Amenorrhea

Amenorrhea due to ovulatory dysfunction

Amenorrhea due to ovulatory dysfunction is usually secondary but may be primary if ovulation never begins—eg, because of gonadal dysgenesis or due to an endocrinologic disorder. Patients with primary amenorrhea due to ovulatory dysfunction usually present with delayed puberty.

The most common causes of ovulatory dysfunction involve a disruption of the hypothalamic-pituitary-ovarian axis (See table Some Etiologies of Ovulatory Dysfunction). Thus, causes include:

• Perimenarche or perimenopause

• Primary ovarian insufficiency

• Androgen excess (particularly due to polycystic ovary syndrome)

• Pituitary dysfunction (eg, hyperprolactinemia cause by pituitary adenoma, pituitary irradiation),

• Hypothyroidism

• Idiopathic (sometimes occurring when gonadotropin levels are normal)

Hypothalamic dysfunction may result in decreased GnRH production, which in turn may cause decreased gonadotropin production. A common cause is insufficient energy intake due to dietary restriction, undernutrition, or strenuous exercise or emotional stress. Women with amenorrhea due to hypothalamic dysfunction have lower levels of serum leptin (an anorectic hormone produced by fat cells); lower levels may contribute to decreased gonadotropin production (3).

The Central Nervous System-Hypothalamic-Pituitary-Gonadal Target Organ Axis

Ovarian hormones have direct and indirect effects on other tissues (eg, bone, skin, muscle). FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone.

Amenorrhea due to structural reproductive tract abnormalities

In patients with anatomic or other structural abnormalities of the reproductive tract, menses are absent because either:

• Menstrual blood is not produced: uterus is absent (due to congenital agenesis of the uterus) or the endometrium is not functioning (eg, due to intrauterine adhesions)

• Menstrual flow is blocked: uterus, cervix, or vagina are blocked (due to congenital anomalies or acquired blockage [eg, cervical stenosis])

Mullerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) is a syndrome that involves congenital anomalies of the female reproductive tract, sometimes with associated urinary tract abnormalities (4). It is the most common cause of primary amenorrhea, occurring in approximately 1 in 5000 females (5). Primary amenorrhea caused by obstructive abnormalities is usually accompanied by normal hormonal function, thus, external genital organs and other secondary sexual characteristics develop normally.

Likewise, patients with secondary amenorrhea due to structural abnormalities usually have normal reproductive endocrine function.

Obstruction results in accumulation of blood within the genital tract, which can cause the following complications:

• Hematometra (accumulation of blood in the uterus), which can cause pelvic pain and uterine distention may be noted as a pelvic mass or bulging of the cervix

• Hematocolpos (accumulation of menstrual blood in the vagina), which can cause vaginal or pelvic pain and bulging of the obstructing tissue (eg, imperforate hymen)

Some congenital disorders (eg, those accompanied by vaginal aplasia or a vaginal septum) also cause urinary tract and skeletal abnormalities. (See table Some Causes of Amenorrhea due to Structural Reproductive Tract Abnormalities.)

Etiology references

1. 1. Gordon CM, Ackerman KE, Berga SL, et al. Functional hypothalamic amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 102 (5):1413–1439, 2017. doi: 10.1210/jc.2017-00131

2. 2. Saadedine M, Kapoor E, Shufelt C. Functional Hypothalamic Amenorrhea: Recognition and Management of a Challenging Diagnosis. Mayo Clin Proc. 2023;98(9):1376-1385. doi:10.1016/j.mayocp.2023.05.027

3. 3. Bouzoni E, Perakakis N, Mantzoros CS. Circulating profile of activin-follistatin-inhibin axis in women with hypothalamic amenorrhea in response to leptin treatment. Metabolism 113:154392, 2020. doi: 10.1016/j.metabol.2020.154392 Epub 2020 Oct 10.

4. 4. Committee on Adolescent Health Care. ACOG Committee Opinion No. 728: Müllerian Agenesis: Diagnosis, Management, And Treatment. Obstet Gynecol. 2018;131(1):e35-e42. doi:10.1097/AOG.0000000000002458

5. 5. Herlin M, Bjørn AM, Rasmussen M, Trolle B, Petersen MB. Prevalence and patient characteristics of Mayer-Rokitansky-Küster-Hauser syndrome: a nationwide registry-based study. Hum Reprod. 2016;31(10):2384-2390. doi:10.1093/humrep/dew220

History

History of present illness includes questions about menstrual function (see table Normal Menstrual Parameters [2]):

• Date of first day of last menstrual period

• Cycle frequency

• Cycle regularity in the past 3 to 12 months and whether periods have ever been regular

• Duration of bleeding

• Volume of bleeding

Questions about associated symptoms or factors include:

• Does the patient have cyclic breast tenderness and mood changes (moliminal symptoms), which, if present, may indicate that the hormonal changes of the menstrual cycles are occurring (even if menses are absent)?

• What are the patient's dietary and exercise habits?

• Are there hot flashes or other menopausal symptoms?

• Is there nipple discharge?

• Is there a history of a pelvic infection, particularly in the setting of an intrauterine procedure (eg, dilation and curettage)?

For adolescents and some young patients, questions about pubertal development should be included:

• At what ages did growth and development milestones occur?

• Has menarche occurred (to distinguish primary from secondary amenorrhea) and, if so, at what age?

• Have the changes of puberty occurred (eg, breast development, growth spurt, presence of axillary and pubic hair)?

• Are there any congenital urinary tract anomalies?

Review of systems should cover symptoms suggesting possible causes, including the following:

• Weigh gain, acne, excess facial or body hair: Polycystic ovary syndrome

• Galactorrhea, headaches, hearing loss, and visual field defects: Pituitary disorders

• Fatigue, weight gain, and cold intolerance: Hypothyroidism

• Palpitations, anxiety, tremor, and heat intolerance: Hyperthyroidism

• Palpitations with electrolyte abnormalities (eg, hypokalemia, hypomagnesemia): Anorexia nervosa

• Acne, hirsutism, and deepening of the voice: Androgen excess

• Hot flashes, vaginal dryness, sleep disturbance, and mood swings: Primary ovarian insufficiency

Past medical history should note risk factors for the following:

• Functional hypothalamic amenorrhea: stress; chronic illness; new medications; a recent change in weight, diet, or exercise intensity; history or current symptoms of eating disorders

• Endometrial scarring (Asherman syndrome): prior dilation and curettage procedure (particularly if there was also uterine infection); endometrial ablation; endometritis; obstetric injury; uterine surgery

Medication history should include specific questions about current or past medications, such as the following:

• Hormonal contraceptives

• Hormones that can cause virilization (eg, androgens, high-dose androgenic progestins, anabolic steroids)

• Herbs or supplements, if they impact endocrine function or contain bovine hormones

• Medications that affect dopamine (eg, antihypertensives, antipsychotics, opioids, tricyclic antidepressants, antiseizure drugs)

• Systemic corticosteroids

• Substance abuse, including opioid abuse, which may affect the secretion of pituitary hormones and lead to oligomenorrhea or amenorrhea

• Cancer chemotherapy (eg, alkylating agents such as bendamustine, cyclophosphamide, and ifosfamide; busulfan; chlorambucil)Cancer chemotherapy (eg, alkylating agents such as bendamustine, cyclophosphamide, and ifosfamide; busulfan; chlorambucil)

Family history should include any cases of delayed puberty or genetic disorders, including Fragile X syndrome, primary ovarian insufficiency, or autoimmune disorders.

Physical examination

Clinicians should note vital signs and calculate body mass index (BMI).

In adolescents, pubertal development of secondary sexual characteristics is evaluated; breast and pubic hair development are staged using the Tanner method (see Sexual Maturation). If axillary and pubic hair is present, adrenarche has occurred.

A breast examination should be done to check for galactorrhea (breast milk secretion not temporally associated with childbirth); it can be distinguished from other types of nipple discharge by a finding of fat globules in the fluid under microscopic examination.

Pelvic examination is done to check for findings associated with estrogen deficiency (eg, vaginal pallor, loss of rugae) or androgen excess (clitoromegaly). In women of reproductive age, the presence of cervical mucus with spinnbarkeit (a stringy, stretchy quality) usually indicates adequate estrogen; thin, pale vaginal mucosa without rugae and pH > 6.0 indicates estrogen deficiency. The uterus is palpated, enlargement may indicate a pregnancy, hematometra, or tumor.

In girls or some young women, examination may detect anatomic genital abnormalities (eg, imperforate hymen, vaginal septum, vaginal, cervical, or uterine agenesis). A bulging hymen may be caused by hematocolpos, which suggests genital outflow obstruction.

General physical examination focuses on evidence of virilization, including hirsutism, temporal balding, acne, voice deepening, increased muscle mass, and defeminization (a decrease in previously normal secondary sexual characteristics, such as decreased breast size). Virilization results from increased androgen production by the adrenal glands or ovaries. Hypertrichosis (excessive growth of hair on the extremities, head, and back), which is common in some families, is differentiated from true hirsutism, which is characterized by excess hair on the upper lip and chin and between the breasts.

A finding of black patches on the skin consistent with acanthosis nigricans is a possible sign of polycystic ovary syndrome (PCOS) or diabetes.

If a pituitary tumor is suspected (in patients with headaches or galactorrhea), a visual field examination is done.

Clinicians should check for hypothermia, bradycardia, hypotension, and reduced subcutaneous fat, which suggest anorexia nervosa, and for dental erosion, palatal lesions, reduced gag reflex, subconjunctival hemorrhage, and subtle hand changes with calluses on the dorsum of the hand (due to frequent vomiting), which suggest bulimia.

Red flags

The following findings are of particular concern in patients with amenorrhea:

• Delayed puberty

• Virilization

• Visual field defects

• Impaired sense of smell (anosmia)

• A spontaneous milky nipple discharge

• A significant increase or decrease in weight

Interpretation of findings

History and physical examination findings may suggest an etiology of amenorrhea, even before laboratory testing (see table History or Findings Suggesting Causes of Amenorrhea).

In primary amenorrhea, the presence of normal secondary sexual characteristics usually reflects normal hormonal function; amenorrhea is usually ovulatory and typically due to a congenital anatomic genital tract obstruction. Primary amenorrhea accompanied by abnormal secondary sexual characteristics is usually caused by ovulatory dysfunction (eg, due to gonadal dysgenesis).

In secondary amenorrhea, clinical findings sometimes suggest a mechanism:

• Galactorrhea suggests hyperprolactinemia (eg, pituitary dysfunction, use of certain drugs); if visual field defects and headaches are also present, pituitary tumors should be considered.

• Symptoms and signs of estrogen deficiency (eg, hot flashes, night sweats, vaginal dryness or atrophy) suggest primary ovarian insufficiency (premature ovarian failure) or functional hypothalamic amenorrhea (eg, due to excessive exercise, a low body weight, or low body fat)

• Virilization and clitoral enlargement suggest androgen excess (eg, androgen-secreting tumor, Cushing syndrome, use of certain medications). If patients have hirsutism with overweight or obesity and/or acanthosis nigricans, polycystic ovary syndrome is likely.

Testing

The diagnostic approach to primary amenorrhea (see algorithm Evaluation of Primary Amenorrhea) differs from that to secondary amenorrhea (see algorithm Evaluation of Secondary Amenorrhea), although no specific general approaches or algorithms are universally accepted.

If patients have primary amenorrhea and normal secondary sexual characteristics, testing should begin with pelvic ultrasound to check for congenital genital tract obstruction. MRI may be needed if abnormalities are identified.

A pregnancy test is required, even before menarche, if it is possible that ovulation has started. Pregnancy should not be excluded based on sexual or menstrual history. The beta subunit of human chorionic gonadotropin should be measured with high-sensitivity urine tests or serum tests. Results of urine tests are usually accurate several days before a missed menstrual period and often as early as several days after conception. Some over-the-counter (OTC) tests are less sensitive and accurate.

Evaluation of Primary Amenorrhea [a]

[a] Normal values (may depend on the laboratory used) are DHEAS: 250–300 ng/dL (0.7–0.8 mcmol/L) FSH: 5‒20 IU/L LH: 5‒40 IU/L Karyotype (female): 46,XX Prolactin: 50 ng/mL (see below) Testosterone: 20–80 ng/dL (0.7–2.8 nmol/L) Although these values are representative, normal ranges may vary between laboratories. Prolactin 50–100 ng/mL is considered mildly elevated and is usually due to use of a medication. Prolactin > 100 ng/mL is considered elevated and is more likely to be due to a tumor.

[b] Some clinicians measure LH levels when they measure FSH levels or when FSH levels are equivocal.

[c] If patients have primary amenorrhea and normal secondary sexual characteristics, testing should begin with pelvic examination and ultrasound to check for congenital anatomic genital tract obstruction.

[d] Constitutional delay of growth and puberty is possible.

[e] Possible diagnoses include functional hypothalamic chronic anovulation and genetic disorders (eg, congenital gonadotropin-releasing hormone deficiency, Prader-Willi syndrome).

[f] Possible diagnoses include Cushing syndrome, exogenous androgens, congenital adrenal hyperandrogenism, and polycystic ovary syndrome.

[g] Possible diagnoses include Turner syndrome and disorders characterized by Y chromosome material.

[h] Pubic hair may be sparse.

DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; LH = luteinizing hormone.

Reference: Yatsenko SA, Witchel SF, Gordon CM. Primary Amenorrhea and Premature Ovarian Insufficiency. Endocrinol Metab Clin North Am. 2024;53(2):293-305. doi:10.1016/j.ecl.2024.01.009

Evaluation of Secondary Amenorrhea*

* Normal values are DHEAS: 250–300 ng/dL (0.7–0.8 mcmol/L) FSH: 5‒20 IU/L Karyotype (female): 46,XX Prolactin: 50 ng/mL (see below) Testosterone: 20–80 ng/dL (0.7–2.8 nmol/L) Although these values are representative, normal ranges may vary between laboratories. Prolactin 50–100 ng/mL is considered mildly elevated and is usually due to a drug adverse effect. Prolactin > 100 ng/mL is considered elevated and is more likely to be due to a tumor.

† Some clinicians simultaneously measure FSH and LH levels.

‡ Clinicians should check for the presence of Y chromosome and Fragile X syndrome (premutation for the FMR1 gene).

DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; LH = luteinizing hormone; PCOS = polycystic ovary syndrome; TSH = thyroid-stimulating hormone.

Additional blood tests that are commonly done (to exclude specific etiologies) include:

• Follicle-stimulating hormone (ovarian insufficiency); if the level is high, it should be remeasured monthly at least twice

• Thyroid stimulating hormone (thyroid disease)

• Prolactin (if the level is high [hyperprolactinemia], it should be remeasured)

• Total serum testosterone or dehydroepiandrosterone sulfate (PCOS or other causes of hirsutism or virilization)

Amenorrhea with high follicle-stimulating hormone (FSH) levels (hypergonadotropic hypogonadism) suggests ovarian dysfunction. Amenorrhea with low FSH and LH and normal TSH levels (hypogonadotropic hypogonadism) suggests hypothalamic or pituitary dysfunction.

Mildly elevated levels of testosterone or DHEAS suggest PCOS, but levels can be elevated in women with hypothalamic or pituitary dysfunction and are sometimes normal in hirsute women with PCOS. The cause of elevated levels can sometimes be determined by measuring serum luteinizing hormone (LH). In polycystic ovary syndrome, circulating LH levels are often increased, increasing the ratio of LH to FSH.

If symptoms or signs suggest an underlying disorder, specific tests may be indicated. For example, patients with abdominal striae, moon facies, a buffalo hump, truncal obesity, and thin extremities should be tested for Cushing syndrome. Patients with headaches and visual field defects or evidence of pituitary dysfunction require brain MRI. If clinical evaluation suggests a chronic disease, liver and kidney function tests are done, and erythrocyte sedimentation rate (ESR) is determined.

Evaluation references

1. 1. Rebar R. Evaluation of amenorrhea, anovulation, and abnormal bleeding [updated, 2018]. In Endotext [Internet], edited by KR Feingold, B Anawalt, A Boyce, et al. South Dartmouth (MA), MDText.com Inc, 2000. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279144/

2. 2. Munro MG, Critchley HOD, Fraser IS; FIGO Menstrual Disorders Committee. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions [published correction appears in Int J Gynaecol Obstet. 2019 Feb;144(2):237. doi: 10.1002/ijgo.12709.]. Int J Gynaecol Obstet. 2018;143(3):393-408. doi:10.1002/ijgo.12666