Secondary Amenorrhea

Secondary amenorrhea is defined as the absence of menses for 3 months in a woman with previously regular menstrual cycles or for 6 months in a woman with previously irregular cycles. Etiologies involve either disruptions to the hypothalamic–pituitary–ovarian (HPO) axis or acquired obstructions in the uterus or outflow tract. The most common cause of secondary amenorrhea is pregnancy. The most common pathologic etiologies include functional hypothalamic amenorrhea, polycystic ovary syndrome, hyperprolactinemia, premature ovarian insufficiency, and Asherman’s syndrome. The diagnosis is made with a thorough history and physical examination, measurement of hormone levels, a pregnancy test, and imaging with pelvic ultrasonography. A progestin and/or combined estrogen–progestin challenge can help further identify the location of the abnormality. Management depends on the underlying etiology, clinical presentation, and patient desires regarding fertility. Treatment can include lifestyle, medical, and surgical management options.

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Overview

Definition

Secondary amenorrhea is defined as:

  • Absence of menses for 3 months in a woman with previously regular menstrual cycles
  • Absence of menses for 6 months in a woman with previously irregular menstrual cycles
  • Absence of menses for 3 cycle lengths (for women with longer cycle lengths)

Normal physiology

Hormones of the hypothalamic–pituitary–ovarian (HPO) axis and all relevant anatomy must be present and functioning in order for menstruation to occur regularly. 

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.

Image by Lecturio.
  • HPO axis: 
    • Hypothalamus → gonadotropin-releasing hormone (GNRH)
    • Pituitary → follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
    • Ovary → estrogen and progesterone 
    • Overall: GNRH → FSH and LH → estrogen and progesterone
  • Follicular/proliferative phase:
    • GNRH pulse stimulates the release of FSH.
    • FSH stimulates follicular development within the ovaries.
    • Developing follicles produce estrogen, specifically estradiol.
    • Estrogen:
      • Stimulates endometrial proliferation
      • Inhibits FSH secretion (feedback inhibition)
  • Ovulation: triggered by an LH surge
  • Luteal/secretory phase:
    • The ovulated follicle is now called the corpus luteum.
    • The corpus luteum produces both estradiol and progesterone.
    • Progesterone:
      • Stabilizes the endometrium 
      • Causes the endometrium to mature into secretory endometrium capable of sustaining a pregnancy
      • Study tip: progesterone = “progestational hormone” → produced only after ovulation, when gestation is possible
    • Estradiol and progesterone are secreted for 14 days following ovulation (enough time for a fertilized embryo to implant).
    • If pregnant: The corpus luteum continues producing progesterone until the placenta can take over.
    • If not pregnant: The corpus luteum becomes involuted → estradiol and progesterone levels fall
  • Menstrual phase:
    • Loss of stabilizing hormones (particularly progesterone) triggers breakdown of the endometrium → menses
    • Key point: Progesterone withdrawal triggers bleeding.
      • No ovulation → no progesterone
      • No progesterone → no regular menses (though abnormal uterine bleeding may still occur)
      • Many causes of secondary amenorrhea involve disrupted ovulation.
Ovarian cycle

Hormone changes throughout the menstrual cycle:
This chart shows the changing concentrations of FSH, LH, estradiol, and progesterone throughout the length of the menstrual cycle. Notice the sudden rise in estradiol, LH, and FSH around day 14 (green line) during ovulation and the rise in progesterone during the luteal phase in anticipation of fertilization and implantation of the ovum. Disruptions in ovulation can lead to amenorrhea.

Image by Lecturio.

Etiology and Pathophysiology

Obstetric causes

Pregnancy is the most common cause of secondary amenorrhea. Always rule this out first!

Hypothalamic and pituitary causes

  • Pathophysiology: 
    • If GNRH is not being released or is dysfunctional, there is: 
      • No FSH/LH released from the pituitary
      • No ovarian stimulation
      • No estrogen production
      • No endometrial proliferation
      • No menses 
  • Functional hypothalamic amenorrhea: 
    • The most common cause of non–pregnancy-related secondary amenorrhea
    • The body’s way of preventing reproduction during times of severe physical or psychological stress:
      • Stress (↑ cortisol)
      • Lack of nutrition or weight loss (eating disorders or famine)
      • Overexercise (common in female athletes)
    • Female athlete triad: 
      • Menstrual dysfunction
      • ↓ Energy (with or without an eating disorder)
      • ↓ Bone density
  • Hyperprolactinemia: 
    • ↑ Prolactin → ↓ GNRH
    • Many medications can ↑ prolactin: 
      • Antipsychotics
      • Cyclic 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.
    • Common examples include:
      • Diabetes mellitus type 1
      • Celiac disease
      • Inflammatory bowel disease (IBD)
  • Infiltrative diseases: 
    • Sarcoidosis
    • Hemochromatosis
  • Neoplasia/sellar mass: 
    • Craniopharyngioma
    • Lymphoma
    • Langerhans cell histiocytosis
  • Empty sella syndrome
  • Sheehan syndrome: 
    • Severe postpartum hemorrhage → ischemic pituitary infarction → hypopituitarism
    • Can cause amenorrhea, ↓ prolactin, hypothyroidism, and adrenal insufficiency

Ovarian causes

  • Pathophysiology: 
    • Ovaries or oocytes are abnormal.
    • No healthy oocytes → no estrogen or progesterone → no endometrial stimulation → no menses
    • ↑ FSH because ovaries are not responding appropriately
  • Premature ovarian insufficiency (POI):
    • The depletion of oocytes and clinical menopause at < 40 years old
    • Causes of POI:
      • FMR1 (the gene that causes fragile X syndrome) premutation
      • Turner syndrome
      • Chemotherapy or radiation 
      • Idiopathic

Other causes of ovulatory dysfunction or chronic anovulation

  • Pathophysiology: 
    • Hormonal interference in the HPO axis
    • Follicular development is abnormal → oocytes are nonovulatory → progesterone is not produced → no menses
    • Full mechanism is often incompletely understood.
    • May include: 
      • ↑ Androgens
      • Disruptions in FSH or LH
      • Excess estrogen exposure → feedback inhibition in pituitary → ↓ FSH
      • ↑ Adrenocorticotropic hormone (ACTH), cortisol, or other glucocorticoids (endogenous or exogenous)
  • Polycystic ovary syndrome (PCOS): 
    • Oligomenorrhea/amenorrhea plus ↑ androgens 
    • Polycystic-appearing ovaries may or may not be present.
    • A condition of chronic anovulation
    • Associated with metabolic syndrome: 
      • Insulin resistance
      • Hyperlipidemia
      • Hypertension 
      • Associated with obesity
  • Nonclassical congenital adrenal hyperplasia (NC-CAH): 
    • Congenital 21-hydroxylase deficiency → ↑ androgen levels
    • Clinically indistinguishable from PCOS, except on laboratory evaluation
  • Androgen-secreting tumors (ovarian or adrenal)
  • Estrogen-secreting tumors (ovarian)
  • Hyperthyroidism
  • Cushing syndrome: ↑ cortisol or glucocorticoids (endogenous or exogenous) → disrupts HPO axis (↓ FSH)
  • Adrenal insufficiency: ↓ cortisol production → ↑ ACTH → disrupts HPO axis (↓ FSH)

Anatomic causes

  • Pathophysiology: 
    • Physical obstruction of the outflow tract
    • By definition, there is history of prior menses → normal uterine and vaginal anatomy at birth 
    • Any defects are acquired.
  •  Asherman’s syndrome:
    • Uterine adhesions
    • May result from:
      • Uterine surgeries (e.g., dilation and curettage)
      • Infections (e.g., pelvic inflammatory disease)
  • Cervical stenosis:
    • Scarring after cervical procedures done to treat cervical dysplasia
    • More likely after multiple procedures

Summary of the most common causes

The most common causes of secondary amenorrhea and their frequency
Cause of secondary amenorrhea Approximate frequency
Functional hypothalamic amenorrhea 35%
PCOS 30%
Hyperprolactinemia 13%
POI 10%
Asherman’s syndrome 5%
Other 7%

Clinical Presentation

A woman of reproductive age with absence of menses for:

  • 3 months with a history of previously regular menstrual cycles
  • 6 months with a history of previously irregular menstrual cycles
  • 3 cycle lengths (for women with longer cycle lengths)

Clinical features depend on underlying etiology but may include:

  • Signs of pregnancy: 
    • Fatigue
    • Nausea
    • Enlarged uterus
  • Signs of functional hypothalamic amenorrhea: 
    • Underweight or recent weight loss
    • History of eating disorder 
    • Female athlete or history of excessive exercise
    • Osteoporotic fracture
  • Signs of hyperprolactinemia: 
    • Galactorrhea
    • Breast engorgement
  • Signs of hypothyroidism
    • Fatigue
    • Constipation
    • Thinning hair, skin, or nails
    • Feeling cold
  • Signs of hyperandrogenism (consider PCOS, CAH, and androgen-secreting tumors):
    • Hirsutism (facial and body hair growth)
    • Cystic acne
    • Male pattern hair loss
    • Virilization (occurs only when androgens are ↑↑)
  • Signs of menopause/POI: 
    • Hot flashes
    • Night sweats
    • Mood swings
    • Vaginal dryness
    • Decreased libido

Diagnosis

Laboratory evaluation

Initial tests:

  • Positive urine pregnancy test or qualitative hCG → pregnant
  • ↑ Prolactin → hyperprolactinemia
  • Thyroid function testing:
    • ↓ or normal TSH with ↓ thyroxine (T4) → central hypothyroidism
    • ↑ TSH with ↓ T4 → primary hypothyroidism
    • ↓ TSH with ↓ T4 → hyperthyroidism
  • FSH and estrogen:
    • ↑ FSH and ↓ estradiol: POI
    • ↓ FSH and ↓ estradiol: hypothalamic hypogonadism → functional hypothalamic amenorrhea, systemic illness, infiltrative disease, brain tumors
    • ↓ FSH and ↑ estradiol: estrogen is suppressing FSH → look at testosterone
  • Testosterone:
    • ↑ Testosterone and ↑ estradiol: PCOS
    • ↓ Testosterone and ↑ estradiol: estrogen-secreting ovarian tumor
    • ↑ Testosterone and ↓ estradiol: testosterone-secreting ovarian tumor

If signs of ↑ androgens are present, but testosterone is normal:

  • Dehydroepiandrosterone sulfate (DHEA-S): 
    • An adrenal androgen that can cause menstrual irregularities when ↑ 
    • May be ↑ in adrenal tumors
  • 17-hydroxyprogesterone: 
    • The substrate for 21-hydroxylase
    • ↑ in NC-CAH
  • PCOS: 
    • 2-hour glucose tolerance test 
    • Fasting lipid panel

Imaging

  • Pelvic ultrasonography:
    • PCOS: polycystic-appearing ovaries and a thickened endometrium (due to estrogen exposure without postovulatory progesterone)
    • POI: thin endometrium (due to lack of estrogen exposure)
    • Hormone-secreting ovarian tumors: solid ovarian mass
  • Brain MRI: 
    • If a hypothalamic (or pituitary) cause other than functional hypothalamic amenorrhea or systemic illness is suspected
    • Hyperprolactinemia: likely secondary to a pituitary adenoma
    • Infiltrative diseases
    • Masses or tumors
  • DEXA scan:
    • To assess bone mineral density in patients with hypothalamic hypogonadism
    • Especially important in eating disorders and in athletes at risk for the female athlete triad

Progestin challenge

  • Assess for bleeding following a 10-day course of a progestin.
  • If withdrawal bleeding occurs: 
    • Proves the patient can menstruate with proper hormone exposure
    • Suggests anovulation → estrogen without progesterone
    • Consider PCOS or other conditions with unopposed estrogen.
  • If withdrawal bleeding does not occur:
    • Suspect an HPO axis issue or outflow tract obstruction.
    • Do an estrogen–progestin challenge.
Progesterone challenge test algorithm

Progesterone challenge test

Image by Lecturio.

Estrogen–progestin challenge

  • Give estrogen to stimulate the endometrium, followed by a short course of progestin → assess for bleeding
  • If withdrawal bleeding occurs: 
    • Proves the patient can menstruate with the proper hormone exposure
    • Suggests no production of ovarian hormone → no estrogen or progesterone
    • Consider hypothalamic causes and POI.
  • If withdrawal bleeding does not occur: 
    • Proves the problem is in the uterus or outflow tract
    • Consider Asherman’s syndrome (history of pelvic inflammatory disease (PID) or prior uterine surgery) or cervical stenosis (history of cervical procedures).

Management

Management depends on the etiology.

Treat other medical conditions:

  • Obstetric care, if pregnant
  • Hypothyroidism or hyperthyroidism management
  • Systemic illness

Lifestyle management:

  • Functional hypothalamic amenorrhea:
    • Weight gain (to a BMI > 19)
    • ↓ Exercise intensity 
    • Psychotherapy
    • Stress management
  • PCOS: weight loss, if overweight

Medical management:

  • Ensure patient has exposure to estrogen and progesterone through:
    • Resumption of normal ovulation
    • Oral contraceptive pills (OCPs)
    • Hormone replacement therapy (HRT)
  • Hyperprolactinemia: 
    • Dopamine agonists → ↓ prolactin → restore HPO function
    • Options: cabergoline, bromocriptine
  • Hyperandrogenism/PCOS: 
    • OCPs
    • Spironolactone
    • Insulin-sensitizing agents (metformin)

Surgical management:

  • Correct anatomic obstructions.
  • Excise tumors.

Fertility treatment, if desired:

  • Ovulation induction
  • In vitro fertilization

References

  1. Welt CK, Barbieri RL. (2020). Epidemiology and causes of secondary amenorrhea. In Martin KA (Ed.), UpToDate. Retrieved January 23, 2021, from https://www.uptodate.com/contents/epidemiology-and-causes-of-secondary-amenorrhea
  2. Welt CK, Barbieri RL. (2020). Evaluation and management of secondary amenorrhea. In Martin KA (Ed.), UpToDate. Retrieved January 24, 2021, from https://www.uptodate.com/contents/evaluation-and-management-of-secondary-amenorrhea
  3. Welt CK, Barbieri RL. (2020). Clinical manifestations of polycystic ovary syndrome in adults. In Martin KA (Ed.), UpToDate. Retrieved January 24, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-polycystic-ovary-syndrome-in-adults 
  4. Schorge JO, Schaffer JI, et al. (2008). Williams Gynecology (pp. 365-382).
  5. Pinkerton JV. (2020). Amenorrhea. Merck Manual Professional Version. Retrieved February 14, 2021, from https://www.merckmanuals.com/professional/gynecology-and-obstetrics/menstrual-abnormalities/amenorrhea
  6. Tough DeSapri KA. (2019). Amenorrhea. In Lucidi RS (Ed.), Medscape. Retrieved February 14, 2021, from https://emedicine.medscape.com/article/252928-overview

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