Endometrial hyperplasia pathophysiology: Difference between revisions
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**Any patient who develops bleeding while on [[tamoxifen]] needs evaluation | **Any patient who develops bleeding while on [[tamoxifen]] needs evaluation | ||
*Endometrial hyperplasia may rarely result from the peripheral conversion of [[androgen]]s to [[estrogen]]s in androgen-secreting tumors of the [[adrenal cortex]].<ref>Endometrial hyperplasia. Wiley Online Library.http://onlinelibrary.wiley.com/doi/10.1576/toag.10.4.211.27436/full Accessed on March 7, 2016</ref> | *Endometrial hyperplasia may rarely result from the peripheral conversion of [[androgen]]s to [[estrogen]]s in androgen-secreting tumors of the [[adrenal cortex]].<ref>Endometrial hyperplasia. Wiley Online Library.http://onlinelibrary.wiley.com/doi/10.1576/toag.10.4.211.27436/full Accessed on March 7, 2016</ref> | ||
==Mtor== | |||
In young mice, mTOR signaling is required for estrogen-mediated growth of endometrial cells, and dysregulated mTOR signaling leads to female infertility due to defects in ovarian, oviductal, and endometrial functions [35–39]. Rapamycin treatment of young rats (5mg/kg i.p. on alternate days for 10wks) increases the ovarian follicular reserve [40], suggesting that treatment with this drug might prolong the reproductive lifespan, delay menopause, and improve reproductive fitness. However, all the rapamycin-rats displayed irregular estrous cycle and were unable to get pregnant [40]. It is now clear that several of the side effects of long-term treatment of rapamycin are due to disruption of mTORC2 signaling [13]. Because mTORC2 signaling is essential for follicular survival and endometrial development [41], it is likely that some of the reproductive functional defects observed after rapamycin treatment are due, at least in part, to altered mTORC2 signaling. Recently, two independent studies have shown that intermittent dosing of rapamycin delivers many of the benefits of rapamycin treatment on lifespan and healthspan with minimum negative effects on glucose homeostasis and immune system [42, 43]. It will be an interest of our future studies to examine if these new treatment regimens will have similar beneficial effects on reproductive functions of mice. In this study, we have shown that hyperactive mTOR signaling is present in the hyperplastic endometrium of aged women and mice, and inhibition of this pathway leads to suppression of endometrial lesions in mice.<ref name="pmid22128018">{{cite journal |vauthors=Tanaka Y, Park JH, Tanwar PS, Kaneko-Tarui T, Mittal S, Lee HJ, Teixeira JM |title=Deletion of tuberous sclerosis 1 in somatic cells of the murine reproductive tract causes female infertility |journal=Endocrinology |volume=153 |issue=1 |pages=404–16 |date=January 2012 |pmid=22128018 |pmc=3249683 |doi=10.1210/en.2011-1191 |url=}}</ref><ref name="pmid25733860">{{cite journal |vauthors=Wang Y, Zhu L, Kuokkanen S, Pollard JW |title=Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17β is mediated by a PKC-ERK1/2-mTOR signaling pathway |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=112 |issue=11 |pages=E1382–91 |date=March 2015 |pmid=25733860 |pmc=4371960 |doi=10.1073/pnas.1418973112 |url=}}</ref><ref name="pmid20519781">{{cite journal |vauthors=Blagosklonny MV |title=Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives |journal=Aging (Albany NY) |volume=2 |issue=5 |pages=265–73 |date=May 2010 |pmid=20519781 |pmc=2898017 |doi=10.18632/aging.100149 |url=}}</ref> | |||
==Microscopic Pathology== | ==Microscopic Pathology== | ||
Revision as of 16:27, 8 February 2019
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Endometrial hyperplasia Microchapters |
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Endometrial hyperplasia pathophysiology On the Web |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Soujanya Thummathati, MBBS [2]
Overview
Endometrial hyperplasia is a condition of excessive proliferation of the endometrial cells (inner lining of the uterus) associated with an increased gland to stroma ratio. The majority of cases of endometrial hyperplasia result from high concentrations of estrogen combined with insufficient concentration of the progesterone-like hormones which normally counteract the proliferative effects of estrogen on the endometrial tissue.[1] Anovulation results in the prolonged release of estrogen and the relative lack of progesterone resulting in excessive stimulation of the endometrium. Unopposed oestrogen stimulation may be either from an endogenous or exogenous source.[1][2]
Pathophysiology
Pathogenesis
- Endometrial hyperplasia is a condition of excessive proliferation of the endometrial cells (inner lining of the uterus) associated with an increased gland to stroma ratio.
- The majority of cases of endometrial hyperplasia result from high concentrations of estrogen combined with insufficient concentration of the progesterone-like hormones which normally counteract the proliferative effects of estrogen on the endometrial tissue.[1]
- Normal endometrial changes during menstrual cycle:[3]
- The proliferative phase is the second phase in normal mentrual cycle when estrogen causes the lining of the uterus to proliferate. As the ovarian follicles mature, they begin to secrete increasing amounts of estradiol and estrogen. The estrogens initiate the formation of a new layer of endometrium in the uterus, histologically identified as the proliferative endometrium.
- After ovulation, the remains of the dominant follicle in the ovary become a corpus luteum which produces large amounts of progesterone.
- Anovulation results in the prolonged release of estrogen and the relative lack of progesterone resulting in excessive stimulation of the endometrium.
- Unopposed estrogen stimulation may be either from an endogenous or exogenous source.[2][1]
- Excessive endogenous estrogen in pre or perimenopausal women may result from chronic anovulation caused by obesity, polycystic ovary disease, and estrogen producing tumors (e.g. granulosa cell tumor).
- Excessive exogenous estrogen may result from hormone replacement therapy or non-prescription herbal medications.
- Tamoxifen therapy in breast cancer patients results in an endometrial lesion within 6-36 months of therapy.[4]
- Tamoxifen is a non-steroidal anti-estrogen that binds to the estrogen receptor and is used primarily for adjuvant therapy in breast cancer
- Tamoxifen may also act as an estrogen agonist in a low estradiol environment
- Any patient who develops bleeding while on tamoxifen needs evaluation
- Endometrial hyperplasia may rarely result from the peripheral conversion of androgens to estrogens in androgen-secreting tumors of the adrenal cortex.[5]
Mtor
In young mice, mTOR signaling is required for estrogen-mediated growth of endometrial cells, and dysregulated mTOR signaling leads to female infertility due to defects in ovarian, oviductal, and endometrial functions [35–39]. Rapamycin treatment of young rats (5mg/kg i.p. on alternate days for 10wks) increases the ovarian follicular reserve [40], suggesting that treatment with this drug might prolong the reproductive lifespan, delay menopause, and improve reproductive fitness. However, all the rapamycin-rats displayed irregular estrous cycle and were unable to get pregnant [40]. It is now clear that several of the side effects of long-term treatment of rapamycin are due to disruption of mTORC2 signaling [13]. Because mTORC2 signaling is essential for follicular survival and endometrial development [41], it is likely that some of the reproductive functional defects observed after rapamycin treatment are due, at least in part, to altered mTORC2 signaling. Recently, two independent studies have shown that intermittent dosing of rapamycin delivers many of the benefits of rapamycin treatment on lifespan and healthspan with minimum negative effects on glucose homeostasis and immune system [42, 43]. It will be an interest of our future studies to examine if these new treatment regimens will have similar beneficial effects on reproductive functions of mice. In this study, we have shown that hyperactive mTOR signaling is present in the hyperplastic endometrium of aged women and mice, and inhibition of this pathway leads to suppression of endometrial lesions in mice.[6][7][8]
Microscopic Pathology
- Prolonged estrogenic stimulation results in larger, more complex, and proliferating endometrial glands.[2]
- On microscopic histopathological analysis, the proliferating endometrium is characterized by the following:[9]
| Character | Simple hyperplasia | Complex hyperplasia |
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Gland to stroma ratio |
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Endometrium |
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Mitoses |
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Location |
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Nuclear atypia |
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Gallery
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![Diagram illustrating how the uterus lining builds up and breaks down during the menstrual cycle[10]](/images/9/9f/Lining_of_Uterine_Wall.jpg)
Diagram illustrating how the uterus lining builds up and breaks down during the menstrual cycle[10]
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![Low magnification micrograph of simple endometrial hyperplasia without nuclear atypia. Normal gland-to-stroma ratio (~1:3); proliferating pseudostratified glandular epithelium; irregular endometrial glands: dilated glands or glands with variable size; non-ovoid/non-circular glands[11]](/images/3/3d/Simple_endometrial_hyperplasia_-_low_mag_%281%29.jpg)
Low magnification micrograph of simple endometrial hyperplasia without nuclear atypia. Normal gland-to-stroma ratio (~1:3); proliferating pseudostratified glandular epithelium; irregular endometrial glands: dilated glands or glands with variable size; non-ovoid/non-circular glands[11]
![Diagram illustrating how the uterus lining builds up and breaks down during the menstrual cycle[10]](/index.php/File:Lining_of_Uterine_Wall.jpg)
![Low magnification micrograph of simple endometrial hyperplasia without nuclear atypia. Normal gland-to-stroma ratio (~1:3); proliferating pseudostratified glandular epithelium; irregular endometrial glands: dilated glands or glands with variable size; non-ovoid/non-circular glands[11]](/index.php/File:Simple_endometrial_hyperplasia_-_low_mag_(1).jpg)
References
- ↑ 1.0 1.1 1.2 1.3 Endometrial hyperplasia. Wikipedia. https://en.wikipedia.org/wiki/Endometrial_hyperplasia Accessed on March 7, 2016.
- ↑ 2.0 2.1 2.2 Owings RA, Quick CM (2014). "Endometrial intraepithelial neoplasia". Arch Pathol Lab Med. 138 (4): 484–91. doi:10.5858/arpa.2012-0709-RA. PMID 24678678.
- ↑ Menstrual cycle. Wikipedia. https://en.wikipedia.org/wiki/Menstrual_cycle Accessed on March 7, 2016
- ↑ Tamoxifen associated endometrial changes. Radiopedia. http://radiopaedia.org/articles/tamoxifen-associated-endometrial-changes Accessed on March 10, 2016
- ↑ Endometrial hyperplasia. Wiley Online Library.http://onlinelibrary.wiley.com/doi/10.1576/toag.10.4.211.27436/full Accessed on March 7, 2016
- ↑ Tanaka Y, Park JH, Tanwar PS, Kaneko-Tarui T, Mittal S, Lee HJ, Teixeira JM (January 2012). "Deletion of tuberous sclerosis 1 in somatic cells of the murine reproductive tract causes female infertility". Endocrinology. 153 (1): 404–16. doi:10.1210/en.2011-1191. PMC 3249683. PMID 22128018.
- ↑ Wang Y, Zhu L, Kuokkanen S, Pollard JW (March 2015). "Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17β is mediated by a PKC-ERK1/2-mTOR signaling pathway". Proc. Natl. Acad. Sci. U.S.A. 112 (11): E1382–91. doi:10.1073/pnas.1418973112. PMC 4371960. PMID 25733860.
- ↑ Blagosklonny MV (May 2010). "Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives". Aging (Albany NY). 2 (5): 265–73. doi:10.18632/aging.100149. PMC 2898017. PMID 20519781.
- ↑ McCluggage WG (2006). "My approach to the interpretation of endometrial biopsies and curettings". J Clin Pathol. 59 (8): 801–12. doi:10.1136/jcp.2005.029702. PMC 1860448. PMID 16873562.
- ↑ Menstrual cycle. Wikipedia. https://en.wikipedia.org/wiki/Menstrual_cycle Accessed on March 7, 2016
- ↑ Endometrial hyperplasia. Wikipedia. https://en.wikipedia.org/wiki/Endometrial_hyperplasia#/media/File:Simple_endometrial_hyperplasia_-_low_mag.jpg Accessed on March 7, 2016
