What are the causes of low estrogen levels?

Causes of Low Estrogen

Low estrogen results from either ovarian failure (primary hypogonadism) or hypothalamic-pituitary dysfunction (central hypogonadism), with specific causes including natural/premature menopause, surgical removal of ovaries, chemotherapy/radiation exposure, chronic liver disease, and low energy availability in athletes.

Primary Ovarian Causes (Ovarian Failure)

Natural and Premature Menopause

• Natural menopause occurs between ages 46-55 years (median 51 years) when ovarian estrogen production ceases 1
• Premature ovarian insufficiency (POI) is defined as ovarian failure before age 40, resulting in hypo-estrogenic state with elevated gonadotropins and oligomenorrhea/amenorrhea 2, 3
• Early menopause (ages 40-45) also causes estrogen deficiency and requires similar management to POI 3

Surgical Causes

• Bilateral oophorectomy induces acute surgical primary ovarian insufficiency, creating immediate and severe estrogen deficiency 4
• Oophorectomy is a documented cause of primary ovarian failure regardless of whether performed for cancer treatment or risk reduction 1

Cancer Treatment-Related

• Alkylating chemotherapy agents (classical and nonclassical) and heavy metals cause dose-dependent ovarian failure, with risk directly correlated to cumulative dose and age at exposure 1
• Ovarian radiation causes acute ovarian failure (AOF) and premature ovarian failure (POF):
  • Doses as low as 5 Gy affect ovarian function in postpubertal girls 1
  • Doses ≥10 Gy confer higher risk in prepubertal girls 1
  • Sterilizing dose is 20.3 Gy in infants, 18.4 Gy at age 10, and 16.5 Gy at age 20 1
• Risk-associated radiation fields include spine, flank, abdomen, pelvis, vagina, bladder, and total body irradiation 1
• Breast cancer treatment with aromatase inhibitors inhibits peripheral conversion of androgens to estrogens by >95%, causing severe estrogen deficiency 1

Central (Hypothalamic-Pituitary) Causes

Structural and Treatment-Related

• Hypothalamic/pituitary damage from tumor, radiation, or surgery impairs release of GnRH, LH, and FSH, resulting in central hypogonadism 1
• CNS radiation used to treat childhood cancers can adversely affect hormonal regulation 1

Low Energy Availability (Functional Hypothalamic Amenorrhea)

• Energy deficit in female athletes causes disruptions of LH pulsatility, which disturbs GnRH pulsatility and gonadotropin release 1
• This leads to menstrual dysfunction (oligo-amenorrhea) and systemic reductions in estradiol 1
• Energy availability <30 kcal/kg FFM/day discriminates between amenorrheic vs. eumenorrheic status 1
• Low energy states cause decreased estradiol, decreased progesterone, and multiple other hormonal alterations 1

Chronic Liver Disease

Metabolic and Hormonal Disruption

• Advanced liver disease causes altered estrogen metabolism and disruption of the hypothalamic-pituitary axis with low FSH and LH 1
• This leads to anovulation, amenorrhea, and infertility in women with cirrhosis 1
• Amenorrhea or oligomenorrhea occurs in >25% of women with advanced liver disease and nearly 75% of premenopausal women awaiting liver transplant 1
• Excess alcohol intake affects the hypothalamic-pituitary axis or directly affects ovarian function 1

Postmenopausal Estrogen Production

Extragonadal Sources

• In postmenopausal women, the ovaries cease producing estrogen as an endocrine hormone 5
• Estrogen is then produced in extragonadal sites (adipose tissue, bone, vascular endothelium, brain) where it acts locally as a paracrine/intracrine factor 5
• Circulating estrogen levels in postmenopausal women reflect rather than direct estrogen action, as they originate from local tissue production 5

Clinical Pitfalls

• Do not assume menstruation indicates normal estrogen levels: Women with cirrhosis can still become pregnant despite menstrual irregularities 1
• Premature menopause is often underdiagnosed: Women with POI before age 40 have substantially increased stroke risk and require hormone replacement until natural menopause age 1
• Cancer survivors need long-term monitoring: Young survivors who ceased menstruating ≥5 years after diagnosis have acute ovarian failure requiring assessment 1
• Hormone replacement is underutilized in POI: Inappropriate extrapolation of risks from older postmenopausal women leads to inadequate treatment of young women with premature ovarian insufficiency 2, 4