Amenorrhea pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
Pathophysiology
Physiology of normal puberty
Menarche and Menstruation
- After a decrease in menarche age in 1800-1900 in United States and Europe, the mean age of menarche did not change in last 30 years.[1]
- Median age of menstruation onset in girls is 12.43 years in US, 80% of them experience menarche between 11 and 13.75 years of age.[2] Almost all (98%) of the girls experiencing the menarche until age of 15.[3]
- Gonadotropin releasing hormone (GnRH) is the main determinant of puberty onset, which is secreted by neuro-secretory neurons located in hypothalamus into hypophysial portal system. Then, it transferred to anterior pituitary gland, where it stimulates production and secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH). The amplitude and frequency of GnRH pulses are significantly increased during puberty.
- GnRH secretion is also mediated by some neurotransmitters in brain, such as dopamine, endogenous opioids, norepinephrine, gamma amino butyric acid (GABA), and corticotropin releasing hormone (CRH). Each of these neurotransmitters would be defected in specific types of amenorrhea. For example, stress, exercise, and malnutrition are affected CRH, β-endorphin, and dopamine, respectively.[1]
- After initiating puberty, the negative feedback on GnRH will be gone, pulsatile GnRH secretion induce the LH and FSH, that finally lead to ovulation. Without pregnancy, the ovum will become to corpus luteum, proliferate the endometrium through estrogen release. Withdrawal of progesterone from estrogen-mediated proliferated endometrium make it bleeding.
Hypothalamic-pituitary-ovarian (HPO) axis maturation
- After activation of the HPO axis during 2nd trimester of pregnancy, gonadotropins will be in peak from mid to term pregnancy. After removing placental hormones' feedback, FSH and LH increase slightly, mild secondary peak.
- Negative feedback due to adrenal androgens hold the gonadotropins in low plasma level until puberty.[4]
- Right before puberty the sensitivity of hypothalamus to adrenal androgens' negative feedback is decreased and make it possible for GnRH to be raised in magnitude and frequency, therefore increase LH and FSH.[5]
- It takes about 5-7 years from menstruation initiation to HPO axis become completely mature. Generally, during the first two years of menstruation, the cycles are mostly anovulatory.
Pathogenesis
- It is thought that amenorrhea is absence of menstrual cycle, from the beginning of puberty (primary amenorrhea) or after many normal cycles (secondary amenorrhea).
- Distinguishing between primary and secondary amenorrhea is based on history, solely; because upon every cause of secondary amenorrhea can be a cause of primary amenorhea, indeed.[1]
- Mainly the pathophysiology of amenorrhea is described in many categories, include hypothalamic, pituitary, thyroid, adrenal, ovarian, uterine, and vaginal pathogenesis.
Hypothalamic pathogenesis
- The most common cause of amenorrhea in adolescents is hypothalamic pathogenesis, called hypothalamic amenorrhea.
- During 2-3 years after menarche, HPO axis is developing. Therefore, anovulatory cycles may lead to some abnormalities in menstrual cycles.
- The most common causes of amenorrhea, after 2-3 years of puberty, include eating disorders, excessive exercise, medications, and psychosocial stress.[6][7]
- Leptin plays an important role in energy consumption, body composition, food intake, and their regulations; along with sexual maturation and reproductive improvement. It is assumed that leptin has an important role in hypothalamic amenorrhea. Leptin receptors are in close relationship with hypothalamus and it is revealed that they have some effects on GnRH production and secretion. The main reason of amenorrhea in patients with anorexia nervosa or excessive exercise is down-regulation of leptin receptors, which is elevated by refeeding.[8][9][10]
- Leptin level in cachexic patients will increase after gaining appropriate weight in normal people, but will remain low in patients with amenhorrea.[11][12]
- It is found that leptin levels in amenorrheic athletes are lower than non-athletes women or athletes with regular menses.[13][14]
- Administration of recombinant leptin for 3 months in women involving in hypothalamic amenorrhea, with excessive exercises or weight loss, increase their LH, FSH, and estradiol and lead to ovulatory cycles.[15]
- Antipsychotic drugs and all the medicines that may have inhibitory effects on dopamine D2 receptor can deteriorate the inhibitory influence of dopamine on prolactin. It means that they increase prolactin. Higher levels of prolactin suppress pulsatile GnRH and also block positive feedback of estradiol on hypothalamus, thus, disturb the HPO axis.[16]
- Stress and strenuous activities as like as any other metabolic or cardiovascular responses are regulated through corticotropin releasing hormone (CRH), secreted by paraventricular nuclei of hypothalamus. CRH induce the release of β-endorphin, an endogenous opioid. Both CRH and β-endorphin suppress GnRH release. On the other hand, glucocorticoids suppress LH production from pituitary and also estrogen/progesterone from ovaries.[17]
- Kallmann syndrome, genetic disorder caused by KAL gene mutation, has disturbance in migration of olfactory nerves along with GnRH neurons. Lack of GnRH in this syndrome encounter the patient with absence of secondary sexual characteristics and also amenorrhea.[18]
Pituitary pathogenesis
- One of the most prevalent anterior pituitary tumors is prolactinoma. Both effect of the mass itself and also secreted prolactin by the mass suppress the GnRH pulsatility, decrease LH and FSH.
- Second prevalent tumor in suprasellar region is craniopharyngioma. The tumor leads to LH and FSH disturbances, which may cause amenorrhea.[19]
Thyroid pathogenesis
- In hypothyroidism, the main mechanism that can lead to amenorrhea is the influence of thyrotropin releasing hormone (TRH) on lactotroph cells, increasing prolactin levels. Since the TRH is increased in hypothyroidism, it leads to functional hyperprolactinemia as well. The concluded increased prolactin can suppress the GnRH pulsatility and lead to amenorrhea.[20]
- In hyperthyroidism, the main mechanism of amenorrhea is not clear. It is assumed that increased level of sex hormone binding globulins (SHBGs) in hyperthyroidism can lead to increase androgens along with estrogen. Conclusively, the LH surge become absent and amenorrhea happens.[21]
Adrenal pathogenesis
- Congenital adrenal hyperplasia (CAH) is a group of genetic enzyme deficiency in adrenal gland. Most of the time the defect is in 21-hydroxylase enzyme, leading to decreasing the main enzymes. To overcome the enzyme deficiency, CRH production is increased by hypothalamus. As mentioned before increased CRH can suppress GnRH and lead to amenorrhea.[22]
- Cushing syndrome has increased level of cortisol, that can directly inhibit HPO axis and cause amenorrhea.
Ovarian pathogenesis
- Polycystic ovary syndrome (PCOS) is mainly due to insulin resistance, that can be lead to androgen over-production (insulin reduces the SHBG circulating in plasma, causes increasing testosterone). In the ovary there will be increased response to GnRH for 17-hydroxy progesterone and also cytochrome P450c17; both lead to increasing androgens biosynthesis.[23][24] Finally, the pulsatility of GnRH will be disrupted and amenorrhea happens.[25]
- Primary ovarian insufficiency occurs due to several pathologies, all of them lead to ovarian failure and decrease in esterogen. In galactosemia, it is assumed that galactose and its metabolites are toxic to ovarian tissue.[26]
Uterine pathogenesis
- The main pathogenesis of amenorrhea in androgen insensitivity syndrome is absence of uterus. The patient is genotypely male, 46 XY; but has not experienced sexual characteristics due to lack of functional effect of androgen hormones on their receptors.
- One of the acquired conditions that can lead to amenorrhea is Asherman syndrome. The base of this syndrome is any condition that can harm the endometrium, such as scarring from surgical procedure or adhesion from severe infection.
- Mayer-Rokitansky-Kuster-Hauser syndrome is complete agenesis of uterine, blind ended vagina. The lack of uterine and endometrium is the main pathogenesis of amenorrhea. The main reason of uterine agenesis is overactivation of anti-mullerian hormone in embryogenesis period.[27] Cervical agenesis also follow the similar process.
- Imperforated hymen, transverse vaginal septum, and vaginal agenesis are other anatomical disorders of female reproductive system that can lead to amenorrhea.[28]
Genetics
- [Disease name] is transmitted in [mode of genetic transmission] pattern.
- Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
- The development of [disease name] is the result of multiple genetic mutations.
Associated Conditions
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Pathophysiology
Hypogonadotropic amenorrhoea refers to conditions where there are very low levels of serum FSH and LH. Generally, inadequate levels of these hormones lead to inadequately stimulated ovaries who then fail to produce enough estrogen to stimulate the endometrium (uterine lining), hence amenorrhoea. This is typical for conditions of pubertal delay, hypothalamic or pituitary dysfunction. In general, women with hypogonadotropic amenorrhoea are potentially fertile.
Hypergonadotropic amenorrhoea refers to conditions with high levels of FSH (and LH). FSH levels are typically in the menopausal range. This implies that the ovary or gonad does not respond to pituitary stimulation. Gonadal dysgenesis or premature menopause are possible causes. Chromosome testing is usually indicated in younger individuals with hypergonadotropic amenorrhoea.
In normogonadotropic amenorrhoea, FSH levels are in the normal range. This would suggest that the hypothalamic-pituitary-ovarian axis is functional. Amenorrhoea may be due to outflow obstruction, or abnormal ovarian regulation or excess androgens as seen in polycystic ovary syndrome.
Cushing's Disease/Syndrome can also cause amenorrhoea due to excessive amounts of cortisol in the blood stream.
Primary amenorrhea
In primary amenorrhea there is absence of menarche by the age of 16. Menstruation cycles never begin. There will be a delay of menses one year beyond the family history of first menses.
There is no defining sexual characteristics by age 14. Primary amenorrhea may be caused by developmental problems such as the congenital absence of the uterus, or failure of the ovary to receive or maintain egg cells. Also, delay in pubertal development will lead to primary amenorrhoea.
Secondary amenorrhea
Secondary amenorrhea is defined as absence of menses in a woman who had previously menstruated for at least 3 cycles or 6 months. Secondary amenorrhea is more common than primary amenorrhea.
Secondary amenorrhea is often caused by hormonal disturbances from the hypothalamus and the pituitary gland or from premature menopause, or intrauterine scar formation.
Specific types of amenorrhoea
Exercise amenorrhoea
Female athletes or women who perform considerable amounts of exercise on a regular basis are at risk of developing 'athletic' amenorrhoea. It was thought for many years that low body fat levels and exercise related chemicals (such as beta endorphins and catecholamines) disrupt the interplay of the sex hormones estrogen and progesterone. However recent studies have shown that there are no differences in the body composition, or hormonal levels in amenorrheic athletes. Instead, amenorrhea has been shown to be directly attributable to a low energy availability. Many women 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. [2]
A second serious risk factor of amenorrhea is severe bone loss sometimes resulting in osteoporosis and osteopenia. It is the third component of an increasingly common disease known as female athlete triad syndrome. The other two components of this syndrome are osteoporosis and disordered eating. Awareness and intervention can usually prevent this occurrence in most female athletes.
Drug-induced 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 contain only progestogen like the oral contraceptive Micronor, and especially higher-dose formulations like the injectable Depo Provera commonly induce this side-effect. Recently, an extended cycle combined oral contraceptive pill which aims to purposefully induce amenorrhea (Lybrel), has been approved by the FDA.
References
- ↑ 1.0 1.1 1.2 Golden NH, Carlson JL (2008). "The pathophysiology of amenorrhea in the adolescent". Ann. N. Y. Acad. Sci. 1135: 163–78. doi:10.1196/annals.1429.014. PMID 18574222.
- ↑ Chumlea WC, Schubert CM, Roche AF, Kulin HE, Lee PA, Himes JH, Sun SS (2003). "Age at menarche and racial comparisons in US girls". Pediatrics. 111 (1): 110–3. PMID 12509562.
- ↑ "Menstruation in Girls and Adolescents: Using the Menstrual Cycle as a Vital Sign - ACOG".
- ↑ Apter D (1997). "Development of the hypothalamic-pituitary-ovarian axis". Ann. N. Y. Acad. Sci. 816: 9–21. PMID 9238251.
- ↑ Boyar RM, Rosenfeld RS, Kapen S, Finkelstein JW, Roffwarg HP, Weitzman ED, Hellman L (1974). "Human puberty. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep". J. Clin. Invest. 54 (3): 609–18. doi:10.1172/JCI107798. PMC 301594. PMID 4852310.
- ↑ Wiksten-Almströmer M, Hirschberg AL, Hagenfeldt K (2007). "Menstrual disorders and associated factors among adolescent girls visiting a youth clinic". Acta Obstet Gynecol Scand. 86 (1): 65–72. doi:10.1080/00016340601034970. PMID 17230292.
- ↑ Perkins RB, Hall JE, Martin KA (2001). "Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea". Hum. Reprod. 16 (10): 2198–205. PMID 11574516.
- ↑ Hebebrand J, Muller TD, Holtkamp K, Herpertz-Dahlmann B (2007). "The role of leptin in anorexia nervosa: clinical implications". Mol. Psychiatry. 12 (1): 23–35. doi:10.1038/sj.mp.4001909. PMID 17060920.
- ↑ Grinspoon S, Gulick T, Askari H, Landt M, Lee K, Anderson E, Ma Z, Vignati L, Bowsher R, Herzog D, Klibanski A (1996). "Serum leptin levels in women with anorexia nervosa". J. Clin. Endocrinol. Metab. 81 (11): 3861–3. doi:10.1210/jcem.81.11.8923829. PMID 8923829.
- ↑ Haas V, Onur S, Paul T, Nutzinger DO, Bosy-Westphal A, Hauer M, Brabant G, Klein H, Müller MJ (2005). "Leptin and body weight regulation in patients with anorexia nervosa before and during weight recovery". Am. J. Clin. Nutr. 81 (4): 889–96. PMID 15817868.
- ↑ Misra M, Miller KK, Almazan C, Ramaswamy K, Aggarwal A, Herzog DB, Neubauer G, Breu J, Klibanski A (2004). "Hormonal and body composition predictors of soluble leptin receptor, leptin, and free leptin index in adolescent girls with anorexia nervosa and controls and relation to insulin sensitivity". J. Clin. Endocrinol. Metab. 89 (7): 3486–95. doi:10.1210/jc.2003-032251. PMID 15240636.
- ↑ Katzman DK, Golden NH, Neumark-Sztainer D, Yager J, Strober M (2000). "From prevention to prognosis: clinical research update on adolescent eating disorders". Pediatr. Res. 47 (6): 709–12. PMID 10832726.
- ↑ Thong FS, McLean C, Graham TE (2000). "Plasma leptin in female athletes: relationship with body fat, reproductive, nutritional, and endocrine factors". J. Appl. Physiol. 88 (6): 2037–44. PMID 10846016.
- ↑ Weimann E, Blum WF, Witzel C, Schwidergall S, Böhles HJ (1999). "Hypoleptinemia in female and male elite gymnasts". Eur. J. Clin. Invest. 29 (10): 853–60. PMID 10583427.
- ↑ Welt, Corrine K.; Chan, Jean L.; Bullen, John; Murphy, Robyn; Smith, Patricia; DePaoli, Alex M.; Karalis, Aspasia; Mantzoros, Christos S. (2004). "Recombinant Human Leptin in Women with Hypothalamic Amenorrhea". New England Journal of Medicine. 351 (10): 987–997. doi:10.1056/NEJMoa040388. ISSN 0028-4793.
- ↑ Wieck A, Haddad PM (2003). "Antipsychotic-induced hyperprolactinaemia in women: pathophysiology, severity and consequences. Selective literature review". Br J Psychiatry. 182: 199–204. PMID 12611781.
- ↑ Magiakou MA, Mastorakos G, Webster E, Chrousos GP (1997). "The hypothalamic-pituitary-adrenal axis and the female reproductive system". Ann. N. Y. Acad. Sci. 816: 42–56. PMID 9238254.
- ↑ Seminara SB, Hayes FJ, Crowley WF (1998). "Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations". Endocr. Rev. 19 (5): 521–39. doi:10.1210/edrv.19.5.0344. PMID 9793755.
- ↑ Karavitaki N, Cudlip S, Adams CB, Wass JA (2006). "Craniopharyngiomas". Endocr. Rev. 27 (4): 371–97. doi:10.1210/er.2006-0002. PMID 16543382.
- ↑ Koutras DA (1997). "Disturbances of menstruation in thyroid disease". Ann. N. Y. Acad. Sci. 816: 280–4. PMID 9238278.
- ↑ Poppe K, Velkeniers B, Glinoer D (2007). "Thyroid disease and female reproduction". Clin. Endocrinol. (Oxf). 66 (3): 309–21. doi:10.1111/j.1365-2265.2007.02752.x. PMID 17302862.
- ↑ Speiser, Phyllis W.; White, Perrin C. (2003). "Congenital Adrenal Hyperplasia". New England Journal of Medicine. 349 (8): 776–788. doi:10.1056/NEJMra021561. ISSN 0028-4793.
- ↑ Gilling-Smith C, Story H, Rogers V, Franks S (1997). "Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome". Clin. Endocrinol. (Oxf). 47 (1): 93–9. PMID 9302378.
- ↑ Ehrmann DA, Barnes RB, Rosenfield RL (1995). "Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion". Endocr. Rev. 16 (3): 322–53. doi:10.1210/edrv-16-3-322. PMID 7671850.
- ↑ Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS, Marshall JC (1998). "Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone". J. Clin. Endocrinol. Metab. 83 (2): 582–90. doi:10.1210/jcem.83.2.4604. PMID 9467578.
- ↑ Kaufman FR, Kogut MD, Donnell GN, Goebelsmann U, March C, Koch R (1981). "Hypergonadotropic hypogonadism in female patients with galactosemia". N. Engl. J. Med. 304 (17): 994–8. doi:10.1056/NEJM198104233041702. PMID 6782485.
- ↑ Varner RE, Younger JB, Blackwell RE (1985). "Müllerian dysgenesis". J Reprod Med. 30 (6): 443–50. PMID 4020785.
- ↑ Edmonds DK (2003). "Congenital malformations of the genital tract and their management". Best Pract Res Clin Obstet Gynaecol. 17 (1): 19–40. PMID 12758224.