gynecology and obstetrics
Amenorrhea
Evaluation of Amenorrhea
Girls are evaluated forprimary amenorrheaif menarche has not occurred and they reach one of the following milestones: Age 13 and they have no signs of puberty (eg, breast development, growth spurt) Three years after thelarche (onset of breast development) Age 15 (in patients with normal growth and development of secondary sexual characteristics) Girls and women of reproductive age should be evaluated forsecondary amenorrheaif they have previously been menstruating and have 3 months if they previously had regular menstrual cycles or ≥ 6 months if they previously had irregular menstrual cycles ( Evaluation references ) <9 menses a year or cycle length > 38 days (oligomenorrhea) A new and persistent change in menstrual pattern (frequency, volume, duration) includes questions about menstrual function (see table Normal Menstrual Parameters* [ 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 Are menses accompanied by significant discomfort? (Rarely, discomfort indicates structural abnormalities.) Does the patient have cyclic breast tenderness and mood changes (moliminal symptoms), which, if absent, may indicate abnormal uterine bleeding, not cyclic menses? What are the patient's dietary and exercise habits? For adolescents and some young patients, questions about pubertal development should be included: Has menarche occurred (to distinguish primary from secondary amenorrhea) and, if so, what was the age at menarche? At what ages did growth and development milestones occur? Have the changes of puberty occurred (eg, breast development, growth spurt, presence of axillary and pubic hair)? Review of systemsshould cover symptoms suggesting possible causes, including the following: Galactorrhea, headaches, hearing loss, and visual field defects: Introduction to Pituitary Disorders None Fatigue, weight gain, and cold intolerance: Hypothyroidism None Palpitations, nervousness, tremor, and heat intolerance: Hyperthyroidism None Palpitations: Anorexia Nervosa with electrolyte abnormalities (eg, Acne, hirsutism, and deepening of the voice: Adrenal Virilism None For patients with secondary amenorrhea, hot flushes, vaginal dryness, sleep disturbance, fragility fractures, and decreased libido: Primary Ovarian Insufficiency None Past medical historyshould note risk factors for the following: Functional hypothalamic amenorrhea, such as stress; chronic illness; new medications; a recent change in weight, diet, or exercise intensity; and a history or current symptoms of Introduction to Eating Disorders None Endometrial scarring (Asherman syndrome), as may occur in patients with a history of dilation and curettage (particularly if they also had a uterine infection), endometrial ablation, endometritis, obstetric injury, uterine surgery Medication historyshould include specific questions about current or past medications, such as the following: Medications that affectdopamine(eg, antihypertensives, antipsychotics, opioids, tricyclic antidepressants, antiseizure drugs) Cancer chemotherapy (eg, alkylating agents such asbendamustine,cyclophosphamide, andifosfamide;busulfan;chlorambucil) Hormones that can cause virilization (eg, androgens, high-dose androgenic progestins, over-the-counter [OTC] anabolic steroids) Hormonal contraceptives Systemic corticosteroids OTC products and supplements, some of which contain bovine hormones Substance abuse, including opioid abuse, which may affect the secretion of pituitary hormones and lead to oligomenorrhea or amenorrhea should include any cases of delayed puberty or genetic disorders, including Fragile X Syndrome . Clinicians should note vital signs and calculate body mass index (BMI). If pubertal development may be abnormal, secondary sexual characteristics are 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 Prolactinoma (breast milk secretion not temporally associated with childbirth); it can be distinguished from other types of Pelvic examinationis done to check for enlargement of the uterus (possibly due to pregnancy or a tumor), ovaries, and clitoris (clitoromegaly). Pelvic examination findings also help determine whetherestrogenhas been deficient. In women of reproductive age, the presence of cervical mucus with spinnbarkeit (a stringy, stretchy quality) usually indicates adequateestrogen; thin, pale vaginal mucosa without rugae and pH>6.0 indicatesestrogendeficiency. In girls or some young women, examination may detect anatomic genital abnormalities (eg, imperforate hymen, vaginal septum, vaginal, cervical, or uterine aplasia). A bulging hymen may be caused by hematocolpos, which suggests genital outflow obstruction. focuses on evidence of virilization, including Hirsutism and Hypertrichosis , temporal balding, acne, voice deepening, increased muscle mass, and defeminization (a decrease in previously normal secondary sexual characteristics, such as decreased breast size and vaginal atrophy). Virilization results from increased androgen production by the adrenal glands or ovaries. Finding black patches on the skin due to acanthosis nigricans is a possible sign of Polycystic Ovary Syndrome (PCOS) (PCOS) or diabetes. 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 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 If amenorrhea occurs in girls with normal secondary sexual characteristics or in women of reproductive age, do a pregnancy test before proceeding with further evaluation. History and physical examination findings may suggest an etiology of amenorrhea, even before laboratory testing (see table Findings Suggesting Possible Causes of Amenorrhea ). Inprimary 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 a genetic disorder). Insecondary 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 ofestrogendeficiency (eg, hot flushes, 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, polycystic ovary syndrome, androgen-secreting tumor, Cushing syndrome, use of certain drugs). If patients have a high BMI, acanthosis nigricans, or both, polycystic ovary syndrome is likely. History and physical examination help direct testing. The approach to primary amenorrhea (see algorithm Evaluation of primary amenorrhea [a] ) differs from that to secondary amenorrhea (see algorithm If patients have primary amenorrhea and normal secondary sexual characteristics, testing should begin with pelvic ultrasonography to check for congenital anatomic 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 ofhuman chorionic gonadotropinshould 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. [a] Normal values 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 ultrasonography 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 virilism, 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. * 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 theFMR1gene). 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 serumtestosteroneor 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 levels (hypogonadotropic hypogonadism) suggests hypothalamic or pituitary dysfunction. Mildly elevated levels oftestosteroneor 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. If patients have secondary amenorrhea with normal prolactin and FSH levels and normal thyroid function and do not have virilization, a trial of a progestin can be given to try to evaluateestrogenstatus. If theestrogenlevel is sufficient, a course of a progestin should stimulate withdrawal bleeding after the progestin is stopped (progestin challenge test; also called progestin withdrawal test). The progestin challenge test begins by givingmedroxyprogesterone5 to 10 mg orally once a day or another progestogen for 7 to 10 days. After the last dose, If bleeding occurs within a few days, the estrogen level is sufficient and amenorrhea is probably caused by hypothalamic-pituitary dysfunction, ovarian insufficiency, orestrogenexcess. If bleeding does not occur, an estrogen/progestin challenge test is done. Theestrogen/progestin challenge test is done by giving an estrogen (eg, conjugated equine estrogen 1.25 mg,estradiol2 mg) orally once a day for 21 days, followed bymedroxyprogesterone10 mg orally once a day or another progestogen for 7 to 10 days. After the last dose of the progestin, if bleeding does not occur, patients may have an endometrial lesion (eg, Asherman syndrome) or outflow tract obstruction (eg, cervical stenosis). However, bleeding may not occur in patients who do not have these abnormalities because the uterus is insensitive toestrogendue to prolonged use of estrogen/progestin contraceptives or rare endocrine disorders (estrogen insensitivity syndrome, estrogen resistance). Thus, the trial using estrogen and progestin may be repeated for confirmation. Because this trial takes weeks and results can be inaccurate, diagnosis of some serious disorders may be delayed significantly; thus, brain MRI should be considered before or during the trial if a pituitary or other brain lesion is suspected. 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. 2.Munro MG, Critchley HOD, Fraser ISfor the FIGO (International Federation of Gynecology and Obstetrics) 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.Int J Gynaecol Obstet143 (3):393–408, 2018. doi: 10.1002/ijgo.12666 Epub 2018 Oct 10. 