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Reproductive Phamacology Study Notes

Reproductive Pharmacology

  • Lecturer: A/Prof Lindsay Wu, PhD

  • Affiliation: School of Biomedical Sciences, UNSW

  • Contact: lindsay.wu@unsw.edu.au (Use “BDG-A” in the subject line)

  • Lab head at the Laboratory for Ageing Research, School of Biomedical Sciences, UNSW.

  • Background in molecular biology, metabolic disease, and the biochemistry of ageing.

  • Focus on age-related female infertility.

  • Former Cancer Institute NSW Early Career Fellow and NHMRC RD Wright Biomedical Fellow.

  • Current American Federation for Aging Research (AFAR) / Hevolution Investigator (2023-2025).

Lecture Foundations

This lecture builds upon topics covered in Pharmacology 3, including:

  • Receptors (Nuclear Receptors, GPCRs)

  • Cell Signalling

  • Adrenergic Mechanisms (α1-adrenoceptor antagonists, β2-adrenergic receptor agonists)

  • Physiology of male and female reproduction

  • Fertilization and implantation

  • Initiation of labor at term and before term

Learning Objectives

By the end of this lecture, students should be able to:

  • Describe the mechanism of action of estrogens and progestins in oral contraceptive pills.

  • Identify side effects of hormonal contraceptives.

  • Identify contraindications and disease risks for combination oral contraceptives.

  • Describe the mechanism of action of drugs used to treat infertility.

  • Describe the mechanism of action of drugs used to modulate uterine contraction.

  • Describe the mechanism of action, side effects, and contraindications of sildenafil in treating erectile dysfunction.

Recap: Ovarian Biology 101

  • Ovaries have both reproductive and endocrine roles.

  • They contain oocytes (egg cells) surrounded by protective cells, forming the follicle.

  • The ovarian follicle reserve is established during in utero development; no new oocytes are generated after birth.

  • Females are born with a finite, non-renewable reserve of oocytes.

  • Oocytes remain in a dormant stage, the primordial follicle, for decades.

  • Each month, a small fraction of oocytes are mobilized as part of a wave of follicles that enters folliculogenesis (follicle growth and maturation).

  • These mature through primary and secondary follicles into a large, dominant antral (or pre-ovulatory) follicle.

  • Most follicles (thousands) are lost in follicle atresia; only one is ovulated per cycle.

  • Following ovulation, the remaining follicle cells form the corpus luteum, which releases progesterone.

Recap: HPO Axis

  1. Gonadotropin-releasing hormone (GnRH) is released from the hypothalamus and binds to receptors in the pituitary gland.

  2. GnRH signaling triggers the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

  3. FSH stimulates the growth of a dominant follicle.

  4. The growing follicle produces estradiol (E2).

  5. Circulating E2 suppresses GnRH, FSH release (negative feedback).

  6. An LH surge triggers ovulation (oocyte release).

  7. After ovulation, the follicle stops producing estrogen, and the remaining cells (corpora lutea) produce progesterone (luteinisation).

  8. Progesterone inhibits GnRH, FSH, and LH release (luteal phase).

  9. The corpus luteum degrades into corpus albicans (fibrous scar tissue) and stops producing progesterone.

  10. Absence of E2 and progesterone removes inhibition on GnRH, FSH, and LH, restarting the cycle.

  11. E2 and progesterone promote endometrial lining thickening; their decline leads to endometrial shedding and bleeding (menstruation).

Phases of the Menstrual Cycle

  • Menstruation: Both E2 and progesterone are low, causing endometrial lining shedding.

  • Follicular Phase: Rising E2 from the growing follicle inhibits GnRH and FSH.

Ovulation: An LH surge promotes oocyte release.

LH surge promotes Oocyte release:

The LH (luteinizing hormone) surge triggers a cascade of events that lead to oocyte release (ovulation). Here's a more in-depth explanation:

  1. Resumption of Meiosis: The oocyte is arrested in prophase I of meiosis. The LH surge triggers the oocyte to resume meiosis, progressing to metaphase II. This maturation step is essential for fertilization.

  2. Cumulus Expansion: The cumulus cells surrounding the oocyte undergo expansion, becoming sticky and facilitating oocyte capture by the fimbriae of the fallopian tube.

  3. Prostaglandin Production: LH surge stimulates the production of prostaglandins within the follicle. Prostaglandins mediate local inflammation and are crucial for ovulation.

  4. Proteolytic Enzyme Release: The LH surge induces the release of proteolytic enzymes (e.g., collagenases) that weaken the follicular wall. This enzymatic degradation is necessary for the oocyte to break free.

  5. Vascular Changes: The LH surge promotes angiogenesis and increases blood flow to the dominant follicle. This vascular remodeling is essential for follicular rupture.

  6. Follicular Rupture: The combined effects of weakened follicular wall, increased pressure, and muscular contractions lead to follicular rupture and oocyte release.

  • Luteal Phase: Low estrogen levels, corpus luteum releases progesterone, which inhibits GnRH, FSH, and LH (negative feedback).

  • The corpus luteum degenerates, progesterone decreases.

HPO Axis – Drug Interventions

  • Common scenarios:

    1. Contraception: Preventing pregnancy.

    2. Assisted Reproduction: Facilitating pregnancy.

Female Contraceptive Options

Different types of hormonal and non-hormonal contraceptive options are discussed, including combined oral contraceptive pills, progestin-only pills, vaginal rings, intramuscular injections, subcutaneous implants, and intrauterine devices (IUDs).

Combined Contraceptive Pill
  • Contains synthetic estrogen (ethinyl estradiol, EE) and a progestin (desogestrel, levonorgestrel, norethindrone, gestodene).

  • Duration: Daily oral dose for 3 weeks, followed by an inert pill for 1 week.

  • Pros: Can decrease acne, allows regular menstruation.

  • Contraindications: Breastfeeding, history/risk of thromboembolism, previous ER+ cancer, cardiovascular disease.

(ER+ cancer refers to cancer that is estrogen receptor positive. This means the cancer cells have receptors that can bind to estrogen, potentially promoting cancer growth when estrogen is present.)

  • Adverse reactions: Mastalgia (tender breasts), nausea, breakthrough bleeding, risk of venous thromboembolism, depression, hypertension.

Progestin-Only Pill (Mini-Pill)
  • Contains only a synthetic progesterone (progestin): levonorgestrel, norethindrone, drospirenone.

  • Duration: Daily oral dose, must be taken at the same time each day.

  • Pros: Can be used while breastfeeding.

  • Contraindications: History/risk of thromboembolism, pregnancy, hepatic disease.

  • Adverse reactions: Headache, acne, changes in HDL/LDL (high-density lipoprotein and low-density lipoprotein levels), breakthrough bleeding. Lowers estrogen production, but impact on bone health is unclear.

Hormonal Vaginal Ring
  • Contains etonogestrel (progestin) and ethinylestradiol for extended release.

  • Duration: Three weeks in, one week out, replace.

  • Pros: No need for daily pill, regular menstruation.

  • Contraindications & Adverse reactions: Similar to combined contraceptive pill.

Intramuscular Injection
  • Microcrystalline medroxyprogesterone.

  • Duration: 3 months.

  • Pros: Extended release, can be used while breastfeeding.

  • Contraindications & Adverse reactions: As per minipill.

Subcutaneous Implant
  • Etonogestrel (progestin).

  • Duration: 3 years.

  • Pros: Extended release, can be used while breastfeeding.

  • Contraindications & Adverse reactions: As per minipill.

Levonorgestrel IUD
  • Levonorgestrel (progestin) extended release.

  • Duration: 5 years.

  • Pros: Extended release, can be used while breastfeeding.

  • Contraindications & Adverse reactions: As per minipill.

Copper IUD
  • Releases copper, which is spermicidal and prevents fertilization.

  • Duration: 5-10 years.

  • Pros: Can also be used for emergency contraception within 5 days of unprotected sex.

  • Contraindications: Pregnancy, infections, history of heavy menstrual bleeding.

  • Adverse reactions: Heavy menstrual bleeding, risk of perforations.

Hormonal Contraceptives

The combined oral contraceptive pill contains estrogen and a progestin.

  • Exogenous estrogen mimics the follicular phase, preventing FSH and LH release: follicles don’t mature (FSH) and the oocyte is not released (LH).

  • Synthetic progestins (progesterone analogs) mimic the luteal phase, blocking GnRH release: FSH and LH are not released. Therefore, no follicle maturation or ovulation.

  • Progestin-only contraceptive pill (mini-pill) contains no estrogen.

Combined Contraceptive Pill

  • Ethinylestradiol (EE): Synthetic estradiol with improved bioavailability and half-life.

    • Mimics the follicular phase of negative feedback to the HPO axis, prevents FSH and LH release.

    • Can be used in hormone replacement therapy (HRT) for menopausal symptoms.

    • Contraindicated for hormone-sensitive breast cancer and cardiovascular disease.

    • Lowers milk production during breastfeeding.

  • Progestins: e.g., desogestrel, levonorgestrel.

    • Mimics the luteal phase of negative feedback, blocks GnRH release.

    • Contraindicated in thrombosis and unexplained bleeding.

    • Effective as a standalone contraceptive.

    • Lowers estrogen production, but the impact on bone health is unclear.

Mechanism of Action: Ethinyl Estradiol (EE)

  • Synthetic form of estradiol with improved bioavailability and half-life.

  • Indications:

    • Combination contraceptive pill with a progestin (e.g., levonorgestrel).

    • Slow-release vaginal rings.

    • Hormone replacement therapy (HRT) for menopausal symptoms.

  • Contraindications:

    • Estrogen receptor positive (ER+) breast cancer.

    • Cardiometabolic disease (type II diabetes, hypertension, heart disease).

    • Smoking.

    • History of deep vein thrombosis (DVT) or pulmonary embolism (PE).

    • Lowers milk production during breastfeeding.

  • Route of Administration: Oral, transdermal, subcutaneous injection/implant, vaginal ring/cream.

  • Adverse Effects:

    • Common: Breast tenderness (mastalgia), nausea, headaches.

    • Long-term: Increased risk of venous thromboembolism (VTE) due to hepatic production of coagulation factors.

  • Pharmacokinetic Parameters: Half-life of 18 hours under chronic dosing.

  • Chemical structures of ethinylestradiol (EE) and estradiol (E2) are shown.

Mechanism of Action: Desogestrel

  • Synthetic agonist of the progesterone receptor—more potent binding than levonorgestrel.

  • Indications: Used in combination with ethinyl estradiol (EE) for the combination contraceptive pill.

  • Contraindications: History or risk of thromboembolism (genetic risks include prothrombin, Factor V Leiden mutations).

  • Route of Administration: Oral.

  • Adverse Effects: Increased risk of venous thromboembolism and pulmonary embolism, irregular menstrual bleeding, headache.

  • Pharmacokinetic Parameters: Half-life of ~24-30 hours.

  • Chemical structures of desogestrel and progesterone (P4) are shown.

Mechanism of Action: Levonorgestrel

  • Synthetic agonist of the progesterone receptor; also has weak androgen receptor agonism.

  • Indications:

    1. Combined contraceptive pill with ethinyl estradiol (EE).

    2. Stand-alone contraceptive (“mini-pill”) at 30 µg/day.

    3. Emergency contraceptive: “morning-after pill,” “Plan B”: two 750 µg doses, 12 hours apart, within 72 hours of unprotected sex (clinical guidelines emphasize speed to access emergency contraception).

  • Note: If 750 µg or 1.5 mg formulations are not easily accessed, take 25 levonorgestrel 30 µg tablets twice, 12 hours apart.

  • Contraindications: History or risk of thromboembolism (genetic risks include prothrombin, Factor V Leiden mutations).

  • Route of Administration: As prophylactic – oral, slow-release subcutaneous implant, or intrauterine device. As post-coital emergency contraceptive: oral.

  • Adverse Effects:

    • Chronic use as a contraceptive: increased risk of venous thromboembolism, pulmonary embolism, irregular menstrual bleeding, headache.

    • Acute, high doses as a postcoital emergency contraceptive: nausea, vomiting, mastalgia.

  • Pharmacokinetic Parameters: Half-life ~24-26 hours.

Key Risk of Oral Contraceptives: Increased Risk of Thromboembolism

  • Levonorgestrel, noresthisterone: ~5-fold increase in risk.

  • Gestodene, desogestrel: ~8-fold increase in risk.

  • Pregnancy: ~12-fold increase in risk.

Emergency Contraception: High Dose Levonorgestrel

  • High dose levonorgestrel (two 750 {\mu}g doses 12 hours apart or one 1.5 mg) is used as an emergency prophylactic following unprotected sex, must be taken as soon as possible (within 72 hours).

  • "Plan B" emergency contraception has been described as working via three mechanisms of action:

    • Blocking ovulation: strong evidence.

    • Thickening cervical mucus to impair sperm migration: weak to contradictory evidence.

    • Blocking embryo implantation: contradicted by evidence, consensus view is this does not occur. No longer included in consumer information guidelines.

  • Efficacy of ~80% likely due entirely to inhibition of ovulation.

Scenario 2: Make a Baby (Assisted Reproduction)

  • Most common two goals:

    1. Don’t make a baby (contraception).

    2. Make a baby (assisted reproduction, IVF).

First Line Therapy: Inhibit Estrogen Signalling

  • The first line approach to infertility is to block estrogen signalling and negative feedback to the HPO axis in the follicular phase.

  • This increases the endogenous production of GnRH, FSH, and LH: assists follicle maturation (FSH) and ovulation (LH).

  • Orally bioavailable, can conceive through having intercourse, i.e., can avoid needing oocyte pickup (OPU).

  • Must include transvaginal ultrasound monitoring to lower the risk of having more than one dominant antral follicle, which can lead to multiple births (twins etc.).

  • Two drug approaches to blocking estrogen:

    1. Selective estrogen receptor modulator (SERM) to block estrogen receptor signalling.

    2. Aromatase inhibitors to block estrogen production.

Selective Estrogen Receptor Modulators (SERMs)

  • Agents include clomiphene, tamoxifen, raloxifene.

  • Work by blocking the interaction between estrogen and the estrogen receptor to prevent estrogen signalling.

  • Antagonize ER in breast, pituitary, hypothalamus, but agonize ER in other tissues, e.g., bone.

  • Clomiphene commonly used in reproductive medicine to promote FSH, LH production.

  • Tamoxifen, raloxifene used in ER+ breast, endometrial cancer (including as long-term follow-up).

How do SERMs achieve tissue-specific actions?

  • Two forms of the estrogen receptor: ERα and Erβ: different tissue expression patterns.

  • Transcriptional activity of ERs requires dimerization: can be ERα2 homodimers, ERβ2 homodimers, ER αβ heterodimers: different combinations for different gene targets.

  • Transcriptional co-activators: tissue-specific expression.

Mechanism of Action: Clomiphene

  • Inhibition of estrogen signaling in the hypothalamus and pituitary removes negative feedback to the HPO axis during the follicular phase, resulting in increased follicle growth and maturation.

  • Indication: Ovulation induction.

  • Patient compliance is essential: must abstain from unprotected sex and have transvaginal ultrasound to verify the presence of a single dominant follicle, otherwise there is a risk of multiple pregnancies (twins, triplets), which are high-risk pregnancies.

  • Contraindications: Breastfeeding, pregnancy.

  • Route of Administration: Orally bioavailable.

  • Adverse Effects: Headaches, abnormal menstrual bleeding, hot flashes, mood changes, vaginal dryness, altered sleep, night sweats, and mastalgia. Increased risk of multiple ovulation.

  • Pharmacokinetic Parameters: Half-life of 5 days.

  • Some patients experience clomiphene resistance, respond better to letrozole.

Aromatase Inhibitors (Drug Class Notes)

  • Block estrogen production through inhibiting the enzyme CYP19A1, which converts testosterone and androstenedione into estrogen.

  • Indications:

    1. Ovulation induction: blocks estrogen-mediated negative feedback to the HPO axis, resulting in increased follicle growth and maturation.

    2. Block estrogen production in estrogen receptor-positive (ER+) cancer patients, including long-term follow-up use to lower the risk of recurrence.

    3. Treatment of gynecomastia in young girls and males (“man-boobs”).

  • Adverse Effects: Menopause-like symptoms: hot flushes, mood changes, vaginal dryness, altered sleep, night sweats.

  • Long-term follow-up to prevent recurrence in ER+ cancer results in significant osteoporosis and risk of bone fractures – must be complemented by bone anti-resorptive drugs (e.g., bisphosphonates, anti-RANKL mAb denusomab).

  • Other long-term adverse effects: increased risk of cardiovascular disease.

  • Contraindications: Pregnancy. Long-term use should be avoided in pre-menopausal patients.

  • Route of Administration: Orally bioavailable.

Mechanism of Action: Letrozole

  • Aromatase inhibitor: blocks estrogen production through inhibiting the enzyme CYP19A1.

  • Indication:

    1. Treatment and long-term follow-up of ER+ cancer to prevent recurrence.

    2. Ovulation induction: Considered a “mild” form of ovarian stimulation, can be used in PCOS patients ONLY UNDER CLOSE OBSERVATION.

  • Contraindications: Breastfeeding, pregnancy. Chronic use contraindicated prior to menopause due to impacts on bone.

  • Route of Administration: Orally bioavailable.

  • Adverse Effects: Fatigue, headaches, abnormal bleeding, hot flushes, mood changes, vaginal dryness, altered sleep, night sweats.

  • Pharmacokinetic Parameters: Half-life of 42 hours, increased to 3-4 days in breast cancer patients.

  • Letrozole and clomiphene are two competing options for an orally bioavailable drug for ovulation induction. Letrozole has a shorter half-life and is considered a “milder” option that is preferred in PCOS patients; it also has a lower risk of multiple pregnancies (twins).

Clomiphene vs Letrozole for Ovulation Induction

Characteristic

Clomiphene

Letrozole

Mechanism

Selective estrogen receptor modulator (SERM): inhibits estrogen receptor in hypothalamus and pituitary. Decreased estrogen signaling blocks

Aromatase inhibitor: blocks estrogen production. Decreased estrogen signaling blocks negative feedback in HPO axis.

Uses

First-line therapy for ovulation induction in anovulatory infertility.

First-line therapy for ovulation induction in PCOS. Seen as a “milder” form of stimulation.

Multiple Births

Higher risk of multiple births

No increase in risk of multiple births.

Pharmacokinetics

5 days

42 hours

Mode of Delivery

Orally bioavailable

Orally bioavailable

When Oral Therapy Fails: In Vitro Fertilisation (IVF)

Note: Intracytoplasmic sperm injection (ICSI) is used to address male factor infertility or poor sperm quality.

Oral Therapies Can Improve Ovulation

  • However, oocyte age is the rate-limiting factor for fertility.

  • The existing solution is to increase throughput by obtaining many oocytes from hormonal stimulation, hoping that at least one works.

  • The key is to obtain good-quality blastocysts, which relies on young oocytes.

  • What matters is the age of the oocyte, not the age of the uterus!

When Oral Therapy Fails: In Vitro Fertilisation (IVF)

Humans normally only ovulate one oocyte, how do we increase the number of oocytes available for IVF?

  • The per-oocyte success rate is low, so it relies heavily on collecting multiple oocytes for subsequent fertilization.

Hormonal Stimulation for IVF

  • Reminder: GnRH promotes:

    • FSH, which leads to follicle growth.

    • LH, which leads to ovulation.

  • The goal in IVF is to have many mature eggs, but NOT for them to be ovulated: they need to remain in place for collection (a.k.a. oocyte pickup, OPU).

How to achieve one without the other?

  1. GnRH antagonist blocks endogenous production of both FSH and LH: prevent ovulation from the LH surge.

  2. Recombinant FSH is used to promote the growth of multiple follicles, due to inhibition of endogenous FSH production.

  3. Ultrasound is used to monitor the number of antral follicles available.

  4. When ready, the patient receives human chorionic gonadotropin (hCG): replacement for LH. This “hCG trigger” must be precisely timed and administered when there is a dominant follicle (confirmed by ultrasound) and when it is convenient to schedule an oocyte pickup (OPU).

  5. Precisely 34-36 hours later, oocytes retrieved just prior to release.

    • Too early: oocyte not yet completed meiosis II.

    • Too late: oocyte is ovulated, cannot be picked up by the clinician.

Common IVF Stimulation Protocol

A timeline is provided illustrating the hormonal stimulation protocol, including menstruation, follicular phase, gonadotropins (FSH), GnRH antagonists, ovulation induction (hCG), and puncture.

GnRH Antagonists

  • Delivered to block GnRH signalling in the pituitary, blocking FSH and LH secretion.

  • Commonly used during IVF to block the endogenous LH surge during IVF.

Mechanism of Action: GnRH Antagonists

  • Inhibits gonadotrophin-releasing hormone (GnRH) receptor in the pituitary, preventing FSH and LH production.

  • Delivered in combination with recombinant FSH to replace the downregulation of endogenous FSH.

  • Indications: Used in IVF to block the endogenous LH surge, preserving the dominant follicle for the timed hCG trigger and oocyte pickup (OPU).

  • Contraindications: Pregnancy, breastfeeding.

  • Route of Administration: Subcutaneous injection.

  • Adverse Effects: Chronic use in adolescents impairs bone formation.

  • Pharmacokinetic Parameters: Cetrorelix half-life is 30 hours; ganirelix half-life is 13 hours.

Mechanism of Action: GnRH Agonists

  • Chronically activate gonadotrophin-releasing hormone (GnRH) receptor in the pituitary, leading to long-term receptor down-regulation and preventing FSH and LH production.

  • Indications:

    • Used in IVF to block the endogenous LH surge, preserving the dominant follicle for the timed hCG trigger and oocyte pickup (OPU).

    • Approved for treating precocious puberty; however, it results in a significant loss in bone density (potentially irreversible).

    • Used off-label as a “puberty blocker” for transgender care: strong deficit in long-term safety data, known impacts on bone. Recently discontinued for adolescent use in the UK.

    • Chronic use to induce chemical castration in androgen-dependent prostate cancer.

    • Chemical castration of sex offenders.

  • Contraindications: Pregnancy, breastfeeding.

  • Route of Administration: Subcutaneous injection, subcutaneous implants, nasal spray (nafarelin, buserelin).

  • Adverse Effects: Mimics hypogonadism – acute side effects include hot flushes, decreased sex drive, and fatigue. Chronic use in adolescents can impair long-term bone formation, gonad development, and sexual development.

GnRH Agonist vs Antagonists in IVF

  • Note the initial “flare” in LH from GnRH agonist treatment: due to immediate GnRH receptor activation.

  • Agonists are better suited to longer-term inhibition, where prolonged follicle growth may be required.

Mechanism of Action: Recombinant FSH

  • Recombinant version of endogenous follicle-stimulating hormone (FSH) promotes ovarian follicle growth.

  • Indications: Used to increase the number of growing follicles available for collection in IVF.

  • Contraindications: Polycystic ovarian syndrome (PCOS).

  • Route of Administration: Subcutaneous injection.

  • Adverse Effects: Headache, nausea, vomiting, bloating, and weight gain.

  • Pharmacokinetic Parameters: ~30 hours.

Historical Detour: The Origins of FSH Treatment

  • FSH treatments used in reproductive medicine today are derived from recombinant FSH protein.

  • Piero Donini discovered in the 1940s that FSH could be found in female urine and was highest after menopause (absence of E2-mediated follicular feedback).

  • Dr. Donini introduced a family member of Pope Pius XII (board member of Serono, 25% owned by the Vatican!).

  • Pope Pius XII requests that retired nuns donate urine to Serono!

  • Very low yields required ongoing collection.

  • FSH used from the 1960s-1990s derived from the urine of menopausal nuns!

  • Recombinant protein production was not invented until the 1970s; the first recombinant therapy in 1982 (insulin): FSH used today is now from recombinant sources.

  • Rebranded as “Gonal-F” – still used today.

Mechanism of Action: Human Chorionic Gonadotropin (hCG)

  • Recombinant hCG protein also binds to the luteinizing hormone (LH) receptor: mimics the endogenous LH surge that triggers ovulation.

  • Indications: Used as part of the ovarian stimulation cycle, which aims to mature and collect oocytes from multiple follicles for in vitro fertilization (IVF).

  • Delivered as a one-off injection to trigger the final stage of follicle growth and meiosis in preparation for oocyte pickup in IVF (“hCG trigger”).

  • Timing and planning are critical – once administered, oocyte pickup must occur exactly 34-36 hours later.

  • Contraindications: Polycystic ovarian syndrome (PCOS).

  • Route of Administration: One-off injection at the end of IVF.

  • Adverse Effects: Headache, bloating. Risk of ovarian hyperstimulation syndrome (OHSS) in PCOS patients.

  • Pharmacokinetic Parameters: Half-life ~2 days: longer than endogenous LH (~90 min). Used instead of LH to achieve practical dosing: required for 34-36 hours to achieve oocyte maturation prior to oocyte pickup (OPU).

Why not just use LH as a trigger? Why use hCG instead?

  • hCG and LH activate the same receptor (LHCGR).

  • LHCGR is a G-protein coupled receptor: the same receptor can signal through GSα and Gqα.

Why not just use LH as a trigger? Why use hCG instead?

  • LH has a short half-life: Oocyte maturation takes 34-36 hours, would need to dose almost hourly.

t_{1/2} LH serum half-life: ~90 min
  • hCG has a longer half-life; recombinant material is glycosylated for a one-off dose

t_{1/2} hCG serum half-life: ~2 days
  • hCG and LH interact with the same receptor

PCOS: Contraindication for Ovarian Stimulation, hCG Trigger

Polycystic ovarian syndrome (PCOS): chronically high levels of endogenous LH production, leads to androgen (male hormone) production.

  • Adding an exogenous hCG trigger to already high LH background in PCOS patients can trigger ovarian hyperstimulation syndrome (OHSS): ascites fluid accumulation, ovarian enlargement; this can be life-threatening.

  • Common condition, up to ~18% of women

    • Peripheral insulin resistance

    • Android obesity

    • Hirsutism (facial hair, chest hair)

    • Acne

    • Male pattern baldness (androgenic alopecia)

    • Menstrual disorders

    • Infertility

  • LH / hCG increase vascular permeability

Alternative to Ovarian Stimulation: In Vitro Maturation (IVM)

Rather than using FSH and hCG to trigger follicle growth and oocyte maturation, collect small, immature follicles from the ovary and mature with those hormones in vitro.

  • Slightly lower success rates for “ordinary” IVF, but does not require extensive hormone treatment.

  • Suited for patients with PCOS, endometriosis, fertility preservation prior to cancer treatment, hormone-sensitive cancers.

Treatments Used to Induce Labour

  • Oxytocin

  • Prostaglandin E2 (PGE2).

Treatments Used to Delay Pre-Term Labour (Tocolytics)

  • Salbutamol

  • Atosiban (oxytocin antagonist) - Not approved for use in Australia

Mechanism of Action: Oxytocin

Causes rhythmic uterine contractions, it has vasodilator actions and is a weak antidiuretic.

  • Indications: Induction of labour, postpartum hemorrhage.

  • Contraindication: Fetal distress.

  • Adverse Effects:

    • Hypotension → reflex tachycardia.

    • Water retention → maternal and neonatal hyponatraemia.

  • Overdose: Can lead to uterine overstimulation, which may cause foetal distress, asphyxia and death, hypertonicity, tetanic contractions, or rupture of the uterus.

  • Route of Administration: IV or IM.

Mechanism of Action: Dinoprostone (PGE2)

Plays a role in the biochemical and structural alterations involved in cervical ripening and uterine contraction.

  • Indications: Induction of labour or softening of the cervix. Softening of the cervix for induction of labour substantially shortens the time to onset of labor and the delivery time.

  • Contraindications: Oxytocin administration

  • Adverse Effects: Uterine tachysystole, fetal distress, uterine hyperstimulation.

  • Route of Administration: As a gel (0.5 mg PGE2 every 6 hours; maximum 24-hour cumulative dose of 1.5 mg) or as a controlled-release vaginal insert (10 mg PGE2) that releases PGE2 over 12 hours.

Anti-progestins/Selective Progesterone Receptor Modulators (SPRM)

Mifepristone

  • Mechanism of Action: Orally active progesterone and glucocorticoid receptor antagonist. Sensitizes the uterus to the actions of prostaglandins.

  • Indications: Medical termination of pregnancy (used in combination with a prostaglandin), Cushing's syndrome

  • Contraindications: Women receiving chronic glucocorticoid therapy

  • Route of Administration: Oral.

  • Adverse Reactions: Abdominal pain (cramping) (96%), nausea (43% to 61%), headache (2% to 31%), vomiting (18% to 26%), diarrhea (12% to 20%), dizziness (1% to 12%), fatigue (10%)

Treatment of Erectile Dysfunction: PDE5B Inhibition

Diagram illustrating the mechanism of action of PDE5B inhibitors in treating erectile dysfunction, highlighting the roles of nitric oxide, guanylyl cyclase, cGMP, and phosphodiesterase 5B in vascular smooth muscle relaxation.

Mechanism of Action: Sildenafil

Inhibits the enzyme phosphodiesterase 5B: prevents the hydrolysis of cyclic GMP into GMP, activating PKG, which blocks Ca^{2+} release and promotes arterial smooth muscle relaxation: increased blood flow, erection.

  • Indication: Erectile dysfunction in men.

  • Contraindications:

    • Any form of nitrates (e.g., nitrate glycerine, amyl nitrate) are absolutely contraindicated.

    • Should not be used by patients with low blood pressure (hypotension), recent stroke or heart attack, or hepatic failure.

    • Contraindicated for non-arteritic anterior optic neuropathy vasodilation (NAION), though the mechanism is unclear.

  • Route of Administration: Orally bioavailable.

  • Adverse Effects: Headaches, nausea, dizziness. Can cause significant reductions in blood pressure. Associated with increased incidence of NAION.

  • Pharmacokinetic Parameters: Half-life of 3-5 hours.

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