Patient #3: Norethindrone acetate
A 41-year-old G3P3 with a tubal ligation, migraine with aura, depression, and VTE during her third pregnancy presents to the Emergency Department with regular heavy menstrual bleeding. She has been bleeding for 5 days and is hemodynamically stable with moderate continued bleeding and a hemoglobin of 9.2 g/dL.
You counsel your patient that due to her migraine with aura and history of VTE, estrogen-containing medications are not an option for her (MEC category 4, unacceptable health risk with method).4 However, for a rapid response and amenorrhea, contraceptive dosing of progestins may not be adequate. Available evidence shows that contraceptive doses of norethindrone acetate (0.35 mg) do not increase VTE risk. However, VTE data on higher doses of norethindrone acetate 2.5 mg to 15 mg commonly used for AUB15 are less clear. Your patient elects to start norethindrone acetate 2.5 mg and you both agree to start with the lowest dose that controls her bleeding. You schedule follow-up in your clinic to discuss longer-term options including the LNG-IUS and endometrial ablation.
Norethindrone acetate is FDA-approved for contraception at a dose of 0.35 mg, and for secondary amenorrhea, endometriosis, and AUB at a dose of 5 to 15 mg.15 The FDA does list “active deep vein thrombosis, pulmonary embolism or history of these conditions” as a contraindication for use of the higher doses of norethindrone but not for the contraceptive dose.15
Several large studies on norethindrone acetate 0.35 mg used for contraception conclude that there is no increased risk of VTE with this dose.8-10 However, there are no studies on VTE risk with the higher doses of the drug used to manage AUB. Interestingly, a small study measured in vivo conversion of norethindrone acetate to ethinyl estradiol and concluded that 20 mg of norethindrone acetate may be equivalent to taking a pill containing 30 mcg of ethinyl estradiol.16 Prior small studies had varied results, with one suggesting no clinically significant conversion,17 another suggesting significant conversion at higher doses of norethindrone acetate,18 and a third suggesting rates of conversation of 6 µg ethinyl estradiol per 1 mg norethindrone acetate which could be significant based on dose.19 The in vivo impact of this conversion on VTE risk has not been evaluated, however, these findings could have implications for the VTE risk of the higher doses of norethindrone acetate used for AUB.
Oral medroxyprogesterone acetate is also used for AUB management at a dose of 5 to 10 mg, and is an option in this scenario. Little research has been done on VTE risk with oral medroxyprogesterone in premenopausal woman. A single relevant study was identified that included low-risk patients taking oral Provera; there was no association between VTE and progestin-only agents including oral medroxyprogesterone acetate, however, the size was small.20 Clearly, this is an area where more research is needed.
- 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.