|Classification and external resources|
Amenorrhoea (BE), amenorrhea (AmE), or amenorrhœa, is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen during pregnancy and lactation (breastfeeding), the latter also forming the basis of a form of contraception known as the lactational amenorrhoea method. Outside of the reproductive years there is absence of menses during childhood and after menopause.
Amenorrhoea is a symptom with many potential causes. Primary amenorrhoea (menstruation cycles never starting) may be caused by developmental problems such as the congenital absence of the uterus, failure of the ovary to receive or maintain egg cells, and genetic diseases such as 5-alpha-reductase deficiency which causes one to be intersex. Also, delay in pubertal development will lead to primary amenorrhoea. It is defined as an absence of secondary sexual characteristics by age 14 with no menarche or normal secondary sexual characteristics but no menarche by 16 years of age. Secondary amenorrhoea (menstruation cycles ceasing) is often caused by hormonal disturbances from the hypothalamus and the pituitary gland, from premature menopause or intrauterine scar formation. It is defined as the absence of menses for three months in a woman with previously normal menstruation or nine months for women with a history of oligomenorrhoea.
In preindustrial societies, menarche typically occurred later than in current industrial societies. After menarche, menstruation was suppressed during much of a woman's reproductive life by either pregnancy or nursing. Reductions in age of menarche and lower fertility rates mean that modern women menstruate far more often than they did under the conditions prevalent for most of human evolutionary history.
There are two primary ways to classify amenorrhoea. Types of amenorrhoea are classified as primary or secondary, or based on functional "compartments". The latter classification relates to the hormonal state of the patient that could be hypo-, eu-, or hypergonadotropic (whereby interruption to the communication between gonads and follicle stimulating hormone (FSH) causes FSH levels to be either low, normal or high).
- By primary vs. secondary: Primary amenorrhoea is the absence of menstruation in a woman by the age of 16. As pubertal changes precede the first period, or menarche, women by the age of 14 who still have not reached menarche, plus having no sign of secondary sexual characteristics, such as thelarche or pubarche—thus are without evidence of initiation of puberty—are also considered as having primary amenorrhoea. Secondary amenorrhoea is where an established menstruation has ceased—for three months in a woman with a history of regular cyclic bleeding, or nine months in a woman with a history of irregular periods. This usually happens to women aged 40–55. However, adolescent athletes are more likely to experience disturbances to the menstrual cycle than athletes of any other age. Amenorrhoea may cause serious pain in the back near the pelvis and spine. This pain has no cure, but can be relieved by a short course of progesterone to trigger menstrual bleeding.
- By compartment: The reproductive axis can be viewed as having four compartments: 1. outflow tract (uterus, cervix, vagina), 2. ovaries, 3. pituitary gland, and 4. hypothalamus. Pituitary and hypothalamic causes are often grouped together.
|P/S||Outflow tract anomalies/obstruction||Gonadal/end-organ disorders||Pituitary and hypothalamic/central regulatory disorders|
|Overview||The hypothalamic-pituitary-ovarian axis is functional.||The ovary or gonad does not respond to pituitary stimulation. Gonadal dysgenesis or premature menopause are possible causes. Chromosome testing is usually indicated in younger individuals with hypergonadotropic amenorrhoea. Low oestrogen levels are seen in these patients and the hypo-oestrogenism may require treatment.||Generally, inadequate levels of FSH lead to inadequately stimulated ovaries which then fail to produce enough oestrogen to stimulate the endometrium (uterine lining), hence amenorrhoea. In general, women with hypogonadotropic amenorrhoea are potentially fertile.|
|FSH||Outflow tract abnormalities tend to be normogonadotropic and FSH levels are in the normal range.||Gonadal, usually ovarian, abnormalities tend to be linked to elevated FSH levels or hypergonadotropic amenorrhoea. FSH levels are typically in the menopausal range.||Both hypothalamic and pituitary disorders are linked to low FSH levels leading to hypogonadotropic amenorrhoea.|
Women who perform considerable amounts of exercise on a regular basis or lose a significant amount of weight are at risk of developing hypothalamic (or 'athletic') amenorrhoea. Functional Hypothalamic Amenorrhea (FHA) can be divided into three categories of cause: stress, weight loss and excessive exercise. It was thought for many years that low body fat levels and exercise related hormones (such as beta endorphins and catecholamines) disrupt the interplay of the sex hormones estrogen and progesterone. However, recent studies have shown that there are no differences in the body composition, or hormonal levels in amenorrhoeic athletes as compared to regularly cycling athletes.
Instead, amenorrhoea has been shown to be directly attributable to low energy availability. Many women who diet or who exercise at a high level do not take in enough calories to expend on their exercise as well as to maintain their normal menstrual cycles. The difference between excersise and weight loss-induced symptoms is difficult to distinguish, as the overall trigger pertains to an insufficient storage of fat, necessary for hormone production.
In both cases, ghrelin acts as a metabolic signal and detects abnormal body weight or unsuitable eating habits, and inhibits the hypothalamic-pituitary-ovarial axis. Elevated concentrations of ghrelin alter the frequency and amplitude of GnRH pulses, which causes diminished pituitary release of LH and follicle-stimulating hormone (FSH), hormones that maintain normal ovulation. The altered interaction between ghrelin and the hypothalamic-pituitary-ovarial axis (also referred to as the hypothalamic-pituitary-gonadal axis) is also responsible for the prolongation of amenorrhea in subjects who have regained normal weight. Women with eating disorders, such as anorexia nervosa are likely to suffer from secondary amenorrhoea. This can be attributed to low levels of the hormone leptin. A critical leptin level is necessary to maintain regular menstrual cycles, and eating disorders decrease the amount of leptin circulating in a woman's body. Like ghrelin, Leptin also acts as a transmitter of energy deficiency, informing the reproductive axis of the body's fat stores. Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing. Thus, women who suffer from FHA but maintain a normal weight experience less severe menstrual irregularities than under-weight amenorrheic patients.
A serious risk associated with amenorrhoea is severe bone loss sometimes resulting in osteoporosis and osteopenia. It is the third component of a syndrome known as female athlete triad. The other two components of this syndrome are osteoporosis and disordered eating. Awareness and intervention can reduce the prevalence and negative health effects in female athletes. Many may not realize that they have a problem until they are trying to conceive and their amenorrhoea leads them to seek the treatment of a reproductive endocrinologist.
Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman. The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping a medication. Hormonal contraceptives that contain only progestogen like the oral contraceptive Micronor, and especially higher-dose formulations like the injectable Depo Provera commonly induce this side-effect. Extended cycle use of combined hormonal contraceptives also allow suppression of menstruation. Patients who use and then cease using contraceptives like the combined oral contraceptive pill may experience secondary amenorrhea as a withdrawal symptom.  The link is not well understood, as studies have found no difference in hormone levels between women who develop amenorrhea as a withdrawal sympton following the cessation of OCOP use and women who experience secondary amenorrhea because of other reasons. New contraceptive pills, like continuous oral contraceptive pills (OCPs) which do not have the normal 7 days of placebo pills in each cycle, have been shown to increase rates of amenorrhea in women. Studies show that women are most likely to experience amenorrhea after 1 year of treatment with continuous OCP use. 
The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users.
Anti-psychotic drugs used to treat schizophrenia have been known to cause amenorrhoea as well. New research suggests that adding a dosage of Metformin to an anti-psychotic drug regimen can restore menstruation. Metformin decreases resistance to the hormone insulin, as well as levels of prolactin, testosterone, and lutenizing hormone (LH). Metformin also decreases the LH/FSH ratio. Results of the study on Metformin further implicate the regulation of these hormones as a main cause of secondary amenorrhoea.
Breastfeeding is a common cause of secondary amenorrhea, and often the condition lasts for over six months.  Breastfeeding typically lasts longer than lactational amenorrhea, and the duration of amenorrhea varies depending on how often a women breastfeeds. Lactational amenorrhea has been advocated as a method of family planning, especially in developing countries where access to other methods of contraception may be limited. Breastfeeding is said to prevent more births in the developing world than any other method of birth control or contraception. Lactational amenorrhea is 98% percent effective as a method of preventing pregnancy in the first six months postpartum.
Amenorrhea can also be caused by physical deformities. One example of this is Mayer–Rokitansky–Küster–Hauser syndrome, the second-most common cause of primary amenorrhea. The syndrome is characterized by Müllerian agenesis. In MRKH Syndrome, the Müllerian ducts do not develop, which prevents menstruation. The syndrome usually develops during the first trimester of pregnancy. MRI techniques can be helpful in determining the extent of the problem. Women may recover from MRKH syndrome, but other times primary amenorrhea, which is characteristic of the disorder, may prevent pregnancy for life.
Diagnosing Primary Amenorrhea
Primary amenorrhea can be diagnosed in women by age 14 if no secondary sex characteristics, such as enlarged breasts and body hair, are present. In the absence of secondary sex characteristics, the most common cause of amenorrhea is low levels of FSH and LH caused by a delay in puberty. Gonadal dysgenesis, often associated with Turner's Syndrome, or premature ovarian failure may also be to blame. If secondary sex characteristics are present, but menstruation is not, primary amenorrhea can be diagnosed by age 16. A reason for this occurrence may be that a person phenotypically female but genetically male, a situation known as androgen insensitivity syndrome. If undescended testes are present, they are often removed because there are health risks associated with their presence. In the absence of undescended testes, an MRI can be used to determine whether or not a uterus is present. Müllerian agenesis causes around 15% of primary amenorrhea cases. If a uterus is present, outflow track obstruction may be to blame for primary amenorrhea.
Diagnosing Secondary Amenorrhea
Secondary amenorrhea's most common and most easily diagnosable causes are pregnancy, thyroid disease, and hyperprolactinemia. A pregnancy test is a common first step for diagnosis. Hyperprolactinemia, characterized by high levels of the hormone prolactin, is often associated with a pituitary tumor. A dopamine agonist can often help relieve symptoms. The subsiding of the causal syndrome is usually enough to restore menses after a few months. Secondary amenorrhea may also be caused by outflow track obstruction, often related to Asherman's Syndrome. Polycystic ovary syndrome can cause secondary amenorrhea, although the link between the two is not well understood. Ovarian failure related to early onset menopause can cause secondary amenorrhea, and although the condition can usually be treated, it is not always reversible. Secondary amenorrhea is also caused by stress, extreme weight loss, and excessive exercise. Young athletes are particularly vulnerable, although normal menses usually return with healthy body weight. Causes of secondary amenorrhea can also result in primary amenorrhea, especially if present before onset of menarche. 
Treatments vary based on the underlying condition. Key issues are problems of surgical correction if appropriate and oestrogen therapy if oestrogen levels are low. For those who do not plan to have biological children, treatment may be unnecessary if the underlying cause of the amenorrhoea is not threatening to their health. However, in the case of athletic amenorrhoea, deficiencies in estrogen and leptin often simultaneously result in bone loss, which can prove highly detrimental to a patients overall bone structure, causing irreversible damage that could correlate to long term infertility.
Unless receiving eggs from an egg donor or in vitro fertilization, a woman is unable to conceive while she is amenorrhoeic. On the other hand, 'athletic' and drug-induced amenorrhoea has no effect on long term fertility as long as menstruation can recommence. The best way to treat 'athletic' amenorrhoea is to decrease the amount and intensity of exercise; but weight recovery, or increased rest does not always catalyze the return of a menses. Recommencement of ovulation suggests a dependency on a whole network of neurotransmitters and hormones, altered in response to the initial triggers of secondary amenorrhoea. To treat drug-induced amenorrhoea, stopping the medication on the advice of a doctor is a usual course of action.
Looking at Hypothalamic amenorrhoea, studies have provided that the administration of a selective serotonin reuptake inhibitor (SSRI) might correct FHA abnormalities related to the condition of stress-related amenorrhea. This involves the repair of the PI3K signaling pathway, which facilitates the integration of metabolic and neural signals regulating gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH). In other words, it regulates the neuronal activity and expression of neuropeptide systems that promote GnRH release. However, SSRI therapy represents a possible hormonal solution to just one hormonal condition of hypothalamic amenorrhoea. Furthermore, because the condition involves the inter workings of many different neurotransmitters, much research is still to be done on presenting hormonal treatment that would counteract the hormonal affects.
As for physiological treatments to hypothalamic amenorrhoea, injections of R-metHuLeptin have been tested as treatment to oestrogen deficiency resulting from low gonadotropins and other neuroendocrine defects such as low concentrations of thyroid and IGF-1. R-metHuLeptin has appeared effective in restoring defects in the hypothalamic-pituitary-gonadal axis and improving reproductive, thyroid, and IGF hormones, as well as bone formation, thus curing the amenorrhoea and infertility. However, it has not proved effective in restoring of cortisol and adrenocorticotropin levels, or bone resorption.
The social effects of amenorrhea on a person vary significantly. Amenorrhea is often associated with anorexia nervosa and other eating disorders, which have their own effects. If secondary amenorrhea is triggered early in life, for example through excessive exercise or weight loss, menarche may not return later in life. A woman in this situation may be unable to become pregnant, even with the help of drugs. Long-term amenorrhea leads to an estrogen deficiency which can bring about menopause at an early age. The hormone estrogen plays a significant role in regulating calcium loss after ages 25-30. When her ovaries no longer produce estrogen because of amenorrhea, a woman is more likely to suffer rapid calcium loss, which in turn can lead to osteoporosis.  Increased testosterone levels cause by amenorrhea may lead to body hair growth and decreased breast size.  Increased levels of androgens, especially testosterone, can also lead to ovarian cysts. Some research among amenorrheic runners indicates that the loss of menses may be accompanied by a loss of self-esteem.
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