L17 - Reproductive Pharmacology

• Effectiveness of Contraceptive Methods:

  • Least effective: Withdrawal methods, female condoms (rely heavily on user technique).

  • Increasingly effective: Male condoms (effectiveness increases with proper and consistent use).

  • Combined pills, mini pills, patch, vaginal ring: Require strict daily/weekly use; effectiveness hinges on adherence.

  • Hormone injections: Required every 1-3 months; more effective due to reduced user dependence.

  • Most effective (one-time procedures): Implants, female sterilization, vasectomy, intrauterine devices (IUDs); eliminate user error.

• Contraceptive Mechanisms:

  • Physical barriers: Prevent sperm from reaching the ovum (e.g., condoms, diaphragms).

  • Drugs preventing implantation of the blastocyst: Primarily IUDs, which alter the uterine environment to prevent implantation.

  • Drugs preventing fertilization of the ovum: Hormonal methods (pills, patches) that inhibit ovulation.

• Hormonal Contraception:

  • Effectiveness: Up to 99.9% when used correctly (pills, patch): success depends on perfect adherence.

  • Injections: Very reliable but require doctor visits; provide a sustained hormone release.

  • IUDs and implants: Long-lasting, one-time procedures; offer extended protection without daily intervention.

Hypothalamic-Pituitary-Gonadal (HPG) Axis

• Female HPG Axis:

  • Hypothalamus releases Gonadotropin-Releasing Hormone (GnRH): pulsatile release is critical for stimulating the pituitary.

  • GnRH controls the synthesis and release of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) from the anterior pituitary: these gonadotropins regulate ovarian function.

  • LH and FSH stimulate the ovaries to release oestrogen and progesterone: these steroid hormones drive the menstrual cycle.

  • Oestrogen has both negative and positive feedback on the anterior pituitary and hypothalamus; preoperative surge stimulates activity: complex feedback loops regulate hormone production.

  • Progesterone primarily exerts negative feedback: stabilizes the cycle and prepares the uterus for implantation.

  • Inhibins inhibit FSH secretion by the pituitary: provides specific control over FSH levels.

• Male HPG Axis:

  • Hypothalamus releases GnRH.

  • Anterior pituitary releases LH and FSH.

  • LH and FSH act on the testes to promote the release of testosterone: LH stimulates Leydig cells to produce testosterone; FSH supports spermatogenesis via Sertoli cells.

  • Testosterone has negative feedback on the anterior pituitary and hypothalamus: maintains stable testosterone levels.

Female Reproductive System - Hormonal Control

• Hypothalamus \implies GnRH \implies Anterior Pituitary \implies FSH and LH \implies Ovaries.

• FSH and LH role in follicle maturation and ovulation: FSH stimulates follicle growth; LH triggers ovulation.

• Ovaries release oestrogen and progesterone, which act on the reproductive tract and other tissues: hormones prepare the uterus for implantation and affect various organs.

• Graafian follicle develops and involutes to form the corpus luteum after ovum release: corpus luteum secretes progesterone to maintain the early stages of pregnancy.

• Estrogen controls the proliferative phase of the endometrium and has negative feedback effects on the anterior pituitary: prepares the uterine lining for potential implantation.

• Progesterone controls the secretory phase and has negative feedback effects on both the hypothalamus and anterior pituitary: stabilizes the endometrium and prevents further ovulation.

Menstrual Cycle Hormonal Fluctuations

• Hormone Levels:- Small initial peak in FSH.

  • Higher peak in FSH subsequently decreasing.

  • Oestrogen increases and then decreases.

  • Oestrogen surge \implies LH surge \implies ovulation.

  • Peak in progesterone levels post-ovulation.

Oestrogens

• Production:

  • Mainly produced by the placenta and ovaries.

  • Release from ovaries controlled by the hypothalamic-pituitary axis.

  • Small amounts released by the adrenal cortex and testes.

• Mechanism of Action:

  • Interact with oestrogen receptors: oestrogen receptor alpha and oestrogen receptor beta.

  • Tissue-specific activity depending on receptor location.

  • Activation results in the modification of gene transcription.

• Receptor Locations:

  • oestrogen receptor alpha: Uterus, ovary, breast, bone, brain, testes.

  • oestrogen receptor beta: Uterus, brain.

• Main Endogenous Estrogens:

  • Estradiol, estrone, and estriol.

• Physiological Effects:

  • Before puberty: Stimulates development of secondary sexual characteristics.

  • Female adult: Cyclic administration induces artificial menstrual cycle (contraception).

  • At/after menopause: Prevents menopausal symptoms, protects against osteoporosis but increases thromboembolism risk.

• Effects Throughout the Body:

  • Brain: Increased body temperature and memory, affects mood and emotions.

  • Cardiovascular system: Role in blood clotting, vasodilation.

  • Ovaries: Follicle growth, maintains menstrual cycle.

  • Uterus: Growth, vasodilation, maintains menstrual cycle.

  • Liver: Decreases cholesterol.

  • Breast: Increases growth and nipple development.

  • Bones: Inhibits osteoclasts, stimulates OPG expression.

  • Skin: Regulation of collagen, elastin fiber, hyaluronic acid, and sebum production.

Progesterone

• Production:

  • Exogenous steroid hormone from adrenal cortex and gonads.

  • Secreted by the ovarian corpus luteum during the first ten weeks of pregnancy.

  • Later phases: Placenta.

• Mechanism of Action:

  • Readily crosses the cell membrane.

  • Binds to progesterone receptors in the cytoplasm.

  • Complex translocates to the nucleus, binds to DNA, enhances or suppresses gene expression.

• Progestogens:

  • Synthetic forms of progesterone (e.g., in mini pill, combined pill).

  • Act via progesterone nuclear receptors.

  • Most synthetic progesterones are testosterone derivatives.

• Physiological Effects:

  • Decreases oestrogen-mediated endometrial proliferation.

  • Key role in pregnancy maintenance (early and late stages).

  • Thickens cervical mucus.

  • Increases basal body temperature.

  • Diuretic.

  • Effect on mood (anti-depressive, anti-anxiety).

  • Promotes normal sleep patterns.

  • Facilitates thyroid hormone function.

  • Regulates insulin release.

  • Increases fat use for energy.

  • Stimulates new bone formation.

  • Anti-inflammatory.

Hormonal Contraceptive Options

• Combined Oral Contraceptive (COC):- Contains oestrogens and progestogens.

• Progesterone-Only Oral Contraceptive (POP):- Mini pill.

• Long-Term Hormonal Contraceptives:- Implants, intrauterine devices, vaginal rings.

• Postcoital Emergency Hormonal Contraceptive:- Morning-after pill; administer within 72 hours of unprotected sex.

Combined Oral Contraceptives (COCs) - The Pill

• Composition:

  • Combination of an oestrogen and a progestogen (synthetic progesterone).

• Administration:

  • Taken for 21 consecutive days, followed by 7 pill-free days.

• Indications:

  • Contraception.

  • Treatment of endometriosis.

• Mechanism of Action:

  • Estrogen: Inhibits FSH secretion via negative feedback on the anterior pituitary, suppressing ovarian follicle development. This prevents the selection of a dominant follicle and thus, ovulation.

  • Progesterone: Inhibits LH secretion, preventing ovulation; makes cervical mucus less suitable for sperm passage by increasing its viscosity; alters the endometrium to discourage implantation by thinning the uterine lining.

• Adverse Effects:

  • Weight gain, mild nausea, flushing, dizziness, depression or irritability, skin changes, and amenorrhea.

• Contraindications:

  • Risk of thromboembolism.

  • Risk of cardiovascular disease, cardiovascular or cerebrovascular disorders.

  • Breast cancer or past history.

  • Use with caution in patients with liver disease, asthma, eczema, migraine, diabetes, or hypertension.

• Beneficial Effects:

  • Contraception.

  • Decreases menstrual symptoms such as irregular periods and ensure menstrual bleeding in women.

  • Reduced iron deficiency, anemia, and premenstrual tension.

  • Also, benign breast disease, uterine fibroids, and functional cysts of the ovaries are reduced.

Progesterone Only Oral Contraceptive (POP) - Mini Pill

• Indication:

  • Contraception.

• Mechanism of Action:

  • Thickens cervical mucus, decreasing sperm penetration: Progestin increases the viscosity of cervical mucus, creating a barrier to sperm migration.

  • Blocks ovulation in about 60-80% of cycles: Progestin can suppress LH secretion, preventing ovulation in a significant proportion of cycles.

• Contraindications:

  • Active thromboembolic disorders.

  • Pregnancy.

  • Severe hepatic disease.

• Administration:

  • Oral; timing critically important (delay >3 hours requires alternative contraceptive method): Consistent daily administration is crucial due to the short half-life of progestin.

• Adverse Reactions:

  • Disturbances of menstruation (irregular bleeding).

  • Acne, headaches.

  • Decreases in HDL levels, increases in LDL levels.

  • Decreased bone density.

• Indications:

  • Hypertension.

  • History of thromboembolism.

  • Biliary tract disease or thyroid disease.

  • Epilepsy.

  • Diabetes without vascular disease.

  • Breastfeeding mothers (6 weeks - 6 months postpartum).

Long Term Hormonal Contraceptive Options

• Vaginal Ring: 3 weeks duration; combined contraceptive; use in adolescents, malabsorption conditions, irregular menstrual cycle; delivers a constant dose of estrogen and progestin locally.

• Injection: 3 months duration; progestogen only; use in postpartum, breastfeeding, malabsorption, enzyme-inducing medications; may cause weight gain, irregular bleeding; provides sustained progestin release, suppressing ovulation.

• Implant: 3 years duration; progestogen only; use in breastfeeding, postpartum, women > 40, adolescents, malabsorption conditions; may cause weight gain, irregular bleeding; releases progestin at a steady rate, inhibiting ovulation.

• Progestogen Releasing IUD (Mirena): 5 years duration; progestogen only; use in women > 40, breastfeeding, malabsorption conditions, postpartum (4 weeks after birth); may cause headache, acne, breast soreness, irregular bleeding; releases progestin directly into the uterus, thinning the endometrial lining and thickening cervical mucus.

Pharmacokinetics & Drug Interactions (Oral Contraceptives)

• Metabolized by hepatic cytochrome P450 enzyme: Oestrogens and progestogens are primarily metabolized by CYP3A4 enzymes in the liver.

• Minimum effective oestrogen doses used to minimize thromboembolism risk: Lower oestrogen doses reduce the risk of venous thromboembolism.

• Increased clearance may result in contraceptive failure: Drugs that induce CYP450 enzymes can increase the metabolism and clearance of contraceptive hormones.

• Enzyme-Inducing Drugs:

  • Rifampicin, carbamazepine, phenytoin, St. John's Wort.

  • Affect both combined and progestin-only pills.

Emergency Contraception - Morning After Pill

• Administration:

  • Oral progesterone alone or combined with oestrogen.

  • Effective if taken within 72 hours of unprotected sex and repeated 12 hours later.

• Mechanism of Action:

  • Binds to progesterone and androgen receptors, slows the release of GnRH from the hypothalamus: Inhibits LH surge, preventing follicle rupture and viable egg release (preventing ovulation).

  • Suppresses LH surge, inhibiting follicle rupture and viable egg release (preventing ovulation).

• Contraindications:

  • Pregnancy.

  • Severe hepatic dysfunction.

• Adverse Reactions:

  • Nausea and vomiting (replacement tablets with anti-emetic).

  • Fatigue and dizziness.

Adverse Effects of Hormone Classes

• Exogenous Estrogens:

  • Increased risk of endometrial carcinoma.

  • Risk for thromboembolic disease.

  • Hypertension.

  • Increased gallbladder disease (increased cholesterol in bile).

  • Migraine.

• Exogenous Progestins:

  • Acne and hirsutism.

  • Thromboembolism.

  • Fluid retention and weight change.

  • Change in libido.

  • Breast discomfort.

• Cardiovascular System Effects:

  • Effects on atherosclerosis, thrombosis, vasomotion, and arrhythmia.

Menopausal Hormone Therapy (MHT) - Hormone Replacement Therapy (HRT)

• Menopause: End of a woman's reproductive years (ages 45-55), natural biological aging process.

• Cause: Loss of ovarian follicular function, decline in circulating oestrogen levels.

• Symptoms:

  • Hot flushes and night sweats.

  • Changes in menstrual cycle, cessation of menstruation.

  • Vaginal dryness and pain during sex.

  • Incontinence.

  • Difficulty sleeping/insomnia.

  • Changes in mood, depression, or anxiety.

• Interventions:

  • Non-hormonal and hormonal interventions to alleviate symptoms.

• Benefits of HRT/MHT:

  • Improves menopausal symptoms, vasomotor symptoms, urogenital symptoms, and sleep.

  • Helps with joint pain, sexual problems.

  • Reduces risk of osteoporosis fracture.

  • Reduces risk of colorectal cancer and diabetes.

• Administration:

  • Cyclic or continuous administration of low doses of one or more oestrogens with or without progestogen.

• Types of MHT:

  • Combination HRT/MHT: Estrogen and progestin (prevents endometrial hyperplasia, reduces endometrial cancer risk).

  • Oestrogen-only therapies: Use in patients with hysterectomy or with progestogen (Mirena) if an intact uterus.

  • Both HRT/MHT: Prevents osteoporosis.

• Risks & Adverse Effects:

  • Oestrogen replacement does not reduce the risk of coronary heart disease.

  • Cyclic withdrawal bleeding.

  • Adverse effects related to progestogen.

  • Increased risk of endometrial cancer if oestrogen given unopposed by progestogen.

  • Increased risk of breast cancer related to the duration of HRT/MHT use (disappears within 5 years of stopping).

  • Increased risk of venous thromboembolism (doubled in patients using combined HRT/MHT for about 5 years).

Selective Oestrogen Receptor Modulators (SERMs)

• Used for treatment of pain during/after sex during menopause (vulval/vaginal atrophy, vaginal dryness).

• Action depends on:

  • Expression level of oestrogen receptor alpha and oestrogen receptor beta.

  • Conformational changes induced by SERM on binding of coactivators and corepressors.

  • Expression level of coactivators and corepressors.

• Action types:

  • Agonistic/antagonist effect on oestrogen receptors leading to reduced expression of target genes.

  • Modulatory effect with undefined coactivator binding, either increasing or decreasing gene expression.

  • Agonist effects whereby SERM binds activator interaction leading to expression of oestrogen receptor target genes.

• Ospemifene:

  • Common SERM used in treatment of patients with menopause experiencing symptoms including pain during/after sex and also vaginal dryness

  • Selectively binds to estrogen receptors.

  • Agonistic effects on the endometrium.

  • Reverses structural changes with vulvar vaginal atrophy and relieves the symptoms of dyspareunia.

• Contraindications:

  • History of or current venous thrombosis.

  • Pregnancy.

  • Breastfeeding.