Amenorrhea

AUTHORS: Noushine Sadeghi, MD and Rachel Wright Heinle, MD, FACOG

Description

Amenorrhea means absence of menstruation. It is classified as either primary or secondary depending on whether the patient has had previous menstrual cycles.
Workup for primary amenorrhea is indicated for any adolescent age 15 or older who has not reached menarche or who does not reach menarche within 3 yr of thelarche.
Secondary amenorrhea is the absence of menses for more than 6 mo in a patient who has had previous normal menstrual progesterone withdrawal cycles.

ICD-10CM CODES
N91.0		Primary amenorrhea
N91.1		Secondary amenorrhea
N91.2		Amenorrhea, unspecified

Epidemiology & Demographics

Incidence of primary amenorrhea and secondary amenorrhea in the U.S. is <1% and 5% to 7%, respectively.
There is no racial or ethnic predilection.

Etiology

Physiologic amenorrhea:
1. Pregnancy
2. Lactation
3. Constitutional delay of puberty
4. Menopause
Pathologic amenorrhea

	Primary Amenorrhea	Secondary Amenorrhea
Hypergonadotropic hypogonadism	45 X (27%) 46 XX (14%) 46 XY (2%)	46, XX with gonadal failure (10%) Abnormal karyotype (0.5%)
Eugonadism	Müllerian agenesis (15%) Vaginal septum (3%) Imperforate hymen (1%) Polycystic ovarian syndrome (7%) Congenital adrenal hyperplasia (1%) Cushing and thyroid disease (2%) Androgen insensitivity (1%, Table E1)	Polycystic ovary syndrome (PCOS) (28%) Eating disorders, stress (15.5%) Hypothyroidism (1.5%) Sheehan syndrome (1.5%) Cushing syndrome (1%) Pituitary tumor/empty sella (2%)
Hypogonadotropic hypogonadism	Constitutional delay (14%) GnRH deficiency (5%) Other CNS disease (1%) Pituitary diseases (5%) Eating disorders, stress (2%)	Nonclassic congenital adrenal hyperplasia (0.5%) Ovarian tumor (1%)
Other causes		Hyperprolactinemia (13%) Anatomic (7%, Asherman syndrome)

TABLE E1 Congenital Anatomic Causes of Primary Amenorrhea With Normal Breast Development ∗

Diagnosis	Müllerian Agenesis	Androgen Insensitivity (AI)	Transverse Vaginal Septum	Imperforate Hymen
Patients with primary amenorrhea ^†	15%	1%	3%	1%
Patients with primary amenorrhea and apparent obstruction or absence of vagina ^†	75%	5%	15%	5%
Chromosomes ^‡	46,XX	46,XY	46,XX	46,XX
Gonads	Ovaries	Testes	Ovaries	Ovaries
Serum testosterone ^‡	Normal female level	Normal male level (high)	Normal female level	Normal female level
Vagina	Absent or shallow	Absent or shallow	Obstructed by septum, which may be thick or thin, high or low	Obstructed by thin membrane, which may look blue from hematocolpos
Axillary/pubic hair	+	Absent unless AI is incomplete	+	+
Cyclic pain	±	–	+	+
Uterus	Absent or rudimentary	–	+	+
Mass	–	–	+ Can present with acute urinary retention as hematocolpos mass obstructs urethra	+ Can present with acute urinary retention
Introitus bulges with Valsalva maneuver	–	–	–	+
Associated anomalies	Urinary tract and skeletal	Inguinal hernias; gonadal malignancy in adulthood	Major urinary tract abnormalities in 15%	Possibly some increase in urinary tract abnormalities
Treatment	Vaginal dilation or surgical neovagina	Gonadectomy after age 16-18 yr Vaginal dilation or surgical neovagina	Surgical approach depends on extent and location of septum; may be extensive; should be done as soon as possible	Excision of hymen as soon as possible; diagnostic needle aspiration contraindicated because of risk of infection
Fertility	Advanced reproductive technology required; in vitro fertilization surrogate with uterus to gestate pregnancy	Not fertile	Variable, low septa have a better prognosis than do high septa	Usually fertile

+, Present; –, absent; ±, may be present or absent.

^∗Cervix not visible on pelvic examination. Short vagina; may be absent or obstructed.

^†Data from Reindollar RH, Byrd JR, McDonough PG: Delayed sexual development: a study of 252 patients, Am J Obstet Gynecol 140:371, 1981.

^‡Sometimes useful in differentiating Müllerian agenesis from androgen insensitivity.

From Kliegman RM et al: Practical strategies in pediatric diagnosis and therapy, ed 2, Philadelphia, 2004, Elsevier.

Physical Findings & Clinical Presentation

Turner syndrome:
1. Usually manifests with primary amenorrhea unless mosaic
2. Short stature
3. Epicanthic folds
4. Low-set ears
5. High-arched palate
6. Micrognathia
7. Sensorineural hearing loss
8. Otitis media
9. Webbing of the neck
10. Pigmented nevi
11. Square/shield chest
12. Widely spaced nipples
13. Absent breast development
14. Bicuspid aortic valve
15. Coarctation of aorta
16. Cubit valgus
17. Short fourth metacarpal
18. Hyperconvex nails
19. Leg edema
20. Renal abnormalities
21. Autoimmune disorders including thyroiditis
22. Diabetes mellitus
Pure gonadal dysgenesis:
1. Unlike Turner syndrome, has no dysmorphic features
Müllerian agenesis:
1. Sporadic inheritance
2. Primary amenorrhea
3. Normal breast development
4. Normal pubic and axillary hair
5. Normal female external genitalia
6. Absent uterus and upper part of vagina
7. Ovaries present
8. Renal and vertebral anomalies in some patients; renal agenesis should be evaluated
Transverse vaginal septum and imperforate hymen:
1. Primary amenorrhea
2. Progressive cyclic lower abdominal pain
3. Imperforate hymen or transverse vaginal septum on pelvic examination
4. Perirectal fullness from hematocolpos
Androgen insensitivity syndrome:
1. Primary amenorrhea
2. X-linked recessive inheritance in some patients
3. Normal breast development
4. Absent pubic and axillary hair
5. Testis may be present in the groin or inguinal canal
6. Uterus and vagina absent
7. No associated renal or vertebral anomalies
Adult-onset congenital adrenal hyperplasia:
1. More frequently seen in Ashkenazi Jewish, Inuit Native American, French Canadian, and Mexican populations than other populations
2. Mimics the presentation of PCOS
3. Features of hyperandrogenism (virilization, hirsutism, acne)
4. Hypertension
5-Alpha reductase deficiency:
1. Primary amenorrhea
2. Undergo virilization at puberty
PCOS:
1. Usually presents with secondary amenorrhea and oligomenorrhea
2. Diagnosed with ≥2/3 of the Rotterdam Criteria:
  1. Oligo/anovulation
  2. Hyperandrogenism
  3. Polycystic ovaries on ultrasound (in one or both ovaries, either ≥12 follicles measuring 2 to 9 mm in diameter, or increased ovarian volume >10 cm³)
3. Associated with the metabolic syndrome and obesity (60% to 80% of PCOS patients)
4. Insulin resistance, predisposition to type 2 diabetes mellitus
Cushing syndrome (rare disorder, prevalence 1/1,000,000):
1. Secondary amenorrhea
2. Features of hyperandrogenism
3. Abnormal fat distribution (dorsocervical fat pad, spider legs, significant central obesity)
4. Abdominal striae due to weakening of skin integument
5. Easy bruising
6. Hypertension
7. Proximal muscle weakness
Hypothyroidism:
1. Secondary amenorrhea
2. Lethargy
3. Constipation
4. Decreased appetite
5. Weight gain
6. Cold intolerance
7. Hair loss
8. Dry skin
9. Bradycardia
Primary ovarian insufficiency (previously premature ovarian failure):
1. Secondary amenorrhea prior to the age of 40 and elevated gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH])
2. History of oophorectomy or pelvic radiation or chemotherapy
3. Vasomotor symptoms
4. Dry, thin vaginal mucosa without rugosity
5. Associated autoimmune or karyotypic abnormalities possible
Hyperprolactinemia:
1. Usually presents with secondary amenorrhea
2. History of use of drugs such as antipsychotics, oral contraceptive (OC) pills, antidepressants, antihypertensives, H₂ blockers, opioids, etc.
3. Pituitary adenomas may be associated with headache, vomiting, vision changes
4. Galactorrhea
Sheehan syndrome:
1. History of secondary amenorrhea following postpartum hemorrhage
2. Failure of lactation
3. Other features of hypopituitarism
Asherman syndrome:
1. History of D&C
2. Secondary amenorrhea
3. Recurrent miscarriage/infertility
Functional hypothalamic disorders:
1. Usually presents with secondary amenorrhea
2. History of eating disorders, severe exercise or stress
3. Use of street drugs
Kallmann syndrome:
1. Usually presents with anosmia, congenital defect of development of both the GnRH neurons and olfactory placode

Diagnosis ⬆ ⬇

First step in the workup of amenorrhea is to rule out pregnancy by serum/urine pregnancy test.
Diagnostic workup depends on history and physical (Fig. E1).
Physical examination, determining the presence or absence of advanced breast Tanner stage and presence or absence of uterus can help guide evaluation (e.g., presence of breasts but absence of uterus can only be Müllerian agenesis or androgen insensitivity syndrome).
Primary amenorrhea:
1. Pelvic ultrasonography or MRI to detect any anatomic abnormalities of uterus, cervix, ovaries, or vagina.
2. Karyotyping (46,XX in Müllerian agenesis; 46,XY in AIS; 45,XO in Turner syndrome) is done when uterus is absent or Turner syndrome is suspected.
3. Serum FSH, thyroid-stimulating hormone [TSH]/FT4, prolactin, estradiol:
  1. FSH 40 mIU/ml along with estradiol <20 pg/ml is indicative of primary ovarian insufficiency.
  2. Prolactin >200 ng/ml is suggestive of prolactinoma. Threshold levels may vary by laboratory, and providers are advised to become familiar with their institution’s normal range.
4. Check serum testosterone (male range in AIS; female range in Müllerian agenesis) when uterus is absent or in presence of features of hyperandrogenism.
5. 17-Alpha hydroxyprogesterone level in presence of features of hyperandrogenism to rule out CAH. In addition to high level of 17 alpha hydroxyprogesterone due to compromised 21-hydroxylase activity, these patients may have elevated level of serum progesterone and deoxycorticosterone, hypernatremia, and hypokalemia.
6. MRI of head in presence of:
  1. Hyperprolactinemia.
  2. Visual field defects.
  3. Signs of hypothalamic pituitary dysfunction.
Secondary amenorrhea:
1. Serum FSH, TSH/FT4, prolactin, estradiol:
  1. Low serum FSH with low estradiol indicates hypogonadotropic hypogonadism.
  2. High serum FSH with low estradiol suggests hypergonadotropic hypogonadism.
2. Progesterone withdrawal bleeding:
  1. 10 mg medroxyprogesterone is given for 10 days.
  2. Withdrawal bleeding suggests euestrogenic anovulation in presence of normal end organ (outflow tract) and ovarian function.
3. Estrogen-progesterone withdrawal bleeding:
  1. In the absence of progesterone withdrawal bleeding, the patients are exposed to 25 to 35 days of estrogen (0.625 to 2.5 mg Premarin daily) followed by 10 days of medroxyprogesterone.
  2. Withdrawal bleeding indicates hypogonadism.
  3. Absence of bleeding suggests defects with end organ (e.g., Asherman syndrome).
4. Serum LH, testosterone and DHEA-S:
  1. When features of hyperandrogenism are seen these tests are ordered.
  2. Serum testosterone >200 ng/ml suggests androgen-producing adrenal or ovarian tumors (high index of suspicion with moderate elevation; threshold value not required in cases of ovarian or adrenal tumors). This level may be mildly elevated in patients with PCOS.
  3. DHEA-S >700 mcg/dl suggests adrenal origin over ovarian (high index of suspicion with moderate elevation; threshold value not required in cases of ovarian or adrenal tumors).
  4. LH/FSH ratio >2 may be present in patients with PCOS, although this is not part of diagnostic criteria according to the Rotterdam consensus conference.
5. Imaging:
  1. Pelvic ultrasound when PCOS or ovarian tumor suspected.
  2. Abdominal CT when adrenal tumor suspected.
  3. MRI of head when indicated.
  4. Hysterosalpingography, sonohysterography, or diagnostic hysteroscopy in patients with suspected Asherman syndrome.
6. Other tests which are rarely needed:
  1. Serum transferrin when hemochromatosis is suspected.
  2. Serum ACE when sarcoidosis is suspected.
  3. Karyotyping is indicated when primary ovarian insufficiency occurs before the age of 40.

Figure E1 A diagnostic algorithm for amenorrhea.

DHEAS, Dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; FT4, free thyroxine; hCG, human chorionic gonadotropin; LH, luteinizing hormone; PCOS, polycystic ovary syndrome; PRL, prolactin; TSH, thyroid-stimulating hormone.

From McPherson RA, Pincus MR: Henry’s clinical diagnosis and management by laboratory methods, ed 23, Philadelphia, 2017, Elsevier.

Treatment ⬆ ⬇

The treatment of amenorrhea depends on the etiology, as well as the aims of the patient, such as a desire to treat hirsutism or to become pregnant.
Estrogen replacement along with calcium and vitamin D should be instituted in patients with hypogonadism to avoid osteoporosis. Women with a uterus require continuous or intermittent progesterone administration to protect against endometrial hyperplasia or cancer. Often, combination oral contraceptive pills are used.
Many patients with anatomic abnormalities may require surgical correction. Creation of a new vagina for patients with Müllerian agenesis is usually delayed until the woman is emotionally mature and ready to participate in the serial dilation or postoperative care required to maintain vaginal patency. However, if adequate correction is impossible, pregnancy will often require a surrogate to carry a gestation. Always assess for the associated urogenital anomalies, such as renal agenesis, in these patients and, when present, treat them appropriately.
In patients with androgen insensitivity syndrome, the incidence of gonadal malignancy is 22%. However, it rarely occurs before the age of 20. Gonadectomy is performed by laparoscopy following breast development and the attainment of adult stature. In the absence of a uterus these individuals only need estrogen replacement without progesterone.
Women with adult-onset CAH may be treated with low-dose corticosteroids in addition to sex steroids to partially block ACTH stimulation of adrenal function and thereby decrease overproduction of adrenal androgens.
Patients with primary ovarian insufficiency (POI) will need estrogen and progesterone replacement. These patients will require in vitro fertilization using donor oocytes to conceive. These patients have an increased risk of osteoporosis and heart disease. It can also be associated with autoimmune disorders such as hypothyroidism, Addison disease, and diabetes mellitus. Therefore fasting blood glucose, TSH, and, if clinically appropriate, morning cortisol should be measured. In the presence of a Y chromosome, removal of gonadal tissue is recommended at the time of diagnosis to avoid gonadal tumors.
Hypothyroidism should be treated with thyroid replacement.
Hyperprolactinemia is treated by avoiding the culprit drugs or by giving dopamine agonists, such as bromocriptine or cabergoline. Pituitary adenomas rarely require surgery but surgery may be performed if secondary deficits such as visual changes are observed, when they are resistant to medical therapy, or the lesion is rapidly growing.
Treatment of hypothalamic amenorrhea depends on the etiology. Patients with eating disorders or who exercise excessively will require behavioral modification and nutritional counseling. Elite athletes may choose not to alter their exercise regimens and will therefore require estrogen treatment and prevention of osteoporosis. When associated with infertility, ovulation induction with clomiphene citrate, exogenous gonadotropins, or pulsatile GnRH therapy should be offered.
The primary treatment of PCOS is weight loss through diet and exercise. Other treatment options include:
1. Use of oral contraceptive pills or cyclic progestational agents to help maintain a normal endometrium.
2. Insulin-sensitizing agents such as metformin to reduce insulin resistance and improve ovulatory function. Recent studies suggest that insulin-sensitizing agents may not be as effective in improving ovulatory effort.
3. Oral contraceptives and/or spironolactone to treat hyperandrogenism.
4. Clomiphene citrate or an aromatase inhibitor such as letrozole to induce ovulation.
In patients with Asherman syndrome, hysteroscopic lysis of intrauterine adhesions is followed by administration of long-term exogenous estrogen to stimulate regrowth of endometrial tissue.
Geneticist consult is given in patients with hereditary causes of amenorrhea.
Psychiatrist consult is needed in patients with major depression, anorexia nervosa, bulimia nervosa, or other major psychiatric disorders.

Complications

Osteoporosis
Endometrial hyperplasia and uterine cancer
Infertility

Prognosis

Depends on the etiology of amenorrhea

Patient & Family Education

Patients with amenorrhea should be reassured that this is, in and of itself, not a concern.
All women with an intact endometrium should understand the risks of unopposed estrogen action, whether the estrogen is exogenous such as through hormone therapy, or endogenous such as PCOS.
Hypoestrogenic women should be counseled about the importance of estrogen replacement to protect against bone loss.
Potential for future childbearing should be discussed.

Related Content

Hypothalamic Amenorrhea (Patient Information)

Infertility (Related Key Topic)

Pituitary Adenoma (Related Key Topic)

Polycystic Ovary Syndrome (Related Key Topic)

Prolactinoma (Related Key Topic)

Sheehan Syndrome (Related Key Topic)

Turner Syndrome (Related Key Topic)

section name header

Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Suggested Readings ⬆