Ovulation Inducers (Clomiphene Citrate / Gonadotropins)

Mechanism

Mechanism of Action

Ovulation inducers act by stimulating the development, growth and maturation of the ovarian follicle through different direct central or peripheral mechanisms.

Clomiphene Citrate (SERM Central)

It is an orally active triphenylethylene derivative:

• Competitively blocks estrogen receptors in the hypothalamus and adenohypophysis.
• Prevents the normal negative feedback of circulating estrogens.
• Causes increased pulsatile secretion of FSH and endogenous LH.
• Stimulates multiple ovarian follicular growth.

Recombinant Gonadotropins (rFSH / hCG)

Direct injectable peptide hormones:

• rFSH (Follitropin alfa/beta): It binds directly to the FSH receptor in the ovarian granulosa cells, stimulating follicular maturation in a dose-dependent manner in ART protocols.
• recombinant hCG (Choriogonadotropin alfa): Shares structural homology with LH. It acts as a high affinity agonist of the LH/hCG receptor, mimicking the physiological LH surge to induce ovulation and oocyte maturation.

Pharmacokinetics

Pharmacokinetics

• Clomiphene Citrate: Oral administration. Fast absorption. It undergoes extensive hepatic metabolism and is excreted mainly via the bile-fecal route. It has a very long elimination half-life of approx. 5 to 7 days, due to its enterohepatic circulation, and active traces may persist in plasma for more than a month.
• Follitropin Alfa (rFSH): Daily subcutaneous administration. Slow absorption that reaches serum plateau in about 12 hours. Bioavailability of 70-80%. Elimination half-life of 24 to 36 hours, which allows the cumulative daily regimen.
• Alpha Choriogonadotropin (hCG): Single subcutaneous injection. Bioavailability of 80%. Renal glomerular clearance metabolism. It has a long half-life of approx. 30 hours, inducing ovulatory follicular rupture in a predictable manner at 36 to 40 hours after subcutaneous injection.

Indicators and dose

Indications

• Treatment of chronic anovulation or ovulatory dysfunction (WHO Group II, notably Polycystic Ovary Syndrome) in low-risk women who desire pregnancy in a targeted manner.
• Controlled ovarian stimulation for the development of multiple follicles in highly complex assisted reproduction protocols (IVF, ICSI or artificial insemination).
• Final induction of follicular maturation and ovulation after stimulation.

Dosage and Schemes

• Clomiphene Citrate (Anovulation): 50 mg orally once a day for 5 consecutive days (starting the cycle between day 3 and day 5 of the menstrual cycle). If ovulation is not achieved, it can be escalated to 100 mg per day in subsequent successive cycles. Do not exceed a maximum of 6 cumulative cycles due to the risk of granulosa cell tumor.
• Folitropin Alfa (Controlled stimulation): Individualized initial dose of 75 to 225 IU subcutaneously once a day, adjusting the dose every 3 to 5 days according to ultrasound monitoring of the number and diameter of developing follicles and serum estradiol levels.
• Choriogonadotropin Alfa (Final Maturation): Single subcutaneous injection of 250 µg (equivalent to about 6,500 IU of purified hCG) once the ultrasound criterion of at least 2 to 3 dominant follicles with a diameter of 17-18 mm is reached.

Pregnancy and Breastfeeding

Totally contraindicated if pregnancy has already been confirmed or during active postpartum breastfeeding.

Security

Contraindications

• Undiagnosed primary ovarian failure (premature ovarian failure, where there are no residual ovarian follicles to stimulate).
• Confirmed pregnancy (risk of abortion or teratogenic alteration).
• Active ovarian or genital tract neoplasia sensitive to gonadotropins.
• Presence of ovarian cysts of undiagnosed underlying etiology.
• History of severe episodes of refractory Ovarian Hyperstimulation Syndrome (OHSS).

Critical Adverse Effects

Critical Complication: Ovarian Hyperstimulation Syndrome (OHSS)

OHSS is a life-threatening systemic complication induced by an excessive ovarian response to gonadotropin therapy following administration of the induction dose of hCG. It is characterized by:

• Massive Capillary Permeability: Extreme ovarian stimulation promotes the massive synthesis of local mediators, mainly vascular endothelial growth factor (VEGF), which induces the opening of cell junctions in the capillary endothelium throughout the body.
• Passage to the Third Space: There is a massive outflow of protein-rich fluids from the intravascular space to the third space, giving rise to severe ascites, unilateral pleural and pericardial effusion.
• Hemoconcentration and Hypercoagulability: The depletion of circulating plasma volume increases hematocrit and blood viscosity extremely, predisposing to the development of arterial or deep venous thrombosis and acute renal failure due to hypoperfusion.

It is actively prevented by discontinuing the hCG dose if serum estradiol levels exceed 3000-4000 pg/mL, or by inducing final follicular maturation with a GnRH agonist instead of hCG.

• Multiple Pregnancy: Occurs in 5-10% with clomiphene and up to 15-20% with gonadotropins due to uncontrolled multiple follicular recruitment.
• Peripheral Antiestrogenic Effect (Clomiphene): Prolonged estrogen blockade can cause severe endometrial thinning and impermeability of cervical mucus, paradoxically decreasing actual embryo implantation rates.