Amenorrhea

Amenorrhea is the absence of menstruation. It is normal in girls prior to reaching puberty, in women after menopause, in women who are pregnant or shortly after pregnancy, and in women who are using hormone therapy for birth control. The term amenorrhea is usually used to refer to women who should be having menstrual periods but do not.

Types
There are two types of amenorrhea:

Primary amenorrhea
Primary amenorrhea refers to a woman who has never had a period. Primary amenorrhea is defined as: [1]


 * No menstrual period by age 16 years in the presence of normal breast development
 * No menstrual period by age 14 years in the absence of normal breast development
 * No menstrual period for more than 2 years after the beginning of normal breast development

Secondary amenorrhea
Secondary amenorrhea describes someone who used to have a regular period but then it has stopped.


 * Periods have stopped for at least three months, in a woman whose periods are usually regular.
 * Periods have stopped for at least 6 months, in a woman whose periods are usually irregular.
 * Although pregnancy is often the cause of secondary amenorrhea, if a woman is known to be pregnant, she is usually not referred to as having "secondary amenorrhea."

In addition to the main categories of primary and secondary amenorrhea, the condition of amenorrhea can be further divided into hypogonadotropic and hypergonadotropic amenorrhea, which further categorize the amenorrhea and help determine the cause of the problem. These conditions are also called hypogonadotropic hypogonadism and hypergonadotropic hypogonadism, respectively.

Signs and Symptoms
The main sign of amenorrhea is missing the menstrual period. Other symptoms depend on the cause of the amenorrhea.

Causes
Source: Wikimedia Commons 1 Clitoris 2 Urethra 3 Bladder 4 Fallopian tubes 5 Uterus 6 Vulva 7 Ovaries 8 Vagina 9 Endometrium 10 Labium majora (minora pudendi) 11 Labium 12 Cervix

The causes of amenorrhea depend on whether the amenorrhea is primary or secondary.

Primary amenorrhea
Girls or women with primary amenorrhea can be subdivided into one of two categories: either (1) those with an abnormal body shape, syndrome, or with delayed sexual development, or (2) those with a normal body shape and otherwise normal sexual development.

Primary amenorrhea with delayed sexual development
Chromosomal or genetic abnormalities can cause the eggs and follicles involved in menstruation to deplete too early in life. Some genetic defects have a direct effect on growth, development, and sexual development. Some conditions causing primary amenorrhea:


 * Down syndrome
 * Turner syndrome:[2] A girl with Turner syndrome may have a lack of periods and delayed sexual maturation as the only signs, and the condition may only be diagnosed because of the lack of periods.
 * Prader-Willi syndrome[3][4]
 * Constitutional delay (family history of delayed puberty in the mother or aunts)
 * Chronic diseases and/or malnutrition: In general, any chronic disease that results in the girl being sick for long periods of time, frequent admissions to the ICU, or frequent periods of malnutrition, can result in delayed puberty. Chronic malnutrition, either due to another disease or due to not eating enough, can delay puberty and the onset of periods.
 * Crohn disease[5]
 * Sickle-cell disease and thalassemia, which can cause growth delay and delayed puberty[6]
 * Congenital heart disease
 * Cystic fibrosis, which can delay puberty[7]
 * Leukemia

Primary amenorrhea with otherwise normal sexual development
Hypothalamic or pituitary diseases and problems with the reproductive organs can prevent menstruation from beginning. It is useful to first categorize whether the problem originates from (1) hormones from the hypothalamus or pituitary, or (2) the reproductive organs themselves. A simple blood test can tell these two types of amenorrhea apart.

Hypogonadotropic amenorrhea
Hypogonadotropic amenorrhea means there is a problem in the hypothalamus or pituitary gland. This type of amenorrhea is associated with low levels of sex hormones (FSH, LH, and GnRH). Since these hormones are produced in the pituitary gland (a gland in the brain), and these hormones are regulated in the hypothalamus (a control structure in the brain), this condition is understood to be caused by a defect in the brain rather than a defect in the ovaries or uterus. Also, psychological factors can influence the regulation of the hypothalamus. The ovaries may be normal. The problem lies "above" the level of the ovaries. Some examples:


 * Kallman syndrome: a congenital defect where the nerves that supply the pituitary gland (and also supply the smell receptors) do not migrate to their destination, and so the individual is unable to produce sex hormones from the pituitary gland and is also unable to detect smell.[8]
 * Hypopituitarism: a defect in the pituitary gland where not enough pituitary hormones are produced, including the sex hormones (FSH, LH, and GnRH).

Hypergonadotropic amenorrhea
Refers to a normal hypothalamus and pituitary gland, but abnormal ovaries. If the ovaries do not produce estrogen and progesterone, then the pituitary glands will continue to produce the sex hormones at higher and higher levels to try to compensate. The problem in these cases lie at the level of the ovaries.


 * Ovarian failure, due to the ovaries not developing properly, or in cases where the girl is a hemaphrodite. Ordinarily, a female has two X chromosomes and are "XX". Sex chromosomal abnormalities in females include the following.


 * XO, in the case of Turner syndrome. One X chromosome is missing. Turner syndrome, which is caused by sex chromosomes of XO, presents with short stature, mild mental retardation, poor math skills, poor social skills, webbed neck, delayed puberty, and absence of periods with infertility. Symptoms in Turner syndrome can vary, with some girls appearing normal or simply short for their age. These girls may only be diagnosed when they do not have their periods.
 * XY, the same as the male sex chromosomes, in the case of androgen insensitivity syndrome
 * 1) XX/XY in the case of a mosaic, in which half the cells have the female sex chromosomes and half of them the male sex chromosomes
 * 2) True hermaphroditism
 * 3) XX/XO, a syndrome in which half the cells are normal and half are lacking one X chromosome, as in Turner syndrome.

Structural abnormalities
In some cases, girls can be born with absent or structurally abnormal reproductive organs (vagina, ovaries, uterus or cervix). Amenorrhea is permanent in these conditions.

Secondary amenorrhea
The following are causes of amenorrhea after normal periods have been present at an earlier time:

Hypothalamic causes

 * Weight loss, which could be due to disease, simple dieting, excessive exercise, or anorexia nervosa.
 * Excessive weight gain (obesity). Obesity itself can disrupt the control of sex hormones. Fat cells can change the female hormone estrogen to the male hormone androgen, and a large enough number of fat cells can cause acne, facial hair, and loss of periods. The condition polycystic ovarian syndrome can come about from obesity (although sometimes obesity is not present). Also, obesity can give rise to type 2 diabetes mellitus, which can disrupt menstruation if it is severe and poorly controlled.
 * Excessive exercise. Although exercise is generally healthy, excessive exercise can be associated with amenorrhea. [9] This generally happens if the girl or woman exercises the equivalent of running over 25 miles per week. Participation in other competitive sports, such as basketball, soccer, volleyball, and tennis, can also frequently entail daily, vigorous exercise and running. Furthermore, certain sports and activities, such as cheerleading, gymnastics, and modeling, are associated with high rates of anorexia, as there may be strong social pressure to keep a low body weight.
 * Stress. It is not uncommon for a high stress level to delay menstrual periods or cause a missed period altogether. This was known in one college as "finals-week amenorrhea." Although stress-induced amenorrhea may be short-lived, it may be particularly anxiety-producing, especially in young girls who are otherwise prone to stress and are already in a stressful environment. The possibility of pregnancy may add to the anxiety. In some cases, the stress may continue for a prolonged period and may fit the definition of secondary amenorrhea, lasting 3 months or more. If there is a death of a close friend or relative, bereavement may also delay menstrual periods, as a subtype of stress-induced amenorrhea. Physical stress can result in amenorrhea. Some female soldiers deployed in Iraq *Chronic illness. Any systemic illness may apply stress on the body, resulting in the body's need to conserve strength and resources; this may lead to amenorrhea.
 * Medications (drug-induced amenorrhea). Medications that can cause amenorrhea include oral contraceptives, other medications containing estrogen or progesterone, phenothiazine, or some illicit drugs of abuse.

Pituitary causes

 * Craniopharyngioma, a tumor in the stalk of the pituitary gland. Due to direct damage to the pituitary gland, this tumor results in a lack of production of the hormones LH, FSH, and GnRH, as well as TSH and prolactin. This tumor generally occurs in children between 5 and 10 years of age, and accounts for 9% of all brain tumors in children.
 * Prolactinoma, a prolactin-producing tumor in the pituitary gland. Small prolactinomas have been found in about 10% of normal people, based on autopsy results, but significant prolactinomas are rare, found in only 14 out of 100,000 people. The high levels of the prolactin hormone inhibit the other hormones and the large mass in the pituitary gland also prevents the other hormones from regulating the menstrual cycle.
 * Sheehan syndrome, which is hemorrhage (bleeding) and necrosis (cell death) of the pituitary gland due to the sudden loss of blood and loss of blood pressure during childbirth. This condition occurs only with extreme losses of blood, although milder variants of this condition may be more common than expected. The condition may be mild or severe, temporary or permanent. It can result in *Hypothalamic hamartoma, a blood deposit or mass in the hypothalamus, causing an inability to regulate the pituitary gland. This can result in delayed puberty and amenorrhea, although it can also result in precocious puberty.

Ovarian causes

 * Ovarian failure, or ovaries that once were normal now failing to produce enough estrogen and progesterone to cause menstrual cycles or fertility
 * Radiation to the ovaries can occur in the treatment of some cancers, or may be due to radiation exposure in the environment
 * Surgery: Surgical removal of the ovaries, called oophorectomy, is an obvious cause of the ovaries not functioning. Other surgeries in the general abdominal region may cause adhesions to form and may then cause damage to the ovaries. This would be rare, as both ovaries need to stop functioning in order to produce ovarian failure.
 * Chemotherapy slows or kills the fastest-growing cells in the body, and in young women of reproductive age, this includes the cells of the ovaries. Also, certain chemotherapy agents are known to cause specific damage to the ovaries. The ovarian failure may be temporary, while chemotherapy is actively being taken, or may be permanent.
 * Autoimmune disease: The body may make antibodies that attack the cells of the ovaries, resulting in autoimmune ovarian failure. This is very rare, but may occur in women who already have other autoimmune diseases, such as lupus or Addison's disease.
 * Endometriosis occurs in 5% to 10% of women. Ovarian failure may be due to the complications of endometriosis and the destruction of the ovaries, or it may be due to the surgical removal of the ovaries as a treatment for endometriosis.
 * Polycytic ovarian disease, which is associated with obesity, insulin resistance, glucose intolerance, high levels of LH in relation to FSH, amenorrhea, acne, and hirsutism (excessive body hair growth).

Uterine causes

 * Asherman syndrome, which describes a uterus crisscrossed by scar tissue or adhesions. The syndrome is usually caused by dilation and curettage (D&amp;C), a procedure in which the uterus is cleaned out after complicated miscarriages or elective abortions, in order to remove any remaining portions of placenta, tissue, or fetal matter. The adhesions that sometimes form after this procedure then lead to amenorrhea and infertility.

Hormonal causes

 * Pregnancy: This is the most common cause of secondary amenorrhea, even out of cases where the cause is initially not known. Even if several months have elapsed since the last period, the woman with secondary amenorrhea may have a pregnancy she doesn't know about, as some women may have little weight gain or symptoms of pregnancy in the first few months other than a loss of periods.
 * Lactation amenorrhea occurs normally after childbirth if a woman continues breastfeeding. If a woman breastfeeds regularly and exclusively, she may have her periods delayed for even a year, and on average, about 7 months. This time period also is a natural form of delaying childbirth, as the woman is infertile during this time period.[10] However, the absence of periods can not be wholly relied upon as contraception: the first ovulation occurs 2 weeks before the first menstrual period after childbirth, and a woman could conceive a child even before having her first period after childbirth.
 * Cushing syndrome: High levels of cortisol, as happens in Cushing syndrome, can inhibit menstruation


 * Hyperthyroidism: Hyperthyroidism can decrease, disrupt, or stop menstrual cycles


 * Hypothyroidism: Hypothyroidism can interfere with menstrual cycles, making menstual cycles irregular, and in some cases, can cause amenorrhea. Even if hypothyroidism is found in a particular woman with amenorrhea, care should be taken to ensure that the woman does not have a general lack of pituitary hormone production, as can be seen in a prolactinoma or craniopharyngioma.
 * Androgen excess: Signs of virilization (becoming more male-like) may be seen in androgen excess. This could be due to a tumor that is secreting male sex hormones. This tumor may be in the adrenal glands or in the ovaries. Also to be considered is the actual ingestion of male sex hormones, such as testosterone or androstenedione.

History
A careful menstrual history may give clues about the cause of amenorrhea. Important questions include:


 * Age at first menstrual cycle (menarche)
 * Presence of irregular menstrual periods
 * Fertility history
 * Date of last menstrual cycle
 * Whether there is abdominal pain
 * Whether there is galactorrhea (milky discharge from the breats)
 * Whether there are symptoms of hypothyroidism or hyperthyroidism, including:
 * Feeling hot or cold
 * Changes in the skin or hair
 * Feelings of depression or anxiety
 * Weight loss or weight gain
 * Sexual history
 * Family history, especially for children who have primary amenorrhea

Physical exam
A thourough physical examination is done. Height and weight should be carefully noted. The presence of normal or delayed sexual development should also be noted. Abdominal examination (looking for pain and/or masses in the abdomen) and careful examination of the genitals and secondary sexual characteristics (breast development, pattern of hair growth) are very important, as is looking for signs of other disease (dry skin, abdominal obesity, stretch marks, abnormal facial features or other signs of genetic syndromes).

Testing
The most important test is a pregnancy test, as pregnancy is a common and simple explanation for amenorrhea. Blood testing to determine the levels of sex hormones will immediately divide the causes into categories, where further testing can be done to narrow down the cause.

Blood tests
Some of the blood tests that may be ordered to determine the cause of amenorrhea include: Tests to evaluate pituitary gland and adrenal gland function:


 * FSH (follicle-stimulating hormone)
 * LH (luteinizing hormone)
 * An LH:FSH ratio can also be calculated to help diagnose polycystic ovarian syndrome
 * DHEAS (dehydroepiandrosterone sulfate) (sometimes taken if polycystic ovarian syndrome is suspected)
 * GnRH (gonadotropin releasing hormone)
 * TSH (thyroid stimulating hormone) and thyroid hormones (T3 and T4) check for hypothyroidism and hyperthyroidism
 * Prolactin
 * Estrogen
 * Progesterone
 * β-HCG (pregnancy test) to check for pregnancy, a common cause of amenorrhea, as well as rare ovarian tumors which may also produce β-HCG.
 * Cortisol level if Cushing syndrome is suspected
 * Antibodies to ovarian cells
 * Karyotype (examination of chromosomes) in cases of primary amenorrhea, to check for Turner syndrome (XO), androgen insensitivity (XY), and other forms of abnormal sex organ dvelopment (XX/XY, XX/XO, XXX, XXXX)

Imaging studies

 * Ultrasound of abdomen and pelvis to look for the presence of ovaries and a uterus and to rule out any masses or large cysts
 * CT scan of the head to look for brain tumors and abnormalities of the pituitary gland
 * MRI of the head to look for prolactinoma and pituitary hemorrhage

Other tests

 * Pap smear: Doing a Pap smear of the cervix (the entrance to the uterus) can show whether there is estrogen present. If more than 10% of the cells collected from a Pap smear are of a certain type, then estrogen is present. This can help confirm the function of the ovaries.
 * Ferning of the cervical mucus: Examining the mucus from the cervix (the entrance to the uterus) can show whether estrogen is present. If the mucus dries in such a way that it creates a pattern shaped like a fern, then there is adequate estrogen.
 * Hormone trials: Sometimes, in cases of primary amenorrhea, physicians give sex hormones to see whether a period can be induced. Progesterone is given to determine if the cause of the amenorrhea is simply that the menstrual tissue is building up and has not yet come out. If this does not work, then estrogen can be given over a few days, then progesterone, to induce a period. If this works, then the system of the ovaries and uterus is working.

Treatment
Treatment for amenorrhea depends on the underlying cause. Sometimes lifestyle changes can help if weight, stress, or physical activity is causing the amenorrhea. Other times medications and oral contraceptives can help the problem. In cases of genetic causes, there may not be any treatment. In many cases, treatment of estrogen and progesterone can be given to allow girls and women to have pseudo-periods, for social and psychological benefit, although fertility may not be able to be restored.

If there is no serious underlying cause and there are no other problems, then sometimes the patient is counseled in "acceptance" of the condition and a change in outlook.

Clinical Trials
There are numerous clinical trials related to amenorrhea. A list of American government-sponsored trials recruiting participants is available at ClinicalTrials.gov.

Recent discoveries
Some recent research related to amenorrhea: The U.S. National Institutes of Health (NIH):


 * Published a study in 2002 showing that amenorrhea in young women put them at increased risk of osteoporosis later in life. [11]
 * Discovered a gene that may play a role in premature ovarian failure. [12]

Expected Outcome
The outcome of amenorrhea depends on the cause. Primary amenorrhea is often permanent and will affect fertility. Many causes of secondary infertility can be corrected and regular menses may resume.

Etymology
The word amenorrhea comes from the Greek word a (not) + men (month) and rrhea (flow). The Greek suffix rrhea can be seen in other common words such as diarrhea as well as less common words such as rhinorrhea, galactorrhea, and logorrhea.