Infertility drugs are pharmacological agents designed to stimulate the reproductive system, primarily to induce ovulation in females, promote spermatogenesis in males, or support early pregnancy. These therapies are indicated for individuals who cannot conceive after a minimum of one year of regular, unprotected intercourse.

• Humans are actually one of the least fertile species on earth. The most fertile couple only has about a 20% chance of conception taking place in any given month.
• Fertility status begins to decline progressively with age.
• Approximately 10% of the population suffers from fertility problems, and this number is increasing every year due to delayed childbearing, lifestyle factors, and environmental exposures.

• Infertility: Defined as the inability to conceive after regularly having unprotected sex for at least one year.
• Sterility: Defined as the absolute, irreversible failure to conceive.

Female infertility can stem from multiple physiological, anatomical, and immunological disruptions:

1. Hormonal Causes:
   • Hypothalamic-pituitary hormone deficiency: Lack of GnRH, FSH, or LH.
   • Polycystic Ovarian Disease (PCOD/PCOS): Characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries.
   • Corpus Luteal Phase Defect: Either the duration of the luteal phase is shortened, or there is decreased production of progesterone, which interferes with proper endometrial receptivity and embryo implantation.
   • Decreased Progesterone.
   • Hyperprolactinemia: Increased prolactin suppresses GnRH pulsatility.
   • Hypothyroidism / Hyperthyroidism.
2. Infection: Pelvic Inflammatory Disease (PID) due to Tuberculosis (T.B.), Gonorrhea, or Chlamydia can cause severe tubal scarring.
3. Immunological: Presence of cervical or serum anti-sperm antibodies that immobilize or destroy sperm.
4. Anatomical/Structural: Endometriosis, Retroversion of the uterus, or Uterine Fibroids (leiomyomas).
5. Congenital: Hypoplasia or malformation of the genital tract, congenital tubal blockage.
6. Others: Poor or lack of cervical mucus (hostile cervical mucus).
7. Risk Factors: Advanced maternal age, smoking, alcohol consumption, being overweight/obese, excessive strenuous exercise, and high caffeine intake.

• Pharmacological Drugs (Ovulation inducers, hormones).
• Surgical treatment (Corrective surgery, laparoscopic ovarian drilling, tubal reconstruction).
• Assisted Reproduction Techniques (ART) like IUI (Intrauterine Insemination) and IVF (In Vitro Fertilization).
• Counseling and Lifestyle Modifications.
• Adoption.

Women without primary ovarian failure (meaning they have functioning ovaries) who cannot get pregnant are candidates for fertility drugs. These drugs work either directly to stimulate follicles or stimulate the hypothalamus to increase FSH and LH levels. Given in sequence with hCG to maintain the follicle, they treat infertility in women whose partners are fertile, or are used to stimulate multiple follicles for harvesting ova for IVF.

First-line therapy for anovulatory infertility, especially in PCOD.

• Mechanism of Action: It is a selective estrogen receptor modulator (SERM) that acts as a pure estrogen antagonist at estrogen receptors (ERα & ERβ) in the hypothalamus. By blocking estrogen's negative feedback, it induces the release of GnRH, leading to increased FSH and LH secretion. This stimulates the ovaries to enlarge and triggers follicular growth and ovulation.
• Pharmacokinetics: Orally active. Half-life (T1/2) is about 6 days (it deposits in adipose tissues). Metabolism and excretion are primarily through the bile.
• Indications: Anovulation, PCOD, and oligospermia in males.
• Dosage: Starting dose is 50 mg/day orally for 5 days. It is typically started within 5 days of the onset of menstruation (preferably day 2 to day 6, or day 5 to day 9). If ovulation does not occur, the dose can be doubled (100 mg/day) in subsequent cycles.
• Success Rate: Ovulation rate is around 80%, but the pregnancy rate is lower (approx. 40%). Most evidence points toward a lesser pregnancy rate if the dose exceeds 100 mg.
• Clinical Guidelines: Cumulative pregnancy rate rises until 10 cycles. The RCOG recommends that up to 12 cycles of treatment should be considered, though prolonged use increases risks. Ovulation induction should be monitored via ovarian ultrasound.
• Adverse Effects:
  • Anti-estrogenic effects: Regression of estrogen-induced proliferative endometrium and hostile effect on cervical mucus (making it thick and impenetrable to sperm).
  • Systemic: Hot flushes, headache, fluid retention, nausea, bloating, gastric upset, vertigo, allergic dermatitis.
  • Ovarian: Polycystic ovaries, multiple pregnancies (6-10% risk of twins), ovarian enlargement.
  • Long-term risks: Osteoporosis (if treated >8 months), and potential association with epithelial ovarian cancer with prolonged use.

• Mechanism of Action: They reversibly inhibit the aromatase enzyme, which blocks the peripheral conversion of androgens to estrogens. The resulting drop in estrogen levels removes the negative feedback on the hypothalamus and pituitary, increasing FSH output and driving follicular development. Unlike Clomiphene, they do not deplete estrogen receptors centrally or peripherally, leaving cervical mucus and the endometrial lining intact.
• Indications: Increasingly preferred as first-line therapy for PCOD/PCOS, especially in Clomiphene-resistant patients.
• Dosage: Letrozole is typically given at 2.5 mg to 5 mg orally once daily for 5 days, or as a single 20 mg dose on day 3 of the menstrual cycle.

Gonadotropins are glycoproteins with a variable half-life. They are highly effective but very expensive, have high complication rates (like OHSS), and require close ultrasound and hormonal monitoring. Pregnancy wastage (miscarriage) is similar to clomiphene, but the multiple pregnancy rate is much higher (approx. 20%).

1. Perform baseline oestradiol assay and ultrasound scanning.
2. Administer hMG, 2 ampoules (75 IU each) per day for 3 days.
3. Repeat oestradiol. If doubled, monitor hMG dosage; if not, increase hMG dosage by 50% for 3 days. Repeat until oestradiol doubles.
4. Perform ultrasound scan every 2-3 days till the size of the leading follicle becomes 14-20 mm.
5. 24 hours later, administer hCG 5000 IU. Recommend IUI or natural timed intercourse.
6. Administer a second injection of hCG 3000 IU 7 days later for luteal support.
7. Await onset of menses or perform urine pregnancy test.

Note: Recombinant versions (rFSH, rLH, rHCG) are more purified, more expensive, and have largely replaced urine preparations in developed countries. They are administered IM or SC and do not elicit antibodies like older urine-derived preparations could.

Natural GnRH is a decapeptide synthesized in the hypothalamus. Its half-life is 2-8 minutes and it cannot be given orally. It is an alternative to hMG and an adjuvant in IVF, with less risk of hyperstimulation than hMG, but it is very expensive.

• Mechanism: Initial administration causes a "flare" (initial stimulation of release of FSH and LH). Continuous, prolonged administration leads to desensitization and down-regulation of pituitary gonadotropes, ultimately causing a complete loss of FSH and LH release (medical menopause).
• Examples & Dosing:
  • Leuprolide acetate: 1 mg SC daily.
  • Buserelin acetate: 40 mcg/kg/d, in divided doses or 1 mg SC daily.
  • Nafarelin: 200 - 400 mcg intranasally, twice daily.
  • Triptorelin microspheres: 4 mg IM monthly.
  • Goserelin acetate: 3.6 mg SC monthly implant in the anterior abdominal wall.
• Uses in Infertility:
  • Pulsatile Fashion (using a pump): Promotes synthesis and release of FSH/LH to mimic natural physiology (10-20 mcg IV over 1 min every 90 min). Used for Hypothalamic Hypogonadism (Kallmann syndrome).
  • Continuous Fashion (IVF Regimens): Used in Controlled Ovarian Hyperstimulation. Continuous pretreatment suppresses endogenous FSH/LH, preventing an untimely, premature release of LH from the pituitary before follicles are fully mature.
• Adverse Effects: Hyperstimulation, multiple pregnancy. Prolonged use (>6 months) causes severe estrogen deprivation: hot flushes, loss of libido, vaginal dryness, osteoporosis, emotional lability. (May require Add Back Therapy with low-dose estrogen/progesterone).

• Mechanism: Act by competitive inhibition of binding of endogenous GnRH to its receptors. They suppress release of LH and FSH immediately from the onset of administration, without the initial stimulation (flare) seen with agonists.
• Examples: Ganirelix, Cetrorelix (Cetrotide), Abarelix, Degarelix.
• Advantages: Quick suppression of gonadotropins, less ovarian hyperstimulation, and a shorter duration of injections. Very expensive and can cause the release of histamine at the injection site (Ganirelix releases less histamine).
• Use: Given in IVF regimens to rapidly prevent the LH surge during ovarian stimulation.

Used to treat infertility caused by hyperprolactinemia (prolactin suppresses GnRH). They inhibit prolactin release from the anterior pituitary and restore the normal cyclic release of gonadotropins.

• Bromocriptine (Parlodel): A selective D2 agonist. Initiated at 1.25 mg at bed time every day for 7 days. Dose is gradually increased by 1.25 mg/week to a usual dose of 2.5 mg three times a day with food, until hyperprolactinemia is corrected (max 30mg daily). Side effects include severe nausea, vomiting, orthostatic hypotension, headache, and constipation.
• Cabergoline (Dostinex): A long-acting oral tablet. Dose is 0.25 - 1 mg twice weekly. Highly preferred due to better efficacy and dramatically better tolerability than bromocriptine.
• Pergolide: Available as vaginal tab and injectables. Causes acute reduction in tumor size and prolactin levels.
• Quinagolide: 25-150 μg daily followed by a maintenance dose.

• Tamoxifen: A SERM and anticancer drug evaluated for infertility. Improves folliculogenesis via direct action on the ovary. Has a beneficial effect on cervical mucus and endometrium compared to Clomiphene. Dose in CC-resistant PCOD: 20-40 mg OD for 5 days.
• Metformin: An insulin sensitizer used in insulin-resistant patients (common in PCOD) to lower androgens and restore spontaneous ovulation.
• N-acetyl cysteine (NAC): 1.2 gm daily. PCOD patients often have raised levels of homocysteine. NAC acts as a mucolytic and insulin sensitizer.
• Prednisolone: A corticosteroid used in anovulation with high androstenedione. Dose: 5 mg at night and 2.5 mg in the morning until spontaneous ovulation occurs.
• Progesterone: Used to treat Corpus Luteal Phase Defect to support the endometrium and maintain implantation. Dose: 100 mg IM or 300-600 mg micronized vaginal tablets daily.
• Danazol: The first FDA-approved drug for Endometriosis. It is a synthetic steroid with progesterone-like, hypoestrogenic, and hyperandrogenic effects causing atrophy of the endometrium. It suppresses the LH surge, preventing ovulation. Side effect: masculinizing/virilizing effects (acne, voice deepening, hirsutism).

• Clomiphene Citrate: 25 mg/day for 24 days & gap of 6 days. Duration: 6 months. It blocks estrogen receptors centrally, causing an increase in FSH/LH, which stimulates the testes to produce testosterone and sperm.
• hCG (Human Chorionic Gonadotropin): 1000-2500 IU twice/thrice a week IM or SC. Mimics LH to stimulate Leydig cells to produce testosterone. Yields 90% spermatogenesis. Can add hMG 75-150 u thrice a week.
• FSH: Has higher specific activity for stimulating Sertoli cells for spermatogenesis. Can be given with hCG.
• GnRH (Pulsatile): Alternative to hCG/hMG for Kallmann syndrome. Administered 50ug/kg 2 hrly SC. Not effective in defective spermatogenesis if FSH is already raised.

• Antiestrogens (Clomiphene and Tamoxifen): Stimulate the secretion of FSH & LH by blocking estrogen and testosterone receptors in the hypothalamus. Tamoxifen acts directly on spermatogenesis by interfering with the testicular estrogen receptor.
• Combination: Tamoxifen + Testosterone Undecanoate (40 mg TDS) helps in spermatid differentiation, increases sperm number, and improves sperm function.
• Anastrozole (Aromatase Inhibitor): Blocks the conversion of testosterone to estrogen. Used in males with severe infertility and a low testosterone/estrogen ratio to increase sperm count and motility and correct hormonal abnormalities.
• FSH therapy: For severe male infertility to improve sperm structure and functions (75-150 IU for 2 months).

• Androgens: Used to correct testosterone deficiency in patients with primary hypogonadism.
  • Testosterone enanthate: 250mg every 3-4 weeks IM.
  • Testosterone undecanoate: 120-160 mg/day orally.
  • Cutaneous applications (scrotal patches or gels) are also available.

• Mast Cell Stabilizers (Ketotifen): Inhibits the release of histamine and vasoactive substances from mast cells. Prevents progressive intratesticular fibrosis and blocks harmful effects of mast cell products (like IL-6 or tryptase) on spermatozoa. Improves sperm count and motility.
• Pentoxifylline: A methylxanthine derivative. It inhibits phosphodiesterase (PDE), which increases sperm cAMP. This directly increases sperm count and motility. Dose: 400-600 mg TDS Orally for 3-6 months.
• Methylprednisolone: An immunosuppressant used for the treatment of antisperm antibodies. Dose: 40-60 mg for 4-6 weeks in decreasing doses (for low-grade auto-immune orchitis).
• Antioxidants (Tocopherol / Vitamin E): A fat-soluble vitamin. It has a protective action on lipid peroxidation in sperm membranes by scavenging free oxygen radicals. Useful in asthenozoospermia and abnormal acrosome reactions. Dose: 300-600 mg daily.
• Treatment for Emission & Ejaculatory Failure (Retrograde Ejaculation): Often secondary to retroperitoneal lymphadenectomy or Diabetes Mellitus. Treated with Alpha-sympathomimetics and Anticholinergics which tighten the bladder neck during ejaculation:
  • Midodrine: 5-15 mg IV.
  • Imipramine: 25-75 mg oral.
  • Brompheniramine: 8 mg TDS.

• Allergy to fertility drug: Prevent hypersensitivity.
• Primary ovarian failure: These drugs only work to stimulate functioning ovaries. If there are no viable eggs, stimulation is ineffective.
• Thyroid or adrenal dysfunction: Drugs have profound effects on the hypothalamic-pituitary axis which can exacerbate endocrine dysfunction.
• Ovarian cysts: Can be hyper-stimulated by the drugs and can rupture or become dangerously larger.
• Pregnancy: Strictly contraindicated due to the potential for serious fetal effects and teratogenicity.
• Idiopathic uterine bleeding: Can represent an underlying problem (like endometrial cancer) that could be exacerbated by the stimulatory effects of estrogens and fertility drugs.
• Lactation: Risk of adverse effects on the nursing infant.
• Thromboembolic disease: Increased risk of thrombus formation due to high circulating estrogen levels during ovarian stimulation.
• Women with respiratory diseases: Alterations in fluid volume, pleural effusions (seen in OHSS), and blood flow can severely overtax the respiratory system.

• Ovarian Hyperstimulation Syndrome (OHSS): A severe, life-threatening complication characterized by massive ovarian enlargement, abdominal pain, distention, ascites, pleural effusion, shock, and hemoconcentration.
• Greatly increased risk of multiple births: Twins, triplets, or more. This inherently carries a higher risk of premature birth and birth defects.
• Systemic Effects: Headache, massive fluid retention, nausea, bloating.
• Gynecological Effects: Uterine bleeding, ovarian enlargement, gynecomastia in males.
• Febrile reactions: Possibly due to the stimulation of massive progesterone release.

• Maheshwari, N. (2017). Pharmacotherapy of INFERTILITY [PDF Presentation].
• Shaw's Textbook of Gynaecology (Reference cited within the PDF material).
• American Academy of Pediatrics (AAP) Guidelines on Pediatric Choking and First Aid (Note: Erroneously included in source material but acknowledged for completeness).
• Standard Pharmacological Guidelines for Assisted Reproductive Technology (ART) and Ovulation Induction.