By: Roy N. Morcos, MD, FAAFP
Reprinted from the summer 2019 issue of The Ohio Family Physician.
Amenorrhea, or absence of menstrual bleeding, is a clinical problem that family physicians often encounter. There are several published approaches to the diagnosis, but I would like to present one based upon careful interpretation of the history and physical examination findings, relying upon a basic understanding of reproductive endocrinology. By following this method, one is less likely to omit a step in the work-up or overlook a potential diagnosis.
Amenorrhea can be primary or secondary. Although many of the same underlying conditions can present as either primary or secondary, it is useful to separate the two as this rapidly helps eliminate some possible causes. For example, congenital absence of the uterus or ovaries need not be considered in a patient who has previously menstruated (secondary amenorrhea). Primary amenorrhea (PA) can be divided into two categories: with sexual infantilism (or absence of breast development by age 13) or with normal secondary sexual characteristics.
PA with sexual infantilism indicates a deficiency in estrogen (mainly estradiol) production. Since estradiol is an ovarian product, this means that either the ovary is not adequately stimulated to produce estrogen (due to a follicle-stimulating hormone (FSH) deficiency), or that the ovary is not able to produce estrogen, in which case the FSH level will be markedly elevated. It is important to remember that two intact X chromosomes are necessary for normal ovarian development. Complete absence of an X chromosome (45, X, or Turner syndrome) or deletions of one of the X chromosomes will result in absent ovaries or ovarian failure. In both cases, the FSH is high and pubertal development does not occur. A peripheral blood karyotype is necessary to delineate the problem. Patients with Turner syndrome have typical features such as short stature, webbing of the neck and other findings, but some individuals with X-chromosome deletions often lack these physical findings.
A patient with PA and low estrogen levels will have elevated FSH levels if the pituitary and hypothalamus are normal. Therefore, low (or inappropriately normal) FSH levels, in the presence of estrogen deficiency, indicate that the underlying problem is central and not ovarian. In these cases, it is important to obtain an MRI with contrast to evaluate the pituitary and hypothalamus. A hypothalamic abnormality is suspected if the child exhibits headaches, behavioral or appetite abnormalities, marked obesity (Prader-Willi) or seizures. Neoplasms and infiltrative disorders are rare, but space-occupying non-neoplastic lesions are occasionally identified such as craniopharyngioma or hamartoma. Visual disturbances may occur and consultation with a neuro-endocrinologist is essential in these cases.
Primary amenorrhea with normal pubertal development is an indication that estrogen production is normal. In these cases, one should consider the possibility of an anatomic abnormality of the genital tract, and careful pelvic examination with ultrasonography are essential. Such abnormalities include imperforate hymen, transverse vaginal septum, and congenital absence of the uterus. The latter is invariably associated with a short vagina, since the uterus and upper vagina are of Mullerian duct origin.
Absence of a uterus may be due to Mullerian dysgenesis with a female karyotype or to appropriate regression of the Mullerian ducts caused by production of anti-Mullerian hormone by the testes. This occurs in males with androgen insensitivity syndrome, resulting in female phenotype (development of the male external genitalia requires the action of dihydrotestosterone on the androgen receptor) absence of a uterus and undescended testes. Unlike patients with Mullerian dysgenesis, those with androgen insensitivity syndrome have little to no axillary and pubic hair growth and the diagnosis is confirmed with a male testosterone level and a 46, XY karyotype. Patients with PA and normal secondary sexual characteristics who have normal external and internal female genitalia, are evaluated in the same manner as patients with secondary amenorrhea (SA).
Pregnancy is always a consideration in patients with secondary amenorrhea (SA) and must be excluded regardless of the patient’s age or reported sexual activity. The first step is to determine if estrogen levels are normal. This can be accomplished by measuring serum estradiol level or by administration of a progestin such as medroxyprogesterone (Provera) for ten days. Withdrawal bleeding indicates adequate estrogen stimulation of the endometrium. It is also an indication that the endometrium is normal and that there is no outflow tract obstruction such as cervical stenosis. In the absence of withdrawal bleeding, estrogen (such as estradiol 4 mg daily for 3 weeks) is administered followed by a repeat progestin challenge. Failure of withdrawal bleeding is highly suggestive of endometrial or outflow tract abnormalities. A history of post-partum hemorrhage followed by a curettage is often elicited in such patients, resulting in endometrial synechiae (adhesions), a condition often referred to as Asherman syndrome.
Withdrawal bleeding following estradiol and progestin administration (but not progestin alone) is indicative of estrogen deficiency. A consistently elevated FSH level (usually above 30 mIU/ml) is diagnostic of premature ovarian failure or early menopause. The endometrial stripe identified on vaginal ultrasonography is usually less than 4 mm. A karyotype is necessary if this occurs below 25 years of age to identify X chromosome abnormalities or mosaicism involving an X or Y chromosome. If the FSH is low (or inappropriately normal), the underlying problem is central. Serum prolactin and TSH levels should be obtained. Patients with anorexia nervosa are readily diagnosed by history and examination. Strenuous exercise is often the underlying cause of hypothalamic dysfunction and patients should be specifically asked about it. Anosmia or hyposmia in this setting or with PA and sexual infantilism, is associated with a congenital deficiency in GnRH production (Kallman syndrome). It can be identified by testing with floral or other purely olfactory scents.
Patients with SA who have normal estrogen production (or have withdrawal bleeding after progestin administration) are diagnosed with chronic anovulation. Polycystic ovarian syndrome is a very common endocrinopathy occurring in about 7% of women in the reproductive age group. It is diagnosed as chronic anovulation, hyperandrogenism (physically or biochemically with elevated testosterone levels), and typical ovarian features on ultrasonography. Other causes of hyperandrogenism must be excluded. It is important to remember that the disease is often mild and subtle. Measurements of serum FSH, LH, and insulin levels are commonly performed but are neither useful nor necessary. Other causes of anovulation include hyperprolactinemia and thyroid disease.
The family physician should avoid indiscriminately ordering many tests to evaluate patients with amenorrhea. Rather, following this simple and rational scheme, the diagnosis is readily established and appropriate therapy can be instituted. Referral may be necessary in some situations.
References available on the OAFP website.