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KembaraXtra-Medicine – Amenorrhea
Amenorrhea means the absence of menstruation. It is classified as primary or secondary depending on whether the patient has had previous menstrual cycles. A 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 years of thelarche. Secondary amenorrhea is defined as the absence of menses for more than 6 months in a patient who previously had normal menstrual progesterone withdrawal cycles. ICD-10CM codes include N91.0 (Primary amenorrhea), N91.1 (Secondary amenorrhea), and N91.2 (Amenorrhea, unspecified).
From an epidemiologic standpoint, the incidence in the United States is <1% for primary amenorrhea and 5% to 7% secondary amenorrhea, with no racial or ethnic predilection.< />pan>
Amenorrhea can be physiologic or pathologic. Physiologic causes include pregnancy, lactation, constitutional delay of puberty, and menopause. Pathologic causes differ by whether amenorrhea is primary or secondary. For primary amenorrhea, major categories include hypergonadotropic hypogonadism (including 45,X, 46,XX, 46,XY, and 46,XX with gonadal failure), eugonadism (including Müllerian agenesis, vaginal septum, imperforate hymen, polycystic ovarian syndrome, congenital adrenal hyperplasia, Cushing disease, thyroid disease, and androgen insensitivity), and hypogonadotropic hypogonadism (including constitutional delay, GnRH deficiency, and other CNS disease). For secondary amenorrhea, common causes include PCOS (about 28%), eating disorders/stress (about 15.5%), hypothyroidism (about 1.5%), Sheehan syndrome (about 1.5%), Cushing syndrome (about 1%), pituitary tumor/empty sella (about 2%), pituitary diseases (about 5%), eating disorders/stress (about 2%), nonclassic congenital adrenal hyperplasia (about 0.5%), ovarian tumor (about 1%), hyperprolactinemia (about 13%), and anatomic causes (about 7%, including Asherman syndrome). An abnormal karyotype is also listed as a possible contributor in secondary amenorrhea (0.5%).
Among congenital anatomic causes of primary amenorrhea with normal breast development (cervix not visible on pelvic exam; short vagina that may be absent or obstructed), key diagnoses include Müllerian agenesis, androgen insensitivity (AI), transverse vaginal septum, and imperforate hymen. These account for about 15%, 1%, 3%, and 1% of primary amenorrhea cases, respectively; among those with apparent obstruction or absence of the vagina, proportions are approximately 75%, 5%, 15%, and 5%, respectively. Chromosomes are 46,XX for Müllerian agenesis, transverse vaginal septum, and imperforate hymen, and 46,XY for androgen insensitivity. Gonads are ovaries in Müllerian agenesis, transverse vaginal septum, and imperforate hymen, and testes in androgen insensitivity. Serum testosterone is at normal female levels in Müllerian agenesis, transverse vaginal septum, and imperforate hymen, and at normal male (high) levels in androgen insensitivity. The vagina is absent or shallow in Müllerian agenesis and androgen insensitivity, obstructed by a septum (thick or thin; high or low) in transverse vaginal septum, and obstructed by a thin membrane (sometimes bluish from hematocolpos) in imperforate hymen. Axillary/pubic hair is present in Müllerian agenesis, transverse vaginal septum, and imperforate hymen, but absent in complete androgen insensitivity (unless incomplete). Cyclic pain may be variable in Müllerian agenesis, absent in androgen insensitivity, and present in transverse vaginal septum and imperforate hymen. The uterus is absent or rudimentary in Müllerian agenesis, absent in androgen insensitivity, and present in transverse vaginal septum and imperforate hymen. A mass is typically absent in Müllerian agenesis and androgen insensitivity, but may be present in transverse vaginal septum and imperforate hymen and can cause acute urinary retention due to hematocolpos obstructing the urethra; with imperforate hymen, the introitus may bulge with Valsalva. Associated anomalies include urinary tract and skeletal anomalies in Müllerian agenesis, inguinal hernias and risk of gonadal malignancy in adulthood in androgen insensitivity, major urinary tract abnormalities in ~15% with transverse vaginal septum, and possibly some increased urinary tract abnormalities in imperforate hymen. Treatment includes vaginal dilation or surgical neovagina for Müllerian agenesis and transverse vaginal septum, gonadectomy after age 16–18 for androgen insensitivity, surgery tailored to septum extent/location (often as soon as possible) for transverse vaginal septum, and excision of hymen as soon as possible for imperforate hymen (diagnostic needle aspiration is contraindicated due to infection risk). Fertility usually requires advanced reproductive technology (including IVF with a surrogate uterus) in Müllerian agenesis, is not possible in androgen insensitivity, is variable in transverse vaginal septum (low septa have better prognosis than high septa), and is usually preserved in imperforate hymen.
Clinical presentation varies by etiology. Turner syndrome usually presents with primary amenorrhea (unless mosaic) and may include short stature, epicanthic folds, low-set ears, high-arched palate, micrognathia, sensorineural hearing loss, otitis media, webbed neck, pigmented nevi, square/shield chest, widely spaced nipples, absent breast development, bicuspid aortic valve, coarctation of the aorta, cubit valgus, short fourth metacarpal, hyperconvex nails, leg edema, renal abnormalities, and autoimmune/metabolic issues including thyroiditis and diabetes mellitus. Pure gonadal dysgenesis causes amenorrhea but lacks Turner’s dysmorphic features. Müllerian agenesis is typically sporadic and presents with primary amenorrhea, normal breast development, normal pubic/axillary hair, normal female external genitalia, absent uterus and upper vagina, and present ovaries; some patients have renal and vertebral anomalies, and renal agenesis should be evaluated. Transverse vaginal septum and imperforate hymen present with primary amenorrhea, progressive cyclic lower abdominal pain, exam findings of septum/hymen abnormality, and perirectal fullness from hematocolpos. Androgen insensitivity syndrome presents with primary amenorrhea, may be X-linked recessive in some, with normal breast development, absent pubic/axillary hair, possible testes in groin/inguinal canal, and absent uterus and vagina, without renal/vertebral anomalies. Adult-onset congenital adrenal hyperplasia is more frequent in Ashkenazi Jewish, Inuit Native American, French Canadian, and Mexican populations, mimics PCOS, causes hyperandrogenism (virilization, hirsutism, acne), and can be associated with hypertension. 5-alpha reductase deficiency may cause primary amenorrhea with virilization at puberty. PCOS often presents with secondary amenorrhea/oligomenorrhea and is diagnosed by at least 2 of 3 Rotterdam criteria (oligo/anovulation, hyperandrogenism, polycystic ovaries on ultrasound defined by ≥12 follicles 2-9 mm or ovarian volume >10 cm³); it is associated with metabolic syndrome/obesity (60%–80%), insulin resistance, and predisposition to type 2 diabetes. Cushing syndrome (rare; prevalence about 1/1,000,000) can cause secondary amenorrhea, hyperandrogenism, dorsocervical fat pad, central obesity with thin extremities, abdominal striae, easy bruising, hypertension, and proximal muscle weakness. Hypothyroidism can cause secondary amenorrhea with lethargy, constipation, decreased appetite, weight gain, cold intolerance, hair loss, dry skin, and bradycardia. Primary ovarian insufficiency (previously premature ovarian failure) presents with secondary amenorrhea before age 40 with elevated FSH/LH, possible history of oophorectomy/radiation/chemotherapy, vasomotor symptoms, and thin dry vaginal mucosa without rugosity, and may be associated with autoimmune/karyotypic abnormalities. Hyperprolactinemia commonly causes secondary amenorrhea and may be medication-related (antipsychotics, OCPs, antidepressants, antihypertensives, H2 blockers, opioids, etc.) or due to pituitary adenoma (headache, vomiting, vision changes), and may present with galactorrhea. Sheehan syndrome follows postpartum hemorrhage with secondary amenorrhea, failure of lactation, and other hypopituitarism features. Asherman syndrome is associated with a history of D&C, secondary amenorrhea, and recurrent miscarriage/infertility. Functional hypothalamic disorders cause secondary amenorrhea associated with eating disorders, excessive exercise, stress, or street drug use. Kallmann syndrome is associated with anosmia due to developmental defects of GnRH neurons and the olfactory placode.
Diagnosis begins with the first step: rule out pregnancy using a serum or urine pregnancy test. Further evaluation depends on history and physical exam, including assessment of breast Tanner stage and whether a uterus is present, since the combination of present breasts with absent uterus narrows the differential primarily to Müllerian agenesis or androgen insensitivity syndrome. In primary amenorrhea, pelvic ultrasound or MRI is used to detect anatomic abnormalities of the uterus, cervix, ovaries, or vagina. Karyotyping is performed when the uterus is absent or Turner syndrome is suspected (e.g., 46,XX in Müllerian agenesis, 46,XY in AIS, 45,XO in Turner syndrome). Recommended labs include FSH, TSH/FT4, prolactin, and estradiol; an FSH ~40 mIU/mL with estradiol <20 pg />L suggests primary ovarian insufficiency, and prolactin >200 ng/mL suggests prolactinoma (noting thresholds vary by lab). Serum testosterone is checked when the uterus is absent or hyperandrogenism is present (male-range in AIS; female-range in Müllerian agenesis). 17-alpha hydroxyprogesterone is checked when hyperandrogenism is present to rule out CAH; these patients may also have elevated progesterone and deoxycorticosterone, hypernatremia, and hypokalemia. MRI of the head is obtained in the presence of hyperprolactinemia, visual field defects, or signs of hypothalamic–pituitary dysfunction.
In secondary amenorrhea, evaluation includes FSH, TSH/FT4, prolactin, and estradiol; low FSH with low estradiol indicates hypogonadotropic hypogonadism, and high FSH with low estradiol indicates hypergonadotropic hypogonadism. A progesterone withdrawal test is performed by giving medroxyprogesterone 10 mg for 10 days; withdrawal bleeding suggests euestrogenic anovulation with normal outflow tract and ovarian function. If no bleeding occurs, an estrogen-progesterone withdrawal is done using 25-35 days of estrogen (Premarin 0.625-2.5 mg daily) followed by 10 days of medroxyprogesterone; withdrawal bleeding indicates hypogonadism, while lack of bleeding suggests an end-organ/outflow tract problem such as Asherman syndrome. When hyperandrogenism is present, additional labs include LH, testosterone, and DHEA-S; testosterone >200 ng/mL raises concern for androgen-producing ovarian/adrenal tumors (may be mildly elevated in PCOS), and DHEA-S >700 mcg/dL suggests an adrenal source (again, moderate elevations warrant high suspicion and thresholds are not required when a tumor is evident). An LH/FSH ratio >2 can be seen in PCOS but is not part of Rotterdam diagnostic criteria. Imaging is tailored to suspected cause: pelvic ultrasound for PCOS or ovarian tumor, abdominal CT for adrenal tumor, head MRI when indicated, and hysterosalpingography, sonohysterography, or diagnostic hysteroscopy when Asherman syndrome is suspected. Rare additional tests include serum transferrin (hemochromatosis), serum ACE (sarcoidosis), and karyotyping when POI occurs before age 40.
Treatment depends on the underlying cause and the patient’s goals (e.g., treating hirsutism or achieving pregnancy). Patients with hypogonadism should receive estrogen replacement plus calcium and vitamin D to prevent osteoporosis; those with a uterus also need continuous or intermittent progesterone to prevent endometrial hyperplasia or cancer, often using combined oral contraceptives. Many anatomic abnormalities require surgical correction; creation of a neovagina for Müllerian agenesis is usually delayed until emotional maturity and readiness for dilation or postoperative care, and if correction is not feasible, pregnancy may require a surrogate. Associated urogenital anomalies (e.g., renal agenesis) must be assessed and treated appropriately. In androgen insensitivity syndrome, gonadal malignancy risk is about 22% but rarely occurs before age 20; laparoscopic gonadectomy is performed after breast development and adult stature, and because there is no uterus, patients require estrogen only (no progesterone). Adult-onset CAH may be treated with low-dose corticosteroids plus sex steroids to reduce ACTH-driven androgen excess. Primary ovarian insufficiency requires estrogen and progesterone replacement, and conception typically requires IVF using donor oocytes; these patients have increased risk of osteoporosis and heart disease and may have autoimmune associations (hypothyroidism, Addison disease, diabetes), so fasting glucose, TSH, and (when appropriate) morning cortisol should be checked. If a Y chromosome is present, gonadal tissue removal is recommended at diagnosis to reduce tumor risk. Hypothyroidism is treated with thyroid replacement. Hyperprolactinemia is treated by stopping culprit drugs when possible and/or using dopamine agonists such as bromocriptine or cabergoline; surgery for pituitary adenomas is uncommon but may be needed for visual compromise, resistance to medical therapy, or rapid growth. Hypothalamic amenorrhea is treated by addressing the cause (behavioral modification and nutritional counseling for eating disorders/excess exercise; estrogen therapy and osteoporosis prevention for those who cannot reduce training), and infertility can be treated with clomiphene citrate, exogenous gonadotropins, or pulsatile GnRH therapy. For PCOS, primary therapy is weight loss with diet and exercise, with additional options including OCPs or cyclic progestins for endometrial protection, metformin to improve insulin resistance and ovulatory function (noting mixed effectiveness in recent studies), OCPs and/or spironolactone for hyperandrogenism, and ovulation induction with clomiphene citrate or letrozole. Asherman syndrome is treated with hysteroscopic lysis of adhesions followed by long-term exogenous estrogen to promote endometrial regrowth. A genetics consultation is appropriate for hereditary causes, and psychiatry consultation may be required for major depression, anorexia nervosa, bulimia nervosa, or other major psychiatric disorders.
Complications of amenorrhea include osteoporosis, endometrial hyperplasia and uterine cancer, and infertility. Prognosis depends on the underlying cause.
Patient and family education should include reassurance that amenorrhea itself is not automatically dangerous, but patients with an intact endometrium must understand the risks of unopposed estrogen (whether exogenous hormone therapy or endogenous estrogen exposure as in PCOS). Hypoestrogenic patients should be counseled on the importance of estrogen replacement to prevent bone loss, and the patient’s future fertility goals and potential for childbearing should be discussed.
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