During the menses, low ovarian levels of estrogen stimulate the production of FSH. Final maturation of the follicle occurs under the stimulation of FSH. As the ovarian production of estrogen increases, the rising estrogen levels have a negative effect on FSH and a positive effect on LH. During the second half of this phase, estrogen stimulates growth of the endometrium.

The surge in LH secondary to positive estrogen feedback results in ovulation. As LH levels peak, estrogen levels fall.

This phase corresponds to the lifespan of the corpus luteum, which secretes progesterone and estrogen. Under the influence of these hormones, the endometrium becomes thicker and more vascular. Plasma levels of LH and FSH decline. If fertilization does not occur, the corpus luteum involutes within 14 days and estrogen and progesterone levels fall. With a fall in the levels of these hormones, the endometrium becomes necrotic and sloughs off in the process known as menstruation.

Any condition associated with a deficiency of GnRH can cause amenorrhea. Constitutional delay of puberty is a common etiology of primary amenorrhea. This condition may be associated with short stature and a family history of delayed puberty or delayed menarche in an older sibling or parent. Other conditions that cause GnRH deficiency include hypothalamic tumors, isolated GnRH insufficiency, and Kallmann syndrome (GnRH deficiency and anosmia). Any type of chronic disease, such as inflammatory bowel disease, cystic fibrosis, systemic lupus erythematosus, and diabetes; nutritional problems (e.g., anorexia, bulimia, obesity), rigorous exercise, stress, and substance abuse can also result in GnRH deficiency.

Pituitary disorders that can cause amenorrhea include tumors such as prolactinomas and craniopharyngiomas. Other causes are idiopathic hypopituitarism and a history of central nervous system infection.

Turner syndrome is one of the most common chromosomal disorders in humans and one of the most frequent causes of primary amenorrhea. It is characterized by a 45,XO karyotype, although up to 50% of affected persons may exhibit mosaicism (46,XX/45,XO). Some of the stigmata of Turner syndrome include short stature, webbed neck, shield chest, and streak ovaries.

Female gonadal dysgenesis is characterized by a 46,XX karyotype and streak ovaries.

Gonadal dysgenesis with a variety of other abnormal karyotypes such as XY or XXY may also occur. They are a rare cause of amenorrhea. Other ovarian conditions that result in amenorrhea include polycystic ovary syndrome and ovarian failure secondary to infection, radiation, chemotherapy, autoimmune disease, or an idiopathic cause.

Any sort of genital tract obstruction can result in amenorrhea. An imperforate hymen or a transverse vaginal septum will often present with cyclic pain resulting from the accumualtion of blood behind the obstruction. Asherman syndrome is iatrogenic scarring of the uterine lining, usually secondary to trauma sustained during a dilation and curettage procedure or infection. Mullerian agenesis refers to partial or complete agenesis of the vagina. The uterus and fallopian tubes are usually absent or rudimentary and the karyotype is 46,XX. In complete androgen insensitivity syndrome, the individual appears phenotypically female with normal female breasts and external genitalia. However, the vagina ends in a blind pouch and pubic hair is absent or sparse. The karyotye is 46,XY and inguinal or intra-abdominal testes are present. Because of the risk of malignancy, the testes should be removed after breast development and adult stature have been achieved.

Pregnancy should always be considered in both primary and secondary amenorrhea. Other considerations include hormonal contraception and endocrinopathies such as diabetes, thyroid disease, and adrenal disease.

Begin the evaluation of primary and secondary amenorrhea with a detailed history of the patient’s growth and development (Table 46.2). In the case of primary amenorrhea, specifically inquire about the age at thelarche (development of breast buds), adrenarche (growth of pubic hair), and the growth spurt. Important details of the menstrual history include the age at menarche, frequency and duration of menses, presence of dysmenorrhea, and breast changes associated with menses. Inquire about a history of chronic disease or a serious childhood illness, such as a central nervous system infection. The family history should include the ages of puberty and menarche for parents and siblings. Inquire about a history of psychiatric illness, environmental stress, medications, and drug abuse. Has the patient experienced a recent weight change? Take a detailed dietary history and ask about body image to explore the possibility of an eating disorder. Extreme exercise habits and participation in
competitive sports can cause amenorrhea in the female athlete. Obtain a sexual history regarding past and present sexual activity. Inquire about signs of androgen excess or virilization, such as acne and hirsutism. Also ask about galactorrhea associated with conditions causing hyperprolactinemia.