Evaluation and management of primary amenorrhea

INTRODUCTION — Amenorrhea (absence of menses) can be a transient, intermittent, or permanent condition resulting from dysfunction of the hypothalamus, pituitary, ovaries, uterus, or vagina (table 1 and table 2). It is often classified as either primary (absence of menarche by age 15 years or thereafter) or secondary (absence of menses for more than three months in girls or women who previously had regular menstrual cycles or six months in girls or women who had irregular menses).

The causes and diagnosis of primary amenorrhea, as well as a brief summary of treatment options, are reviewed here. The etiology, diagnosis, and treatment of secondary amenorrhea are discussed separately. (See "Causes of primary amenorrhea" and "Epidemiology and causes of secondary amenorrhea" and "Evaluation and management of secondary amenorrhea".)

EVALUATION

Background — Primary amenorrhea is defined as the absence of menses at age 15 years in the presence of normal growth and secondary sexual characteristics. However, at age 13 years, if no menses have occurred and there is a complete absence of secondary sexual characteristics such as breast development, evaluation for primary amenorrhea should also begin. In addition, some girls with secondary sexual characteristics may present before age 15 years with amenorrhea and cyclic pelvic pain. These girls should be evaluated for possible outflow tract obstruction. (See "Causes of primary amenorrhea", section on 'Outflow tract disorders'.)

Primary amenorrhea is usually the result of a genetic or anatomical abnormality. However, all causes of secondary amenorrhea can also present as primary amenorrhea (table 1 and table 2). In a large case series of primary amenorrhea, the most common etiologies were [1]:

●Gonadal dysgenesis, including Turner syndrome – 43 percent (algorithm 1)

●Müllerian agenesis (absence of vagina, sometimes with absence of uterus) – 15 percent (algorithm 2)

●Physiological delay of puberty (constitutional delay of puberty, chronic systemic disease, acute illness) – 14 percent (of note, constitutional delay of puberty is common in boys but uncommon in girls) (see "Causes of primary amenorrhea", section on 'Constitutional delay of puberty')

●Polycystic ovary syndrome (PCOS) – 7 percent

●Isolated gonadotropin-releasing hormone (GnRH) deficiency – 5 percent (extremely rare; the frequency seen in this study likely reflects that it was performed in an academic referral center; the incidence in females based upon a national hospital database was only 1 out of 125,000 [2]) (see "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)")

●Transverse vaginal septum – 3 percent

●Weight loss/anorexia nervosa – 2 percent

●Hypopituitarism – 2 percent

The least common etiologies (≤1 percent each) included imperforate hymen, complete androgen insensitivity syndrome, hyperprolactinemia/prolactinoma, other pituitary tumors, congenital adrenal hyperplasia, hypothyroidism, central nervous system defects, craniopharyngioma, and Cushing disease. (See "Causes of primary amenorrhea", section on 'Causes'.)

In geographies with a high incidence of tuberculosis, pelvic tuberculosis can also be a cause of primary amenorrhea [3].

A logical approach to the woman with either primary or secondary amenorrhea is to consider disorders based upon the level of control of the menstrual cycle: hypothalamus and pituitary, ovary, and uterus and vagina (algorithm 3). In addition, steroid receptor abnormalities and deficiencies in enzymes of steroidogenesis cause primary amenorrhea at the level of the ovary and the adrenal gland.

Initial approach — Primary amenorrhea is evaluated most efficiently by focusing on the presence or absence of breast development (a marker of estrogen action and therefore function of the ovary), the presence or absence of the uterus (as determined by ultrasound, or in more complex cases by magnetic resonance imaging [MRI]), and the follicle-stimulating hormone (FSH) level (algorithm 3) [4].

●If the serum FSH concentration is elevated, the probable diagnosis is gonadal dysgenesis and a karyotype should be obtained. The most common karyotypes observed are 45X Turner syndrome, 45X/46XX Turner mosaic, and 46,XY. In this scenario, a 46,XY karyotype is associated with a high risk for the development of gonadoblastoma and dysgerminoma, and surgical removal of the gonads may be necessary. (See "Causes of primary amenorrhea", section on 'Gonadal dysgenesis/primary ovarian insufficiency (POI)'.)

●If FSH is normal and the ultrasound indicates that the uterus is absent, the probable diagnosis is müllerian agenesis or androgen insensitivity syndrome (algorithm 2). In the case of müllerian agenesis, the circulating testosterone is in the normal range for women, and in the case of androgen insensitivity, the circulating testosterone is in the male range and testes may be present in the inguinal area or found intra-abdominal on ultrasound. (See "Causes of primary amenorrhea", section on 'Müllerian agenesis' and "Causes of primary amenorrhea", section on 'Complete androgen insensitivity syndrome'.)

●If the FSH is normal, breast development is present, and the ultrasound or MRI detects accumulated blood in the uterus (hematometra) or vagina (hematocolpos), an obstructed outflow tract is present. (See "Causes of primary amenorrhea", section on 'Outflow tract disorders'.)

●If the FSH is low or normal and the uterus is present, further evaluation is guided by the degree of pubertal development. This could include distinguishing between constitutional delay of puberty and congenital GnRH deficiency, or investigating some of the common causes of secondary amenorrhea that also cause primary amenorrhea. (See "Approach to the patient with delayed puberty" and "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)" and "Epidemiology and causes of secondary amenorrhea".)

History — Although there are several unique causes of primary amenorrhea, all causes of secondary amenorrhea can also cause primary disease (see "Evaluation and management of secondary amenorrhea"). Thus, the following questions should be asked of a woman with primary amenorrhea:

●Has she completed other stages of puberty, including a growth spurt, development of axillary and pubic hair, apocrine sweat glands, and breast development? Lack of pubertal development suggests deficient estradiol secretion, which could be due to a hypothalamic or pituitary disorder, ovarian failure, and/or a chromosomal abnormality.

●Is there a family history of delayed or absent puberty (suggesting a possible familial disorder)?

●What is the woman's height relative to family members? Short stature may indicate Turner syndrome or growth hormone deficiency due to hypothalamic-pituitary disease.

●Were neonatal and childhood health normal? Neonatal crisis suggests congenital adrenal hyperplasia. Alternatively, poor health may be a manifestation of hypothalamic-pituitary disease.

●Are there any symptoms of hyperandrogenism (acne, hirsutism) or virilization? The presence of acne or hirsutism is consistent with a diagnosis of PCOS, while virilization suggests more severe androgen excess, due to an androgen-secreting ovarian or adrenal tumor, or 5-alpha-reductase deficiency.

●Has there been stress; change in weight, diet, or exercise habits; or illness that might result in hypothalamic amenorrhea?

●Is she taking any drugs that might cause or be associated with amenorrhea? The medication may be taken for a systemic illness that itself can cause hypothalamic amenorrhea (eg, sarcoidosis). Alternatively, drugs such as heroin and methadone can decrease GnRH and, therefore, gonadotropin secretion.

●Does she have galactorrhea, which would suggest excess prolactin? This could be caused by hypothalamic or pituitary disease or by drugs, such as metoclopramide and antipsychotic drugs. (See "Causes of hyperprolactinemia".)

●Are there symptoms of other hypothalamic-pituitary disease, including headaches, visual field defects, fatigue, or polyuria and polydipsia?

Physical examination — The single most important step in the evaluation is to determine by physical examination (or ultrasonography or MRI if needed) if a uterus is present [4]. In addition, the vagina and cervix should be examined for anatomic abnormalities. Anatomic abnormalities that can cause primary amenorrhea include an intact hymen, transverse vaginal septum, or vaginal agenesis, also known as müllerian agenesis or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, which refers to congenital absence of the vagina with variable uterine development. It is usually accompanied by cervical and uterine agenesis; however, 7 to 10 percent of women have a normal but obstructed or rudimentary uterus with functional endometrium. (See "Causes of primary amenorrhea".)

Other findings on physical examination that can provide clues to the etiology of the amenorrhea include:

●Breast development, as assessed by Tanner staging (table 3 and figure 1). (See "Normal puberty".)

●Growth, including height, weight, and arm span (normal arm span for adults is within 5 cm of height) and the growth chart.

●Skin findings such as hirsutism, acne, striae, increased pigmentation, and vitiligo.

●Physical features of Turner syndrome such as low hairline, webbed neck, shield chest, and widely spaced nipples. The blood pressure should be measured in both arms if Turner syndrome is suspected because it is associated with an increased incidence of coarctation of the aorta. (See "Clinical manifestations and diagnosis of Turner syndrome".)

●A careful genital examination should be performed for clitoral size, pubic hair development, intactness of the hymen, vaginal length, and presence of a cervix, uterus, and ovaries. If the vagina cannot be penetrated with a small cotton swab (Q-tip) or finger, rectal examination may allow evaluation of the internal organs.

Pelvic ultrasound — If a normal vagina or uterus is not obviously present on physical examination, pelvic ultrasonography should be performed to confirm the presence or absence of ovaries, uterus, and cervix. In addition, ultrasonography can be useful to look for vaginal or cervical outlet obstruction in patients with amenorrhea and cyclic pain.

Initial laboratory testing — All women with primary amenorrhea should have serum human chorionic gonadotropin (hCG), FSH, thyroid-stimulating hormone (TSH), and prolactin (PRL) measured, similar to the approach for women with secondary amenorrhea (algorithm 3) (see "Evaluation and management of secondary amenorrhea"). Some clinicians suggest additional testing, including serum estradiol (E2) to assess estrogen status and free thyroxine (T4) to look for central hypothyroidism (in these cases TSH may be low or normal). However, serum E2 measurements may be variable in women with either early ovarian failure or functional hypothalamic amenorrhea during recovery, and they may not reflect exposure to estradiol over weeks. On the other hand, E2 can be helpful when trying to interpret FSH values. We measure free T4 only when central hypothyroidism is suspected.

Additional testing depends upon the results of the physical exam; in particular, whether müllerian structures are present or absent.

Further evaluation

Uterus present — Most women with primary amenorrhea have a uterus; most of these have chromosomal abnormalities causing gonadal dysgenesis (ovarian insufficiency due to the premature depletion of all oocytes and follicles). For women with a uterus, further evaluation is determined by the initial lab results (most importantly FSH, and sometimes PRL or TSH), the presence or absence of breast development (usually a marker of ovarian function, except in the case of complete androgen insensitivity syndrome), and the presence or absence of any anatomic abnormalities on physical exam that suggest an outflow tract disorder (algorithm 3).

High FSH

●A high serum follicle-stimulating hormone (FSH) concentration is indicative of primary ovarian insufficiency (POI; premature ovarian failure). A karyotype is then required and may demonstrate complete or partial deletion of the X chromosome (Turner syndrome) and/or the presence of Y chromatin. The presence of a Y chromosome material (SRY) is associated with a higher risk of gonadal tumors and makes gonadectomy mandatory (algorithm 3) [5-7]. (See "Causes of primary amenorrhea", section on 'Gonadal dysgenesis/primary ovarian insufficiency (POI)'.)

In addition, evaluation for other diseases associated with the specific type of ovarian insufficiency should be performed. As examples, congenital heart disease, hypertension, and hearing loss are common in women with Turner syndrome. Although 46,XX spontaneous POI typically presents as secondary amenorrhea, it can sometimes present as primary amenorrhea. If the etiology is thought to be autoimmune, additional evaluation for autoimmune thyroid and adrenal disease should be done. (See "Clinical manifestations and diagnosis of Turner syndrome" and "Autoimmune primary ovarian insufficiency (premature ovarian failure)" and "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)

For girls with high FSH who are also hypertensive (and who may have other features of 17-alpha-hydroxylase [CYP17] deficiency, such as minimal body hair and absent secondary sexual characteristics), blood tests should be drawn for evaluation for CYP17 deficiency. The characteristic findings are elevations in serum progesterone (>3 ng/mL [9.5 nmol/L]) and deoxycorticosterone and low values for serum 17-alpha-hydroxyprogesterone (<0.2 ng/mL [0.6 nmol/L]) (algorithm 3). (See "Uncommon congenital adrenal hyperplasias", section on 'CYP17A1 deficiencies'.)

Low or normal FSH

●A low or normal serum follicle-stimulating hormone (FSH) concentration suggests a central hypothalamic-pituitary process, outflow tract disorder due to an anatomic abnormality, or an endocrine disorder (that more typically causes secondary amenorrhea). The presence or absence of breast development (an indicator of ovarian function and estrogen secretion) helps to further categorize these disorders (algorithm 3).

●Girls with low/normal FSH and breast development have either an anatomic abnormality (which is identified on ultrasound) or an endocrine disorder such as PCOS, hyperprolactinemia, or thyroid disease, disorders that more commonly cause secondary amenorrhea. (See "Evaluation and management of secondary amenorrhea".)

•Approximately 15 percent of girls with primary amenorrhea will have an anatomic abnormality identified on ultrasound or exam such as imperforate hymen, transverse vaginal septum, or müllerian agenesis (congenital absence of the vagina with variable uterine development). Cyclic pelvic or lower abdominal pain is a common presenting symptom in these girls. (See "Causes of primary amenorrhea".)

The evaluation of endocrine disorders that cause secondary amenorrhea are reviewed in detail separately. Although uncommon, all of these disorders can cause primary amenorrhea, including hyperprolactinemia, thyroid disease, and PCOS. A high serum prolactin should be repeated once to confirm hyperprolactinemia prior to performing pituitary MRI. Hypothyroidism as a cause of hyperprolactinemia should be ruled out by measuring serum TSH. (See "Clinical manifestations and evaluation of hyperprolactinemia" and "Laboratory assessment of thyroid function".)

If there are signs or symptoms of hyperandrogenism, serum testosterone and dehydroepiandrosterone sulfate (DHEAS) should be measured. While most adolescents presenting with hyperandrogenism and primary amenorrhea likely have PCOS, androgen-secreting tumors must be ruled out in those with virilization and/or severe hyperandrogenemia (algorithm 3). (See "Evaluation of premenopausal women with hirsutism".)

●Girls with low or normal FSH and no evidence of breast development most likely have a central hypothalamic-pituitary disorder; they should have a second serum sample obtained for both luteinizing hormone (LH) and FSH measurements (algorithm 3).

•If LH and FSH are both very low (undetectable or near the lower limit of the assay), congenital GnRH deficiency, constitutional delay of puberty, or other disorders of the hypothalamic-pituitary axis should be considered. Constitutional delay of puberty is very uncommon in girls and is a diagnosis of exclusion. For girls with primary amenorrhea due to hypogonadotropic hypogonadism who are undergoing evaluation for hypothalamic or pituitary disease, a serum T4 and TSH should be drawn to look for central hypothyroidism. The evaluation of both disorders is reviewed in detail separately. (See "Approach to the patient with delayed puberty" and "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)

•If LH is low and FSH is low or normal, functional hypothalamic amenorrhea is likely if there is also a history of an eating disorder, excessive exercise, or stress. Systemic illness may be associated with menstrual cycle disorders (including delayed puberty/primary amenorrhea) when it is severe enough to result in a decrease in hypothalamic GnRH secretion and/or when it is associated with nutritional deficiencies. Examples include celiac disease, type 1 diabetes mellitus, and inflammatory bowel disease. We therefore suggest measurement of fasting blood glucose or glycated hemoglobin (A1C) to rule out diabetes mellitus and serologic screening for celiac disease with immunoglobulin A (IgA) antibodies against tissue transglutaminase (tTG-IgA). (See "Epidemiology and causes of secondary amenorrhea", section on 'Functional hypothalamic amenorrhea' and "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents" and "Diagnosis of celiac disease in children".)

•Contrast-enhanced MRI of the sella region is indicated in most cases of primary amenorrhea due to hypogonadotropic hypogonadism to evaluate for hypothalamic or pituitary disease. We recommend pituitary MRI in all women with hypogonadotropic hypogonadism, visual field defects, headaches, and/or any other signs of hypothalamic-pituitary dysfunction. Pituitary MRI may not be required in those with a clear explanation for their hypogonadotropic amenorrhea (eg, celiac disease, type 1 diabetes mellitus, or inflammatory bowel disease).

Uterus absent — For those with absence of the uterus, further evaluation should include a karyotype and measurement of serum total testosterone (algorithm 2 and algorithm 3). The history, physical exam, and results of these tests should distinguish between abnormal müllerian development (a normal 46,XX karyotype, female phenotype, and normal female serum testosterone concentrations) and complete androgen insensitivity syndrome (46,XY karyotype, normal female phenotype, sparse axillary and pubic hair, and normal male serum testosterone concentrations) (algorithm 2). (See "Congenital uterine anomalies: Clinical manifestations and diagnosis" and "Pathogenesis and clinical features of disorders of androgen action".)

Patients with 5-alpha-reductase deficiency also have a 46,XY karyotype and normal male serum testosterone concentrations, but in contrast to the androgen insensitivity syndrome (which is associated with a female phenotype), these patients undergo striking virilization at the time of puberty (normal development of secondary sexual hair, muscle mass, and deepening of the voice). This disorder is reviewed in detail separately. (See "Steroid 5-alpha-reductase 2 deficiency".)

MANAGEMENT — Treatment of primary amenorrhea is directed at correcting the underlying pathology (if possible), helping the woman to achieve fertility (if desired), and prevention of complications of the disease process (eg, estrogen replacement to prevent osteoporosis). A brief summary of treatment options is presented here, while the treatment of specific disorders is discussed in detail in the appropriate topic reviews.

●All women with primary amenorrhea should be counseled regarding its cause, potential treatment, and their reproductive potential. Psychological counseling is particularly important in patients with absent müllerian structures and/or a Y chromosome. (See "Congenital anomalies of the hymen and vagina" and "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis", section on 'Association with gonadoblastoma'.)

●Surgery may be required in patients with either congenital anatomic lesions or Y chromosome material. The etiology of the primary amenorrhea will determine the type of surgical procedure required. As an example, surgical correction of a vaginal outlet obstruction is necessary as soon as the diagnosis is made after menarche to allow passage of menstrual blood. Creation of a neovagina for patients with müllerian failure is usually delayed until the women are emotionally mature and ready to participate in the postoperative care required to maintain vaginal patency. (See "Congenital anomalies of the hymen and vagina" and "Congenital uterine anomalies: Surgical repair".)

In those patients in whom Y chromosomal material is found, gonadectomy should be performed to prevent the development of gonadal neoplasia [5-7]. Gonadectomy is now typically delayed until after puberty in patients with complete androgen insensitivity syndrome, but this was not true in the past. These patients have a normal pubertal growth spurt and feminize at the time of expected puberty; tumors do not usually develop until after this time. (See "Diagnosis and treatment of disorders of the androgen receptor".)

●Women with primary ovarian insufficiency (POI) should be counseled regarding the benefits and risks of hormone therapy. For young women, the benefits and risks of hormone therapy are markedly different than those for a 50-year-old woman. In general, in women of reproductive age with hypoestrogenism, hormone replacement is important to prevent bone loss and to prevent the potential excess risk of premature coronary heart disease. The management of POI is reviewed in detail separately. (See "Management of primary ovarian insufficiency (premature ovarian failure)" and "Menopausal hormone therapy: Benefits and risks".)

●Polycystic ovary syndrome (PCOS) is not a common cause of primary amenorrhea. In these patients, treatment is directed toward achieving the patient's goals (eg, relief of hirsutism, resumption of menses, fertility) and preventing the long-term consequences of PCOS (eg, endometrial hyperplasia/cancer, obesity, and metabolic defects). The management of PCOS is reviewed in detail separately. (See "Treatment of polycystic ovary syndrome in adults" and "Treatment of polycystic ovary syndrome in adolescents".)

●Functional hypothalamic amenorrhea can usually be reversed by weight gain, reduction in the intensity of exercise, and/or resolution of illness or emotional stress. For women who want to continue to exercise or are unable to improve their nutritional health, estrogen-progestin replacement therapy should be given to those not seeking fertility as it has been demonstrated to improve bone mineral density [8]. Hormonal contraceptives do not appear to provide the same benefit. For women who desire regular menses, cyclic estrogen-progestin treatment, often in the form of a contraceptive formulation, can be prescribed.

Women who want to become pregnant can be treated with exogenous gonadotropins or pulsatile gonadotropin-releasing hormone (GnRH) (not available in United States at this time, available in Europe), but increased caloric intake is simpler and clearly preferable. Furthermore, if a woman does not eat enough to have regular cycles and normal fertility, her nutrient intake during a hormonally induced pregnancy is likely to remain inadequate, increasing the probability of having a newborn who has a low weight for gestational age at birth. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Evaluation and management of secondary amenorrhea".)

●The same considerations apply to women with hypothalamic or pituitary dysfunction that is not reversible (eg, congenital GnRH deficiency). For women who want to become pregnant, either exogenous gonadotropins or pulsatile GnRH can be given. In a retrospective comparative study, pulsatile GnRH produced a higher rate of conception (96 versus 72 percent) and a lower rate of higher-order multiple gestations [9-11]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)

●Advances in assisted reproductive technologies (ART) now make it possible for many women with primary amenorrhea to participate in reproduction.

For women with Turner syndrome, the use of donor oocytes and their partners' sperm with in vitro fertilization (IVF) allows the women to carry a pregnancy in their own uterus. However, these pregnancies are associated with important cardiovascular risks. The use of donor oocytes, as well as other options including cryopreservation of oocytes or ovarian tissue in women with mosaic Turner syndrome are reviewed separately. (See "Management of Turner syndrome in adults", section on 'Management of fertility and pregnancy'.)

For women with an absent uterus, use of their own oocytes in IVF and transfer of their embryos to a gestational carrier can allow these women to have genetically related children.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Amenorrhea".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Absent or irregular periods (The Basics)" and "Patient education: Late puberty (The Basics)")

●Beyond the Basics topics (see "Patient education: Absent or irregular periods (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Primary amenorrhea is defined as the absence of menses at age 15 years in the presence of normal growth and secondary sexual characteristics. However, at age 13 years, if no menses have occurred and there is a complete absence of secondary sexual characteristics such as breast development, evaluation for primary amenorrhea should also begin. (See 'Background' above.)

●Causes – All causes of secondary amenorrhea can also present as primary amenorrhea. However, primary amenorrhea is usually the result of genetic or anatomic abnormalities (table 1). (See "Causes of primary amenorrhea".)

●Initial evaluation – Primary amenorrhea is evaluated initially by determining the presence or absence of a uterus, the presence or absence of breast development (a marker of estrogen action and therefore function of the ovary, except in complete androgen insensitivity syndrome), and the serum follicle-stimulating hormone (FSH) level (algorithm 3). (See 'Initial approach' above.)

●Uterus present – Most women with primary amenorrhea have a uterus (algorithm 1); most of these have chromosomal abnormalities causing gonadal dysgenesis (ovarian insufficiency due to the premature depletion of all oocytes and follicles). For women with a uterus, further evaluation is determined by the initial lab results (prolactin [PRL], thyroid-stimulating hormone [TSH], and, most importantly, FSH), the presence or absence of breast development (a marker of ovarian function, except in complete androgen insensitivity syndrome), and the presence or absence of any anatomic abnormalities on physical exam that suggest an outflow tract disorder (algorithm 3). (See 'Uterus present' above.)

•High FSH – If there is a uterus and the FSH level is elevated, the probable diagnosis is gonadal dysgenesis, and a karyotype should be obtained. In this scenario, a 46,XY karyotype is associated with a high risk for the development of gonadoblastoma and dysgerminoma, and surgical removal of the gonads is necessary. (See 'Initial approach' above.)

•FSH low or normal – If the estradiol is low and the FSH is low or normal and the uterus is present, the probable diagnosis is secondary hypogonadism, which could be caused by constitutional delay of puberty, congenital gonadotropin-releasing hormone (GnRH) deficiency, or some of the common causes of secondary amenorrhea that also cause primary amenorrhea. (See 'Initial approach' above.)

●Uterus absent – For those with absence of the uterus, further evaluation should include a karyotype and measurement of serum total testosterone. These tests should then allow the clinician to distinguish between abnormal müllerian development (a normal 46,XX karyotype with normal female serum testosterone concentrations) and androgen insensitivity syndrome (46,XY karyotype and normal male serum testosterone concentrations) (algorithm 3). (See 'Uterus absent' above.)

●Management – Treatment of primary amenorrhea is directed at correcting the underlying pathology (if possible), helping the woman to achieve fertility (if desired), and prevention of complications of the disease process (eg, estrogen replacement to prevent osteoporosis). A brief summary of treatment options is presented in this topic, while the treatment of specific disorders is discussed in detail in the appropriate topic reviews. (See 'Management' above.)