J Menopausal Med.  2016 Dec;22(3):174-179. 10.6118/jmm.2016.22.3.174.

Raloxifene Administration in Women Treated with Long Term Gonadotropin-releasing Hormone Agonist for Severe Endometriosis: Effects on Bone Mineral Density

• Cho YH
• Um MJ
• Kim SJ
• Kim SA
• Jung H

• KMID: 2378238
• DOI: http://doi.org/10.6118/jmm.2016.22.3.174

Abstract

OBJECTIVES
To evaluate the efficacy of raloxifene in preventing bone loss associated with long term gonadotropin-releasing hormone agonist (GnRH-a) administration.
METHODS
Twenty-two premenopausal women with severe endometriosis were treated with leuprolide acetate depot at a dosage of 3.75 mg/4 weeks, for 48 weeks. Bone mineral density (BMD) was evaluated at admission, and after 12 treatment cycles.
RESULTS
At cycle 12 of GnRH-a plus raloxifene treatment, lumbar spine, trochanter femoral neck, and Ward's BMD differed from before the treatment. A year after treatment, the lumbar spine and trochanter decreased slightly, but were not significantly different.
CONCLUSIONS
Our study shows that the administration of GnRH-a plus raloxifene in pre-menopausal women with severe endometriosis, is an effective long-term treatment to prevent bone loss.

Keyword

Bone mineral density; Endometriosis; Gonadotropin-releasing hormone agonist; Raloxifene hydrochloride

MeSH Terms

Bone Density*
Endometriosis*
Female
Femur
Femur Neck
Gonadotropin-Releasing Hormone*
Humans
Leuprolide
Raloxifene Hydrochloride*
Spine
Gonadotropin-Releasing Hormone
Leuprolide
Raloxifene Hydrochloride

Reference

1. Haney AF. The pathogenesis and etiology of endometriosis. In : Thomas EJ, Rock JA, editors. Modern approaches to endometriosis. Dordrecht, NL: Kluwer Academic;1991. p. 113–128.

2. Howell R, Edmonds DK, Dowsett M, Crook D, Lees B, Stevenson JC. Gonadotropin-releasing hormone analogue (goserelin) plus hormone replacement therapy for the treatment of endometriosis: a randomized controlled trial. Fertil Steril. 1995; 64:474–481.

3. McLachlan RI, Healy DL, Burger HG. Clinical aspects of LHRH analogues in gynaecology: a review. Br J Obstet Gynaecol. 1986; 93:431–454.

4. Erickson LD, Ory SJ. GnRH analogues in the treatment of endometriosis. Obstet Gynecol Clin North Am. 1989; 16:123–145.

5. Meldrum DR, Chang RJ, Lu J, Vale W, Rivier J, Judd HL. “Medical oophorectomy” using a long-acting GNRH agonist--a possible new approach to the treatment of endometriosis. J Clin Endocrinol Metab. 1982; 54:1081–1083.

6. Lemay A, Maheux R, Faure N, Jean C, Fazekas AT. Reversible hypogonadism induced by a luteinizing hormone-releasing hormone (LH-RH) agonist (Buserelin) as a new therapeutic approach for endometriosis. Fertil Steril. 1984; 41:863–871.

7. Fogelman I. Gonadotropin-releasing hormone agonists and the skeleton. Fertil Steril. 1992; 57:715–724.

8. Lemay A, Surrey ES, Friedman AJ. Extending the use of gonadotropin-releasing hormone agonists: the emerging role of steroidal and nonsteroidal agents. Fertil Steril. 1994; 61:21–34.

9. Orwoll ES, Yuzpe AA, Burry KA, Heinrichs L, Buttram VC Jr, Hornstein MD. Nafarelin therapy in endometriosis: long-term effects on bone mineral density. Am J Obstet Gynecol. 1994; 171:1221–1225.

10. Crosignani P, Olive D, Bergqvist A, Luciano A. Advances in the management of endometriosis: an update for clinicians. Hum Reprod Update. 2006; 12:179–189.

11. Surrey ES. Steroidal and nonsteroidal “add-back” therapy: extending safety and efficacy of gonadotropin-releasing hormone agonists in the gynecologic patient. Fertil Steril. 1995; 64:673–685.

12. Pickersgill A. GnRH agonists and add-back therapy: is there a perfect combination? Br J Obstet Gynaecol. 1998; 105:475–485.

13. Palomba S, Affinito P, Tommaselli GA, Nappi C. A clinical trial of the effects of tibolone administered with gonadotropin-releasing hormone analogues for the treatment of uterine leiomyomata. Fertil Steril. 1998; 70:111–118.

14. Palomba S, Affinito P, Di Carlo C, Bifulco G, Nappi C. Long-term administration of tibolone plus gonadotropin-releasing hormone agonist for the treatment of uterine leiomyomas: effectiveness and effects on vasomotor symptoms, bone mass, and lipid profiles. Fertil Steril. 1999; 72:889–895.

15. Di Carlo C, Palomba S, Tommaselli GA, Guida M, Di Spiezio Sardo A, Nappi C. Use of leuprolide acetate plus tibolone in the treatment of severe premenstrual syndrome. Fertil Steril. 2001; 75:380–384.

16. Palomba S, Pellicano M, Affinito P, Di Carlo C, Zullo F, Nappi C. Effectiveness of short-term administration of tibolone plus gonadotropin-releasing hormone analogue on the surgical outcome of laparoscopic myomectomy. Fertil Steril. 2001; 75:429–433.

17. Taskin O, Yalcinoglu AI, Kucuk S, Uryan I, Buhur A, Burak F. Effectiveness of tibolone on hypoestrogenic symptoms induced by goserelin treatment in patients with endometriosis. Fertil Steril. 1997; 67:40–45.

18. Adashi EY. Long-term gonadotrophin-releasing hormone agonist therapy: the evolving issue of steroidal ‘add-back’ paradigms. Hum Reprod. 1994; 9:1380–1397.

19. Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997; 138:863–870.

20. Khovidhunkit W, Shoback DM. Clinical effects of raloxifene hydrochloride in women. Ann Intern Med. 1999; 130:431–439.

21. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 1998; 279:1445–1451.

22. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999; 282:637–645.

23. Mosca L. Rationale and overview of the Raloxifene Use for the Heart (RUTH) trial. Ann N Y Acad Sci. 2001; 949:181–185.

24. Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 2002; 287:847–857.

25. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999; 281:2189–2197.

26. Cohen FJ, Watts S, Shah A, Akers R, Plouffe L Jr. Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60. Obstet Gynecol. 2000; 95:104–110.

27. Goldstein SR, Scheele WH, Rajagopalan SK, Wilkie JL, Walsh BW, Parsons AK. A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium. Obstet Gynecol. 2000; 95:95–103.

28. Dawood MY, Lewis V, Ramos J. Cortical and trabecular bone mineral content in women with endometriosis: effect of gonadotropin-releasing hormone agonist and danazol. Fertil Steril. 1989; 52:21–26.

29. Whitehouse RW, Adams JE, Bancroft K, Vaughan-Williams CA, Elstein M. The effects of nafarelin and danazol on vertebral trabecular bone mass in patients with endometriosis. Clin Endocrinol (Oxf). 1990; 33:365–373.

30. Stevenson JC, Lees B, Gardner R, Shaw RW. A comparison of the skeletal effects of goserelin and danazol in premenopausal women with endometriosis. Horm Res. 1989; 32:Suppl 1. 161–163. discussion 4.

31. Clemett D, Spencer CM. Raloxifene: a review of its use in postmenopausal osteoporosis. Drugs. 2000; 60:379–411.

32. Díez JL. Skeletal effects of selective oestrogen receptor modulators (SERMs). Hum Reprod Update. 2000; 6:255–258.

33. Prestwood KM, Gunness M, Muchmore DB, Lu Y, Wong M, Raisz LG. A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women. J Clin Endocrinol Metab. 2000; 85:2197–2202.

34. Lufkin EG, Whitaker MD, Nickelsen T, Argueta R, Caplan RH, Knickerbocker RK, et al. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res. 1998; 13:1747–1754.

35. Meunier PJ, Vignot E, Garnero P, Confavreux E, Paris E, Liu-Leage S, et al. Treatment of postmenopausal women with osteoporosis or low bone density with raloxifene. Raloxifene Study Group. Osteoporos Int. 1999; 10:330–336.

36. Silverman SL, Minshall ME, Shen W, Harper KD, Xie S. The relationship of health-related quality of life to prevalent and incident vertebral fractures in postmenopausal women with osteoporosis: results from the Multiple Outcomes of Raloxifene Evaluation Study. Arthritis Rheum. 2001; 44:2611–2619.

37. Palomba S, Orio F Jr, Morelli M, Russo T, Pellicano M, Nappi C, et al. Raloxifene administration in women treated with gonadotropin-releasing hormone agonist for uterine leiomyomas: effects on bone metabolism. J Clin Endocrinol Metab. 2002; 87:4476–4481.

38. Finkelstein JS, Brockwell SE, Mehta V, Greendale GA, Sowers MR, Ettinger B, et al. Bone mineral density changes during the menopause transition in a multiethnic cohort of women. J Clin Endocrinol Metab. 2008; 93:861–868.