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Amenorrhea

Updated: Jan 16



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.

Amenorrhoea is a symptom with many potential causes.[2] Primary amenorrhea 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] Another potential cause for amenorrhea is in the presence of a severe eating disorder, like anorexia nervosa, characterized by food restriction and being underweight. 66–85% of patients with anorexia nervosa present amenorrhea as a symptom.[5] [6]


Classification

There are two primary ways to classify amenorrhoea. Types of amenorrhoea are classified as primary or secondary, or based on functional "compartments".[7] 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.[8] 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.[9] 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.[10] 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.


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.[12] 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.[13]

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.[14] Elevated concentrations of ghrelin alter the amplitude of GnRH pulses, which causes diminished pituitary release of LH and follicle-stimulating hormone (FSH).[15]

Secondary amenorrhea is caused by low levels of the hormone leptin in females with low body weight.[16] Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis.[17] 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.[18] A lack of eating causes amenorrhoea and bone loss leading to osteopenia and sometimes progressing to osteoporosis.[19]

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.[20] Increased testosterone levels cause by amenorrhoea may lead to body hair growth and decreased breast size.[21] 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.[22]


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.[23] 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.[24] 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.[25]

The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users.[26][27]

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.[28] 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.[29] Breastfeeding typically lasts longer than lactational amenorrhoea, and the duration of amenorrhoea varies depending on how often a woman breastfeeds.[30] 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.[31]


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.[32][33]


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.[34] 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.[35][36]


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.[37] 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.[38] 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.[35][36]


Treatments

Treatments vary based on the underlying condition.[39] 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.[40] 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.[40] 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.[41] 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.[42]


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.[43]


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).




Menopause


This article is about women. For the condition called male menopause, see Andropause. For the medical journal, see Menopause (journal).

Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children.[1][7] Menopause typically occurs between 49 and 52 years of age.[2] Medical professionals often define menopause as having occurred when a woman has not had any menstrual bleeding for a year.[3] It may also be defined by a decrease in hormone production by the ovaries.[8] In those who have had surgery to remove their uterus but still have ovaries, menopause may be considered to have occurred at the time of the surgery or when their hormone levels fell.[8] Following the removal of the uterus, symptoms typically occur earlier, at an average of 45 years of age.[9]

In the years before menopause, a woman's periods typically become irregular,[10][11] which means that periods may be longer or shorter in duration or be lighter or heavier in the amount of flow.[10] During this time, women often experience hot flashes; these typically last from 30 seconds to ten minutes and may be associated with shivering, sweating, and reddening of the skin.[10] Hot flashes often stop occurring after a year or two.[7] Other symptoms may include vaginal dryness, trouble sleeping, and mood changes.[10] The severity of symptoms varies between women.[7] While menopause is often thought to be linked to an increase in heart disease, this primarily occurs due to increasing age and does not have a direct relationship with menopause.[7] In some women, problems that were present like endometriosis or painful periods will improve after menopause.[7]

Menopause is usually a natural change.[4] It can occur earlier in those who smoke tobacco.[3][12] Other causes include surgery that removes both ovaries or some types of chemotherapy.[3] At the physiological level, menopause happens because of a decrease in the ovaries' production of the hormones estrogen and progesterone.[1] While typically not needed, a diagnosis of menopause can be confirmed by measuring hormone levels in the blood or urine.[13] Menopause is the opposite of menarche, the time when a girl's periods start.[14]

Specific treatment is not usually needed.[5] Some symptoms, however, may be improved with treatment.[5] With respect to hot flashes, avoiding smoking, caffeine, and alcohol is often recommended.[5] Sleeping in a cool room and using a fan may help.[5] The following medications may help: menopausal hormone therapy (MHT), clonidine, gabapentin, or selective serotonin reuptake inhibitors.[5][6] Exercise may help with sleeping problems.[5] While MHT was once routinely prescribed, it is now only recommended in those with significant symptoms, as there are concerns about side effects.[5] High-quality evidence for the effectiveness of alternative medicine has not been found.[7] There is tentative evidence for phytoestrogens.[15]


Signs and symptoms

Symptoms of menopause

During early menopause transition, the menstrual cycles remain regular but the interval between cycles begins to lengthen. Hormone levels begin to fluctuate. Ovulation may not occur with each cycle.[16]

The term menopause refers to a point in time that follows one year after the last menstruation.[16] During the menopausal transition and after menopause, women can experience a wide range of symptoms.


Vagina and uterus

Size of the vaginal canal before and after menopause, demonstrating vaginal atrophy.

During the transition to menopause, menstrual patterns can show shorter cycling (by 2–7 days);[16] longer cycles remain possible.[16] There may be irregular bleeding (lighter, heavier, spotting).[16] Dysfunctional uterine bleeding is often experienced by women approaching menopause due to the hormonal changes that accompany the menopause transition. Spotting or bleeding may simply be related to vaginal atrophy, a benign sore (polyp or lesion), or may be a functional endometrial response. The European Menopause and Andropause Society has released guidelines for assessment of the endometrium, which is usually the main source of spotting or bleeding.[17]

In post-menopausal women, however, any genital bleeding is an alarming symptom that requires an appropriate study to rule out the possibility of malignant diseases.

Symptoms that may appear during menopause and continue through postmenopause include:

painful intercourse[16]

vaginal dryness[16]

atrophic vaginitis – thinning of the membranes of the vulva, the vagina, the cervix, and the outer urinary tract, along with considerable shrinking and loss in elasticity of all of the outer and inner genital areas.


Other physical

Bone mineral density, especially of the vertebrae, decreases with menopause

Other physical symptoms of menopause include lack of energy, joint soreness, stiffness, back pain, breast enlargement, breast pain, heart palpitations, headache, dizziness, dry, itchy skin, thinning, tingling skin,[16] rosacea,[18] weight gain,[16] urinary incontinence,[16][19] urinary urgency,[16] interrupted sleeping patterns,[16][20][21][22] heavy night sweats,[16] and hot flashes.[16]


Mood and memory effects

Psychological symptoms include anxiety, poor memory, inability to concentrate, depressive mood, irritability, mood swings, and less interest in sexual activity.[16][23]

Menopause-related cognitive impairment can be confused with the mild cognitive impairment that precedes dementia.[24] Tentative evidence has found that forgetfulness affects about half of menopausal women[25] and is probably caused by the effects of declining estrogen levels on the brain,[25] or perhaps by reduced blood flow to the brain during hot flashes.[26]


Long-term effects

Menopause confers:

A possible but contentious increased risk of atherosclerosis.[27] The risk of acute myocardial infarction and other cardiovascular diseases rises sharply after menopause, but the risk can be reduced by managing risk factors, such as tobacco smoking, hypertension, increased blood lipids and body weight.[28][29]

Increased risk of osteopenia, osteoporosis,[30] and accelerated lung function decline.[31][32]

Women who experience menopause before 45 years of age have an increased risk of heart disease,[33] death,[34] and impaired lung function.[31]


Causes

Menopause can be induced or occur naturally. Induced menopause occurs as a result of medical treatment such as chemotherapy, radiotherapy, oophorectomy, or complications of tubal ligation, hysterectomy, unilateral or bilateral salpingo-oophorectomy or leuprorelin usage.[35]


Age

Menopause typically occurs between 49 and 52 years of age.[2] Half of women have their last period between the ages of 47 and 55, while 80% have their last period between 44 and 58.[36] The average age of the last period in the United States is 51 years, in the United Kingdom is 52 years, in Ireland is 50 years and in Australia is 51 years. In India and the Philippines, the median age of natural menopause is considerably earlier, at 44 years.[37] The menopausal transition or perimenopause leading up to menopause usually lasts 7 years (sometimes as long as 14 years).[1][11]

In rare cases, a woman's ovaries stop working at a very early age, ranging anywhere from the age of puberty to age 40. This is known as premature ovarian failure and affects 1 to 2% of women by age 40.[38]

Undiagnosed and untreated coeliac disease is a risk factor for early menopause. Coeliac disease can present with several non-gastrointestinal symptoms, in the absence of gastrointestinal symptoms, and most cases escape timely recognition and go undiagnosed, leading to a risk of long-term complications. A strict gluten-free diet reduces the risk. Women with early diagnosis and treatment of coeliac disease present a normal duration of fertile life span.[39][40]

Women who have undergone hysterectomy with ovary conservation go through menopause on average 3.7 years earlier than the expected age. Other factors that can promote an earlier onset of menopause (usually 1 to 3 years early) are smoking cigarettes or being extremely thin.[41]


Premature ovarian failure

Premature ovarian failure (POF) is when the ovaries stop functioning before the age of 40 years.[42][43] It is diagnosed or confirmed by high blood levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) on at least three occasions at least four weeks apart.[44]

Known causes of premature ovarian failure include autoimmune disorders, thyroid disease, diabetes mellitus, chemotherapy, being a carrier of the fragile X syndrome gene, and radiotherapy.[43] However, in about 50–80% of spontaneous cases of premature ovarian failure, the cause is unknown, i.e., it is generally idiopathic.

Women who have a functional disorder affecting the reproductive system (e.g., endometriosis, polycystic ovary syndrome, cancer of the reproductive organs) can go into menopause at a younger age than the normal timeframe. The functional disorders often significantly speed up the menopausal process.

An early menopause can be related to cigarette smoking, higher body mass index, racial and ethnic factors, illnesses, and the surgical removal of the ovaries, with or without the removal of the uterus.[45]

Rates of premature menopause have been found to be significantly higher in fraternal and identical twins; approximately 5% of twins reach menopause before the age of 40. The reasons for this are not completely understood. Transplants of ovarian tissue between identical twins have been successful in restoring fertility.


Surgical menopause

Menopause can be surgically induced by bilateral oophorectomy (removal of ovaries), which is often, but not always, done in conjunction with removal of the Fallopian tubes (salpingo-oophorectomy) and uterus (hysterectomy).[46] Cessation of menses as a result of removal of the ovaries is called "surgical menopause". Surgical treatments, such as the removal of ovaries, might cause periods to stop altogether.[33] The sudden and complete drop in hormone levels usually produces extreme withdrawal symptoms such as hot flashes, etc. The symptoms of early menopause may be more severe.[33]

Removal of the uterus without removal of the ovaries does not directly cause menopause, although pelvic surgery of this type can often precipitate a somewhat earlier menopause, perhaps because of a compromised blood supply to the ovaries.[citation needed]. The time between surgery and possible early menopause is due to the fact that ovaries are still producing hormones.[33]


Mechanism

Bone loss due to menopause occurs due to changes in a woman's hormone levels.

The menopausal transition, and postmenopause itself, is a natural change, not usually a disease state or a disorder. The main cause of this transition is the natural depletion and aging of the finite amount of oocytes (ovarian reserve). This process is sometimes accelerated by other conditions and is known to occur earlier after a wide range of gynecologic procedures such as hysterectomy (with and without ovariectomy), endometrial ablation and uterine artery embolisation. The depletion of the ovarian reserve causes an increase in circulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels because there are fewer oocytes and follicles responding to these hormones and producing estrogen.

The transition has a variable degree of effects.[47]

The stages of the menopause transition have been classified according to a woman's reported bleeding pattern, supported by changes in the pituitary follicle-stimulating hormone (FSH) levels.[48]

In younger women, during a normal menstrual cycle the ovaries produce estradiol, testosterone and progesterone in a cyclical pattern under the control of FSH and luteinizing hormone (LH), which are both produced by the pituitary gland. During perimenopause (approaching menopause), estradiol levels and patterns of production remain relatively unchanged or may increase compared to young women, but the cycles become frequently shorter or irregular.[49] The often observed increase in estrogen is presumed to be in response to elevated FSH levels that, in turn, is hypothesized to be caused by decreased feedback by inhibin.[50] Similarly, decreased inhibin feedback after hysterectomy is hypothesized to contribute to increased ovarian stimulation and earlier menopause.[51][52]

The menopausal transition is characterized by marked, and often dramatic, variations in FSH and estradiol levels. Because of this, measurements of these hormones are not considered to be reliable guides to a woman's exact menopausal status.[50]

Menopause occurs because of the sharp decrease of estradiol and progesterone production by the ovaries. After menopause, estrogen continues to be produced mostly by aromatase in fat tissues and is produced in small amounts in many other tissues such as ovaries, bone, blood vessels, and the brain where it acts locally.[53] The substantial fall in circulating estradiol levels at menopause impacts many tissues, from brain to skin.

In contrast to the sudden fall in estradiol during menopause, the levels of total and free testosterone, as well as dehydroepiandrosterone sulfate (DHEAS) and androstenedione appear to decline more or less steadily with age. An effect of natural menopause on circulating androgen levels has not been observed.[54] Thus specific tissue effects of natural menopause cannot be attributed to loss of androgenic hormone production.[55]

Hot flashes and other vasomotor symptoms accompany the menopausal transition. While many sources continue to claim that hot flashes during the menopausal transition are caused by low estrogen levels, this assertion was shown incorrect in 1935, and, in most cases, hot flashes are observed despite elevated estrogen levels. The exact cause of these symptoms is not yet understood, possible factors considered are higher and erratic variation of estradiol level during the cycle, elevated FSH levels which may indicate hypothalamic dysregulation perhaps caused by missing feedback by inhibin. It has been also observed that the vasomotor symptoms differ during early perimenopause and late menopausal transition and it is possible that they are caused by a different mechanism.[49]

Long-term effects of menopause may include osteoporosis, vaginal atrophy as well as changed metabolic profile resulting in cardiac risks.


Ovarian aging

Decreased inhibin feedback after hysterectomy is hypothesized to contribute to increased ovarian stimulation and earlier menopause. Hastened ovarian aging has been observed after endometrial ablation. While it is difficult to prove that these surgeries are causative, it has been hypothesized that the endometrium may be producing endocrine factors contributing to the endocrine feedback and regulation of the ovarian stimulation. Elimination of these factors contributes to faster depletion of the ovarian reserve. Reduced blood supply to the ovaries that may occur as a consequence of hysterectomy and uterine artery embolisation has been hypothesized to contribute to this effect.[51][52]

Impaired DNA repair mechanisms may contribute to earlier depletion of the ovarian reserve during aging.[56] As women age, double-strand breaks accumulate in the DNA of their primordial follicles. Primordial follicles are immature primary oocytes surrounded by a single layer of granulosa cells. An enzyme system is present in oocytes that ordinarily accurately repairs DNA double-strand breaks. This repair system is called "homologous recombinational repair", and it is especially effective during meiosis. Meiosis is the general process by which germ cells are formed in all sexual eukaryotes; it appears to be an adaptation for efficiently removing damages in germ line DNA.[57]

Human primary oocytes are present at an intermediate stage of meiosis, termed prophase I (see Oogenesis). Expression of four key DNA repair genes that are necessary for homologous recombinational repair during meiosis (BRCA1, MRE11, Rad51, and ATM) decline with age in oocytes.[56] This age-related decline in ability to repair DNA double-strand damages can account for the accumulation of these damages, that then likely contributes to the depletion of the ovarian reserve.


Diagnosis

Ways of assessing the impact on women of some of these menopause effects, include the Greene climacteric scale questionnaire,[58] the Cervantes scale[59] and the Menopause rating scale.[20]


Premenopause

Premenopause is a term used to mean the years leading up to the last period, when the levels of reproductive hormones are becoming more variable and lower, and the effects of hormone withdrawal are present.[46] Premenopause starts some time before the monthly cycles become noticeably irregular in timing.[60]


Perimenopause

The term "perimenopause", which literally means "around the menopause", refers to the menopause transition years before the date of the final episode of flow.[1][11][61][62] According to the North American Menopause Society, this transition can last for four to eight years.[63] The Centre for Menstrual Cycle and Ovulation Research describes it as a six- to ten-year phase ending 12 months after the last menstrual period.[64]

During perimenopause, estrogen levels average about 20–30% higher than during premenopause, often with wide fluctuations.[64] These fluctuations cause many of the physical changes during perimenopause as well as menopause, especially during the last 1–2 years of perimenopause (before menopause).[61][65] Some of these changes are hot flashes, night sweats, difficulty sleeping, mood swings, vaginal dryness or atrophy, incontinence, osteoporosis, and heart disease.[64] During this period, fertility diminishes but is not considered to reach zero until the official date of menopause. The official date is determined retroactively, once 12 months have passed after the last appearance of menstrual blood.

The menopause transition typically begins between 40 and 50 years of age (average 47.5).[66][67] The duration of perimenopause may be for up to eight years.[67] Women will often, but not always, start these transitions (perimenopause and menopause) about the same time as their mother did.[68]

In some women, menopause may bring about a sense of loss related to the end of fertility. In addition, this change often occurs when other stressors may be present in a woman's life:

Caring for, and/or the death of, elderly parents

Empty nest syndrome when children leave home

The birth of grandchildren, which places people of "middle age" into a new category of "older people" (especially in cultures where being older is a state that is looked down on)

Some research appears to show that melatonin supplementation in perimenopausal women can improve thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing depression associated with menopause.[69]


Postmenopause

The term "postmenopausal" describes women who have not experienced any menstrual flow for a minimum of 12 months, assuming that they have a uterus and are not pregnant or lactating.[46] In women without a uterus, menopause or postmenopause can be identified by a blood test showing a very high FSH level. Thus postmenopause is the time in a woman's life that takes place after her last period or, more accurately, after the point when her ovaries become inactive.

The reason for this delay in declaring postmenopause is because periods are usually erratic at this time of life. Therefore, a reasonably long stretch of time is necessary to be sure that the cycling has ceased. At this point a woman is considered infertile; however, the possibility of becoming pregnant has usually been very low (but not quite zero) for a number of years before this point is reached.

A woman's reproductive hormone levels continue to drop and fluctuate for some time into post-menopause, so hormone withdrawal effects such as hot flashes may take several years to disappear.

A period-like flow during postmenopause, even spotting, may be a sign of endometrial cancer.


Management

Perimenopause is a natural stage of life. It is not a disease or a disorder. Therefore, it does not automatically require any kind of medical treatment. However, in those cases where the physical, mental, and emotional effects of perimenopause are strong enough that they significantly disrupt the life of the woman experiencing them, palliative medical therapy may sometimes be appropriate.


Hormone replacement therapy

Main article: Hormone replacement therapy (menopause)

In the context of the menopause, hormone replacement therapy (HRT) is the use of estrogen in women without a uterus and estrogen plus progestin in women who have an intact uterus.[70]

HRT may be reasonable for the treatment of menopausal symptoms, such as hot flashes.[71] It is the most effective treatment option, especially when delivered as a skin patch.[72][73] Its use, however, appears to increase the risk of strokes and blood clots.[74] When used for menopausal symptoms some recommend it be used for the shortest time possible and at the lowest dose possible.[74] Evidence to support long-term use, however, is poor.[72]

It also appears effective for preventing bone loss and osteoporotic fracture,[75] but it is generally recommended only for women at significant risk for whom other therapies are unsuitable.[76]

HRT may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer.[76] There is some concern that this treatment increases the risk of breast cancer.[77]

Adding testosterone to hormone therapy has a positive effect on sexual function in postmenopausal women, although it may be accompanied by hair growth, acne and a reduction in high-density lipoprotein (HDL) cholesterol.[78] These side effects diverge depending on the doses and methods of using testosterone.[78]


Selective estrogen receptor modulators

SERMs are a category of drugs, either synthetically produced or derived from a botanical source, that act selectively as agonists or antagonists on the estrogen receptors throughout the body. The most commonly prescribed SERMs are raloxifene and tamoxifen. Raloxifene exhibits oestrogen agonist activity on bone and lipids, and antagonist activity on breast and the endometrium.[79] Tamoxifen is in widespread use for treatment of hormone sensitive breast cancer. Raloxifene prevents vertebral fractures in postmenopausal, osteoporotic women and reduces the risk of invasive breast cancer.[80]


Other medications

Some of the SSRIs and SNRIs appear to provide some relief from vasomotor symptoms.[6] Low dose paroxetine is the only non-hormonal medication that was FDA-approved to treat moderate-to-severe vasomotor symptoms associated with menopause as of 2016.[81][82] They may, however, be associated with appetite and sleeping problems, constipation and nausea.[6][83]

Gabapentin or clonidine may help but do not work as well as hormone therapy.[6] Gabapentin can decrease the amount of hot flashes. Side effects associated with its use include drowsiness and headaches. Clonidine is used to improve vasomotor symptoms and may be associated with constipation, dizziness, nausea and sleeping problems.[6][83]


Therapy

One review found mindfulness and cognitive behavioural therapy decreases the amount women are affected by hot flushes.[84] Another review found not enough evidence to make a conclusion.[85] A 2018 study found that 85% of study participants reported reduced hot flashes and night sweats when using a climate control system in their beds.[86]


Exercise

Exercise has been thought to reduce postmenopausal symptoms through the increase of endorphin levels, which decrease as estrogen production decreases.[87] Additionally, high BMI is a risk factor for vasomotor symptoms in particular. However, there is insufficient evidence to support the benefits of weight loss for symptom management.[88] There are mixed perspectives on the benefits of physical exercise. While one review found that there was a lack of quality evidence supporting a benefit of exercise,[87] another review recommended regular healthy exercise to reduce comorbidities, improve mood and anxiety symptoms, enhance cognition, and decrease the risk of fractures.[89] Yoga may help with postmenopausal symptoms similar to other exercise.[90] There is insufficient evidence to suggest that relaxation techniques reduce menopausal symptoms.[91]


Alternative medicine

There is no evidence of consistent benefit of alternative therapies for menopausal symptoms despite their popularity.[92]

The effect of soy isoflavones on menopausal symptoms is promising for reduction of hot flashes and vaginal dryness.[15][93] Evidence does not support a benefit from phytoestrogens such as coumestrol,[94] femarelle,[95] or the non-phytoestrogen black cohosh.[15][96] As of 2011 there is no support for herbal or dietary supplements in the prevention or treatment of the mental changes that occur around menopause.[97]

Hypnosis may reduce the severity of hot flashes. In addition, relaxation training with at-home relaxation audiotapes such as deep breathing, paced respiration, and guided imagery may have positive effects on relaxing muscles and reducing stress.[98]

There is no evidence to support the efficacy of acupuncture as a management for menopausal symptoms.[99][92] A 2016 Cochrane review found not enough evidence to show a difference between Chinese herbal medicine and placebo for the vasomotor symptoms.[100]


Other efforts

Lack of lubrication is a common problem during and after perimenopause. Vaginal moisturizers can help women with overall dryness, and lubricants can help with lubrication difficulties that may be present during intercourse. It is worth pointing out that moisturizers and lubricants are different products for different issues: some women complain that their genitalia are uncomfortably dry all the time, and they may do better with moisturizers. Those who need only lubricants do well using them only during intercourse.

Low-dose prescription vaginal estrogen products such as estrogen creams are generally a safe way to use estrogen topically, to help vaginal thinning and dryness problems (see vaginal atrophy) while only minimally increasing the levels of estrogen in the bloodstream.

In terms of managing hot flashes, lifestyle measures such as drinking cold liquids, staying in cool rooms, using fans, removing excess clothing, and avoiding hot flash triggers such as hot drinks, spicy foods, etc., may partially supplement (or even obviate) the use of medications for some women.

Individual counseling or support groups can sometimes be helpful to handle sad, depressed, anxious or confused feelings women may be having as they pass through what can be for some a very challenging transition time.

Osteoporosis can be minimized by smoking cessation, adequate vitamin D intake and regular weight-bearing exercise. The bisphosphonate drug alendronate may decrease the risk of a fracture, in women that have both bone loss and a previous fracture and less so for those with just osteoporosis.[101]

A surgical procedure where a part of one of the ovaries is removed earlier in life and frozen and then over time thawed and returned to the body has been tried. While at least 11 women have undergone the procedure and paid over £6,000, there is no evidence it is safe or effective.[102]


Society and culture

The cultural context within which a woman lives can have a significant impact on the way she experiences the menopausal transition. Menopause has been described as a subjective experience, with social and cultural factors playing a prominent role in the way menopause is experienced and perceived.

The word menopause was invented by French doctors at the beginning of the nineteenth century. Some of them noted that peasant women had no complaints about the end of menses, while urban middle-class women had many troubling symptoms. Doctors at this time considered the symptoms to be the result of urban lifestyles of sedentary behaviour, alcohol consumption, too much time indoors, and over-eating, with a lack of fresh fruit and vegetables.[103] Within the United States, social location affects the way women perceive menopause and its related biological effects. Research indicates that whether a woman views menopause as a medical issue or an expected life change is correlated with her socio-economic status.[104] The paradigm within which a woman considers menopause influences the way she views it: Women who understand menopause as a medical condition rate it significantly more negatively than those who view it as a life transition or a symbol of aging.[105]

Ethnicity and geography play roles in the experience of menopause. American women of different ethnicities report significantly different types of menopausal effects. One major study found Caucasian women most likely to report what are sometimes described as psychosomatic symptoms, while African-American women were more likely to report vasomotor symptoms.[106]

It seems that Japanese women experience menopause effects, or konenki, in a different way from American women.[107] Japanese women report lower rates of hot flashes and night sweats; this can be attributed to a variety of factors, both biological and social. Historically, konenki was associated with wealthy middle-class housewives in Japan, i.e., it was a "luxury disease" that women from traditional, inter-generational rural households did not report. Menopause in Japan was viewed as a symptom of the inevitable process of aging, rather than a "revolutionary transition", or a "deficiency disease" in need of management.[107]

In Japanese culture, reporting of vasomotor symptoms has been on the increase, with research conducted by Melissa Melby in 2005 finding that of 140 Japanese participants, hot flashes were prevalent in 22.1%.[108] This was almost double that of 20 years prior.[109] Whilst the exact cause for this is unknown, possible contributing factors include significant dietary changes, increased medicalisation of middle-aged women and increased media attention on the subject.[109] However, reporting of vasomotor symptoms is still significantly lower than North America.[110]

Additionally, while most women in the United States apparently have a negative view of menopause as a time of deterioration or decline, some studies seem to indicate that women from some Asian cultures have an understanding of menopause that focuses on a sense of liberation and celebrates the freedom from the risk of pregnancy.[111] Diverging from these conclusions, one study appeared to show that many American women "experience this time as one of liberation and self-actualization".[112]


Etymology

Menopause literally means the "end of monthly cycles" (the end of monthly periods or menstruation), from the Greek word pausis ("pause") and mēn ("month"). This is a medical calque; the Greek word for menses is actually different. In Ancient Greek, the menses were described in the plural, ta emmēnia, ("the monthlies"), and its modern descendant has been clipped to ta emmēna. The Modern Greek medical term is emmenopausis in Katharevousa or emmenopausi in Demotic Greek.

The word "menopause" was coined specifically for human females, where the end of fertility is traditionally indicated by the permanent stopping of monthly menstruations. However, menopause exists in some other animals, many of which do not have monthly menstruation;[113] in this case, the term means a natural end to fertility that occurs before the end of the natural lifespan.


Evolutionary rationale

See also: Disposable soma theory of aging and Patriarch hypothesis

Few animals have a menopause: humans are joined by just four other species in which females live substantially longer than their ability to reproduce. The others are all cetaceans: beluga whales, narwhals, killer whales and short-finned pilot whales.[114] Various theories have been suggested that attempt to suggest evolutionary benefits to the human species stemming from the cessation of women's reproductive capability before the end of their natural lifespan. Explanations can be categorized as adaptive and non-adaptive:


Non-adaptive hypotheses

The high cost of female investment in offspring may lead to physiological deteriorations that amplify susceptibility to becoming infertile. This hypothesis suggests the reproductive lifespan in humans has been optimized, but it has proven more difficult in females and thus their reproductive span is shorter. If this hypothesis were true, however, age at menopause should be negatively correlated with reproductive effort,[115] and the available data do not support this.[116]

A recent increase in female longevity due to improvements in the standard of living and social care has also been suggested.[117] It is difficult for selection, however, to favor aid to offspring from parents and grandparents.[118] Irrespective of living standards, adaptive responses are limited by physiological mechanisms. In other words, senescence is programmed and regulated by specific genes.[119]


Early human selection shadow

While it is fairly common for extant hunter-gatherers to live past age 50 provided that they survive childhood, fossil evidence shows that mortality in adults has decreased over the last 30,000 to 50,000 years and that it was extremely unusual for early Homo sapiens to live to age 50. This discovery has led some biologists to argue that there was no selection for or against menopause at the time at which the ancestor of all modern humans lived in Africa, suggesting that menopause is instead a random evolutionary effect of a selection shadow regarding aging in early Homo sapiens. It is also argued that since the population fraction of post-menopausal women in early Homo sapiens was so low, menopause had no evolutionary effect on mate selection or social behaviors related to mate selection.[120][121]


Adaptive hypotheses


"Survival of the fittest" hypothesis

This hypothesis suggests that younger mothers and offspring under their care will fare better in a difficult and predatory environment because a younger mother will be stronger and more agile in providing protection and sustenance for herself and a nursing baby. The various biological factors associated with menopause had the effect of male members of the species investing their effort with the most viable of potential female mates.[122][page needed] One problem with this hypothesis is that we would expect to see menopause exhibited in the animal kingdom,[113] and another problem is that in the case of extended child development, even a female who was relatively young, still agile, and attractive when producing a child would lose future support from her male partner due to him seeking out fertile mates when she reaches menopause while the child is still not independent. That would be counterproductive to the supposed adaptation of getting male support as a fertile female and ruin survival for children produced over much of the female's fertile and agile life, unless children were raised in ways that did not rely on support from a male partner which would eliminate that type of resource diverting selection anyway.[123][124]


Young female preference hypothesis

The young female preference hypothesis proposes that changes in male preferences for younger mates allowed late-age acting fertility mutations to accumulate in females without any evolutionary penalty, giving rise to menopause. A computer model was constructed to test this hypothesis, and showed that it was feasible.[125] However, in order for deleterious mutations that affect fertility past roughly age fifty to accumulate, human maximum lifespan had to first be extended to about its present value. As of 2016 it was unclear if there has been sufficient time since that happened for such an evolutionary process to occur.[126]


Male-biased philopatry hypothesis

The male-biased philopatry theory proposes that male-biased philopatry in social species leads to increased relatedness to the group in relation to female age, making inclusive fitness benefits older females receive from helping the group greater than what they would receive from continued reproduction, which eventually led to the evolution of menopause.[127] In a pattern of male-biased dispersal and local mating, the relatedness of the individuals in the group decreases with female age, leading to a decrease in kin selection with female age.[127] This occurs because a female will stay with her father in her natal group throughout life, initially being closely related to the males and females. Females are born and stay in the group, so relatedness to the females stays about the same. However, throughout time, the older male relatives will die and any sons she gives birth to will disperse, so that local relatedness to males, and therefore the whole group, declines. The situation is reversed in species where males are philopatric and either females disperse, or mating is non-local.[127] Under these conditions, a female's reproductive life begins away from her father and paternal relatives because she was either born into a new group from non-local mating or because she dispersed. In the case of female-biased dispersal, the female is initially equally unrelated with every individual in the group, and with non-local mating, the female is closely related to the females of the group, but not the males since her paternal relatives are in another group. As she gives birth, her sons will stay with her, increasing her relatedness to males in the group over time and thus her relatedness with the overall group. The common feature that connects these two otherwise different behaviors is male-biased philopatry, which leads to an increase in kin selection with female age.

While not conclusive, evidence does exist to support the idea that female-biased dispersal existed in pre-modern humans. The closest living relatives to humans, chimpanzees, bonobos, and both mountain gorillas and western lowland gorillas, are female-biased dispersers.[128] Analysis of sex specific genetic material, the non-recombining portions of the Y chromosome and mitochondrial DNA, show evidence of a prevalence of female-biased dispersal as well; however, these results could also be affected by the effective breeding numbers of males and females in local populations.[129] Evidence of female-biased dispersion in hunter-gatherers is not definitive, with some studies supporting the idea,[128] and others suggesting there is no strong bias towards either sex.[130] In killer whales, both sexes mate non-locally with members of a different pod but return to the pod after copulation.[131] Demographic data shows that a female's mean relatedness to the group does increase over time due to increasing relatedness to males.[132] While less well-studied, there is evidence that short-finned pilot whales, another menopausal species, also display this behavior.[133] However, mating behavior that increases local relatedness with female age is prevalent in non-menopausal species,[128] making it unlikely that it is the only factor that determines if menopause will evolve in a species.


Mother hypothesis

The mother hypothesis suggests that menopause was selected for humans because of the extended development period of human offspring and high costs of reproduction so that mothers gain an advantage in reproductive fitness by redirecting their effort from new offspring with a low survival chance to existing children with a higher survival chance.[134]


Grandmother hypothesis

The grandmother hypothesis suggests that menopause was selected for humans because it promotes the survival of grandchildren. According to this hypothesis, post-reproductive women feed and care for children, adult nursing daughters, and grandchildren whose mothers have weaned them. Human babies require large and steady supplies of glucose to feed the growing brain. In infants in the first year of life, the brain consumes 60% of all calories, so both babies and their mothers require a dependable food supply. Some evidence suggests that hunters contribute less than half the total food budget of most hunter-gatherer societies, and often much less than half, so that foraging grandmothers can contribute substantially to the survival of grandchildren at times when mothers and fathers are unable to gather enough food for all of their children. In general, selection operates most powerfully during times of famine or other privation. So although grandmothers might not be necessary during good times, many grandchildren cannot survive without them during times of famine.

Post-reproductive female killer whales tend to lead their pods, especially during years of food scarcity.[135] Furthermore, the increased mortality risk of a killer whale individual due to losing a grandmother is stronger in years food scarcity[136]

Analysis of historical data found that the length of a female's post-reproductive lifespan was reflected in the reproductive success of her offspring and the survival of her grandchildren.[137] Another study found comparative effects but only in the maternal grandmother—paternal grandmothers had a detrimental effect on infant mortality (probably due to paternity uncertainty).[138] Differing assistance strategies for maternal and paternal grandmothers have also been demonstrated. Maternal grandmothers concentrate on offspring survival, whereas paternal grandmothers increase birth rates.[139]

Some believe variations on the mother, or grandmother effect fail to explain longevity with continued spermatogenesis in males (oldest verified paternity is 94 years, 35 years beyond the oldest documented birth attributed to females).[140] Notably, the survival time past menopause is roughly the same as the maturation time for a human child. That a mother's presence could aid in the survival of a developing child, while an unidentified father's absence might not have affected survival, could explain the paternal fertility near the end of the father's lifespan.[141] A man with no certainty of which children are his may merely attempt to father additional children, with support of existing children present but small. Note the existence of partible paternity supporting this.[142] Some argue that the mother and grandmother hypotheses fail to explain the detrimental effects of losing ovarian follicular activity, such as osteoporosis, osteoarthritis, Alzheimer's disease and coronary artery disease.[143]

The theories discussed above assume that evolution directly selected for menopause. Another theory states that menopause is the byproduct of the evolutionary selection for follicular atresia, a factor that causes menopause. Menopause results from having too few ovarian follicles to produce enough estrogen to maintain the ovarian-pituitary-hypothalamic loop, which results in the cessation of menses and the beginning of menopause. Human females are born with approximately a million oocytes, and approximately 400 oocytes are lost to ovulation throughout life.[144][145]


Reproductive conflict hypothesis

In social vertebrates, the sharing of resources among the group places limits on how many offspring can be produced and supported by members of the group. This creates a situation in which each female must compete with others of the group to ensure they are the one that reproduces.[146] The reproductive conflict hypothesis proposes that this female reproductive conflict favors the cessation of female reproductive potential in older age to avoid reproductive conflict, increasing the older female's fitness through inclusive benefits. Female-biased dispersal or non-local mating leads to an increase in relatedness to the social group with female age.[127] In the human case of female-biased dispersal, when a young female enters a new group, she is not related to any individual and she reproduces to produce an offspring with a relatedness of 0.5. An older female could also choose to reproduce, producing an offspring with a relatedness of 0.5, or she could refrain from reproducing and allow another pair to reproduce. Because her relatedness to males in the group is high, there is a fair probability that the offspring will be her grandchild with a relatedness of 0.25. The younger female experiences no cost to her inclusive fitness from using the resources necessary to successfully rear offspring since she is not related to members of the group, but there is a cost for the older female. As a result, the younger female has the advantage in reproductive competition. Although a female killer whale born into a social group is related to some members of the group, the whale case of non-local mating leads to similar outcomes because the younger female relatedness to the group as a whole is less than the relatedness of the older female. This behavior makes more likely the cessation of reproduction late in life to avoid reproductive conflict with younger females.

Research using both human and killer whale demographic data has been published that supports the role of reproductive conflict in the evolution of menopause. Analysis of demographic data from pre-industrial Finnish populations found significant reductions in offspring survivorship when mothers-in-laws and daughters-in-laws had overlapping births,[147] supporting the idea that avoiding reproductive conflict is beneficial to offspring survivorship. Humans, more so than other primates, rely on food sharing for survival,[148] so the large survivorship reduction values could be caused by a straining of community resources. Avoiding such straining is a possible explanation for why the reproductive overlap seen in humans is much lower than other primates.[149] Food sharing is also prevalent among another menopausal species, killer whales.[150] Reproductive conflict has also been observed in killer whales, with increased calf mortality seen when reproductive overlap between a younger and older generational female occurred.[132]


Other animals

Menopause in the animal kingdom appears to be uncommon, but the presence of this phenomenon in different species has not been thoroughly researched. Life histories show a varying degree of senescence; rapid senescing organisms (e.g., Pacific salmon and annual plants) do not have a post-reproductive life-stage. Gradual senescence is exhibited by all placental mammalian life histories.

Menopause has been observed in several species of nonhuman primates,[113] including rhesus monkeys[151] and chimpanzees.[152] Some research suggests that wild chimpanzees do not experience menopause, as their fertility declines are associated with declines in overall health.[153] Menopause also has been reported in a variety of other vertebrate species including elephants,[154] short-finned pilot whales,[155] killer whales,[156] narwhals,[157] beluga whales,[157] and the guppy.[158]However, with the exception of the short-finned pilot whale, killer whale, narwhals, and beluga whales,[157] such examples tend to be from captive individuals, and thus they are not necessarily representative of what happens in natural populations in the wild.

Dogs do not experience menopause; the canine estrus cycle simply becomes irregular and infrequent. Although older female dogs are not considered good candidates for breeding, offspring have been produced by older animals.[159] Similar observations have been made in cats.[160]




Anorexia nervosa


"Anorexia" and "Anorexic" redirect here. For lack of appetite, see Anorexia (symptom). For the medication, see Anorectic. For other uses, see Anorexia (disambiguation).

Anorexia nervosa, often referred to simply as anorexia,[11] is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin.[1] Anorexia is a term of Greek origin: an- (ἀν-, prefix denoting negation) and orexis (ὄρεξις, "appetite"), translating literally to "a loss of appetite"; the adjective nervosa indicating the functional and non-organic nature of the disorder. Anorexia nervosa was coined by Gull in 1873 but, despite literal translation, the symptom of hunger is frequently present and the pathological control of this instinct is a source of satisfaction for the patients.

Patients with anorexia nervosa commonly see themselves as overweight, although they are in fact underweight.[1][2] The DSM-5 describes this perceptual symptom as "disturbance in the way in which one's body weight or shape is experienced".[7] In research and clinical settings, this symptom is called "body image disturbance".[12] Patients with anorexia nervosa also often deny that they have a problem with low weight.[3] They may weigh themselves frequently, eat small amounts, and only eat certain foods.[1] Some exercise excessively, force themselves to vomit (in the "anorexia purging" subtype), or use laxatives to lose weight and control body shapes.[1] Medical complications may include osteoporosis, infertility, and heart damage, among others.[1] Women will often stop having menstrual periods.[3] In extreme cases, patients with anorexia nervosa who continually refuse significant dietary intake and weight restoration interventions, and are declared incompetent to make decisions by a psychiatrist, may be fed by force under restraint via nasogastric tube[13] after asking their parents or proxies[14] to make the decision for them.[15]

The cause of anorexia is currently unknown.[2] There appear to be some genetic components with identical twins more often affected than fraternal twins.[2] Cultural factors also appear to play a role, with societies that value thinness having higher rates of the disease.[3] Additionally, it occurs more commonly among those involved in activities that value thinness, such as high-level athletics, modeling, and dancing.[3][4] Anorexia often begins following a major life-change or stress-inducing event.[3] The diagnosis requires a significantly low weight[3] and the severity of disease is based on body mass index (BMI) in adults with mild disease having a BMI of greater than 17, moderate a BMI of 16 to 17, severe a BMI of 15 to 16, and extreme a BMI less than 15.[3] In children, a BMI for age percentile of less than the 5th percentile is often used.[3]

Treatment of anorexia involves restoring the patient back to a healthy weight, treating their underlying psychological problems, and addressing behaviors that promote the problem.[1] While medications do not help with weight gain, they may be used to help with associated anxiety or depression.[1] Different therapy methods may be useful, such as cognitive behavioral therapy or an approach where parents assume responsibility for feeding their child, known as Maudsley family therapy.[1][16] Sometimes people require admission to a hospital to restore weight.[7] Evidence for benefit from nasogastric tube feeding is unclear;[17] such an intervention may be highly distressing for both anorexia patients and healthcare staff when administered against the patient's will under restraint.[13] Some people with anorexia will have a single episode and recover while others may have recurring episodes over years.[7] Many complications improve or resolve with the regaining of weight.[7]

Globally, anorexia is estimated to affect 2.9 million people as of 2015.[9] It is estimated to occur in 0.9% to 4.3% of women and 0.2% to 0.3% of men in Western countries at some point in their life.[18] About 0.4% of young women are affected in a given year and it is estimated to occur ten times more commonly among women than men.[3][18] Rates in most of the developing world are unclear.[3] Often it begins during the teen years or young adulthood.[1] While anorexia became more commonly diagnosed during the 20th century it is unclear if this was due to an increase in its frequency or simply better diagnosis.[2] In 2013, it directly resulted in about 600 deaths globally, up from 400 deaths in 1990.[19] Eating disorders also increase a person's risk of death from a wide range of other causes, including suicide.[1][18] About 5% of people with anorexia die from complications over a ten-year period, a nearly six times increased risk.[3][8] The term "anorexia nervosa" was first used in 1873 by William Gull to describe this condition.[20]

In recent years, evolutionary psychiatry as an emerging scientific discipline has been studying mental disorders from an evolutionary perspective. It is still debated whether eating disorders such as anorexia have evolutionary functions or if they are problems resulting from a modern lifestyle.[21][22][23]


Signs and symptoms

The back of a person with anorexia

Anorexia nervosa is an eating disorder characterized by attempts to lose weight to the point of starvation. A person with anorexia nervosa may exhibit a number of signs and symptoms, the type and severity of which may vary and be present but not readily apparent.[24]

Anorexia nervosa, and the associated malnutrition that results from self-imposed starvation, can cause complications in every major organ system in the body.[25] Hypokalaemia, a drop in the level of potassium in the blood, is a sign of anorexia nervosa.[26][27] A significant drop in potassium can cause abnormal heart rhythms, constipation, fatigue, muscle damage, and paralysis.[28]

Signs and symptoms may be classified in physical, cognitive, affective, behavioral and perceptual:


Physical symptoms

A low body mass index for one's age and height

Amenorrhea, a symptom that occurs after prolonged weight loss, causing menstruation to stop

Dry hair and skin, as well as hair thinning

Fear of even the slightest weight gain; taking all precautionary measures to avoid weight gain or becoming "overweight"[29]

Rapid, continuous weight loss[30]

Lanugo: soft, fine hair growing over the face and body[27]

Bradycardia or tachycardia.

Chronic fatigue[29]

Orange discoloration of the skin, particularly the feet (Carotenosis)

Infertility

Halitosis (from vomiting or starvation-induced ketosis)

Hypotension or orthostatic hypotension

Having severe muscle tension, aches and pains

Insomnia

Abdominal distension


Cognitive symptoms

An obsession with counting calories and monitoring fat contents of food.

Preoccupation with food, recipes, or cooking; may cook elaborate dinners for others, but not eat the food themselves or consume a very small portion.

Admiration of thinner people.

Thoughts of being fat or not thin enough

An altered mental representation of one's body

Difficulty in abstract thinking and problem solving

Rigid and inflexible thinking

Poor self-esteem

Hypercriticism and clinical perfectionism


Affective symptoms

Depression

Ashamed of oneself or one's body

Anxiety disorders

Rapid mood swings

Emotional dysregulation

Alexithymia


Behavioral symptoms

Food restrictions despite being underweight or at a healthy weight.

Food rituals, such as cutting food into tiny pieces, refusing to eat around others, and hiding or discarding of food.

Purging (only in the anorexia purging subtype) with laxatives, diet pills, ipecac syrup, or water pills to flush food out of their system after eating or engage in self-induced vomiting.

Excessive exercise,[31] including micro-exercising, for example making small persistent movements of fingers or toes.[32]

Self-harming or self-loathing.

Solitude: may avoid friends and family and become more withdrawn and secretive.


Perceptual symptoms

Perception of self as overweight, in contradiction to an underweight reality (namely "body image disturbance" [12])

Intolerance to cold and frequent complaints of being cold; body temperature may lower (hypothermia) in an effort to conserve energy due to malnutrition.[33]

Altered body schema (i.e. an implicit representation of the body evoked by acting)

Altered interoception


Interoception

Interoception involves the conscious and unconscious sense of the internal state of the body, and it has an important role in homeostasis and regulation of emotions.[34] Aside from noticeable physiological dysfunction, interoceptive deficits also prompt individuals with anorexia to concentrate on distorted perceptions of multiple elements of their body image.[35] This exists in both people with anorexia and in healthy individuals due to impairment in interoceptive sensitivity and interoceptive awareness.[35]

Aside from weight gain and outer appearance, people with anorexia also report abnormal bodily functions such as indistinct feelings of fullness.[36] This provides an example of miscommunication between internal signals of the body and the brain. Due to impaired interoceptive sensitivity, powerful cues of fullness may be detected prematurely in highly sensitive individuals, which can result in decreased calorie consumption and generate anxiety surrounding food intake in anorexia patients.[37] People with anorexia also report difficulty identifying and describing their emotional feelings and the inability to distinguish emotions from bodily sensations in general, called alexithymia.[36]

Interoceptive awareness and emotion are deeply intertwined, and could mutually impact each other in abnormalities.[37] Anorexia patients also exhibit emotional regulation difficulties that ignite emotionally-cued eating behaviors, such as restricting food or excessive exercising.[37] Impaired interoceptive sensitivity and interoceptive awareness can lead anorexia patients to adapt distorted interpretations of weight gain that are cued by physical sensations related to digestion (e.g., fullness).[37] Combined, these interoceptive and emotional elements could together trigger maladaptive and negatively reinforced behavioral responses that assist in the maintenance of anorexia.[37] In addition to metacognition, people with anorexia also have difficulty with social cognition including interpreting others’ emotions, and demonstrating empathy.[38] Abnormal interoceptive awareness and interoceptive sensitivity shown through all of these examples have been observed so frequently in anorexia that they have become key characteristics of the illness.[36]


Comorbidity

Other psychological issues may factor into anorexia nervosa. Some people have a previous disorder which may increase their vulnerability to developing an eating disorder and some develop them afterwards.[39] The presence of psychiatric comorbidity has been shown to affect the severity and type of anorexia nervosa symptoms in both adolescents and adults.[40]

Obsessive-compulsive disorder (OCD) and obsessive-compulsive personality disorder (OCPD) are highly comorbid with AN.[41][42] OCD is linked with more severe symptomatology and worse prognosis.[43] The causality between personality disorders and eating disorders has yet to be fully established.[44] Other comorbid conditions include depression,[45] alcoholism,[46] borderline and other personality disorders,[47][48] anxiety disorders,[49] attention deficit hyperactivity disorder,[50] and body dysmorphic disorder (BDD).[51] Depression and anxiety are the most common comorbidities,[52] and depression is associated with a worse outcome.[52] Autism spectrum disorders occur more commonly among people with eating disorders than in the general population.[53] Zucker et al. (2007) proposed that conditions on the autism spectrum make up the cognitive endophenotype underlying anorexia nervosa and appealed for increased interdisciplinary collaboration.[54]


Causes

Dysregulation of the serotonin pathways has been implicated in the cause and mechanism of anorexia.[55]

There is evidence for biological, psychological, developmental, and sociocultural risk factors, but the exact cause of eating disorders is unknown.[55]


Genetic

Genetic correlations of anorexia with psychiatric and metabolic traits.

Anorexia nervosa is highly heritable.[55] Twin studies have shown a heritability rate of between 28 and 58%.[56] First-degree relatives of those with anorexia have roughly 12 times the risk of developing anorexia.[57] Association studies have been performed, studying 128 different polymorphisms related to 43 genes including genes involved in regulation of eating behavior, motivation and reward mechanics, personality traits and emotion. Consistent associations have been identified for polymorphisms associated with agouti-related peptide, brain derived neurotrophic factor, catechol-o-methyl transferase, SK3 and opioid receptor delta-1.[58] Epigenetic modifications, such as DNA methylation, may contribute to the development or maintenance of anorexia nervosa, though clinical research in this area is in its infancy.[59][60]

A 2019 study found a genetic relationship with mental disorders, such as schizophrenia, obsessive–compulsive disorder, anxiety disorder and depression; and metabolic functioning with a negative correlation with fat mass, type 2 diabetes and leptin.[61]


Environmental

Obstetric complications: prenatal and perinatal complications may factor into the development of anorexia nervosa, such as preterm birth,[62] maternal anemia, diabetes mellitus, preeclampsia, placental infarction, and neonatal heart abnormalities.[63] Neonatal complications may also have an influence on harm avoidance, one of the personality traits associated with the development of AN.[64]

Neuroendocrine dysregulation: altered signalling of peptides that facilitate communication between the gut, brain and adipose tissue, such as ghrelin, leptin, neuropeptide Y and orexin, may contribute to the pathogenesis of anorexia nervosa by disrupting regulation of hunger and satiety.[65][66]

Gastrointestinal diseases: people with gastrointestinal disorders may be more at risk of developing disorders of eating practices than the general population, principally restrictive eating disturbances.[67] An association of anorexia nervosa with celiac disease has been found.[68] The role that gastrointestinal symptoms play in the development of eating disorders seems rather complex. Some authors report that unresolved symptoms prior to gastrointestinal disease diagnosis may create a food aversion in these persons, causing alterations to their eating patterns. Other authors report that greater symptoms throughout their diagnosis led to greater risk. It has been documented that some people with celiac disease, irritable bowel syndrome or inflammatory bowel disease who are not conscious about the importance of strictly following their diet, choose to consume their trigger foods to promote weight loss. On the other hand, individuals with good dietary management may develop anxiety, food aversion and eating disorders because of concerns around cross contamination of their foods.[67] Some authors suggest that medical professionals should evaluate the presence of an unrecognized celiac disease in all people with eating disorder, especially if they present any gastrointestinal symptom (such as decreased appetite, abdominal pain, bloating, distension, vomiting, diarrhea or constipation), weight loss, or growth failure; and also routinely ask celiac patients about weight or body shape concerns, dieting or vomiting for weight control, to evaluate the possible presence of eating disorders,[68] especially in women.[69]

Studies have hypothesized the continuance of disordered eating patterns may be epiphenomena of starvation. The results of the Minnesota Starvation Experiment showed normal controls exhibit many of the behavioral patterns of AN when subjected to starvation. This may be due to the numerous changes in the neuroendocrine system, which results in a self-perpetuating cycle.[70][71][72]

Anorexia nervosa is more likely to occur in a person's pubertal years. Some explanatory hypotheses for the rising prevalence of eating disorders in adolescence are "increase of adipose tissue in girls, hormonal changes of puberty, societal expectations of increased independence and autonomy that are particularly difficult for anorexic adolescents to meet; [and] increased influence of the peer group and its values."[73]


Psychological

Early theories of the cause of anorexia linked it to childhood sexual abuse or dysfunctional families;[74][75] evidence is conflicting, and well-designed research is needed.[55] The fear of food is known as sitiophobia [76] or cibophobia,[77] and is part of the differential diagnosis.[78][79] Other psychological causes of anorexia include low self-esteem, feeling like there is lack of control, depression, anxiety, and loneliness.[80] Anorexic people are, in general, highly perfectionistic[81] and most have obsessive compulsive personality traits[82] which may facilitate sticking to a restricted diet.[83] It has been suggested that anorexic patients are rigid in their thought patterns, and place a high level of importance upon being thin.[84][85]


Sociological

Anorexia nervosa has been increasingly diagnosed since 1950;[86] the increase has been linked to vulnerability and internalization of body ideals.[73] People in professions where there is a particular social pressure to be thin (such as models and dancers) were more likely to develop anorexia,[87] and those with anorexia have much higher contact with cultural sources that promote weight loss.[88] This trend can also be observed for people who partake in certain sports, such as jockeys and wrestlers.[89] There is a higher incidence and prevalence of anorexia nervosa in sports with an emphasis on aesthetics, where low body fat is advantageous, and sports in which one has to make weight for competition.[90] Family group dynamics can play a role in the cause of anorexia including negative expressed emotion in overprotective families where blame is frequently experienced among its members.[91][92][93] When there is a constant pressure from people to be thin, teasing and bullying can cause low self-esteem and other psychological symptoms.[80]


Media effects

Persistent exposure to media that present body ideals may constitute a risk factor for body dissatisfaction and anorexia nervosa. The cultural ideal for body shape for men versus women continues to favor slender women and athletic, V-shaped muscular men. A 2002 review found that, of the magazines most popular among people aged 18 to 24 years, those read by men, unlike those read by women, were more likely to feature ads and articles on shape than on diet.[94] Body dissatisfaction and internalization of body ideals are risk factors for anorexia nervosa that threaten the health of both male and female populations.[95]

Websites that stress the importance of attainment of body ideals extol and promote anorexia nervosa through the use of religious metaphors, lifestyle descriptions, "thinspiration" or "fitspiration" (inspirational photo galleries and quotes that aim to serve as motivators for attainment of body ideals).[96] Pro-anorexia websites reinforce internalization of body ideals and the importance of their attainment.[96]

The media portray a false view of what people truly look like. In magazines and movies and even on billboards most of the actors/models are digitally altered in multiple ways. People then strive to look like these "perfect" role models when in reality they are not near perfection themselves.[97]


Mechanisms

Evidence from physiological, pharmacological and neuroimaging studies suggest serotonin (also called 5-HT) may play a role in anorexia. While acutely ill, metabolic changes may produce a number of biological findings in people with anorexia that are not necessarily causative of the anorexic behavior. For example, abnormal hormonal responses to challenges with serotonergic agents have been observed during acute illness, but not recovery. Nevertheless, increased cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid (a metabolite of serotonin), and changes in anorectic behavior in response to acute tryptophan depletion (tryptophan is a metabolic precursor to serotonin) support a role in anorexia. The activity of the 5-HT2A receptors has been reported to be lower in patients with anorexia in a number of cortical regions, evidenced by lower binding potential of this receptor as measured by PET or SPECT, independent of the state of illness. While these findings may be confounded by comorbid psychiatric disorders, taken as a whole they indicate serotonin in anorexia.[98][99] These alterations in serotonin have been linked to traits characteristic of anorexia such as obsessiveness, anxiety, and appetite dysregulation.[72]

Neuroimaging studies investigating the functional connectivity between brain regions have observed a number of alterations in networks related to cognitive control, introspection, and sensory function. Alterations in networks related to the dorsal anterior cingulate cortex may be related to excessive cognitive control of eating related behaviors. Similarly, altered somatosensory integration and introspection may relate to abnormal body image.[100] A review of functional neuroimaging studies reported reduced activations in "bottom up" limbic region and increased activations in "top down" cortical regions which may play a role in restrictive eating.[101]

Compared to controls, recovered anorexics show reduced activation in the reward system in response to food, and reduced correlation between self reported liking of a sugary drink and activity in the striatum and anterior cingulate cortex. Increased binding potential of 11C radiolabelled raclopride in the striatum, interpreted as reflecting decreased endogenous dopamine due to competitive displacement, has also been observed.[102]

Structural neuroimaging studies have found global reductions in both gray matter and white matter, as well as increased cerebrospinal fluid volumes. Regional decreases in the left hypothalamus, left inferior parietal lobe, right lentiform nucleus and right caudate have also been reported[103] in acutely ill patients. However, these alterations seem to be associated with acute malnutrition and largely reversible with weight restoration, at least in nonchronic cases in younger people.[104] In contrast, some studies have reported increased orbitofrontal cortex volume in currently ill and in recovered patients, although findings are inconsistent. Reduced white matter integrity in the fornix has also been reported.[105]


Diagnosis

A diagnostic assessment includes the person's current circumstances, biographical history, current symptoms, and family history. The assessment also includes a mental state examination, which is an assessment of the person's current mood and thought content, focusing on views on weight and patterns of eating.


DSM-5

Anorexia nervosa is classified under the Feeding and Eating Disorders in the latest revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM 5). There is no specific BMI cut-off that defines low weight required for the diagnosis of anorexia nervosa.[106][3]

The diagnostic criteria for anorexia nervosa (all of which needing to be met for diagnosis) are:[7][107]

Restriction of energy intake relative to requirements leading to a low body weight. (Criterion A)

Intense fear of gaining weight or persistent behaviors that interfere with gaining weight. (Criterion B)

Disturbance in the way a person's weight or body shape is experienced or a lack of recognition about the risks of the low body weight. (Criterion C)

Relative to the previous version of the DSM (DSM-IV-TR), the 2013 revision (DSM5) reflects changes in the criteria for anorexia nervosa. Most notably, the amenorrhea (absent period) criterion was removed.[7][108] Amenorrhea was removed for several reasons: it does not apply to males, it is not applicable for females before or after the age of menstruation or taking birth control pills, and some women who meet the other criteria for AN still report some menstrual activity.[7]


Subtypes

There are two subtypes of AN:[25][109]

Binge-eating/purging type: patients with anorexia could show binge eating and purging behavior.[109] It is different from bulimia nervosa in terms of the individual's weight. An individual with binge-eating/purging type anorexia is usually significantly underweight. People with bulimia nervosa on the other hand can sometimes be normal-weight or overweight.[29]

Restricting type: the individual uses restricting food intake, fasting, diet pills, or exercise as a means for losing weight;[25] they may exercise excessively to keep off weight or prevent weight gain, and some individuals eat only enough to stay alive.[25][29] In the restrictive type, there are no recurrent episodes of binge-eating or purging present.[106]


Levels of severity

Body mass index (BMI) is used by the DSM-5 as an indicator of the level of severity of anorexia nervosa. The DSM-5 states these as follows:[110]

Mild: BMI of greater than 17

Moderate: BMI of 16–16.99

Severe: BMI of 15–15.99

Extreme: BMI of less than 15


Investigations

Medical tests to check for signs of physical deterioration in anorexia nervosa may be performed by a general physician or psychiatrist, including:

Complete Blood Count (CBC): a test of the white blood cells, red blood cells and platelets used to assess the presence of various disorders such as leukocytosis, leukopenia, thrombocytosis and anemia which may result from malnutrition.[111]

Urinalysis: a variety of tests performed on the urine used in the diagnosis of medical disorders, to test for substance abuse, and as an indicator of overall health[112]

Chem-20: Chem-20 also known as SMA-20 a group of twenty separate chemical tests performed on blood serum. Tests include cholesterol, protein and electrolytes such as potassium, chlorine and sodium and tests specific to liver and kidney function.[113]

Glucose tolerance test: Oral glucose tolerance test (OGTT) used to assess the body's ability to metabolize glucose. Can be useful in detecting various disorders such as diabetes, an insulinoma, Cushing's Syndrome, hypoglycemia and polycystic ovary syndrome.[114]

Serum cholinesterase test: a test of liver enzymes (acetylcholinesterase and pseudocholinesterase) useful as a test of liver function and to assess the effects of malnutrition.[115]

Liver Function Test: A series of tests used to assess liver function some of the tests are also used in the assessment of malnutrition, protein deficiency, kidney function, bleeding disorders, and Crohn's Disease.

Luteinizing hormone (LH) response to gonadotropin-releasing hormone (GnRH): Tests the pituitary glands' response to GnRh, a hormone produced in the hypothalamus. Hypogonadism is often seen in anorexia nervosa cases.[26]

Creatine kinase (CK) test: measures the circulating blood levels of creatine kinase an enzyme found in the heart (CK-MB), brain (CK-BB) and skeletal muscle (CK-MM).[117]

Blood urea nitrogen (BUN) test: urea nitrogen is the byproduct of protein metabolism first formed in the liver then removed from the body by the kidneys. The BUN test is primarily used to test kidney function. A low BUN level may indicate the effects of malnutrition.[118]

BUN-to-creatinine ratio: A BUN to creatinine ratio is used to predict various conditions. A high BUN/creatinine ratio can occur in severe hydration, acute kidney failure, congestive heart failure, and intestinal bleeding. A low BUN/creatinine ratio can indicate a low protein diet, celiac disease, rhabdomyolysis, or cirrhosis of the liver.[119][120]

Electrocardiogram (EKG or ECG): measures electrical activity of the heart. It can be used to detect various disorders such as hyperkalemia.[121]

Electroencephalogram (EEG): measures the electrical activity of the brain. It can be used to detect abnormalities such as those associated with pituitary tumors.[122]

Thyroid screen: test used to assess thyroid functioning by checking levels of thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3).[123]


Differential diagnoses

Main article: Anorexia nervosa (differential diagnoses)

A variety of medical and psychological conditions have been misdiagnosed as anorexia nervosa; in some cases the correct diagnosis was not made for more than ten years.

The distinction between binge purging anorexia, bulimia nervosa and Other Specified Feeding or Eating Disorders (ORFED) is often difficult for non-specialist clinicians. A main factor differentiating binge-purge anorexia from bulimia is the gap in physical weight. Patients with bulimia nervosa is ordinarily at a healthy weight, or slightly overweight. Patients with binge-purge anorexia is commonly underweight.[124] Moreover, patients with the binge-purging subtype may be significantly underweight and typically do not binge-eat large amounts of food.[124] In contrast, those with bulimia nervosa tend to binge large amounts of food.[124] It is not unusual for patients with an eating disorder to "move through" various diagnoses as their behavior and beliefs change over time.[54]


Treatment

There is no conclusive evidence that any particular treatment for anorexia nervosa works better than others.[11][125]

Treatment for anorexia nervosa tries to address three main areas.

Restoring the person to a healthy weight;

Treating the psychological disorders related to the illness;

Reducing or eliminating behaviors or thoughts that originally led to the disordered eating.[126]

In some clinical settings a specific body image intervention is performed to reduce body dissatisfaction and body image disturbance. Although restoring the person's weight is the primary task at hand, optimal treatment also includes and monitors behavioral change in the individual as well.[17] There is some evidence that hospitalization might adversely affect long term outcome, but sometimes is necessary.[127] Psychotherapy for individuals with AN is challenging as they may value being thin and may seek to maintain control and resist change.[128] Initially, developing a desire to change is fundamental.[129] Despite no evidence for better treatment in adults patients, research stated that family based therapy is the primary choice for adolescents with AN.[11][130]


Therapy

Family-based treatment (FBT) has been shown to be more successful than individual therapy for adolescents with AN.[8][131] Various forms of family-based treatment have been proven to work in the treatment of adolescent AN including conjoint family therapy (CFT), in which the parents and child are seen together by the same therapist, and separated family therapy (SFT) in which the parents and child attend therapy separately with different therapists.[8] Proponents of family therapy for adolescents with AN assert that it is important to include parents in the adolescent's treatment.[8]

A four- to five-year follow up study of the Maudsley family therapy, an evidence-based manualized model, showed full recovery at rates up to 90%.[132] Although this model is recommended by the NIMH,[133] critics claim that it has the potential to create power struggles in an intimate relationship and may disrupt equal partnerships.[132] Cognitive behavioral therapy (CBT) is useful in adolescents and adults with anorexia nervosa.[134] One of the most known psychotherapy in the field is CBT-E, an enhanced cognitive-behavior therapy specifically focus to eating disorder psychopatology. Acceptance and commitment therapy is a third-wave cognitive-behavioral therapy which has shown promise in the treatment of AN.[135] Cognitive remediation therapy (CRT) is also used in treating anorexia nervosa.[136] Schema-Focused Therapy (a form of CBT) was developed by Dr. Jeffrey Young and is effective in helping patients identify origins and triggers for disordered eating. https://www.tandfonline.com/doi/pdf/10.1080/20797222.2017.1326728


Diet

Diet is the most essential factor to work on in people with anorexia nervosa, and must be tailored to each person's needs. Food variety is important when establishing meal plans as well as foods that are higher in energy density.[137] People must consume adequate calories, starting slowly, and increasing at a measured pace.[31] Evidence of a role for zinc supplementation during refeeding is unclear.[17]


Medication

Pharmaceuticals have limited benefit for anorexia itself.[138][106] There is a lack of good information from which to make recommendations concerning the effectiveness of antidepressants in treating anorexia.[139] Administration of olanzapine has been shown to result in a modest but statistically significant increase in body weight of anorexia nervosa patients.[140]


Admission to hospital

AN has a high mortality[141] and patients admitted in a severely ill state to medical units are at particularly high risk. Diagnosis can be challenging, risk assessment may not be performed accurately, consent and the need for compulsion may not be assessed appropriately, refeeding syndrome may be missed or poorly treated and the behavioural and family problems in AN may be missed or poorly managed.[142] Guidelines published by the Royal College of Psychiatrists recommend that medical and psychiatric experts work together in managing severely ill people with AN.[143]


Refeeding syndrome

The rate of refeeding can be difficult to establish, because the fear of refeeding syndrome (RFS) can lead to underfeeding. It is thought that RFS, with falling phosphate and potassium levels, is more likely to occur when BMI is very low, and when medical comorbidities such as infection or cardiac failure, are present. In those circumstances, it is recommended to start refeeding slowly but to build up rapidly as long as RFS does not occur. Recommendations on energy requirements vary, from 5–10 kcal/kg/day in the most medically compromised patients, who appear to have the highest risk of RFS, to 1900 kcal/day.[144][145]


Prognosis