Continuing Education Activity

Amenorrhea is generally defined as the absence of menstruation in a female of reproductive age. It can be classified as either primary or secondary amenorrhea. Primary amenorrhea is the failure to reach menarche (ie, the first menstrual cycle) during normal development. It is clinically diagnosed when there is no history of menstruation by the age of 15 years or 3 years after menarche. Patients meeting the criteria for primary amenorrhea warrant an evaluation. Additionally, an assessment for delayed puberty is indicated in adolescents aged 13 years and younger without initial breast development or other secondary sex characteristics (eg, pubic and axillary hair).

Most of the underlying causes of primary amenorrhea can be classified into general groups: anatomic and sexual development abnormalities, ovarian insufficiency, hypothalamic or pituitary disorders, and other endocrine gland disorders. Physiology and medications may also cause primary amenorrhea; however, they are more commonly associated with secondary amenorrhea. The initial work-up usually includes a comprehensive history and physical examination, a urine pregnancy test, serum hormone testing, and pelvic imaging. Additional testing may also be indicated based on the clinical presentation. Treatment depends on the underlying etiology and may include lifestyle interventions, hormone therapy or other medications, surgery, and mental health services. Therefore, this activity for healthcare professionals is designed to enhance the learner's competence when managing primary amenorrhea, equipping them with updated knowledge, skills, and strategies for timely diagnosis, effective interventions, and improved care coordination, leading to better patient outcomes.

Objectives:

• Identify primary amenorrhea and determine when an evaluation of primary amenorrhea is warranted.

• Assess the potential etiologies of primary amenorrhea.

• Delineate the general approach to evaluating primary amenorrhea.

• Coordinate among the interprofessional team and implement proper communication in the diagnosis and management of patients with primary amenorrhea in order to improve patient outcomes.

Introduction

Amenorrhea is abnormal uterine bleeding characterized by the absence of menstruation in a female of reproductive age.[1] Amenorrhea can be classified as either primary or secondary amenorrhea. Primary amenorrhea is defined as having no history of menstruation by the age of 15 years or 3 years after thelarche; secondary amenorrhea is defined as the absence of menses for ≥3 months in a woman with previously regular menstrual cycles or ≥6 months in any woman with at least one previous spontaneous menstruation.[1][2] 

The median age of menarche is approximately 12.4 years, though this varies somewhat by patient-specific factors (eg, ethnicity, weight, and nutrition status).[3][4][5] Menarche typically occurs within 2 to 3 years of initial breast development, which occurs between the ages of 8 and 10 years, known as thelarche.[6][7] Patients meeting the criteria for either primary or secondary amenorrhea warrant an evaluation. However, an evaluation for delayed puberty is also indicated in adolescents aged 13 years with primary amenorrhea and no breast development or other secondary sex characteristics (eg, pubic and axillary hair).[3][8]

Most underlying causes of primary amenorrhea can be classified into general groups: anatomic and sexual development abnormalities, ovarian insufficiency, hypothalamic or pituitary disorders, and other endocrine gland disorders. Physiology and medications may also cause primary amenorrhea; however, they are more commonly associated with secondary amenorrhea. The initial work-up usually includes a comprehensive history and physical examination, a urine pregnancy test, serum hormone testing, and pelvic imaging. Additional testing may also be indicated based on the clinical presentation. Treatment depends on the underlying etiology and may include lifestyle interventions, hormone therapy or other medications, surgery, and mental health services. Therefore, all healthcare professionals should strive to enhance their competence when managing primary amenorrhea and equip themselves with updated knowledge, skills, and strategies for timely diagnosis, effective interventions, and improved care coordination, leading to better patient outcomes.

Etiology

A Systematic Approach to Considering the Etiologies of Primary Amenorrhea

The basic requirements for normal menstrual function include four anatomically and functionally distinct structural components: the hypothalamus, anterior pituitary gland, ovary, and the genital outflow tract composed of the uterus/endometrium, cervix, and vagina. If any of these components are nonfunctional or abnormal, menstrual bleeding cannot occur.[9][10]

Despite the numerous potential causes of primary amenorrhea, the majority of cases are caused by gonadal dysfunction (43%), müllerian agenesis (10%-15%), and constitutional delay of growth and puberty (14%).[11][9] Other relatively common etiologies, accounting for between 2% and 7% of cases, include functional hypothalamic amenorrhea (FHA), transverse vaginal septum, polycystic ovary syndrome (PCOS), and hypopituitarism.[11] Various other rare etiologies are also possible, and because ovulation occurs before menstruation, pregnancy must always be considered as well. Furthermore, any etiology of secondary amenorrhea may also present as primary amenorrhea. Determining the underlying cause of amenorrhea will assist in guiding management decisions.[9]

Anatomic Abnormalities and Other Disorders of Sexual Development (DSD)

Disorders of sexual development (DSD) refer to congenital conditions associated with abnormal development of the reproductive tract and external genitalia. These conditions are typically categorized as anatomic, gonadal, and chromosomal anomalies.[12] 

Agenesis of the müllerian ducts (ie, the paramesonephric ducts) results in the complete or partial absence of the müllerian structures, which include the fallopian tubes, uterus, and upper one-third of the vagina. This condition, also known as Mayer-Rokitansky-Kuster-Hauser syndrome, accounts for approximately 10% to 15% of primary amenorrhea cases.[10][11] These patients typically have normal ovarian function, external female genitalia, and development of female secondary sex characteristics, with the complete or partial absence of the müllerian structures; however, the condition is also frequently associated with other urogenital abnormalities, such as unilateral renal agenesis, and skeletal anomalies, such as scoliosis.[13]

Some enzyme deficiencies or receptor anomalies also cause atypical sexual development and primary amenorrhea. For instance, aromatase deficiency leads to testosterone overproduction due to the inability of the ovary to convert testosterone to estrogen, resulting in virilization and ambiguous genitalia.[14] Similarly, patients with a 17α-hydroxylase deficiency will typically present without pubertal development along with significant hypertension due to mineralocorticoid excess. Patients with this enzyme deficiency and a 46,XX karyotype typically have a small uterus and ovaries; those with a 46,XY karyotype will have a blind vaginal pouch without a uterus. Another cause of primary amenorrhea in the setting of absent müllerian structures is complete androgen insensitivity syndrome (CAIS), which can occur in 46,XY individuals with mutations affecting the function or quantity of androgen receptors.[15] This leads to complete androgen resistance and elevated serum testosterone levels. Because these individuals have testes, they secrete antimüllerian hormone (AMH) in utero, which causes regression of the müllerian structures. Testosterone is also secreted but is ineffectual due to androgen receptor abnormalities; however, aromatase converts the testosterone to estrogen, leading to the development of a female phenotype. Therefore, these patients are born with external female genitalia but absent müllerian structures and typically present at puberty with primary amenorrhea. Anomalies in the development of these patients include sparse pubic hair due to abnormal androgen receptors, well-developed breasts due to the presence of estrogen, and a blind vaginal pouch without a uterus on an exam.[16][15]

Congenital obstructions to the menstrual outflow tract include an imperforate hymen, transverse vaginal septum secondary to a failure of the junction between the müllerian ducts and vaginal plate to regress, and isolated agenesis of the vagina resulting from a failure of the vaginal plate to canalize.[10] These obstructive anomalies typically present with cyclic pelvic pain in the setting of otherwise normal pubertal development.

Hypothalamic and Pituitary Disorders

Abnormalities in the hypothalamus result in abnormal gonadotropin-releasing hormone (GnRH) secretion, which in turn results in low follicle-stimulating hormone (FSH) secretion from the pituitary; primary pituitary abnormalities can also result in poor FSH secretion. In both cases, insufficient FSH is in circulation to stimulate the ovarian follicles to mature. The follicles, therefore, do not produce estrogen. The endometrium does not develop without estrogen, so menstruation cannot occur. Additionally, without proper follicular development, there is no luteinizing hormone (LH) surge, ovulation, or luteal phase progesterone production. With hypothalamic and pituitary etiologies of primary amenorrhea, both FSH and estrogen levels are low, and this state is known as hypogonadotropic hypogonadism.

The most common intracranial causes of primary amenorrhea are a constitutional delay of growth and puberty (CDGP) and functional hypothalamic amenorrhea (FHA), both of which cause reduced production of GnRH and can be difficult to distinguish from one another.[6] CDGP is simply a transient delay in the maturation of the hypothalamic-pituitary-ovarian (HPO) axis, typically due to individual genetic variation, and resolves with time.[6] Conversely, FHA is a pathologic suppression of the body's reproductive cycle due to a relative deficiency of available energy, most frequently resulting from disordered eating, excessive exercise or athletic training, and substantial perceived life stress.[10] Many chronic systemic diseases or prolonged illnesses can also cause hypothalamic suppression of the reproductive cycle. 

Other hypothalamic and pituitary causes of primary amenorrhea are much less common. Inherited deficiency of gonadotropin-releasing hormone (GnRH) is one type of these rarer hypogonadotropic hypogonadism etiologies. The most well-known of these genetic mutations is Kallman syndrome, characterized by amenorrhea, delayed puberty, and a lack of olfactory neurons, causing anosmia. Other rare hypothalamic and pituitary etiologies include infiltrative diseases (eg, cancer, sarcoidosis, hemochromatosis); pituitary infarction or necrosis; prolactin-secreting tumors (ie, prolactinomas); other hormone-secreting pituitary tumors affecting the HPO axis (eg, tumors secreting adrenocorticotropin hormone [ACTH], thyroid stimulating hormone [TSH], or growth hormone [GH]); craniopharyngioma; autoimmune disease; and empty sella syndrome due to the structural, traumatic, or iatrogenic shrinking of the pituitary gland.[9][10][17]

Ovarian Dysfunction

Ovarian dysfunction is one of the most common causes of primary amenorrhea. Patients with primary ovarian dysfunction typically have normal function in the hypothalamus and pituitary but nonresponsive ovaries. This results in low estrogen production leading to a lack of endometrial growth and, due to a lack of negative feedback at the pituitary, elevated FSH levels.[10] This state is known as hypergonadotropic hypogonadism.

Primary amenorrhea due to ovarian dysfunction is most frequently a result of gonadal dysgenesis, which can be seen with Turner syndrome 45,X karyotype, or in patients with mosaicism. Less commonly, gonadal dysfunction can also be seen in patients with pure gonadal dysgenesis with either 46,XX or 46,XY karyotypes, the latter known as Swyer syndrome. Patients with Swyer syndrome have nonfunctional testicular tissue; therefore, they do not secrete antimüllerian hormone (AMH) or testosterone in utero. The lack of AMH allows the müllerian ducts to persist and develop into typical internal female reproductive structures, including the fallopian tubes, uterus, cervix, and upper vagina. The lack of testosterone also causes the external genitalia to develop as female. Therefore, these patients develop typical internal and external female genital structures but fail to develop secondary sex characteristics at puberty because their gonads are nonfunctional. 

Causes of primary ovarian insufficiency (POI) include premutation in the FMR1 gene, which causes Fragile X syndrome, chemotherapy, radiation, autoimmune disease, as well as the previously discussed enzyme deficiencies that affect ovarian hormone production (eg, aromatase or 17α-hydroxylase deficiency).[18][16] 

Other Hormonal Abnormalities Affecting the HPO Axis

In general, hormonal abnormalities affecting the HPO axis are more frequently associated with secondary amenorrhea than primary. However, these causes should still be considered when evaluating adolescents with primary amenorrhea.

Hyperandrogenemia can lead to suppression of the HPO axis. The most common cause of amenorrhea in females with evidence of androgen excess is polycystic ovarian syndrome (PCOS). PCOS is a common condition characterized by menstrual abnormalities, hyperandrogenism, and metabolic dysfunction.[19] Individuals with PCOS often have chronic anovulatory cycles, which results in chronic unopposed estrogen (ie, estrogen "unopposed" by progesterone) that can lead to endometrial hyperplasia. Other causes of hyperandrogenism, which are much less common than PCOS but may still present as primary amenorrhea, include nonclassical congenital adrenal hyperplasia (NCCAH), androgen-secreting tumors from the adrenal gland or ovary, and Cushing syndrome.[9]

Hyperprolactinemia is frequently due to pituitary prolactinomas; however, it can also be caused by stress, exercise, chronic kidney disease, and some medications, particularly antipsychotics and opiates. Additionally, both hypo- and hyperthyroidism and uncontrolled diabetes can also suppress HPO axis function and menstruation, though these are all more commonly associated with secondary rather than primary amenorrhea.[20]  

Physiologic and Medication Induced Amenorrhea

Though this group of etiologies is more commonly associated with secondary amenorrhea, any cause of secondary amenorrhea may also present as primary amenorrhea.[9] 

Physiologic amenorrhea includes pregnancy and lactation, with the most common cause of amenorrhea overall being pregnancy. During pregnancy, prolonged elevations in sex hormones suppress the HPO axis and create a stable intrauterine environment where the gestation can develop. After delivery, the persistent hyperprolactinemia that occurs during lactation also suppresses the HPO axis and maintains the patient in a state known as "lactational amenorrhea" until the frequency and duration of nipple stimulation decrease.[21]

Medication-induced amenorrhea can result from several drugs (eg, chemotherapy, illicit substances). Since synthetic progestins, found in hormonal contraceptives, cause endometrial atrophy, prolonged use can lead to secondary amenorrhea, even during a typical hormone-free interval. Some medications (eg, antipsychotics) may also cause hyperprolactinemia resulting in amenorrhea.[9]

Epidemiology

In the US, only about 2% of adolescent girls have not reached menarche by 15 years of age.[3] Müllerian agenesis has an estimated incidence of 1:4,500 to 5,000 females, while CAIS has an estimated incidence of 1:20,000 to 99,000 genetic males.[22][23][15] The incidence of uterovaginal anomalies overall has been reported to be up to 7% in females.[24] 

Pathophysiology

Regular menstruation depends on a complex sequence of events consisting of hormone production leading to ovulation, the effects of hormonal fluctuations from ovulation and the absence of fertilization on the endometrium, and an anatomically normal reproductive tract where this physiologic process can occur. The basic requirements for normal menstrual cycles include four anatomically and functionally distinct structural components: the hypothalamus, anterior pituitary gland, ovary, and the genital outflow tract composed of the uterus, endometrium, cervix, and vagina. If any of these components are nonfunctional or abnormal, menstrual bleeding may not occur; however, the precise pathophysiology associated with amenorrhea may vary based on the underlying etiology and sometimes may be unclear.[9][10]

History and Physical

Clinical Features

Primary amenorrhea is a menstrual symptom characterized by the complete absence of menstruation in a female of reproductive age.[1][25] A complete evaluation is indicated in females presenting with any of the following clinical features: 

• No history of menstruation with secondary sex characteristics present (eg, thelarche, pubic and axillary hair) by the age of 15 years or 3 years after thelarche 
• No history of menstruation and no breast development or other secondary sex characteristics present in an adolescent girl aged 13 years [1][2][3][8]

History

Obtaining a  comprehensive history in patients with clinical features of amenorrhea is critical in diagnosing the underlying etiology. The history should begin by asking about the last menstrual period (LMP) date. If the patient has never menstruated, the patient has primary amenorrhea. The timing of initial breast bud and sexual hair development and general growth trends should be noted to differentiate patients with isolated primary amenorrhea from those with globally delayed pubertal development. The development of breast buds indicates the presence of estrogen, presumably from functional ovaries; the growth of sexual hair indicates the presence of androgens. The patient should also be asked about cyclic abdominal pain, which may be caused by an obstruction in the menstrual outflow tract, such as an imperforate hymen, transverse vaginal septum, or vaginal or cervical atresia.[26][27]

Additionally, it is important to review the patient's medical history, general health, lifestyle, and current medications, which can help identify any chronic illnesses, exposure to chemotherapy or radiation, and potential relative energy deficiencies due to eating disorders or strenuous athletic training. A history of extreme weight loss should be noted. Any history of anosmia, galactorrhoea, headaches, or visual changes may indicate a central nervous system or pituitary disorder. A careful family history should also be obtained, as certain conditions, including CDGP and CAIS, can often have a hereditary component.[26][27]

Physical Examination

Patients presenting with primary amenorrhea also require a complete physical examination to assist in determining an etiology. This should include height, weight, and body mass index (BMI) measurements. Short stature in the absence of all secondary sex characteristics is a hallmark of gonadal dysgenesis, while low body weight can be associated with FHA resulting from malnutrition or physical, psychological, or emotional stress. The following are some clinical findings associated with various causes of primary amenorrhea that, in combination with historical features, can assist in guiding what diagnostic studies are indicated.[6]

• Head and neck: Focal neurological deficits or vision changes suggest an intracranial process affecting the hypothalamus or pituitary gland; thyroid nodularity or enlargement may indicate a thyroid disorder. Several stigmata of Turner syndrome can be seen on examination of the head and neck, including a low hairline, a high-arched palate, and a webbed neck. Signs of Cushing syndrome include moon facies and buffalo hump.
• Skin and hair: The presence and maturation of sexual hair (axillary and pubic hair), which indicates exposure to androgens, should be assessed. Note that the absence of sexual hair suggests the patient has never been exposed to androgens. Signs of androgen excess include hirsutism, excessive acne, and virilization (ie, enlarged clitoris, deepening of the voice). Multiple pigmented naevi may be seen with Turner syndrome. Patients with PCOS or uncontrolled diabetes mellitus may develop acanthosis nigricans. Skin, hair, and nail changes can also be seen with thyroid disorders. Clinicians should be aware that many women remove undesired male-pattern hair growth, so it may not be present on physical exam; it is essential to inquire about any hair removal practices (eg, shaving, waxing, laser).[19]
• Breasts: The stage of breast development should be noted (eg, Tanner staging), which is a reliable indicator of estrogen production or exposure to exogenous estrogen. The absence of breast budding indicates the patient has never been exposed to estrogens. Widely spaced nipples can be seen with Turner syndrome. A finding of galactorrhea may be a sign of hyperprolactinemia.
• Cardiovascular and pulmonary: Heart and lung exam abnormalities may indicate a chronic disease or illness. Patients with excess corticosteroids (eg, Cushing syndrome, 17α-hydroxylase deficiency) can present with hypertension.
• Abdomen: The abdomen should be examined for any palpable masses and signs of chronic disease (eg, hepatomegaly). Pelvic masses may represent a uterus distended by retained menstrual fluid due to an outflow obstruction; less commonly, it may signal an ovarian or uterine neoplasm.
• Pelvic: The pelvic exam should include a thorough inspection of the external genitalia, and an internal digital, bimanual, and speculum examination should be performed as tolerated by the patient. The clinician should note the maturation of the external genitalia and pubic hair and any abnormal enlargement of the clitoris. An imperforate hymen is diagnosed by a bulging membrane without hymenal fringe near the introitus that distends during the Valsalva maneuver. A shortened vagina without a palpable cervix suggests müllerian or vaginal agenesis, a transverse vaginal septum, or CAIS. Therefore, a patent vagina and normal cervix exclude vaginal agenesis, complete AIS, and obstructive causes of amenorrhea such as an imperforate hymen or transverse vaginal septum. Additionally, low estrogen can result in an atrophic vaginal mucosa, which may also be appreciated on an exam.[9][10] 
• Rectal: Although not always necessary, a rectal examination can detect hematocolpos in patients with an obstructive anomaly, which can be felt in the rectum as a bulge of the proximal vagina.[26][28][22]
• Extremity: Additional stigmata of Turner syndrome may be noted on examination of the extremities, including cubitus valgus, genu varum or valgum, a shortened fourth metacarpal, and small metatarsal bones. Joint pain may be present in patients with chronic inflammatory disorders.[6]

Evaluation

Initial Diagnostic Studies

Diagnostic studies performed for the evaluation of primary amenorrhea vary depending on the age of the patient and the findings on the exam. Initially, however, the following are indicated in all patients:

• Urine pregnancy test
• Pelvic ultrasound (typically transabdominal)
• Serum FSH, LH, and estradiol
• Serum prolactin
• Serum thyroid-stimulating hormone (TSH) [9][6][18][29]

Subsequent Diagnostic Studies

Based on clinical indications, additional studies may be required to determine the cause of a patient's amenorrhea. Further evaluation, if clinical findings of the following conditions are noted, may include:

• Hyperandrogenism
  • Total testosterone
  • Fasting morning serum 17-hydroxyprogesterone 
  • Dehydroepiandrosterone sulfate (DHEAS) [9][30][31][32]
• Adolescents with globally delayed puberty
  • Bone age radiography
  • Insulin-like growth factor I (IGF-1) to screen for growth hormone deficiency if growth velocity is low [6]
• Chronic disease (eg, liver disease, inflammatory bowel disease)
  • Complete blood count (CBC)
  • Complete metabolic profile (CMP) and liver function tests
  • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
  • Tissue transglutaminase-immunoglobulin A antibodies (tTG-IgA) to screen for celiac disease if BMI is low [6][9][6]
• POI, gonadal dysgenesis, Turner syndrome, müllerian agenesis, or CAIS (eg, classic stigmata of Turner syndrome, elevated FSH levels, absent müllerian structures on ultrasound)
  • Karyotype 
  • Consider magnetic resonance imaging (MRI) of the pelvis [33][18][15][34]
• Intracranial process (eg, elevated serum prolactin level or focal neurologic deficits)
  • Consider an MRI or CT of the head [33]

 Additionally, if a genetic defect is suggested on history or exam (eg, Kallman syndrome), referral to a genetic counselor and targeted, genetic testing is also warranted.[33]

Interpretation of Initial Testing

Pelvic ultrasound: A transabdominal pelvic ultrasound should be performed to confirm the presence or absence of a uterus and internal gonads. Absence of the uterus indicates müllerian agenesis or other DSD (eg, CAIS). A uterus distended with heterogeneous material is seen with hematometra due to outflow tract obstructions (eg, transverse septum, vaginal agenesis). A thin endometrial lining will be seen in patients without estrogen exposure. In contrast, a thickened endometrial lining suggests the presence of estrogen and chronic anovulation if the outflow tract is patent. Gonadal dysgenesis may be indicated by the inability to visualize the ovaries or findings consistent with streak gonads. If the presence or absence of müllerian structures cannot be confirmed on ultrasound, a pelvic magnetic resonance imaging (MRI) study is an appropriate next step.[13]

Serum testing: It is always important to first rule out pregnancy, as a patient ovulates before their first period and, therefore, may become pregnant before menarche.[9] The FSH and estradiol levels can help distinguish primary hypothalamic and pituitary abnormalities from primary ovarian etiologies. If the screening FSH level is low, the diagnosis of hypogonadotropic hypogonadism can be confirmed, indicating the primary defect is in the hypothalamus or pituitary gland. If the FSH level is elevated, this indicates hypergonadotropic hypogonadism, pointing to a primary defect in the ovary which is unable to respond to normal gonadotropin secretion.[29][6] Since estrogen suppresses FSH release, estradiol is also usually ordered to interpret the FSH level correctly. Estrogen levels are typically low in primary hypothalamic, pituitary, and ovarian disorders, while normal FSH and estradiol levels are seen with structural anomalies.

Abnormal TSH levels indicate thyroid disease and elevated prolactin levels may be secondary to a pituitary adenoma, hypothyroidism, or some medications. Elevated testosterone or DHEA is most likely due to PCOS but may also be seen in Cushing syndrome or hormone-secreting ovarian neoplasms. An abnormal CBC, renal or liver function test, ESR, or CRP can indicate chronic illness.[9] 

Bone age radiography: A bone age radiograph indicates the degree to which sex steroids have affected bone maturation and can identify future growth potential.[6] A patient's bone age can help clinicians provide appropriate counseling around predicted adult height.

Clinical and Diagnostic Findings of Common Primary Amenorrhea Etiologies 

Combining the history, exam, and initial assessment studies, the most common etiologies of primary amenorrhea will typically have the following findings on clinical and diagnostic evaluation:

• Gonadal dysgenesis or POI 
  • Patent vagina and normal cervix and uterus noted on exam with signs of decreased estrogen (ie, no breast bud development, vaginal atrophy) or androgen (ie, no pubic hair)
  • Elevated serum FSH and LH
  • Decreased serum estrogen
  • Ovaries may or may not be visible on ultrasound imaging
• Müllerian agenesis
  • Normal breast, sexual hair development, and external female genitalia; short vagina, ending in a blind pouch often noted
  • Partial or complete absence of the müllerian structures (ie, upper vagina, cervix, uterus, and fallopian tubes) on clinical exam and ultrasound imaging
  • Normal serum FSH and estrogen
  • Other urogenital anomalies may also be noted on imaging [24][9]
• Transverse vaginal septum
  • Similar findings to müllerian agenesis, except that müllerian structures are present on exam and ultrasound imaging [24]
• Imperforate hymen
  • Normal breast, sexual hair development, and external female genitalia
  • A bulging membrane (ie, the hymen) is visible when spreading the labia
  • Normal serum FSH and estrogen
  • Hematocolpos may be seen with transabdominal pelvic ultrasound [24]
• Constitutional delay of growth and puberty (CDGP)
  • Little evidence of estrogen or androgens on an exam
  • Normal anatomy on the pelvic exam and ultrasound
  • Decreased FSH and estrogen levels
  • Delayed bone age on radiography
  • Family history is often consistent with CDGP [6][29]
• Functional hypothalamic amenorrhea (FHA)
  • Similar presentation to CDGP, often with low BMI
  • Typically associated with disordered eating, vigorous exercise, and systemic chronic disease [6][29]
• Polycystic ovary syndrome (PCOS)
  • Normal thelarche and adrenarche on an exam, often with hirsutism and acne on an exam
  • Serum FSH and estrogen within the normal range for reproductive-aged females
  • Polycystic appearing ovaries on ultrasound imaging
  • No clear consensus on diagnosing PCOS within 2 years of menarche exists; caution with diagnosis recommend in this age group [35]
• Complete androgen insensitivity syndrome (CAIS) 
  • Normal thelarche, often with very well-developed breasts but absent or sparse sexual hair
  • Normal external female genitalia but no müllerian structures
  • Testes within the pelvic cavity will be undescended and may be identified on ultrasound imaging [9]

Table: Clinical and Diagnostic Findings of Primary Amenorrhea Etiologies

T: thelarche, A: adrenarche, FSH: follicle-stimulating hormone, CDGP: constitutional delay of growth and puberty, FHA: functional hypothalamic amenorrhea, PCOS: polycystic ovary syndrome, CAIS: complete androgen insensitivity syndrome, US: ultrasound 

Treatment / Management

The management of primary amenorrhea should be directed at correcting the underlying etiology and preventing potential complications. Depending on the etiology, additional testing and monitoring are frequently indicated as well; a detailed discussion on specific management points for all of the various potential diagnoses is beyond the scope of this document.

Outflow Tract Abnormalities

Patients with some types of outflow obstructions (eg, imperforate hymen, cervical stenosis) can be treated with a surgical correction to relieve the obstruction. However, they may have residual issues, including endometriosis and pelvic adhesions due to the initial obstruction.[10][9] Individuals with congenital anomalies affecting vaginal length who desire receptive vaginal intercourse may consider various management options, including surgical techniques or conservative interventions (eg, vaginal dilators). Conservative management alone is successful in 90% to 96% of patients.[22] In patients with a Y chromosome and streak gonads, the gonads should be removed due to their high risk of malignancy.[36][37] Furthermore, all these patients should be referred to clinicians with the expertise and appropriate resources to obtain the desired results following a management plan determined through shared decision-making. Because of the psychological issues patients with congenital anomalies may have, they should also receive counseling and be provided information on available support groups.[38][39]

Hypothalamic, Pituitary, and Gonadal Disorders

Patients of typical reproductive age who lack endogenous sex hormones (eg, POI, Kallman syndrome) require hormone therapy to protect their skeletal and cardiovascular health. Therefore, patients with hypogonadotropic and hypergonadotropic hypogonadism usually require referral to an endocrinologist for long-term hormone therapy. A standard maintenance regimen for hormone replacement therapy includes either a transdermal patch of estradiol 100 mcg daily or conjugated estrogen 0.625 mg orally daily. For 12 days each month, oral micronized progesterone 200 mg daily is added if endometrial protection is needed. In adolescent girls with possible constitutional delay of growth and puberty hormone therapy to initiate pubertal development (ie, jumpstart therapy) may be attempted for 3 to 6 months, after which patients may be monitored for signs of pubertal development without assistance from exogenous hormones for the following 4 to 6 months. Initial expectant management with observation only for the first 6 months is also an appropriate alternative.[6][29] Calcium 1,200 mg orally and vitamin D 1,000 IU orally every day, combined with routine weight-bearing exercises, is also recommended to maintain bone density. A small percentage of patients with POI have reproductive capabilities and may desire contraceptive management. In these patients, either intrauterine contraceptives may be used in addition to HRT, or combined hormonal contraceptives can be used for both HRT and pregnancy prevention. However, as with standard contraceptive counseling, patients should be informed about the potentially increased thromboembolic risk. Screening for comorbid conditions (eg, hypothyroidism) should also be performed as they are more prevalent in this population.[9]

The primary management of amenorrhea due to FHA is the reversal of the contributing factors, including weight gain, stress reduction, lifestyle changes, and dietary modification.[9][40] Patients with FHA due to eating disorders should be provided with appropriate education and counseling programs (eg, nutrition counseling and mental health services) to treat and manage their condition's physical and psychological aspects. Proper nutrition and maintaining a normal weight are the preferred management for amenorrheic patients with this underlying etiology (eg, gluten-free diet for celiac disease, weight restoration for malnutrition); conversely, combination hormone contraceptives alone are not recommended therapy for amenorrhea.[9][40] Cognitive behavioral therapy is effective for FHA secondary to severe stress.[41] 

The dopamine agonist cabergoline is considered first-line therapy in patients with a prolactin-secreting tumor.[42] Larger prolactinomas can be treated surgically. Medication-induced hyperprolactinemia should be treated by discontinuing the offending agent; if discontinuation is not possible, a dopamine agonist can be cautiously considered.[42]

Other Endocrine Abnormalities Affecting the HPO Axis

Similarly, patients with other endocrine abnormalities resulting in amenorrhea should be managed with the improvement of the underlying etiology as the primary goal. For instance, lifestyle interventions promoting a healthy diet and exercise program are the most beneficial therapy for some conditions (eg, PCOS, diabetes). In contrast, others may require pharmacological treatment (eg, thyroid disorders) or a combination.[9] Some medicines also aim to treat complications that may arise due to these conditions. In patients with chronic anovulatory cycles (eg, PCOS), combined hormonal contraceptives are first-line therapy to prevent the development of endometrial hyperplasia and malignancy and treat hirsutism and acne.[19] Clinicians should also perform preventive management and screen patients for hypertension and an elevated body mass index at each visit. Furthermore, patients should be screened for dyslipidemia and impaired glucose tolerance (eg, 2-hour oral glucose tolerance testing or hemoglobin A1C level) every three to five years.[9]

Physiologic- and Medication-Induced Amenorrhea

In patients with these underlying etiologies, amenorrhea typically resolves after discontinuation of the contributing physiologic event or medication. Clinicians should consider the benefits and risks before deciding on medication changes.[9] For example, medication-induced hyperprolactinemia is often treated by discontinuing the offending agent; however, if discontinuation is not possible, a dopamine agonist can be cautiously considered.[42]

Differential Diagnosis

Amenorrhea is a symptomatic presentation of an underlying condition; therefore, differential diagnoses should consider these various potential etiologies, including:

• Physiologic and Medication-Induced
  • Pregnancy
  • Lactation
  • Menopause
  • Medications, chemotherapy, or radiation
• Hypothalamic and Pituitary
  • CDGP
  • FHA
  • Prolactinoma or other hormone-secreting pituitary tumors
  • Kallman syndrome
  • Pituitary infarction or necrosis
  • Autoimmune disease
  • Empty sella syndrome
• Ovarian
  • POI
  • Gonadal dysgenesis
  • Autoimmune disease
  • Aromatase deficiency, 17α-hydroxylase deficiency
• Other Endocrine Abnormalities
  • PCOS or other causes of hyperandrogenism (NCCAH, Cushing syndrome)
  • Hormonally active ovarian or adrenal tumors
  • Thyroid disease
  • Uncontrolled diabetes 
• Outflow Tract Abnormalities
  • Complete or partial müllerian agenesis
  • CAIS
  • Intrauterine adhesions or endometrial scarring
  • Cervical stenosis
  • Vaginal agenesis
  • Transverse vaginal septum
  • Imperforate hymen [9][40]

Prognosis

The prognosis of primary amenorrhea depends on the underlying etiology, and a full discussion on this topic is beyond the scope of this document. Generally, however, reversible or transient causes of primary amenorrhea, such as CDPG and FHA, have a better prognosis than gonadal etiologies, such as gonadal dysgenesis. The prognosis for future fertility varies significantly, depending on the etiology. In patients with functional hypogonadotropic hypogonadism (eg, female athletes) or CDPG, future fertility rates are essentially normal once the HPO axis begins functioning normally. For patients with gonadal dysgenesis or POI; however, fertility rates are much lower. The best fertility option for patients with müllerian agenesis is typically using a surrogate gestational carrier.[22]

Complications

Complications associated with specific underlying conditions (eg, chronic hypoestrogenic state, unopposed estrogen) can arise, including:

• Vasomotor symptoms
• Osteoporotic fractures 
• Endometrial hyperplasia 
• Metabolic and cardiovascular disease
• Infertility 
• Galactorrhea
• Hyperandrogenism effects (eg, virilization, hirsutism, and acne)
• Psychological effects (eg, anxiety, depression) [9][40]

Consultations

Multiple specialties often must be involved in treating patients with complex underlying etiologies of their amenorrhea. Patients with outflow tract anomalies, especially congenital types, should be referred to clinicians (eg, pediatric gynecologists, pediatric endocrinologists)  with the expertise and appropriate resources to obtain the desired results following a management plan determined through shared decision-making. Because of the psychological issues patients with congenital anomalies may have, they should also receive counseling and be provided information on available support groups. These diagnoses in particular can have a significant impact on an adolescent's sense of identity, body image, self-esteem, and overall well-being.[38][39] Patients who lack endogenous sex hormones (eg, POI, Kallman syndrome) also require specialist consultation (eg, endocrinologist) for pubertal and maintenance hormone therapy.[6] Furthermore, patients with FHA due to eating disorders should be referred to appropriate education and counseling programs (eg, nutrition counseling and mental health services) to treat and manage their condition's physical and psychological aspects.[9]

Deterrence and Patient Education

Patients should be informed that regular menstruation is an essential sign of health in women of reproductive age who do not take hormonal medications to suppress it. They should be advised that the absence of menstruation may indicate a severe underlying medical disorder and warrants an evaluation. Additionally, the importance of a healthy lifestyle, including a nutritious diet, appropriate levels of exercise, and attention to one's mental health should be stressed. Clinicians should make anticipatory counseling about the stages of a woman's reproductive life cycle and the menstrual cycle a routine part of every wellness visit. Counseling on the reproductive life cycle should include the average ages for upcoming transitions (eg, puberty, menopause), expected physiologic changes, and family planning preferences. Menstrual cycle education should include tracking the first day of menstruation to the first day of the next cycle, the average interval between cycles, and what constitutes an abnormal cycle. This will help in earlier diagnosis of health problems and assist in easing patient anxiety sometimes experienced when facing predictable reproductive transitions (eg, puberty and menopause). Patients should also be introduced to valuable tools to help track menstrual cycles.[3][43]

Pearls and Other Issues

When evaluating a person with amenorrhea, first consider the physiologic causes of amenorrhea, then think through the reproductive pathway "from head to toe": hypothalamus, pituitary gland, ovaries, endometrium, cervix, and vagina. Other endocrine disorders and systemic diseases that may affect the HPO axis should also be considered.

When performing diagnostic studies, pregnancy should be excluded first; FSH, LH, prolactin, and TSH laboratory studies will then identify most endocrine causes of amenorrhea.

Clinicians should make anticipatory counseling about the stages of a woman's reproductive life cycle and the menstrual cycle a routine part of every wellness visit.[9]

All adults require sex hormones. If a patient does not produce their own hormones after a reasonable observation period or has a condition associated with permanent hypogonadism, referral to a specialist for hormone therapy is warranted.

Enhancing Healthcare Team Outcomes

An interprofessional team including clinicians (MDs, DOs, NPs, PAs), specialists (particularly endocrinologists and gynecologists), nurses, and pharmacists must collaborate, openly sharing information and coordinating patient evaluation, education, and treatment to optimize outcomes. Additionally, during the diagnostic process, radiology and laboratory staff members play an essential role in assessing patients and providing accurate and timely reports to treating clinicians. Mental health clinicians and social workers also play an important role in managing these patients, especially those receiving a diagnosis with long-term implications regarding their fertility which may cause significant emotional distress (eg, disorders of sexual development). Patients diagnosed with functional hypothalamic amenorrhea may also require mental health and nutrition counseling, and those with intracranial abnormalities may require care from a neurosurgery specialist. Therefore, a well-coordinated, multidisciplinary team is best suited to manage these patients. [27] 

Furthermore, as with any complex medical condition, proper documentation in the medical record and excellent communication between team members is crucial in optimizing care for these patients. The clinician, nurse, and pharmacist must coordinate care, treatment, and education of the family and patient to ensure close follow-up. Only with an interprofessional team approach can the best outcomes be reached.