Primary Amenorrhea

Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic–pituitary–ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Sometimes other endocrinopathies interfere with the sex hormones enough to suppress menstruation. Important factors to assess when working through the differential diagnosis are whether the patient has breast development (indicating exposure to estrogen from functional ovaries), the presence or absence of a uterus (indicating a potential genetic anomaly), and whether follicle-stimulating hormone (FSH) levels are high, low, or normal (providing insight into the HPO axis). Management includes correcting the underlying hormonal or anatomic issue, providing hormone replacement therapy (HRT), addressing fertility implications, and psychotherapy.

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Primary amenorrhea is defined as:

  • No menses by age 13 in absence of secondary sex characteristics 
  • No menses by age 15 regardless of secondary sex characteristics
  • Secondary sex characteristics include: 
    • Breast development 
    • Axillary hair
    • Pubic hair

Normal physiology

Hormones of the hypothalamic–pituitary–ovarian (HPO) axis and all relevant anatomy must be present and functioning in order for a girl to get her first menses. 

Summary of the hypothalamic–pituitary–ovarian axis

Summary of the hypothalamic–pituitary–ovarian axis:
The hypothalamus secretes gonadotropin-releasing hormone (GNRH), which stimulates the anterior pituitary to release the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The gonadotropins then stimulate the ovary to produce estrogen and progesterone, which in turn lead to endometrial growth and maturation. Any disruption in this pathway could lead to amenorrhea.

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  • Normal physiology review:
    • Hypothalamus releases gonadotropin-releasing hormone (GNRH) → stimulates the pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH) → ovary releases estrogen and progesterone
    • Estrogen and progesterone:
      • Produced by developing follicles within the ovary
      • Estrogen stimulates the endometrium to grow.
      • Progesterone matures and stabilizes the endometrium (produced only after ovulation).
      • Both ↓ at the end of the cycle → loss of “stabilizing” hormones (particularly progesterone) triggers efflux of menstrual fluid
  • Structural origins:
    • Genital ridge → primordial gonads → testes or ovaries
    • Müllerian ducts (paramesonephric ducts) → Fallopian tubes, uterus, cervix, and proximal two-thirds of the vagina
    • Urogenital sinus → distal ⅓ of the vagina
    • Wolffian ducts (mesonephric ducts) → epididymis, vas deferens, and seminal vesicles
  • Process of sex differentiation:
    • Presence of the sex-determining region of the Y chromosome (SRY) gene → primordial gonads into testes, which secrete:
      • Anti-Müllerian hormone (AMH), also called Müllerian-inhibiting substance → stimulates regression of Müllerian ducts
      • Testosterone → stimulates virilization of the Wolffian ducts into the epididymis, vas deferens, and seminal vesicles
    • In the absence of the SRY gene, the primordial gonads become ovaries.
      • Without testes producing high amounts of AMH, the Müllerian ducts persist → Fallopian tubes, uterus, cervix, and proximal vagina develop
      • Patients with Müllerian anomalies will usually have a normal HPO axis, normal ovaries, and normal external female genitalia
Human sex differentiation

Human sex differentiation:
Males and female fetuses develop in an identical fashion for the first 6 weeks, developing both Wolffian (male) and Müllerian (female) ducts. The presence or absence of the SRY gene causes the gonads to develop into either testes or ovaries.

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Etiology and Pathophysiology

Hypothalamic and pituitary etiologies

  • Pathophysiology: 
    • If GNRH is not being released or release is dysfunctional, there is: 
      • No FSH or LH released from the pituitary
      • No ovarian stimulation
      • No estrogen production
      • No endometrial proliferation
      • This results in no menses. 
  • Functional hypothalamic amenorrhea: 
    • Stress
    • Lack of nutrition: 
      • Eating disorders
      • Famine
    • Overexercise (common in female athletes)
  • Idiopathic hypogonadotropic hypogonadism (IHH): 
    • A family of genetic disorders resulting in GNRH deficiency or defects
    • Kallmann syndrome: IHH with anosmia
  • Constitutional delay of puberty: 
    • Overall delay of puberty
    • Uncommon in girls (diagnosis of exclusion)
    • Difficult to distinguish from IHH
  • Hyperprolactinemia: 
    • ↑ Prolactin can suppress the release of GNRH.
    • Usually presents as secondary amenorrhea, but can present as primary
    • Implicated medications: 
      • Antipsychotics
      • Tricyclic antidepressants
      • Metoclopramide
    • Often caused by pituitary adenomas
    • A similar mechanism can result from primary and central hypothyroidism: ↑ thyroid-releasing hormone → ↑ prolactin release
  • Systemic illness: 
    • Severe illness can ↓ GNRH.
    • Examples:
      • Type 1 diabetes mellitus
      • Celiac disease
      • Inflammatory bowel disease (IBD)
  • Infiltrative diseases: 
    • Sarcoidosis
    • Hemochromatosis
  • Neoplasia/sellar mass:
    • Craniopharyngioma
    • Germinoma
    • Langerhans cell histiocytosis

Ovarian/gonadal etiologies

  • Pathophysiology: 
    • The ovaries, oocytes, or follicles are abnormal.
    • No healthy oocytes/follicles → no estrogen or progesterone → no endometrial stimulation → no menses
  • Gonadal dysgenesis: 
    • When the gonads fail to form correctly and do not secrete sex hormones
    • Turner syndrome (45,X or mosaic forms): Ovaries are replaced with fibrotic tissue.
    • 46,XX gonadal dysgenesis: results in nonfunctional streak ovaries
    • Swyer syndrome (46,XY), failure of testicular development resulting in the absence of:
      • Testosterone → Wolffian structures do not develop.
      • AMH →  Müllerian structures persist.
  • Premature ovarian insufficiency (POI): 
    • Clinical menopause at < 40 years old
    • Often presents as secondary amenorrhea, but can present as primary
    • Causes:
      • FMR1 (the gene that causes fragile X syndrome) premutation
      • Chemotherapy
      • Radiation 
      • Autoimmune oophoritis

Uterine and vaginal etiologies

  • Pathophysiology: absence or obstruction of the uterus and/or vagina 
  • Müllerian agenesis (Mayer–Rokitansky–Küster–Hauser syndrome): 
    • Results in complete absence of the vagina with variable uterine development
    • Uterus may be: 
      • Normal and obstructed
      • Rudimentary with some functional endometrium
    • Ovaries are typically present and functional: 
      • HPO axis is intact → estrogen is produced
      • Breasts develop at puberty.
    • External female genitalia is normal.
  • Vaginal outflow obstruction: 
    • Transverse vaginal septum
    • Imperforate hymen

Other hormonal etiologies

  • Pathophysiology: hormonal interference in the HPO axis
  • Polycystic ovary syndrome (PCOS): 
    • Amenorrhea plus ↑ androgen levels 
    • Folliculogenesis is abnormal → oocytes are nonovulatory → progesterone is not produced → no menses
    • Usually presents as secondary amenorrhea, but rarely can present as primary
  • Complete androgen insensitivity syndrome (AIS): 
    • X-linked recessive disorder seen in 46,XY individuals
    • Testes, which make Müllerian-inhibiting substance, are present → causes regression of the Fallopian tubes, uterus, and upper vagina
    • The mutation results in defective androgen receptors → patients are resistant to testosterone (which tends to be ↑↑)
    • Testosterone is unable to virilize the Wolffian structures or external genitalia → phenotypically female
    • ↑ Testosterone is converted to estrogen → breasts develop at puberty
  • Congenital adrenal hyperplasia: 
    • Gene mutations lead to deficiencies in enzymes required for steroid biogenesis. 
    • Results in ↑ androgen levels → affects ovulation

Clinical Presentation and Diagnosis


  • No menses by age 13 years in the absence of secondary sex characteristics 
  • No menses by age 15 years regardless of secondary sex characteristics
  • Other manifestations depend on the underlying etiology.

Physical exam

  • Assess signs of secondary sex characteristics: 
    • Breast development → indicates exposure to estrogen
    • Axillary hair and pubic hair (sexual hair) → indicate exposure to testosterone
    • Hirsutism → androgen excess
  • Pelvic exam:
    • Look for an outflow obstruction.
    • Presence or absence of uterus and vagina
    • Ambiguous genitalia suggests a disorder of sexual differentiation.

Diagnostic considerations

  • To remember the differential diagnosis for primary amenorrhea, think about:
    • What can go wrong at each level of the HPO axis 
    • What can go wrong anatomically
  • Breast development and sexual hair means exposure to estrogen and testosterone, which indicates that:
    • The HPO axis is intact.
    • The gonads are functional.
  • No breasts or sexual hair → indicates no exposure to sex hormones:
    • The defect is at or above the level of the ovary.
    • Exception: presence of breasts, but no sexual hair → suspect AIS


Start by assessing 4 things: 

  1. Rule out pregnancy! (urine pregnancy test)
  2. Prolactin, thyroid-stimulating hormone (TSH), and thyroxine (T4) levels: 
    • ↑ Prolactin → hyperprolactinemia
    • ↓ or normal TSH with ↓ T4 → central hypothyroidism
    • ↑ TSH with ↓ T4 → primary hypothyroidism
  3. Presence of a uterus and vagina:
    • Pelvic exam and ultrasonography 
    • MRI for more complex cases
    • If the vagina is abnormal → examine under anesthesia; surgical management:
      • Transverse septum
      • Imperforate hymen
    • If the uterus is absent → order karyotype and testosterone measurement to look for:
      • 46,XX: Müllerian agenesis → normal testosterone
      • 46,XY: Complete AIS → ↑ testosterone
  4. FSH level (with uterus present):
    • FSH = issue is in the ovaries, which are not responding to FSH (but hypothalamus and pituitary are likely normal)
      • POI
      • Turner syndrome → confirm with karyotype
    • FSH = issue is in the brain: 
      • Functional hypothalamic amenorrhea (stress, undernutrition, overexercise)
      • Systemic illness (celiac, type 1 diabetes mellitus, IBD)
      • Kallmann syndrome
      • Congenital GNRH deficiency
      • Consider MRI to rule out sellar mass.


Management is dependent on the etiology and is usually aimed at correcting the underlying hormonal or anatomic issue.

  • General measures:
    • Resolve medical issues or stress.
    • Gain weight or ↓ exercise intensity (functional hypothalamic amenorrhea)
  • Medical therapy:
    • Hormone replacement therapy (HRT): ensures adequate estrogen exposure to maintain cardiovascular and bone health
    • Antiandrogen therapy (spironolactone)
  • Surgery:
    • Correction of congenital anatomic lesions
    • Removal of abnormal gonads: Patients are at risk for neoplasia (e.g., germ cell tumors, gonadoblastomas)
  • Consider fertility implications:
    • Pulsatile GNRH
    • In vitro fertilization
  • Counseling: 
    • Fertility
    • Issues with sexual differentiation
    • Eating disorders


  1. Welt CK, Barbieri RL. (2019). Causes of primary amenorrhea. In Martin KA (Ed.), UpToDate. Retrieved January 22, 2021, from
  2. Welt CK, Barbieri RL. (2020). Evaluation and management of primary amenorrhea. In Martin KA (Ed.), UpToDate. Retrieved January 22, 2021, from
  3. Hiort O. (2021). Typical sex development. In Martin KA (Ed.), UpToDate. Retrieved January 22, 2021, from 
  4. Welt CK. (2020). Clinical manifestations and diagnosis of spontaneous primary ovarian insufficiency (premature ovarian failure). In Martin KA (Ed.), UpToDate. Retrieved January 22, 2021, from
  5. Schorge JO, Schaffer JI, et al. (2008). Williams Gynecology (pp. 365-382).
  6. Pinkerton JV. (2020). Amenorrhea. Merck Manual Professional Version. Retrieved January 22, 2021, from
  7. Tough DeSapri KA. (2019). Amenorrhea. In Lucidi RS (Ed.), Medscape. Retrieved January 22, 2021, from

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