Can anorexia cause estrogen deficiency?

Can Anorexia Cause Estrogen Deficiency?

Yes, anorexia nervosa directly causes estrogen deficiency through energy deficit-induced suppression of the hypothalamic-pituitary-gonadal axis, resulting in decreased GnRH pulsatility, reduced LH secretion, and subsequently low estradiol levels. 1, 2

Mechanism of Estrogen Deficiency in Anorexia

The pathophysiology operates through a central hypothalamic mechanism rather than ovarian failure:

• Energy deficit disrupts GnRH pulsatility, which preferentially suppresses luteinizing hormone (LH) secretion while FSH remains relatively preserved 1
• Low LH levels fail to stimulate adequate ovarian estradiol production, leading to hypoestrogenism and amenorrhea 3, 2
• The LH:FSH ratio typically falls below 1 in approximately 82% of patients with functional hypothalamic amenorrhea (FHA), the condition underlying anorexia-related estrogen deficiency 1
• This is a functional, reversible problem—the ovaries remain capable of responding to appropriate hormonal stimulation, as demonstrated by successful ovulation induction with pulsatile GnRH therapy 1

Hormonal Cascade Beyond Estrogen

Energy deficiency in anorexia triggers multiple hormonal alterations beyond just estrogen:

• Decreased estradiol and progesterone are the primary reproductive hormone changes 3, 2
• Metabolic hormones shift dramatically: decreased leptin, increased ghrelin, increased cortisol, decreased insulin and IGF-1 3
• Thyroid function becomes suppressed: decreased T3, decreased free T3, and decreased free T4 3
• Growth hormone resistance develops with paradoxically increased GH but decreased IGF-1, contributing to stunted linear growth in adolescents 3

Clinical Consequences of Estrogen Deficiency

Bone Health (Most Critical for Morbidity)

The most serious consequence is severe osteoporosis with increased fracture risk, even in young patients:

• Women with anorexia nervosa have significantly reduced bone density compared to healthy controls (0.64 vs. 0.72 g/cm², P<0.001), with vertebral compression fractures documented even in young patients 4
• Over 90% of patients develop osteopenia and 26% meet WHO criteria for osteoporosis 5
• The severity of bone loss in anorexia exceeds that seen in other forms of hypothalamic amenorrhea (spine t-score: -1.80 in AN vs. -0.80 in HA, P<0.01) 6
• Fracture risk is doubled compared to eumenorrheic women 3

Cardiovascular Effects

Hypoestrogenism induces a post-menopausal-like cardiovascular physiology:

• Endothelial dysfunction develops, with approximately one-third of FHA patients showing decreased reactive hyperemia index 3
• Lipid profiles worsen with elevated LDL, total cholesterol, and triglycerides 3
• Long-term cardiovascular risk remains uncertain but cycle irregularities increase subsequent coronary heart disease risk 3

Reproductive Complications

If pregnancy occurs despite amenorrhea, significant obstetric risks emerge:

• 3-4 times increased risk of preterm birth 3
• Increased risk of miscarriage, hyperemesis, cesarean section for severe fetal growth restriction, and small for gestational age babies 3

Critical Diagnostic Distinction

A common pitfall is confusing anorexia-related FHA with PCOS, which has opposite hormonal patterns:

• **FHA shows LH:FSH ratio <1**, while PCOS shows ratio >2 1
• Gonadotropins are low or low-normal in FHA, not elevated as in primary ovarian insufficiency 1
• FHA patients lack the insulin resistance and elevated androgens characteristic of PCOS 1

Treatment Implications for Estrogen Deficiency

Weight Restoration is Primary

The Endocrine Society recommends BMI should reach ≥18.5 kg/m² before ovulation induction is offered 1, as weight restoration is the primary therapeutic intervention 1.

Estrogen Replacement Controversy

The role of estrogen/progestin replacement remains controversial and appears less effective than in other hypoestrogenic states:

• Estrogen-progestin therapy did not significantly increase bone mineral density compared to standard treatment alone in a prospective study of 50 adolescents with AN (no significant difference at 1-year follow-up with 80% power to detect 3% BMD difference) 5
• Nutritional factors, particularly lean body mass and BMI, are more important determinants of bone density than estrogen status itself 6, 7
• Multiple factors beyond estrogen deficiency contribute to bone loss in anorexia nervosa, including low IGF-1, hypercortisolemia, and malnutrition 8, 7

Bone Density Monitoring

Baseline DEXA scan is recommended after ≥6 months of amenorrhea, or earlier with risk factors for osteoporosis 3.

Important Caveats

• Physical activity may provide some skeletal protection despite estrogen deficiency—physically active anorexic patients had greater bone density than sedentary patients (P<0.001), though the mechanism is unclear 4
• Duration of amenorrhea inversely correlates with bone density at all sites, emphasizing the importance of early intervention 6
• Osteopenia can be persistent and progressive even with treatment over 2-3 years 5