Medicine:Amenorrhea

From HandWiki
Short description: Absence of a menstrual period in a woman of reproductive age
Amenorrhea
Other namesAmenorrhea, amenorrhœa
SpecialtyGynecology

Amenorrhea is the absence of a menstrual period in a female who has reached 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 from 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 syndrome, and Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome.[13][14]

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.[15] Examples of secondary amenorrhea include hypothyroidism, hyperthyroidism, hyperprolactinemia, polycystic ovarian syndrome, primary ovarian insufficiency, and functional hypothalamic amenorrhea.[16][17]

Causes

Primary amenorrhea

Turner syndrome

Turner syndrome, monosomy 45XO, is a genetic disorder characterized by a missing, or partially missing, X chromosome.[18] Turner syndrome is associated with a wide spectrum of features that vary with each case.[18] However, one common feature of this syndrome is ovarian insufficiency due to gonadal dysgenesis.[18][19] Most people with Turner syndrome experience ovarian insufficiency within the first few years of life, prior to menarche.[18] Therefore, most patients with Turner syndrome will have primary amenorrhea.[18] 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.[18]

MRKH

MRKH (Mayer–Rokitansky–Küster–Hauser) syndrome is the second-most common cause of primary amenorrhoea.[20] The syndrome is characterized by Müllerian agenesis.[21] In MRKH Syndrome, the Müllerian ducts develop abnormally and result in the absence of a uterus and cervix.[21] 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.[21]

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.[22][23]

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.[24] Constitutional delay of puberty is not due to a pathologic cause. It is considered a variant of the timeline of puberty.[24] 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.[25] This may be due to genetics, as some cases of constitutional delay of puberty are familial.[25]

Secondary amenorrhea

Breastfeeding

Physiologic amenorrhea is present before menarche, during pregnancy and breastfeeding, and after menopause.[3]

Breastfeeding or lactational amenorrhea is also a common cause of secondary amenorrhoea.[26] Lactational amenorrhea is due to the presence of elevated prolactin and low levels of LH, which suppress ovarian hormone secretion.[27] Breastfeeding typically prolongs postpartum lactational amenorrhoea, and the duration of amenorrhoea varies depending on how often a woman breastfeeds.[28] 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.[27]

Diseases of the thyroid

Disturbances in thyroid hormone regulation has been a known cause of menstrual irregularities, including secondary amenorrhea.[29][30]

Patients with hypothyroidism frequently present with changes in their menstrual cycle.[29] It is hypothesized that this is due to increased TRH, which goes on to stimulate the release of both TSH and prolactin.[29] Increased prolactin inhibits the release of LH and FSH which are needed for ovulation to occur.[29]

Patients with hyperthyroidism may also present with oligomenorrhea or amenorrhea.[29] Sex hormone binding globulin is increased in hyperthyroid states.[29] This, in turn, increases the total levels of testosterone and estradiol.[29] Increased levels of LH and FSH have also been reported in patients with hyperthyroidism.[29]

Hypothalamic and pituitary causes

Changes in the hypothalamic-pituitary axis is a common cause of secondary amenorrhea.[3] 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.[3] Any pathology in the hypothalamus or pituitary can alter the way this feedback mechanism works and can cause secondary amenorrhea.[3]

Pituitary adenomas are a common cause of amenorrhea.[31] Prolactin secreting pituitary adenomas cause amenorrhea due to the hyper-secretion of prolactin which inhibits FSH and LH release.[31] 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.[32]

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 4–8% of women worldwide.[33] It is characterized by multiple cysts on the ovary, amenorrhea or oligomenorrhea, and increased androgens.[33] Although the exact cause remains unknown, it is hypothesized that increased levels of circulating androgens is what results in secondary amenorrhea.[34] PCOS may also be a cause of primary amenorrhea if androgen access is present prior to menarche.[34] Although multiple cysts on the ovary are characteristic of the syndrome, this has not been noted to be a cause of the disease.[34]

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.[35] Functional hypothalamic amenorrhoea (FHA) can be caused by stress, weight loss, or excessive exercise.[35] Many women who diet or who exercise at a high level do not take in enough calories to maintain their normal menstrual cycles.[35] 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.[36] Amenorrhoea is often associated with anorexia nervosa and other eating disorders.[37] Relative energy deficiency in sport, also known as the female athlete triad, is when a woman experiences amenorrhoea, disordered eating, and osteoporosis.[37]

Energy imbalance and weight loss can disrupt menstrual cycles through several hormonal mechanisms.[38] Weight loss can cause elevations in the hormone ghrelin which inhibits the hypothalamic-pituitary-ovarial axis.[38] Elevated concentrations of ghrelin alter the amplitude of GnRH pulses, which causes diminished pituitary release of LH and follicle-stimulating hormone (FSH).[39] Low levels of the hormone leptin are also seen in females with low body weight.[40] Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis.[3] Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing.[3]

Drug-induced

Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman.[41] The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping its use.[41] 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.[42][43] 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.[43] 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.[41] 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.[42] Studies show that women are most likely to experience amenorrhoea after one year of treatment with continuous OCP use.[42]

The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users.[44][45]

Anti-psychotic drugs, which are commonly used to treat schizophrenia, have been known to cause amenorrhoea as well.[46] Research suggests that anti-psychotic medications affect levels of prolactin, insulin, FSH, LH, and testosterone.[46] Recent research suggests that adding a dosage of Metformin to an anti-psychotic drug regimen can restore menstruation.[46] Metformin has been shown to decrease resistance to the hormone insulin, as well as levels of prolactin, testosterone, and luteinizing hormone (LH).[46]

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.[47] Although the cause of POI can vary, it has been linked to chromosomal abnormalities, chemotherapy, and autoimmune conditions.[16] Hormone levels in POI are similar to menopause and are categorized by low estradiol and high levels of gonadotropins.[15] 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.[15]

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.[15] 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.[13] Gonadal dysgenesis, often associated with Turner syndrome, or premature ovarian failure may also be to blame.[17] If secondary sex characteristics are present, but menstruation is not, primary amenorrhoea can be diagnosed by age 16.[17]

Evaluation of primary amenorrhea begins with a pregnancy test, prolactin, FSH, LH, and TSH levels.[13] Abnormal TSH levels prompt evaluation for hyper- and hypo-thyroidism with additional thyroid function tests.[13] Elevated prolactin levels prompt evaluation of the pituitary with an MRI to assess for any masses or malignancies.[13] A pelvic ultrasound can also be obtained in the initial evaluation.[13] If a uterus is not present on ultrasound, karyotype analysis and testosterone levels are obtained to assess for MRKH or androgen insensitivity syndrome.[48] If a uterus is present, LH and FSH levels are used to make a diagnosis.[13] Low levels of LH and FSH suggest delayed puberty or functional hypothalamic amenorrhea.[13] Elevated levels of FSH and LH suggest primary ovarian insufficiency, typically due to Turner syndrome.[13] Normal levels of FSH and LH can suggest an anatomical outflow obstruction.[13][48][49]

Secondary amenorrhea

Secondary amenorrhea's most common and most easily diagnosable causes are pregnancy, thyroid disease, and hyperprolactinemia.[50] A pregnancy test is a common first step for diagnosis.[50]

Similar to primary amenorrhea, evaluation of secondary amenorrhea also begins with a pregnancy test, prolactin, FSH, LH, and TSH levels.[13] A pelvic ultrasound is also obtained.[13] Abnormal TSH should prompt a thyroid workup with a full thyroid function test panel.[13] Elevated prolactin should be followed with an MRI to look for masses.[51][13] If LH and FSH are elevated, menopause or primary ovarian insufficiency should be considered.[13] Normal or low levels of FSH and LH prompts further evaluation with patient history and the physical exam.[13] Testosterone, DHEA-S, and 17-hydroxyprogesterone levels should be obtained if there is evidence of excess androgens, such as hirsutism or acne.[13] 17-hydroxyprogesterone is elevated in congenital adrenal hyperplasia.[13] Elevated testosterone and amenorrhea can suggest PCOS.[13][34] Elevated androgens can also be present in ovarian or adrenal tumors, so additional imaging may also be needed.[13] History of disordered eating or excessive exercise should raise concern for hypothalamic amenorrhea.[52] Headache, vomiting, and vision changes can be signs of a tumor and needs evaluation with MRI.[13] Finally, a history of gynecologic procedures should lead to evaluation of Asherman syndrome with a hysteroscopy or progesterone withdrawal bleeding test.[13][49]

Treatment

Treatment for amenorrhea varies based on the underlying condition.[53] Treatment not only focuses on restoring menstruation, if possible, but also preventing additional complications associated with the underlying cause of amenorrhea.[3]

Primary amenorrhea

In primary amenorrhea, the goal is to continue pubertal development, if possible.[3] For example, most patients with Turner syndrome will be infertile due to gonadal dysgenesis.[54] However, patients are frequently prescribed growth hormone therapy and estrogen supplementation to achieve taller stature and prevent osteoporosis.[54] In other cases, such as MRKH, hormones do not need to be prescribed since the ovaries are able to function normally.[55] 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.[56]

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.[7] Multidisciplinary treatment with monitoring from a physician, dietitian, and mental health counselor is recommended, along with support from family, friends, and coaches.[7] 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.[7]

Patients with hyperprolactinemia are often treated with dopamine agonists to reduce the levels of prolactin and restore menstruation.[51] Surgery and radiation may also be considered if dopamine agonists, such as cabergoline and bromocriptine are ineffective.[51] Once prolactin levels are lowered, the resulting secondary amenorrhea is typically resolved.[51] Similarly, treatment of thyroid abnormalities often resolves the associated amenorrhea.[57] For example, administration of thyroxine in patients with low thyroid levels restored normal menstruation in a majority of patients.[57]

Although there is currently no definitive treatment for PCOS, various interventions are used to restore more frequent ovulation in patients.[34] Weight loss and exercise have been associated with a return of ovulation in patients with PCOS due to normalization of androgen levels.[34] Metformin has also been recently studied to regularize menstrual cycles in patients with PCOS.[34] 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.[34] Anti-androgen medications, such as spironolactone, can also be used to lower body androgen levels and restore menstruation.[34] 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.[34]

References

  1. ↑ 1.0 1.1 1.2 "Amenorrhea" (in en). 31 January 2017. https://www.nichd.nih.gov/health/topics/amenorrhea. 
  2. ↑ "Who is at risk of amenorrhea?". 31 January 2017. https://www.nichd.nih.gov/health/topics/amenorrhea/conditioninfo/risk. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 "Amenorrhea: evaluation and treatment". American Family Physician 73 (8): 1374–82. April 2006. PMID 16669559. http://www.aafp.org/afp/20060415/1374.html. 
  4. ↑ "Absent menstrual periods - primary: MedlinePlus Medical Encyclopedia" (in en). https://medlineplus.gov/ency/article/001218.htm. 
  5. ↑ Fitzpatrick, Kathleen Kara; Lock, James (2011-04-11). "Anorexia nervosa". BMJ Clinical Evidence 2011: 1011. ISSN 1752-8526. PMID 21481284. 
  6. ↑ Broome, J. D.; Vancaillie, T. G. (June 1999). "Fluoroscopically guided hysteroscopic division of adhesions in severe Asherman syndrome". Obstetrics and Gynecology 93 (6): 1041–1043. doi:10.1016/s0029-7844(99)00245-8. ISSN 0029-7844. PMID 10362178. https://pubmed.ncbi.nlm.nih.gov/10362178. 
  7. ↑ 7.0 7.1 7.2 7.3 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. https://pubmed.ncbi.nlm.nih.gov/20660404. 
  8. ↑ 8.0 8.1 8.2 8.3 Nawaz, Gul; Rogol, Alan D. (2022), "Amenorrhea", StatPearls (Treasure Island (FL): StatPearls Publishing), PMID 29489290, http://www.ncbi.nlm.nih.gov/books/NBK482168/, retrieved 2022-02-17 
  9. ↑ 9.0 9.1 9.2 9.3 Nath, Chandan K.; Barman, Bhupen; Das, Ananya; Rajkhowa, Purnima; Baruah, Polina; Baruah, Mriganka; Baruah, Arup (January 2019). "Prolactin and thyroid stimulating hormone affecting the pattern of LH/FSH secretion in patients with polycystic ovary syndrome: A hospital-based study from North East India". Journal of Family Medicine and Primary Care 8 (1): 256–260. doi:10.4103/jfmpc.jfmpc_281_18. ISSN 2249-4863. PMID 30911516. 
  10. ↑ Clinical Gynecologic Endocrinology and Infertility.. Lippincott Williams & Wilkins (2005). 2005. p. 403ff. ISBN 978-0-7817-4795-0. 
  11. ↑ "Amenorrhea, Primary: eMedicine Obstetrics and Gynecology". http://emedicine.medscape.com/article/252928-overview. 
  12. ↑ Speroff, Leon; Glass, Robert H.; Kase, Nathan G. (1 June 1999). Clinical gynecologic endocrinology and infertility. Lippincott Williams & Wilkins. ISBN 978-0-683-30379-7. https://books.google.com/books?id=yORsAAAAMAAJ. 
  13. ↑ 13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 13.10 13.11 13.12 13.13 13.14 13.15 13.16 13.17 13.18 13.19 13.20 13.21 Klein, David A.; Poth, Merrily A. (2013-06-01). "Amenorrhea: an approach to diagnosis and management". American Family Physician 87 (11): 781–788. ISSN 1532-0650. PMID 23939500. https://pubmed.ncbi.nlm.nih.gov/23939500. 
  14. ↑ Gündoğdu, Elif; Emekli, Emre; Oğuzman, Mehmet; Kebapçı, Mahmut (2019-09-25). "Evaluation of the abdominopelvic region using MRI in patients with primary amenorrhea". Journal of Pediatric Endocrinology and Metabolism 32 (9): 995–1003. doi:10.1515/jpem-2019-0223. ISSN 2191-0251. PMID 31369396. https://www.degruyter.com/document/doi/10.1515/jpem-2019-0223/html. 
  15. ↑ 15.0 15.1 15.2 15.3 "Amenorrhea: evaluation and treatment". American Family Physician. 8 73 (8): 1374–82. April 2006. PMID 16669559. http://www.aafp.org/afp/2006/0415/p1374.html. 
  16. ↑ 16.0 16.1 McGlacken-Byrne, Sinéad M.; Conway, Gerard S. (2021-11-16). "Premature ovarian insufficiency". Best Practice & Research. Clinical Obstetrics & Gynaecology 81: S1521–6934(21)00167–X. doi:10.1016/j.bpobgyn.2021.09.011. ISSN 1532-1932. PMID 34924261. https://pubmed.ncbi.nlm.nih.gov/34924261. 
  17. ↑ 17.0 17.1 17.2 Marsh, Courtney A.; Grimstad, Frances W. (October 2014). "Primary amenorrhea: diagnosis and management". Obstetrical & Gynecological Survey 69 (10): 603–612. doi:10.1097/OGX.0000000000000111. ISSN 1533-9866. PMID 25336070. https://pubmed.ncbi.nlm.nih.gov/25336070. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 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. 
  19. ↑ Castelo-Branco, Camil (December 2014). "Management of Turner syndrome in adult life and beyond". Maturitas 79 (4): 471–475. doi:10.1016/j.maturitas.2014.08.011. ISSN 1873-4111. PMID 25438673. https://pubmed.ncbi.nlm.nih.gov/25438673. 
  20. ↑ "Ultrasonography and MRI features of the Mayer-Rokitansky-Küster-Hauser syndrome". Clinical Radiology 68 (9): 945–52. September 2013. doi:10.1016/j.crad.2013.04.005. PMID 23725784. 
  21. ↑ 21.0 21.1 21.2 Friedler, Shevach; Grin, Leonti; Liberti, Gad; Saar-Ryss, Buzhena; Rabinson, Yaakov; Meltzer, Semion (January 2016). "The reproductive potential of patients with Mayer-Rokitansky-Küster-Hauser syndrome using gestational surrogacy: a systematic review". Reproductive Biomedicine Online 32 (1): 54–61. doi:10.1016/j.rbmo.2015.09.006. ISSN 1472-6491. PMID 26626805. 
  22. ↑ Maleki, N; Kalantar Hormozi, M; Iranparvar Alamdari, M; Tavosi, Z (2013). "5-alpha-reductase 2 deficiency in a woman with primary amenorrhea.". Case Reports in Endocrinology 2013: 631060. doi:10.1155/2013/631060. PMID 24383016. 
  23. ↑ Jarzabek, Katarzyna; Philibert, Pascal; Koda, Mariusz; Sulkowski, Stanislaw; Kotula-Balak, Malgorzata; Bilinska, Barbara; Kottler, Marie-Laure; Wolczynski, Slawomir et al. (January 2007). "Primary amenorrhea in a young Polish woman with complete androgen insensitivity syndrome and Sertoli–Leydig cell tumor: Identification of a new androgen receptor gene mutation and evidence of aromatase hyperactivity and apoptosis dysregulation within the tumor" (in en). Gynecological Endocrinology 23 (9): 499–504. doi:10.1080/09513590701553852. ISSN 0951-3590. PMID 17852420. https://doi.org/10.1080/09513590701553852. 
  24. ↑ 24.0 24.1 Master-Hunter, Tarannum; Heiman, Diana L. (2006-04-15). "Amenorrhea: evaluation and treatment". American Family Physician 73 (8): 1374–1382. ISSN 0002-838X. PMID 16669559. https://pubmed.ncbi.nlm.nih.gov/16669559. 
  25. ↑ 25.0 25.1 Sedlmeyer, Ines L.; Palmert, Mark R. (April 2002). "Delayed puberty: analysis of a large case series from an academic center". The Journal of Clinical Endocrinology and Metabolism 87 (4): 1613–1620. doi:10.1210/jcem.87.4.8395. ISSN 0021-972X. PMID 11932291. 
  26. ↑ "The resumption of ovulation and menstruation in a well-nourished population of women breastfeeding for an extended period of time". Fertility and Sterility 55 (3): 529–36. March 1991. doi:10.1016/S0015-0282(16)54180-6. PMID 2001754. http://cat.inist.fr/?aModele=afficheN&cpsidt=19753535. 
  27. ↑ 27.0 27.1 Edozien, L. (September 1994). "The contraceptive benefit of breastfeeding". Africa Health 16 (6): 15, 17. ISSN 0141-9536. PMID 12318872. https://pubmed.ncbi.nlm.nih.gov/12318872. 
  28. ↑ "Physiology of lactational amenorrhea and its implications for spacing of pregnancies". http://www.popline.org/node/310066. 
  29. ↑ 29.0 29.1 29.2 29.3 29.4 29.5 29.6 29.7 Koutras, D. A. (1997-06-17). "Disturbances of menstruation in thyroid disease". Annals of the New York Academy of Sciences 816 (1): 280–284. doi:10.1111/j.1749-6632.1997.tb52152.x. ISSN 0077-8923. PMID 9238278. Bibcode: 1997NYASA.816..280K. https://pubmed.ncbi.nlm.nih.gov/9238278. 
  30. ↑ Krassas, G. E.; Pontikides, N.; Kaltsas, T.; Papadopoulou, P.; Paunkovic, J.; Paunkovic, N.; Duntas, L. H. (May 1999). "Disturbances of menstruation in hypothyroidism". Clinical Endocrinology 50 (5): 655–659. doi:10.1046/j.1365-2265.1999.00719.x. ISSN 0300-0664. PMID 10468932. https://pubmed.ncbi.nlm.nih.gov/10468932. 
  31. ↑ 31.0 31.1 Molitch, Mark E. (2017-02-07). "Diagnosis and Treatment of Pituitary Adenomas: A Review". JAMA 317 (5): 516–524. doi:10.1001/jama.2016.19699. ISSN 1538-3598. PMID 28170483. https://pubmed.ncbi.nlm.nih.gov/28170483. 
  32. ↑ "Primary Amenorrhea due to Pituitary Disease" (in en-US). 2019-01-17. https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/labmed/primary-amenorrhea-due-to-pituitary-disease/. 
  33. ↑ 33.0 33.1 Franik, Sebastian; Eltrop, Stephanie M.; Kremer, Jan Am; Kiesel, Ludwig; Farquhar, Cindy (2018-05-24). "Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome". The Cochrane Database of Systematic Reviews 2018 (5): CD010287. doi:10.1002/14651858.CD010287.pub3. ISSN 1469-493X. PMID 29797697. 
  34. ↑ 34.0 34.1 34.2 34.3 34.4 34.5 34.6 34.7 34.8 34.9 Ibáñez, Lourdes; Oberfield, Sharon E.; Witchel, Selma; Auchus, Richard J.; Chang, R. Jeffrey; Codner, Ethel; Dabadghao, Preeti; Darendeliler, Feyza et al. (2017). "An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence". Hormone Research in Paediatrics 88 (6): 371–395. doi:10.1159/000479371. ISSN 1663-2826. PMID 29156452. https://pubmed.ncbi.nlm.nih.gov/29156452. 
  35. ↑ 35.0 35.1 35.2 "Low energy availability, not stress of exercise, alters LH pulsatility in exercising women". Journal of Applied Physiology 84 (1): 37–46. January 1998. doi:10.1152/jappl.1998.84.1.37. PMID 9451615. 
  36. ↑ "Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset". Science 185 (4155): 949–51. September 1974. doi:10.1126/science.185.4155.949. PMID 4469672. Bibcode: 1974Sci...185..949F. 
  37. ↑ 37.0 37.1 "Bones, Muscles, and Joints" (in en). https://kidshealth.org/en/parents/bones-muscles-joints.html. 
  38. ↑ 38.0 38.1 "Psychoneuroendocrinology of anorexia nervosa". Psychoneuroendocrinology 31 (10): 1149–53. November 2006. doi:10.1016/j.psyneuen.2006.09.006. PMID 17084040. 
  39. ↑ "Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women". The Journal of Clinical Endocrinology and Metabolism 88 (1): 297–311. January 2003. doi:10.1210/jc.2002-020369. PMID 12519869. 
  40. ↑ "Low leptin levels predict amenorrhea in underweight and eating disordered females". Molecular Psychiatry 2 (4): 335–40. July 1997. doi:10.1038/sj.mp.4000287. PMID 9246675. 
  41. ↑ 41.0 41.1 41.2 "Fertility after discontinuation of oral contraceptives". Clinical Reproduction and Fertility 1 (4): 261–72. December 1982. PMID 6764883. 
  42. ↑ 42.0 42.1 42.2 "Evaluation of extended and continuous use oral contraceptives". Therapeutics and Clinical Risk Management 4 (5): 905–11. October 2008. doi:10.2147/TCRM.S2143. PMID 19209272. 
  43. ↑ 43.0 43.1 Willacy, Hayley (31 August 2021). "Combined Oral Contraceptive (Follow-up and Common Problems)". http://www.patient.info/doctor/Combined-Oral-Contraceptive-(Follow-Up-and-Common-Problems).htm. 
  44. ↑ "Mechanism of action of narcotics in the production of menstrual dysfunction in women". Fertility and Sterility 26 (6): 538–48. June 1975. doi:10.1016/S0015-0282(16)41173-8. PMID 236938. 
  45. ↑ "Opioid induced hypogonadism". BMJ 341: c4462. August 2010. doi:10.1136/bmj.c4462. PMID 20807731. 
  46. ↑ 46.0 46.1 46.2 46.3 "Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study". The American Journal of Psychiatry 169 (8): 813–21. August 2012. doi:10.1176/appi.ajp.2012.11091432. PMID 22711171. 
  47. ↑ Tucker, Elena J.; Grover, Sonia R.; Bachelot, Anne; Touraine, Philippe; Sinclair, Andrew H. (December 2016). "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. 
  48. ↑ 48.0 48.1 Seppä, Satu; Kuiri-Hänninen, Tanja; Holopainen, Elina; Voutilainen, Raimo (2021-05-04). "MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary amenorrhea and female delayed puberty". European Journal of Endocrinology 184 (6): R225–R242. doi:10.1530/EJE-20-1487. ISSN 1479-683X. PMID 33687345. 
  49. ↑ 49.0 49.1 Practice Committee of American Society for Reproductive Medicine (November 2008). "Current evaluation of amenorrhea". Fertility and Sterility 90 (5 Suppl): S219–225. doi:10.1016/j.fertnstert.2008.08.038. ISSN 1556-5653. PMID 19007635. 
  50. ↑ 50.0 50.1 Welt, Corrine. "Etiology, diagnosis, and treatment of secondary amenorrhea". http://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-secondary-amenorrhea. 
  51. ↑ 51.0 51.1 51.2 51.3 Wang, Amy T.; Mullan, Rebecca J.; Lane, Melanie A.; Hazem, Ahmad; Prasad, Chaithra; Gathaiya, Nicola W.; Fernández-Balsells, M. Mercè; Bagatto, Amy et al. (2012-07-24). "Treatment of hyperprolactinemia: a systematic review and meta-analysis". Systematic Reviews 1: 33. doi:10.1186/2046-4053-1-33. ISSN 2046-4053. PMID 22828169. 
  52. ↑ Sophie Gibson, Marie Eve; Fleming, Nathalie; Zuijdwijk, Caroline; Dumont, Tania (2020-02-06). "Where Have the Periods Gone? The Evaluation and Management of Functional Hypothalamic Amenorrhea". Journal of Clinical Research in Pediatric Endocrinology 12 (Suppl 1): 18–27. doi:10.4274/jcrpe.galenos.2019.2019.S0178. ISSN 1308-5735. PMID 32041389. 
  53. ↑ "What are the treatments for amenorrhea?" (in en). 31 January 2017. https://www.nichd.nih.gov/health/topics/amenorrhea/conditioninfo/treatments. 
  54. ↑ 54.0 54.1 Morgan, Thomas (2007-08-01). "Turner syndrome: diagnosis and management". American Family Physician 76 (3): 405–410. ISSN 0002-838X. PMID 17708142. https://pubmed.ncbi.nlm.nih.gov/17708142. 
  55. ↑ Morcel, Karine; Camborieux, Laure; Programme de Recherches sur les Aplasies Müllériennes; Guerrier, Daniel (2007-03-14). "Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome". Orphanet Journal of Rare Diseases 2: 13. doi:10.1186/1750-1172-2-13. ISSN 1750-1172. PMID 17359527. 
  56. ↑ Dye, Alyssa M.; Nelson, Grace B.; Diaz-Thomas, Alicia (2018-01-01). "Delayed Puberty". Pediatric Annals 47 (1): e16–e22. doi:10.3928/19382359-20171215-01. ISSN 1938-2359. PMID 29323692. https://pubmed.ncbi.nlm.nih.gov/29323692. 
  57. ↑ 57.0 57.1 Ylöstalo, P.; Kujala, P.; Kontula, K. (1980). "Amenorrhea with low normal thyroid function and thyroxine treatment". International Journal of Gynaecology and Obstetrics 18 (3): 176–180. doi:10.1002/j.1879-3479.1980.tb00275.x. ISSN 0020-7292. PMID 6109649. https://pubmed.ncbi.nlm.nih.gov/6109649. 

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