What are the implications of hypogonadism in a 40-year-old woman on combined oral contraceptives (COCs)?

Estradiol <5 pg/mL in a 40-Year-Old on Combined Oral Contraceptives

This finding is expected and does not indicate hypogonadism—combined oral contraceptives suppress endogenous estradiol production through negative feedback on the hypothalamic-pituitary-ovarian axis, making serum estradiol levels unreliable for assessing ovarian function while on COCs.

Understanding the Physiology

Combined oral contraceptives work by suppressing gonadotropin-releasing hormone and subsequently follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which prevents follicular maturation and ovulation 1. This suppression means:

• Endogenous estradiol production is markedly reduced because the ovaries are not cycling normally 1
• Serum estradiol levels do not reflect the estrogenic effect the patient is receiving from the ethinyl estradiol in the COC 2
• Low or undetectable estradiol (<5 pg/mL) is the expected finding in women taking COCs, not a sign of pathology 2

Key Clinical Pitfall

Do not interpret low serum estradiol as hypogonadism in a woman actively taking COCs. The synthetic ethinyl estradiol in COCs (typically 20-35 μg) provides adequate estrogenic effects but is not measured by standard estradiol assays 1. Checking serum estradiol while on COCs is not clinically useful for assessing ovarian function 2.

If Assessing Ovarian Function Is Necessary

To determine true ovarian status in a 40-year-old woman (e.g., to assess if she is approaching menopause and could transition to hormone replacement therapy):

• Stop the COC for 7-14 days before checking hormone levels 2
• Measure FSH and estradiol after this washout period 2
• In reproductive-age women, estradiol increases and FSH rebounds to follicular phase levels within one week off the pill 2
• In perimenopausal/menopausal women over 40, FSH rises substantially and estradiol remains at basal levels (does not increase) after stopping COCs 2

Clinical Management Algorithm

For this 40-year-old patient:

1. Reassure the patient that low estradiol on COCs is physiologically normal and does not indicate a problem 2

2. If she has symptoms potentially related to inadequate estrogen (though unlikely on COCs):

   • Consider switching to a COC with higher ethinyl estradiol content (30-35 μg rather than 20 μg) 1
   • Evaluate for other causes of symptoms unrelated to estrogen status

3. If assessing menopausal status is the goal:

   • Discontinue COCs for 7-14 days 2
   • Check FSH and estradiol 2
   • FSH >25-30 mIU/mL with low estradiol suggests menopause 2

4. Continue COCs if contraception is needed and no contraindications exist (hypertension, smoking >35 years, history of VTE, migraine with aura) 1, 3, 4

Important Contraindications at Age 40

Be vigilant for conditions that make COC use inappropriate 1, 3:

• Smoking (absolute contraindication in women >35 years) 1, 3
• Hypertension (systolic ≥160 or diastolic ≥100 mm Hg) 1
• History of venous thromboembolism 1, 3, 4
• Migraine with aura 1, 3

If any contraindications exist, switch to progestin-only methods (progestin-only pills, levonorgestrel IUD, etonogestrel implant, or DMPA) which do not carry the same VTE risk 5, 4.