Amenorrhea

Template:Short description Template:Use American English Template:Infobox medical condition (new) Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age.<ref name=":28">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding).<ref name=":28" /> In humans, it is where a woman or girl who has reached reproductive age who is not on birth control does not menstruate.

Amenorrhoea is a symptom with many potential causes.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Primary amenorrhea is defined as an absence of secondary sexual characteristics by age 13 with no menarche or normal secondary sexual characteristics but no menarche by 15 years of age.<ref name=":210">Template:Cite journal</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Secondary amenorrhoea, ceasing of menstrual cycles after menarche, 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.<ref name=":210"/> It is often caused by hormonal disturbances from the hypothalamus and the pituitary gland, premature menopause, intrauterine scar formation, or eating disorders.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name=":10"/>

Pathophysiology

Although amenorrhea has multiple potential causes, ultimately, it is the result of hormonal imbalance or an anatomical abnormality.<ref name=":0">Template:Citation</ref>

Physiologically, menstruation is controlled by the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus.<ref name=":0" /> GnRH acts on the pituitary to stimulate the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH).<ref name=":0" /> FSH and LH then act on the ovaries to stimulate the production of estrogen and progesterone which, respectively, control the proliferative and secretary phases of the menstrual cycle.<ref name=":0" /> Prolactin also influences the menstrual cycle as it suppresses the release of LH and FSH from the pituitary.<ref name=":14">Template:Cite journal</ref> Similarly, thyroid hormone also affects the menstrual cycle.<ref name=":14" /> Low levels of thyroid hormone stimulate the release of TRH from the hypothalamus, which in turn increases both TSH and prolactin release.<ref name=":14" /> This increase in prolactin suppresses the release of LH and FSH through a negative feedback mechanism.<ref name=":14" /> Amenorrhea can be caused by any mechanism that disrupts this hypothalamic-pituitary-ovarian axis, whether that it be by hormonal imbalance or by disruption of feedback mechanisms.

Classification

Amenorrhea is classified as either primary or secondary.<ref>Template:Cite book</ref>

Primary amenorrhea

Primary amenorrhoea is the absence of menstruation in a woman by the age of 16.<ref name="urlAmenorrhea, Primary: eMedicine Obstetrics and Gynecology2">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Females who have not reached menarche at 14 and who have no signs of secondary sexual characteristics (thelarche or pubarche) are also considered to have primary amenorrhea.<ref name="SperoffGlass19992">Template:Cite book</ref> Examples of amenorrhea include constitutional delay of puberty, Turner syndrome, and Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome.<ref name=":72">Template:Cite journal</ref><ref>Template:Cite journal</ref>

It produces the appearance of secondary sexual characteristics, which are the sprouting of pubic and armpit hair, development of the breasts, and a lack of definition in the female body structure, such as the waist and hips.

Secondary amenorrhea

Secondary amenorrhoea is defined as the absence of menstruation for three months in a woman with a history of regular cyclic bleeding or six months in a woman with a history of irregular menstrual periods.<ref name="pmid166695594">Template:Cite journal</ref> Examples of secondary amenorrhea include hypothyroidism, hyperthyroidism, hyperprolactinemia, polycystic ovarian syndrome, primary ovarian insufficiency, and functional hypothalamic amenorrhea.<ref name=":292">Template:Cite journal</ref><ref name=":252">Template:Cite journal</ref>

Causes

Primary amenorrhea

Turner syndrome

Turner syndrome, monosomy 45XO, is a genetic disorder characterized by a missing, or partially missing, X chromosome.<ref name=":1">Template:Cite journal</ref> Turner syndrome is associated with a wide spectrum of features that vary with each case.<ref name=":1" /> However, one common feature of this syndrome is ovarian insufficiency due to gonadal dysgenesis.<ref name=":1" /><ref>Template:Cite journal</ref> Most people with Turner syndrome experience ovarian insufficiency within the first few years of life, prior to menarche.<ref name=":1" /> Therefore, most patients with Turner syndrome will have primary amenorrhea.<ref name=":1" /> However, the incidence of spontaneous puberty varies between 8–40% depending on whether or not there is a complete or partial absence of the X chromosome.<ref name=":1" />

MRKH

MRKH (Mayer–Rokitansky–Küster–Hauser) syndrome is the second-most common cause of primary amenorrhoea.<ref name="pmid237257842">Template:Cite journal</ref> The syndrome is characterized by Müllerian agenesis.<ref name=":15">Template:Cite journal</ref> In MRKH Syndrome, the Müllerian ducts develop abnormally and result in the absence of a uterus and cervix.<ref name=":15" /> Even though patients with MRKH have functioning ovaries, and therefore have secondary sexual characteristics, they experience primary amenorrhea since there is no functioning uterus.<ref name=":15" />

Other Intersex conditions

Individuals with a female phenotype can present with primary amenorrhea due to complete androgen insensitivity syndrome (CAIS), 5-alpha-reductase 2 deficiency, pure gonadal dysgenesis, 17β-hydroxysteroid dehydrogenase deficiency, and mixed gonadal dysgenesis.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Constitutional delay of puberty

Constitutional delay of puberty is a diagnosis of exclusion that is made when the workup for primary amenorrhea does not reveal another cause.<ref name=":16">Template:Cite journal</ref> Constitutional delay of puberty is not due to a pathologic cause. It is considered a variant of the timeline of puberty.<ref name=":16" /> Although more common in boys, girls with delayed puberty present with onset of secondary sexual characteristics after the age of 14, as well as menarche after the age of 16.<ref name=":17">Template:Cite journal</ref> This may be due to genetics, as some cases of constitutional delay of puberty are familial.<ref name=":17" />

Secondary amenorrhea

Breastfeeding

Physiologic amenorrhea is present before menarche, during pregnancy and breastfeeding, and after menopause.<ref name=":210"/>

Breastfeeding or lactational amenorrhea is also a common cause of secondary amenorrhoea.<ref>Template:Cite journal</ref> Lactational amenorrhea is due to the presence of elevated prolactin and low levels of LH, which suppress ovarian hormone secretion.<ref name=":3">Template:Cite journal</ref> Breastfeeding typically prolongs postpartum lactational amenorrhoea, and the duration of amenorrhoea varies depending on how often a woman breastfeeds.<ref>Template:Cite journal</ref> Due to this reason, breastfeeding has been advocated as a method of family planning, especially in developing countries where access to other methods of contraception may be limited.<ref name=":3" />

Diseases of the thyroid

Disturbances in thyroid hormone regulation has been a known cause of menstrual irregularities, including secondary amenorrhea.<ref name=":4">Template:Cite journal</ref><ref>Template:Cite journal</ref>

Patients with hypothyroidism frequently present with changes in their menstrual cycle.<ref name=":4" /> It is hypothesized that this is due to increased TRH, which goes on to stimulate the release of both TSH and prolactin.<ref name=":4" /> Increased prolactin inhibits the release of LH and FSH which are needed for ovulation to occur.<ref name=":4" />

Patients with hyperthyroidism may also present with oligomenorrhea or amenorrhea.<ref name=":4" /> Sex hormone binding globulin is increased in hyperthyroid states.<ref name=":4" /> This, in turn, increases the total levels of testosterone and estradiol.<ref name=":4" /> Increased levels of LH and FSH have also been reported in patients with hyperthyroidism.<ref name=":4" />

Hypothalamic and pituitary causes

Changes in the hypothalamic-pituitary axis is a common cause of secondary amenorrhea.<ref name=":210"/> GnRH is released from the hypothalamus and stimulates the anterior pituitary to release FSH and LH, which in turn stimulate the ovaries to release estrogen and progesterone.<ref name=":210"/> Any pathology in the hypothalamus or pituitary can alter the way this feedback mechanism works and can cause secondary amenorrhea.<ref name=":210"/>

Pituitary adenomas are a common cause of amenorrhea.<ref name=":18">Template:Cite journal</ref> Prolactin secreting pituitary adenomas cause amenorrhea due to the hyper-secretion of prolactin which inhibits FSH and LH release.<ref name=":18" /> Other space occupying pituitary lesions can also cause amenorrhea due to the inhibition of dopamine, an inhibitor of prolactin, due to compression of the pituitary gland.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 4–8% of women worldwide.<ref name=":5">Template:Cite journal</ref> It is characterized by multiple cysts on the ovary, amenorrhea or oligomenorrhea, and increased androgens.<ref name=":5" /> Although the exact cause remains unknown, it is hypothesized that increased levels of circulating androgens is what results in secondary amenorrhea.<ref name=":13">Template:Cite journal</ref> PCOS may also be a cause of primary amenorrhea if androgen access is present prior to menarche.<ref name=":13"/> Although multiple cysts on the ovary are characteristic of the syndrome, this has not been noted to be a cause of the disease.<ref name=":13"/>

Low body weight

Women who perform extraneous exercise on a regular basis or lose a significant amount of weight are at risk of developing hypothalamic amenorrhoea or exercise amenorrhoea.<ref name=":19">Template:Cite journal</ref> Functional hypothalamic amenorrhoea (FHA) can be caused by stress, weight loss, or excessive exercise.<ref name=":19" /> Many women who diet or who exercise at a high level do not take in enough calories to maintain their normal menstrual cycles.<ref name=":19" /> 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.<ref>Template:Cite journal</ref> Amenorrhoea is often associated with anorexia nervosa and other eating disorders.<ref name=":20">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Relative energy deficiency in sport, also known as the female athlete triad, is when a woman experiences amenorrhoea, disordered eating, and osteoporosis.<ref name=":20" />

Energy imbalance and weight loss can disrupt menstrual cycles through several hormonal mechanisms.<ref name=":21">Template:Cite journal</ref> Weight loss can cause elevations in the hormone ghrelin which inhibits the hypothalamic-pituitary-ovarial axis.<ref name=":21" /> Elevated concentrations of ghrelin alter the amplitude of GnRH pulses, which causes diminished pituitary release of LH and follicle-stimulating hormone (FSH).<ref name="pmid125198692">Template:Cite journal</ref> Low levels of the hormone leptin are also seen in females with low body weight.<ref name="pmid92466752">Template:Cite journal</ref> Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis.<ref name=":210"/> Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing.<ref name=":210"/>

Drug-induced

Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman.<ref name=":23">Template:Cite journal</ref> The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping its use.<ref name=":23" /> Hormonal contraceptives that contain only progestogen, like the oral contraceptive Micronor, and especially higher-dose formulations, such as the injectable Depo-Provera, commonly induce this side effect.<ref name="pmid192092722">Template:Cite journal</ref><ref name=":24">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Extended cycle use of combined hormonal contraceptives also allow suppression of menstruation. Patients who stop using combined oral contraceptive pills (COCP) may experience secondary amenorrhoea as a withdrawal symptom.<ref name=":24" /> 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.<ref name=":23" /> New contraceptive pills which do not have the normal seven days of placebo pills in each cycle, have been shown to increase rates of amenorrhoea in women.<ref name="pmid192092722" /> Studies show that women are most likely to experience amenorrhoea after one year of treatment with continuous OCP use.<ref name="pmid192092722" />

The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Anti-psychotic drugs, which are commonly used to treat schizophrenia, have been known to cause amenorrhoea as well.<ref name="pmid227111712">Template:Cite journal</ref> Research suggests that anti-psychotic medications affect levels of prolactin, insulin, FSH, LH, and testosterone.<ref name="pmid227111712" /> Recent research suggests that adding a dosage of metformin to an anti-psychotic drug regimen can restore menstruation.<ref name="pmid227111712" /> Metformin has been shown to decrease resistance to the hormone insulin, as well as levels of prolactin, testosterone, and luteinizing hormone (LH).<ref name="pmid227111712" />

Primary ovarian insufficiency

Primary ovarian insufficiency (POI) affects 1% of females and is defined as the loss of ovarian function before the age of 40.<ref>Template:Cite journal</ref> Although the cause of POI can vary, it has been linked to chromosomal abnormalities, chemotherapy, and autoimmune conditions.<ref name=":292"/> Hormone levels in POI are similar to menopause and are categorized by low estradiol and high levels of gonadotropins.<ref name="pmid166695594"/> Since the pathogenesis of POI involves the depletion of ovarian reserve, restoration of menstrual cycles typically does not occur in this form of secondary amenorrhea.<ref name="pmid166695594"/>

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.<ref name="pmid166695594"/> 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.<ref name=":72"/> Gonadal dysgenesis, often associated with Turner syndrome, or premature ovarian failure may also be to blame.<ref name=":252"/> If secondary sex characteristics are present, but menstruation is not, primary amenorrhoea can be diagnosed by age 16.<ref name=":252" />

Evaluation of primary amenorrhea begins with a pregnancy test, prolactin, FSH, LH, and TSH levels.<ref name=":72" /> Abnormal TSH levels prompt evaluation for hyper- and hypo-thyroidism with additional thyroid function tests.<ref name=":72" /> Elevated prolactin levels prompt evaluation of the pituitary with an MRI to assess for any masses or malignancies.<ref name=":72" /> A pelvic ultrasound can also be obtained in the initial evaluation.<ref name=":72" /> If a uterus is not present on ultrasound, karyotype analysis and testosterone levels are obtained to assess for MRKH or androgen insensitivity syndrome.<ref name=":26">Template:Cite journal</ref> If a uterus is present, LH and FSH levels are used to make a diagnosis.<ref name=":72" /> Low levels of LH and FSH suggest delayed puberty or functional hypothalamic amenorrhea.<ref name=":72" /> Elevated levels of FSH and LH suggest primary ovarian insufficiency, typically due to Turner syndrome.<ref name=":72" /> Normal levels of FSH and LH can suggest an anatomical outflow obstruction.<ref name=":72" /><ref name=":26" /><ref name=":8">Template:Cite journal</ref>

Secondary amenorrhea

Secondary amenorrhea's most common and most easily diagnosable causes are pregnancy, thyroid disease, and hyperprolactinemia.<ref name=":27">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A pregnancy test is a common first step for diagnosis.<ref name=":27" />

Similar to primary amenorrhea, evaluation of secondary amenorrhea also begins with a pregnancy test, prolactin, FSH, LH, and TSH levels.<ref name=":72" /> A pelvic ultrasound is also obtained.<ref name=":72" /> Abnormal TSH should prompt a thyroid workup with a full thyroid function test panel.<ref name=":72" /> Elevated prolactin should be followed with an MRI to look for masses.<ref name=":112">Template:Cite journal</ref><ref name=":72" /> If LH and FSH are elevated, menopause or primary ovarian insufficiency should be considered.<ref name=":72" /> Normal or low levels of FSH and LH prompts further evaluation with patient history and the physical exam.<ref name=":72" /> Testosterone, DHEA-S, and 17-hydroxyprogesterone levels should be obtained if there is evidence of excess androgens, such as hirsutism or acne.<ref name=":72" /> 17-hydroxyprogesterone is elevated in congenital adrenal hyperplasia.<ref name=":72" /> Elevated testosterone and amenorrhea can suggest PCOS.<ref name=":72" /><ref name=":13"/> Elevated androgens can also be present in ovarian or adrenal tumors, so additional imaging may also be needed.<ref name=":72" /> History of disordered eating or excessive exercise should raise concern for hypothalamic amenorrhea.<ref>Template:Cite journal</ref> Headache, vomiting, and vision changes can be signs of a tumor and needs evaluation with MRI.<ref name=":72" /> Finally, a history of gynecologic procedures should lead to evaluation of Asherman syndrome with a hysteroscopy or progesterone withdrawal bleeding test.<ref name=":72" /><ref name=":8" />

Treatment

Treatment for amenorrhea varies based on the underlying condition.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Treatment not only focuses on restoring menstruation, if possible, but also preventing additional complications associated with the underlying cause of amenorrhea.<ref name=":210"/>

Primary amenorrhea

In primary amenorrhea, the goal is to continue pubertal development, if possible.<ref name=":210"/> For example, most patients with Turner syndrome will be infertile due to gonadal dysgenesis.<ref name=":9">Template:Cite journal</ref> However, patients are frequently prescribed growth hormone therapy and estrogen supplementation to achieve taller stature and prevent osteoporosis.<ref name=":9" /> In other cases, such as MRKH, hormones do not need to be prescribed since the ovaries are able to function normally.<ref>Template:Cite journal</ref> Patients with constitutional delay of puberty may be monitored by an endocrinologist, but definitive treatment may not be needed as there will eventually be progression to normal puberty.<ref>Template:Cite journal</ref>

Secondary amenorrhea

Treatment for secondary amenorrhea varies greatly based on the root cause. Functional hypothalamic amenorrhoea is typically treated by weight gain through increased calorie intake and decreased expenditure.<ref name=":10">Template:Cite journal</ref> Multidisciplinary treatment with monitoring from a physician, dietitian, and mental health counselor is recommended, along with support from family, friends, and coaches.<ref name=":10" /> Although oral contraceptives can cause 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.<ref name=":10" />

Patients with hyperprolactinemia are often treated with dopamine agonists to reduce the levels of prolactin and restore menstruation.<ref name=":112"/> Surgery and radiation may also be considered if dopamine agonists, such as cabergoline and bromocriptine are ineffective.<ref name=":112" /> Once prolactin levels are lowered, the resulting secondary amenorrhea is typically resolved.<ref name=":112" /> Similarly, treatment of thyroid abnormalities often resolves the associated amenorrhea.<ref name=":12">Template:Cite journal</ref> For example, administration of thyroxine in patients with low thyroid levels restored normal menstruation in a majority of patients.<ref name=":12" />

Although there is currently no definitive treatment for PCOS, various interventions are used to restore more frequent ovulation in patients.<ref name=":13"/> Weight loss and exercise have been associated with a return of ovulation in patients with PCOS due to normalization of androgen levels.<ref name=":13" /> Metformin has also been recently studied to regularize menstrual cycles in patients with PCOS.<ref name=":13" /> Although the exact mechanism still remains unknown, it is hypothesized that this is due to metformin's ability to increase the body's sensitivity to insulin.<ref name=":13" /> Anti-androgen medications, such as spironolactone, can also be used to lower body androgen levels and restore menstruation.<ref name=":13" /> Oral contraceptive pills are also often prescribed to patients with secondary amenorrhea due to PCOS in order to regularize the menstrual cycle, although this is due to the suppression of ovulation.<ref name=":13" />

External links

• Disability Online's amenorrhoea page
• Disability Online's athletic amenorrhoea page
• Amenorrhea