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Menstruation: Absent Periods (Amenorrhea)

Description

An in-depth report on the causes and treatment of absent periods.

Alternative Names

Menstrual Disorders

Causes

According to some evidence, the four major causes of primary amenorrhea (in which a woman has never had a period) are the following: ovarian failure (48.5% of cases of amenorrhea); born with no uterus and vagina (15.2%); deficiencies in reproductive hormones, such as in hypogonadotropic hypogonadism (8.3%); and delayed puberty (6%). Until recently, the great majority of these women were unable to become pregnant. Advances in reproductive techniques, however, are enabling many to have children.

There are many causes of secondary amenorrhea, including eating disorders, polycystic ovarian syndrome, and a number of medications and medical conditions.

Delayed Puberty

The most common cause of primary amenorrhea is delayed puberty due to some genetic factor that delays physical development. Being short is the most common sign of this, although sometimes a family history of delayed menstruation can indicate this situation. Time usually resolves the problem.

Functional Hypothalamic Amenorrhea (FHA) and Eating Disorders

Functional hypothalamic amenorrhea (FHA) is the absence of menstruation due to disturbances in the thyroid gland and hypothalamus-pituitary-adrenal (HPA) system, which regulates reproduction and other important functions. The eating disorders anorexia and bulimia are most often associated with FHA. FHA may be due to other different factors, most unknown.

Severe weight loss, changes of appetite, or both appear to cause hormonal abnormalities that can cause FHA. How this occurs is not entirely clear. Some observations include the following:

  • Extreme weight loss and reduced fat stores lead to hormonal changes that include low thyroid levels (hypothyroidism) and elevated stress hormone levels (hypercortisolism). These changes effect a reduction in reproductive hormones. Some experts theorize that such changes may be due to a primitive protective biologic mechanism that was designed to prevent potentially harmful pregnancies during times of famine.
  • Amenorrhea can also occur in young women with eating disorders whose weights are normal or above normal. Factors other than low fat stores, then, may be involved in reproductive abnormalities. Changes in appetite itself may have an effect on chemicals in the hypothalamus. One such important chemical in this system that may play a major role in FHA is leptin. Leptin is involved with regulation of appetite and is released by fat cells. Levels fall as less fat is stored in the cells. Low levels of leptin appear to interfere with reproductive hormones, particularly luteinizing hormone and so may contribute to amenorrhea.
  • A syndrome known as the female athlete triad is associated with hormonal changes that occur with eating disorders in young women who excessively exercise. It comprises anorexia (severe weight loss), amenorrhea, and osteoporosis (decrease in bone density). One 2001 study suggested that repeated exercise modifies the hormonal responses to both activity and rest and may interfere with cyclic variations in reproductive hormones, particularly luteinizing hormone (LH), which triggers ovulation.

Treatments for Functional Hypothalamus Amenorrhea. In one small 2002 study, 70% of women with FHA recovered with no therapy at all after an average of eight years. The important factors associated with recovery were weight gain or maintenance of normal weight, lowering stress hormone levels, and restoring normal estrogen levels. If anorexia is the cause of FHA, it should be treated immediately and aggressively, since severe anorexia can be life threatening.An important goal is to reduce or prevent bone mass depletion, which occurs in almost 90% of women with anorexia. Estrogen replacement is usually not useful, but there are many available bone protective agents, such as calcium and vitamin D supplements and bisphosphonate, such as alendronate (Fosamax). Other agents showing promise for improving bone density and other symptoms of anorexia include dehydroepiandrosterone (DHEA), a weak male hormone, and recombinant human IGF-I (rhIGF-I), which is a growth hormone. Other supplements that might be required, particularly in women with the female athlete triad, include B vitamins, zinc, and iron.

[For more information, see Well-Connected Report # 49, Eating Disorders.]

Polycystic Ovarian Syndrome (PCOS)

Polycystic ovarian syndrome (PCOS) is a condition in which the ovaries produce high amounts of androgens (male hormones), particularly testosterone. PCOS occurs in about 6% of women, and amenorrhea or oligomenorrhea (infrequent menses) is quite common. According to a 2002 study, nearly 30% of obese women with PCOS had amenorrhea. (The rate was lower--4.7%--in women with normal weight.)

Overproductive ovaries
If the ovaries produce too much androgen (hormones such as testosterone) a woman may develop male characteristics. This ovarian imbalance can be caused by tumors in the ovaries or adrenal glands, or polycystic ovarian disease. Virilization may include growth of excess body and facial hair, amenorrhea (loss of menstrual period) and changes in body contour.

In PCOS, increased androgen production produces high LH levels and low FSH levels, so that follicles are prevented from producing a mature egg. Without egg production, the follicles swell with fluid and form into cysts. Every time an egg is trapped within the follicle, another cyst forms, so the ovary swells, sometimes reaching the size of a grapefruit. Without ovulation, progesterone is no longer produced, whereas estrogen levels remain normal.

The elevated levels of androgens (hyperandrogenism) can cause obesity, facial hair, and acne, although not all women with PCOS have such symptoms. Other male characteristics, such as deepening voice and clitoral enlargement, are rare.

PCOS also poses a high risk for insulin resistance, particularly in women who are also obese. Insulin resistance is associated with diabetes type 2, in which insulin levels are normal or high but the body cannot use this hormone efficiently. About half of PCOS patients, in fact, also have diabetes.

The drug valproate (used to treat seizures and bipolar disease) has been associated with PCOS. In most cases, the cause of PCOS is unknown.

Treating Polycystic Ovary Syndrome. Treatments for PCOS include the following:

  • Weight loss and a moderate exercise program. In women who are both obese and have PCOS, this approach has produced marked improvements in PCOS symptoms and in hormone levels.
  • Metformin. Metformin (Glucophage) is commonly used to increase insulin levels and control blood sugar in people with type 2 diabetes. This agent and similar ones used in diabetes are showing great promise in reversing symptoms, reducing male hormones, and restoring regular menstrual cycles and ovulation in some women with PCOS. Studies suggest it might even be beneficial in nonobese women and in those who are not insulin resistant.
  • Oral contraceptives. Oral contraceptives (OCs) may be used to restore regular periods in women who do not wish to become pregnant or who are not candidates for other approaches. It should be noted that OCs can be estrogen plus progestins or progestins alone. The progestins in any OCs should be newer ones, which are less apt to produce male characteristics.
  • Fertility treatments. PCOS has typically been treated with clomiphene, even for women who do not want to conceive. This fertility drug blocks estrogen, which tricks the pituitary into producing the reproductive hormones FSH and LH. Gonadorelin (GnRH) administered in pulses, used alone or in combination with clomiphene, gonadotropins, or oral contraceptives, has been successful in some cases where clomiphene alone has failed. Women who want to become pregnant can take either clomiphene or superovulation agents (FSH agents or hMG) with or without assisted reproductive technologies (ART). [See also the Well-Connected Report #22 Infertility in Women.]
  • Male-hormone blockers. Agents that block male hormone, such as flutamide, spironolactone, or finasteride, may be helpful alone or in combination with OCs to reduce male symptoms. They can cause birth defects in male offspring and so should be used by women who are also taking an OC.
  • D-chiro-inositol. This natural substance, found in fruits and vegetables, improves insulin sensitivity and is under investigation
  • Drugs that treat prolactin. Drugs, such as cabergoline or bromocriptine, which reduce hyperprolactinemia, (high levels of prolactin) may be useful for some women with PCOS. (They do not appear to be useful in women with PCOS and normal prolactin levels.)
  • Ovarian procedures. Operations that cauterize or open up the ovaries may be helpful for some women. A procedure called ovarian drilling, in which the surgeon opens six to 12 small holes in the ovary, is proving to be safe and effective for PCOS. It also reduces the risk for multiple pregnancies compared to fertility treatments. Ultrasound guided injection of hot saline (salt water) into the ovaries has achieved ovulation in 73% of women and is a promising alternative to ovarian drilling.

Elevated Prolactin Levels (Hyperprolactinemia)

Prolactin is a hormone produced in the pituitary gland that stimulates breast development and milk production in association with pregnancy. High levels of prolactin (hyperprolactinemia) in women who are not pregnant or nursing can reduce gonadotropin hormones and inhibit ovulation, thus causing amenorrhea. It is the cause of between 10% and 40% of cases of secondary amenorrhea. Secretions from the breast not related to pregnancy or nursing (called galactorrhea) is a telltale symptom of high prolactin levels and should be investigated.

Hyperprolactinemia can be caused by hypothyroidism or pituitary adenomas. (These are benign tumors that secrete prolactin. They can cause headache and visual problems as well as breast secretions.) Some drugs, including oral contraceptives and some antipsychotic drugs, can also elevate levels of prolactin.

Medications Used to Treat Hyperprolactemia. Agents known as dopamine agonists are used for women with hyperprolactinemia caused by tumors in the pituitary gland.

  • Bromocriptine (Parlodel), the standard agent, reduces prolactin levels by 70% to 100% and also shrinks tumors. Treatments are given for one to two years then stopped when prolactin levels are normal. Common side effects include nausea, constipation, headache, dizziness, and fatigue. (Dopamine agonists are also used in Parkinson's disease.)
  • Cabergoline (Dostinex), another dopamine agonist, is proving to be more effective than bromocriptine in shrinking tumors and may have fewer side effects. Once ovulation starts, women who want to become pregnant should stop cabergoline one month before attempting conception.

Surgery. Surgery may be needed for women who do not respond to medications or whose tumors are large, but recurrence occurs in as many as 40% of patients within five years.

Premature Ovarian Failure (POF)

Premature ovarian failure (POF) is the early depletion of follicles before age 40, which, in most cases, leads to premature menopause. It affects about 1% of women and is typically preceded by irregular periods, which might continue for years. In this condition, follicle-stimulating hormones (FSH) are elevated, as they are during perimenopause. Premature ovarian failure is a significant cause of infertility and women who have this condition have only a 5% to 10% chance to conceive without fertility treatments.

Causes of Premature Ovarian Failure. There are a number of causes of POF. Often the cause of this disorder or other causes of POF is unknown. In some cases, it may represent an acceleration of the aging process.

The following may conditions may produce POF:

  • Adrenal, pituitary, or thyroid gland deficiencies.
  • Genetic factors related to the X chromosome. A woman needs two functioning X chromosomes for normal reproduction. When one is abnormal, ovarian function fails. The most severe example is Turner's syndrome, a genetic condition, in which one of the two X-chromosomes is missing or malfunctioning. Milder cases of ovarian failure can occur in fragile X syndrome and other rare inherited conditions that cause partial X-chromosome abnormalities.
  • Other genetic factors. Some cases of POF and amenorrhea may be due to other genetic abnormalities. For example, researchers have reported POF in women with genetic defects in the production of growth factors called inhibins, which are produced by the ovaries. As yet, however, investigators have not identified specific genetic factors that might explain many cases of POF.
  • Cancer treatments (radiation, chemotherapy, or both). Women who are undergoing such treatments and who want to become pregnant should ask about assisted reproductive technologies, possibly freezing embryos before their cancer treatments, which gives them the best odds. Ovarian transplantation procedures are under investigation. Investigators are testing a natural hormone called a gonadotropin-releasing hormone analogue that puts women in a temporary pre-pubescent state during chemotherapy and which may preserve fertility in many women.
  • Autoimmunity. Autoimmune diseases, including diabetes type 1, systemic lupus erythematosus, autoimmune hypothyroidism, and autoimmune Addison's disease, are associated with a higher risk for early menopause. Autoimmunity, however, may also play a role in some cases of POF without the presence of specific autoimmune diseases. In such cases, antibodies specifically attack the cells that secrete reproductive hormones thus causing ovarian failure.
  • Other causes: sarcoidoisis, mumps, some sexually transmitted diseases, and tuberculosis. Women with epilepsy are at higher risk for POF.

Managing Premature Ovarian Failure. There is no treatment available that will restore ovarian function in women with premature ovarian failure. Women who wish to be pregnant usually will require in vitro fertilization with donor eggs. Hormone replacement therapy may be used to prevent bone loss and reduce menopause symptoms. Freezing ovarian tissue is under investigation for women who are at risk for premature ovarian failure, such as young women with a genetic history of this condition or those who need to undergo cancer treatments.

Idiopathic Hypogonadotropic Hypogonadism

Idiopathic hypogonadotropic hypogonadism is a rare condition in which follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are underproduced and prevent the development of functional ovaries. There are no other abnormalities in the hypothalamus-pituitary axis (such as tumors or abnormal stress hormones or prolactin). In most cases, the causes of hypergonadotropic hypogonadism are unknown. Genetic factors, including Kallman's syndrome, have been identified in about 20% of these cases.

Structural Problems Causing Obstruction

In some cases, structure problems or scarring in the uterus may prevent menstrual flow. Inborn genital tract abnormalities may also cause primary amenorrhea. Ashermans syndrome, for example, is scarring in the uterus that can cause obstructions and secondary amenorrhea. It may be caused by surgery, repeated injury, or unknown factors. A specific malformation called Mullerian agenesis, in which no vagina or uterus develops, is rare but still causes about 16% of primary amenorrhea cases.

Medical Conditions That Cause Secondary Amenorrhea

Epilepsy. Epilepsy is associated with a number of reproductive disorders that cause amenorrhea, including polycystic ovary syndrome, functional hypothalamic amenorrhea, hyperprolactinemia, and high levels of male hormones. Evidence suggests that any of the following conditions may account for such associations:

  • Brain lesions that cause epilepsy may also affect hormonal production.
  • Drugs that treat epilepsy can affect reproductive hormones in different ways.
  • Complications of epilepsy can cause weight changes that increase the risk for conditions such as polycystic ovary. [SeeWell-Connected Report #44 Epilepsy.]

Thyroid Problems. Thyroid problems, either too much thyroid hormone (hyperthyroidism) or too little (hypothyroidism), can interrupt cycles. Hypothyroidism can result in excess prolactin. Most women with hypothyroidism fail to produce eggs, and they may receive a diagnosis of hypothyroidism for the first time during a fertility evaluation. [SeeWell-Connected Report #38 Hypothyroidism.]

Hypothroidism Click the icon to see an image of hypothyroidism.
Hyperthyroidism Click the icon to see an image of hyperthyroidism.

Celiac Sprue. Celiac sprue is an inability to tolerate gluten, a protein found in wheat, rye, oats, barley, and other grains. Exposure to gluten damages the lining of the intestinal tract. It is also associated with late puberty, early menopause, and amenorrhea. This disorder is now considered more common than previously believed and may even be linked to non-intestinal symptoms, such as depression, discolored teeth, and neurologic problems.

Celiac sprue - foods to avoid Click the icon to see an image about celiac sprue.

Metabolic Syndrome. A set of conditions referred to metabolic syndrome (also called syndrome X) consists of obesity marked by abdominal fat, unhealthy cholesterol levels, high blood pressure, and insulin resistance. Metabolic syndrome is a pre-diabetic condition that is significantly associated with heart disease. A 2002 study also reported that, as with PCOS, women with metabolic syndrome have higher levels of male hormones and are, therefore, at risk for irregular periods and infertility. A 2002 study estimated that 24% of the population now has this condition.

Other Conditions. Cushing's disease, which is a disorder of the adrenal gland, can cause amenorrhea. Other medical conditions associated with delayed puberty and amenorrhea include Crohn's disease, sickle cell disease, HIV, kidney disease, and diabetes.

Other Factors That May Cause or Contribute to Amenorrhea

Stress. Physical and emotional stress may block the release of luteinizing hormone, causing temporary amenorrhea.

Obesity. Obesity is a significant risk factor for amenorrhea, independent of its association with polycystic ovarian syndrome (PCOS). In one 2003 study, overweight women without PCOS were classified in one of five grades, depending on the severity of the obesity. The risk for irregular or absent periods increased two fold with each increase in grade. In this group, amenorrhea was also highly associated with type 2 diabetes and other blood sugar abnormalities.

Normal Causes of Skipped or Irregular Periods

Adolescence. During adolescence, it may take a while for ovulation to occur regularly. In fact, during the first year, 95% of young girls skip about 90 days between periods. (It should be noted, however, that periods occurring less frequently than 90 days might indicate estrogen deficiencies.)

Pregnancy. A woman should always check for pregnancy if her period is unduly late, although any stressful situation, including anxiety over the possibility of pregnancy, can delay a period.

Breastfeeding. When women breastfeed after delivery, menstruation usually stops. (Some nonmenstrual bleeding or spotting may occur during the time she is breastfeeding, usually within two months after delivery.) Even while they are still nursing, most breastfeeding mothers will resume menstruation after six months. In general, the more intensively a baby is breastfed, the later the onset of the mother's period. Two or more consecutive days of bleeding are usually an indicator that periods have returned. (It should be noted, however, that ovulation, and therefore, fertility, can occur before menstruation resumes, although it is less likely within six months of delivery, particularly if the mother is intensively breast feeding.)

Hormonal Contraception. Amenorrhea can occur from hormonal contraceptives, particularly medroxyprogesterone (Depo-Provera). Amenorrhea can occur even months after discontinuing certain contraceptive methods, including oral contraceptive pills (OCs), depo-medroxyprogesterone acetate (Depo-Provera), and levonorgestrel (implant systems). (Women should always check to be sure they aren't pregnant in such cases.)

Perimenopause. In women over 40 who are approaching menopause, ovulation becomes irregular and may even stop for several months and then start up again before ceasing completely at the menopause.

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