Progestins for AUB in women at risk of VTE

Abnormal uterine bleeding (AUB) is common among premenopausal women.1 For many women, hormonal medications including estrogen and/or progestins is the mainstay of AUB management. Every provider, no matter how experienced with hormonal management of AUB, faces difficult clinical situations concerning the best hormonal regimen to choose in women at increased risk for venous thromboembolism (VTE). 

Incidence of VTE in women of childbearing age is 1 to 10 in 10,000 yearly.2 The risk increases with age, weight, smoking, certain clotting disorders, and use of combined hormonal contraceptives.^3,4 Initially it was thought that estrogen alone increased VTE risk, however, it is now known that different progestins have varied VTE risk.⁵ This article reviews the current literature and guidelines to assist ob/gyns in evidence-based management of AUB with progestins, focusing on risk of VTE. Four patient cases are presented, each centered on a commonly used progestin for management of AUB in premenopausal women: the levonorgestrel intrauterine system (LNG-IUS), depot medroxyprogesterone, norethindrone acetate (DMPA), and megestrol acetate. Also included are guidance on patient counseling and a review of the available literature (Table 1). 

Patient #1: LNG-IUS
A 25-year-old G0P0 with systemic lupus erythematosus (SLE) and positive anti-phospholipid antibodies presents to discuss management of heavy periods, a hemoglobin of 10.5 g/dL and a need for contraception. She denies a personal or family history of VTE. The woman doesn’t remember to take her other medications regularly and desires an option that lightens her cycle, while also providing longer-term effective contraception. 

You counsel your patient that the Centers for Disease Control and Prevention Medical Eligibility Criteria (CDC-MEC)¹ guidelines characterize the LNGIUS as category 3 (risks generally outweigh benefits) in patients with SLE and positive antiphospholipid antibodies. However, you also educate her that citations behind the MEC recommendation are mostly based on a theoretical risk of VTE rather than studies of LNG-IUS use in her specific situation. Based on this patient’s positive antiphospholipid antibodies, the MEC guidelines recommend only one option for her: the copper IUD;5 however, with her heavy bleeding and mild anemia, it is not an ideal option. You counsel her that the literature does not demonstrate any increased risk of VTE with LNG-IUS use, in both low- and high-risk populations, and engage in shared decision-making. 

Literature 
The LNG-IUS is available in several versions, with its active progestin component levonorgesterol ranging from 13.5 to 52 mg. With use of the device, the stable plasma level of levonorgestrel is at most approximately 3% of the level seen with a levonorgestrel-containing combination oral contraceptive (COC) pill.^6,7 The 52-mg LNG-IUS is approved by the US Food and Drug Administration (FDA) for contraception for up to 5 years and for heavy menstrual bleeding. There is no FDA warning for VTE risk on the package insert.6

Multiple studies have evaluated use of the 52-mg LNG-IUS and VTE risk in a low-risk population.^8-9 The largest was a 2009 national registry cohort study in Denmark involving non-pregnant women aged 15 to 49, with no history of cardiovascular disease or malignancy.8 The study evaluated 10.4 million woman-years and reported 4,214 VTE episodes. The authors concluded that compared to non-use of hormones, use of the 52-mg LNG-IUS was not associated with increased risk of VTE (RR 0.90; 95% CI 0.64-1.26).8 Two systematic reviews were conducted, one prior to and one including this article,9,10 both of which concluded that the 52-mg LNG-IUS does not increase VTE risk in low-risk populations.  

The relationship between the 52-mg LNG-IUS and VTE risk also has been evaluated in populations at higher VTE risk. A 2016 systematic review included nine studies of the the device in high-risk women with SLE, hypertension, smoking, thrombophilia, and history of VTE. The study concluded that there was no statistically significant increased risk of VTE in women using the 52-mg LNG-IUS in these high-risk populations.9

Patient #2: DMPA
A 21-year-old G0P0 presents with amenorrhea for 6 months using intramuscular (IM) DMPA, which was started for menorrhagia. She is not sexually active and tells you she “doesn’t want a foreign object in my body.” Her friend was recently diagnosed with deep vein thrombosis after a car accident and leg fracture. Although your patient doesn’t have any other personal risk factors for VTE, she is concerned about her own VTE risk on an upcoming trip while using DMPA.   

You counsel your patient that a meta-analysis that found no increased VTE risk with other progestin-only agents did find a doubling in VTE risk with DMPA use.10 Despite this increased relative risk, the baseline risk of VTE is 1 to 10 per 10,000 yearly in a young, healthy population,2 so her absolute risk of VTE remains low on the order of 2 to 20 per 10,000. MEC guidelines are category 2 (benefits generally outweigh risks) for DMPA use in women with current VTE, history of VTE, or risk factors for it.5 You discuss with your patient that estrogen-containing options including COC pills would also be an option for her, however, they increase VTE risk 3-5 fold,11 which is a greater risk compared to progestin-only agents.

Literature
Injectable DMPA is FDA-approved for prevention of pregnancy at a dose of 150 mg IM every 3 months.12 Contraindications listed on the package insert include active VTE and history of VTE.13

A 2012 Dutch metaanalysis in women at low risk of VTE found no increased risk of VTE among overall users of a progestin-only contraceptive compared to non-users (relative risk 1.03; 95% CI 0.76 to 1.39). Importantly, the subgroup analysis of DMPA users demonstrated that, unlike other progestin-only options like the LNG-IUS and norethindrone, DMPA was associated with a doubling in VTE risk compared to that in non-users of hormones (relative risk 2.67; 95% CI 1.29 to 5.53).10

Two studies assessed VTE risk with DMPA use in populations at higher VTE risk. The first found a trend toward an increased risk of VTE in smokers using DMPA (OR 7.0; 95% CI 0.4–138) compared to smokers not using hormones (OR 1.3; 95% CI 0.97–1.6), however, the confidence intervals were wide and the results were not statistically significant.4 The second is a case control study of women with Factor V Leiden mutations, which found no increased risk of VTE in women using other progestin-only agents, however, an increased risk of VTE was found in users of DMPA (OR 2.2; 95% CI 1.3-4.0).14

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. 

Literature
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. 

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. 

Literature
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. 

Conclusions
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.

References:

• 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 ThrombHemost 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.