Amenorrhea: Difference between revisions

Amenorrhea
Amenorrhea
Other names	Amenorrhea, amenorrhœa
Specialty	Gynecology

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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).^[1] Outside the reproductive years, there is absence of menses during childhood and after menopause.^[1]

Amenorrhoea is a symptom with many potential causes.^[2] 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.^[3] 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.^[4] 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.^[3] It is often caused by hormonal disturbances from the hypothalamus and the pituitary gland, premature menopause, intrauterine scar formation, or eating disorders. ^[5]^[6]^[7]

Pathophysiology

Although amenorrhea has multiple potential causes, ultimately, it is the result of hormonal imbalance or an anatomical abnormality. ^[8]

Physiologically, menstruation is controlled by the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus.^[8] GnRH acts on the pituitary to stimulate the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH).^[8] 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.^[8] Prolactin also influences the menstrual cycle as it suppresses the release of LH and FSH form the pituitary.^[9] Similarly, thyroid hormone also affects the menstrual cycle.^[9] Low levels of thyroid hormone stimulate the release of TRH from the hypothalamus, which in turn increases both TSH and prolactin release.^[9] This increase in prolactin suppresses the release of LH and FSH through a negative feedback mechanism.^[9] 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.^[10]

Primary Amenorrhea

Primary amenorrhoea is the absence of menstruation in a woman by the age of 16.^[11] 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.^[12] Examples of amenorrhea include constitutional delay of puberty, Turner's syndrome, and Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome.^[13]

Secondary Amenorrhea

Secondary amenorrhoea is when 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.^[14] Examples of secondary amenorrhea include hypothyroidism, hyperthyroidism, hyperprolactinemia, polycystic ovarian syndrome, primary ovarian insufficiency, and functional hypothalamic amenorrhea.^[15]^[16]

Causes

Primary Amenorrhea

Turner's Syndrome

Turner's Syndrome, monosomy 45XO, is a genetic disorder characterized by a missing, or partially missing, X chromosome.^[17] Turner's syndrome is associated with a wide spectrum of features that vary with each case.^[17] However, one common feature of this syndrome is ovarian insufficiency due to gonadal dysgenesis.^[17]^[18] Most people with Turner's syndrome experience ovarian insufficiency within the first few years of life, prior to menarche.^[17] Therefore, most patients with Turner's syndrome will have primary amenorrhea.^[17] 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.^[17]

MRKH

MRKH (Mayer–Rokitansky–Küster–Hauser) syndrome is the second-most common cause of primary amenorrhoea.^[19] The syndrome is characterized by Müllerian agenesis.^[20] In MRKH Syndrome, the Müllerian ducts develop abnormally and result in the absence of a uterus and cervix.^[20] Even though patient's with MRKH have functioning ovaries, and therefore have secondary sexual characteristics, they experience primary amenorrhea since there is no functioning uterus.^[20]

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.^[21] Constitutional delay of puberty is not due to a pathologic cause. It is considered a variant of the timeline of puberty.^[21] 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.^[22] This may be due to genetics, as some cases of constitutional delay of puberty are familial.^[22]

Secondary Amenorrhea

Breastfeeding

Physiologic amenorrhea is present before menarche, during pregnancy and breastfeeding, and after menopause.^[23]

Breastfeeding or lactational amenorrhea is also a common cause of secondary amenorrhoea.^[24] Lactational amenorrhea is due to the presence of elevated prolactin and low levels of LH, which suppress ovarian hormone secretion.^[25] Breastfeeding typically prolongs postpartum lactational amenorrhoea, and the duration of amenorrhoea varies depending on how often a woman breastfeeds.^[26] 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.^[25]

Diseases of the Thyroid

Disturbances in thyroid hormone regulation has been a known cause of menstrual irregularities, including secondary amenorrhea.^[27]^[28]

Patients with hypothyroidism frequently present with changes in their menstrual cycle.^[27] It is hypothesized that this is due to increased TRH, which goes on to stimulate the release of both TSH and prolactin.^[27] Increased prolactin inhibits the release of LH and FSH which are needed for ovulation to occur.^[27]

Patients with hyperthyroidism may also present with oligomenorrhea or amenorrhea.^[27] Sex hormone binding globulin is increased in hyperthyroid states.^[27] This, in turn, increases the total levels of testosterone and estradiol.^[27] Increased levels of LH and FSH have also been reported in patients with hyperthyroidism.^[27]

Hypothalamic and Pituitary Causes

Changes in the hypothalamic-pituitary axis is a common cause of secondary amenorrhea.^[23] GnRH is released form the hypothalamus and stimulates the anterior pituitary to release FSH and LH, which in turn stimulate the ovaries to release estrogen and progesterone.^[23] Any pathology in the hypothalamus or pituitary can alter the way this feedback mechanism works and can cause secondary amenorrhea.^[23]

Pituitary adenomas are a common cause of amenorrhea.^[29] Prolactin secreting pituitary adenomas cause amenorrhea due to the hyper-secretion of prolactin which inhibits FSH and LH release.^[29] 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.^[30]

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 4-8% of women worldwide.^[31] It is characterized my multiple cysts on the ovary, amenorrhea or oligomenorrhea, and increased androgens.^[31] Although the exact cause remains unknown, it is hypothesized that increased levels of circulating androgens is what results in secondary amenorrhea.^[32] PCOS may also be a cause of primary amenorrhea if androgen access is present prior to menarche.^[32] Although multiple cysts on the ovary are characteristic of the syndrome, this has not been noted to be a cause of the disease.^[33]

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.^[34] Functional Hypothalamic Amenorrhoea (FHA) can be caused by stress, weight loss, or excessive exercise.^[34] Many women who diet or who exercise at a high level do not take in enough calories to maintain their normal menstrual cycles.^[34] 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.^[35] Amenorrhoea is often associated with anorexia nervosa and other eating disorders.^[36] The female athlete triad is when a woman experiences amenorrhoea, disordered eating, and osteoporosis.^[36]

Energy imbalance and weight loss can disrupt menstrual cycles through several hormonal mechanisms.^[37] Weight loss can cause elevations in the hormone ghrelin which inhibits the hypothalamic-pituitary-ovarial axis.^[37] Elevated concentrations of ghrelin alter the amplitude of GnRH pulses, which causes diminished pituitary release of LH and follicle-stimulating hormone (FSH).^[38] Low levels of the hormone leptin are also seen in females with low body weight.^[39] Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis.^[23] Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing.^[23]

Drug-induced

Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman.^[40] The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping its use.^[40] 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.^[41]^[42] 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.^[42] 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.^[40] New contraceptive pills which do not have the normal 7 days of placebo pills in each cycle, have been shown to increase rates of amenorrhoea in women.^[41] Studies show that women are most likely to experience amenorrhoea after 1 year of treatment with continuous OCP use.^[41]

The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users.^[43]^[44]

Anti-psychotic drugs, which are commonly used to treat schizophrenia, have been known to cause amenorrhoea as well.^[45] Research suggests that anti-psychotic medications effect levels of prolactin, insulin, FSH, LH, and testosterone.^[45] Recent research suggests that adding a dosage of Metformin to an anti-psychotic drug regimen can restore menstruation.^[45] Metformin has been shown to decrease resistance to the hormone insulin, as well as levels of prolactin, testosterone, and luteinizing hormone (LH).^[45]

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.^[46] Although the cause of POI can vary, it has been linked to chromosomal abnormalities, chemotherapy, and autoimmune conditions.^[47] Hormone levels in POI are similar to menopause and are categorized by low estradiol and high levels of gonadotropins.^[48] 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.^[48]

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.^[49] 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

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.^[50] 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.^[51]^[52]

Treatments

Treatments vary based on the underlying condition.^[53] 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 typically treated by weight gain through increased calorie intake and decreased expenditure.^[54] 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.^[54] 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.^[55] 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.^[56]

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.^[57]

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).

References

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^ McGlacken-Byrne, Sinéad M.; Conway, Gerard S. (2021-11-16). "Premature ovarian insufficiency". Best Practice & Research. Clinical Obstetrics & Gynaecology: S1521–6934(21)00167–X. doi:10.1016/j.bpobgyn.2021.09.011. ISSN 1532-1932. PMID 34924261.
^ ^a ^b Master-Hunter T, Heiman DL (April 2006). "Amenorrhea: evaluation and treatment". American Family Physician. 8. 73 (8): 1374–82. PMID 16669559. Archived from the original on 2013-11-11.
^ Master-Hunter T, Heiman DL (April 2006). "Amenorrhea: evaluation and treatment". American Family Physician. 8. 73 (8): 1374–82. PMID 16669559. Archived from the original on 2013-11-11.
^ Welt C. "Etiology, diagnosis, and treatment of secondary amenorrhea". Archived from the original on 2013-11-11.
^ Newson L. "Amenorrhea".
^ Welt CK. "Etiology, diagnosis, and treatment of primary amenorrhea". Archived from the original on 2013-11-11.
^ "What are the treatments for amenorrhea?". nichd.nih.gov/. Retrieved 2018-11-08.
^ ^a ^b
American Medical Society for Sports Medicine (24 April 2014), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, American Association of Blood Banks, archived from the original on 29 July 2014, retrieved 29 July 2014, which cites
- De Souza MJ, Nattiv A, Joy E, Misra M, Williams NI, Mallinson RJ, Gibbs JC, Olmsted M, Goolsby M, Matheson G (February 2014). "2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad: 1st International Conference held in San Francisco, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013". British Journal of Sports Medicine. 48 (4): 289. doi:10.1136/bjsports-2013-093218. PMID 24463911.
- Javed A, Tebben PJ, Fischer PR, Lteif AN (September 2013). "Female athlete triad and its components: toward improved screening and management". Mayo Clinic Proceedings. 88 (9): 996–1009. doi:10.1016/j.mayocp.2013.07.001. PMID 24001492.
- Nazem TG, Ackerman KE (July 2012). "The female athlete triad". Sports Health. 4 (4): 302–11. doi:10.1177/1941738112439685. PMC 3435916. PMID 23016101.
^ Acosta-Martínez M (24 January 2012). "PI3K: An Attractive Candidate for the Central Integration of Metabolism and Reproduction". Frontiers in Endocrinology. 2: 110. doi:10.3389/fendo.2011.00110. PMC 3356143. PMID 22654843.
^ Chan JL, Mantzoros CS (8 July 2005). "Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa". Lancet. 366 (9479): 74–85. doi:10.1016/S0140-6736(05)66830-4. PMID 15993236. S2CID 37180870.
^ Gladwell, Malcolm (2000-03-10). "John Rock's Error". The New Yorker. Archived from the original on 2013-12-03. Retrieved 2013-11-30.

External links

[:28-1] "Amenorrhea". nichd.nih.gov/. Retrieved 2018-11-07.

[2] "Who is at risk of amenorrhea?". nichd.nih.gov/. Retrieved 2018-11-08.

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[4] "Absent menstrual periods - primary: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2018-11-07.

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[7] Gordon, Catherine M. (2010-07-22). "Clinical practice. Functional hypothalamic amenorrhea". The New England Journal of Medicine. 363 (4): 365–371. doi:10.1056/NEJMcp0912024. ISSN 1533-4406. PMID 20660404.

[:0-8] Nawaz, Gul; Rogol, Alan D. (2022), "Amenorrhea", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 29489290, retrieved 2022-02-17

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[10] Speroff L, Fritz MA (2005). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins (2005). p. 403ff. ISBN 978-0-7817-4795-0.

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[SperoffGlass19992-12] Speroff L, Glass RH, Kase NG (1 June 1999). Clinical gynecologic endocrinology and infertility. Lippincott Williams & Wilkins. ISBN 978-0-683-30379-7.

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[:25-16] Marsh, Courtney A.; Grimstad, Frances W. (2014-10). "Primary amenorrhea: diagnosis and management". Obstetrical & Gynecological Survey. 69 (10): 603–612. doi:10.1097/OGX.0000000000000111. ISSN 1533-9866. PMID 25336070. {{cite journal}}: Check date values in: |date= (help)

[:1-17] ^ ^a ^b ^c ^d ^e ^f Dabrowski, Elizabeth; Jensen, Rachel; Johnson, Emilie K.; Habiby, Reema L.; Brickman, Wendy J.; Finlayson, Courtney (2019). "Turner Syndrome Systematic Review: Spontaneous Thelarche and Menarche Stratified by Karyotype". Hormone Research in Paediatrics. 92 (3): 143–149. doi:10.1159/000502902. ISSN 1663-2826. PMID 31918426.

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[46] Tucker, Elena J.; Grover, Sonia R.; Bachelot, Anne; Touraine, Philippe; Sinclair, Andrew H. (2016-12). "Premature Ovarian Insufficiency: New Perspectives on Genetic Cause and Phenotypic Spectrum". Endocrine Reviews. 37 (6): 609–635. doi:10.1210/er.2016-1047. ISSN 1945-7189. PMID 27690531. {{cite journal}}: Check date values in: |date= (help)

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[50] Welt C. "Etiology, diagnosis, and treatment of secondary amenorrhea". Archived from the original on 2013-11-11.

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[Welt-52] Welt CK. "Etiology, diagnosis, and treatment of primary amenorrhea". Archived from the original on 2013-11-11.

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Nazem TG, Ackerman KE (July 2012). "The female athlete triad". Sports Health. 4 (4): 302–11. doi:10.1177/1941738112439685. PMC 3435916. PMID 23016101.

[55] De Souza MJ, Nattiv A, Joy E, Misra M, Williams NI, Mallinson RJ, Gibbs JC, Olmsted M, Goolsby M, Matheson G (February 2014). "2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad: 1st International Conference held in San Francisco, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013". British Journal of Sports Medicine. 48 (4): 289. doi:10.1136/bjsports-2013-093218. PMID 24463911.

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@@ Line 41: / Line 41: @@
 Secondary amenorrhoea is when 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="pmid166695592">{{cite journal|vauthors=Master-Hunter T, Heiman DL|date=April 2006|title=Amenorrhea: evaluation and treatment|url=http://www.aafp.org/afp/2006/0415/p1374.html|url-status=live|journal=American Family Physician|series=8|volume=73|issue=8|pages=1374–82|pmid=16669559|archive-url=https://web.archive.org/web/20131111220842/http://www.aafp.org/afp/2006/0415/p1374.html|archive-date=2013-11-11}}</ref> Examples of secondary amenorrhea include hypothyroidism, hyperthyroidism, hyperprolactinemia, polycystic ovarian syndrome, primary ovarian insufficiency, and functional hypothalamic amenorrhea.<ref name=":29">{{Cite journal|last=McGlacken-Byrne|first=Sinéad M.|last2=Conway|first2=Gerard S.|date=2021-11-16|title=Premature ovarian insufficiency|url=https://pubmed.ncbi.nlm.nih.gov/34924261|journal=Best Practice & Research. Clinical Obstetrics & Gynaecology|pages=S1521–6934(21)00167–X|doi=10.1016/j.bpobgyn.2021.09.011|issn=1532-1932|pmid=34924261}}</ref><ref name=":25">{{Cite journal|last=Marsh|first=Courtney A.|last2=Grimstad|first2=Frances W.|date=2014-10|title=Primary amenorrhea: diagnosis and management|url=https://pubmed.ncbi.nlm.nih.gov/25336070|journal=Obstetrical & Gynecological Survey|volume=69|issue=10|pages=603–612|doi=10.1097/OGX.0000000000000111|issn=1533-9866|pmid=25336070}}</ref>
-== Cause ==
+== Causes ==
-=== Low body weight ===
+=== Primary Amenorrhea ===
-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.<ref>{{cite journal | vauthors = Loucks AB, Verdun M, Heath EM | s2cid = 2927046 | title = Low energy availability, not stress of exercise, alters LH pulsatility in exercising women | journal = Journal of Applied Physiology | volume = 84 | issue = 1 | pages = 37–46 | date = January 1998 | pmid = 9451615 | doi = 10.1152/jappl.1998.84.1.37 }}</ref> 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>{{cite journal | vauthors = Frisch RE, McArthur JW | title = Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset | journal = Science | volume = 185 | issue = 4155 | pages = 949–51 | date = September 1974 | pmid = 4469672 | doi = 10.1126/science.185.4155.949 | bibcode = 1974Sci...185..949F | s2cid = 25005866 }}</ref>
+==== Turner's Syndrome ====
-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.<ref>{{cite journal | vauthors = Södersten P, Bergh C, Zandian M | title = Psychoneuroendocrinology of anorexia nervosa | journal = Psychoneuroendocrinology | volume = 31 | issue = 10 | pages = 1149–53 | date = November 2006 | pmid = 17084040 | doi = 10.1016/j.psyneuen.2006.09.006 | s2cid = 18379119 }}</ref> Elevated concentrations of ghrelin alter the  amplitude of [[GnRH]] pulses, which causes diminished pituitary release of [[Luteinizing hormone|LH]] and [[follicle-stimulating hormone]] (FSH).<ref name="pmid12519869">{{cite journal | vauthors = Loucks AB, Thuma JR | title = Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 1 | pages = 297–311 | date = January 2003 | pmid = 12519869 | doi = 10.1210/jc.2002-020369 | doi-access = free }}</ref>
+[[Turner syndrome|Turner's Syndrome,]] monosomy 45XO, is a genetic disorder characterized by a missing, or partially missing, X chromosome.<ref name=":1">{{Cite journal|last=Dabrowski|first=Elizabeth|last2=Jensen|first2=Rachel|last3=Johnson|first3=Emilie K.|last4=Habiby|first4=Reema L.|last5=Brickman|first5=Wendy J.|last6=Finlayson|first6=Courtney|date=2019|title=Turner Syndrome Systematic Review: Spontaneous Thelarche and Menarche Stratified by Karyotype|url=https://pubmed.ncbi.nlm.nih.gov/31918426|journal=Hormone Research in Paediatrics|volume=92|issue=3|pages=143–149|doi=10.1159/000502902|issn=1663-2826|pmid=31918426}}</ref> Turner's 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>{{Cite journal|last=Castelo-Branco|first=Camil|date=2014-12|title=Management of Turner syndrome in adult life and beyond|url=https://pubmed.ncbi.nlm.nih.gov/25438673|journal=Maturitas|volume=79|issue=4|pages=471–475|doi=10.1016/j.maturitas.2014.08.011|issn=1873-4111|pmid=25438673}}</ref> Most people with Turner's syndrome experience ovarian insufficiency within the first few years of life, prior to menarche.<ref name=":1" /> Therefore, most patients with Turner's 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 ====
-Secondary amenorrhea is caused by low levels of the hormone [[leptin]] in females with low body weight.<ref name="pmid9246675">{{cite journal | vauthors = Köpp W, Blum WF, von Prittwitz S, Ziegler A, Lübbert H, Emons G, Herzog W, Herpertz S, Deter HC, Remschmidt H, Hebebrand J | title = Low leptin levels predict amenorrhea in underweight and eating disordered females | journal = Molecular Psychiatry | volume = 2 | issue = 4 | pages = 335–40 | date = July 1997 | pmid = 9246675 | doi = 10.1038/sj.mp.4000287 | doi-access = free }}</ref> Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis.<ref>{{cite journal | vauthors = Chan JL, Matarese G, Shetty GK, Raciti P, Kelesidis I, Aufiero D, De Rosa V, Perna F, Fontana S, Mantzoros CS | title = Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 22 | pages = 8481–6 | date = May 2006 | pmid = 16714386 | pmc = 1482518 | doi = 10.1073/pnas.0505429103 | bibcode = 2006PNAS..103.8481C | doi-access = free }}</ref> Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing.
+[[MRKH]] (Mayer–Rokitansky–Küster–Hauser) syndrome is the second-most common cause of primary amenorrhoea.<ref name="pmid237257842">{{cite journal|vauthors=Rousset P, Raudrant D, Peyron N, Buy JN, Valette PJ, Hoeffel C|date=September 2013|title=Ultrasonography and MRI features of the Mayer-Rokitansky-Küster-Hauser syndrome|journal=Clinical Radiology|volume=68|issue=9|pages=945–52|doi=10.1016/j.crad.2013.04.005|pmid=23725784}}</ref> The syndrome is characterized by [[Müllerian agenesis]].<ref name=":15">{{Cite journal|last=Friedler|first=Shevach|last2=Grin|first2=Leonti|last3=Liberti|first3=Gad|last4=Saar-Ryss|first4=Buzhena|last5=Rabinson|first5=Yaakov|last6=Meltzer|first6=Semion|date=2016-01|title=The reproductive potential of patients with Mayer-Rokitansky-Küster-Hauser syndrome using gestational surrogacy: a systematic review|url=https://pubmed.ncbi.nlm.nih.gov/26626805|journal=Reproductive Biomedicine Online|volume=32|issue=1|pages=54–61|doi=10.1016/j.rbmo.2015.09.006|issn=1472-6491|pmid=26626805}}</ref> In MRKH Syndrome, the Müllerian ducts develop abnormally and result in the absence of a uterus and cervix.<ref name=":15" /> Even though patient's with MRKH have functioning ovaries, and therefore have secondary sexual characteristics, they experience primary amenorrhea since there is no functioning uterus.<ref name=":15" />
-{{Anchor|eating disorder|Eating disorders|Eating disorder|eating disorder}}
-When a woman is experiencing amenorrhoea, an [[eating disorder]], and [[osteoporosis]] together, this is called [[female athlete triad]] syndrome.<ref>{{Cite web|url=https://kidshealth.org/en/parents/bones-muscles-joints.html|title=Bones, Muscles, and Joints|website=kidshealth.org|language=en|access-date=2018-11-07}}</ref> A lack of eating causes amenorrhoea and bone loss leading to [[osteopenia]] and sometimes progressing to [[osteoporosis]].<ref>{{Cite web|url=https://www.bones.nih.gov/health-info/bone/osteoporosis/conditions-behaviors/anorexia-nervosa|title=What People With Anorexia Nervosa Need to Know About Osteoporosis {{!}} NIH Osteoporosis and Related Bone Diseases National Resource Center|website=bones.nih.gov|language=en|access-date=2018-11-07}}</ref>
+==== Constitutional Delay of Puberty ====
-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.<ref>{{cite web|last=Konstantinovsky|first=Michelle | name-list-style = vanc |title=Amenorrhea: Dieting to the extreme|date=26 February 2013 |url=http://www.sheknows.com/health-and-wellness/articles/814110/amenorrhea-dieting-to-the-extreme-1|url-status=live|archive-url=https://web.archive.org/web/20131203040840/http://www.sheknows.com/health-and-wellness/articles/814110/amenorrhea-dieting-to-the-extreme-1|archive-date=2013-12-03}}</ref> Increased testosterone levels cause by amenorrhoea may lead to body hair growth and decreased breast size.<ref>{{cite web|last=Hickson|first=Anna-Sofie| name-list-style = vanc |title=Amenorrhea Side Effects|url=http://www.livestrong.com/article/99448-amenorrhea-side-effects/|url-status=live|archive-url=https://web.archive.org/web/20131203054629/http://www.livestrong.com/article/99448-amenorrhea-side-effects/|archive-date=2013-12-03}}</ref> 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.<ref>{{cite journal|last=Comenitz|first=Linda| name-list-style = vanc |title=The psychological effects of secondary amenorrhea in women runners|journal=Clinical Social Work Journal|year=1983|volume=11|issue=1|pages=87–96|doi=10.1007/BF00755658|s2cid=143591523}}</ref>
+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">{{Cite journal|last=Master-Hunter|first=Tarannum|last2=Heiman|first2=Diana L.|date=2006-04-15|title=Amenorrhea: evaluation and treatment|url=https://pubmed.ncbi.nlm.nih.gov/16669559|journal=American Family Physician|volume=73|issue=8|pages=1374–1382|issn=0002-838X|pmid=16669559}}</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">{{Cite journal|last=Sedlmeyer|first=Ines L.|last2=Palmert|first2=Mark R.|date=2002-04|title=Delayed puberty: analysis of a large case series from an academic center|url=https://pubmed.ncbi.nlm.nih.gov/11932291|journal=The Journal of Clinical Endocrinology and Metabolism|volume=87|issue=4|pages=1613–1620|doi=10.1210/jcem.87.4.8395|issn=0021-972X|pmid=11932291}}</ref> This may be due to genetics, as some cases of constitutional delay of puberty are familial.<ref name=":17" />
-=== Drug-induced ===
+=== Secondary Amenorrhea ===
-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 [[Progestogen only pill|contain only progestogen]] like the oral contraceptive Micronor, and especially higher-dose formulations like the injectable [[Depo Provera]] commonly induce this [[adverse effect|side effect]]. [[Extended cycle combined hormonal contraceptive|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.<ref>{{cite web|last=Willacy|first=Hayley| name-list-style = vanc |title=Combined Oral Contraceptive (Follow-up and Common Problems)|url=http://www.patient.info/doctor/Combined-Oral-Contraceptive-(Follow-Up-and-Common-Problems).htm}}</ref> 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>{{cite journal | vauthors = Weisberg E | title = Fertility after discontinuation of oral contraceptives | journal = Clinical Reproduction and Fertility | volume = 1 | issue = 4 | pages = 261–72 | date = December 1982 | pmid = 6764883 }}</ref>  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.<ref name="pmid19209272">{{cite journal | vauthors = Wright KP, Johnson JV | title = Evaluation of extended and continuous use oral contraceptives | journal = Therapeutics and Clinical Risk Management | volume = 4 | issue = 5 | pages = 905–11 | date = October 2008 | pmid = 19209272 | pmc = 2621397 | doi = 10.2147/TCRM.S2143 }}</ref>
+====Breastfeeding====
-The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users.<ref>{{cite journal | vauthors = Santen FJ, Sofsky J, Bilic N, Lippert R | title = Mechanism of action of narcotics in the production of menstrual dysfunction in women | journal = Fertility and Sterility | volume = 26 | issue = 6 | pages = 538–48 | date = June 1975 | pmid = 236938 | doi = 10.1016/S0015-0282(16)41173-8 }}</ref><ref>{{cite journal | vauthors = Reddy RG, Aung T, Karavitaki N, Wass JA | title = Opioid induced hypogonadism | journal = BMJ | volume = 341 | pages = c4462 | date = August 2010 | pmid = 20807731 | pmc = 2974597 | doi = 10.1136/bmj.c4462 }}</ref>
+Physiologic amenorrhea is present before menarche, during pregnancy and breastfeeding, and after menopause.<ref name=":22">{{cite journal|vauthors=Master-Hunter T, Heiman DL|date=April 2006|title=Amenorrhea: evaluation and treatment|url=http://www.aafp.org/afp/20060415/1374.html|url-status=live|journal=American Family Physician|volume=73|issue=8|pages=1374–82|pmid=16669559|archive-url=https://web.archive.org/web/20080723214026/http://www.aafp.org/afp/20060415/1374.html|archive-date=2008-07-23}}</ref>
+Breastfeeding or lactational amenorrhea is also a common cause of secondary amenorrhoea.<ref>{{cite journal|vauthors=Lewis PR, Brown JB, Renfree MB, Short RV|date=March 1991|title=The resumption of ovulation and menstruation in a well-nourished population of women breastfeeding for an extended period of time|url=http://cat.inist.fr/?aModele=afficheN&cpsidt=19753535|url-status=live|journal=Fertility and Sterility|volume=55|issue=3|pages=529–36|doi=10.1016/S0015-0282(16)54180-6|pmid=2001754|archive-url=https://web.archive.org/web/20131111214939/http://cat.inist.fr/?aModele=afficheN&cpsidt=19753535|archive-date=2013-11-11}}</ref> Lactational amenorrhea is due to the presence of elevated prolactin and low levels of LH, which suppress ovarian hormone secretion.<ref name=":3">{{Cite journal|last=Edozien|first=L.|date=1994-09|title=The contraceptive benefit of breastfeeding|url=https://pubmed.ncbi.nlm.nih.gov/12318872|journal=Africa Health|volume=16|issue=6|pages=15, 17|issn=0141-9536|pmid=12318872}}</ref> Breastfeeding typically prolongs postpartum [[lactational amenorrhoea]], and the duration of amenorrhoea varies depending on how often a woman breastfeeds.<ref>{{cite web|title=Physiology of lactational amenorrhea and its implications for spacing of pregnancies|url=http://www.popline.org/node/310066|url-status=live|archive-url=https://web.archive.org/web/20131111220940/http://www.popline.org/node/310066|archive-date=2013-11-11|vauthors=Labbok M}}</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" />
-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.<ref name="pmid22711171">{{cite journal | vauthors = Wu RR, Jin H, Gao K, Twamley EW, Ou JJ, Shao P, Wang J, Guo XF, Davis JM, Chan PK, Zhao JP | title = Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study | journal = The American Journal of Psychiatry | volume = 169 | issue = 8 | pages = 813–21 | date = August 2012 | pmid = 22711171 | doi = 10.1176/appi.ajp.2012.11091432 }}</ref> 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.
+==== Diseases of the Thyroid ====
-===Breastfeeding===
+Disturbances in thyroid hormone regulation has been a known cause of menstrual irregularities, including secondary amenorrhea.<ref name=":4">{{Cite journal|last=Koutras|first=D. A.|date=1997-06-17|title=Disturbances of menstruation in thyroid disease|url=https://pubmed.ncbi.nlm.nih.gov/9238278|journal=Annals of the New York Academy of Sciences|volume=816|pages=280–284|doi=10.1111/j.1749-6632.1997.tb52152.x|issn=0077-8923|pmid=9238278}}</ref><ref>{{Cite journal|last=Krassas|first=G. E.|last2=Pontikides|first2=N.|last3=Kaltsas|first3=T.|last4=Papadopoulou|first4=P.|last5=Paunkovic|first5=J.|last6=Paunkovic|first6=N.|last7=Duntas|first7=L. H.|date=1999-05|title=Disturbances of menstruation in hypothyroidism|url=https://pubmed.ncbi.nlm.nih.gov/10468932|journal=Clinical Endocrinology|volume=50|issue=5|pages=655–659|doi=10.1046/j.1365-2265.1999.00719.x|issn=0300-0664|pmid=10468932}}</ref>
-Breastfeeding is a common cause of secondary amenorrhoea, and often the condition lasts for over six months.<ref>{{cite journal | vauthors = Lewis PR, Brown JB, Renfree MB, Short RV | title = The resumption of ovulation and menstruation in a well-nourished population of women breastfeeding for an extended period of time | journal = Fertility and Sterility | volume = 55 | issue = 3 | pages = 529–36 | date = March 1991 | pmid = 2001754 | url = http://cat.inist.fr/?aModele=afficheN&cpsidt=19753535 | archive-url = https://web.archive.org/web/20131111214939/http://cat.inist.fr/?aModele=afficheN&cpsidt=19753535 | url-status = live | archive-date = 2013-11-11 | doi = 10.1016/S0015-0282(16)54180-6 }}</ref> Breastfeeding typically lasts longer than [[lactational amenorrhoea]], and the duration of amenorrhoea varies depending on how often a woman breastfeeds.<ref>{{cite web| vauthors = Labbok M |title=Physiology of lactational amenorrhea and its implications for spacing of pregnancies|url=http://www.popline.org/node/310066|url-status=live|archive-url=https://web.archive.org/web/20131111220940/http://www.popline.org/node/310066|archive-date=2013-11-11}}</ref> 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.<ref>{{cite journal|last=Kennedy|first=Kathy| name-list-style = vanc |title=Lactation and contraception|journal=Ginecologia y Obstetricia de Mexico|date=April–May 1990|volume=58|issue=1|pages=25–34|pmid=2276655|url=http://pdf.usaid.gov/pdf_docs/PNABG104.pdf|url-status=live|archive-url=https://web.archive.org/web/20131111232405/http://pdf.usaid.gov/pdf_docs/PNABG104.pdf|archive-date=2013-11-11}}</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" />
-===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.<ref name="TersigniCastellani2014">{{cite journal | vauthors = Tersigni C, Castellani R, de Waure C, Fattorossi A, De Spirito M, Gasbarrini A, Scambia G, Di Simone N | title = Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms | journal = Human Reproduction Update | volume = 20 | issue = 4 | pages = 582–93 | year = 2014 | pmid = 24619876 | doi = 10.1093/humupd/dmu007 | doi-access = free }}{{free access}}</ref><ref name=SacconeBerghella2015>{{cite journal | vauthors = Saccone G, Berghella V, Sarno L, Maruotti GM, Cetin I, Greco L, Khashan AS, McCarthy F, Martinelli D, Fortunato F, Martinelli P | title = Celiac disease and obstetric complications: a systematic review and metaanalysis | journal = American Journal of Obstetrics and Gynecology | volume = 214 | issue = 2 | pages = 225–234 | date = February 2016 | pmid = 26432464 | doi = 10.1016/j.ajog.2015.09.080 }}</ref>
+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" />
-===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.<ref name="pmid23725784">{{cite journal | vauthors = Rousset P, Raudrant D, Peyron N, Buy JN, Valette PJ, Hoeffel C | title = Ultrasonography and MRI features of the Mayer-Rokitansky-Küster-Hauser syndrome | journal = Clinical Radiology | volume = 68 | issue = 9 | pages = 945–52 | date = September 2013 | pmid = 23725784 | doi = 10.1016/j.crad.2013.04.005 }}</ref> The syndrome is characterized by [[Müllerian agenesis]]. In MRKH Syndrome, the Müllerian ducts develop abnormally and can result in [[vaginal anomalies|vaginal obstructions]] preventing menstruation. The syndrome develops prenatally early in the development of the female reproductive system.
+==== Hypothalamic and Pituitary Causes ====
-===Stress===
+Changes in the hypothalamic-pituitary axis is a common cause of secondary amenorrhea.<ref name=":22" /> GnRH is released form 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=":22" /> Any pathology in the hypothalamus or pituitary can alter the way this feedback mechanism works and can cause secondary amenorrhea.<ref name=":22" />
-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.<ref name="Newson">{{cite web|last=Newson|first=Louise| name-list-style = vanc |title=Amenorrhea|url=http://www.patient.info/doctor/amenorrhea}}</ref><ref name="Welt">{{cite web|last=Welt|first=Corrine K| name-list-style = vanc |title=Etiology, diagnosis, and treatment of primary amenorrhea|url=http://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-primary-amenorrhea?detectedLanguage=en&source=search_result&search=diagnosis+and+treatment+of+secondary+amenorrhea&selectedTitle=3~27&provider=noProvider|url-status=live|archive-url=https://web.archive.org/web/20131111220327/http://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-primary-amenorrhea?detectedLanguage=en&source=search_result&search=diagnosis+and+treatment+of+secondary+amenorrhea&selectedTitle=3~27&provider=noProvider|archive-date=2013-11-11}}</ref>
+Pituitary adenomas are a common cause of amenorrhea.<ref name=":18">{{Cite journal|last=Molitch|first=Mark E.|date=2017-02-07|title=Diagnosis and Treatment of Pituitary Adenomas: A Review|url=https://pubmed.ncbi.nlm.nih.gov/28170483|journal=JAMA|volume=317|issue=5|pages=516–524|doi=10.1001/jama.2016.19699|issn=1538-3598|pmid=28170483}}</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>{{Cite web|date=2019-01-17|title=Primary Amenorrhea due to Pituitary Disease|url=https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/labmed/primary-amenorrhea-due-to-pituitary-disease/|access-date=2022-02-21|website=Cancer Therapy Advisor|language=en-US}}</ref>
+==== Polycystic Ovary Syndrome ====
+[[Polycystic ovary syndrome]] (PCOS) is a common endocrine disorder affecting 4-8% of women worldwide.<ref name=":5">{{Cite journal|last=Franik|first=Sebastian|last2=Eltrop|first2=Stephanie M.|last3=Kremer|first3=Jan Am|last4=Kiesel|first4=Ludwig|last5=Farquhar|first5=Cindy|date=2018-05-24|title=Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/29797697|journal=The Cochrane Database of Systematic Reviews|volume=5|pages=CD010287|doi=10.1002/14651858.CD010287.pub3|issn=1469-493X|pmc=6494577|pmid=29797697}}</ref> It is characterized my 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=":6">{{Cite journal|last=Ibáñez|first=Lourdes|last2=Oberfield|first2=Sharon E.|last3=Witchel|first3=Selma|last4=Auchus|first4=Richard J.|last5=Chang|first5=R. Jeffrey|last6=Codner|first6=Ethel|last7=Dabadghao|first7=Preeti|last8=Darendeliler|first8=Feyza|last9=Elbarbary|first9=Nancy Samir|last10=Gambineri|first10=Alessandra|last11=Garcia Rudaz|first11=Cecilia|date=2017|title=An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence|url=https://pubmed.ncbi.nlm.nih.gov/29156452|journal=Hormone Research in Paediatrics|volume=88|issue=6|pages=371–395|doi=10.1159/000479371|issn=1663-2826|pmid=29156452}}</ref> PCOS may also be a cause of primary amenorrhea if androgen access is present prior to menarche.<ref name=":6" /> Although multiple cysts on the ovary are characteristic of the syndrome, this has not been noted to be a cause of the disease.<ref>{{Cite journal|last=Ibáñez|first=Lourdes|last2=Oberfield|first2=Sharon E.|last3=Witchel|first3=Selma|last4=Auchus|first4=Richard J.|last5=Chang|first5=R. Jeffrey|last6=Codner|first6=Ethel|last7=Dabadghao|first7=Preeti|last8=Darendeliler|first8=Feyza|last9=Elbarbary|first9=Nancy Samir|last10=Gambineri|first10=Alessandra|last11=Garcia Rudaz|first11=Cecilia|date=2017|title=An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence|url=https://pubmed.ncbi.nlm.nih.gov/29156452|journal=Hormone Research in Paediatrics|volume=88|issue=6|pages=371–395|doi=10.1159/000479371|issn=1663-2826|pmid=29156452}}</ref>
+==== 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.<ref name=":19">{{cite journal|vauthors=Loucks AB, Verdun M, Heath EM|date=January 1998|title=Low energy availability, not stress of exercise, alters LH pulsatility in exercising women|journal=Journal of Applied Physiology|volume=84|issue=1|pages=37–46|doi=10.1152/jappl.1998.84.1.37|pmid=9451615|s2cid=2927046}}</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>{{cite journal|vauthors=Frisch RE, McArthur JW|date=September 1974|title=Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset|journal=Science|volume=185|issue=4155|pages=949–51|bibcode=1974Sci...185..949F|doi=10.1126/science.185.4155.949|pmid=4469672|s2cid=25005866}}</ref> Amenorrhoea is often associated with anorexia nervosa and other eating disorders.<ref name=":20">{{Cite web|title=Bones, Muscles, and Joints|url=https://kidshealth.org/en/parents/bones-muscles-joints.html|access-date=2018-11-07|website=kidshealth.org|language=en}}</ref> 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">{{cite journal|vauthors=Södersten P, Bergh C, Zandian M|date=November 2006|title=Psychoneuroendocrinology of anorexia nervosa|journal=Psychoneuroendocrinology|volume=31|issue=10|pages=1149–53|doi=10.1016/j.psyneuen.2006.09.006|pmid=17084040|s2cid=18379119}}</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 [[Luteinizing hormone|LH]] and [[follicle-stimulating hormone]] (FSH).<ref name="pmid125198692">{{cite journal|vauthors=Loucks AB, Thuma JR|date=January 2003|title=Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=1|pages=297–311|doi=10.1210/jc.2002-020369|pmid=12519869|doi-access=free}}</ref> Low levels of the hormone [[leptin]] are also seen in females with low body weight.<ref name="pmid92466752">{{cite journal|vauthors=Köpp W, Blum WF, von Prittwitz S, Ziegler A, Lübbert H, Emons G, Herzog W, Herpertz S, Deter HC, Remschmidt H, Hebebrand J|date=July 1997|title=Low leptin levels predict amenorrhea in underweight and eating disordered females|journal=Molecular Psychiatry|volume=2|issue=4|pages=335–40|doi=10.1038/sj.mp.4000287|pmid=9246675|doi-access=free}}</ref> Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis.<ref name=":22" /> Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing.<ref name=":22" />
+==== Drug-induced ====
+Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman.<ref name=":23">{{cite journal|vauthors=Weisberg E|date=December 1982|title=Fertility after discontinuation of oral contraceptives|journal=Clinical Reproduction and Fertility|volume=1|issue=4|pages=261–72|pmid=6764883}}</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 [[Adverse effect|side effect]].<ref name="pmid192092722">{{cite journal|vauthors=Wright KP, Johnson JV|date=October 2008|title=Evaluation of extended and continuous use oral contraceptives|journal=Therapeutics and Clinical Risk Management|volume=4|issue=5|pages=905–11|doi=10.2147/TCRM.S2143|pmc=2621397|pmid=19209272}}</ref><ref name=":24">{{cite web|last=Willacy|first=Hayley|name-list-style=vanc|title=Combined Oral Contraceptive (Follow-up and Common Problems)|url=http://www.patient.info/doctor/Combined-Oral-Contraceptive-(Follow-Up-and-Common-Problems).htm}}</ref> Extended cycle use of combined hormonal contraceptives also allow suppression of menstruation. Patients who stop using [[combined oral contraceptive pill]]<nowiki/>s (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 7 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 1 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>{{cite journal|vauthors=Santen FJ, Sofsky J, Bilic N, Lippert R|date=June 1975|title=Mechanism of action of narcotics in the production of menstrual dysfunction in women|journal=Fertility and Sterility|volume=26|issue=6|pages=538–48|doi=10.1016/S0015-0282(16)41173-8|pmid=236938}}</ref><ref>{{cite journal|vauthors=Reddy RG, Aung T, Karavitaki N, Wass JA|date=August 2010|title=Opioid induced hypogonadism|journal=BMJ|volume=341|pages=c4462|doi=10.1136/bmj.c4462|pmc=2974597|pmid=20807731}}</ref>
+Anti-psychotic drugs, which are commonly used to treat [[schizophrenia]], have been known to cause amenorrhoea as well.<ref name="pmid227111712">{{cite journal|vauthors=Wu RR, Jin H, Gao K, Twamley EW, Ou JJ, Shao P, Wang J, Guo XF, Davis JM, Chan PK, Zhao JP|date=August 2012|title=Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study|journal=The American Journal of Psychiatry|volume=169|issue=8|pages=813–21|doi=10.1176/appi.ajp.2012.11091432|pmid=22711171}}</ref> Research suggests that anti-psychotic medications effect 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>{{Cite journal|last=Tucker|first=Elena J.|last2=Grover|first2=Sonia R.|last3=Bachelot|first3=Anne|last4=Touraine|first4=Philippe|last5=Sinclair|first5=Andrew H.|date=2016-12|title=Premature Ovarian Insufficiency: New Perspectives on Genetic Cause and Phenotypic Spectrum|url=https://pubmed.ncbi.nlm.nih.gov/27690531|journal=Endocrine Reviews|volume=37|issue=6|pages=609–635|doi=10.1210/er.2016-1047|issn=1945-7189|pmid=27690531}}</ref> Although the cause of POI can vary, it has been linked to chromosomal abnormalities, chemotherapy, and autoimmune conditions.<ref name=":292">{{Cite journal|last=McGlacken-Byrne|first=Sinéad M.|last2=Conway|first2=Gerard S.|date=2021-11-16|title=Premature ovarian insufficiency|url=https://pubmed.ncbi.nlm.nih.gov/34924261|journal=Best Practice & Research. Clinical Obstetrics & Gynaecology|pages=S1521–6934(21)00167–X|doi=10.1016/j.bpobgyn.2021.09.011|issn=1532-1932|pmid=34924261}}</ref> Hormone levels in POI are similar to menopause and are categorized by low estradiol and high levels of gonadotropins.<ref name="pmid166695593">{{cite journal|vauthors=Master-Hunter T, Heiman DL|date=April 2006|title=Amenorrhea: evaluation and treatment|url=http://www.aafp.org/afp/2006/0415/p1374.html|url-status=live|journal=American Family Physician|series=8|volume=73|issue=8|pages=1374–82|pmid=16669559|archive-url=https://web.archive.org/web/20131111220842/http://www.aafp.org/afp/2006/0415/p1374.html|archive-date=2013-11-11}}</ref> 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="pmid166695593" />
 ==Diagnosis==
@@ Line 80: / Line 98: @@
 ===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.<ref>{{cite web|last=Welt|first=Corrine| name-list-style = vanc |title=Etiology, diagnosis, and treatment of secondary amenorrhea|url=http://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-secondary-amenorrhea?detectedLanguage=en&source=search_result&search=diagnosis+and+treatment+of+secondary+amenorrhea&selectedTitle=1~27&provider=noProvider|url-status=live|archive-url=https://web.archive.org/web/20131111220236/http://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-secondary-amenorrhea?detectedLanguage=en&source=search_result&search=diagnosis+and+treatment+of+secondary+amenorrhea&selectedTitle=1~27&provider=noProvider|archive-date=2013-11-11}}</ref> 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.<ref name="Newson"/><ref name="Welt"/>
+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.<ref>{{cite web|last=Welt|first=Corrine| name-list-style = vanc |title=Etiology, diagnosis, and treatment of secondary amenorrhea|url=http://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-secondary-amenorrhea?detectedLanguage=en&source=search_result&search=diagnosis+and+treatment+of+secondary+amenorrhea&selectedTitle=1~27&provider=noProvider|url-status=live|archive-url=https://web.archive.org/web/20131111220236/http://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-secondary-amenorrhea?detectedLanguage=en&source=search_result&search=diagnosis+and+treatment+of+secondary+amenorrhea&selectedTitle=1~27&provider=noProvider|archive-date=2013-11-11}}</ref> 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.<ref name="Newson">{{cite web|last=Newson|first=Louise|name-list-style=vanc|title=Amenorrhea|url=http://www.patient.info/doctor/amenorrhea}}</ref><ref name="Welt">{{cite web|last=Welt|first=Corrine K|name-list-style=vanc|title=Etiology, diagnosis, and treatment of primary amenorrhea|url=http://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-primary-amenorrhea?detectedLanguage=en&source=search_result&search=diagnosis+and+treatment+of+secondary+amenorrhea&selectedTitle=3~27&provider=noProvider|url-status=live|archive-url=https://web.archive.org/web/20131111220327/http://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-primary-amenorrhea?detectedLanguage=en&source=search_result&search=diagnosis+and+treatment+of+secondary+amenorrhea&selectedTitle=3~27&provider=noProvider|archive-date=2013-11-11}}</ref>
 == Treatments ==

Classification	D ICD-10: N91.0-N91.2 ICD-9-CM: 626.0 MeSH: D000568 DiseasesDB: 14843
External resources	MedlinePlus: 001218 eMedicine: article/953850 Patient UK: Amenorrhea