Key Points
- Functional hypothalamic amenorrhea (FHA) is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof.
- Investigations should include assessment of systemic and endocrinologic etiologies, since FHA is a diagnosis of exclusion.
- A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support.
- Medical complications include, among others, bone loss and infertility.
- Appropriate therapies are under debate and investigation.
DIagnosis
- Endocrine Society (ES) suggests that clinicians make the diagnosis of functional hypothalamic amenorrhea (FHA) only after excluding the anatomic or organic pathology of amenorrhea. (U)
- ES suggests diagnostic evaluation for FHA in adolescents and women whose menstrual cycle interval persistently exceeds 45 days and/or those who present with amenorrhea for ≥3 months. (2|⊕⊕)
- ES suggests screening patients with FHA for psychological stressors (patients with FHA may be coping with stressors, and stress sensitivity has multiple determinants). (2|⊕⊕⊕)
- Once clinicians establish the diagnosis of FHA, the ES suggests they provide patient education about various menstrual patterns occurring during the recovery phase. ES suggests clinicians inform patients that irregular menses do not require immediate evaluation and that menstrual irregularity does not preclude conception. (U)
Grading System
Strength of Recommendation | 1 = strong | 2 = weak | U = ungraded | |||
Quality of Evidence | ⊕⊕⊕⊕ = high | ⊕⊕⊕ = moderate | ⊕⊕ = low | ⊕ = very low | ||
Table 1. Potential Etiologies of Amenorrhea
Congenital malformation |
|---|
Septo-optic dysplasia |
Holoprosencephaly |
Encephalocele |
Constitutional delay |
Genetic conditions |
Congenital deficiency of hypothalamic or pituitary transcription factors (gonadotropin deficiency) |
Single-gene mutations (hypogonadotropic hypogonadism) |
Hyperprolactinemia |
Pituitary gland or stalk damage |
Tumors and cysts [hypothalamic or pituitary tumor (hormone-secreting), craniopharyngioma, Rathke cleft cyst, other cysts, and tumors] |
Infiltrative disorders (germinoma, autoimmune hypophysitis, sarcoidosis, hemochromatosis, tuberculosis, Langerhans cell histiocytosis, IgG4-related hypophysitis) |
Irradiation |
Infarction [apoplexy in pre-existing pituitary tumors, or following postpartum hemorrhage (Sheehan syndrome)] |
Surgery |
Trauma |
Others |
Eating disorders |
Competitive athletics |
Chronic disease |
Mood disorders |
Stress or psychiatric illness |
Drugs |
Thyroid |
Hypothyroidism or hyperthyroidism |
Adrenals |
Congenital adrenal hyperplasia (select types) |
Cushing syndrome |
Addison disease (adrenal insufficiency) |
Tumor (androgen-secreting) |
Ovaries |
Associated with high levels of gonadotropins |
Gonadal agenesis or dysgenesis (in the setting of Turner syndrome/other) |
Ovarian insufficiency |
Autoimmune oophoritis |
Irradiation or surgery |
Not associated with high levels of gonadotropins |
Polycystic ovary syndrome |
Tumor (estrogen- or androgen-secreting) |
Uterus (eugonadism) |
Müllerian anomalies (obstructive outflow anomalies) |
Asherman syndrome |
Synechiae (integral to Asherman syndrome) |
Pregnancy |
Infectious (e.g., tuberculous endometritis) |
Agenesis (uterine or cervical) |
Vagina (eugonadism) |
Agenesis |
Transverse septum |
Hymen (eugonadism) |
Imperforate |
Table 2. Common Causes of Anovulation and Accompanying Laboratory Patterns
Functional hypothalamic anovulation | Ovarian insufficiency Menopause | PCOS | Nonclassical CAH | Hyperprolactinemia | |
|---|---|---|---|---|---|
LH | <10 | >15 | <15 | <15 | <10 |
FSH (IU/L) | <10 | >15 | <10 | <10 | <10 |
LH/FSH | ~1 | LH < FSH | LH > FSH | LH > FSH | LH < FSH |
E2 | <50 | <50 | <50 | <50 | <50 |
P4 | <1 | <1 | <1 | ≤1 | <1 |
AMH | >1 | <0.5 | nl or ↑ | nl | nl |
PRL | Low nl | nl | High nl | nl | ↑ |
TSH | Low nl | nl or ↑ | nl | nl | nl or ↑ |
T4 | Low nl | nl or ↓ | nl | nl | nl |
DHEA-S (μg/dL) | nl | nl | High nl | High nl | nl or slight ↑ |
17-OHP (ng/dL) | nl | nl | nl | ↑ | nl |
T | Low nl | Low nl | High nl or slight ↑ | ↑ | nl |