What could cause low estradiol (hypogonadism) in a 20-year-old female?

Causes of Estradiol <5 pg/mL in a 20-Year-Old Female

In a 20-year-old female, estradiol <5 pg/mL indicates severe hypogonadism, which can result from either primary ovarian failure (from chemotherapy, radiation, or surgery) or central hypogonadism (from hypothalamic suppression due to low energy availability, eating disorders, excessive exercise, or hypothalamic-pituitary damage). 1

Primary (Ovarian) Causes

Chemotherapy-induced ovarian failure is the most common iatrogenic cause in young women:

• Alkylating agents (cyclophosphamide, busulfan, melphalan, ifosfamide) and platinum compounds cause dose-dependent ovarian damage 1
• Cyclophosphamide equivalent dose (CED) >8000 mg/m² drops fertility probability below 50% 1
• Risk increases with older age at exposure due to smaller oocyte pool 1

Radiation-induced ovarian failure occurs with abdominal/pelvic radiation:

• Doses as low as 5 Gy affect ovarian function in postpubertal females 1
• At age 20 years, the sterilizing dose is approximately 16.5 Gy 1
• Fields affecting ovaries include spine, flank, whole abdomen, pelvis, and total body irradiation 1

Hematopoietic stem cell transplantation (HSCT) causes ovarian failure in 44-100% of recipients:

• The conditioning regimen itself damages ovarian reserve 1
• This occurs even in non-oncological conditions (hemoglobinopathies, immunodeficiencies) 1

Surgical oophorectomy directly removes estrogen-producing tissue 1

Central (Hypothalamic-Pituitary) Causes

Functional hypothalamic amenorrhea (FHA) from low energy availability is the most common non-iatrogenic cause:

• Energy deficit disrupts GnRH pulsatility, preferentially suppressing LH secretion while FSH remains relatively preserved 2
• Low LH fails to stimulate adequate ovarian estradiol production, resulting in hypoestrogenism 2
• The LH:FSH ratio typically falls below 1 in approximately 82% of FHA patients 2

Specific triggers for FHA include:

• Eating disorders (anorexia nervosa): Energy restriction disrupts the hypothalamic-pituitary-gonadal axis 3, 2
• Female athlete triad/RED-S: Low energy availability from excessive exercise relative to caloric intake causes LH pulsatility disruptions 1, 3
• Energy availability <30 kcal/kg FFM/day discriminates between amenorrheic versus eumenorrheic status 1

Hypothalamic-pituitary damage from tumors, cranial radiation, or neurosurgery:

• Cranial or cranio-spinal radiotherapy affecting the hypothalamic-pituitary area causes hypogonadotropic hypogonadism 1
• Tumors infiltrating sellar or supra-sellar regions directly impair gonadotropin release 1
• This results in low gonadotropins (LH, FSH) with secondary low estradiol 1

Critical Diagnostic Distinctions

Measure FSH and LH to differentiate primary from central causes:

• Primary ovarian failure: Elevated FSH and LH (>10-20 IU/L) with low estradiol 3
• Central hypogonadism: Low or low-normal FSH and LH (<5 IU/L) with low estradiol 1, 2
• Important caveat: In cancer survivors with co-occurrence of central hypogonadism and ovarian damage, the ovarian failure may be disguised by low gonadotropins from hypothalamic-pituitary damage 1

Check for FHA versus PCOS in women with low estradiol:

• FHA shows LH:FSH ratio <1, while PCOS shows ratio >2 2
• FHA patients lack insulin resistance and elevated androgens characteristic of PCOS 2
• Some women with FHA may have polycystic ovarian morphology (FHA-PCOM), affecting 40-47% of FHA patients, but they have quiescent hyperandrogenic ovaries due to low gonadotropins 3, 4

Important Confounding Factor

Hormonal contraceptive use fundamentally alters hormone assessment:

• Ovarian function cannot be reliably assessed during hormonal contraceptive use because exogenous hormones suppress the HPG axis 5
• Withdrawal bleeding on oral contraceptives is pharmacologic, not evidence of ovarian function 5
• For accurate assessment, stop oral contraceptives and wait at least 7-14 days before measuring FSH and estradiol 5
• Anti-Müllerian hormone (AMH) is the only useful marker of ovarian reserve in women on hormonal contraception 5

Additional Considerations

Other causes to evaluate:

• Hyperprolactinemia: Accounts for approximately 20% of secondary amenorrhea cases 3
• Thyroid dysfunction: Both hypothyroidism and hyperthyroidism can cause amenorrhea with low estradiol 3
• Advanced liver disease: Alters estrogen metabolism and disrupts the hypothalamic-pituitary axis 3

Age-related changes (less relevant at age 20 but important context):

• Normal follicular phase estradiol levels in reproductive-age women range from 130-210 pmol/L (approximately 35-57 pg/mL) 6
• Estradiol <5 pg/mL is profoundly abnormal at age 20 and requires urgent evaluation 6