I AMENORRHEA
Amenorrhea, the absence or abnormal cessation of menstruation, affects 2-5% of all women of childbearing age in the United States. Primary amenorrhea is defined as no menarche by 16 years of age.
Secondary amenorrhea occurs when menstruating women fail to menstruate for 3-6 months. Amenorrhea has variable etiologies and implications in patients depending on age, severity, and associated symptoms.Normal Menstrual Cycles
The menstrual cycle is an important component in the assessment of overall health status, and the American College of Obstetricians and Gynecologists recommends including the menstrual cycle as an additional vital sign. The median age of menarche in the United States and other developed countries is between 12 years and 13 years of age, but because age at menarche may vary internationally, health care providers should be aware of potential differences within their populations. Menstrual cycles are often irregular through adolescence, but by the third year after menarche approximately 60-80% of cycles are 21-34 days long. After the onset of menarche, cycles should occur at least every 90 days; longer intervals may represent an underlying etiology.
Etiology
There are numerous etiologies for amenorrhea, but among the most common are polycystic ovary syndrome (PCOS), hypothalamic causes, primary ovarian insufficiency, and hyperprolactinemia (see also the “Polycystic Ovary Syndrome” section later in Part 4). Table 4-1 and Table 4-2 list the common causes of primary and secondary amenorrhea, respectively, by the frequency they are encountered in clinical practice.
Table 4-1. Common Causes of Primary Amenorrhea
| Category | Approximate Frequency (%) |
| Breast development | 30 |
| Mullerian agenesis | 10 |
| Androgen insensitivity | 9 |
| Vaginal septum | 2 |
| Imperforate hymen | 1 |
| Constitutional delay | 8 |
| No breast development: high FSH | 40 |
| 46,XX | 15 |
| 46,XY | 5 |
| Abnormal karyotype | 20 |
| No breast development: low FSH | 30 |
| Constitutional delay | 10 |
| Prolactinomas | 5 |
| Kallmann syndrome | 2 |
| Other CNS | 3 |
| Stress, weight loss, anorexia | 3 |
| PCOS | 3 |
| Congenital adrenal hyperplasia | 3 |
| Other | 1 |
Abbreviations: CNS, central nervous system; FSH, follicle-stimulating hormone; PCOS, polycystic ovary syndrome.
Modified from Current evaluation of amenorrhea. Practice Committee of American Society for Reproductive Medicine. Fertil Steril 2008;90:S222. Copyright 2008, with permission from Elsevier.
Evaluation
Because the evaluation and treatment of amenorrhea may vary depending on the underlying etiology, a thorough history, physical examination, and often laboratory evaluation are critical for appropriate care of these patients. Although primary amenorrhea has been defined as no menarche by 16 years of age, many diagnosable and treatable disorders can and should
| Table 4-2. Common Causes of Secondary Amenorrhea ^ | |
| Category | Approximate Frequency (%) |
| Low or normal FSH | 66 |
| Weight loss, anorexia, or both | |
| Nonspecific hypothalamic | |
| Chronic anovulation including PCOS | |
| Hypothyroidism | |
| Cushing syndrome | |
| Pituitary tumor, empty sella, | |
| Sheehan syndrome | |
| Gonadal failure: high FSH | 12 |
| 46,XX | |
| Abnormal karyotype | |
| High prolactin | 13 |
| Anatomic | 7 |
| Asherman syndrome | |
| Hyperandrogenic states | 2 |
| Ovarian tumor | |
| Nonclassic congenital adrenal hyperplasia | |
| Undiagnosed | |
Abbreviations: FSH, follicle-stimulating hormone; PCOS, polycystic ovary syndrome.
Modified from Current evaluation of amenorrhea. Practice Committee of American Society for Reproductive Medicine. Fertil Steril 2008;90:S222. Copyright 2008, with permission from Elsevier.
be detected earlier. Thus, an evaluation for primary amenorrhea should be considered for any girl who has not reached menarche by 15 years of age or has not done so within 3 years of thelarche. Lack of breast development by 13 years of age also should be evaluated. The American Society for Reproductive Medicine recommends an evaluation for secondary amenorrhea after 3 months of amenorrhea in a regularly menstruating woman.
A thorough patient history should be taken and include inquiries about the following: past medical illnesses; date of last menstrual period; history of amenorrhea; exercise (amount per day and per week); dietary history (restrictions, special diets); eating disorders; medications; illicit drug use; psychiatric history; and a history of conditions such as hirsutism, acne, and galactorrhea.
Physical examination should include assessment of pubertal development (Tanner staging); evaluation of genital tract anatomy; presence of hirsutism, acne, or both; and measurement of body mass index. The need for imaging studies, such as ultrasonography, magnetic resonance imaging (MRI), and computed tomography, will depend on the patient’s medical history and whether the evaluation is for primary or secondary amenorrhea.
Laboratory studies used in the assessment of amenorrhea include pregnancy testing and measurement of levels of thyroid-stimulating hormone, prolactin, and follicle-stimulating hormone (FSH). Thyroid-stimulating hormone level is evaluated to rule out subclinical hypothyroidism. A persistently elevated prolactin level may indicate a prolactinoma, and the American Society for Reproductive Medicine recommends follow-up evaluation with MRI. The most common diagnoses when FSH levels are normal or low are hypothalamic amenorrhea and PCOS (see also the “Polycystic Ovary Syndrome” section later in Part 4).
An elevated FSH level in women younger than 40 years may signify primary ovarian insufficiency. Once confirmed by repeat testing, elevated FSH levels should prompt evaluation of autoimmune antibodies; the most commonly associated condition is autoimmune thyroiditis. The American Society for Reproductive Medicine recommends completion of a chromosomal analysis, including premutation analysis for Fragile X syndrome, in women in whom primary ovarian insufficiency is diagnosed.Management
Management of amenorrhea depends on the etiology. Patients requiring therapy that is beyond the scope and expertise of the general obstetriciangynecologist should be referred to appropriate health care providers for treatment.
Patients with primary amenorrhea that is due to constitutional delay require no treatment. Management of amenorrhea that is due to genetic (inherited) abnormalities includes supplemental hormone therapy (HT) to enable the development of normal secondary sex characteristics (breast development, pubic hair growth) and prevent osteoporosis. Patients with structural abnormalities (eg, vaginal agenesis) should be referred for treatment. Individuals who are found to have 46, XY karyotype are at increased risk of gonadal malignancy and will need to have gonads removed following breast development and attainment of adult stature.
The management of amenorrhea caused by primary ovarian insufficiency may involve HT and adequate consumption of calcium and vitamin D (see also the “Menopause” section in Part 3). Management of amenorrhea that is due to PCOS includes lifestyle modification, HT (such as combined oral contraceptive pills), and ovulation induction with clo- miphene citrate when pregnancy is desired (see also the “Polycystic Ovary Syndrome” section later in Part 4). Patients with pituitary gland dysfunction, especially hyperprolactinemia, should be evaluated with MRI of the pituitary gland and referred for treatment, as needed.
Emotional or physical stress, eating disorders, restricted caloric intake, and increased or excessive exercise all may result in hypothalamic amenorrhea, though the treatment may vary greatly depending on the specific issue.
All of these etiologies, however, may result in osteoporosis because of the effect of hypoestrogenism on bone remodeling. Current research indicates that the most effective means of improving bone mass is to treat the underlying condition; increasing caloric intake to improve energy availability has been shown to be critical for bone health (see also the “Osteoporosis” section in Part 3). If the underlying cause cannot be easily treated, the American Society for Reproductive Medicine recommends initiation of therapy with cyclic estrogen-progestin or oral contraceptives to prevent excessive bone loss. These treatments, however, do not normalize the metabolic factors that negatively affect bone health and have not been demonstrated to reduce the risk of fractures. Furthermore, there are no established guidelines addressing when, or if, HT should be used for the treatment of hypothalamic amenorrhea in females younger than 16 years. Hypothalamic amenorrhea that is due to other etiologies, such as disorders of the central nervous system, pituitary gland, or hypothalamus, requires referral to an appropriate specialist for management.Bibliography
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