Patient #4: Megestrol acetate
DD is a 52-year-old G2P2 obese, perimenopausal hypertensive and diabetic woman with irregular heavy bleeding. You perform an in-office endometrial biopsy, which demonstrates disordered proliferative endometrium. She is started on norethindrone acetate 5 mg daily, increased to 15 mg, however, she continues to bleed heavily.
You counsel your patient that some data, mostly from small studies in patients with active malignancy using MA in varying doses, did show a small increased VTE risk. However, these study populations are at inherently higher risk for VTE and may not be representative of this woman’s personal risk. There is very limited research on megestrol acetate for AUB.
Megestrol acetate is FDA-approved in doses of 40 to 320 mg/day for palliative treatment of advanced carcinoma of the breast or endometrium and treatment of cachexia in patients with AIDS.21 Regarding VTE risk, the FDA states that “thromboembolic phenomena including thrombophlebitis and pulmonary embolism (in some cases fatal) have been reported.”21
Megestrol acetate is clinically used off-label for AUB, however, there are few data on this use. A retrospective chart review of 49 patients with AUB suggested efficacy of megestrol acetate in decreasing mean days of bleeding.22 A 2013 Cochrane review evaluating 1,602 patients using megestrol acetate for treatment of cachexia in patients with cancer, AIDS, and other pathologies found an increased relative risk of VTE of 1.84 (1.05- 3.18).23 Four studies have focused specifically on MA and VTE risk, including a retrospective case control study of 435 women with cancer using megestrol acetate as an appetite stimulant,24 a retrospective descriptive study in nursing home residents,25 a cohort study in 97 patients with advanced cancer receiving chemotherapy,26 and a randomized study of 179 patients with breast cancer patients whose disease failed to respond to tamoxifen.27 Three of these small studies suggest an increased risk of VTE with megestrol acetate use24,25,27 with odds ratios ranging from 3.424 to 12.2.27 Because these studies all focused on patients at inherently higher risk of VTE, however, the results have very limited generalizability to a population of premenopausal women.
This review demonstrates the complexities of treating women with progestins for AUB. Shared decision-making between clinicians and their patients is indicated using the available data. The current data, clinical use, and expert opinion are often contradictory. This highlights the need for additional research on VTE risk of progestins used for management of AUB, especially in the context of other common risk factors for VTE, such as obesity, older age, and smoking.
- Committee on Practice Bulletins—Gynecology. Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012 Jul;120(2):197-206..
- Eichinger S, Evers JLH, Glasier A, et al.Venous thromboembolism in women: a specific reproductive health risk. Hum Reprod Update 2013;19:471-482.
- Trenor CC 3rd, Chung RJ, Michelson AD, et al.Hormonal contraception and thrombotic risk: a multidisciplinary approach. Pediatrics 2011;127:347-357.
- Curtis KM, Tepper NK, Jatlaoui TC, et al.U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep2016;65:1-103.
- Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Contraception 1998;57(5):315-324.
- US Food and Drug Administration. Levonorgestrel-releasing intrauterine system. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021225s019lbl.pdf.
- Gaspard UJ, Romus MA, Gillain D, Duvivier J, Demey-Ponsart E, Franchimont P. Plasma hormone levels in women receiving new oral contraceptives containing ethinyl estradiol plus levonorgestrel or desogestrel. Contraception 1983;27:577-590.
- Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ2009;339:b2890.
- Tepper NK, Whiteman MK, Marchbanks PA, James AH, Curtis KM. Progestin-only contraception and thromboembolism: A systematic review. Contraception 2016;94:678-700.
- Mantha S, Karp R, Raghavan V, Terrin N, Bauer KA, Zwicker JI. Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. BMJ 2012;345:e4944.
- Gialeraki A, Valsami S, Pittaras T, Panayiotakopoulos G, Politou M. Oral Contraceptives and HRT Risk of Thrombosis. Clin Appl Thromb Hemost 2018;24:217-225.
- US Food and Drug Administration. Depo-provera. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020246s036lbl.pdf.
- US Food and Drug Administration. Oral provera. US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011839s071lbl.pdf.
- Bergendal A, Persson I, Odeberg J, et al.Association of venous thromboembolism with hormonal contraception and thrombophilic genotypes. Obstet Gynecol 2014;124:600-609.
- US Food and Drug Administration. Norethindrone. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf.
- Chu MC, Zhang X, Gentzschein E, Stanczyk FZ, Lobo RA. Formation of ethinyl estradiol in women during treatment with norethindrone acetate. J Clin Endocrinol Metab 2007;92:2205-2207.
- Klehr-Bathmann I, Kuhl H. Formation of ethinylestradiol in postmenopausal women during continuous treatment with a combination of estradiol, estriol and norethisterone acetate. Maturitas 1995;21:245-250.
- Reed MJ, Ross MS, Lai LC, Ghilchik MW, James VH. In vivo conversion of norethisterone to ethynyloestradiol in perimenopausal women. J Steroid Biochem Mol Biol 1990;37:301-303.
- Kuhnz W, Heuner A, Hümpel M, Seifert W, Michaelis K. In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women. Contraception 1997;56:379-385.
- Barsoum MK, Heit JA, Ashrani AA, Leibson CL, Petterson TM, Bailey KR. Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. Thromb Res 2010;126:373-378.
- US Food and Drug Administration. Megestrol acetate. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020264s017lbl.pdf.
- Muneyyirci-Delale O, Gupta A, Abraham C, Chandrareddy A, Bowers CH Jr, Cutler JB. Management of dysfunctional uterine bleeding based on endometrial thickness. Int J Womens Health 2010;2:297-302.
- Ruiz-García V, López-Briz E, Carbonell-Sanchis R, Bort-Martí S, Gonzálvez-Perales JL. Megestrol acetate for cachexia-anorexia syndrome. A systematic review. J Cachexia Sarcopenia Muscle 2018;9:444-452.
- Incidence of Venous Thromboembolism (VTE) in Patients Prescribed Megestrol for Appetite Stimulation | January 2017 | ACP. https://www.acponline.org/membership/medical-students/acp-impact/archive/january-2017/incidence-of-venous-thromboembolism-vte-in-patients-prescribed-megestrol-for-appetite-stimulation (accessed Oct 12, 2019).
- Bolen JC, Andersen RE, Bennett RG. Deep vein thrombosis as a complication of megestrol acetate therapy among nursing home residents. J Am Med Dir Assoc 2000;1:248-252.
- Ordu C, Pilanci KN, Koksal UI, et al.Can megestrol acetate induce thrombosis in advanced oncology patients receiving chemotherapy? Asian Pac J Cancer Prev 2014;15:10165-10169.
- Thürlimann B, Castiglione M, Hsu-Schmitz SF, et al.Formestane versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: a phase III prospective randomised cross over trial of second-line hormonal treatment (SAKK 20/90). Swiss Group for Clinical Cancer Research (SAKK). Eur J Cancer 1997;33:1017-1024.