Reproductive Pharmacology & Hormone Therapy
Hormone Categories & General Overview
Four primary reproductive‐hormone groups
repeatedly referenced in lecture, categorized by chemical structure and physiological action:
Gonadotropins (FSH, LH, LTH): Peptide hormones secreted by the anterior pituitary, vital for gonadal function.
Androgens: Steroid hormones, primarily male sex hormones, synthesized from cholesterol.
Estrogens: Steroid hormones, primarily female sex hormones, also synthesized from cholesterol.
Progesterone: A steroid hormone primarily involved in the menstrual cycle, pregnancy, and embryogenesis.
Master gland involvement in hormone regulation:
Anterior pituitary lobe: This is the source of all three gonadotropins (FSH, LH, LTH, which is prolactin in broader contexts), acting under the influence of Gonadotropin-Releasing Hormone (GnRH) from the hypothalamus.
Posterior pituitary lobe: Responsible for the release of oxytocin, which plays a crucial role in uterine contractions during labor and milk let-down during lactation.
Gonadotropins
Follicle-Stimulating Hormone (FSH):
In females, it stimulates the growth and maturation of ovarian follicles, which contain the developing egg. It also promotes estrogen synthesis by the granulosa cells of the follicle.
In males, it initiates spermatogenesis within the seminiferous tubules of the testes, crucial for sperm production.
Luteinizing Hormone (LH):
In females, it triggers ovulation, the release of the mature egg from the ovarian follicle. It also supports corpus luteum formation by transforming the ruptured follicle into this transient endocrine gland in the ovary.
In males, LH stimulates the Leydig cells in the testes to produce testosterone, which is essential for secondary male characteristics and spermatogenesis.
Luteotropic Hormone (LTH = prolactin context):
Known more broadly as Prolactin, LTH primarily promotes progesterone secretion by the corpus luteum, especially in early pregnancy, which helps maintain the uterine lining.
It directly stimulates milk production in mammary tissue following childbirth, preparing the breasts for lactation.
Clinical connections:
FSH & LH assays are routinely used to evaluate fertility problems in both men and women, helping diagnose conditions like polycystic ovary syndrome (PCOS) or hypogonadism.
Excess or deficiency of these hormones can be treated with synthetic analogs (e.g., recombinant FSH or LH), but lecture emphasized naming & natural physiology rather than specific dosing regimens.
Androgens (Male Sex Hormones)
Physiological roles:
Essential for the development and maintenance of secondary male characteristics, including facial hair growth, deepening of the voice, increased muscle mass, and bone density.
They also play a critical role in male libido, sperm production, and overall energy levels.
Primary examples: Testosterone (the most potent and abundant androgen) and Androsterone (a less potent metabolite of testosterone).
Therapeutic uses:
Replacement therapy:
Used for conditions causing insufficient natural testosterone production, such as ext{Congenital hypogonadism} (e.g., Klinefelter syndrome) or ext{Acquired hypogonadism} (e.g., due to testicular injury or aging).
Palliative care in estrogen-dependent or metastatic breast cancer: Androgens exert an anti-estrogenic effect by competing for estrogen receptors and suppressing estrogen production, which can slow the growth of certain breast cancers, particularly in postmenopausal women.
Agent spotlight: Methyl-testosterone, an orally active synthetic androgen.
Treatment of endometriosis & fibrocystic breast disease: Androgens like Danazol suppress ovarian function, leading to decreased estrogen levels and regression of endometrial implants or breast cysts.
Agent spotlight: Danazol (brand Danocrine), a synthetic androgen that is mildly androgenic but significantly decreases estrogen production.
Appetite/weight-gain support in cachexia: Due to their anabolic properties, androgens promote muscle mass and stimulate appetite, which is beneficial in wasting syndromes associated with chronic diseases like AIDS or COPD.
Drug–drug interactions:
Major risk of increased bleeding when combined with oral anticoagulants (e.g., warfarin) due to effects on clotting factors. Physicians must counsel on vigilant International Normalized Ratio (INR) monitoring to prevent hemorrhage.
Highlight table (keep straight):
Depro-testosterone (Testosterone cypionate/enanthate): Primarily used for long-acting congenital hypogonadism replacement therapy via intramuscular injection.
Danazol (Danocrine): Key indications include endometriosis and fibrocystic breast disease, with additional use for appetite/weight gain in cachexia.
Erectile-Dysfunction (ED) Medications – PDE-5 Inhibitors
Drugs:
Sildenafil (Viagra): The first oral PDE-5 inhibitor, typically used for on-demand treatment.
Tadalafil (Cialis): Known for its longer half-life (up to 36 hours), providing a wider “any-time” window for sexual activity and also approved for benign prostatic hyperplasia (BPH).
Physiologic mnemonic: “Fill the penis with blood” – reflecting their mechanism of action which is to enhance the effect of nitric oxide (NO) which leads to vasodilation.
Mechanism of Action: These drugs selectively inhibit phosphodiesterase-5 (PDE-5), an enzyme responsible for breaking down cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. By increasing cGMP levels, they prolong the relaxation of smooth muscle and enhance blood flow into the penis, facilitating an erection in response to sexual stimulation.
Adverse effects:
Vision changes: Can include a temporary blue haze (cyanopsia), blurred vision, or heightened light sensitivity. Rarely, more serious issues like non-arteritic anterior ischemic optic neuropathy (NAION) can occur.
Risk of severe hypotension: Life-threatening drop in blood pressure when combined with nitrates (e.g., nitroglycerin for angina) due to synergistic vasodilation. Also caution with α-blockers (e.g., Flomax for BPH) due to additive hypotensive effects.
Insurance anecdote: Some insurers may cover PDE-5 inhibitors for their ext{BPH} indication (especially Tadalafil) but often deny coverage for erectile dysfunction alone, leading to out-of-pocket costs for patients.
Estrogens (Female Sex Hormones)
Biological functions:
Crucial for the development of female secondary sexual characteristics at puberty (e.g., breast development, wider hips) and regulation of the menstrual cycle.
They prepare the uterine lining (endometrium) by promoting its proliferation, creating an environment suitable for fertilization, implantation of an embryo, and early embryonic nutrition.
Beyond reproduction, estrogens play vital roles in bone density maintenance, cardiovascular health, and cognitive function.
The three major natural estrogens are Estradiol (E2, most potent and prevalent in reproductive years), Estrone (E1, dominant after menopause), and Estriol (E3, primarily produced during pregnancy).
Perimenopause / Menopause physiology:
The natural decline in ovarian estrogen production leads to a constellation of symptoms including hot flashes, vaginal dryness (due to thinning of vaginal epithelium), challenging mood swings, insomnia, and an increased risk of osteoporosis due to reduced bone mineral density.
Surgical removal of ovaries (oophorectomy) or drug-induced menopause (e.g., using GnRH analogs for estrogen-driven breast cancer) can accelerate the onset of this syndrome.
Therapy considerations:
Unopposed estrogen: Administering estrogen alone to a woman with an intact uterus significantly increases the risk of endometrial carcinoma due to continuous proliferative stimulation of the uterine lining without the balancing effect of progesterone, which induces secretory changes and shedding.
Therefore, it is crucial to combine estrogen with a progestin (progesterone or a synthetic progestogen) when the uterus is intact to reduce this cancer risk by mimicking a more natural cycle.
Primary clinical uses:
Combined oral contraceptives (+ progestin): Highly effective for pregnancy prevention.
Cycle regulation: Used to treat menstrual disorders such as dysmenorrhea (painful periods) or menorrhagia (heavy bleeding).
Menopausal symptom relief: Hormone Replacement Therapy (HRT) to alleviate bothersome vasomotor symptoms (hot flashes), improve vaginal atrophy, and mitigate osteoporosis risk.
Serious ADRs (dose & age dependent):
ext{Thromboembolic events}: Increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), especially in predisposed individuals, due to estrogen's effects on increasing coagulation factors.
ext{Myocardial infarction, stroke}: The risk is significantly heightened, particularly if the patient is over 30 years old and a smoker, due to prothrombotic and potentially pro-inflammatory effects on the cardiovascular system.
Hypertension: Can exacerbate or induce high blood pressure.
Real-world anecdote: A cautionary tale was stressed in lecture about a 31-year-old smoker on Oral Contraceptive Pills (OCPs) who suffered a fatal MI and stroke, underscoring the critical importance of patient selection and counseling regarding these risks.
Representative estrogen products (know brand↔generic)
Estradiol (a natural human estrogen) → Estrace (oral tables, transdermal patches, vaginal cream/ring)
Conjugated equine estrogens (mixture of estrogens from pregnant mare urine) → Premarin (cream & oral tablets), widely used for HRT.
Conjugated estrogens + medroxyprogesterone (combination product for women with an intact uterus) → Premphase (sequential regimen) / Prempro (continuous combined regimen).
Progesterone
Source: Primarily secreted by the corpus luteum in the ovary after ovulation, and also in smaller amounts by the adrenal cortex and, during pregnancy, by the placenta.
Actions:
Transforms the proliferative endometrium (stimulated by estrogen) into a secretory endometrium, making it receptive for embryo implantation and providing initial nourishment.
It also increases basal body temperature, thickens cervical mucus (making it less penetrable by sperm), and inhibits uterine contractions.
If fertilization and implantation do not occur (fail-to-implant scenario), the corpus luteum degenerates, leading to a sharp drop in progesterone levels, which triggers the shedding of the uterine lining (menstruation).
Synthetic progestins – clinical uses:
Treat amenorrhea / irregular cycles: Can induce a withdrawal bleed in women with secondary amenorrhea or regulate irregular menstrual bleeding patterns.
Part of hormone-replacement therapy (HRT): Used to oppose unopposed estrogen in women with an intact uterus, significantly reducing the risk of endometrial hyperplasia and cancer.
Adjunct/palliative therapy in metastatic endometrial or breast cancer: High doses of progestins can have an anti-estrogenic effect or direct cytotoxic effects on some hormone-sensitive cancers.
Megestrol acetate (Megace) is a potent synthetic progestin used for this purpose.
Megestrol acetate (Megace) also demonstrates significant appetite-boosting effects, making it valuable in managing AIDS-related or cancer-related cachexia (wasting syndrome).
Key drug list:
Medroxyprogesterone → Provera (oral tablets for cycle regulation/HRT) / Depo-Provera (long-acting injectable for contraception).
Levonorgestrel (a potent synthetic progestin, widely used in various contraceptive formulations) → e.g., various Intrauterine Devices (IUDs), Plan-B emergency contraception.
Contraceptive Agents
Combined Estrogen + Progestin OCPs
Mechanism: Primarily inhibit ovulation by suppressing FSH and LH release, preventing follicular development and egg release. They also thicken cervical mucus (impeding sperm transport) and alter the endometrial lining (making it less receptive to implantation).
Effectiveness: Highly effective when used consistently and correctly.
Risks: Carry estrogen-related risks, including increased risk of thromboembolic events, cardiovascular issues, and hypertension, especially in higher-risk individuals.
Examples: Triphasic combinations (which provide varying hormone doses across the cycle to mimic natural fluctuations and reduce total hormone exposure) or monophasic pills (constant dose).
Progestin-Only Methods
Indications:
Preferred for women with contraindications to estrogen, such as a history of breast cancer, migraines with aura, or a history of thromboembolic disorders.
Also suitable for breastfeeding mothers as estrogen can reduce milk supply.
Forms:
Pills (“mini-pill”): Contain only progestin; must be taken at the exact same time every day for maximum efficacy, as they primarily work by thickening cervical mucus and altering the endometrium, with ovulation inhibition being less consistent than combined OCPs.
Depo-Provera (medroxyprogesterone acetate): An intramuscular injection administered every 12 weeks. It provides highly effective contraception but its duration of use is generally limited (e.g., 2 years) due to a risk of significant bone-density loss, which is largely reversible upon discontinuation but can be concerning for long-term health.
Levonorgestrel IUD (Mirena, Liletta, Skyla, Kyleena): A small, T-shaped device inserted into the uterus, releasing levonorgestrel directly into the uterine cavity. Provides effective contraception for up to 3-5 years, depending on the specific product. Primarily works by thickening cervical mucus and thinning the uterine lining.
Risks associated with IUDs: Though rare, potential risks include expulsion of the device, uterine perforation during insertion, pelvic inflammatory disease (especially in the first few weeks post-insertion), and a very rare risk of ectopic pregnancy if conception occurs with the IUD in situ.
General contraindications / caution for all hormonal contraception
Absolute contraindications: History of or current thrombophlebitis, thromboembolic disorders (DVT/PE), cerebrovascular disease, coronary artery disease.
Smoking: Particularly strong contraindication for women over 35 years old who smoke ext{>= 15} cigarettes/day due to significantly elevated risk of myocardial infarction and stroke.
Extensive drug-interaction list: Many medications can reduce the efficacy of hormonal contraceptives, leading to breakthrough bleeding or unintended pregnancy. These include certain pain relievers (NSAIDs, though less clinically significant than others), some antibiotics (e.g., rifampin, which induces hepatic enzymes), anticonvulsants (e.g., phenytoin, carbamazepine, also enzyme inducers), St. John’s Wort, and even high doses of Vitamin C.
Patient counseling:
Emphasize taking oral contraceptives at the same time each day for consistent hormone levels and maximum efficacy.
Advise using backup contraception (e.g., condoms) during the first cycle of OCP use and whenever interacting medications are being concurrently used, to ensure effectiveness.
Emergency (“Post-Coital”) Contraception
Purpose: A method to prevent pregnancy after unprotected sexual intercourse or contraceptive failure.
Important Note: Should NOT replace regular, consistent contraception as it is less effective than routine methods and has more side effects if used frequently.
Timing: Must be used within 72 hours (ideally as soon as possible) of unprotected intercourse for optimal effectiveness; efficacy significantly decreases after this window.
Plan B One-Step (single ext{1.5 mg} levonorgestrel): An over-the-counter (OTC) option available without a prescription or age restriction. Works primarily by delaying or inhibiting ovulation.
Next Choice (two ext{0.75 mg} tablets; ext{T}_{0} then ext{+12 h}): Similar levonorgestrel regimen, also OTC, but split into two doses.
Ulipristal acetate (Ella): A selective progesterone receptor modulator. It is a prescription-only medication and can be effective up to 120 hours (5 days) after unprotected intercourse. It works by delaying or inhibiting ovulation even closer to the expected time of ovulation than levonorgestrel, and may also impair implantation.
Mechanism: These agents primarily work by inhibiting or delaying ovulation. They can also affect sperm and egg transport and may impair implantation by altering the endometrium, though they are not effective if implantation has already occurred.
ADRs: Common self-limited side effects include nausea, vomiting, headache, and breast tenderness. Taking with food or an antiemetic can help manage nausea.
Drugs for Labor & Delivery
Oxytocin (Pitocin)
Classification: A synthetic peptide hormone identical to natural oxytocin, produced in the hypothalamus and released from the posterior pituitary.
Actions: Potently stimulates uterine contractions by acting on specific oxytocin receptors in the myometrium and facilitates milk let-down during breastfeeding.
Indications:
Uterine inertia / induction of labor: Administered intravenously to initiate or augment labor when contractions are weak or ineffective.
Post-partum uterine atony: Used immediately after birth to prevent or treat postpartum hemorrhage by promoting sustained uterine contractions that compress blood vessels.
Care: Requires continuous fetal monitoring to detect signs of fetal distress due to potential uterine hyper-stimulation (contractions that are too strong or too frequent), which can reduce blood flow to the fetus.
Prostaglandins for Cervical Ripening & Abortions
Mechanism: Prostaglandins promote cervical ripening (softening and effacement of the cervix) by stimulating collagen breakdown and increasing water content in the cervical tissue. They also stimulate uterine contractions.
Dinoprostone (PGE₂): Administered as a vaginal gel or insert.
Indications: Used to soften and prepare the cervix prior to labor induction, especially when the cervix is unfavorable. It is also utilized for second-trimester therapeutic abortion to expel uterine contents.
Ergot Alkaloids
Methylergonovine (Methergine):
Mechanism: Directly stimulates uterine smooth muscle, causing rapid, sustained tetanic contractions which significantly reduce uterine bleeding.
Indications: Primarily used to prevent or treat postpartum or post-abortion hemorrhage, particularly when uterine atony is the cause.
Care: Essential to monitor blood pressure closely as methylergonovine has vasoconstrictive properties that can lead to hypertension, especially in patients with preeclampsia or underlying cardiovascular disease.
Medical Abortion Mention (brief)
The standard medical abortion regimen involves a combination of Mifepristone (an anti-progestin that blocks the action of progesterone, leading to breakdown of the uterine lining) followed by misoprostol (a prostaglandin analog that causes uterine contractions and cervical softening). Lecture only cursorily referenced this combination.
Pre-Term Labor Management (Tocolytics)
Purpose: Tocolytic agents are drugs used to suppress uterine contractions in women experiencing premature labor, aiming to delay delivery.
β-Adrenergic Tocolytic – Terbutaline
Classification: Originally known as a bronchodilator (beta-2 adrenergic agonist) for asthma, it has significant effects on uterine smooth muscle due to the presence of beta-2 receptors.
Mechanism: By stimulating beta-2 adrenergic receptors in the uterine smooth muscle, terbutaline causes relaxation, thereby inhibiting contractions.
Goals: The primary goal is to delay delivery for at least 48 hours, which allows time for the administration of corticosteroids (e.g., betamethasone or dexamethasone) to the mother. These corticosteroids accelerate fetal lung maturation, significantly reducing the incidence and severity of respiratory distress syndrome (RDS) in the newborn.
Maternal ADRs: Common side effects include nervousness, tachycardia (maternal heart rate often ext{>120 bpm}), tremor, headache, and hyperglycemia due to systemic beta-2 effects.
Fetal ADRs: Can cause increased fetal heart rate (often ext{>180 bpm}) indirectly due to maternal tachycardia, and potential hyperbilirubinemia postpartum.
Lecturer’s anecdote: A personal account of using terbutaline at 22 weeks gestation led to neonatal jaundice requiring prolonged phototherapy, but successfully achieved good lung maturity, ultimately avoiding the NICU, highlighting the benefits of delaying delivery despite side effects.
Preeclampsia / Eclampsia
Preeclampsia: A serious hypertensive disorder of pregnancy diagnosed by a triad of symptoms: elevated blood pressure ( ext{BP > 140/90 mmHg} or a significant increase from baseline) occurring after 20 weeks gestation, accompanied by proteinuria, and often generalized edema. It is thought to be caused by placental dysfunction leading to widespread maternal endothelial cell dysfunction and vasospasm.
Eclampsia: Defined as the progression of preeclampsia to generalized tonic-clonic seizures, representing a severe and life-threatening medical emergency for both mother and fetus.
Magnesium Sulfate (IV)
Mechanism: Administered intravenously, Magnesium Sulfate acts as a central nervous system (CNS) depressant. It works by blocking NMDA receptors, reducing acetylcholine release at the neuromuscular junction, and depressing cortical irritability, thereby preventing and controlling eclamptic seizures without sedating the mother or fetus acutely.
Monitoring: Close monitoring is crucial, including deep tendon reflexes (e.g., patellar reflex, absence indicates toxicity), respiratory rate (respiratory depression is a serious sign of overdose), and serum Magnesium²⁺ levels (therapeutic range is typically ext{4-7 mEq/L}). Calcium gluconate is the antidote for magnesium toxicity.
ADRs: Overdose or excessive levels can lead to severe side effects such as flaccid paralysis (loss of muscle tone and reflexes), profound CNS depression (somnolence, coma), and respiratory arrest.
Other Hormonal/Antineoplastic Therapy
GnRH Analog – Leuprolide (Lupron, Lupron Depot, Eligard)
Mechanism: Gonadotropin-Releasing Hormone (GnRH) analogs like leuprolide initially stimulate LH and FSH release (
Androgens
Uses replacement in cases of diminished testicular hormone
Congenital Hypogonadism- delayed puberty in the male. Depotestosterone is used to treat hypogonadism
Acquired Hypogonadism- orchitis, trauma, tumor, radiation, surgery of the testicles, or drug induced
Palliative treatment of females with advanced metastatic carcinoma of the the breast, for example, Methyltestosterone( acting as an antiestrogen)
Treatment of endometriosis and fibrocystic breast disease
Interactions- oral anticoagulants may cause bleeding
Danazol/ Danocrine- used for endometriosis
Erectile Dysfunction
Cialis is used for ED
Phosphodiesterase PDE Inhibitors
Side effects- vision abnormalities
Precautions or contraindications- Nitrates or alpha- Blockers ( flomax, Cardura) potentiates the hypotensive effects if used concurrently
Sildenafil/ Viagra
Tadalafil/ Cialis
Estrogen
Side effects- increased risk of thromboembolic disorders, hypertension, myocardial infarction, and stroke
Progestins
Used- Megace- is also used for anorexia, weight loss, and cache is associated with acquired immunodeficiency syndrome (AIDS)
Estradio/ Estrace
Conjugated estrogens/ Premarin used for menopause symptoms
Medroxyprogesterone/ Provera Depo Provera
Conjugated estrogens/ Medroxyprogesterone is generic for Premphase and Prempro
Contraceptive Agents
Precautions- thrombophlebitis or thromboembolic disorder or history thereof
Used with caution in women over 35 and currently smoking 15 or more cigarettes a day
Interactions- many drugs interact with oral contraceptives and alter the effectiveness, including pain relievers, alcohol, anticoagulants, antidepressants, tranquilizers, or barbiturates, corticosteroids, rifampin, antiretroviral, asthma drugs, beta blockers, anticonvulsants, oral hypoglycemic drugs, St. John’s wart, vitamin C
Side effects- Deep Vein Thrombosis
Using backup contraceptives when taking other medications that may alter effectiveness
Estrogen Progestin Contraceptives
Triphasic contains three sequences of progestin doses and less than 50 mcg estrogen
Progestin only contraceptives
These preparations are recommended for patients who do not tolerate estrogen or whom it is contraindicated
Progestin Containing Intrauterine Device
Mirena- five years of continuous contraception protection
Postcoital Contraception
Morning after pill
Should not be used as regular method of birth control not as effective as others
Women on certain estrogen progestin contraceptives can take a high dose of their regular pill for use as emergency contraceptives within 72H of unprotected sex
Next choice is a emergency contraceptives
Ulipristal acetate/ Ella- needs a prescription not intended for more than one use per unprotected sex per menstrual cycle
BCP Contraceptive
Yasmin
Take with evening meal or same time every day
Oxytocin
Oxytocin/ piloting
Uterine inertia occurs- the uterus is not contracting enough to deliver the baby so they would give oxytocin to help contractions along
Prostaglandins
Uses- dinoprostone intravaginal gel or vaginal insert include cervical ripening
Dinoprostone vaginal Suppositories- therapeutic abortion in the second trimester beyond the 12th week
Methylergonovine
Side effects- nausea and vomiting
Terbutaline
Used with careful monitoring in the management of preterm labor- inhibits uterine contractions by smooth muscle relaxation
Side effects- hyperglycemia, fetal tachycardia
Magnesium Sulfate
Preeclampsia is characterized by new onset hypertension, edema, and proteinuria during pregnancy. Patients become eclamptic when they develop new onset grand mal seizures in the presence of preeclampsia and require immediate medical intervention.
Magnesium sulfa prevent and control of seizures- CNS Depressant
Side effects- flaccid paralysis and CNS depressant
Other gonadtropic Drugs
Lupron has been used as an antineoplastic agent to inhibit the growth of hormone dependent tumors
Management of endometriosis
Leuprolide acetate/ Lupron Depot Eligard