Secondary Amenorrhea

Etiology

The underlying etiologies of secondary amenorrhea vary widely, involving physiologic, hypothalamic, pituitary, ovarian, endometrial, and cervical etiologies, as well as other endocrine and hormonal causes that can also affect the HPO axis. 

Physiologic Causes of Secondary Amenorrhea

Hormone levels during certain physiologic states result in secondary amenorrhea, including:

• Pregnancy: Prolonged elevations in estrogen, progesterone, and other hormones produced by the placenta suppress the HPO axis and maintain a stabilized endometrium throughout pregnancy.
• Lactation: Elevated prolactin levels are responsible for producing breastmilk and suppressing the HPO axis.
• Menopause: Natural gonadal senescence at the end of the reproductive years results in decreasing gonadal hormone production and cessation of natural menses.[4]

Hypothalamic and Pituitary Causes of Secondary Amenorrhea

Abnormalities in the hypothalamus or pituitary gland disrupt the HPO axis and thus can suppress menses. If the hypothalamus does not release GnRH or the pituitary gland does not release FSH or LH, the ovaries will not be stimulated to develop follicles. If follicles do not develop, the gonadal hormones estrogen and progesterone will not be produced in significant quantities. Therefore, the endometrium will not receive the hormonal stimulation required to grow and shed, resulting in amenorrhea.

Numerous potential causes of hypothalamic and pituitary dysfunction can result in secondary amenorrhea, including:

• Functional hypothalamic amenorrhea: The relative energy deficiency that can result from eating disorders, frequent vigorous exercise, or even substantial stress can lead to suppression of the GnRH pulse.[5][6][7] Williams Gynecology describes this phenomenon as "a mechanism to prevent pregnancy at a time in which resources are suboptimal for supporting a child."[5]
• Prolactinomas: Prolactinomas are a type of pituitary adenoma that secrete prolactin, suppressing gonadotropin release.
• Infarction/necrosis (Sheehan syndrome): The pituitary gland can infarct during episodes of acute hypovolemia, eg, a severe postpartum hemorrhage, leading to a nonfunctional pituitary gland.
• Infectious: Some intracranial infections, including tuberculosis, encephalitis/meningitis, and syphilis, may result in hypothalamic or pituitary dysfunction.
• Infiltrative disease: Conditions, eg, cancer, sarcoidosis, and hemochromatosis can lead to dysfunction or destruction of hormonally active tissue.
• Inherited etiologies (Kallman syndrome): Several genetic mutations have been identified that result in deficiencies of olfactory and GnRH-producing neurons, leading to a clinical syndrome characterized by hypogonadotropic hypogonadism and anosmia.
• Empty sella syndrome: Shrinking of the pituitary gland due to structural, traumatic, or iatrogenic causes leads to gland hypofunction.[3][4]

Of this group, functional hypothalamic amenorrhea and prolactinomas are the most commonly encountered etiologies of secondary amenorrhea.[3]

Other Hormonal and Endocrine Causes of Secondary Amenorrhea

In addition to direct abnormalities in the hypothalamus or pituitary gland, numerous other hormonal abnormalities may interact with and affect HPO axis function and result in abnormal menstruation or secondary amenorrhea, including:

• Hyperprolactinemia due to other causes, including lactation, stress, exercise, medications, especially antipsychotics and opiates, and chronic kidney disease
• Hyperandrogenism, which is seen in polycystic ovarian syndrome, exogenous androgen use (eg, as part of gender-affirming therapy), and, less commonly, in non-classical congenital adrenal hyperplasia and with androgen-secreting tumors in the adrenal gland or ovary
• Thyroid disorders (both hyperthyroidism and hypothyroidism)
• Uncontrolled diabetes
• Cushing syndrome 
• Other hormonally active tumors (eg, ovarian and thyroid masses) [3][4][8]

Ovarian Dysfunction: Primary Ovarian Insufficiency and Natural Menopause

Primary ovarian insufficiency (POI) refers to the depletion or dysfunction of ovarian follicles that leads to the cessation of menses before 40. POI may be inherited or acquired, with numerous potential causes of both.[9] POI represents impaired ovarian function; however, the function may not be completely suppressed, and approximately 5% to 10% of individuals still achieve spontaneous pregnancy.[10] Additionally, natural menopause may occur earlier than expected (eg, in the early to mid-40s), though it will not be classified as POI if the patient is older than 40.

• Inherited causes of POI: Chromosomal disorders causing gonadal dysgenesis (eg, Turner syndrome, mosaicism), single gene mutations, and premutation in the FMR1 gene, which causes fragile x syndrome [3][11]
• Acquired causes of POI: Autoimmune oophoritis, which is typically associated with anti-adrenal antibodies and adrenal insufficiency, chemotherapy, radiation, environmental toxins, and mumps oophoritis [3][11]

Endometrial Abnormalities and Outflow Tract Obstruction

The major acquired causes of uterine and outflow tract abnormalities include:

• Iatrogenic endometrial suppression: Progestins found in hormonal contraceptives are synthetic and result in endometrial atrophy. With prolonged use, the endometrium may become chronically suppressed, resulting in a lack of bleeding even during a scheduled hormone-free interval.
• Intrauterine adhesions (Asherman syndrome): If the basal layer of the endometrium is destroyed, deep scarring develops, and the endometrium cannot proliferate despite normal hormone profiles, resulting in secondary amenorrhea. Intrauterine adhesions may be caused by vigorous curettage, often in the setting of an intrauterine infection, after a miscarriage, therapeutic abortion, or postpartum hemorrhage. Additionally, tuberculous endometritis, seen primarily in developing regions of the world, can lead to extensive intrauterine adhesions and secondary amenorrhea.
• Cervical stenosis: Narrowing and obstruction of the cervical canal can be caused by scarring, neoplasia, and atrophy. Scarring may develop after infectious cervicitis or a cervical excision procedure (eg, electrosurgical excision procedure or cold knife cone) typically performed to treat cervical dysplasia or malignancy.[3][4]

Except for natural menopause, almost all of the etiologies of amenorrhea, including physiologic, hypothalamic, pituitary, hormonal/endocrine, and ovarian causes, can present as either primary or secondary amenorrhea. Some causes of amenorrhea, however, only present as primary amenorrhea, including Müllerian agenesis, transverse vaginal septum, imperforate hymen, and some disorders of sexual development (eg, complete androgen insensitivity syndrome).

Epidemiology

Pregnancy, lactation, and menopause are common physiologic causes of secondary amenorrhea. The prevalence of secondary amenorrhea due to all other causes is approximately 2% to 5%.[12][13][14] Of all patients presenting with secondary amenorrhea, about 30% to 40% will have a chronic anovulatory disorder (most often PCOS), about 35% will have functional hypothalamic amenorrhea, about 10% will have hyperprolactinemia, and about 10% will have POI.[3][15][16][17]

History and Physical

As with any patient encounter, a complete history and physical exam should help narrow the differential diagnoses. When obtaining a clinical history, the date of the last menstrual period should be determined, and the patient should be asked if there were any potential inciting events, including childbirth, procedures (eg, uterine curettage or loop electrosurgical excision procedure), trauma, or pelvic infection. The clinician should consider how any potential inciting events may lead to one of the etiologies of secondary amenorrhea. Previous menstrual patterns should be characterized, including the frequency, duration, regularity, and flow of prior menstrual bleeding.[18] 

After collecting the initial history, the clinician should systematically consider the potential etiologies of secondary amenorrhea. One such approach is to consider physiologic causes, then move head through the menstrual pathway, asking about potential historical factors or associated symptoms that may suggest a specific etiology. Next, a comprehensive medical history should be completed and a full physical exam performed, including assessments of the vital signs, body mass index, vision, thyroid gland, heart/lungs, breasts, abdomen (eg, speculum and bimanual pelvic exam), and skin. Additional exam components (eg, neurologic exam) may be indicated based on the history. Specific history and exam findings that can suggest a specific cause of secondary amenorrhea include:

• Pregnancy or hormonal suppression of the endometrium: Pregnancy must always be considered in patients presenting with secondary amenorrhea; therefore, the clinician should always ask about pregnancy intention, contraceptive methods used, and sexual activity (eg, the timing of the most recent sexual encounter, sex of partner(s), or type of sex). Symptoms of pregnancy may include fatigue, nausea/vomiting, constipation, and breast tenderness or enlargement. The type and use of hormonal contraceptives should be characterized because incorrect use may increase the risk of unintended pregnancy, and the chance of progestin-induced endometrial atrophy increases when contraceptives are taken in a continuous or semi-continuous manner. On pelvic exam, pregnancy results in uterine enlargement and softening of the cervix; additionally, the genital mucous membranes can appear blue, known as the Chadwick sign.

• Functional hypothalamic amenorrhea and other intracranial causes: Patients should be screened for eating disorders and asked about dietary intake, exercise habits/athletic training, attitudes about weight, and life stressors, all of which may point to functional hypothalamic amenorrhea (FHA), though this is a diagnosis of exclusion.[7] An inability to smell suggests Kallman syndrome, while infiltrative disease may be associated with headaches and other neurologic dysfunctions. A history of severe postpartum hemorrhage followed by difficulty breastfeeding or other symptoms of pituitary dysfunction suggests Sheehan syndrome. On exam, a low body mass index is common in FHA, and dental erosions may be present with bulimia nervosa. A neurologic exam is indicated for patients who report symptoms of neurologic dysfunction. 

• Hyperprolactinemia: Prolactin stimulates breast milk production and suppresses the HPO axis. Therefore, secondary amenorrhea associated with galactorrhea or abnormal nipple discharge strongly suggests hyperprolactinemia. However, amenorrhea is more common than galactorrhea in hyperprolactinemia.[19] Headaches and vision changes, especially peripheral vision, may suggest a pituitary prolactinoma. Hyperprolactinemia can also be caused by certain medications, especially antipsychotics and opiates, so a careful medication review is warranted. A breast exam should be performed to look for easily expressable fluid and to assess any fluid noted. A neurologic exam is also indicated if the patient reports any neurologic symptoms.
• Polycystic ovarian syndrome and other hyperandrogenic disorders: Polycystic ovarian syndrome (PCOS) is the most common cause of hyperandrogenism associated with secondary amenorrhea and is characterized by a combination of menstrual abnormalities, hyperandrogenism, and metabolic dysfunction.[3][20] These patients will frequently have a longer history of irregular cycles before their current period of amenorrhea, along with evidence of hirsutism (ie, male pattern hair growth), acne, obesity, or insulin resistance. Non-classical congenital adrenal hyperplasia, androgenic tumors, and Cushing syndrome can have similar presentations to PCOS, though androgenic tumors are often associated with much higher levels of abnormal androgen production, potentially leading to virilization (eg, clitoromegaly, deepening of the voice) that is not typically seen in PCOS. Additionally, patients with Cushing syndrome often have other associated symptoms and clinical findings. All patients with secondary amenorrhea should be examined for signs of hyperandrogenism (eg, hirsutism, acne, and virilization) and asked about undesired hair growth that may have already been removed (eg, shaving, waxing, laser).

• POI or early menopausal transition: POI is often associated with symptoms typically seen during the menopausal transition, especially vasomotor symptoms (eg, hot flashes, night sweats), vaginal dryness, dyspareunia, decreased libido, mood swings, and sleep disturbances. Although the average age of the final menstrual period is in the early 50s, many women have their final menses in their 40s. The patient should be asked about the age at which their mother or older siblings experienced menopause. During the exam, the clinician should look for vulvovaginal atrophy, a sign of estrogen deficiency.[10]

• Other endocrine causes: Thyroid enlargement or changes in weight, energy, skin, hair, nails, and bowel habits may suggest thyroid disorders. Tachycardia, hypertension, and palpitations may also suggest hyperthyroidism. Polyuria, polydipsia, and acanthosis nigricans suggest uncontrolled diabetes. Cushing syndrome may be suggested by moon facies, skin changes (eg, striae, atrophy, easy bruising, and hyperpigmentation), hyperandrogenism, or metabolic dysfunction. Additionally, patients may already have an endocrine diagnosis (eg, diabetes or thyroid disease). During the exam, the clinician should note the patient's vital signs and body mass index and examine the thyroid gland and skin.

• Outflow tract abnormalities: Endometrial and outflow tract abnormalities are often suggested by medical history findings, including a history of prior septic miscarriage or abortion, multiple uterine curettage procedures, or pelvic tuberculosis, all of which increase the risk of Asherman syndrome/intrauterine adhesions, or a history of multiple loop electrosurgical excision procedures in conjunction with abdominopelvic pain, which suggests cervical stenosis and retained menstrual fluid.

Evaluation

The first step in evaluating any patient with secondary amenorrhea is a urine pregnancy test.[4][9] Every contraceptive method has a failure rate, and anyone who is menstruating is potentially fertile, regardless of age.[21][22] Additionally, all hormonal contraceptive methods can cause amenorrhea, and this should not be considered pathologic; no additional assessment beyond a pregnancy test is required in long-term users of hormonal contraceptives unless additional symptoms are present.

Initial Diagnostic Testing

Considering the most common causes of secondary amenorrhea, the initial evaluation should include:

• Urine beta-human chorionic gonadotropin (ie, urine pregnancy test)
• Serum follicle-stimulating hormone (FSH) and estradiol (E2)
• Serum prolactin
• Serum thyroid-stimulating hormone (TSH) 
• Pelvic ultrasound [7][16]

The exogenous hormones found in hormonal contraceptives suppress the HPO axis and thus will suppress follicle-stimulating hormone and E2 levels. Therefore, patients should be off hormones for at least 3 months before testing follicle-stimulating hormone and E2 levels for an accurate assessment. Additionally, professional guidelines recommend screening for thyroid disease when evaluating a patient for either POI or PCOS, as both hyper- and hypothyroidism can lead to menstrual dysfunction.[11][23] Clinical evidence on history or exam of hyperandrogenism in addition to secondary amenorrhea should prompt appropriate initial testing, including:

• Serum total and free testosterone
• Fasting morning serum 17-hydroxyprogesterone level 
• Consideration of dehydroepiandrosterone sulfate (DHEAS) and androstenedione

According to the 2023 international evidence-based guideline for PCOS assessment, DHEAS and androstenedione can be considered to assess patients for biochemical hyperandrogenism if the testosterone is not elevated. However, DHEAS and androstenedione have lower sensitivity and specificity. Additionally, DHEAS has an age-associated decrease.[23] On the other hand, testing for these additional androgens is indicated when assessing patients for androgen-secreting adrenal tumors in those who experience rapid virilization.[20] Androgens reach adult levels by 12 to 15 years of age.[23] 

Interpretation of Initial Evaluation Findings and Further Testing

A positive urine pregnancy test identifies a pregnancy. An elevated prolactin level identifies hyperprolactinemia. Because a pituitary adenoma frequently causes hyperprolactinemia, the patient then requires imaging of the gland, typically with magnetic resonance imaging. Similarly, abnormalities in the TSH identify thyroid disease, and additional serum and imaging tests generally are warranted.

The FSH and estradiol levels can help identify functional abnormalities in the hypothalamus, pituitary, and ovary (see Table. Type of Hypogonadism and Levels of FSH and E2). Depending on the etiology, secondary amenorrhea can be classified as hypogonadotropic, hypergonadotropic, or eugonadotropic, based on the gonadotropin (ie, FSH) level, which helps the clinician pinpoint the location of the abnormality. For example, in secondary amenorrhea caused by a primary defect in the hypothalamus or pituitary, FSH secretion is low, resulting in low E2 production in the ovary. Conversely, in POI, the ovary cannot produce E2 regardless of the stimulation it gets; low estrogen levels signify a lack of feedback inhibition in the pituitary, and FSH levels are elevated. The pituitary is "yelling'" at the ovaries to make estrogen, but the ovaries cannot respond to the call.)

Table.Type of Hypogonadism and Levels of FSH and E2

FHA, functional hypothalamic amenorrhea; PCOS, polycystic ovarian syndrome; POI, premature ovarian insufficiency

Hypogonadotropic findings

Although FHA is considered a diagnosis of exclusion, low FSH and E2, in the setting of normal prolactin and thyroid function tests in patients with a potential risk factor for FHA (eg, low body mass index, competitive athlete) strongly suggests FHA as the most likely etiology. Additional serum testing, including a comprehensive metabolic panel, complete blood count, and C-reactive protein, can be ordered in these patients. A baseline dual-energy x-ray absorptiometry is also often appropriate, especially if amenorrhea has been prolonged.[7] Patients should be offered appropriate counseling and interventions, as HPO axis function can be restored once the underlying stressor is corrected. Patients with hypogonadotropic amenorrhea who do not respond to initial management strategies may require brain imaging to evaluate the hypothalamus and pituitary gland further.

Hypergonadotropic findings

FSH level is considered elevated at levels above 30 to 40 mIU/mL when assessed in the early follicular phase of the menstrual cycle (or at any time in patients with secondary amenorrhea). A low E2 is indicated by levels less than about 50 pg/mL.[11] If the FSH and E2 levels suggest POI, the tests should be repeated in 1 month. The diagnosis of POI can be made after ruling out pregnancy and prolactin and thyroid abnormalities in the setting of 3 months of amenorrhea and elevated FSH levels with concurrently low E2 levels on 2 random occasions.[24] Antimüllerian hormone is a serum marker frequently used to assess ovarian reserve and is generally low in POI; its value for diagnosing POI is still yet to be determined, though it may be helpful in management.[11][25] Once a patient is diagnosed with POI, they should have additional testing ordered to look for underlying etiologies, including a karyotype, genetic testing for the FMR1 premutation, immunologic testing for adrenal antibodies (eg, 21-hydroxylase by immunoprecipitation), and a pelvic ultrasound if not done as part of the initial assessment.[11] 

Eugonadotropic findings

By far, the most common cause of eugonadotropic secondary amenorrhea is PCOS. Several different sets of criteria may be utilized to diagnose PCOS, but one of the most common is the Rotterdam Consensus Criteria, which requires 2 out of 3 criteria for diagnosis: evidence of hyperandrogenism (either clinical hirsutism or biochemical hyperandrogenemia), oligomenorrhea or amenorrhea, and polycystic ovaries on ultrasound defined as either 12 or more follicles measuring 2 to 9 mm in diameter or an ovarian volume in an ovary without a dominant follicle of more than 10 cm³ in either ovary.[20] Based on these criteria, a patient with secondary amenorrhea and hirsutism can be diagnosed with PCOS even if laboratory and imaging tests are normal.[23] Elevated testosterone levels identify biochemical hyperandrogenism. Most of these patients will have a normal 17-OH-P, typically defined as a value less than 2 ng/mL.[20] An elevated fasting 17-OH-P, typically defined as greater than 2 ng/mL on a morning fasting sample, suggests nonclassical congenital adrenal hyperplasia as the cause of hyperandrogenism and should be followed up with an adrenocorticotropic hormone stimulation test.[20] Markedly elevated dehydroepiandrosterone sulfate may be seen in some androgen-secreting adrenal tumors, and further evaluation is warranted.

In addition to identifying polycystic appearing ovaries, the pelvic ultrasound may identify other ovarian abnormalities (eg, neoplasm, atrophy) and provide information about the uterus and cervix. For example, a thin endometrial lining suggests a hypoestrogenic state, while a thickened endometrial lining suggests the presence of estrogen and chronic anovulation. Hematometra (menstrual blood trapped within the uterus) identifies an outflow tract obstruction (eg, cervical stenosis). Intrauterine adhesions are typically not able to be identified on a regular ultrasound, though there may be some evidence of deep endometrial scarring at the myometrial junction.

Hormone Challenge Tests

If the initial evaluation is unclear, one common approach is to give a progestin challenge (eg, oral medroxyprogesterone acetate 5 to 10 mg once daily for 10 days), which should trigger a withdrawal bleed after stopping the progestin if endogenous estrogen is present. The following findings may help identify the underlying etiology:

• Positive test results: If the patient bleeds, this proves that estrogen is present, the endometrium can grow in response to that estrogen and shedding after progestin withdrawal, and the outflow tract is patent. Therefore, a positive test result suggests that the patient is experiencing chronic anovulatory cycles. In these situations, estrogen is produced, but ovulation is not occurring; without ovulation, progesterone is not produced, and subsequent withdrawal is not occurring to trigger menses.[26]
• Negative test results: If no withdrawal bleed occurs, this can indicate any of the following:
  • Endogenous estrogen is insufficient to stimulate the growth of the endometrium (eg, POI, hypothalamic or pituitary dysfunction)
  • The endometrium has been damaged and is unable to grow (eg, Asherman syndrome)
  • The outflow of menstrual blood has been obstructed (eg, cervical stenosis)

An estrogen-progestin challenge can be performed to test whether or not sufficient endogenous estrogen is present. The patient is typically given a 3-week course of both estrogen and progestin (usually given in the form of combined oral contraceptive pills) and then observed for evidence of a withdrawal bleed. If the patient bleeds with the added estrogen, this suggests insufficient endogenous estrogen present to grow the endometrium. If there is no withdrawal bleeding, the endometrium is damaged (eg, Asherman syndrome), or the outflow tract is obstructed. A saline-infusion sonogram (SIS) or hysteroscopy can further evaluate these potential etiologies.

Saline-Infusion Sonography and Hysteroscopy

An SIS or hysteroscopy can be used to evaluate the cervical canal and uterine cavity for stenosis and adhesions, respectively. In an SIS, a catheter is threaded into the endometrial canal, which is then instilled with sterile saline. This allows the cavity to distend, and intracavitary defects such as intrauterine adhesions can be identified. Hysteroscopy allows for direct visualization of both the cervical canal and intrauterine cavity and offers the potential benefit of performing concurrent therapeutic procedures, such as lysis of adhesions. 

Treatment / Management

Although treatment depends on the underlying etiology, several fundamental management principles should be considered in all patients with secondary amenorrhea. First, clinicians should keep in mind a patient's fertility desires when developing a management plan and assist with pregnancy, if desired. Next, the hormones present in the patient's body, both endogenous and exogenous, should be considered. Estrogen is required for healthy bone growth, so patients with chronic hypoestrogenic states (eg, FHA or POI) require either a resumption of endogenous estrogen production or hormone replacement therapy (HRT) to prevent bone mineral density (BMD) loss. Conversely, chronic unopposed estrogen, which occurs in chronic anovulatory cycles (eg, PCOS), can lead to endometrial hyperplasia and malignancy. Hence, these patients require some type of progestin therapy to trigger periodic endometrial shedding and prevent hypertrophy. Etiology-specific management will vary depending on the etiology (Please refer to the Etiology section for more information on the etiologies of secondary amenorrhea), including:

• FHA is treated with patient education, counseling, and other appropriate support (eg, nutrition counseling, mental health services). Hormone replacement therapy, often with oral contraceptive pills (OCPs), can be used to prevent the BMD loss that occurs in a prolonged hypoestrogenic state.
• PCOS is treated with a multimodal approach. Weight loss is encouraged if patients are overweight/obese; metformin and nutrition counseling are often used in patients with insulin resistance; progestins are used to protect the endometrium against hyperplasia that can occur with the unopposed estrogen present with chronic anovulatory cycles; and multiple options exist to treat androgenic symptoms, the most common of which are OCPs that work by inhibiting luteinizing hormone, thus reducing androgen production.[20]
• POI is treated with HRT, depending on the patient's age, symptoms, and fertility desires. In natural menopause (ie, after age 40), HRT can be used to treat other bothersome symptoms, such as hot flashes and vaginal dryness.[11]
• Hyperprolactinemia is treated with bromocriptine, cabergoline, or excision of a prolactinoma. If potential medications are identified that may be causing hyperprolactinemia, these should be adjusted if possible.
• Hypothyroidism is treated with thyroxine replacement, while hyperthyroidism is treated with thioamides, ablation, or surgery.
• Asherman syndrome is treated with hysteroscopic lysis of adhesions.
• Cervical stenosis is treated with cervical dilation.[27][28] 
(B3)

Differential Diagnosis

The following differential diagnoses should be considered in the evaluation of secondary amenorrhea:

• Physiologic
  • Pregnancy
  • Lactation
  • Menopause
• Disruptions in the HPO Axis
  • Iatrogenic endometrial suppression (eg, prolonged progestin use)
  • Functional hypothalamic amenorrhea etiologies (eg, eating disorders, relative energy deficiency in sport, chronic stress/unaddressed mental health issues)
  • Conditions causing hyperprolactinemia (eg, prolactinoma, medications, and lactation)
  • Other intracranial conditions affecting the hypothalamus or pituitary gland (eg, tumors, infections, infarction, infiltrative disease)
  • PCOS and other causes of hyperandrogenism (eg, nonclassical congenital adrenal hyperplasia, adrenal tumors, and Cushing syndrome)
  • Other endocrine conditions, including thyroid disorders and severe insulin resistance
  • POI 
• Structural Abnormalities
  • Intrauterine adhesions/Asherman syndrome
  • Cervical stenosis

Prognosis

The prognosis of secondary amenorrhea depends on the underlying etiology.

Complications

Prolonged hypoestrogenic states can result in BMD loss and osteoporotic fractures, as well as sexual dysfunction due to vaginal dryness. Conversely, prolonged exposure to unopposed estrogen during anovulatory cycles can lead to endometrial hyperplasia and malignancy. Secondary amenorrhea also reduces the likelihood of pregnancy until the underlying pathology is corrected, though in most cases, pregnancy is still possible with appropriate management. Additional complications are possible depending on the etiology.