Synthetic ovulation stimulants

Definition and Clinical Role
Synthetic ovulation stimulants are a class of fertility-enhancing agents that stimulate the release of eggs from the ovaries in women who are anovulatory or oligo-ovulatory. These drugs are synthetic, nonsteroidal, or steroidal compounds that act on the hypothalamic–pituitary–ovarian axis to induce or regulate ovulation. They are most commonly used in the management of female infertility, especially in conditions such as polycystic ovary syndrome (PCOS), unexplained infertility, or in controlled ovarian stimulation during assisted reproductive technologies (ART) such as in vitro fertilization (IVF).

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Mechanism of Action

Synthetic ovulation stimulants act through various mechanisms depending on their class:

1. Selective Estrogen Receptor Modulators (SERMs) – e.g., Clomiphene citrate

   • Act by blocking estrogen receptors in the hypothalamus, leading to increased GnRH secretion.

   • This in turn stimulates the pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), promoting follicular development and ovulation.

2. Aromatase Inhibitors – e.g., Letrozole

   • Inhibit aromatase enzyme, reducing estrogen levels.

   • This leads to reduced negative feedback on the hypothalamic-pituitary axis, increasing FSH and LH secretion.

3. Exogenous Gonadotropins – recombinant or urinary forms

   • These are not synthetic oral agents but are often used in tandem with synthetic agents.

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Primary Agents in the Class

Generic Name	Brand Names	Class
Clomiphene citrate	Clomid, Serophene	SERM
Letrozole	Femara	Aromatase Inhibitor
Tamoxifen (off-label)	Nolvadex	SERM
Raloxifene (investigational use)	Evista	SERM
Enclomiphene (enantiomer of clomiphene)	Androxal	SERM

Indications

• Anovulatory infertility (e.g., PCOS)

• Luteal phase deficiency

• Unexplained infertility

• Ovulation induction prior to intrauterine insemination (IUI) or IVF

• Male hypogonadism (enclomiphene used investigationally)

• Oligomenorrhea or amenorrhea with underlying hormonal dysregulation

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Clomiphene Citrate (Clomid)

• Mechanism: Competitive estrogen antagonist at hypothalamic estrogen receptors

• Dosing: 50 mg/day for 5 days starting on Day 3–5 of menstrual cycle

• Titration: Can be increased to 100–150 mg/day based on response

• Ovulation Rate: ~80%

• Pregnancy Rate: ~30–40% per cycle

• Half-life: Long (~5–7 days); active isomers persist longer

• Time to effect: Ovulation typically occurs ~5–10 days after last dose

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Letrozole (Femara)

• Mechanism: Aromatase inhibition reduces estradiol, lifting negative feedback

• Dosing: 2.5–5 mg/day for 5 days (Day 3–7 or Day 5–9)

• Use in PCOS: Now often first-line over clomiphene

• Advantages: Shorter half-life (~45 hours), lower multiple pregnancy rate

• Pregnancy Rate: Comparable or superior to clomiphene in PCOS

• Off-label in infertility, though widely accepted in clinical practice

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Tamoxifen (Off-label)

• Less commonly used due to greater risk profile and fewer studies

• Dosing: 10–20 mg twice daily for 5 days

• Useful in women resistant to clomiphene or with estrogen-sensitive conditions

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Enclomiphene

• Pure trans-isomer of clomiphene (active isomer)

• Under investigation for male hypogonadism and ovulation induction

• Potentially fewer anti-estrogenic endometrial effects compared to racemic clomiphene

• Shorter half-life than clomiphene citrate

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Pharmacokinetics

Parameter	Clomiphene	Letrozole	Tamoxifen
Oral bioavailability	High	High	High
Half-life	5–7 days	45 hours	5–7 days
Metabolism	Hepatic (CYP2D6)	Hepatic (CYP3A4)	Hepatic (CYP3A4)
Excretion	Fecal/urinary	Renal	Biliary

Adverse Effects

Effect	Clomiphene	Letrozole	Tamoxifen
Hot flashes	Common	Less common	Common
Mood swings	Yes	Rare	Yes
Visual disturbances	~2% (serious warning)	Rare	Rare
Ovarian cysts	Occasionally	Rare	Possible
Multiple gestation	5–10%	<5%	<5%
Endometrial thinning	Yes (anti-estrogenic)	Less likely	Yes
Bone loss (long-term use)	No	Possible	No
Hepatotoxicity	Rare	Rare	Rare

Contraindications

• Pregnancy (Category X)

• Liver disease

• Unexplained uterine bleeding

• Ovarian cysts not due to PCOS

• Hypersensitivity to the drug

• Endometrial carcinoma or estrogen-dependent tumors (tamoxifen/clomiphene)

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Precautions

• Limit duration of treatment to avoid long-term effects (e.g., clomiphene not recommended for >6 cycles)

• Monitor ovarian response via ultrasound to reduce OHSS risk

• Ensure accurate diagnosis of anovulation before initiating therapy

• Watch for luteinized unruptured follicle syndrome (LUFS), a known risk

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Drug Interactions

Interacting Agent	Effect
Gonadotropins	Synergistic effect in stimulation
Estrogens	Antagonize clomiphene effect
CYP3A4 inhibitors	May increase letrozole/tamoxifen levels
SSRIs (e.g., fluoxetine)	May inhibit tamoxifen metabolism (CYP2D6)
Alcohol	May worsen mood lability and hot flashes
Warfarin	Increased anticoagulant effect (tamoxifen)

Clinical Guidelines and Recommendations

• American Society for Reproductive Medicine (ASRM):

  • Letrozole is now first-line therapy for ovulation induction in PCOS due to higher live birth rates and lower risk of multiple pregnancies compared to clomiphene

• NICE Guidelines (UK):

  • Letrozole preferred in women with anovulatory infertility (especially PCOS)

• World Health Organization (WHO):

  • Classifies clomiphene and letrozole as essential fertility medications

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Efficacy Overview

Agent	Ovulation Rate	Pregnancy Rate	Multiple Birth Risk
Clomiphene	~70–80%	~30–40%	~5–10%
Letrozole	~70–75%	~35–45%	<5%
Tamoxifen	~60–70%	~20–30%	Rare

Use in Special Populations

• Obese Women:

  • Letrozole more effective than clomiphene in obese women with PCOS

• Women with PCOS:

  • First-line: Letrozole

  • Second-line: Clomiphene ± Metformin

• Male Infertility (Enclomiphene):

• Under investigation; may stimulate endogenous testosterone and spermatogenesis