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Hormonal Regulation of Endometriosis and Clinical Significance

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Hormonal Regulation of Endometriosis and Clinical Significance Indian Journal of Biochemistry & Biophysics Vol. 55, October 2018, pp. 351-360 Hormonal regulation of endometriosis and clinical significance Anuradha Pandit, Yasmin Begum, Kasturi Chatterjee & Snehasikta Swarnakar* Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata-700 032, India Received 20 May 2018; revised 26 June 2018 Worldwide almost 10% of reproductive-aged women are affected by endometriosis and suffer from dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. Endometriosis is a gynecological condition in which endometrial cells are deposited outside the uterine cavity and eventually develop into functional endometrial glands and stroma. It is an estrogen- dependent disease and is critically modulated by other hormones of the reproductive system. Estrogen promotes the cell survival and pro-inflammatory roles for both endometrial epithelial and stromal cells. Overexpression of ER-β promotes invasion of endometriotic lesions as well as epithelial-mesenchymal transition. Moreover, estrogen stimulates the production of prostaglandin E2 (PGE2), which supports angiogenesis in the ectopic lesions. Progesterone counteracts estrogen and inhibits the growth of the endometrial glandular cells. Progesterone resistant endometrial cells confer apoptotic-resistance and aggravate disease condition. Oxytocin stimulates the contraction of uterine muscles by upregulating PGF2α secretion via calcium-mediated pathways leading to dysmenorrhea in endometriosis. On the contrary, gonadotropin and its receptor produce amenorrhea by inducing mitochondrial apoptosis and reducing angiogenesis. Scientists are now exploring these hormone-dependent pathologies of endometriosis to develop anti-endometriotic drugs, which mostly include androgen- based drugs and/or potential estrogen inhibitors. This review highlights the role of some important hormones e.g. estrogen, progesterone, prostaglandin, oxytocin, gonadotropin and melatonin in endometriosis progression and their pharmaceutical potentials. Keywords: Endometriosis, Estrogen, Growth factors, Hormone, Melatonin Hormones are special messenger molecules secreted by endometrial glands outside the uterus. Endometriosis the endocrine glands which are involved with the is associated with severe pelvic pain responses and regulation of several physiological as well as pathological infertility3. The etiology of endometriosis remains responses. Hormones are mostly classified into three unknown; however, several plausible theories have categories: protein derivatives, steroids, and eicosanoids. been proposed. According to Sampson’s retrograde Although endocrine glands are the major source of menstruation theory, the endometrial lining is hormone secretion, the various other cells can also secrete refluxed out of the fallopian tubes into the peritoneal hormones in response to different biochemical signals. cavity, leading to the development of ectopic lesions4. Hormonal signaling encompasses its biosynthesis, storage Another theory states that specialised cells of the and secretion, recognition by its receptor, relay, and normal mesothelial lining transform into ectopic amplification of its signal, and finally degradation. lesion via metaplastic transition. Cyclical sex-steroid Hormones are mostly transported through the circulatory levels are mainly responsible for maintaining the system to act on other distant organs (endocrine), or can endometrial lining by regulating the cell proliferation. also act in an autocrine/paracrine manner. It can be During lack of hormone, mainly estrogen and stimulated or inhibited by various growth factors1,2. progesterone, the endometrium becomes thin and Endometriosis is a hormone- dependent inactive resulting in amenorrhea, whereas excess gynaecological disease characterised by the growth of levels of estrogen lead to hyperplasia and often __________ positively associated with the development of 5,6 *Correspondence: endometriosis . Moreover, similar to the normal E-mail: [email protected] endometrium, endometriotic glands also undergo # Both the authors contributed equally menstrual cycles of shedding, leading to iron Abbreviation: ER, Estrogen receptor; GnRH, Gonadotropin deposition and formation of an inflammatory milieu, releasing hormone; OTR, Oxytocin receptor; OXT, Oxytocin; PG, along with increased oxidative stress and cellular Prostaglandin; PR, Progesterone; TGF, Transforming growth 7 factor; VEGF, Vascular endothelial growth factor proliferation . Aberrant progesterone signaling in the 352 INDIAN J. BIOCHEM. BIOPHYS., VOL. 55, OCTOBER 2018 endometrium plays a significant role in the development The treatment regime for endometriosis is limited of endometriosis8. In addition, endometriotic tissues to surgical procedures and steroidogenic contain 17β-HSD (hydroxysteroid dehydrogenase) treatments23,24. GnRH antagonists as well as anti- type-1, instead of the 17β-HSD type-2, which is more inflammatory drugs such as cyclooxygenase (COX) potent in converting estrone to estradiol and thus locally inhibitors are widely used. In this regard, the role of support the proliferative microenvironment of melatonin an endogenous antioxidant with multiple endometriotic cells9. Hormones promote the production attributes is worth reporting. Melatonin acts as an of several growth factors, including epidermal growth anti-oxidant and anti-inflammatory molecule via both factor (EGF) and insulin-like growth factor (IGF) which direct and melatonin receptor-mediated pathways, modulates cellular proliferation in human endometrium which are present in the uterus. It has potent analgesic and endometrial cells10-12. and anti-estrogenic attributes as well. Moreover, it can Estrogen receptor acts through mainly estrogen modulate matrix metalloproteinase (MMP) levels response element (ERE) and via protein–protein modulating cellular invasiveness and pathological interactions with other transcription factors such as angiogenesis. Studies have shown that melatonin can AP-1 and SP113. ER-α and ER-β have been detected suppress endometriosis development by decreasing throughout the menstrual cycle in the eutopic the oxidative stress and inflammation as well as endometrium of endometriosis patients, where the induces apoptosis in ectopic endometriotic lesions25,26. expression of ER-α is much higher than that of ER-β, while the expression of the ERs does not correlate Role of different hormones in endometriosis with menstrual phases in ectopic endometrium14,15. Estrogen Gonadotropin Releasing Hormone (GnRH) releases Estrogens are sex-steroid hormones, produced the follicle-stimulating hormone (FSH) and primarily from the ovary, corpus luteum, placenta, luteinizing hormone (LH). Both FSH and LH act on adrenal cortex, in smaller amounts from liver, the ovaries to produce estrogen and progesterone and pancreas, bone, adrenal glands, skin, brain, adipose on the testes to produce testosterone. GnRH, FSH, tissue, and breasts. Estrogens are mainly responsible and LH have a critical role in endometriosis for maintaining the window of uterine receptivity progression. Progesterone, on the other hand, along with progesterone. Estradiol, an aromatized counteracts with estrogen by decreasing the ER C18 steroid, is the primary potent form of mammalian receptors in the endometrium and increases the rate of estrogenic steroid. Aromatase P450 is the key enzyme conversion of 17β-estradiol. It plays an anti- for ovarian estrogen biosynthesis, catalyzing the steroidogenic effect on the uterine myometrial cells conversion of androstenedione and testosterone by decreasing their sensitivity to oxytocin16. The produced to estrone and estradiol (E2) (Fig. 1). feedback effect of progesterone is via inhibition of Higher levels of E2 have been reported in menstrual LH surge from the hypothalamic and pituitary axis. blood of endometriosis patients, in comparison with Furthermore, case-control cohort studies have found healthy women2. Endometriotic lesions express 1,27 that promoter polymorphism of ER, PR and aromatase and are able to synthesize their own E2 . cytochrome P450 (CYP1A, 17A, 19A) influence the Ectopic endometrium of patients with ovarian, propensity for endometriosis development in peritoneal, and deep infiltrating endometriosis show women17. Oxytocin receptor (OTR) is expressed in increased aromatase expressions28. The successful normal endometrial and myometrial cells of the treatment of several cases of endometriosis, using human uterus where its expression varies according to aromatase inhibitors, showed inhibition of local the phases of the menstrual cycle, suggesting its estrogen formation27. All the enzymes necessary for involvement in endometrial functions18-20. Oxytocin the local production of estrogens are expressed in the also stimulates PGF2α secretion by using both the human endometrium including aromatase, oxidative extracellular and intracellular Ca2+ in bovine 17βHSD, and sulfotransferases29. Ovarian, peritoneal endometrial tissue21,22. Oxytocin receptor (OTR), and deep-infiltrative endometriosis expresses estrogen receptor (ER), and progesterone receptor predominantly 17βHSD type 1 isoform, as compared (PR) are up-regulated by estradiol stimulation and to the 17βHSD type 29,30. downregulated by progesterone in the uterine Estrogen exerts its actions through both nuclear myometrial cells. estrogen receptors, namely ERα and ERβ, along with PANDIT et al.: HORMONAL REGULATION OF ENDOMETRIOSIS 353 Fig. 1—Hormonal regulatory
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