CHAPTER 4 Amenorrhea
Secondary amenorrhea is defined as the absence of menstruation for at least three cycles in women with established normal menstruation or 9 months in females with previous oligomenorrhea (menstrual periods occurring at intervals of greater than 35 days, with only four to nine periods in a year). The most common causes of secondary amenorrhea are the physiological events of pregnancy, lactation, and menopause.
The production of menstrual flow requires an intact outflow tract, a hormonally responsive uterus, and an integrated hypothalamic-pituitary-ovarian (HPO) axis. An important task in the diagnostic evaluation of amenorrhea is to identify the malfunctioning element. The primary care provider begins investigation of etiological reasons for amenorrhea and uses that knowledge to determine the type of amenorrhea. In turn, the suspected cause guides diagnostic tests, treatment, and referrals. This method of classification directs the clinician to evaluate constitutional causes, congenital or chronic disorders, the lower genital tract, and then dysfunction of any component of the HPO axis.
The normal menstrual cycle begins with the pulsatile delivery of gonadotropin-releasing hormone (GnRH) by the medial-basal hypothalamus. In response, the posterior pituitary releases luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These influence the growth and development of a follicle and its release of estradiol, which causes the uterine endometrium to proliferate and initiates the LH surge, which is followed by ovulation and menstruation (Figure 4-1 and Table 4-1).
FIGURE 4-1 Interrelationships among cerebral hypothalamic, pituitary, ovarian, and uterine functions throughout the menstrual cycle.
(Modified from Lowdermilk DL, Perry SE, Bobak IM: Maternity & women’s health care, ed 6, St Louis, 1997, Mosby.)
The hypothalamus is also affected by the central nervous system (CNS) and the thyroid gland, which can determine the amount of GnRH received by the pituitary. Alterations in the pattern of GnRH pulsatile release decreases circulating LH and FSH levels; the consequence is an anovulatory menstrual cycle and amenorrhea.
About 66% of all amenorrheic women are hypoestrogenic because of either hypothalamic-pituitary hypofunction or end-organ failure. Determining whether the patient is hypoestrogenic can expedite finding the reason for her amenorrhea and setting the sequencing of laboratory tests. The progesterone challenge test (PCT) causes withdrawal bleeding if there is estrogen production and an adequate outflow tract. The functional status of the pituitary-ovarian unit is assessed by measuring the gonadotropins (LH and FSH).
Diagnostic reasoning: focused history
Pregnancy
For any female with a uterus, it is important to rule out pregnancy as the first step in determining the cause of amenorrhea. It is rare, but a young girl can become pregnant before the onset of menses. Pregnancy should be ruled out before the administration of androgenic challenge tests. If the woman is pregnant and there is accompanying bleeding, determination of whether the pregnancy is uterine or ectopic is the next priority (see Chapter 33). Be cognizant of domestic violence and sexual abuse, with consequent unintended pregnancy. Ask direct questions in private about being hit, pushed, or slapped or about having nonconsensual sex.
Contraceptive use
The type and use patterns of contraceptives are important in the search for the cause of amenorrhea. Contraceptive failures can account for an unintended pregnancy. Amenorrhea can occur after discontinuation of oral contraceptives. Measurement of serum gonadotropins is affected by long-acting contraceptives, such as Depo-Provera (medroxyprogesterone acetate [DMPA]), implants, or intrauterine devices (IUDs) containing progestagens; these must be discontinued before testing.
Seeking pregnancy
Knowing that the patient is seeking pregnancy or, if the patient is pregnant, whether it is intended or unintended allows the interview to be structured appropriately. It also aids in proper counseling and referral. Amenorrheic patients seeking pregnancy who do not bleed after androgen challenge tests are most successfully treated by an infertility specialist. Young maternal age and early referral to a specialist increase a woman’s conception rate.
Is this primary or secondary amenorrhea?
Key questions
Have you ever had a menstrual cycle?
Have you started pubertal development? Can you show me how your breasts and pubic hair (PH) look compared with these pictures? (Use Tanner Sexual Maturity Rating [SMR] scales [Figures 4-2 and 4-3].)
At what age did you start your periods?
When was your last normal menstrual period?
What is the nature of your periods (e.g., frequency, duration, amount of flow)?
FIGURE 4-2 Five stages of breast development in females.
(Photographs from Van Wieringen JC, Wafelbakker F, Verbrugge HP, DeHass JH: Growth diagrams 1965 Netherlands: Second National Survey on 0-24-year-olds, Groningen, The Netherlands, 1971, Wolters-Noordhoff; reprinted by permission of Kluwer Academic Publishers.)
FIGURE 4-3 Tanner sexual maturity development in females.
(Photographs from Van Wieringen JC, Wafelbakker F, Verbrugge HP, DeHass JH: Growth diagrams 1965 Netherlands: Second National Survey on 0-24-year-olds, Groningen, The Netherlands, 1971, Wolters-Noordhoff; reprinted by permission of Kluwer Academic Publishers.)
Onset of menstruation
The age range for menarche in the United States is 9 to 17 years. If the woman has had established menses at intervals of every 21 to 38 days, then the classification of secondary amenorrhea would apply. Established menses indicate that there is no outlet flow problem and that the HPO axis and endometrium are functioning.
Pubertal development
Female pubertal development begins with a growth spurt 1 year before the development of breast buds (thelarche) at around age 11 years. Then there is continued growth for 1 year until the peak height velocity is achieved. PH appears (pubarche), followed by axillary hair and the beginning of menarche. The average age of menarche for U.S. girls is 12 years 4 months. The length of time from thelarche to menarche is 2 to 3 years.
A thorough review of pediatric growth charts is helpful in determining the young girl’s norm of growth and development and the centimeters attained by her latest growth spurt. Most adolescent girls have a mean height gain of 29 cm (11.4 inches) and the growth spurt lasts approximately 4 years. Asking adolescents to self-identify their Tanner SMR scales for breast and pubic maturity provides very accurate staging (see Figures 4-2 and 4-3). Additionally, it gives the opportunity for insight into their feelings about their body and self-esteem.
Age of menarche
The lack of menstrual periods and secondary sex characteristics by age 14 or the lack of menses by age 16 in the presence of secondary sex characteristics is considered primary amenorrhea. Fifty-six percent of all adolescents start menses when PH development is at PH stage 4 and 19% at PH stage 3 (see Figure 4-3). If the adolescent is PH stage 4 but has not had a menses, then primary amenorrhea should be diagnosed. However, if the adolescent does not meet the age and maturation criteria, then suspect she is experiencing delayed puberty or is a so-called “late bloomer.” She is likely to have a family history in her mother and sisters of delayed menarche. Almost 80% of amenorrheic adolescents with intact female genitalia and developed breasts have an inappropriate LH feedback, anovulatory cycles, or high levels of androgenic hormones. They will bleed after a PCT and should be monitored for continued menses to avoid endometrial hyperplasia.
Menstrual history
Absence of a menstrual period for the past 3 months in females with established normal menstruation or 9 months in females with previous oligomenorrhea (menstrual periods occurring at intervals of greater than 35 days, with only four to nine periods in a year) is considered secondary amenorrhea. Sudden cessation of menstruation is more likely to indicate pregnancy or stress as a cause, whereas a gradual cessation suggests polycystic ovarian syndrome (PCOS) or premature ovarian failure.
Change in weight, percentage body fat, and athletic training intensity
Underweight persons typically have a low body fat–to–lean muscle ratio. Body fat can be assessed by measuring the body mass index (BMI). The severe stress of anorexia nervosa can produce prolonged amenorrhea. Exercise from various sports—jogging, middle and long distance running, ballet dancing, gymnastics, and track and field events—can lower body fat sufficiently to cause menstrual aberrations. Long distance runners and ballerinas are more apt to be amenorrheic than are swimmers; however, even moderate exercise can cause one or two missed periods a year. The mechanism of action on the HPO axis is unknown but is expressed by delayed puberty, shortened luteal phase, anovulation, and amenorrhea. Obesity can be the cause of amenorrhea or be a sign of PCOS. PCOS causes ovarian dysfunction—elevated androgens, hirsutism, low sex steroid binding globulin (SSBG), and an elevated LH/FSH ratio.
Emotional state
The stress of athletic competition, family situations, school performance, peer relations, and work can disrupt normal cyclic menses. The HPO axis of a teenager is more sensitive to physical and psychological stress than that of an adult female.
Congenital or chronic diseases
Turner syndrome stigmata (see the discussion on performing a head and neck examination later in this chapter) or similar physical findings suggest the probability of an abnormality of one or all components (CNS, structural anomalies, or HPO axis) necessary for menstruation. Most structural anomalies that would prevent outflow of the menstrual blood are detectable on physical examination. Chronic diseases, such as anorexia nervosa, diabetes mellitus, Crohn disease, systemic lupus erythematosus, glomerulonephritis, cystic fibrosis, pituitary adenoma, adrenal diseases, and thyroid dysfunction, can cause amenorrhea.
Hair and skin changes and temperature intolerance
Hypothyroidism and hyperthyroidism are expressed by changes in hair and skin texture. Hyperthyroidism often makes women intolerant of the heat, and this is sometimes confused with menopausal syndrome symptoms. Cold intolerance is frequently exhibited by persons with low-functioning thyroids.
Energy and bowel changes
Increased functioning of the thyroid causes restlessness and diarrhea, whereas decreased functioning results in constipation and fatigue. Even mild thyroid dysfunction can cause menstrual irregularities; therefore a thyroid function test is needed to assess the thyroid status.
Galactorrhea
Women notice breast nipple discharge that is not associated with breastfeeding or medications. Offensive medications are listed in Box 4-1 and include primarily the dopamine antagonist agents and estrogens.
Box 4-1 Drugs That May Cause Amenorrhea
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