Causes 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 secondary (absence of menses for more than three cycle intervals or six months in females who were previously menstruating). Primary amenorrhea should prompt a thorough evaluation to identify the cause.

The causes and diagnosis of primary amenorrhea are reviewed here. The diagnostic evaluation and treatment options for primary amenorrhea and the etiology, diagnosis, and treatment of secondary amenorrhea are discussed separately. (See "Evaluation and management of primary amenorrhea" and "Epidemiology and causes of secondary amenorrhea" and "Evaluation and management of secondary amenorrhea".)

DEFINITION — Primary amenorrhea is defined as the absence of menses at age 15 years in the presence of normal growth and secondary sexual characteristics. The identification of primary amenorrhea should always prompt a thorough evaluation to identify a cause [1]. 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 begin. In addition, some females with secondary sexual characteristics may present before age 15 years with amenorrhea and cyclic pelvic pain. These females should be evaluated for possible outflow tract obstruction.

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

●Gonadal dysgenesis, including Turner syndrome – 43 percent

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

●Physiologic 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 female) (see 'Constitutional delay of puberty' below)

●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 [3]) (see "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)")

●Transverse vaginal septum – 3 percent

●Weight loss/anorexia nervosa – 2 percent

●Hypopituitarism – 2 percent

Less 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.

A logical approach to the female 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. In addition, steroid receptor abnormalities and deficiencies in enzymes of steroidogenesis cause primary amenorrhea at the level of the ovary and the adrenal gland.

Hypothalamic and pituitary disease — Hypothalamic causes of primary amenorrhea are functional hypothalamic amenorrhea and isolated GnRH deficiency. Less commonly, tumors and infiltrative lesions of the hypothalamus or pituitary can result in amenorrhea, usually in association with hyperprolactinemia (table 1).

Functional hypothalamic amenorrhea — Functional hypothalamic amenorrhea is a disorder that, by definition, excludes pathologic disease. It is characterized by abnormal hypothalamic GnRH secretion leading to decreased gonadotropin pulsations, low or normal serum luteinizing hormone (LH) concentrations, absence of normal follicular development, absent LH surges, anovulation, and low serum concentrations of estradiol [4]. Serum follicle-stimulating hormone (FSH) concentrations are often in the normal range, with a high FSH-to-LH ratio similar to the pattern in prepubertal females.

Multiple factors may contribute to the pathogenesis of functional hypothalamic amenorrhea, including eating disorders (such as anorexia nervosa), exercise, and stress. The term hypothalamic amenorrhea is often used interchangeably with functional hypothalamic amenorrhea. The topic of functional hypothalamic amenorrhea is discussed in detail elsewhere. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Functional hypothalamic amenorrhea: Evaluation and management".)

Isolated GnRH deficiency — Although rare, primary amenorrhea can be due to complete congenital gonadotropin-releasing hormone (GnRH) deficiency. This syndrome is called idiopathic hypogonadotropic hypogonadism or, if it is associated with anosmia, Kallmann syndrome [5]. These females have pulsatile and prepubertal low serum gonadotropin concentrations due to the absence of hypothalamic GnRH. This disorder is often difficult to distinguish clinically from constitutional delay of puberty. (See "Approach to the patient with delayed puberty", section on 'Evaluation'.)

Isolated GnRH deficiency can be inherited as an autosomal dominant, autosomal recessive, or X-linked condition. To date, a number of genes have been implicated in the etiology of isolated GnRH deficiency. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Genetics'.)

Constitutional delay of puberty — Constitutional delay of puberty is common in males with a family history of delayed puberty, but it is fivefold less common in females. Constitutional delay is characterized by both delayed adrenarche and gonadarche, and it is often difficult to distinguish clinically from congenital GnRH deficiency. Patients with constitutional delay go on to have completely normal pubertal development, albeit at a later age. Because constitutional delay of puberty is uncommon in females, it should be a diagnosis of exclusion. (See "Approach to the patient with delayed puberty".)

Hyperprolactinemia — Hyperprolactinemia is a common cause of secondary amenorrhea but an uncommon cause of primary amenorrhea. The presentation is similar to hypothalamic amenorrhea except for the additional finding of galactorrhea in some patients. (See "Causes of hyperprolactinemia" and "Clinical manifestations and evaluation of hyperprolactinemia".)

A serum prolactin concentration above the normal range for nonpregnant females of reproductive age (often 15 to 20 ng/mL or 15 to 20 mcg/L) is considered abnormal. Stress, sleep, exercise, intercourse, and meals can raise serum prolactin concentrations transiently. Thus, we recommend that high serum prolactin concentrations be recorded at least twice before magnetic resonance imaging (MRI) is ordered. (See "Clinical manifestations and evaluation of hyperprolactinemia", section on 'Evaluation of hyperprolactinemia'.)

Other

●Infiltrative diseases and tumors – Many infiltrative diseases and tumors of the hypothalamus and pituitary can result in diminished GnRH release or gonadotrope destruction and amenorrhea; these include craniopharyngioma, germinoma, and Langerhans cell histiocytosis. The main indications for MRI are hypogonadotropic hypogonadism, visual field defects, headaches, other evidence of hypothalamic or pituitary dysfunction, or symptoms suggestive of other diseases (such as sarcoidosis). (See "Causes, presentation, and evaluation of sellar masses", section on 'Evaluation of a sellar mass'.)

Iron studies to rule out hemochromatosis should be performed if there is an appropriate family history or if the female has other suggestive manifestations such as bronzed skin, diabetes mellitus, or otherwise unexplained heart or liver disease. (See "Approach to the patient with suspected iron overload".)

●Systemic illness – Systemic illness can cause secondary or primary amenorrhea when it is severe enough to result in a decrease in hypothalamic GnRH secretion. Examples include celiac disease, type 1 diabetes mellitus, and inflammatory bowel disease. (See "Epidemiology and causes of secondary amenorrhea", section on 'Systemic illness'.)

Gonadal dysgenesis/primary ovarian insufficiency (POI) — The most common cause of primary amenorrhea is gonadal dysgenesis caused by chromosomal or genetic abnormalities. These disorders result in premature depletion of all ovarian oocytes and follicles. These individuals have significantly elevated FSH levels due to the absence of ovarian oocytes and follicles, leading to reduced negative feedback on FSH from estradiol and inhibin B. The largest number of patients have Turner syndrome (45,X as well as other karyotypes), followed by 46,XX gonadal dysgenesis (typically autosomal) and, rarely, 46,XY gonadal dysgenesis. (See "Clinical manifestations and diagnosis of Turner syndrome".)

Turner syndrome — Females with Turner syndrome are missing all of one X chromosome in 55 to 60 percent of cases (45,X gonadal dysgenesis) [6]. Amenorrhea occurs because the oocytes and follicles undergo accelerated apoptosis (in utero in most cases). The ovaries are replaced with fibrous tissue, and in the absence of follicles, there is no ovarian estrogen secretion. In contrast, the external female genitalia, uterus, and fallopian tubes develop normally until puberty when estrogen-induced maturation fails to occur. Spontaneous puberty and menstruation occur more commonly in females with a mosaic karyotype (45,X/46,XX) but can occur in females with a 45,X karyotype, although spontaneous pregnancy is unlikely with a 45,X karyotype [7,8]. Females with Turner syndrome whose karyotype includes a Y chromosome (such as 45,X/46,XY mosaicism) are at increased risk for gonadoblastoma, a neoplasm that occurs in dysgenetic gonads. Deletions and translocations on the long arm of the X chromosome also cause primary ovarian insufficiency (POI). (See "Clinical manifestations and diagnosis of Turner syndrome" and "Management of Turner syndrome in children and adolescents".)

Some cases of gonadal dysgenesis result from autosomal recessive or compound heterozygous inheritance (46,XX gonadal dysgenesis). The known genetic causes are increasing in number with the use of next-generation sequencing [9]. There are syndromic forms associated with hearing loss (Perrault syndrome) and neurologic disease. It is increasingly recognized that homozygous or compound heterozygous mutations in genes coding proteins responsible for homologous recombination in meiosis and DNA damage and repair cause XX gonadal dysgenesis in the absence of other syndromic features [10-15]. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)

46,XY gonadal dysgenesis — The estimated prevalence of 46,XY gonadal dysgenesis is 1:100,000 births. In complete 46,XY gonadal dysgenesis, the fibrous streak gonad cannot secrete anti-müllerian hormone (AMH). This results in persistent müllerian structures and a female phenotype. The phenotype of partial gonadal dysgenesis can range from genital ambiguity to an undervirilized male. Mutations in SRY, NR5A1, DHH, FOG2/ZFPM2, and WNT1 have been identified [16,17]. Because of the phenotypic variability, some patients are diagnosed in infancy with ambiguous genitalia, while others are not diagnosed until puberty when they present with primary amenorrhea. (See "Causes of differences of sex development", section on 'XY gonadal dysgenesis'.)

POI — 46,XX primary ovarian insufficiency (POI) is defined as the development of clinical menopause before the age of 40 years in females who have a normal karyotype. POI usually presents as secondary amenorrhea and can be due to chemotherapy or radiation, autoimmune oophoritis, a fragile X messenger ribonucleoprotein 1 (FMR1) premutation, or a number of mutations. Although most females present with secondary amenorrhea, some present with primary amenorrhea. (See "Autoimmune primary ovarian insufficiency (premature ovarian failure)" and "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)

Polycystic ovary syndrome — Most cases of PCOS present with oligomenorrhea, but occasionally secondary amenorrhea and rarely primary amenorrhea, may be present. The menstrual disturbances in females with PCOS classically have a peripubertal onset. The females with PCOS who present with primary amenorrhea typically have higher androgen levels and are more overweight [18]. However, most have a slightly early menarche related to overweight, followed by irregular cycles (oligomenorrhea) or secondary amenorrhea. The diagnosis can be made in a female with clinical and biochemical evidence of hyperandrogenism in the presence of advanced pubertal development (ie, greater than or equal to Tanner stage 4 breast development) and in the absence of other disorders causing amenorrhea and hyperandrogenism [19]. The diagnosis of PCOS is reviewed in detail separately. (See "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents" and "Diagnosis of polycystic ovary syndrome in adults".)

Females with mutations that severely disrupt insulin receptor function (type A insulin resistance) or with high titre anti-insulin receptor antibodies (type B insulin resistance) may sometimes present with acanthosis nigricans, hyperinsulinemia, hyperandrogenism, and primary amenorrhea [20,21] (see "Insulin resistance: Definition and clinical spectrum"). Adolescents and adult females with severe lipodystrophy may also present with hyperinsulinemia, hyperandrogenism, and primary amenorrhea [22]. (See "Lipodystrophic syndromes".)

Outflow tract disorders — Congenital abnormalities of the female reproductive organs account for approximately 20 percent of cases of primary amenorrhea. Menses cannot occur without an intact uterus, endometrium, cervix, cervical os, and vaginal conduit. Pelvic or lower abdominal pain is a common presenting symptom in females with primary amenorrhea and an obstructed reproductive tract. Congenital anomalies of the uterus and vagina will be reviewed briefly in this section and in greater detail elsewhere. (See "Congenital uterine anomalies: Clinical manifestations and diagnosis" and "Congenital anomalies of the hymen and vagina".)

Imperforate hymen — An imperforate hymen is the simplest defect that results in primary amenorrhea. It may be associated with cyclic pelvic pain and a perirectal mass from sequestration of blood in the vagina (hematocolpos). Similar findings can be seen with defects in perineal development, which can result in absence of the distal third of the vagina and therefore absence of an outflow tract. Both of these conditions are diagnosed by physical examination. An imperforate hymen is easily corrected with surgery. (See "Congenital anomalies of the hymen and vagina".)

Transverse vaginal septum — One or more transverse vaginal septae can occur at any level between the hymenal ring and the cervix. After menarche, the major symptoms are similar to those associated with an imperforate hymen. (See "Congenital anomalies of the hymen and vagina".)

Müllerian agenesis — Müllerian agenesis, also known as vaginal agenesis or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, 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 females have a normal but obstructed or rudimentary uterus with functional endometrium (figure 1 and figure 2). The defect results from agenesis or hypoplasia of the müllerian duct system. Heterozygous mutations in WNT4 account for a small subset of these cases. The most commonly cited incidence for vaginal agenesis is 1 in 5000 (range: 1 per 4000 to 10,000 females). (See "Congenital anomalies of the hymen and vagina" and "Congenital uterine anomalies: Clinical manifestations and diagnosis".)

Differential diagnosis of vaginal agenesis includes androgen insensitivity, low-lying transverse vaginal septum, agenesis of the uterus and vagina, imperforate hymen, and maturity onset diabetes of the young (MODY) caused by HNF1 mutations. Vaginal agenesis can be differentiated from androgen insensitivity based upon a normal, female-range serum total testosterone in vaginal agenesis and a male-range serum testosterone in androgen insensitivity. Imaging studies (ultrasound and/or MRI) help to clarify the nature of the vaginal agenesis and to differentiate it from low-lying transverse vaginal septum, agenesis of the uterus and vagina, and imperforate hymen. (See "Congenital anomalies of the hymen and vagina" and "Congenital uterine anomalies: Clinical manifestations and diagnosis".)

Receptor abnormalities and enzyme deficiencies

Complete androgen insensitivity syndrome — The complete androgen insensitivity syndrome is an X-linked recessive disorder in which 46,XY subjects have a normal female phenotype. These patients are resistant to testosterone due to a defect in the androgen receptor and, therefore, fail to develop all of the male sexual characteristics that are dependent upon testosterone. The external genitalia are typically female in appearance, but testes may be palpable in the labia or inguinal area. The testes make müllerian-inhibiting substance, which is functional and causes regression of all müllerian structures: the fallopian tubes, uterus, and upper third of the vagina. At puberty, breast development occurs, but the areolae are pale and pubic and axillary hair is sparse. Carrier females (46,XX) develop normal internal and external genitalia. (See "Pathogenesis and clinical features of disorders of androgen action".)

The diagnosis of this disorder is based upon the absence of the upper vagina, uterus, and fallopian tubes on physical examination and pelvic ultrasonography; high serum testosterone concentrations (in the range for normal men); and a male (46,XY) karyotype. The testes should be surgically excised after puberty if located intraabdominally because of the increased risk (2 to 5 percent) of developing testicular cancer after age 25 years. (See "Diagnosis and treatment of disorders of the androgen receptor".)

5-alpha-reductase deficiency — 5-alpha-reductase deficiency is another congenital defect that can result in primary amenorrhea in a 46,XY subject. At birth, these neonates may appear female or have ambiguous genitalia due to an inability to convert testosterone (via 5-alpha-reductase) to its more potent metabolite dihydrotestosterone (DHT). At puberty, the disorder is more recognizable because of the onset of virilization (male-pattern hair growth, increased muscle mass, and voice deepening) due to the normal peripubertal increase in testosterone secretion in males. However, these individuals do not undergo DHT-dependent masculinization (enlargement of the male external genitalia and prostate). (See "Steroid 5-alpha-reductase 2 deficiency" and "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

17-alpha-hydroxylase deficiency — This rare disorder, which can occur in 46,XX or 46,XY subjects, is characterized by deficiency of the product of the CYP17 gene, which is an enzyme that has both 17-hydroxylase and 17,20-lyase activities (figure 3). As a result, there is decreased cortisol synthesis but overproduction of corticotropin (ACTH), corticosterone, and deoxycorticosterone. Adrenal and gonadal sex steroids are not produced, so that affected subjects typically present as phenotypic females with hypertension (due to mineralocorticoid excess), lack of pubertal development, and either female (if 46,XX) or incompletely developed (if 46,XY) external genitalia. This topic is discussed in detail elsewhere. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)" and "Uncommon congenital adrenal hyperplasias", section on 'CYP17A1 deficiencies'.)

P450 oxidoreductase deficiency — The P450 oxidoreductase (POR) donates electrons to cytochrome P450 enzymes, including 17-alpha-hydroxylase/17,20-lyase. Oxidoreductase deficiency has two unique clinical features. First, affected neonates may present with severe undervirilization in boys and severe virilization in females. In addition, patients may present with a complex, predominantly craniofacial pattern, termed Antley-Bixler syndrome. The spectrum of POR mutations has expanded and includes females with primary amenorrhea and infertility. Females might present with a pattern of atypical congenital adrenal hyperplasia upon ACTH stimulation, including low cortisol and androstenedione levels and elevated 17-hydroxyprogesterone and progesterone levels. Females may also present with amenorrhea in the setting of multiple large ovarian cysts but low estradiol levels. (See "Uncommon congenital adrenal hyperplasias", section on 'P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency)'.)

Estrogen resistance — A mutation in the gene encoding estrogen receptor-alpha (ESR1), which had previously been described only in a male, has now been identified in an 18-year-old female with primary amenorrhea and profound estrogen resistance. She presented with very high serum estradiol concentrations (3500 pg/mL [12,849 pmol/L]), inappropriately elevated serum gonadotropins (LH 9.6 mIU/mL, FSH 6.7 mIU/mL), enlarged multicystic ovaries, and no evidence of endometrial thickening [23]. In spite of the hyperestrogenemia, she had normal serum concentrations of sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), thyroxine-binding globulin (TBG), and triglycerides. She also had delayed bone age (13.5 years), low bone mineral density (BMD) (Z-score -2.4), and her growth velocity chart suggested a lack of an estrogen-induced adolescent growth spurt. DNA sequencing identified a homozygous mutation in ESR1 that severely impaired estrogen signaling except with administration of pharmacologic doses of estrogen, when minimal signaling was observed. The prevalence of ESR1 mutations in humans is unknown, but they are likely to be very rare. Although they have not been identified clinically, milder ESR1 mutations could result in incomplete estrogen resistance analogous to the partial androgen insensitivity syndrome caused by mild mutations in the androgen receptor gene. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Partial androgen insensitivity (PAIS)'.)

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" and "Society guideline links: Turner syndrome".)

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 by age 15 years. 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 begin. (See 'Definition' above.)

●Causes

•The most common cause of primary amenorrhea is chromosomal anomalies resulting in gonadal dysgenesis (43 percent). (See 'Causes' above.)

•Central causes of primary amenorrhea include tumors and infiltrative disorders of the hypothalamus and pituitary, along with congenital gonadotropin-releasing hormone (GnRH) deficiency and hyperprolactinemia. However, functional hypothalamic amenorrhea, in which hypothalamic GnRH pulsation is disrupted because of low energy balance, is the most common. Hypothalamic and pituitary causes combined account for approximately 23 percent of cases. (See 'Hypothalamic and pituitary disease' above.)

•Polycystic ovary syndrome (PCOS) usually presents as secondary amenorrhea but can sometimes present as primary amenorrhea. (See 'Polycystic ovary syndrome' above.)

•Anatomic abnormalities, including absence or abnormalities of the uterus, cervix, and vagina, make up 18 percent of primary amenorrhea. (See 'Outflow tract disorders' above.)

•Rare disorders of steroid synthesis and receptor function also cause primary amenorrhea. (See 'Receptor abnormalities and enzyme deficiencies' above.)

●Evaluation – The evaluation of primary amenorrhea includes a careful history and examination for signs of pubertal development and presence of normal internal structures, follicle-stimulating hormone (FSH) level to determine whether the cause is central or ovarian, and further directed diagnostic testing based on history and physical examination. (See "Evaluation and management of primary amenorrhea", section on 'Evaluation'.)