Amenorrhea

Definition

Amenorrhea is the absence of menstruation and is a symptom, not a diagnosis.

Primary amenorrhea refers to the absence of the onset of menstruation by age 16 whether or not normal growth and secondary sexual characteristics are present, or the absence of menses after age 14 when normal growth and signs of secondary sexual characteristics are present. Secondary amenorrhea is the absence of menses for three cycles or six months in women who have previously menstruated.

In terms of the relationship of amenorrhea to cancer, amenorrhea may be a symptom of a gynecologic tumor, or the pause or cessation in menstruation may develop as a side effect of cancer treatment.

Demographics

The prevalence of primary amenorrhea is 0.3% and secondary amenorrhea occurs in approximately 1%-3% of women. However, among college students and athletes the incidence can range from 3%-5% and 5%-60%, respectively.

For cancer-related amenorrhea, one clinician noted that nine out of ten women under his care reported secondary amenorrhea following bone marrow transplants. Chemotherapy and abdominal-pelvic radiation therapy likewise produce similar outcomes.

Causes

Normal menstrual bleeding occurs between menarche and menopause and has an average length of 28 days but varies from woman to woman. The normal menstrual cycle depends on cyclic changes in estrogen and progesterone levels, as well as the integrity of the clotting system and the ability of the spiral arterioles in the uterus to constrict. Abnormalities in any of these components may cause bleeding to stop or increase.

Primary amenorrhea

There are multiple causes for primary amenorrhea once pregnancy, lactation and missed abortion are ruled out. These include:

• anorexia nervosa/bulimia/malnutrition
• extreme obesity
• hyperthyroidism/hypoglycemia
• congenital heart disease
• cystic fibrosis/Crohn's disease
• genetic abnormalities
• obstructions: imperforate hymen/vaginal or cervical absence
• ovarian, pituitary (craniopharyngioma) or adrenal tumors
• polycystic ovarian disease
• testicular feminization

It is rare for primary amenorrhea to be caused by tumors but it can be a cause and should always be a consideration if other factors are ruled out.

Gonadal failure (a nonfunctioning sex gland) is the most common cause of primary amenorrhea, accounting for almost half the patients with this syndrome. The second most common cause is uterovaginal agenesis (absence of a uterus and/or vagina) with an incidence of about 15% of individuals with this syndrome. One of the most important, and probably most common, causes of amenorrhea in adolescent girls is anorexia nervosa, which occurs in about 1 in 1, 000 white women. It is uncommon in women older than 25 and rare in women of both African and Asian descent. When women lose weight 15% below ideal body weight, amenorrhea can occur due to central nervous system-hypothalamic dys-function. When weight loss drops below 25% ideal body weight, pituitary gonadotrophin function (follicle stimulating hormone and luteinizing hormone) can also become abnormal.

Each year of athletic training before menarche (the beginning of menstrual function) delays menarche about four to five months. Amenorrhea associated with strenuous exercise is related to stress, not weight loss, and is most probably caused by an increase in central nervous system endorphins and other compounds which interfere with gonadotrophin-releasing hormone release.

Secondary amenorrhea

Once pregnancy, lactation and menopause are ruled out, the causes for secondary amenorrhea include:

• extreme obesity
• prolonged or extreme exercise
• anxiety or emotional distress
• non-oral contraceptives (Norplant/Depo-Provera)
• D & C (dilatation and curettage) (Asherman's syndrome)
• early menopause
• autoimmune dysfunction
• pituitary tumors and central nervous system lesions

Cancer and secondary amenorrhea

As mentioned, not only does amenorrhea occur as a symptom of a tumor and/or lesion, but it often develops in women undergoing treatment for cancer.

RADIATION.

Radiation therapy is used in conjunction with chemotherapy in a number of clinical situations, including Hodgkin's disease and childhood leukemia and lymphomas. Ovarian damage occurs under these circumstances to varying degrees, depending upon the total dosage of radiation as well as the age of the patient at the time of exposure.

CHEMOTHERAPY.

Premenopausal women receiving single or multi-agent chemotherapy are at risk for short-term amenorrhea, as well as ovarian damage. Even young women who resume menstruation following chemotherapy are at risk for early menopause; therefore, those treated in childhood and adolescence should be counseled regarding the chance of early menopause in order to plan ahead for childbearing.

WEIGHT LOSS.

Side effects of cancer as well as treatments can cause a decrease in appetite and nausea and vomiting, which, in turn, can cause severe weight loss as associated with malnutrition. Thus, menstruation may cease for the same reasons as it does in young adolescents with anorexia nervosa—hypothalamic dysfunction.

STRESS.

Stress has always been noted to play a large role in the cause of amenorrhea, so the actual stress of having cancer and undergoing treatments may also cause amenorrhea to occur.

RETURN OF NORMAL OVARIAN FUNCTION FOLLOWING TREATMENT.

Research on the recovery of normal ovarian function with young girls and/or young women has not revealed any reliable data. There are individual success stories especially with new advances in assisted reproductive technologies (ARTs), but overall, the return of normal ovarian function seems to be age-dependent. One researcher recently reported on ovarian function in 65 women who underwent high-dose chemotherapy and bone marrow transplants for aplastic anemia. All women younger than 26 years at the time of chemotherapy recovered ovarian function, while 7 of the 18 women aged 26 to 38 years did not recover ovarian function. Thus, the risk of ovarian dysfunction appears to increase with advancing age when ovarian reserve decreases. Additionally, the risk of dysfunction increases with the dose of alkylating agents, notably cyclophosphamide.

Treatments for amenorrhea

Even with the possibility of ovarian compromise, women previously treated for cancer have successfully achieved pregnancy via ART's. Advances in the area of ART's include the use of donor eggs, the possibility of freezing embryos, and eventual oocyte (immature ovum) pretreatment offer more options to young women facing cancer chemotherapy.

Special concerns

The need for effective contraception during and after cancer treatment is imperative. Normal menstrual cycles do not imply normal fertility and likewise, irregular menses or even amenorrhea does not imply a lack of fertility. Women with dysfunctional bleeding or amenorrhea are still capable of spontaneous ovulation and conception.

The most reliable form of birth control for any population of women is injectable progestins, which suppress luteinizing hormone secretion. Depo-Provera, 150 mg injected intramuscularly, will effectively block ovulation for four months. Norplant (six rubber capsules placed under anesthesia in the upper arm) will effectively block ovulation for five years. If the treatment or the specific cancer diagnosis contraindicates the use of either of these contraceptives, other options should be considered, i.e., sterilization for the woman or her partner, an intrauterine device (IUD), or barrier methods (condoms, diaphragm or spermicides).

See Also Fertility and cancer

Resources

BOOKS

Jarvis, Carolyn. Physical Examination and Health Assessment. Philadelphia: W. B. Saunders Company, 2000.

Trimble, E. Cancer Obstetrics and Gynecology. Philadelphia:Lippincott William & Wilkins, 1999.

Youngkin, Ellis Quinn and Marcia Davis Szmania. Women's Health: A Primary Care Clinical Guide. Stamford, CT: Appleton & Lange, 1998.

Linda K. Bennington, C.N.S., M.S.N.

Alkylating agents

—A group of synthetic compounds that act on the deoxyribonucleic acid (DNA) in the nucleus of the cell and are used in cancer chemotherapy.

Aplastic anemia

—Any form of anemia caused by defective development of bone marrow.

Asherman's syndrome

—The presence of adhesions within the uterus following a D & C.

Autoimmune dysfunction

—A disease associated with the production of antibodies directed against one's own tissues.

Craniopharyngioma

—Tumor arising from the cells in the pituitary.

Crohn's disease

—Inflammation of the gastrointestinal tract.

Imperforate hymen

—The lack of an opening in the membranous fold partly or completely closing the opening to the vagina.

Intermenstrual

—Time period between one menstrual cycle to another.

Luteinizing hormone

—A hormone which acts with follicle-stimulating hormone to cause ovulation of mature follicles and secretion of estrogen from the ovary.

Menopause

—The stage of life during which a woman passes from the reproductive to the nonreproductive stage and she experiences the cessation of menstruation.

Menses/Menstruation

—The periodic discharge from the vagina of blood and tissues from a non-pregnant uterus.

Polycystic ovary disease

—Also called Stein-Leventhal syndrome, it is the presence of many cysts in the ovaries.

Postcoital

—Following intercourse.

Progestins

—A steroid sex hormone that maintains the lining of the uterus.

Testicular feminization

—An individual with female external development, including secondary sex characteristics, but with the presence of testes and absence of uterus and tubes.