Primary amenorrhea is defined as failure to menstruate by age 16 in patients with normal secondary sexual characteristics or the failure to menstruate by age 14 in patients with no signs of sexual maturation (Fig. 30.1). Secondary amenorrhea is defined as the absence of three menstrual cycles or the absence of menstrual bleeding for 6 months. The distinction between primary and secondary amenorrhea has traditionally been emphasized because of the higher incidence of genetic and anatomic abnormalities among young women with primary amenorrhea. It remains conceptually useful to make this distinction because of several unique disorders that are found only in patients with one or the other. Still, there is much more overlap in the origins and pathophysiology of the two entities than was originally appreciated. For example, Turner syndrome is a common genetic cause of primary amenorrhea, yet some patients with Turner syndrome have sufficient ovarian reserve to undergo secondary sexual development and menarche before complete ovarian failure results in secondary amenorrhea. Other young women with chronic anovulation due to functional disorders will be classified with primary amenorrhea if the onset of the disorder occurs at puberty. In such cases, it may be more useful to assess the degree to which secondary sexual characteristics have developed in girls with absent menses. Failure of breast and pubic hair development is a sign of delayed or absent puberty and represents a specific subset of reproductive abnormalities (Chapter 29).
As Table 30.1 shows, causes of amenorrhea are extensive and involve all levels of the hypothalamic–pituitary–gonadal–end-organ axis. To avoid confusion, amenorrhea can be divided into two broad categories of abnormalities. The first and largest category is characterized by chronic anovulation. In these patients, a failure to generate cyclic ovarian estrogen and progesterone leads to absent or highly irregular sloughing of an inappropriately stimulated endometrium (Chapters 10 and 14). Chronic anovulation results from four general pathophysiologic mechanisms: (i) the hypothalamus fails to generate a cyclic gonadotropin-releasing hormone (GnRH) signal to the pituitary gland; (ii) the pituitary fails to respond to appropriate signals from the hypothalamus; (iii) the normal sex steroid feedback mechanisms fail to drive the midcycle luteinizing hormone (LH) surge; (iv) interference with gonadal steroid feedback by other endocrine systems. The second, much smaller, category includes end-organ abnormalities that interfere with the ability of these organs to respond to normal cyclic ovarian steroid production and produce visible endometrial bleeding.
Hypothalamic disturbances |
Primary hypothalamic lesions |
Kallmann syndrome |
Secondary hypothalamic lesions |
CNS tumors |
Abnormal CNS–hypothalamic interaction |
Anorexia nervosa |
Exercise-induced amenorrhea |
Primary pituitary disturbances |
Sheehan syndrome (pituitary apoplexy) |
Pituitary adenomas |
Pituitary tumors |
Empty sella syndrome |
Secondary pituitary disturbances |
Inappropriate gonadal steroid feedback |
Pregnancy |
Contraceptive steroids |
Constant estrogen exposure |
Estrogen excess |
Estrogen-producing tumors |
Aromatase excess |
Estrogen deficiency |
Gene mutations in estrogen receptor |
Aromatase deficiency |
Androgen excess |
Androgen-producing tumors |
Functional excess (adrenal or ovarian) |
Inappropriate feedback from other sources |
Polycystic ovary syndrome (PCOS) |
Cushing syndrome |
Hypothyroidism and hyperthyroidism |
Lactation |
Hyperprolactinemia |
Growth hormone excess |
Malnutrition |
Gonadal abnormalities |
Gonadal failure |
Gonadal dysgenesis |
Menopause |
Ovarian ablation or removal |
Gene mutation in LH and FSH receptors |
End-organ abnormalities |
Uterus |
Müllerian agenesis |
Surgical removal of the uterus |
Endometrial ablation |
Asherman syndrome |
Vagina |
Imperforate hymen |
Vaginal septum |
Other |
Complete androgen insensitivity (testicular feminization) |