Amenorrhea

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Michael Wittenberger and Alicia Armstrong Introduction

Amenorrhea is a common gynecologic complaint that generates consternation in patients and clinicians alike. Patients are concerned because cyclic menstrual periods are considered to be a sign of health, and conversely, the absence of menstrual periods are a sign of disease. Additionally, the broad differential diagnosis, perceived complexity of the work up and the ramifications of the diagnoses often intimidate clinicians. The purpose of this chapter is to provide a framework to systematically evaluate and treat primary and secondary amenorrhea.

Many clinicians consider primary and secondary amenorrhea to be the same diagnosis. Although there is a great deal of overlap, a subset of patients with primary amenorrhea differ markedly from those with secondary amenorrhea relative to the possibility of restoration of menses and conception. Traditionally, primary amenor-rhea is defined as no menarche by 14 years of age in the absence of secondary sexual characteristics or absence of menses by 16 years of age in the presence of normal growth and secondary sexual characteristics. This definition has remained unchanged despite a shift towards earlier menarche. Secondary amenorrhea occurs in a woman with prior menses, and represents the absence of menses for a duration equal to at least three of her previous cycle intervals or six months. These definitions provide an initial framework to identify amenorrhea; however, the timelines described should not be strictly adhered to particularly in the presence of anatomic abnormalities and obvious pathology.

Evaluation

Using the patient's history and physical exam to guide the ordering of additional tests, the evaluation of amenorrhea can be both time efficient and cost effective. One such diagnostic approach is depicted in Figures 3.1-3.5. This management algorithm classifies patients by physical evidence of estrogen secretion and the absence of a Y chromosome. Because steroidogenesis is one of the basic functions of the intact gonad, the absence of breast development strongly suggests hypoestrogenemia; and therefore, hypogonadism. However, the presence of breasts does not confirm normal estrogen levels or eugonadism. Breast development is only a marker for past exposure to estrogen. To obtain information on a patient's current estrogen status, it is necessary to evaluate the patient's reproductive organs. Upon speculum examination of the patient's vagina and cervix, a well-estrogenized vagina is characterized by pink, moist mucosa with multiple rugations and the presence of mucous discharge from the cervix. The presence of superficial cells on vaginal cytology is also characteristic of the well-estrogenized state. Conversely, thin, pale appearing vaginal mucosa without cervical discharge

Infertile Discharge
Figure 3.1. Evaluation of amenorrhea.

is suggestive of hypoestrogenism and hypogonadism. In addition to assisting in classifying the patient as eugonadal (normal serum estrogen) versus hypogonadal (hypoestrogenic), examination of the reproductive organs allows many anatomical abnormalities to be discovered, and specifically, perhaps most importantly, the presence of a uterus can be documented. These two features: hypogonadism versus eugonadism and presence or absence of a uterus will provide the direction for subsequent tests.

Eugonadism, Uterus Present

Amenorrheic patients with evidence of estrogen production and an intact uterus require further evaluation to determine the etiology of their amenorrhea (Fig. 3.2). Pregnancy, even in a patient with primary infertility, always needs to be considered and eliminated as an etiology of amenorrhea. Thyroid disorders and hyperprolactinemia are common disorders associated with amenorrhea, therefore thyroid stimulating hormone and prolactin levels should be assessed. It is useful to perform a progestin challenge test in these individuals to assess the amount of estrogen production and the competency of the uterine outflow tract. A progestin challenge test takes advantage of endogenous estradiol and usually causes withdrawal bleeding within 2 to 7 days after cessation of progestins. Multiple formulations of progestins can be used (Table 3.1), and any amount of bleeding is considered a positive test. Lack of withdrawal bleeding should be further evaluated with another progestin challenge test after providing additional estrogen priming (1.25 mg conjugated estrogens or 2 mg estradiol for 21 days). Failure to bleed after this regimen may occur in several situations. First, when there is a lack of functional endometrium or an outflow tract obstruction. Alternatively, the patient may have elevated serum androgen levels that resulted in decidualization of the endometrial lining. In some instances withdrawal bleeding can occur in the presence of gonadal failure. Patients with vasomotor symptoms and a positive withdrawal bleed should have their follicle stimulating hormone (FSH) level assessed.

Hypogonadism (Prior Estrogen Exposure), Uterus Present

Patients with vasomotor symptoms may be transitioning to our next class of amenorrheic patients—those with previous estrogen exposure and intact uteri who present with hypogonadism (Fig. 3.3). Measurement of serum FSH is critical in this group of patients to determine whether the deficiency in estrogen is secondary to a central versus a peripheral abnormality (e.g., hypothalamus and pituitary versus ovary). Low FSH levels indicate central dysregulation. A normal FSH level in the presence of hypoestrogenemia is also abnormal and should be interpreted as a possible central cause of amenorrhea. These patients have increased amounts of sialic acid in the carbohydrate portion of the FSH molecule rendering it biologically inactive. Antibodies in the immunoassay are still able to recognize the

Table 3.1. Progestin challenge test

Parenteral 200 mg progesterone in oil

Oral micronized progesterone 300 mg qhs for 5 days

Oral medroxyprogesterone acetate 10 mg for 5 days

Eugonadism with Uterus hCG TSH, Prolactin Progestin Challenge

Positive hCG

Pregnancy

Positive Progestin Challenge

Anovulation Polycystic Ovarian Syndrome

Negative Progestin Challenge

Elevated TSH

Hypothyroidism

Elevsted Prolactin

Prolactinoma

Repeat after estrogen priming

Positive withdrawal bleed

Negative withdrawal bleed

Asfierman's syndrome

FSH Level

Normal FSH

Anovulation Polycystic Ovary Syndrome

Etevated FSH Repeal in 1 month

Consider Premature Ovarian Failure

Figure 3.2. Eugonadism with uterus.

Progesterone Level

Figure 3.3. Hypogonadism with uterus present and prior estrogen exposure.

Figure 3.3. Hypogonadism with uterus present and prior estrogen exposure.

Kj N

Table 3.2. Gonadotropin levels

Normal adult female levels Ovulatory peak levels Hypogonadotropic state Hypergonadotropic state

Adapted from: Speroff L, Fritz MA, eds. Clinical Gynecologic Endocrinology and Infertility, 7th ed. Lippincott Williams & Wilkins, 2004.

molecules, indicating that immunoreactivity does not always equal bioactivity. Since there are many possible etiologies associated with hypogonadotropic amenorrhea, information from the patient's history and physical should be used to direct further tests. Multiple endocrinopathies, CNS tumors, systemic illnesses, excessive exercise and eating disorders should all be considered and the appropriate endocrine screening tests and imaging studies ordered. For patients with elevated FSH levels (hypergonadotropic amenorrhea) who are less than 30 years old, a karyotype should be ordered because of the higher likelihood of finding a chromosomal abnormality. If a normal karyotype is discovered, a transvaginal ultrasound may be helpful in further differentiating between the remaining patients. If an abnormal karyotype is discovered an ultrasound may identify the presence of testicular tissue.

Eugonadism, Uterus Absent

Eugonadal patients who do not have evidence of a cervix on examination (Fig. 3.4) should undergo imaging studies for confirmation. If an absent uterus is confirmed, a karyotype should be obtained to rule out the presence of a Y chromosome. Testosterone levels are often useful in the differential diagnosis of patients with a 46 XY karyotype.

Primary Amenorrhea
Figure 3.4. Eugonadism without a uterus.

Table 3.3. Causes of primary amenorrhea

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