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PH7.9 | PH7.9 | Infertility Pharmacotherapy — SDL Guide — SDL Guide (Part 2)

Mechanisms, PK, and Clinical Uses of Each Drug Class

The pharmacokinetic properties of infertility drugs determine their timing relative to the menstrual cycle and their adverse effect profiles.

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Clomiphene citrate PK: Orally active; long half-life (~5–7 days for the zuclomiphene isomer); taken days 3–7 of cycle; ovulation expected 5–10 days after the last dose. The long half-life contributes to its anti-oestrogenic endometrial and cervical mucus effects throughout the cycle (negative side effects vs letrozole). Maximum 6 cycles (debated risk of ovarian cancer with longer use).

Letrozole PK: Orally active; shorter half-life (~2 days) — cleared before the implantation window. No cumulative anti-oestrogenic effect on endometrium. Days 3–7 of cycle. Ovulation 5–10 days after last dose.

Gonadotropin protocols (ART): Daily SC or IM injections. Monitoring: transvaginal ultrasound (follicle count and size every 2–3 days) + serum oestradiol levels. hCG trigger when dominant follicle ≥18 mm AND oestradiol within acceptable range. Progesterone supplementation after ovulation/egg retrieval for luteal phase support (vaginal micronised progesterone or IM progesterone). OHSS (Ovarian Hyperstimulation Syndrome): complication of gonadotropin (and clomiphene) therapy — excessive ovarian response to FSH stimulation → multiple follicle development → high oestradiol → vascular permeability increases (via VEGF) → fluid shifts from intravascular to peritoneal space. Mild (bloating, nausea, abdominal discomfort): expectant management. Severe (ascites, pleural effusion, haemoconcentration, thromboembolism, renal failure): hospitalisation, careful IV fluids, anticoagulation. Prevention: careful dose titration, ultrasound monitoring, withhold hCG trigger if OHSS risk high, use GnRH agonist trigger instead of hCG in high-risk cycles, dopamine agonists (cabergoline) reduce OHSS in high-risk patients.

Drug	Class	Mechanism	Indication	ADR
Clomiphene	SERM (anti-oestrogen)	Blocks oestrogen −ve feedback → ↑FSH/LH	PCOS anovulation, unexplained	OHSS, visual blurring, thin endometrium, multiple pregnancy
Letrozole	Aromatase inhibitor	↓ Peripheral oestrogen → ↑FSH centrally	PCOS (preferred), unexplained	OHSS (less than clomiphene), arthralgia, hot flushes
rFSH	Gonadotropin	Directly stimulates follicular development	ART, gonadotropin-resistant cases	OHSS (highest risk)
hCG	LH-like trigger	Triggers ovulation of mature follicle	ART (trigger)	OHSS risk (worsens if overstimulated)
Bromocriptine	Dopamine agonist (D2)	↓ Prolactin → restores GnRH pulsatility	Hyperprolactinaemia anovulation	Nausea, postural hypotension
Metformin	AMPK activator	↓ Insulin resistance in PCOS	PCOS (adjunct)	GI, lactic acidosis (rare)

Clinical Decision-Making: Tailoring Infertility Pharmacotherapy

Rational infertility pharmacotherapy integrates the diagnosis (which level of axis is disrupted?) with the patient's age, ovarian reserve, BMI, and access to monitoring resources.

PCOS-associated anovulatory infertility (most common clinical scenario):

Step 1: Lifestyle modification (3–6 months) — 5–10% weight loss in overweight/obese PCOS restores spontaneous ovulation in ~55% of women. Concurrent metformin 500–1500 mg/day: reduces insulin resistance, lowers androgens, may restore menstrual regularity.

Step 2: Letrozole 2.5–5 mg days 3–7 (first-line per PCOSACT trial). Monitor with ultrasound. If no dominant follicle by day 12: consider increasing to 5 mg (next cycle). If follicle ≥18 mm: administer hCG 5000–10,000 IU to trigger ovulation.

Step 3: Clomiphene 50–150 mg (second-line or where letrozole is unavailable). Monitor similarly. Combine with IUI in unexplained infertility.

Step 4: Gonadotropins (FSH injections) — for clomiphene/letrozole-resistant PCOS. Requires intensive ultrasound + oestradiol monitoring. OHSS risk highest here — start with low dose ('low-and-slow' protocol).

Step 5: IVF — for failed ovulation induction, tubal factor, severe male factor.

Hyperprolactinaemia-induced anovulation:
First-line: Cabergoline 0.5–3 mg weekly (preferred — higher efficacy, fewer ADRs, weekly dosing). Prolactin normalisation in >80% → GnRH pulsatility restored → spontaneous ovulation resumes in most women. No ovulation inducers needed in most cases. Stop cabergoline after confirmed pregnancy (safety in early pregnancy: extensive data support, but consult specialist).

Hypogonadotropic hypogonadism (female):
Pulsatile GnRH pump (SC, 60–90 min intervals) OR gonadotropin injections (FSH + LH). Goal: mono-follicular development (LH/FSH levels carefully titrated — less OHSS risk with GnRH pump).

Male infertility management:
- Hypogonadotropic hypogonadism: hCG 2500–5000 IU SC 3× weekly × 3–6 months → intratesticular testosterone rises → then add rFSH 75–150 IU SC 3× weekly → spermatogenesis. Treatment duration: 6–18 months.
- Idiopathic oligospermia: empirical clomiphene (anti-oestrogen → increases LH/FSH → increases intratesticular T → may improve sperm parameters). Evidence modest. CRITICAL: never use exogenous testosterone — it worsens spermatogenesis.
- Hyperprolactinaemia: dopamine agonist (cabergoline) → LH/FSH restored → testosterone and spermatogenesis recover.

PCOS Anovulatory Infertility: Step-wise Pharmacologic Algorithm

Self-Assessment: Infertility Pharmacology Scenarios

Consolidate your infertility pharmacology understanding with these scenarios:

Scenario A: A 28-year-old woman with PCOS has been trying to conceive for 18 months. BMI 29. She ovulates infrequently (cycles 45–60 days). AMH is elevated (PCOS marker). What is your first-line ovulation induction drug, and what monitoring is required?
Answer: Letrozole 2.5 mg days 3–7 — first-line for PCOS ovulation induction per PCOSACT trial. If no response: uptitrate to 5 mg next cycle. Monitoring: transvaginal ultrasound day 12 (dominant follicle ≥18 mm triggers hCG 10,000 IU); mid-luteal progesterone to confirm ovulation. Offer metformin concurrently (500 mg BD increasing to 1500 mg/day) if BMI >27 or insulin resistance markers present. Lifestyle modification counselling — 5% weight loss may itself restore ovulation.

Scenario B: A 34-year-old woman has oligomenorrhoea, galactorrhoea, and serum prolactin of 142 ng/mL (normal <25 ng/mL). MRI shows a microprolactinoma. She wants to conceive. What do you prescribe?
Answer: Cabergoline 0.5 mg twice weekly — first-line for prolactinoma and hyperprolactinaemia-induced anovulation. Cabergoline is preferred over bromocriptine (higher prolactin normalisation rate, weekly dosing, fewer ADRs). Prolactin should normalise within 4–8 weeks → menstrual cycles restored → spontaneous ovulation returns in most patients. Additional ovulation inducers (letrozole/clomiphene) are usually NOT needed once prolactin is normalised. Monitor: monthly prolactin until normal, then 6-monthly; annual MRI for tumour response. Once pregnant, cabergoline is typically stopped (specialist decision).