Infertility Therapy Drugs: Letrozole, Clomiphene, Gonadotropins, hCG & Male Infertility

Learning objectives

• Define infertility and organise the initial evaluation before prescribing an ovulation-inducing drug.
• Explain the hypothalamic–pituitary–ovarian and hypothalamic–pituitary–testicular axes, including the roles of FSH, LH, hCG and GnRH.
• Compare letrozole, clomiphene, tamoxifen, metformin, gonadotropins, hCG, GnRH agonists/antagonists, dopamine agonists and luteal progesterone.
• Use safe, monitored treatment pathways for PCOS, hypogonadotropic hypogonadism, hyperprolactinaemia and assisted reproduction.
• Recognise ovarian hyperstimulation syndrome (OHSS), ovarian torsion, ectopic pregnancy, multiple gestation, thromboembolism and other emergencies.
• Distinguish treatments that improve fertility from treatments that only improve sexual performance, and identify outdated or unsafe practices in the supplied slide deck.

1. Definitions and the treatment principle

Infertility is failure to achieve pregnancy after 12 months of regular unprotected intercourse. Earlier assessment is appropriate when the woman is older, cycles are absent or very irregular, there is suspected tubal or uterine disease, prior pelvic infection or chemotherapy, or a known male-factor problem. “Sterility” means an absolute inability to conceive; impotence (erectile dysfunction) is inability to achieve or maintain an erection and is not synonymous with infertility.

Drugs cannot overcome every cause. First identify and correct reversible disease: thyroid dysfunction, hyperprolactinaemia, diabetes, undernutrition or obesity, pelvic infection, tuberculosis where relevant, medication effects, an obstructed tube, severe endometriosis, large fibroids, or an obstructive/absent sperm pathway. Treat both partners at the same time.

2. Initial evaluation before medication

Domain	Core assessment	Why it changes treatment
Ovulation	Cycle history, menstrual pattern, mid-luteal progesterone where appropriate, thyroid-stimulating hormone and prolactin when indicated.	Anovulation may respond to letrozole, clomiphene, gonadotropin or treatment of hyperprolactinaemia; ovarian failure will not respond to routine ovulation induction.
Ovaries/reserve	Transvaginal ultrasound, antral follicle count and, when useful, AMH; assess ovarian cysts and baseline follicles.	Predicts response and OHSS risk; an ovarian cyst must not be mistaken for a follicle.
Uterus and tubes	Pelvic ultrasound; hysterosalpingography or sonohysterography to assess tubal patency and uterine cavity.	Ovulation induction alone is futile if both tubes are blocked or the uterine cavity cannot support implantation.
Male partner	At least one semen analysis, repeated if abnormal; history and examination for varicocele, testicular size, infection, drugs and exogenous testosterone.	Severe male factor may require sperm retrieval with ICSI rather than escalating female ovulation drugs.
Preconception safety	Pregnancy test before each treatment cycle; folic acid, blood pressure, BMI, vaccination and control of diabetes, thyroid disease and hypertension.	Letrozole, clomiphene, gonadotropins and hCG are not continued after pregnancy is established unless a specialist has a specific reason.

3. Physiology and pharmacological targets

Hormone/target	Main action	Drug examples
GnRH (hypothalamus)	Pulsatile GnRH stimulates pituitary FSH/LH. Continuous exposure desensitises GnRH receptors and suppresses FSH/LH.	Pulsatile GnRH for hypothalamic amenorrhoea; continuous agonists such as leuprolide for pituitary suppression in IVF.
FSH	Stimulates granulosa-cell proliferation, aromatase activity and follicular growth; in men supports Sertoli cells and spermatogenesis.	Follitropin alfa/beta, urofollitropin, menotropins (hMG).
LH	Stimulates theca-cell androgen production, ovulation and corpus-luteum function; in men stimulates Leydig-cell testosterone.	Lutropin alfa, hCG (an LH analogue), endogenous LH surge.
Estrogen feedback	Normally suppresses hypothalamic GnRH and pituitary FSH/LH; blocking its receptor or synthesis releases gonadotropins.	Clomiphene (SERM), letrozole (aromatase inhibitor), tamoxifen (SERM).
Prolactin	Excess prolactin suppresses GnRH and causes anovulation, amenorrhoea, galactorrhoea and hypogonadism.	Bromocriptine, cabergoline, quinagolide.
Progesterone	Transforms endometrium and supports early implantation and pregnancy; luteal support is protocol-dependent.	Micronised vaginal/oral progesterone, IM progesterone; hCG supports the corpus luteum but increases OHSS risk.

4. Oral ovulation-inducing medicines

4.1 Letrozole

Mechanism: reversible aromatase inhibition lowers ovarian and peripheral estrogen synthesis. Reduced negative feedback increases hypothalamic GnRH and pituitary FSH/LH, allowing a dominant follicle to develop. Its short half-life and minimal anti-estrogenic effect on endometrium and cervical mucus are advantages over clomiphene.

Preferred use: current PCOS guidance places letrozole first-line for anovulatory infertility due to PCOS when no other infertility factor is present. It is commonly used off-label for ovulation induction; the breast-cancer label is not the fertility indication.

Example regimen	Practical notes
2.5 mg orally once daily for 5 days, commonly cycle days 2–6, 3–7 or 5–9.	Confirm no pregnancy and use ultrasound or ovulation evidence where available.
If no ovulation, 5 mg once daily for 5 days in a later cycle.	Increase only after reviewing response and excluding a cyst or other cause.
Maximum commonly used protocol: 7.5 mg once daily for 5 days.	Do not continue indefinitely; reassess diagnosis and move to monitored gonadotropin/IUI or IVF pathways when appropriate.

Adverse effects: headache, fatigue, dizziness, nausea, hot flushes, arthralgia and transient mood change. Multiple pregnancy and OHSS are less common than with gonadotropins but remain possible. Early pregnancy exposure is avoided; perform a pregnancy test if a period is late.

Contraindications/precautions: pregnancy, severe hepatic impairment, unexplained ovarian cyst or mass, uncontrolled endocrine disease and hypersensitivity. Counsel about off-label status and local availability. Avoid combining with clomiphene in routine practice unless a fertility specialist has a specific protocol.

4.2 Clomiphene citrate (clomifene)

Mechanism: a non-steroidal SERM that occupies estrogen receptors in the hypothalamus and pituitary. The brain interprets this as low estrogen, increasing GnRH, FSH and LH; the ovary then develops one or more follicles. It has a long terminal half-life and active metabolites, so anti-estrogenic effects can persist.

Use/dose	Safety and monitoring
Initial: 50 mg orally once daily for 5 days, usually beginning around day 2–5 of a spontaneous or progestin-induced bleed.	Exclude pregnancy, ovarian cyst/enlargement (unless typical PCOS), thyroid/adrenal disease and severe male factor first.
If no ovulation: 100 mg once daily for 5 days in the next cycle.	Higher doses do not reliably improve pregnancy and increase adverse effects; specialist protocols sometimes use 150 mg, but it is not a routine self-escalation dose.
Assess ovulation by mid-luteal progesterone, ovulation predictor or ultrasound.	Stop and investigate if visual symptoms, severe pelvic pain or marked ovarian enlargement occurs.

Indications: anovulatory infertility, including selected PCOS, hypothalamic–pituitary dysfunction with adequate ovarian reserve, and selected amenorrhoea–galactorrhoea syndromes after the cause is addressed. It is not useful for tubal blockage, primary ovarian insufficiency or severe untreated male-factor infertility.

Adverse effects: hot flushes, headache, nausea, breast discomfort, mood change, visual blurring/scotomata, ovarian enlargement, ovarian cysts, OHSS and multiple gestation. Anti-estrogenic effects may thin endometrium and reduce cervical mucus. Rare visual symptoms can be persistent; stop immediately and refer. Ovarian cancer risk has been debated; avoid prolonged or repeated courses outside specialist supervision.

Contraindications: pregnancy, liver disease or previous liver dysfunction, uncontrolled thyroid/adrenal disease, abnormal uterine bleeding not yet evaluated, ovarian cyst/enlargement not due to PCOS, and hypersensitivity. Avoid use beyond the product’s recommended cumulative cycles; if ovulation occurs repeatedly without conception, reassess the couple rather than simply continuing.

4.3 Tamoxifen

Tamoxifen is another SERM. It blocks hypothalamic estrogen feedback but may have a more favourable effect on cervical mucus and endometrium in some patients. It is an alternative when clomiphene is unsuitable or in selected specialist protocols; it is not first-line in current PCOS guidance.

Example fertility protocols from older teaching material: 20–40 mg orally once daily for 5 days. Doses such as 40–80 mg have been studied, but higher doses are not routine and should not be copied without specialist oversight. Nausea, hot flushes, headache, mood change, thromboembolism and visual symptoms are possible; avoid during pregnancy, in active thromboembolic disease and with interacting anticoagulants unless a specialist directs otherwise.

4.4 Metformin and insulin-sensitising therapy in PCOS

Metformin reduces hepatic gluconeogenesis and improves insulin sensitivity. It may restore ovulation in some people with PCOS and is useful for diabetes or prediabetes, but it is less effective as an ovulation agent than letrozole. It can be used alone or as an adjunct when metabolic indications, clomiphene resistance or a specific IVF protocol justify it.

Example adult titration: 500 mg with the evening meal, increase by 500 mg every 1–2 weeks as tolerated to 1,500–2,000 mg/day in divided doses (product and renal function determine the maximum). Check eGFR, gastrointestinal tolerance, vitamin B12 with long-term use and hold during severe sepsis, hypoxia, dehydration or acute kidney injury. Avoid in severe renal impairment or severe hepatic failure because of lactic-acidosis risk.

Other older slide-deck adjuncts: N-acetylcysteine 1.2 g/day has been studied as an insulin-sensitising/mucolytic adjunct in PCOS, but evidence and regulatory status are not equivalent to established ovulation-induction therapy. Do not present it as a replacement for letrozole or monitored fertility care.

5. Injectable gonadotropins and ovulation triggers

5.1 Menotropins (hMG)

Human menopausal gonadotropin contains FSH and LH activity, traditionally 75 IU FSH + 75 IU LH per ampoule. It directly stimulates multiple follicles and is used for anovulatory infertility, hypogonadotropic hypogonadism and controlled ovarian stimulation for IVF.

• Low-dose ovulation induction: many protocols start 37.5–75 IU SC daily, increasing cautiously according to follicular growth and estradiol. The exact product label may use different starting doses.
• ART/IVF: one licensed example starts at 225 IU SC daily on cycle day 2 or 3, then individualises the dose; do not exceed the product-specific maximum.
• Older classroom regimen: 75 IU IM daily for about 10 days followed by hCG is historical; modern practice uses lower-dose step-up regimens and ultrasound to reduce OHSS and multiple gestation.

Monitoring: baseline ultrasound and estradiol, then serial ultrasound (often every 2–3 days during dose adjustment), follicle number/size, estradiol trend, symptoms and pregnancy risk. Do not administer hCG if there are too many follicles, rapidly rising estradiol or ovarian enlargement suggesting OHSS.

5.2 Recombinant FSH

Follitropin alfa and follitropin beta are highly purified FSH preparations given SC; urofollitropin is urinary FSH. They stimulate granulosa cells without the LH component and are often preferred for PCOS or controlled IVF stimulation.

Setting	Illustrative labelled approach
Ovulation induction	Follitropin alfa 75 IU SC daily for 14 days, then individualise; product labels commonly cap at 300 IU/day for this indication.
ART/IVF multiple-follicle development	One labelled regimen starts 150 IU SC daily, adjusts by 75–150 IU after 3–5 days and caps at 450 IU/day; individual products differ.
Male hypogonadotropic hypogonadism	Use only with hCG after restoring intratesticular testosterone; protocols often use FSH 75–150 IU SC two or three times weekly for several months, guided by semen analysis.

Adverse effects: injection-site pain, headache, mood change, breast symptoms, ovarian enlargement, OHSS, thromboembolism and multiple pregnancy. Hypersensitivity to urinary proteins is possible. Contraindications include pregnancy, uncontrolled thyroid/adrenal disease, ovarian/testicular or uterine tumour, unexplained genital bleeding, primary ovarian failure and tumours of the hypothalamus/pituitary.

5.3 Human chorionic gonadotropin (hCG) and recombinant hCG

hCG binds LH/hCG receptors. In women it triggers final follicular maturation and ovulation approximately 36 hours later; in men it stimulates Leydig-cell testosterone. Products include urinary hCG 5,000–10,000 IU and recombinant choriogonadotropin alfa (commonly 250 micrograms SC).

• Female ovulation trigger: 5,000–10,000 IU IM/SC after adequate follicular development, or 250 micrograms recombinant hCG in an appropriate ART protocol. Timed intercourse or IUI is usually planned around the expected ovulation.
• Male hypogonadotropic hypogonadism: commonly 1,000–2,500 IU IM/SC two or three times weekly, or another specialist regimen; add FSH/hMG after testosterone has risen if spermatogenesis is required.
• Do not trigger: if estradiol/ultrasound suggests high OHSS risk, or if there are too many mature follicles and unacceptable multiple-pregnancy risk.

Adverse effects: OHSS, ovarian enlargement, abdominal pain, ascites, thromboembolism, headache, oedema, gynaecomastia, mood change and precocious puberty in children. hCG can remain detectable and cause a false-positive pregnancy test for about 10 days.

6. GnRH agonists, antagonists and pulsatile GnRH

6.1 Continuous GnRH agonists

Leuprolide, buserelin, nafarelin and triptorelin initially cause a flare of FSH/LH, followed by receptor down-regulation and profound suppression. In IVF they prevent an untimely LH surge; they are also used for endometriosis, fibroids and hormone-dependent cancers. The supplied deck lists examples such as leuprolide 1 mg SC daily, buserelin 40 micrograms/kg/day or 1 mg SC daily, nafarelin 200–400 micrograms intranasally twice daily and depot triptorelin formulations. Exact products and doses vary.

Adverse effects: hot flushes, vaginal dryness, reduced libido, headache, mood change, bone loss and initial flare pain/bleeding. Prolonged use may require add-back therapy. Contraindications/precautions include pregnancy, severe osteoporosis risk and hypersensitivity. In IVF, monitor ovarian response and never confuse pituitary suppression with ovarian stimulation.

6.2 GnRH antagonists

Ganirelix and cetrorelix competitively block GnRH receptors immediately, suppressing LH/FSH without the agonist flare. They are used in flexible or fixed antagonist IVF protocols to prevent premature LH surges. Typical labelled examples are ganirelix 250 micrograms SC once daily after FSH begins and cetrorelix 0.25 mg SC once daily; a 3 mg cetrorelix single-dose regimen may cover about four days. They must be used by fertility teams that monitor follicles and administer the trigger at the correct time.

Adverse effects: injection-site reactions, headache, nausea and rare immediate hypersensitivity/anaphylactoid reactions. Stop and treat urgently if wheeze, angio-oedema or hypotension occurs. An antagonist prevents an LH surge but does not mature follicles by itself.

6.3 Pulsatile GnRH

Physiological pulsatile GnRH can restore FSH/LH release in hypothalamic hypogonadism such as Kallmann syndrome. Historical teaching regimens include 10–20 micrograms IV over one minute every 90 minutes, 15–20 micrograms SC or 200 micrograms intranasally every two hours. Modern practice usually uses a programmable pump under specialist supervision. It is ineffective when the pituitary cannot respond, in primary ovarian failure or when FSH is already high.

7. Hyperprolactinaemia and dopamine agonists

7.1 Bromocriptine

Bromocriptine is a D2-receptor agonist that lowers prolactin, restores pulsatile GnRH and may restore ovulation or spermatogenesis. Before treatment, repeat prolactin when appropriate, review drugs (antipsychotics, metoclopramide and some antidepressants), exclude pregnancy and assess thyroid disease; visual-field symptoms require pituitary imaging.

Dose: start 1.25–2.5 mg orally once daily with food, preferably at bedtime; increase gradually (for example by 1.25–2.5 mg every 1–2 weeks) according to prolactin and tolerance. Monitor prolactin, menstrual function, pregnancy and tumour symptoms.

Adverse effects/interactions: nausea, vomiting, postural hypotension, dizziness, headache, nasal congestion, constipation, fatigue and rarely psychosis or impulse-control symptoms. Alcohol and other hypotensive drugs worsen dizziness; dopamine antagonists can reduce efficacy. Warn the patient to rise slowly and avoid driving until effects are known.

7.2 Cabergoline

Cabergoline is a long-acting D2 agonist, often better tolerated and more effective than bromocriptine for hyperprolactinaemia.

Dose: 0.25 mg orally twice weekly; increase by 0.25 mg twice weekly at intervals guided by prolactin, commonly up to 1 mg twice weekly under specialist care. Take with food if nausea occurs.

Safety: nausea, headache, dizziness and postural hypotension are common. Long-term/high cumulative doses can cause valvular fibrosis; consider baseline and follow-up echocardiography when indicated by dose and duration. Avoid in uncontrolled hypertension, serious valvular disease or a history of fibrotic disorders. Dopamine antagonists and macrolides may reduce effect or increase exposure.

7.3 Quinagolide and other agents

Quinagolide is a non-ergot D2 agonist used in some countries (initial low dose followed by daily maintenance, for example 25 micrograms then 50–75 micrograms). Pergolide is rarely used because of valvular toxicity. These are specialist alternatives, not routine emergency medicines.

8. PCOS, luteal support and selected endocrine causes

PCOS pathway

1. Optimise weight, nutrition, exercise, blood pressure, glucose and sleep; give folate and address smoking/alcohol.
2. Confirm ovulatory dysfunction and assess semen and tubal patency before escalating medication.
3. Letrozole is generally first-line. Clomiphene is an alternative where letrozole is unavailable or unsuitable.
4. Metformin is primarily for metabolic indications or as a selected adjunct; explain that it is less effective for ovulation than letrozole.
5. If oral therapy fails, use low-dose gonadotropins with ultrasound and estradiol monitoring, or consider laparoscopic ovarian surgery/IVF according to the couple’s goals and local resources.

Prednisolone/dexamethasone and hyperandrogenism

The deck describes prednisolone 5 mg at night plus 2.5 mg in the morning for high androstenedione and dexamethasone as an adjunct in clomiphene-resistant PCOS. Routine glucocorticoids are not recommended for ordinary PCOS infertility because benefits are uncertain and infection, glucose, blood-pressure and adrenal-suppression risks are real. Consider steroid therapy only for a defined adrenal disorder (for example congenital adrenal hyperplasia) under endocrinology supervision.

Luteal progesterone and hCG

The older term “corpus-luteal phase defect” is not a reliably established cause of infertility; a single progesterone result cannot diagnose it. In stimulated IUI/IVF cycles, progesterone luteal support is often protocol-based:

• Micronised progesterone 200–400 mg vaginally daily or twice daily is commonly used in ART protocols, but product instructions and clinic protocol determine the regimen.
• Progesterone 100 mg IM or 300–600 mg oral/vaginal doses appear in older teaching material; route, bioavailability and adverse effects differ.
• hCG can support the corpus luteum but increases OHSS risk and should not be added routinely when safer progesterone support is adequate.

Adverse effects include sedation, dizziness, breast tenderness, bloating, mood change and injection-site pain. Exclude ectopic pregnancy and investigate bleeding or severe pain rather than simply increasing progesterone.

Endometriosis

Endometriosis-related infertility may require surgery, IUI with ovarian stimulation or IVF depending on age, ovarian reserve, disease severity and tubal status. Danazol suppresses the LH surge and creates a hypo-oestrogenic, androgenic state but causes acne, weight gain, voice deepening, hirsutism, adverse lipids and liver toxicity; it is not used while trying to conceive. GnRH agonists suppress disease activity but also prevent ovulation during treatment; they are not a direct fertility drug and require a planned transition to conception treatment.

9. Male infertility pharmacotherapy

9.1 Identify the problem first

Causes include impaired sperm production or function (varicocele, undescended testis, infection, genetic disease, chemotherapy, diabetes, overheating, alcohol/drugs), impaired delivery (retrograde ejaculation, duct obstruction, hypospadias, cystic fibrosis-related absence of the vas), hypogonadism and sexual dysfunction. Treat infection, obstruction, varicocele or endocrine disease when indicated; refer severe oligospermia/azoospermia for reproductive-urology care.

9.2 Hypogonadotropic hypogonadism

When LH/FSH are low and testosterone is low, hCG replaces LH activity and restores intratesticular testosterone. After testosterone rises, add FSH or hMG to drive spermatogenesis. Treatment commonly takes 6–12 months; semen analysis, testosterone, estradiol and testicular volume must be followed.

• hCG: 1,000–2,500 IU IM/SC two or three times weekly is an illustrative teaching range; some protocols use 1,500–2,000 IU three times weekly.
• FSH/hMG: 75–150 IU SC/IM two or three times weekly after adequate hCG response.
• Pulsatile GnRH: about 50 micrograms/kg SC every two hours in selected Kallmann/hypothalamic disease, using a pump.

Critical warning: exogenous testosterone gel, injections or oral testosterone may improve symptoms but suppress GnRH, LH and FSH and can cause severe oligospermia or azoospermia. Do not prescribe testosterone monotherapy to a man who wants current or future fertility. If androgen replacement is genuinely required, involve an endocrinologist/reproductive urologist.

9.3 SERMs and aromatase inhibitors

Clomiphene or tamoxifen can increase endogenous LH/FSH in selected infertile men with low testosterone or a low testosterone–estradiol ratio. Use is off-label and evidence for pregnancy/live birth is limited. Anastrozole or letrozole inhibits aromatase and may help carefully selected men with obesity, high estradiol and low testosterone–estradiol ratio.

• Clomiphene: specialist examples include 25 mg daily or 25–50 mg on alternate days; monitor testosterone, estradiol, haematocrit and semen.
• Tamoxifen: older teaching material cites 20–40 mg/day; use only under specialist supervision because thromboembolism, visual and hepatic effects are possible.
• Anastrozole: commonly 0.5–1 mg two or three times weekly in specialist practice; monitor estradiol, bone health and lipids. The slide’s “75–150 IU” refers to FSH treatment, not anastrozole.

9.4 Limited-evidence adjuncts

Drug/agent in the supplied deck	Intended rationale	Current teaching position
Pentoxifylline 400–600 mg orally three times daily for 3–6 months	PDE inhibition may increase sperm cAMP and motility.	Not routine guideline therapy; gastrointestinal upset, dizziness and bleeding interactions matter. Consider only in research/specialist settings.
Ketotifen	Mast-cell stabilisation was proposed to reduce intratesticular inflammatory fibrosis.	Evidence is insufficient for routine infertility treatment.
Tocopherol (vitamin E) 300–600 mg/day	Antioxidant protection against lipid peroxidation.	Evidence is mixed; high doses can increase bleeding risk with anticoagulants/antiplatelets.
Methylprednisolone 40–60 mg for 4–6 weeks tapered	Historically used for antisperm antibodies or autoimmune orchitis.	Routine systemic steroid therapy for antisperm antibodies is not recommended; infection, hyperglycaemia and adrenal suppression may outweigh uncertain benefit.

9.5 Retrograde ejaculation and emission failure

After diabetes, pelvic surgery or retroperitoneal lymph-node dissection, sperm may enter the bladder or fail to be emitted. Treat the cause and consider urine sperm retrieval, IUI/IVF or sperm retrieval. Older pharmacology notes list:

• Midodrine 5–15 mg (route and timing must follow local protocol; oral treatment is generally preferred over unsafe unsupervised IV use).
• Imipramine 25–75 mg orally, often divided or taken before intercourse under specialist guidance.
• Brompheniramine 8 mg three times daily in older protocols.

These agents can cause hypertension, urinary retention, anticholinergic effects, arrhythmia or sedation. Avoid in significant cardiovascular disease, glaucoma or urinary obstruction without specialist review.

10. Erectile dysfunction in an infertile couple

Erectile dysfunction can prevent intercourse but PDE5 inhibitors do not increase sperm production. First address diabetes, hypertension, vascular disease, medicines, depression, relationship stress and testosterone deficiency. A PDE5 inhibitor requires sexual stimulation and does not improve libido, orgasm or ejaculation by itself.

Sildenafil

Typical dose is 50 mg orally about one hour before sexual activity; adjust to 25–100 mg according to response, tolerability, age, renal/hepatic function and interacting drugs. Do not use with organic nitrates or riociguat. Use caution with alpha-blockers and strong CYP3A4 inhibitors. Headache, flushing, dyspepsia, nasal congestion, visual disturbance, hypotension and rare priapism or sudden vision/hearing loss require counselling.

Tadalafil and other options

Tadalafil has a longer duration (up to about 36 hours); common ED regimens are 10 mg as needed or 2.5–5 mg daily, not the old “5–20 mg twice weekly” slide wording. Vardenafil has similar PDE5 actions. Intracavernosal/intraurethral alprostadil (PGE1) is an option when oral drugs fail; penile pain, hypotension, fibrosis and priapism require training and urgent safety advice. Papaverine/phentolamine injections are specialist-only because of priapism and fibrosis.

11. Assisted reproduction and where the drugs fit

Step	Drug role	Safety decision
Ovulation induction with timed intercourse	Letrozole or clomiphene; trigger with hCG only after a safe follicle response.	Cancel if excessive follicles or high OHSS/multiple-pregnancy risk.
Stimulated IUI	Low-dose FSH/hMG with ultrasound; timed IUI after ovulation trigger.	Use strict follicle-count criteria; counsel about twins/triplets.
IVF/ICSI stimulation	rFSH or hMG, then GnRH antagonist or agonist protocol, trigger with hCG or GnRH agonist.	Antagonist plus GnRH-agonist trigger is favoured in high-risk patients to reduce OHSS.
Luteal phase	Progesterone support; selected clinics use low-dose hCG.	Avoid additional hCG when OHSS risk is high.
Male factor	hCG + FSH for hypogonadotropic hypogonadism; SERMs/AIs in selected men.	Do not use exogenous testosterone when fertility is desired.

12. Ovarian hyperstimulation syndrome (OHSS): emergency recognition

Immediate approach

1. Stop stimulation and withhold hCG if the patient has not yet been triggered; urgently contact the fertility team.
2. Assess airway, breathing, circulation, vital signs, urine output, weight, abdominal girth and pregnancy/ectopic risk.
3. Check FBC/haematocrit, electrolytes, urea/creatinine, liver tests, albumin and coagulation; ultrasound assesses ovaries and ascites; chest imaging if respiratory symptoms.
4. Admit severe disease. Use cautious isotonic fluid resuscitation, antiemetics, thromboprophylaxis when not contraindicated, analgesia and renal/respiratory support. Large-volume paracentesis may be needed for tense ascites or respiratory compromise.
5. Do not give routine diuretics to a hypovolaemic patient. Escalate for shock, haemoconcentration, oliguria, severe electrolyte abnormality, thrombosis or respiratory failure.

13. Other urgent complications and counselling

• Ovarian torsion: sudden unilateral severe pain, vomiting or peritoneal signs after stimulation is a surgical emergency; ultrasound Doppler can be falsely reassuring.
• Ectopic pregnancy: pain, syncope or bleeding after ovulation induction requires urgent pregnancy testing and ultrasound; fertility treatment increases the need for early localisation.
• Multiple gestation: explain twin/triplet risk before treatment; reduce or cancel cycles according to follicle number and local thresholds.
• Severe allergy: hMG, hCG, GnRH antagonists and other injections can cause urticaria, bronchospasm or anaphylaxis—treat with IM adrenaline and emergency resuscitation.
• Drug errors: IU, micrograms and milligrams are not interchangeable. Confirm vial strength, diluent, route, storage and injection technique with every gonadotropin.
• Pregnancy: stop ovulation-induction tablets once pregnancy is confirmed unless a specialist directs otherwise; review every medicine for fetal safety.

14. High-yield comparison

Drug/class	Main target	Best-known use	Major danger
Letrozole	Aromatase inhibition	First-line PCOS anovulation in current guidance	Pregnancy exposure, multiple gestation, rare OHSS
Clomiphene	Hypothalamic estrogen-receptor blockade	Anovulatory infertility when suitable	Visual toxicity, thin endometrium, ovarian enlargement, twins
Metformin	Insulin sensitisation	PCOS metabolic disease/selected adjunct	GI effects, lactic acidosis in severe renal/hypoxic states
FSH/hMG	Direct follicular or Sertoli stimulation	Monitored ovulation induction, IVF, male hypogonadism	OHSS and high-order multiple pregnancy
hCG	LH-receptor agonism	Ovulation trigger; Leydig stimulation in men	OHSS, fluid shifts, false-positive pregnancy test
GnRH agonist	Initial flare then pituitary down-regulation	IVF suppression, endometriosis	Hypo-oestrogenic bone effects and flare
GnRH antagonist	Immediate competitive GnRH blockade	Prevent premature LH surge in IVF	Hypersensitivity and timing errors
Bromocriptine/cabergoline	D2 agonism, prolactin suppression	Hyperprolactinaemia-related infertility	Postural hypotension; valvular/fibrotic risk with cabergoline
Progesterone	Endometrial/luteal support	ART luteal support in protocol	Sedation, bleeding; can mask ectopic symptoms

15. Clinical cases for revision

16. Examination checklist

• Always evaluate both partners and confirm ovulation, tubal patency and semen status before escalating therapy.
• Letrozole is the current preferred first-line drug for anovulatory PCOS when no other infertility factor exists.
• Clomiphene starts at 50 mg daily for 5 days; visual symptoms require immediate cessation and assessment.
• Gonadotropins and hCG are high-alert medicines: use ultrasound/estradiol monitoring and withhold the trigger if OHSS risk is high.
• Cabergoline starts at 0.25 mg twice weekly; bromocriptine starts at 1.25–2.5 mg daily with food.
• hCG is an LH analogue in both sexes; FSH is needed for Sertoli-cell support and spermatogenesis.
• Exogenous testosterone suppresses sperm production and should not be used as fertility therapy.
• PDE5 inhibitors treat erectile dysfunction, not sperm production; nitrates and sildenafil must never be combined.
• Older slide doses are educational historical examples; always check the current product label, national guideline and fertility-specialist protocol.

17. Sources and further reading

• Supplied SlideShare: Infertility Treatment (65-slide pharmacotherapy deck)
• WHO Guideline for the prevention, diagnosis and treatment of infertility (2025)
• International evidence-based PCOS guideline (ASRM, 2023)
• ASRM fertility evaluation of infertile women
• AUA/ASRM male infertility guideline (amended 2024)
• DailyMed clomiphene citrate label
• DailyMed follitropin alfa (GONAL-f) label
• DailyMed menotropins (MENOPUR) label
• DailyMed chorionic gonadotropin (NOVAREL) label
• DailyMed ganirelix label
• DailyMed cabergoline label
• DailyMed bromocriptine label
• ASRM prevention and treatment of OHSS