Continuing Education Activity

Amenorrhea is the absence of menstruation in a female of reproductive age. 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. Patients meeting the criteria for either primary or secondary amenorrhea warrant an evaluation. Additionally, an assessment for delayed puberty is indicated in adolescents aged 13 years and younger without initial breast development.

Most of the underlying causes of amenorrhea can be classified into general groups: outflow tract abnormalities, ovarian failure or insufficiency, hypothalamic or pituitary disorders, other endocrine gland disorders, and physiologic or medication induced. Proper management of amenorrhea requires an accurate diagnosis of the underlying etiology. The treatment for amenorrhea is based on correcting the underlying etiology and monitoring the patient for complications. This activity for healthcare professionals is designed to enhance the learner's competence when managing amenorrhea, equipping them with updated knowledge, skills, and strategies for timely diagnosis, effective interventions, and improved care coordination, leading to better patient outcomes.

Objectives:

• Differentiate the types of amenorrhea and determine when an evaluation is warranted.

• Identify the potential etiologies of amenorrhea.

• Implement evidence-based and timely evaluation strategies for patients with amenorrhea.

• Apply interprofessional team strategies for improving care coordination for patients with amenorrhea, leading to improved outcomes.

Introduction

Throughout each stage of a woman's reproductive life cycle, from menarche to menopause, there may be variations in their menstrual cycle's length and amount secondary to many causes. This variation may be within the normal range or pathologic. Particularly during stages of the reproductive cycle (eg, menarche and perimenopause), when longer intervals between menstrual cycles commonly occur, clinicians may be unsure of the appropriate diagnostic studies or when an evaluation is indicated.

Amenorrhea is a menstrual symptom characterized by the absence of menstruation in a female of reproductive age.[1][2] It 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][3] Patients meeting the criteria for either primary or secondary amenorrhea warrant an evaluation. However, an evaluation for delayed puberty is indicated in adolescents aged 13 years with primary amenorrhea and no breast development.[4][5]

There are numerous potential etiologies of amenorrhea. Most of the underlying causes of amenorrhea can be classified into general groups: outflow tract abnormalities, ovarian failure or insufficiency, hypothalamic or pituitary disorders, other endocrine gland disorders, and physiologic or medication-induced.[6][7] When evaluating a patient with amenorrhea, a systematic approach should be used to consider each potential etiology. 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.[4][6][7] Treatment depends on the underlying etiology and may include lifestyle interventions, hormone therapy or other medications, surgery, and mental health services.

Etiology

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.[7][6] Any etiology of secondary amenorrhea may also present as primary amenorrhea. Determining the underlying cause of amenorrhea will assist in guiding management decisions.[7]

Outflow Tract Abnormalities 

Anatomic abnormalities cause amenorrhea by preventing endometrial development or obstructing the efflux of menstrual fluid. This group of etiologies includes:

• Mullerian agenesis (ie, Mayer-Rokitansky-Kuster-Hauser syndrome)
• Complete androgen insensitivity syndrome (ie, testicular feminization)
• Intrauterine synechiae (ie, Asherman syndrome)
• Imperforate hymen
• Transverse vaginal septum
• Cervical agenesis or stenosis
• Vaginal agenesis
• Congenital endometrial hypoplasia or aplasia [7]

Primary amenorrhea is primarily seen with congenital anomalies (eg, müllerian agenesis or cervical agenesis) or disorders of sexual development (DSD) in which a uterus does not develop, such as complete androgen insensitivity syndrome (CAIS).[7][8][9] The müllerian structures include the fallopian tubes, uterus, and upper vagina; complete or partial müllerian agenesis can result in amenorrhea if the uterus, cervix, or vagina do not fully develop or are absent altogether. Patients with outflow tract obstructions typically present around the age of menarche with cyclic abdominopelvic pain in the setting of otherwise normal pubertal development.[7] Individuals with CAIS have 46,XY karyotype and androgen receptor abnormalities, which cause them to be utterly resistant to androgens. These patients secrete antimüllerian hormone (AMH) from their functional testes in utero, causing regression of the müllerian structures; however, their androgen resistance results in the development of external female genitalia. At puberty, their excess testosterone is converted by aromatase into estrogen. Hence, individuals with CAIS typically present with primary amenorrhea and are found to have well-developed breasts, sparse sexual hair, an absent uterus, and a shortened vagina ending in a blind pouch.[9]

Secondary amenorrhea can be seen with iatrogenic endometrial suppression, endometrial destruction, and cervical stenosis. The endometrium can also not proliferate if the basal layer of the endometrium is severely damaged and develops deep scarring or significant intrauterine adhesions. Endometrial scarring is most often caused by vigorous curettage in the setting of an intrauterine infection after pregnancy loss, abortion, or postpartum hemorrhage; additionally, in developing regions, tuberculous endometritis can also lead to extensive intrauterine adhesions and secondary amenorrhea. It should be noted, however, that endometrial scarring and intrauterine adhesions are more commonly associated with abnormal or irregular bleeding than complete amenorrhea. [10][11] Finally, amenorrhea can be caused by obstruction of the cervix due to scarring after a cervical procedure, radiation, neoplasia, or atrophy.[7]

Hypothalamic and Pituitary Disorders

The reproductive cycle is controlled by the HPO axis, which directs the pulsatile release of gonadotropin-releasing hormone (GnRH), and, therefore, disorders affecting the function of the hypothalamus or pituitary gland can disrupt menstruation. Suppression of GnRH results in low levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion from the anterior pituitary gland. With decreased levels of FSH and LH, the ovaries lack the stimulation to produce estrogen and progesterone, leading to anovulation and subsequent amenorrhea. Causes of HPO axis impairment include functional hypothalamic amenorrhea (FHA), hyperprolactinemia, disorders of pubertal development, and damage (eg, ischemia, infection, or trauma).[12][7]

The most common etiology of amenorrhea in adolescent girls is functional hypothalamic amenorrhea (FHA).[12][7] FHA is a pathologic condition caused by a relative energy deficiency leading the hypothalamus to suppress the body's reproductive cycle. An underlying eating disorder, excessive exercise or athletic training, and extreme perceived stress typically cause FHA. Constitutional delay of growth and puberty (CDGP) is a common cause of delayed puberty in girls, in which there is a transient delay in the maturation of the HPO axis that resolves with time and usually has a strong genetic component.[13] Additionally, inflammation, trauma, chronic systemic disease, or a serious illness (eg, celiac disease and inflammatory bowel disease) can lead to hypothalamic suppression of the HPO axis and amenorrhea. This is usually identified when the absence of menses is noted following diagnostic features of the primary disease process.[7]

Prolactinomas are prolactin-secreting tumors of the anterior pituitary gland.[14] They create a state of hyperprolactinemia, which suppresses the HPO axis.[15] Although prolactinomas are the most common pituitary tumor resulting in amenorrhea, other hormone-secreting pituitary tumors may also disrupt HPO axis function, including those that produce unregulated levels of adrenocorticotropin hormone (ACTH), thyroid-stimulating hormone (TSH), and growth hormone (GH).[6]

Other rare hypothalamic and pituitary causes of amenorrhea include inherited deficiencies of GnRH-producing neurons, known as Kallman syndrome when amenorrhea is present with anosmia, pituitary infarction (eg, Sheehan syndrome), infiltrative disease (eg, cancer, sarcoidosis, hemochromatosis), craniopharyngioma, autoimmune disease, and empty sella syndrome due to traumatic or iatrogenic causes.[7][6]

Gonadal Disorders

Estrogen stimulates endometrial growth, while progesterone causes endometrial stabilization and maturation. Progesterone withdrawal triggers endometrial shedding (ie, menses). When these sex hormones are not present in significant quantities due to gonadal dysfunction, menstruation does not occur. This ovarian failure can be congenital or acquired.[7]

Primary ovarian insufficiency (POI) is the reduction or dysfunction of ovarian follicles resulting in the cessation of menses in women aged 40 years or younger.[16] POI may occur for various reasons, including chromosomal abnormalities, ovarian damage from radiation or chemotherapy, autoimmune disease, infiltrative and infectious processes, or iatrogenically after ovarian surgery.[1] POI is also frequently associated with a premutation in the FMR1 gene, which causes Fragile X syndrome and other endocrinopathies (eg, hypoadrenalism and hyperparathyroidism).[16]

Primary amenorrhea is also frequently due to gonadal dysgenesis or, rarely, enzymatic impairment (eg, 17α-hydroxylase or aromatase deficiency). Gonadal dysgenesis is often seen in patients with the 45,X karyotype (ie, Turner syndrome) or mosaicism.[6] Less commonly, it can present as pure gonadal dysgenesis in individuals with either a 46,XX or 46,XY karyotype (ie, Swyer syndrome). Patients with Swyer syndrome develop a uterus, fallopian tubes, and upper vagina, as well as external female genitalia, due to the lack of testicular hormone secretion in utero. People with gonadal dysgenesis have nonfunctional gonadal tissue, so they often present in early adolescents with absent pubertal development.[17]

Other Endocrine Abnormalities Affecting the HPO Axis

Numerous additional hormonal abnormalities can also cause HPO axis dysfunction; these disorders are more commonly associated with secondary amenorrhea than primary amenorrhea.

Elevated serum androgens suppress the HPO axis, and the most common cause of amenorrhea in the setting of hyperandrogenemia is polycystic ovary syndrome (PCOS).[6] Individuals with PCOS present with hyperandrogenism, menstrual abnormalities, and metabolic dysfunction.[18] PCOS patients tend to have chronic anovulatory cycles resulting in prolonged periods of estrogen "unopposed" by progesterone, which can lead to endometrial hyperplasia. Less common causes of hyperandrogenemia include nonclassical congenital adrenal hyperplasia (NCCAH), ovarian or adrenal androgen-secreting tumors, and Cushing syndrome.[7]

Hyperprolactinemia is most often due to a prolactinoma; however, it can also be caused by exercise, stress, chronic kidney disease, renal failure, and some medications, especially antipsychotics, antidepressants, opiates, and drugs affecting the dopaminergic pathways.[14][19] Other endocrine disorders affecting HPO axis function include hyper- and hypothyroidism, uncontrolled diabetes mellitus, and adrenal insufficiency.[7] 

Physiologic and Medication Induced Amenorrhea

Physiologic amenorrhea includes pregnancy, lactation, and menopause. The most common cause of amenorrhea overall is 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.[20]

Menopause refers to the state of natural gonadal senescence at the end of the reproductive years. During the menopausal transition, ovarian function naturally declines, and estrogen and progesterone production decreases significantly.[21] Although the typical age of the menopausal transition is in the early 50s, many women can experience this change in their 40s, which is still considered to be within normal limits. 

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.[7]

Epidemiology

In the US, only about 2% of adolescent girls have not reached menarche by age 15 years.[4] The most common causes of primary amenorrhea are gonadal dysfunction in 43% of patients, müllerian agenesis in about 10% to 15%, and CDGP in about 14% of patients.[22][7] Abnormal karyotypes are found in approximately 50% of patients with primary amenorrhea and no associated comorbidities.[16]

The prevalence of secondary amenorrhea not caused by physiologic changes is approximately 3% to 4% of reproductive females.[6][23] The most common causes of secondary amenorrhea include PCOS, FHA, hyperprolactinemia, and POI. An abnormal karyotype is found in approximately 13% of women aged ≤30 years with secondary amenorrhea that is not physiologically induced.[16]

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.[7][6]

History and Physical

Clinical Features

Amenorrhea is a menstrual symptom characterized by the absence of menstruation in a female of reproductive age caused by an underlying condition.[1][2] It can be classified as either primary or secondary amenorrhea. A complete evaluation is indicated in women presenting with the following clinical features for either primary or secondary amenorrhea. 

• Primary amenorrhea: girls with no history of menstruation by either
  • The age of 15 years
  • Three years after thelarche
• Secondary amenorrhea: any woman with the absence of menses for either
  • ≥3 months and previously regular menstrual cycles
  • ≥6 months and at least one previous spontaneous menstruation [1][3] 

However, an evaluation for delayed puberty is indicated in adolescents aged 13 years with primary amenorrhea and no breast development.[4][5]

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 date of the last menstrual period (LMP). 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. If the patient has menstruated previously, menstrual patterns should be fully characterized, including the frequency, duration, flow amounts, and regularity of bleeding.[24] 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.[25][26] Additional clinical history should include:

• Sexual history and pregnancy symptoms (eg, nausea, vomiting, fatigue, and breast tenderness)
• Lifestyle factors suggestive of FHA (eg, restrictive diets, vigorous exercise habits, rigid or negative attitudes about weight, and the presence of life stressors) [27]
• Galactorrhea or the use of any medications associated with hyperprolactinemia (eg, antipsychotics, antidepressants, anticonvulsants, and opiates)
• Vision changes, anosmia, headaches, or other focal neurologic deficits suggestive of an intracranial process
• Vasomotor and other hypoestrogenic symptoms (eg, hot flashes, night sweats, vaginal dryness, dyspareunia, mood swings, or sleep disturbances)
• Cyclic pelvic pain or history of an endometrial  or cervical procedure indicating possible outflow tract obstruction 
• Symptoms of hyperandrogenemia (eg, male-pattern hair growth or hair loss, excessive acne) 
• A known history of metabolic or endocrine disease, such as insulin resistance, obesity, hypertension, or thyroid or adrenal disease
• Autoimmune symptoms (eg, thyroid enlargement, palpitations, weight changes, energy, bowel habits, skin, hair, or nails) or symptoms of other chronic diseases (eg, GI distress, weight loss, or joint pain)
• Uncontrolled diabetes mellitus symptoms (eg, polyuria and polydipsia)[7]

Physical Examination 

Clinicians should also perform a complete physical exam to look for signs of an underlying etiology. The following are some clinical findings associated with various causes of amenorrhea that, in combination with historical features, can assist in guiding what diagnostic studies are indicated.

General: A low body mass index (BMI) or recent weight loss is commonly seen in patients with FHA. Poor adolescent growth trends may indicate CDGP or another process affecting global development. Additionally, short stature in a patient without any secondary sex characteristics strongly suggests gonadal dysgenesis.

Head and Neck: Focal neurological deficits or vision changes suggest an intracranial process affecting the hypothalamus or pituitary gland; thyroid nodularity or enlargement is suggestive of thyroid disease. 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.

Breast: Spontaneous or expressable discharge of milky fluid suggests hyperprolactinemia. In adolescents, the stage of breast development should be noted; absent breast development (eg, Tanner stage 1) indicates the patient has never been exposed to estrogen, while normal maturation indicates estrogen exposure, most likely from functional ovaries. Widely spaced nipples can be seen with Turner syndrome.

Cardiovascular and Pulmonary: Some chronic diseases or serious illnesses may have abnormal heart or lung findings. Hypertension can also be seen in the setting of excess corticosteroids (eg, Cushing syndrome, 17α-hydroxylase deficiency).

Abdominal: A palpable mass in the lower abdomen may represent an enlarged uterus or ovarian mass; the uterus enlarges during pregnancy and in patients with retained menstrual fluid in the setting of an outflow tract obstruction or those with a neoplasm. The abdominal exam may also reveal signs of chronic illness, such as hepatomegaly or ascites. Signs of Cushing syndrome can include abdominal striae and a centripetal fat distribution.[18]

Extremities: Additional stigmata of Turner syndrome may be noted on the extremities, including a cubitus valgus, genu varum or valgum, a shortened fourth metacarpal, or small metatarsal bones. Patients with chronic inflammatory disease may also have joint tenderness or other abnormalities.

Skin and Hair: Adolescent patients with primary amenorrhea should be examined for the presence and maturation of axillary and pubic hair; their presence indicates exposure to androgens, most likely from functional ovaries. All patients should be examined for signs of hyperandrogenism, including male-pattern hair growth, hair loss, and acne. Thyroid disorders may also present with skin, hair, and nail changes, while patients with PCOS or uncontrolled diabetes mellitus may develop acanthosis nigricans. Clinicians should be aware that many women remove undesired male-pattern hair growth, so it may not be present on physical exam; asking about any hair removal practices (eg, shaving, waxing, laser) is essential.[18]

Pelvic: The pelvic exam is most important for excluding outflow tract anomalies, which are much more commonly identified in patients with primary amenorrhea; a pelvic exam should also be performed in those with secondary amenorrhea; however, it is usually normal.[8] The exam ideally includes an inspection of the external genitalia, a bimanual exam, and a speculum examination. An internal examination, however, may not be appropriate for some younger patients; even if a patient cannot tolerate a speculum exam, a single digit inserted into the vagina may provide valuable information, especially in patients with primary amenorrhea. When examining the external genitalia, the degree of pubic hair and vulvar maturation should be noted, along with any signs of hirsutism or virilization (eg, enlarged clitoris). On the internal exam, the clinician should note the patency and approximate length of the vagina, if a cervix and uterus are present, if any uterine lesions, masses, or tenderness are present, and if vaginal atrophy is evident. 

Rectal: In patients with obstructive outflow tract anomalies, a bulge from the proximal vagina may be palpated, indicating retained menstrual fluid.[7]

Evaluation

Initial Diagnostic Studies

The evaluation varies depending on the age of the patient and the findings on the exam. Initially, however, the following diagnostic studies are indicated in all patients with amenorrhea:

• Urine pregnancy test
• Serum FSH, LH, and estradiol
• Serum prolactin
• Serum thyroid-stimulating hormone (TSH)
• Pelvic ultrasound [7][16][27]

Subsequent Diagnostic Studies

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

• Hyperandrogenism
  • Total testosterone
  • Fasting morning serum 17-hydroxyprogesterone 
  • Dehydroepiandrosterone sulfate (DHEAS)[27][28][29]
• 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 [13]
• 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 [13]
• 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 [12][16][9][30]
• Intracranial process (eg, elevated serum prolactin level or focal neurologic deficits)
  • Consider an MRI or CT of the head [12]

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.[12]

Interpretation of Diagnostic Study Findings

A positive urine pregnancy test indicates a pregnancy, an abnormal TSH indicates thyroid disease and an elevated prolactin identifies hyperprolactinemia.

The combination of low FSH and estradiol levels identifies hypogonadotropic hypogonadism and indicates the abnormality affects hypothalamic or pituitary function. The most common causes of hypogonadotropic hypogonadism are CDGP in primary amenorrhea and FHA in secondary amenorrhea.[6][22][13] In patients with hypogonadotropic hypogonadism and other abnormalities in nonhormonal serum testing (eg, abnormal renal or liver function tests), further evaluation for chronic disease is warranted.

The combination of elevated FSH and low estradiol levels identifies hypogonadotropic hypogonadism, indicating the abnormality affects ovarian function. These results suggest primary ovarian insufficiency or gonadal dysgenesis, although the tests are typically repeated at least once before assigning the POI diagnosis.[16]

Patients with PCOS typically have elevated serum testosterone levels and evidence of polycystic ovaries appearing on ultrasound.[18] Other serum tests differentiate PCOS from other less common causes of hyperandrogenemia: an elevated fasting 17-OH-P suggests NCCAH, while an elevated DHEAS suggests an adrenal androgen-secreting tumor.[18]

The pelvic ultrasound can identify many müllerian anomalies, including müllerian agenesis.[8] If the patient has an outflow tract obstruction, such as an imperforate hymen, transverse vaginal septum, or cervical or vaginal agenesis, the uterus can appear distended with heterogeneous material representing the retained menstrual fluid. Patients lacking estrogen exposure, such as those with FHA, POI, and natural menopause, often will have a thin endometrial stripe.

Treatment / Management

The treatment for amenorrhea is based on correcting the underlying etiology and monitoring the patient for complications. 

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.[6][7] 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.[31] However, 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.[32][33]

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. 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. 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.[7]

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.[7][34] 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 normal weight are the preferred management for amenorrheic patients with this underlying etiology; conversely, combination hormone contraceptives alone are not recommended therapy for amenorrhea.[7][34] Cognitive behavioral therapy has been shown to be effective for FHA secondary to severe stress.[35]

The dopamine agonist cabergoline is considered first-line therapy in patients with a prolactin-secreting tumor.[14] Larger prolactinomas can be treated surgically. Medication-induced hyperprolactinemia should be treated by discontinuing the offending agent, if possible, or if discontinuation is not possible, a dopamine agonist can be cautiously considered.[14]

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.[7] 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.[18] 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.[7]

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.[7] 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.[14]

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 Etiologies

• Pregnancy
• Lactation
• Menopause
• Medications, chemotherapy, or radiation

Hypothalamic and Pituitary Etilogies

• CDGP
• FHA
• Prolactinoma or other hormone-secreting pituitary tumors
• Kallman syndrome
• Pituitary infarction or necrosis
• Autoimmune disease
• Empty sella syndrome

Ovarian Etiologies

• 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 [7][34]

Prognosis

The prognosis depends on the underlying etiology, and a complete discussion can be found within the articles on each etiology. Issues related to both general health and fertility should be considered. Generally, etiologies that can be surgically corrected (eg, imperforate hymen) or fully reversed (eg, FHA) have an excellent prognosis. 

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) [7][34]

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 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.[32][33] Patients who lack endogenous sex hormones (eg, POI, Kallman syndrome) also require specialist consultation (eg, endocrinologist) for pubertal and maintenance hormone therapy.[13] 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.[7]

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 and menopause, expected physiological 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.[4][36]

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.

Enhancing Healthcare Team Outcomes

Amenorrhea may occur in most females at some point in their lives. Other than pregnancy, however, determining the cause can be a challenge. Amenorrhea is best managed by an interprofessional team of healthcare workers that often includes a primary care clinician, gynecologist, endocrinologist, dietitian, mental health clinician, fertility specialist, and nursing, laboratory, and radiology staff members. For instance, patients who do not produce endogenous sex hormones are at increased risk for osteoporosis. Therefore, they require long-term monitoring by an endocrinologist and appropriate calcium and vitamin D supplementation to reduce their fracture risk. Other etiologies may be associated with infertility, requiring the assistance of a fertility team and mental health practitioners. Patients with FHA often need nutrition counseling and mental health support, while those with intracranial abnormalities may require care from a neurosurgery specialist.

As with any complex medical condition, proper documentation in the medical record and excellent communication among 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.