• Interstitial cell-stimulating hormone (ICSH) stimulates interstitial cells to produce testosterone.
• Testosterone induces anabolic effects, such as muscle and bone growth in males.

Drugs Affecting Reproductive Function

• Estrogens:
  • Synthesized by ovaries and placenta, and in small amounts by the testes and adrenal cortex.
  • Key endogenous estrogens: estradiol, estrone, estriol.
  • Estradiol is the most potent.
  • Numerous exogenous synthetic forms, including ethinylestradiol.
  • Effects depend on the stage of sexual maturity.
  • In hypogonadism, stimulates secondary sexual characteristics and accelerates growth.
  • In amenorrhea, induces an artificial cycle with progestogen.
  • In sexually mature women, used for contraception with a progestogen.
  • In menopause, prevents symptoms and bone loss.
  • Physiological effects: reduces risk of atherosclerosis in premenopausal women, increases blood coagulability, sensitizes myometrium to oxytocin (labor), prevents osteoporosis, and closes epiphyses in both sexes.
  • Mechanism of action involves binding to nuclear receptors (ERα and ERβ), leading to genomic effects. Additionally, rapid vascular actions are mediated by nitric oxide (NO).
  • Pharmacokinetics: well-absorbed in the gastrointestinal tract but metabolized in the liver.
  • Adverse drug reactions (ADRs): breast tenderness, nausea, vomiting, anorexia, edema, thromboembolism risk, gallbladder disease, possible genital abnormalities in offspring, menstruation-like bleeds with intermittent use.
  • Contraindicated during pregnancy.
• Selective Estrogen Receptor Modulators (SERMs):
  • Tamoxifen: antioestrogenic action in mammary tissue, oestrogenic actions on plasma lipids, and endometrium and bone.
  • Mechanism of action: partial agonist of estrogen receptors, upregulates TGF-β to retard malignancy, and controls bone balance.
  • Use: adjuvant therapy for breast cancer in postmenopausal women.
  • Clomiphene: inhibits oestrogen binding, increases GnRH and gonadotrophin secretion, stimulates ovaries, increases estrogen secretion and induces ovulation.
  • Use: treatment of infertility caused by anovulation.
  • Raloxifene: antioestrogenic effects on breast and uterus, and oestrogenic effects on bone, lipid metabolism and blood coagulation.
  • Use: reduce invasive breast cancer risk in postmenopausal women with osteoporosis or high risk of breast cancer.
  • Fulvestrant: selective estrogen receptor degrader (SERD) ER antagonist.
  • Use: in ER-positive, metastatic breast cancer.
• Aromatase Inhibitors:
  • Anastrozole: blocks estrogen synthesis in the adrenal glands, but not the ovaries, providing an alternative in postmenopausal women with breast cancer
• Clinical Uses (summary):
  • Oestrogen: replacement therapy, contraception
  • Antioestrogens/SERMs and aromatase inhibitors: treatment of oestrogen-sensitive breast cancer, alternative for breast cancer in postmenopausal women, ovulation induction.

Progestogens

• Secreted by the corpus luteum (second part of menstrual cycle) and placenta (pregnancy).
• Minor amounts secreted by the adrenal cortex and testes.
• Act on nuclear receptors.
• Progesterone receptor density is controlled by estrogen.
• Multiple progestogen groups exist; some are biologically inactive orally (due to liver metabolism).
• Some derivatives have androgenic activity (e.g., norethisterone, norgestrel, ethynodiol).
• Newer progestins include desogestrel, gestodene (used in contraception).
• Adverse Reactions (ADRs): weak androgenic actions, acne, fluid retention, weight change, depression, libido changes, breast discomfort, premenstrual symptoms, irregular cycles, breakthrough bleeding, thromboembolism.

Antiprogestogens

• Mifepristone: partial agonist at progesterone receptors; sensitizes the uterus to prostaglandins; oral administration, 21-hour plasma half-life.
• Used in combination with a prostaglandin analogue as a medical abortion alternative.
• Ulipristal: selective progesterone receptor modulator, blocks ovulation.
• Emergency contraception up to 120 hours after intercourse.
• Used to reduce uterine fibroid size preoperatively.

Oral Contraceptives

• Combined pill:
  • Contains estrogen (e.g., ethinylestradiol) and progestogen (e.g., levonorgestrel).
  • Taken 21 days out of 28.
  • "Third-generation" pills include norgestrel, desogestrel, gestodene.
  • Mechanism of action: suppresses FSH, prevents ovulation, alters endometrium
• Progestogen-only pill:
  • Levonorgestrel, norethisterone, ethynodiol
  • Taken continuously; less reliable and irregular bleeding is common.
  • Contraceptive method of choice for some women due to possible contraindications with combined oral contraceptives.
• Emergency contraception:
  • Levonorgestrel (morning-after pill); single or double-dose regimens within 72 hours of intercourse.
  • Ulipristal acetate (morning-after pill); single dose up to 120 hours after intercourse.
  • Medroxyprogesterone: intramuscularly as contraception; infertility risk long term.
  • Mifepristone (Mifeprine): antagonist to progestagen receptors, promotes abortion within a week after intercourse; used up to week 9; often combined with prostaglandins for abortion.

Drugs Acting on the Uterus

• Myometrial Stimulants (Oxytocics):
  • Oxytocin: induces or augments labor.
  • Ergometrine: treats postpartum hemorrhage; initiates strong uterine contractions
• Prostaglandins (PGs):
  • PGE 2, PGF, dinoprostone, carboprost, gemeprost, misoprostol (analogues): induce contractions and cervical relaxation to facilitate uterine expulsion or for inducing abortion.
• Myometrial Relaxants:
  • Ritodrine: beta-2 adrenergic receptor agonist used to delay preterm labor; used in selected patients with otherwise uncomplicated pregnancies (22-33 weeks).
  • Atosiban: oxytocin antagonist that delays preterm labor.

Postmenopausal Hormone Replacement Therapy (HRT)

• HRT commonly uses estrogen and may include a progestogen.
• Short-term benefits: improves symptoms (hot flushes, vaginal dryness), prevents osteoporosis.
• Drawbacks: does not reduce the risk of heart disease, age-related cognitive decline (or specific decline), cyclical withdrawal bleeding. Increased risks of endometrial cancer, breast cancer (related to duration of use), venous thromboembolism, especially in women already at higher risk and if combinatio

Androgens

• Testosterone: main natural androgen; synthesized in interstitial cells of testes and smaller amounts in ovaries, adrenal cortex; cholesterol is the precursor.
  • Actions in general the same as those of testosterone, influenced by age and sex.
• Administration: subcutaneous implants or transdermal patches, intramuscular depot injection, orally.
  • Prepubertal boys: causes premature closure of long bone epiphyses.
  • Pubertal boys: develops secondary sexual characteristics.
  • Adults: increased muscle mass, strength, libido; potential for water retention.
• Pharmacokinetics: short elimination half-life (10–20 min).
  • Synthetic androgens are less rapidly metabolized and may be excreted unchanged in the urine.
• Adverse Reactions (ADRs): prolonged use may cause infertility, edema, and hepatic issues (e.g., liver cancer).

Antiandrogens

• Cyproterone acetate: progesterone derivative used in prostatic cancer, as an adjunct with GnRH agonists or in precocious puberty, masculinization, and acne in women.
• Flutamide: non-steroidal antiandrogen that is used in the treatment of inoperable prostate cancer treatment.
• Finasteride: inhibitor of 5alpha-reductase, enzyme that converts testosterone to dihydrotestosterone, used for benign prostatic hyperplasia (BPH).

Anabolic Steroids

• Nandrolone: increases protein synthesis and muscle growth.
  • Used in treating aplastic anemia to stimulate erythropoiesis
  • But clinical use overall has been limited.
• Adverse Reactions (ADRs): cholestatic jaundice, liver tumors, and increased risk of coronary heart disease with high doses.

GnRH Analogues

• GnRH analogues: given by subcutaneous infusion, stimulate gonadotropin release.
  • Continuous administration: inhibits gonadotropin release
• Indications: treatment of inoperable prostate cancer and infertility treatment.
  • Treatment of inoperable prostate cancer is started after androgen receptor antagonists(e.g., flutamide).
• Danazol: synthetic steroid that inhibits gonadotropin secretion used for sex-hormone dependent conditions such as endometriosis, breast dysplasia, and gyneccomastia. Also used to reduce hereditary angioedema swelling attacks.
• Adverse Reactions (ADRs): gastrointestinal issues, weight gain, fluid retention, dizziness, menopausal symptoms, muscle cramps.