TOPIC 2: Amenorrhea (Primary) – Understand the differential diagnosis, evaluation, and management of primary amenorrhea

Amenorrhea (Primary) – Understand the differential diagnosis, evaluation, and management of primary amenorrhea

BACKGROUND

Primary amenorrhea is the absence of menarche by age 15 in the presence of normal growth and secondary sexual characteristics. Identifying and managing primary amenorrhea is crucial for addressing underlying conditions and ensuring proper pubertal development.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of primary amenorrhea can be categorized according to the level of reproductive system dysfunction:

• Central Causes (Hypothalamic/Pituitary)
  • Functional hypothalamic amenorrhea: Stress, weight loss, excessive exercise leading to suppression of gonadotropin-releasing hormone (GnRH) pulsatility, hypoestrogenism.
  • Isolated GnRH deficiency: Congenital or acquired defects in GnRH synthesis or secretion, often associated with anosmia (Kallmann syndrome).
  • Tumors: Craniopharyngioma, prolactinoma, or other sellar/suprasellar masses causing compression or destruction of the hypothalamus or pituitary gland.
  • Infiltrative diseases: Sarcoidosis, hemochromatosis, or other disorders infiltrating the hypothalamus or pituitary gland.

Ovarian Causes:

• Gonadal dysgenesis: Abnormal development of the ovaries, often associated with chromosomal abnormalities (e.g., Turner syndrome).
• Primary ovarian insufficiency: Premature depletion of ovarian follicles due to genetic, autoimmune, or idiopathic causes.
• Polycystic ovary syndrome (PCOS): Hyperandrogenism, oligomenorrhea or amenorrhea, and polycystic ovarian morphology on ultrasound.

Genital Outflow Tract Anomalies:

• Imperforate hymen: Failure of the hymen to perforate during fetal development, leading to obstruction of menstrual flow.
• Transverse vaginal septum: Incomplete canalization of the vaginal plate resulting in a septum obstructing menstrual flow.
• Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome): Congenital absence of the uterus and variable portions of the vagina.
• Androgen insensitivity syndrome: Resistance to androgens due to mutations in the androgen receptor gene, resulting in a female phenotype in individuals with a 46,XY karyotype.

Other Causes:

• Thyroid disorders: Hypothyroidism or hyperthyroidism can disrupt the hypothalamic-pituitary-ovarian axis.
• Cushing syndrome: Excess cortisol production can suppress gonadotropin secretion and cause amenorrhea.
• Adrenal disorders: Congenital adrenal hyperplasia can lead to hyperandrogenism and amenorrhea.
• Constitutional delay of puberty: A variation of normal pubertal development, characterized by delayed onset of secondary sexual characteristics and menarche.
• Pregnancy: Rare cause of “primary amenorrhea” but should be considered and ruled out.

EVALUATION

Primary amenorrhea should be investigated if there is no menarche by age 15 or if there is no menarche within 3 years of thelarche. Evaluation should also occur in girls aged 13 with no secondary sexual characteristics.

HISTORY

• Timing and progression of pubertal development
• Family history of delayed puberty, genetic disorders, or endocrine abnormalities
• Neonatal history, including gestational age, birth weight, and presence of ambiguous genitalia
• Developmental milestones and growth patterns
• Symptoms of hyperandrogenism (e.g., hirsutism, acne, male-pattern baldness)
• Presence of chronic stress, excessive exercise, or disordered eating
• Medications, including hormonal treatments and illicit drug use
• Review of systems to identify symptoms of systemic illness or endocrine disorders
• Cyclic pelvic pain, indicating a possible outflow tract obstruction

PHYSICAL EXAMINATION

• Height, weight, and BMI, with attention to growth charts
• Vital signs, including blood pressure (to screen for hypertension in Turner syndrome or congenital adrenal hyperplasia)
• Tanner staging of breast and pubic hair development
• Look for signs of Turner syndrome: short stature, webbed neck, wide-spaced nipples
• Detailed genital examination:
  • Inspection of the external genitalia for ambiguity, clitoromegaly, or labial fusion
  • Assessment of hymenal patency and vaginal canal depth
  • Palpation for the presence of a uterus or gonadal masses
• Skin examination for signs of hyperandrogenism, hyperpigmentation, or acanthosis nigricans
• Thyroid palpation and examination for signs of hypo- or hyperthyroidism
• Abdominal examination for masses or enlargement of the liver or spleen
• Neurologic examination, including assessment of olfaction (to screen for Kallmann syndrome)

DIAGNOSTIC TESTS FOR PRIMARY AMENORRHEA

MANAGEMENT

The management of primary amenorrhea depends on the underlying cause and often involves a multidisciplinary approach with input from pediatrics, endocrinology, gynecology, and reproductive medicine.

• Gonadal Dysgenesis (e.g., Turner Syndrome)
  • Hormone replacement therapy (estrogen and progestin) to induce pubertal development and maintain bone health.
  • Screening for associated conditions (e.g., cardiovascular, renal, and autoimmune disorders).
• Müllerian Agenesis (Mayer-Rokitansky-Küster-Hauser Syndrome)
  • Creation of a neovagina through nonsurgical or surgical techniques.
  • Psychosexual counseling and emotional support.
• Androgen Insensitivity Syndrome
  • Gonadectomy to prevent gonadal malignancy (typically after completion of puberty).
  • Hormone replacement therapy with estrogen to maintain bone health and feminine characteristics.
  • Vaginal dilation or surgical creation of a neovagina.
  • Psychosexual counseling and emotional support.
• Functional Hypothalamic Amenorrhea
  • Lifestyle modifications to address underlying stressors, increase caloric intake, and reduce excessive exercise.
  • Cognitive-behavioral therapy to address disordered eating behaviors and body image concerns.
  • Monitoring for recovery of hypothalamic-pituitary-ovarian axis function.
  • Consider hormone replacement therapy with estrogen and progestin to maintain bone health and relieve hypoestrogenic symptoms if lifestyle modifications are ineffective.
• Polycystic Ovary Syndrome (PCOS)
  • Lifestyle modifications to promote weight loss and improve insulin sensitivity.
  • Metformin to improve insulin sensitivity and reduce hyperandrogenism.
  • Combined oral contraceptives to regulate menstrual cycles and reduce hyperandrogenism.
  • Antiandrogens (e.g., spironolactone) to reduce hirsutism and acne.
  • Screening for associated metabolic disorders (e.g., diabetes, dyslipidemia).
• Imperforate Hymen or Transverse Vaginal Septum
  • Surgical correction (e.g., hymenectomy, septum resection) to allow menstrual flow and prevent complications.
• Congenital Adrenal Hyperplasia
  • Glucocorticoid replacement to suppress adrenal androgen production.
  • Mineralocorticoid replacement in salt-wasting forms.
  • Surgical correction of virilized genitalia, if indicated.
• Hypothalamic or Pituitary Tumors
  • Surgical resection or debulking of the tumor.
  • Hormone replacement therapy to address pituitary hormone deficiencies.
  • Radiation therapy or chemotherapy, if indicated.
  • Long-term monitoring for tumor recurrence and endocrine function.

REFERENCES

https://www.uptodate.com/contents/evaluation-and-management-of-primary-amenorrhea/

https://www.uptodate.com/contents/causes-of-primary-amenorrhea/

https://publications.aap.org/pediatricsinreview/article/34/1/6/34750/Menstrual-Disorders