Can a woman with amenorrhea (absence of menstruation) still ovulate?

Can You Ovulate with Amenorrhea?

Yes, ovulation can occur in women with amenorrhea, though it is unpredictable and depends on the underlying cause—women with advanced liver disease, functional hypothalamic amenorrhea, and even those with decompensated cirrhosis can maintain sporadic ovarian function and should not be presumed infertile. 1

Understanding the Relationship Between Amenorrhea and Ovulation

The key insight is that amenorrhea (absence of menstruation) does not always equal anovulation (absence of ovulation). The relationship depends entirely on the etiology:

Conditions Where Ovulation May Still Occur

• Advanced liver disease with amenorrhea: Women with cirrhosis experience amenorrhea or oligomenorrhea in more than 25% of cases and nearly 75% of premenopausal women awaiting liver transplant, yet pregnancies occur even in those with decompensated disease, demonstrating that ovulation can persist despite absent menses. 1

• Functional hypothalamic amenorrhea (FHA): This condition results from disrupted GnRH pulsatility due to low energy availability, stress, or excessive exercise, leading to low LH and FSH levels. 1 However, ovarian function can be unpredictable, and some degree of follicular activity may persist intermittently. 1

• Polycystic ovary syndrome (PCOS) with amenorrhea: Women with PCOS may have amenorrhea but can still ovulate sporadically, particularly if they have some endogenous estrogen production. 2, 3

The Clinical Implication: Contraception Is Still Necessary

• Patients with amenorrhea who wish to avoid pregnancy require contraception because ovarian function remains unpredictable and ovulation can occur without warning. 1

• This is particularly critical in advanced liver disease, where the assumption of infertility due to amenorrhea is dangerous—documented pregnancies in decompensated cirrhosis prove that ovulation can happen. 1

Diagnostic Approach to Determine Ovulatory Status

When evaluating whether a woman with amenorrhea is ovulating, focus on these specific parameters:

Key Clinical and Laboratory Findings

• Progesterone challenge test: Withdrawal bleeding after progesterone administration suggests adequate endogenous estrogen and potential for ovulation. 4, 5 In one study, 73% of amenorrheic women with positive progesterone withdrawal bleeding ovulated with clomiphene, versus only 5% without withdrawal bleeding. 5

• Mid-luteal progesterone level: A level ≥5 ng/mL (≥16 nmol/L) approximately 7 days before expected menses confirms ovulation occurred. 6 However, this requires timing based on cycle length, which is challenging in amenorrheic women. 6

• Gonadotropin levels: Low LH and FSH suggest hypothalamic amenorrhea with potential for ovulation induction, while elevated FSH (>40 mIU/mL) indicates primary ovarian insufficiency where ovulation is unlikely but not impossible. 2, 3

• Endometrial thickness on ultrasound: Low endometrial thickness suggests estrogen deficiency and makes ovulation less likely in FHA. 1

Important Caveat

• The progesterone challenge test has been questioned in recent literature, and ultra-sensitive estradiol assays may be more useful but are not widely available. 1

Treatment Considerations for Ovulation Induction

If pregnancy is desired in amenorrheic women, the approach depends on the underlying cause:

Functional Hypothalamic Amenorrhea

• First-line: Address underlying causes including energy deficit, excessive exercise, low body weight (BMI should be ≥18.5 kg/m² before ovulation induction), and psychological stress. 1

• Clomiphene citrate has limited efficacy in FHA and is only suggested for women with sufficient endogenous estrogen (positive progesterone withdrawal test), though success rates remain uncertain. 1, 4 The FDA label indicates clomiphene is for ovulatory dysfunction but notes reduced estrogen levels are less favorable. 4

• Pulsatile GnRH therapy is highly effective: In hypothalamic amenorrhea resistant to clomiphene, subcutaneous GnRH pulses (5-15 mcg every 90 minutes) achieved ovulation in 83% of cycles with 54% pregnancy rate per ovulatory cycle. 7

• Gonadotropins (hMG-hCG) are effective: In amenorrheic women without progesterone withdrawal bleeding (suggesting severe estrogen deficiency), all 26 patients treated with gonadotropins ovulated, with 58% achieving pregnancy. 5

Polycystic Ovary Syndrome with Amenorrhea

• Clomiphene citrate is first-line: Starting at 50 mg daily for 5 days, with 55% ovulation rate overall and 73% in those with positive progesterone withdrawal bleeding. 4, 5

• Dosing algorithm: If no ovulation at 50 mg daily for 5 days, increase to 100 mg daily for 5 days in the next cycle. 4 Do not exceed 100 mg/day for 5 days or continue beyond 6 total cycles (including 3 ovulatory cycles). 4

Hyperprolactinemic Amenorrhea

• Bromocriptine is the treatment of choice: All 8 patients with amenorrhea-galactorrhea treated with bromocriptine ovulated, with 50% achieving pregnancy. 5

Critical Pitfalls to Avoid

• Never assume infertility based on amenorrhea alone—this is the most dangerous clinical error, particularly in liver disease where pregnancies occur despite decompensation. 1

• Exclude pregnancy first in all amenorrheic women before initiating any diagnostic workup or treatment. 2, 4

• Screen for eating disorders and assess bone density in FHA, as these patients are at high risk for decreased bone mineral density due to hypoestrogenism and low energy availability. 1, 2

• Evaluate for metabolic syndrome in PCOS patients with amenorrhea, as they face increased risk for glucose intolerance and dyslipidemia. 2

• Do not use clomiphene in women with ovarian cysts (except PCOS) or abnormal vaginal bleeding without proper evaluation. 4