Paradigm Shift: The Realization of New Medical Alternatives to Surgery for Endometriosis
Edward M Lichten, MD
PDF
HTML

Keywords

Endometriosis
Environmental toxins
Immunology
Nandrolone
Sex hormone binding globulin
Stanozolol
Xenoestrogens
PDF
HTML

Abstract

Endometriosis is one of the most destructive benign diseases of women. It is established as developing and being present in upward of 70% of adolescents who do not experience relief of menstrual pain with use of oral contraceptives and anti-inflammatory drugs. It occurs in 8%‐10% of women in the United States and is most prevalent in developed countries. Symptoms of endometriosis include disabling pain, hemorrhagic uterine bleeding, and infertility. Women with disease can expect a 12% hysterectomy rate. While present medical therapy may offer relief of many symptoms, there have been no major new directions in pharmacologic therapy since leuprolide acetate was made available in 1977. Danazol remains the only alternative to GnRH agonists with proven efficacy and reasonable side effects, according to Cochrane Reviews, yet, it is underused, and GnRH agonists are favored even when Danazol in combination seems more effective. A previously published case report on use of the combination of nandrolone and stanozolol to treat a young woman scheduled for hemicolectomy is discussed as an alternative to surgery along with the limits of standard therapy. This review will focus on recent research and theories seeking to establish causation for disease and offer treatment recommendations.

PDF
HTML

References

Propst AM, Laufer MR. Endometriosis in adolescents: incidence, diagnosis, and treatment. J Reprod Med. 1999; 44:751–8.
Trabert B, De Roos AJ, Schwartz SM, et al. Non-dioxin-like polychlorinated biphenyls and risk of endometriosis. Environ Health Perspect. 2010; 118:1280–5.
Keshavarz H, Hillis SD, Kieke BA, Marchbanks PA. Hysterectomy surveillance – United States, 1994–1999. MMWR Surveill Summ. 2002; 51(SS05):1–8.
CenterWatch. Lupron Depot (leuprolide acetate for depot suspension) [accessed July 20, 2016]. Available from: http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/293/lupron-depot-leuprolide-acetate-for-depot-suspension
Muzii L, Di Tucci C, Achilli C, et al. Continuous versus cyclic oral contraceptives after laparoscopic excision of ovarian endometriomas: a systematic review and metaanalysis. Am J Obstet Gynecol. 2016; 214:203–11.
Al Kadri H, Hassan S, Al-Fozan HM, Hajeer A. Hormone therapy for endometriosis and surgical menopause. Cochrane Database Syst Rev. 2009;(1):CD005997.
Crosignani PG, Luciano A, Ray A, Bergqvist A. Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain. Hum Reprod. 2006; 21:248–56.
Schlaff WD, Dugoff L, Damewood MD, Rock JA. Megestrol acetate for treatment of endometriosis. Obstet Gynecol. 1990; 75:646–8.
Brown J, Kives S, Akhtar M. Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Database Syst Rev. 2012; 3:CD002122.
Rencoret R, Vargas L. Persistent, obstructive, and recurrent intestinal endometriosis; regression by prolonged treatment with testosterone; report of a case. Obstet Gynecol. 1954; 4:142–6.
Brown J, Farquhar C. Endometriosis: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2014;(3):CD009590.
Kim SH, Chae HD, Kim CH, Kang BM. Update on the treatment of endometriosis. Clin Exp Reprod Med. 2013; 40:55–9.
Edmonds DK. Add-back therapy in the treatment of endometriosis: the European experience. Br J Obstet Gynaecol. 1996; 103(Suppl 14):10–3.
Sakata M, Terakawa N, Mizutani T, et al. Effects of danazol, gonadotropin-releasing hormone agonist, and a combination of danazol and gonadotropin-releasing hormone agonist on experimental endometriosis. Am J Obstet Gynecol. 1990; 163:1679–84.
Gierach GL, Pfeiffer RM, Patel DA, et al. Long-term overall and disease-specific mortality associated with benign gynecologic surgery performed at different ages. Menopause. 2014; 21:592–601.
Mu F, Rich-Edwards J, Rimm EB, et al. Endometriosis and risk of coronary heart disease. Circ Cardiovasc Qual Outcomes. 2016; 9:257–64.
Matsuo H. Bone loss induced by GnRHa treatment in women [in Japanese]. Nihon Rinsho. 2003; 61:314–8.
Fritzer N, Tammaa A, Haas D, et al. When sex is not on fire: a prospective multi-centre study evaluating the short-term effects of radical resection of endometriosis on quality of sex life and dyspareunia. Eur J Obstet Gynecol Reprod Biol. 2016; 197:36–40.
Gao X, Yeh YC, Outley J, et al. Health-related quality of life burden of women with endometriosis: a literature review. Curr Med Res Opin. 2006; 22:1787–97.
Nagai K, Hayashi K, Yasui T, et al. Disease history and risk of comorbidity in women’s life course: a comprehensive analysis of the Japan Nurses’ Health Study baseline survey. BMJ Open. 2015; 5:e006360.
Barbieri RL. Endometriosis 1990: current treatment approaches. Drugs. 1990; 39:502–10.
Sofo V, Götte M, Laganà AS, et al. Correlation between dioxin and endometriosis: an epigenetic route to unravel the pathogenesis of the disease. Arch Gynecol Obstet. 2015; 292:973–86.
Koike N, Higashiura Y, Akasaka J, et al. Epigenetic dysregulation of endometriosis susceptibility genes. Mol Med Rep. 2015; 12:1611–6.
Déchaud H, Ravard C, Claustrat F, et al. Xenoestrogen interaction with human sex hormone-binding globulin (hSHBG). Steroids. 1999; 64:328–34.
Rubin BS. Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol. 2011; 127:27–34.
Pugeat M. Mechanism of action and peripheral metabolism of androgens in women [in French]. Rev Fr Gynecol Obstet. 1989; 84:475–8.
Burke CW, Anderson DC. SHBG is an oestrogen amplifier. Nature. 1972; 240:38–40.
Panidis D, Kokkinos T, Vavilis D, et al. SHBG serum levels in women with endometriosis before, during and after long-term danazol therapy [in German]. Geburtshilfe Frauenheilkd. 1993; 53:121–4.
Forbes KL, Dowsett M, Rose GL, et al. Dosage-related effects of danazol on sex hormone binding globulin and free and total androgen levels. Clin Endocrinol (Oxf). 1986; 25:597–605.
Daan NM, Jaspers L, Koster MP, et al. Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features. Hum Reprod. 2015; 30:2376–86.
Bui HN, Sluss PM, Hayes FJ, et al. Testosterone, free testosterone, and free androgen index in women: reference intervals, biological variation, and diagnostic value in polycystic ovary syndrome. Clin Chim Acta. 2015; 450:227–32.
Campagnoli C, Lesca L, Cantamessa C, Peris C. Long-term hormone replacement treatment in menopause: new choices, old apprehensions, recent findings. Maturitas. 1993; 18:21–46.
Wiegratz I, Jung-Hoffmann C, Kuhl H. Effect of two oral contraceptives containing ethinylestradiol and gestodene or norgestimate upon androgen parameters and serum binding proteins. Contraception. 1995; 51:341–6.
Lichten EM. Novel medical protocol offers alternative to total abdominal hysterectomy with bilateral salpingo-oophorectomy and hemicolectomy in stage IV endometriosis. Obstet Gynecol. 2014; 123(Suppl 1):125S–6S.
Saatok T, Dahlberg E, Gustafsson JA. Relative binding affinity of anabolic-androgenic steroids: comparison of the binding to the androgen receptors in skeletal muscle and in prostate, as well as to sex hormone-binding globulin. Endocrinology. 1984; 114:2100–6.
Agarwal N, Subramanian A. Endometriosis – morphology, clinical presentations and molecular pathology. J Lab Physicians. 2010; 2:1–9.
Wood R, Guidone H, Hummelshoj L. Myths and misconceptions in endometriosis. http://endometriosis.org/resources/articles/myths/. Accessed July 20, 2016 .
Worldwide Endometriosis March. http://www.endomarch.org/. Accessed July 20, 2016 .
Merrill RM. Hysterectomy surveillance in the United States, 1997 through 2005. Med Sci Monit. 2008; 14:CR24–31.
Cleveland Clinic. Recurrent endometriosis: surgical management. https://my.clevelandclinic.org/health/diseases_conditions/hic_Endometriosis/hic_Recurrent_Endometriosis_Surgical_Management. Accessed July 20, 2016 .
Rizk B, Fischer AS, Lotfy HA, et al. Recurrence of endometriosis after hysterectomy. Facts Views Vis Obgyn. 2014; 6:219–27.
Benagiano G, Brosens I, Lippi D. The history of endometriosis. Gynecol Obstet Invest. 2014; 78:1–9.
Redwine DB. Was Sampson wrong? Fertil Steril. 2002; 78:686–93.
Barbieri RL, Callery M, Perez SE. Directionality of menstrual flow: cervical os diameter as a determinant of retrograde menstruation. Fertil Steril. 1992; 57:727–30.
Woodbury RA, Child GP. Electro-uterography and the physiology of the human uterus as related to dysmenorrhea and metrorrhagia. Fed Proc. 1946; 5(1 Pt 2):215.
Csapo AI. A rationale for the treatment of dysmenorrhea. J Reprod Med. 1980; 25(4 Suppl):213–21.
Polak G, Barczyński B, Bednarek W, et al. Increased levels of proteins of the acute inflammatory phase in the peritoneal fluid of women with advanced stages of endometriosis. Ginekol Pol. 2015; 86:414–8.
Nascu PC, Vilos GA, Ettler HC, et al. Histopathologic findings on uterosacral ligaments in women with chronic pelvic pain and visually normal pelvis at laparoscopy. J Minim Invasive Gynecol. 2006; 13:201–4.
Lichten EM, Bombard J. Surgical treatment of primary dysmenorrhea with laparoscopic uterine nerve ablation. J Reprod Med. 1987; 32:37–41.
Jedrzejczak P, Sokalska A, Spaczyński RZ, et al. Effects of presacral neurectomy on pelvic pain in women with and without endometriosis. Ginekol Pol. 2009; 80:172–8.
Moghissi KS. Prostaglandins in reproduction. Obstet Gynecol Annu. 1972; 1:297–337.
De Leon FD, Vijayakumar R, Brown M, et al. Peritoneal fluid volume, estrogen, progesterone, prostaglandin, and epidermal growth factor concentrations in patients with and without endometriosis. Obstet Gynecol. 1986; 68:189–94.
Heilier JF, Nackers F, Verougstraete V, et al. Increased dioxin-like compounds in the serum of women with peritoneal endometriosis and deep endometriotic (adenomyotic) nodules. Fertil Steril. 2005; 84:305–12.
Gupta D, Hull ML, Fraser I, et al. Endometrial biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev. 2016; 4:CD012165.
Lardenoije C, Aardenburg R, Mertens H. Imperforate hymen: a cause of abdominal pain in female adolescents. BMJ Case Rep. 2009; 2009: bcr08.2008.0722 .
Kennedy S, Mardon H, Barlow D. Familial endometriosis. J Assist Reprod Genet. 1995; 12:32–4.
Kobayashi H, Imanaka S, Nakamura H, Tsuji A. Understanding the role of epigenomic, genomic and genetic alternations in the development of endometriosis. Mol Med Rep. 2014; 9:1483–505.
Lu Y, Cuellar-Partida G, Painter JN, et al. Shared genetics underlying epidemiological association between endometriosis and ovarian cancer. Hum Mol Genet. 2015; 24:5955–64.
Benagiano G, Brosens I. In utero exposure and endometriosis. J Matern Fetal Neonatal Med. 2014; 27:303–8.
Cai LY, Izumi S, Suzuki T, et al. Dioxins in ascites and serum of women with endometriosis: a pilot study. Hum Reprod. 2011; 26:117–26.
Troncon JK, Zani AC, Vieira AD, et al. Endometriosis in a patient with Mayer-Rokitansky-Küster-Hauser syndrome. Case Rep Obstet Gynecol. 2014; 2014:376231.
Suginami H. A reappraisal of the coelomic metaphasia theory by reviewing endometriosis occurring in unusual sites and instances. Am J Obstet Gynecol. 1991; 165:214–8.
Laschke MV, Giebels C, Menger MD. Vasculogenesis: a new piece of the endometriosis puzzle. Hum Reprod Update. 2011; 17:628–36.
Miller EJ, Fraser IS. The importance of pelvic nerve fibers in endometriosis. Womens Health (Lond). 2015; 11:611–8.
Barragan F, Irwin JC, Balayan S, et al. Human endometrial fibroblasts derived from mesenchymal progenitors inherit progesterone resistance and acquire an inflammatory phenotype in the endometrial niche in endometriosis. Biol Reprod. 2016; 94:118.
Bruner KL, Eisenberg E, Gorstein F, Osteen KG. Progesterone and transforming growth factor-β coordinately regulate suppression of endometrial matrix metalloproteinases in a model of experimental endometriosis. Steroids. 1999; 64:648–53.
Bulun SE, Monsivais D, Kakinuma T, et al. Molecular biology of endometriosis: from aromatase to genomic abnormalities. Semin Reprod Med. 2015; 33:220–4.
Jurewicz J, Hanke W. Exposure to phthalates: reproductive outcome and children health. A review of epidemiological studies. Int J Occup Med Environ Health. 2011; 24:115–41.
Heilier JF, Donnez J, Lison D. Organochlorines and endometriosis: a mini-review. Chemosphere. 2008; 71:203–10.
Gerhard I, Runnebaum B. The limits of hormone substitution in pollutant exposure and fertility disorders [in German]. Zentralbl Gynakol. 1992; 114:593–602.
Misao R, Nakanishi Y, Fujimoto J, Tamaya T. Expression of sex hormone-binding globulin exon VII splicing variant messenger ribonucleic acid in human ovarian endometriosis. Fertil Steril. 1998; 69:324–8.
Thomas JA. Endocrine Toxicology, 2nd edn. Washington, DC: Taylor & Francis; 1997.
Mean F, Pellaton M, Magrini G. Study on the binding of dihydrotestosterone, testosterone and oestradiol with sex hormone binding globulin. Clin Chim Acta. 1977; 80:171–80.
Zimmerman Y, Eijkemans MJ, Coelingh Bennink HJ, et al. The effect of combined oral contraception on testosterone levels in healthy women: a systemic review and meta-analysis. Hum Reprod Update. 2014; 20:76–105.
Sood R, Faubion SS, Kuhle CL, et al. Prescribing menopausal hormone therapy: an evidence-based approach. Int J Womens Health. 2014; 6:47–57.
Michalek JE, Akhtar FZ, Kiel JL, et al. Serum dioxin, insulin, fasting glucose, and sex hormone-binding globulin in veterans of Operation Ranch Hand. J Clin Endocrinol Metab. 1999; 84:1540–3.
Misao R, Hori M, Ichigo S, et al. Levels of sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) messenger ribonucleic acid (mRNAs) in ovarian endometriosis. Reprod Nutr Dev. 1995; 35:155–65.
Barbieri RL. Comparison of the pharmacology of nafarelin and danazol. Am J Obstet Gynecol. 1990; 162:581–5.
Sinnecker G, Köhler S. Sex hormone-binding globulin response to the anabolic steroid stanozolol: evidence for its suitability as a biological androgen sensitivity test. J Clin Endocrinol Metab. 1989; 68:1195–200.
Gårevik N, Strahm E, Garle M, et al. Long term perturbation of endocrine parameters and cholesterol metabolism after discontinued abuse of anabolic androgenic steroids. J Steroid Biochem Mol Biol. 2011; 127:295–300.
Lovejoy JC, Bray GA, Bourgeois MO, et al. Exogenous androgens influence body composition and regional body fat distribution in obese postmenopausal women – a clinical research center study. J Clin Endocrinol Metab. 1996; 81:2198–203.
Adachi M, Takayanagi R. Effect of anabolic steroids on osteoporosis [in Japanese]. Clin Calcium. 2008; 18:1451–9.
Dickey RP, Taylor SN, Curole DN. Serum estradiol and danazol. I. Endometriosis response, side effects, administration interval, concurrent spironolactone and dexamethasone. Fertil Steril. 1984; 42:709–16.
Dickey RP, Curole DN, Taylor SN. Estradiol target level in treating endometriosis. Fertil Steril. 1992; 57:1361–3.
Pokras R, Hufnagel V. National Center for Health Statistics. Hysterectomies in the United States, 1965–84. Vital and Health Statistics. Series 13, No. 92. DHHS Publication No. (PHS) 88-1753. Public Health Service, U.S. Department of Health and Human Services . Washington, DC: U.S. Government Printing Office; 1987. p. 9.
Diwan PV, Kulkarni DR. Anti-inflammatory activity of nandrolone phenylpropionate. Indian J Exp Biol. 1983; 21:569–71.
Forbes KL, Dowsett M, Rose GL, Mudge JE, Jeffcoate SL. Dosage-related effects of danazol on sex hormone binding globulin and free and total androgen levels. Clin Endocrinol (Oxf). 1986; 25:597–605.
Matalliotakis IM, Neonaki MA, Panidis DK, et al. Three-year follow-up of [CA-125, CA 19-9, CA 15-3, SIL-2R, IL-6, IL-1a, TNF-a, sCD8 and sCD4] in a woman with severe endometriosis. Eur J Obstet Gynecol Reprod Biol. 2000; 93:127–9.
Schmidt PJ, Steinberg EM, Negro PP, et al. Pharmacologically induced hypogonadism and sexual function in healthy young women and men. Neuropsychopharmacology. 2009; 34:565–76.
Grow DR, Williams RF, Hsiu JG, Hodgen GD. Antiprogestin and/or gonadotropin-releasing hormone agonist for endometriosis treatment and bone maintenance: a 1-year primate study. J Clin Endocrinol Metab. 1996; 81:1933–9.
Flory JD, Matthews KA, Sistilli CG, et al. Short-term suppression of ovarian function and immune measures in healthy women. Psychoneuroendocrinology. 2002; 27:749–68.
Liang SG, Taketani Y, Yano T, Mizumo M. Regulation of aromatase activity by gonadotropin-releasing hormone and its agonists in cultured rat granulosa cells [in Japanese]. Nihon Sanka Fujinka Gakkai Zasshi. 1989; 41:1725–30.
Terakawa N. Studies on endocrine therapy of endometriosis [in Japanese]. Nihon Sanka Fujinka Gakkai Zasshi. 1989; 41:981–9.
Jeppsson S, Gershagen S, Johansson ED, Rannevik G. Plasma levels of medroxyprogesterone acetate (MPA), sex-hormone binding globulin, gonadal steroids, gonadotrophins and prolactin in women during long-term use of depo-MPA (Depo-Provera) as a contraceptive agent. Acta Endocrinol (Copenh). 1982; 99:339–43.
Tomasicchio M, Avenant C, Du Toit A, et al. The progestin-only contraceptive medroxyprogesterone acetate, but not norethisterone acetate, enhances HIV-1 Vpr-mediated apoptosis in human CD4+ T cells through the glucocorticoid receptor. PLoS One. 2013; 8:e62895.
Zhang L, Weng L. Clinical study on women with amenorrhea after levonorgestrel intrauterine system [in Chinese]. Zhonghua Fu Chan Ke Za Zhi. 2001; 36:675–7.
Pakarinen P, Lähteenmäki P, Rutanen EM. The effect of intrauterine and oral levonorgestrel administration on serum concentrations of sex hormone-binding globulin, insulin and insulin-like growth factor binding protein-1. Acta Obstet Gynecol Scand. 1999; 78:423–8.
White T, Jain JK, Stanczyk FZ. Effect of oral versus transdermal steroidal contraceptives on androgenic markers. Am J Obstet Gynecol. 2005; 192:2055–9.
Michel KG, Huijbregts RP, Gleason JL, et al. Effect of hormonal contraception on the function of plasmacytoid dendritic cells and distribution of immune cell populations in the female reproductive tract. J Acquir Immune Defic Syndr. 2015; 68:511–8.
Strufaldi R, Pompei LM, Steiner ML, et al. Effects of two combined hormonal contraceptives with the same composition and different doses on female sexual function and plasma androgen levels. Contraception. 2010; 82:147–54.
Chetrite GS, Pasqualini JR. Nomegestrol acetate is an anti-aromatase agent in human MCF-7aro breast cancer cells. Horm Mol Biol Clin Investig. 2010; 3:417–24.
Davis SR, Goldstat R, Papalia MA, et al. Effects of aromatase inhibition on sexual function and well-being in postmenopausal women treated with testosterone: a randomized, placebo-controlled trial. Menopause. 2006; 13:37–45.
Dawood MY, Obasiolu CW, Ramos J, Khan-Dawood FS. Clinical, endocrine, and metabolic effects of two doses of gestrinone in treatment of pelvic endometriosis. Am J Obstet Gynecol. 1997; 176:387–94.
Kodama M, Onoue M, Otsuka H, et al. Efficacy of dienogest in thinning the endometrium before hysteroscopic surgery. J Minim Invasive Gynecol. 2013; 20:790–5.
Benagiano G, Petraglia F, Gordts S, Brosens I. A new approach to the management of ovarian endometrioma to prevent tissue damage and recurrence. Reprod Biomed Online. 2016; 32:556–62.
Ruan X, Seeger H, Mueck AO. The pharmacology of dienogest. Maturitas. 2012; 71:337–44.
Klipping C, Duijkers I, Remmers A, et al. Ovulation-inhibiting effects of dienogest in a randomized, dose-controlled pharmacodynamic trial of healthy women. J Clin Pharmacol. 2012; 52:1704–13.
Nilsson B, Södergård R, Damber MG, von Schoultz B. Danazol and gestagen displacement of testosterone and influence on sex-hormone-binding globulin capacity. Fert Steril. 1982; 38:48–53.
Heikinheimo O, Gordon K, Williams RF, Hodgen GD. Inhibition of ovulation by progestin analogs (agonists vs antagonists): preliminary evidence for different sites and mechanisms of actions. Contraception. 1996; 53:55–64.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 4.0). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.