Clotrimazole reduces endometriosis and the estrogen concentration by downregulating aromatase

in Reproduction
Authors:
Daniel Escorsim Machado Laboratório de Pesquisa de Ciências Farmacêuticas (LAPESF), Unidade de Farmácia, Centro Universitário Estadual da Zona Oeste (UEZO), Rio de Janeiro, Rio de Janeiro, Brasil
Programa de Ciências Morfológicas (PCM), Instituto de Ciências Biomédicas (ICB), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brasil

Search for other papers by Daniel Escorsim Machado in
Current site
Google Scholar
PubMed Close
,
Jéssica Alessandra-Perini Laboratório de Pesquisa de Ciências Farmacêuticas (LAPESF), Unidade de Farmácia, Centro Universitário Estadual da Zona Oeste (UEZO), Rio de Janeiro, Rio de Janeiro, Brasil
Programa de Ciências Morfológicas (PCM), Instituto de Ciências Biomédicas (ICB), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brasil

Search for other papers by Jéssica Alessandra-Perini in
Current site
Google Scholar
PubMed Close
,
Erika Menezes de Mendonça Laboratório de Pesquisa de Ciências Farmacêuticas (LAPESF), Unidade de Farmácia, Centro Universitário Estadual da Zona Oeste (UEZO), Rio de Janeiro, Rio de Janeiro, Brasil
Programa de Pós-Graduação em Saúde Pública e Meio Ambiente, Escola Nacional de Saúde Pública (ENSP), Fundação Osvaldo Cruz (Fiocruz), Rio de Janeiro, Rio de Janeiro, Brasil

Search for other papers by Erika Menezes de Mendonça in
Current site
Google Scholar
PubMed Close
,
Marllow Caetano Claudino Laboratório de Pesquisa de Ciências Farmacêuticas (LAPESF), Unidade de Farmácia, Centro Universitário Estadual da Zona Oeste (UEZO), Rio de Janeiro, Rio de Janeiro, Brasil

Search for other papers by Marllow Caetano Claudino in
Current site
Google Scholar
PubMed Close
,
Luiz Eurico Nasciutti Programa de Ciências Morfológicas (PCM), Instituto de Ciências Biomédicas (ICB), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brasil

Search for other papers by Luiz Eurico Nasciutti in
Current site
Google Scholar
PubMed Close
,
Mauro Sola-Penna Laboratório de Enzimologia e Controle do Metabolismo (LabECoM), Departamento de Biotecnologia Farmacêutica (BioTecFar), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brasil

Search for other papers by Mauro Sola-Penna in
Current site
Google Scholar
PubMed Close
,
Patrícia Zancan Laboratório de Oncobiologia Molecular (LabOMol), Departamento de Biotecnologia Farmacêutica (BioTecFar), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brasil

Search for other papers by Patrícia Zancan in
Current site
Google Scholar
PubMed Close
, and
Jamila Alessandra Perini Laboratório de Pesquisa de Ciências Farmacêuticas (LAPESF), Unidade de Farmácia, Centro Universitário Estadual da Zona Oeste (UEZO), Rio de Janeiro, Rio de Janeiro, Brasil
Programa de Pós-Graduação em Saúde Pública e Meio Ambiente, Escola Nacional de Saúde Pública (ENSP), Fundação Osvaldo Cruz (Fiocruz), Rio de Janeiro, Rio de Janeiro, Brasil

Search for other papers by Jamila Alessandra Perini in
Current site
Google Scholar
PubMed Close

Correspondence should be addressed to D E Machado; Email: danielescorsim@yahoo.com.br
DOI:
https://doi.org/10.1530/REP-19-0502
Volume/Issue:
Volume 159: Issue 6
Page Range:
779–786
Article Type:
Research Article
Online Publication Date:
Jun 2020
Copyright:
© 2020 Society for Reproduction and Fertility 2020
Restricted access
Rent on DeepDyve

Sign up for journal news

This study aimed to analyse the effects of clotrimazole (CTZ) on estrogen production pathway in endometriosis progression. Experimental endometriosis was induced by autologous transplantation in female Wistar rats, and then the rats were treated with clotrimazole (200 mg/kg) or vehicle, both orally and intraperitoneally, for 15 consecutive days. Serum estrogen levels and vaginal smear analyses were performed and ERα (estrogen receptor alpha) and CYP19 (cytochrome P450 aromatase) levels in the endometriotic lesions were analysed morphologically and immunohistochemically. The clotrimazole group presented a reduction in serum estrogen levels, which were not influenced by the estrous cycle of the animals. The expression of ERα and CYP19 in endometriotic lesions was also reduced in the clotrimazole group compared to the control group. Moreover, clotrimazole treatment decreased the size of the lesions, as confirmed by histological examination, which showed glandular atrophy for both routes of administration. These results suggest that clotrimazole interferes with the estrogen production pathway by downregulating CYP19 and, therefore, reducing serum estrogen levels. Thus, the drug decreases endometriotic lesion size and consequently disease progression.

Reproduction is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 1057 11 0
PDF Downloads 810 10 0

 

  • Collapse
  • Expand
Print ISSN:
1470-1626
Online ISSN:
1741-7899

  • Acién P & Velasco I 2013 Endometriosis: a disease that remains enigmatic. ISRN Obstetrics and Gynecology 2013 242149. (https://doi.org/10.1155/2013/242149)

  • Andersen CL, Boisen MM, Sikora MJ, Ma T, Tseng G, Suryawanshi S, Vlad A, Elishaev E, Edwards RP & Oesterreich S 2018 The evolution of estrogen receptor signaling in the progression of endometriosis to endometriosis-associated ovarian cancer. Hormones and Cancer 9 399–407. (https://doi.org/10.1007/s12672-018-0350-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Becker CM, Gattrell WT, Gude K & Singh SS 2017 Reevaluating response and failure of medical treatment of endometriosis: a systematic review. Fertility and Sterility 108 125–136. (https://doi.org/10.1016/j.fertnstert.2017.05.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bedaiwy MA, Allaire C, Yong P & Alfaraj S 2017 Medical management of endometriosis in patients with chronic pelvic pain. Seminars in Reproductive Medicine 35 38–53. (https://doi.org/10.1055/s-0036-1597308)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Buck Louis GM, Hediger ML, Peterson CM, Croughan M, Sundaram R, Stanford J, Chen Z, Fujimoto VY, Varner MW, Trumble A, et al. 2011 Incidence of endometriosis by study population and diagnostic method: the endo study. Fertility and Sterility 96 360–365. (https://doi.org/10.1016/j.fertnstert.2011.05.087)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bulun SE, Yang S, Fang Z, Gurates B, Tamura M, Zhou J & Sebastian S 2001 Role of aromatase in endometrial disease. Journal of Steroid Biochemistry and Molecular Biology 79 19–25. (https://doi.org/10.1016/s0960-0760(01)00134-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cora MC, Kooistra L & Travols G 2015 Vaginal cytology of the laboratory rat and mouse: review and criteria for the staging of the estrous cycle using stained vaginal smears. Toxicologic Pathology 43 776–793. (https://doi.org/10.1177/0192623315570339)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cornel KMC, Delvoux B, Saya T, Xanthoulea S, Konings GFJ, Kruitwagen RPFM, Bongers MY, Kooreman L & Romano A 2018 The sulfatase pathway as estrogen supply in endometrial cancer. Steroids 139 45–52. (https://doi.org/10.1016/j.steroids.2018.09.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Crowley PD & Gallagher HC 2014 Clotrimazole as a pharmaceutical: past, present and future. Journal of Applied Microbiology 117 611–617. (https://doi.org/10.1111/jam.12554)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Delvoux B, Groothuis P, D’Hooghe T, Kyama C, Dunselman G & Romano A 2009 Increased production of 17-estradiol in endometriosis lesions is the result of impaired metabolism. Journal of Clinical Endocrinology and Metabolism 94 876–883. (https://doi.org/10.1210/jc.2008-2218)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dennison WB, Loeser RF, Turner RA, Johnson JA & Wells HB 1990 A double blind placebo controlled trial of low dose clotrimazole in rheumatoid arthritis. Journal of Rheumatology 17 1003–1007.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fauconnier A, Staraci S, Huchon C, Roman H, Panel P & Descamps P 2013 Comparison of patient- and physician-based descriptions of symptoms of endometriosis: a qualitative study: a qualitative study. Human Reproduction 28 2686–2694. (https://doi.org/10.1093/humrep/det310)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Furtado CM, Marcondes MC, Sola-Penna M, Souza MLS & Zancan P 2012 Clotrimazole preferentially inhibits human breast cancer cell proliferation, viability and glycolysis. PLoS ONE 7 e30462. (https://doi.org/10.1371/journal.pone.0030462)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Furtado CM, Marcondes MC, Carvalho RS, Sola-Penna M & Zancan P 2015 Phosphatidylinositol-3-kinase as a putative target for anticanceraction of clotrimazole. International Journal of Biochemistry and Cell Biology 62 132–141. (https://doi.org/10.1016/j.biocel.2015.03.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Giudice LC 2010 Clinical practice. Endometriosis. New England Journal of Medicine 362 2389–2398. (https://doi.org/10.1056/NEJMcp1000274)

  • Grümmer R 2006 Animal models in endometriosis research. Human Reproduction Update 12 641–649. (https://doi.org/10.1093/humupd/dml026)

  • Hemmert R, Schliep KC, Willis S, Peterson CM, Louis GB, Allen-Brady K, Simonsen SE, Stanford JB & Byun SKR 2018 Modifiable life style factors and risk for incident endometriosis. Paediatric and Perinatal Epidemiology 33 19–25. (doi:10.1111/ppe.12516)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Huhtinen K, Desai R, Ståhle M, Salminen A, Handelsman DJ, Perheentupa A & Poutanen M 2012 Endometrial and endometriotic concentrations of estrone and estradiol are determined by local metabolism rather than circulating levels. Journal of Clinical Endocrinology and Metabolism 97 4228–4235. (https://doi.org/10.1210/jc.2012-1154)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jouhari S, Mohammadzadeh A, Soltanghoraee H, Mohammadi Z, Khazali S, Mirzadegan E, Lakpour N, Fatemi F, Zafardoust S, Mohazzab A, et al. 2018 Effects of silymarin, cabergoline and letrozole on rat model of endometriosis. Taiwanese Journal of Obstetrics and Gynecology 57 830–835. (available at: http://creativecommons.org/licenses/by-nc-nd/4.0/) (https://doi.org/10.1016/j.tjog.2018.10.011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kho RM & Abrão MS 2012 Ovarian remnant syndrome: etiology, diagnosis, treatment and impact of endometriosis. Current Opinion in Obstetrics and Gynecology 24 210–214. (https://doi.org/10.1097/GCO.0b013e3283558539)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kinoshita Y & Chen S 2003 Induction of aromatase (CYP19) expression in breast cancer cells through a nongenomic action of estrogen receptor alpha. Cancer Research 63 3546–3555.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kuper KM 2008 Text book of competence assessment tools for health-system pharmacies. In Intravenous to Oral Therapy Conversion, 4th ed., pp. 347–360. ASHP.

  • Lindsay SF, Luciano DE & Luciano AA 2015 Emerging therapy for endometriosis. Expert Opinion on Emerging Drugs 20 449–461. (https://doi.org/10.1517/14728214.2015.1051966)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu X & Shi H 2015 Regulation of estrogen receptor α expression in the hypothalamus by sex steroids: implication in the regulation of energy homeostasis. International Journal of Endocrinology 2015 949085. (https://doi.org/10.1155/2015/949085)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lu Y, Nie J, Liu X, Zheng Y & Guo SW 2010 Trichostatin A, a histone deacetylase inhibitor, reduces lesion growth and hyperalgesia in experimentally induced endometriosis in mice. Human Reproduction 25 1014–1025. (available at: http://humrep.oxfordjournals.org/Downloaded) (https://doi.org/10.1093/humrep/dep472)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Machado DE, Berardo PT, Landgraf RG, Fernandes PD, Palmero C, Alves LM, Abrao MS & Nasciutti LE 2010 A selective cyclooxygenase-2 inhibitor suppresses the growth of endometriosis with an antiangiogenic effect in a rat model. Fertility and Sterility 93 2674–2679. (https://doi.org/10.1016/j.fertnstert.2009.11.037)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Machado DE, Rodrigues-Baptista KC, Alessandra-Perini J, Santos TA, Pereira KG, Marinho da Silva Y, Souza PJ, Nasciutti LE & Perini JA 2016 Euterpe oleracea extract (açaí) is a promising novel pharmacological therapeutic treatment for experimental endometriosis. PLoS ONE 11 e0166059. (https://doi.org/10.1371/journal.pone.0166059)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Machado DE, Perini JA, de Mendonça EM, Branco JR, RodriguesBaptista KC, Alessandra-Perini J, Espíndola-Neto JM, dos Santos TA, Coelho WS, Nasciutti LE, et al. 2018 Clotrimazole is effective for the regression of endometriotic implants in Wistar rat experimental model of endometriosis. Molecular and Cellular Endocrinology 476 17–26. (https://doi.org/10.1016/j.mce.2018.04.005)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Marcondes MC, Sola-Penna M & Zancan P 2010 Clotrimazole potentiates the inhibitory effects of ATP on the key glycolytic enzyme 6-phosphofructo-1-kinase. Archives of Biochemistry and Biophysics 497 62–67. (https://doi.org/10.1016/j.abb.2010.03.013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Marcondes MC, Fernandes ACS, Itabaiana I, de Souza ROMA, Sola-Penna M & Zancan P 2015 Nanomicellar formulation of clotrimazole improves its antitumor action toward human breast cancer cells. PLoS ONE 10 e0130555. (https://doi.org/10.1371/journal.pone.0130555)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Marie-Scemama L, Even M, Joliniere JBDL & Ayoubi JM 2019 Endometriosis and the menopause: why the question merits our full attention. Hormone Molecular Biology and Clinical Investigation 37 20180071. (https://doi.org/10.1515/hmbci-2018-0071)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mattos RM, Machado DE, Perini JA, Alessandra-Perini J, Meireles da Costa NO, Wiecikowski AFDRO, Cabral KMDS, Takiya CM, Carvalho RS & Nasciutti LE 2019 Galectin-3 plays an important role in endometriosis development and in a target to endometriosis treatment. Molecular and Cellular Endocrinology 486 1–10. (https://doi.org/10.1016/j.mce.2019.02.007)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mori T, Ito F, Koshiba A, Kataoka H, Tanaka Y, Okimura H, Khan KN & Kitawaki J 2018 Aromatase as a target for treating endometriosis. Journal of Obstetrics and Gynaecology Research 44 1673–1681. (https://doi.org/10.1111/jog.13743)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nair AB & Jacob S 2016 A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy 7 27–31. (https://doi.org/10.4103/0976-0105.177703)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Naqvi H, Sakr S, Presti T, Krikun G, Komm B & Taylor HS 2014 Treatment with bazedoxifene and conjugated estrogens results in regression of endometriosis in a murine model. Biology of Reproduction 90 121. (https://doi.org/10.1095/biolreprod.113.114165)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Parazzini F, Esposito G, Tozzi L, Noli S & Bianchi S 2017 Epidemiology of endometriosis and its comorbidities. European Journal of Obstetrics, Gynecology, and Reproductive Biology 209 3–7. (https://doi.org/10.1016/j.ejogrb.2016.04.021)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Piccinato CA, Malvezzi H, Gibson DA & Saunders PTK 2018 SULFATION PATHWAYS: Contribution of intracrine oestrogens to the aetiology of endometriosis. Journal of Molecular Endocrinology 61 T253–T270. (https://doi.org/10.1530/JME-17-0297)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Trösken ER, Scholz K, Lutz RW, Völkel W, Zarn JA & Lutz WK 2004 Comparative assessment of the inhibition of recombinant human CYP19 (aromatase) by azoles used in agriculture and as drugs for humans. Endocrine Research 30 387–394. (https://doi.org/10.1081/erc-200035093)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Uebi T, Umeda M & Imai T 2015 Estrogen induces estrogen receptor alpha expression and hepatocyte proliferation in the livers of male mice. Genes to Cells 20 217–223. (https://doi.org/10.1111/gtc.12214)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vanden Bossche H, Marichal P, Gorrens J, Coene MC, Willemsens G, Bellens D, Roels I, Moereels H & Janssen PA 1989 Biochemical approaches to selective antifungal activity. Focus on azole antifungals. Mycoses 32 (Supplement 1) 35–52. (https://doi.org/10.1111/j.1439-0507.1989.tb02293.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vercellini P, Somigliana E, Vigano P, Abbiati A, Barbara G & Crosignani PG 2009 Endometriosis: current therapies and new pharmacological developments. Drugs 69 649–675. (https://doi.org/10.2165/00003495-200969060-00002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vercellini P, Buggio L, Berlanda N, Barbara G, Somigliana E & Bosari S 2016 Estrogen-progestins and progestins for the management of endometriosis. Fertility and Sterility 106 1552.e2–1571.e2. (https://doi.org/10.1016/j.fertnstert.2016.10.022)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vigano P, Parazzini F, Somigliana E & Vercellini P 2004 Endometriosis: epidemiology and aetiological factors. Best Practice and Research: Clinical Obstetrics and Gynaecology 18 177–200. (https://doi.org/10.1016/j.bpobgyn.2004.01.007)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • World Bank 2010 Population projection tables by country and group. (available at: http://go.worldbank.org/KZHE1CQFA0)

  • Zhou X, Li T, Fan S, Zhu Y, Liu X, Guo X & Liang Y 2016 The efficacy and safety of clotrimazole vaginal tablet vs. oral fluconazole in treating severe vulvovaginal candidiasis. Mycoses 59 419–428. (https://doi.org/10.1111/myc.12485)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu TH, Ding SJ, Li TT, Zhu LB, Huang XF & Zhang XM 2018 Estrogen is an important mediator of mast cell activation in ovarian endometriomas. Reproduction 155 73–83. (https://doi.org/10.1530/REP-17-0457)

    • PubMed
    • Search Google Scholar
    • Export Citation