What is the next step in management for a patient with amenorrhea (absence of menstruation) who has had withdrawal bleeding after Provera (medroxyprogesterone acetate) and desires pregnancy, with normal prolactin and thyroid-stimulating hormone (TSH) levels, mildly elevated luteinizing hormone (LH) and normal follicle-stimulating hormone (FSH) levels?

Management of Amenorrhea After Provera in a Patient Desiring Pregnancy

For a patient with amenorrhea who had withdrawal bleeding after Provera and desires pregnancy, with normal prolactin and TSH, elevated LH (17.4) and normal FSH (8.3), clomiphene citrate should be initiated as the next step in management.

Diagnostic Assessment

The patient's presentation suggests a form of functional hypothalamic amenorrhea (FHA) with possible polycystic ovarian morphology (PCOM) based on:

• Positive withdrawal bleeding response to Provera (medroxyprogesterone acetate)
• Normal prolactin and TSH (ruling out hyperprolactinemia and thyroid dysfunction)
• Elevated LH:FSH ratio (17.4:8.3 or approximately 2:1)
• Desire for pregnancy

The LH:FSH ratio >2 is suggestive of polycystic ovary syndrome (PCOS) features 1, while the positive response to Provera indicates adequate estrogen priming of the endometrium.

Treatment Algorithm

Step 1: Clomiphene Citrate Trial

• Start with clomiphene citrate 50 mg daily for 5 days (days 3-7 of a natural cycle or induced cycle)
• This is the most appropriate first-line ovulation induction agent for a patient who has demonstrated estrogen production (as evidenced by withdrawal bleeding after Provera)

Step 2: Monitoring Response

• Transvaginal ultrasound to monitor follicular development 5-7 days after completing clomiphene
• Serum progesterone level 7 days after presumed ovulation to confirm ovulation

Step 3: Dose Adjustment

• If no response to initial dose, increase clomiphene to 100 mg daily for 5 days in the next cycle
• Maximum recommended dose is 150 mg daily

Step 4: Alternative Approaches (if clomiphene fails after 3-6 cycles)

• Consider pulsatile GnRH therapy, which has shown good results in patients with FHA with PCOM features 1
• Gonadotropin therapy (FSH preparations) may be considered if pulsatile GnRH is not available

Rationale for Recommendation

The patient has demonstrated:

1. Adequate estrogen production (evidenced by withdrawal bleeding after Provera)
2. Potential ovulatory dysfunction (amenorrhea with elevated LH:FSH ratio)

Clomiphene citrate works by blocking estrogen receptors at the hypothalamus, which increases GnRH pulsatility and subsequently increases FSH and LH release from the pituitary, stimulating ovarian follicular development 1.

While the Endocrine Society guidelines suggest that clomiphene citrate may not be highly effective in pure FHA 1, this patient's hormonal profile with elevated LH:FSH ratio suggests features of PCOS, where clomiphene has proven efficacy.

Important Considerations

• BMI Assessment: Ensure BMI ≥18.5 kg/m² before initiating ovulation induction, as recommended by the Endocrine Society 1
• Timing: If the patient recently had withdrawal bleeding from Provera, clomiphene should be started on day 3-5 of this bleeding
• Monitoring: Close monitoring for multiple follicle development is essential to reduce the risk of multiple pregnancy
• Duration: If no pregnancy occurs after 3-6 ovulatory cycles with clomiphene, consider alternative treatments

Pitfalls to Avoid

1. Prolonged clomiphene use: Continuing clomiphene beyond 6 cycles without success is not recommended due to diminishing returns and potential adverse effects
2. Overlooking metabolic factors: Consider screening for insulin resistance, especially with the elevated LH:FSH ratio
3. Inadequate monitoring: Failure to confirm ovulation can lead to unnecessary treatment changes
4. Missing the window: Timing intercourse appropriately around ovulation is crucial for success

By following this approach, you maximize the patient's chances of achieving pregnancy while minimizing risks and unnecessary interventions.