Amenorrhea

Amenorrhea is the absence of a menstrual period in a woman of reproductive age.[1] Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding), the latter also forming the basis of a form of contraception known as the lactational amenorrhoea method. Outside the reproductive years, there is absence of menses during childhood and after menopause.

Amenorrhea
Other namesAmenorrhea, amenorrhœa
SpecialtyGynecology

Amenorrhoea is a symptom with many potential causes.[2] Primary amenorrhoea 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. It may be caused by developmental problems, such as the congenital absence of the uterus, failure of the ovary to receive or maintain egg cells, or delay in pubertal development.[3] Secondary amenorrhoea (menstrual 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 six months for women with a history of oligomenorrhoea.[4]

Classification

There are two primary ways to classify amenorrhoea. Types of amenorrhoea are classified as primary or secondary, or based on functional "compartments".[5] The latter classification relates to the hormonal state of the patient that 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.[6] As pubertal changes precede the first period, or menarche, female children 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.[7] Secondary amenorrhoea is where an established menstruation has ceased—for three months in a woman with a history of regular cyclic bleeding, or six 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.[8] 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.
Primary/secondary 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.
Primary
Secondary

Cause

Low body weight

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 Amenorrhoea (FHA) can be caused by stress, weight loss, and/or excessive exercise. 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.[10] The threshold of developing amenorrhoea appears to be dependent on low energy availability rather than absolute weight because a critical minimum amount of stored, easily mobilized energy is necessary to maintain regular menstrual cycles.[11]

Energy imbalance and weight loss can disrupt menstrual cycles through several hormonal mechanisms. Weight loss can cause elevations in the hormone ghrelin which inhibits the hypothalamic-pituitary-ovarial axis.[12] Elevated concentrations of ghrelin alter the amplitude of GnRH pulses, which causes diminished pituitary release of LH and follicle-stimulating hormone (FSH).[13]

Secondary amenorrhea is caused by low levels of the hormone leptin in females with low body weight.[14] Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis.[15] Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing. When a woman is experiencing amenorrhoea, an eating disorder, and osteoporosis together, this is called female athlete triad syndrome.[16] A lack of eating causes amenorrhoea and bone loss leading to osteopenia and sometimes progressing to osteoporosis.[17]

The social effects of amenorrhoea on a person vary significantly. Amenorrhoea is often associated with anorexia nervosa and other eating disorders, which have their own effects. If secondary amenorrhoea 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 amenorrhoea 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 amenorrhoea, a woman is more likely to suffer rapid calcium loss, which in turn can lead to osteoporosis.[18] Increased testosterone levels cause by amenorrhoea may lead to body hair growth and decreased breast size.[19] Increased levels of androgens, especially testosterone, can also lead to ovarian cysts. Some research among amenorrhoeic runners indicates that the loss of menses may be accompanied by a loss of self-esteem.[20]

Drug-induced

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 (COCP) may experience secondary amenorrhoea as a withdrawal symptom.[21] The link is not well understood, as studies have found no difference in hormone levels between women who develop amenorrhoea as a withdrawal symptom following the cessation of COCP use and women who experience secondary amenorrhoea because of other reasons.[22] 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 amenorrhoea in women. Studies show that women are most likely to experience amenorrhoea after 1 year of treatment with continuous OCP use.[23]

The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users.[24][25]

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.[26] 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

Breastfeeding is a common cause of secondary amenorrhoea, and often the condition lasts for over six months.[27] Breastfeeding typically lasts longer than lactational amenorrhoea, and the duration of amenorrhoea varies depending on how often a woman breastfeeds.[28] Lactational amenorrhoea 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 amenorrhoea is 98% percent effective as a method of preventing pregnancy in the first six months postpartum.[29]

Celiac disease

Untreated celiac disease can cause amenorrhea. Reproductive disorders may be the only manifestation of undiagnosed celiac disease and most cases are not recognized. For people with celiac, a gluten-free diet avoids or reduces the risk of developing reproductive disorders.[30][31]

Physical

Amenorrhoea can also be caused by physical deformities. One example of this is MRKH (Mayer–Rokitansky–Küster–Hauser) syndrome, the second-most common cause of primary amenorrhoea.[32] The syndrome is characterized by Müllerian agenesis. In MRKH Syndrome, the Müllerian ducts develop abnormally and can result in vaginal obstructions preventing menstruation. The syndrome develops prenatally early in the development of the female reproductive system.

Stress

Secondary amenorrhea is also caused by stress, extreme weight loss, or 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.[33][34]

Diagnosis

Primary amenorrhoea

Primary amenorrhoea can be diagnosed in female children by age 14 if no secondary sex characteristics, such as enlarged breasts and body hair, are present.[35] In the absence of secondary sex characteristics, the most common cause of amenorrhoea 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 amenorrhoea 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 after puberty (~21 years of age) due to the increased risk of testicular cancer. 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 amenorrhoea cases. If a uterus is present, outflow track obstruction may be to blame for primary amenorrhoea.

Secondary amenorrhea
See also: Functional hypothalamic 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.[36] 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 tract 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, or 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.[33][34]

Treatments

Treatments vary based on the underlying condition.[37] 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, potentially leading to osteoporosis.

"Athletic" amenorrhoea which is part of the female athlete triad is treated by eating more and decreasing the amount and intensity of exercise.[38] If the underlying cause is the athlete triad then a multidisciplinary treatment including monitoring from a physician, dietitian, and mental health counselor is recommended, along with support from family, friends, and coaches. Although oral contraceptives can causes menses to return, oral contraceptives should not be the initial treatment as they can mask the underlying problem and allow other effects of the eating disorder, like osteoporosis, continue to develop.[38] 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 abnormalities of Functional Hypothalamic Amenorrhoea (FHA) related to the condition of stress-related amenorrhoea.[39] 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 metreleptin (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.[40]

History

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.[41]

Etymology

The term is derived from Greek: a = negative, men = month, rhoia = flow. Derived adjectives are amenorrhoeal and amenorrhoeic. The opposite is the normal menstrual period (eumenorrhoea).

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