Amenorrhea

Introduction

Amenorrhea is a medical term for the absence of menstrual bleeding. Women who have missed at least three menstrual periods in a row have amenorrhea, as do girls who haven’t begun menstruation by age 15.

The most common cause of amenorrhea is pregnancy. Other causes of amenorrhea include problems with the reproductive organs or with the glands that help regulate hormone levels. Treatment of the underlying condition often resolves amenorrhea.

Primary amenorrhea is the failure of menses to occur by age 16 years, in the presence of normal growth and secondary sexual characteristics. If by age 13 menses has not occurred and the onset of puberty, such as breast development, is absent, a workup for primary amenorrhea should start.

Secondary amenorrhea is defined as the cessation of menses sometime after menarche has occurred. Oligomenorrhea is defined as menses occurring at intervals longer than 35 days apart.

Associated Anatomy

The female menstrual cycle normally comprises a 28 to 30-day cycle, which contains 2 phases, the proliferative phase, and the secretory phase. At the end of the cycle, the uterine lining starts shedding off which is a normal phenomenon of female menstruation.

Causes

Amenorrhea after puberty can be divided into 2 groups: (1) amenorrhea without evidence of associated androgen excess and (2) amenorrhea with evidence of androgen excess (eg, hirsutism, virilization, sexual ambiguity).

Causes of primary amenorrhea

First and foremost, it is imperative to rule out pregnancy. Additional diagnoses of primary amenorrhea usually result from a genetic or anatomic abnormality. The relative prevalence of primary amenorrhea (percentages rounded to the nearest tenth) includes hypergonadotropic hypogonadism (48.5% of cases), hypogonadotropic hypogonadism (27.8%), and eugonadism (pubertal delay with normal gonadotropins; 23.7%). 

The hypergonadotropic hypogonadism category includes patients with abnormal sex chromosomes (ie, Turner syndrome), who make up 29.7% of all primary amenorrhea cases, and those with normal sex chromosomes. The latter group includes both patients who are 46,XX (15.4%) and those who are 46,XY (3.4%).

Hypogonadotropic hypogonadism includes the following:

• Congenital abnormalities
• Endocrine disorders
• Tumor
• Systemic illness (2.6%)
• Eating disorder (2.3%)

Congenital abnormalities that can cause hypogonadotropic hypogonadism include the following:

• Isolated GnRH deficiency (8.3%)
• Forms of hypopituitarism (2.3%)
• Congenital central nervous system (CNS) defects (0.8%)
• Constitutional delay (6%)

Endocrine disorders that can cause hypogonadotropic hypogonadism include the following:

• Congenital adrenal hyperplasia (CAH) (0.8%)
• Cushing syndrome (0.4%)
• Pseudohypoparathyroidism (0.4%)
• Hyperprolactinemia (1.9%)

Tumors that can cause hypogonadotropic hypogonadism include the following:

• Unclassified pituitary adenoma (0.8%)
• Craniopharyngioma (1.1%)
• Unclassified malignant tumor (0.4%)

Eugonadism may result from anatomic abnormalities or intersex disorders. Anatomic abnormalities include congenital absence of the uterus and vagina (CAUV; 16.2%) and cervical atresia (0.4%). Intersex disorders include androgen insensitivity (1.5%), 17-ketoreductase deficiency (0.4%), and inappropriate feedback (5.3%).

Causes of secondary amenorrhea

Disorders associated with a low or normal FSH, which account for 66% of cases of secondary amenorrhea, include the following:

• Weight loss/anorexia
• Nonspecific hypothalamic
• Chronic anovulation including PCOS
• Hypothyroidism
• Cushing syndrome
• Pituitary tumor, empty sella, Sheehan syndrome

Disorders in which the FSH is high (12%) include the following:

• 46,XX spontaneous POI
• Premature ovarian failure due to abnormal karyotype (45,X mosaic/ring chromosome)
• Pure gonadal dysgenesis

Disorders associated with a high prolactin level make up 13% of cases. Anatomic disorders (ie, Asherman syndrome) account for 7%.

Hyperandrogenic states as a cause of secondary amenorrhea (2%) include the following:

• Polycystic ovarian syndrome (PCOS)
• Ovarian tumor
• Non-classic CAH
• Undiagnosed

Differential Diagnosis

Differential diagnosis of amenorrhea should be made with following conditions:

• Anorexia Nervosa
• Anxiety Disorders
• Congenital Adrenal Hyperplasia
• Depression
• Follicle-Stimulating Hormone Abnormalities
• Iatrogenic Cushing Syndrome
• Luteinizing Hormone Deficiency
• Ovarian Insufficiency
• Pregnancy Diagnosis
• Prolactinoma

Drugs

For primary amenorrhea, hormone therapy, consisting of an estrogen and a progestin, is recommended for women with estrogen deficiency. Girls with primary amenorrhea typically do not have symptoms of estrogen deficiency. However, with inadequate estrogen exposure over time, these patients are at increased risk for developing osteoporosis and possibly other health issues.

Young women in whom secondary sex characteristics have failed to develop fully should be exposed initially to very low doses of estrogen in an attempt to mimic the gradual pubertal maturation process. A typical regimen consists of an estrogen with a dosage equivalent to 25 mcg/day of transdermal estradiol (approximately 0.3 mg of conjugated equine estrogen) given unopposed (ie, no progesterone) daily for 6 months with incremental dose increases at 6-month intervals until the required maintenance dose is achieved.

Gradual dose escalation allows time to balance estrogen supplementation with need to grow in height, develop secondary sexual characters, and often results in optimal breast development. It also allows time for the young woman to adjust psychologically to her physical maturation. 

Cyclic progesterone therapy, given 12-14 days per month, should be instituted once vaginal bleeding begins.

Parenteral estrogen (transdermal or vaginal) is the preferred route of administration because it avoids first-pass liver metabolism. Moreover, it is less likely to increase sex hormone–binding globulin (SHBG) and has little or no effect on circulating lipids, coagulation parameters, or C-reactive protein. However, no long-term controlled studies are available to compare the efficacy and safety of one method over another. Therefore, the choice of therapy should follow consideration of the patient’s preferences and the physician’s experience.

The role of androgen replacement is unclear at this time and is the subject of ongoing investigation. 

For secondary amenorrhea, dopamine agonists are the only medical therapy specifically approved to reverse an underlying pathology that leads to amenorrhea. In most cases, dopamine agonists effectively reduce hyperprolactinemia.

Gonadotropin therapy or pulsatile gonadotropin-releasing hormone (GnRH) therapy is indicated in women who desire fertility yet remain anovulatory because of an unresolved hypothalamic/pituitary disorder. GnRH pump therapy is available in Europe but not in the United States.

Once the diagnosis is established, for some women with oligomenorrhea or amenorrhea who do not wish to become pregnant, oral contraceptives may be a good choice to restore menstrual cyclicity and provide estrogen replacement. The absence of pregnancy should be documented before oral contraceptive therapy is begun.

In patients with amenorrhea or oligomenorrhea withdrawal bleeding should be induced with an injection of progesterone or the administration of 5-10 mg of medroxyprogesterone for 10 days.

Hormone therapy, consisting of an estrogen and a progestin, is needed for women in whom estrogen deficiency remains because ovarian function cannot be restored. The role of androgen replacement is unclear at this time and is the subject of ongoing investigation.

Estrogens:

Estrogens are administered transdermally, transvaginally, or orally. The appropriate dose for young women with ovarian failure or secondary amenorrhea has not been established. The authors recommend full replacement doses for young women. Generally, this is approximately twice as high as doses recommended for hormone therapy in normally postmenopausal women.

The authors prefer to administer estradiol by skin patch (100-mcg transdermal estradiol patch). This avoids the first-pass effect of oral estrogen on the liver. No controlled studies are available to compare the efficacy and safety of one method over another. Therefore, the choice of therapy should follow consideration of the patient’s preferences and the physician’s experience.

Estradiol (Alora, Climara, Esclim, Vivelle-dot, Estrace)

Estradiol increases synthesis of DNA, RNA, and many proteins in target tissues. Transdermal patch available as Alora (0.05, 0.075, and 0.1 mg/d, applied twice weekly), Climara (0.025, 0.05, 0.075, and 0.1 mg/d, applied once weekly), Esclim (0.025, 0.0375, 0.05, 0.075, 0.1 mg/d, applied twice weekly), and Vivelle-dot (0.037, 0.05, 0.075, 0.1 mg/d, applied twice weekly). If transdermal patch is not tolerated, oral form may be used.

Estrogens, conjugated (Premarin)

Use in patients who refuse or do not tolerate other forms of estrogen. Use oral estrogen to achieve adequate estrogenization of vaginal epithelium in young women and adequately maintain bone density.

Progestins:

Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. No long-term controlled studies compare efficacy of medroxyprogesterone with oral progesterone in protecting the endometrium from neoplasia at the doses of estrogen generally required for replacement in young women. The authors recommend use medroxyprogesterone as first-line therapy because of longer-term clinical experience with this agent.

Medroxyprogesterone (Provera, Cycrin, Depo-Provera, Amen)

Administer cyclically 12 d/mo to prevent endometrial hyperplasia that unopposed estrogen may cause. In young women, regular withdrawal bleeding is preferable because even young women with premature ovarian failure have a 5-10% chance of spontaneous pregnancy (unlike postmenopausal women). If an expected withdrawal bleeding is absent, perform a pregnancy test (and a timely diagnosis of pregnancy will not be missed). Other causes of amenorrhea may also remit spontaneously and result in an unexpected pregnancy.

Progesterone (Prometrium)

This agent is used to prevent endometrial hyperplasia.

Epidemiology

The incidence of primary amenorrhea in the United States is less than 1%.  Each year, approximately 5-7% of menstruating women in the US experience 3 months of secondary amenorrhea

No evidence indicates that the prevalence of amenorrhea varies according to national origin or ethnic group. However, local environmental factors related to nutrition and the prevalence of chronic disease undoubtedly have an effect. For instance, the age of the first menses varies by geographic location, as demonstrated by a World Health Organization study comparing 11 countries, which reported a median age of menarche of 13-16 years across centers.

Recent increases in the rates of childhood obesity around the world may also contribute to earlier onset of menarche and increased prevalence of obesity-related menstrual disorders, especially in areas where obesity is more prevalent.  Exposure to environmental toxins, namely hormonally active endocrine disruptors, may also result in increased rates of menstrual and reproductive disorders in endemic areas. 

Natural Progression

If left untreated, all of patients with amenorrhea may progress to develop infertility and osteoporosis. Common complications of amenorrhea are based on the background disease that induced it. Prognosis is generally excellent and the mortality rate of patients with amenorrhea is approximately less than 1%, generally in brain lesions.

Pathophysiology

The absence of menses in a female of reproductive age is related to the disturbance of normal hormonal, physiological mechanism or female anatomic abnormalities. The normal physiological mechanism works by balancing hormones and providing feedback between the hypothalamus, pituitary, ovaries, and uterus.

During normal female menstruation cycle, gonadotropin-releasing hormone (GnRH) is released from hypothalamus, and it works on pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and these 2 hormones from pituitary act on ovaries and ovaries finally make estrogen and progesterone to work on the uterus to carry out the follicular and secretory phase of menstrual cycle. Any defect at any level of this normal physiology of female can cause amenorrhea.

On other hand, deviation from the normal anatomy of reproductive organs of a female can also cause amenorrhea.

Possible Complications

Complications of amenorrhea may include:

• Infertility. If you don’t ovulate and have menstrual periods, you can’t become pregnant.
• Osteoporosis. If your amenorrhea is caused by low estrogen levels, you may also be at risk of osteoporosis — a weakening of your bones.

Possible Treatment

Treatment is determined by the etiology of the amenorrhea and the desires of the patient. Ideally, treatment should be directed at correcting the underlying pathology. In the case of outflow tract abnormalities (eg, imperforate hymen), surgery may be indicated. In other cases, correcting the underlying pathology should restore normal ovarian endocrine function and prevent the development of osteoporosis.

Dopamine agonists are effective in treating hyperprolactinemia. In most cases, this treatment restores normal ovarian endocrine function and ovulation.

Hormone replacement therapy is required to achieve peak bone density in patients whose underlying pathology cannot be reversed to restore normal endocrine function. In conditions leading to estrogen deficiency, hormone replacement therapy is required to maintain bone density, and it may have other possible health benefits in patients whose underlying pathology cannot be reversed to restore normal endocrine function.

Women with evidence of hyperandrogenism and disordered menses have many other medical issues that must be addressed (eg, PCOS with associated diabetes and hypertension).

Gonadotropin therapy or the use of pulsatile gonadotropin-releasing hormone (GnRH) therapy may be required to induce ovulation in patients with infertility whose underlying pathology cannot be reversed. As of 2014, medicinal GnRH for pulsatile SQ pump administration was not available in the United States.

Other than pregnancy, constitutional delay, anovulation, and chronic illness, most other disorders that cause amenorrhea may require referral to a subspecialist for treatment. Many of the treatment methods require surgery or specific therapies. For the adolescent with constitutional delay and anovulation, the goal should be the restoration of ovulatory cycles. If ovulatory cycles are not spontaneously restored, estrogen-progestin therapy is indicated.

 

Diet and Activity

Women with findings suggestive of an eating disorder should be evaluated by a multidisciplinary team with special expertise in these disorders. Nutritional counseling alone is inadequate therapy for these women.

In some cases, nutritional deficiencies induced by dieting and exercise can cause amenorrhea even in the absence of a psychiatric disorder. Strict fat restriction often plays a role. Frequently, simply explaining the need to balance energy expenditure with energy intake resolves the problem. In this situation, nutritional counseling may be all that is required.

More than 8 hours of vigorous exercise a week may cause amenorrhea. As noted above, in some cases this resolves with appropriate adjustment of the diet. A study by Ackerman et al that included 121 athletes with oligo-amenorrhea reported greater improvement over 12 months in bone mineral density with transdermal estradiol when compared to combined oral contraceptives

 

Prognosis

Loss of menstrual regularity has been associated with an increased risk of wrist and hip fractures related to reduced bone density, even without the development of amenorrhea. A later menarche and menstrual cycle intervals longer than 32 days have both been associated with increased fracture rates in later years. Young women with ovarian insufficiency that is unresponsive to therapy require hormone replacement to maintain bone density.

Adolescence is a critical period for bone accretion as over half of peak bone mass is achieved during the teenage years. Regular menses is a sign that the ovaries are producing normal amounts of estrogen, androgens, and progesterone, all of which play an important role in building and maintaining bone mass. Late menarche has been associated with a 3-fold increase in the risk of wrist fracture.

In some cases, loss of menstrual regularity is an early sign of declining fertility and impending premature ovarian failure. Also in some cases, follicle depletion progresses to cause irreversible infertility. Approximately 10% of women evaluated for amenorrhea in a tertiary center are found to have premature ovarian failure.

Women with PCOS have many long-term health issues, including higher risk of diabetes and cardiovascular disease, that should be monitored and treated.

Primary Prevention

Based on US Preventive Services Task Force (USPTSF), there are no established measures for the primary prevention of amenorrhea.

Risk factors

Factors that may increase the risk of amenorrhea may include:

• Family history. If other women in your family have experienced amenorrhea, you may have inherited a predisposition for the problem.
• Eating disorders. If you have an eating disorder, such as anorexia or bulimia, you are at higher risk of developing amenorrhea.
• Athletic training. Rigorous athletic training can increase your risk of amenorrhea.

Secondary Prevention

Osteoporosis prevention

Evidence is mounting that loss of menstrual regularity, especially if related to hypogonadotropic hypogonadism, is a risk factor for later development of osteoporosis and hip fractures. Patients and clinicians need to view the ovary as an important endocrine organ that helps to maintain healthy bones. Excessive delay in the evaluation and treatment of disordered menses can contribute to osteoporosis. At some point, failure to promptly evaluate for the presence of ovarian insufficiency could become a medicolegal pitfall.

Many patients are deficient in their body stores of vitamin D, reflected by a serum 25-hydroxy vitamin D level less than 30 nmol/L. If this is the case, patients should be treated for 8-12 weeks with high-dose vitamin D, 50,000 IU/week, for repletion. Once the 25-OH-D level is greater than 30 nmol/L, 1000 IU/d of vitamin D may be instituted.

Emotional health concerns

Primary amenorrhea and the potential for impaired fertility affect the emotional health of the adolescent and her family. Adolescence encompasses a broad spectrum of emotional maturity, which needs to be considered in assessment and treatment. For the adolescent girl, a reproductive disorder impacts her developing sense of self, body-image, and sexuality, which, in turn, can affect her self-esteem and relationships with others.

Because of the sexual nature of a reproductive disorder, feelings of embarrassment, inadequacy, or protectiveness can make it difficult for families. Families should be encouraged to be open and honest regarding the condition and discouraged from keeping the diagnosis a secret.

The family is an emotional unit and a family systems approach to deal with health issues is most appropriate. Parents must first deal with their own feelings about the condition before they can help their child. They must also be provided with tools to build an ongoing conversation with their child. Physicians need to be culturally sensitive because in some cultures a woman’s identity in adulthood as a mother could play a crucial role in her life. The objective is to help the adolescent girl formulate positive self-esteem and body image, despite impaired fertility.

Long-Term Monitoring

The need for ongoing care is defined by the mechanism disrupting the menstrual cycle and the patient’s desires.

See patients with primary ovarian insufficiency annually to monitor their ovarian hormone replacement and to detect the development of associated conditions that may be related to the original pathogenic mechanism that led to the disruption of the menstrual cycle.

See patient every 3-6 months for the first 2 years to monitor ovarian hormone replacement and to detect the development of associated conditions that may be related to the original pathogenic mechanism that led to the disruption of the menstrual cycle.

Signs or Symptoms

The main sign of amenorrhea is the absence of menstrual periods. Depending on the cause of amenorrhea, you might experience other signs or symptoms along with the absence of periods, such as:

• Milky nipple discharge
• Hair loss
• Headache
• Vision changes
• Excess facial hair
• Pelvic pain
• Acne

Studies

Active Not Recruiting

Number of studies: 3

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Completed

Number of studies: 29

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Enrolling by Invitation

Number of studies: 0

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Not Yet Recruiting

Number of studies: 6

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Recruiting

Number of studies: 23

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Results Available

Number of studies: 9

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Results Not available

Number of studies: 72

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Suspended

Number of studies: 0

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Terminated

Number of studies: 4

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Withdrawn

Number of studies: 6

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Types

Amenorrhea may be classified according to etiology into three subtypes, including primary amenorrhea, secondary amenorrhea, and functional amenorrhea. Primary amenorrhea is basically refers to a young girl who have not experienced menarche, at all, classified as hypergonadotropic hypogonadism, hypogonadotropic hypogonadism, and eugonadotropic state. Secondary amenorrhea reflects a woman who had normal menstruation cycles, experiencing at least 3 months of absence of menstruation cycle. It is classified as polycystic ovary syndrome, hypothalamic-pituitary dysfunction, hypothalamic-pituitary failure, and ovarian failure. Functional amenorrhea is a subtype of the amenorrhea caused by exaggerated different lifestyles, classified as stress, weight loss, and exercise related groups.

Typical Test

Physical examination

In the case of primary amenorrhea, before physical examination, the clinician should engage the adolescent in a discussion to assess her emotional maturity and establish a relationship. As questions emerge, the clinician should share age-appropriate information about the condition, giving the opportunity to respond to the patient’s emotions. After careful preparation and with privacy, the physical and pelvic examination should come later in the assessment

General physical examination

A general physical examination may identify features of many of the disorders that underlie amenorrhea. In addition, it may uncover unexpected findings that are indirectly related to the loss of menstrual regularity (eg, discovery of hepatosplenomegaly, which may lead to detection of a chronic systemic disease).

Physical examination should begin with an overall assessment of sexual development, nutritional status, and general health. Measure height and weight and seek evidence for chronic disease, cachexia, or obesity.

In anorexia nervosa, hypothermia, bradycardia, hypotension, and reduced subcutaneous fat may be observed. Other findings include yellow skin (carotenemia) and a body mass index (BMI) of less than 18 kg/m². In cases of frequent vomiting, look for possible dental erosion, reduced gag reflex, trauma to the palate, subconjunctival hemorrhage, and metacarpophalangeal calluses or bruises.

Examine the skin for evidence of androgen excess, such as hirsutism, hair loss, and acne. Acanthosis nigricans may be present in association with androgen excess related to insulin resistance (eg, diabetes, polycystic ovarian syndrome (PCOS). A BMI of more than 30 kg/m² is common.

Examine for stigmata of Turner syndrome (short stature, webbed neck, low-set hairline and/or ears, pubertal delay, cubitus valgus, nail hypoplasia, short fourth metacarpal, high-arched palate, chronic otitis media, cardiac abnormalities).

Skin examination findings can also give clues to other endocrine disorders. Vitiligo or increased pigmentation of the palmar creases may herald primary adrenal insufficiency. Thin, parchment-like skin, wide purplish striae, and evidence of easy bruising may be signs of Cushing syndrome. Warm, moist skin radiating excessive heat may be a sign of hyperthyroidism.

Large pituitary tumors can cause visual-field cuts by impinging on the optic tract. In some cases, these visual-field cuts can be detected by simple confrontational testing.

Examine for the presence of axillary and pubic hair. These are a marker of adrenal and ovarian androgen secretion. In cases of panhypopituitarism, sources of androgen are low and pubic and axillary hair is sparse.

Also, some women develop the combination of autoimmune premature ovarian failure and autoimmune primary adrenal insufficiency. These women are also markedly androgen deficient and have scant axillary and pubic hair. The same is true for persons with androgen insensitivity syndrome, 17-hydroxylase deficiency, and 17,20-desmolase deficiency.

Breast examination

Assess the state of breast development. Delayed puberty results in underdeveloped breasts with sparse pubic hair, whereas gonadal dysgenesis (eg, Turner syndrome) results in undeveloped breasts with normal growth of pubic hair.

Also examine the breasts for galactorrhea. In some cases, breast discharge can be expressed, yet the condition is not true galactorrhea. If the discharge is indeed milk, this can be confirmed by finding fat globules in the fluid using low-power microscopy.

Pelvic examination

In cases of primary amenorrhea with otherwise normal pubertal development, pelvic examination may help detect imperforate hymen, a transverse vaginal septum, or cervical or uterine aplasia. If the uterus is enlarged, pregnancy must be excluded.

Pelvic examination findings can provide physical evidence indicating the adequacy of estrogen production. Thin and pale vaginal mucosa with absent rugae is evidence of estrogen deficiency.

The presence of cervical mucus with spinnbarkeit is good evidence of estrogen effect. However, evidence of estrogen effect detected on physical examination findings can be misleading in some cases because estrogen is being produced as a result of higher-than-normal follicle-stimulating hormone (FSH) levels (compensated ovarian insufficiency). Women with well-established premature ovarian failure often have intermittent ovarian follicle function that produces enough estrogen to have vaginal and cervical effects.

Measuring the clitoris is an effective method for determining the degree of androgen effect. The clitoral index is the product of the sagittal and transverse diameters of the glans of the clitoris in the anteroposterior and transverse diameter. A clitoral index greater than 35 mm² is evidence of increased androgen effect. A clitoral index greater than 100 mm² is evidence of virilization.

Ovarian enlargement may be found upon pelvic examination in cases of autoimmune oophoritis, 17-hydroxylase deficiency, or 17,20-desmolase deficiency. In these disorders, inadequate negative feedback supplied by the ovary permits excessive gonadotropin stimulation, which may cause ovarian enlargement with multiple follicular cysts. In some cases, these disorders manifest with an acute onset of pain related to ovarian torsion. Ovarian enlargement is also commonly associated with PCOS.

Laboratory workup

Hormonal tests:

Hormonal studies may include assays of prolactin, FSH, LH, estradiol, thyroid hormones, or androgens.

Prolactin

Prolactin levels in excess of 200 ng/mL are not observed except in the case of prolactin-secreting pituitary adenoma (prolactinoma) or anti depressants such as Risperidone. In general, the serum prolactin level correlates with the size of the tumor.

Psychotropic drugs, hypothyroidism, stress, and meals can also raise prolactin levels. Repeat prolactin levels in a fasting state without recent nipple stimulation or sexual intercourse to verify a persistent elevation. Persistent elevations require further evaluation if the cause is not readily apparent.

FSH, LH, and estradiol

An FSH level of approximately 40 mIU/mL is indicative of ovarian insufficiency. However, this is assay-dependent and some patients have a lower menopausal level of FSH; check the reference range for the laboratory where the test is performed. If a repeat value in 1 month confirms this finding and amenorrhea still persists, then the diagnosis of premature ovarian failure/primary ovarian insufficiency is confirmed.

LH levels are elevated in cases of 17,20 lyase deficiency, 17-hydroxylase deficiency, and premature ovarian failure.

Serum estradiol levels undergo wide fluctuations during the normal menstrual cycle. During the early follicular phase of the menstrual cycle, levels may be lower than 50 pg/mL. During the preovulatory estradiol surge, levels in the range of 400 pg/mL are not uncommon. In healthy menopausal women, estradiol levels are routinely lower than 20 pg/mL.

Thyroid hormones

Disorders of the thyroid gland may result in menstrual irregularities; however, for it to present as primary amenorrhea is uncommon. Measure thyrotropin and free thyroxine (T4) if symptoms of hypothyroidism or hyperthyroidism are present.

Androgens

Checking levels of testosterone and dehydroepiandrosterone sulfate helps identify hyperandrogenic conditions resulting in amenorrhea.

Imaging techniques:

Ultrasonography

Pelvic ultrasonography may identify congenital abnormalities of the uterus, cervix, and vagina, or absence of these organs. However, a report of absence of the uterus on ultrasonography does not always mean that the patient does not have a uterus. In primary amenorrhea in association with estrogen deficient states, the uterine fund us may be underdeveloped and may not be readily visible at the time of ultrasonography to less experienced examiners. With proper estrogen replacement, it may reach the normal size.

Pelvic ultrasonography may be helpful in determining ovarian morphology as well. However, in most cases of amenorrhea without androgen access, the information obtained with ovarian ultrasonography does not change clinical management.

Magnetic resonance imaging

MRI of the pituitary and hypothalamus is often indicated in the evaluation of amenorrhea. Request imaging of the hypothalamic/pituitary area specifically, rather than a study of the entire brain. This achieves higher resolution. MRI is indicated in the following circumstances:

• Associated headaches or visual-field cuts
• Profound estrogen deficiency with otherwise unexplained amenorrhea
• Hyperprolactinemia
• Elevated gonadotropins in the setting of markedly elevated serum estradiol level

Progesterone Withdrawal Test

Prior to the development of readily available assays to measure serum levels of estradiol, the progesterone challenge test was used as a bioassay with which to demonstrate estrogen effect at the level of the endometrium. Progesterone has been shown to predictably induce a withdrawal bleed if the circulating serum estradiol level is at least 50 pg/mL. However, the progesterone withdrawal test can provide inappropriately reassuring information that may delay the etiology of ovarian insufficiency.

The progesterone withdrawal test is no substitute for evaluating ovarian health. Demonstrating the presence of normally functioning ovaries requires the concurrent measurement of serum estradiol and FSH.

References:

https://emedicine.medscape.com/article/252928-overview
https://www.mayoclinic.org/diseases-conditions/amenorrhea/symptoms-causes/syc-20369299
https://www.wikidoc.org/index.php/Amenorrhea_overview
https://www.ncbi.nlm.nih.gov/books/NBK482168/
https://clinicaltrials.gov/