Emma Lawrence, MD

Abnormal uterine bleeding (AUB) is common among premenopausal women.

 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.

 weight, smoking, certain clotting disorders, and use of combined hormonal contraceptives.

 Initially it was thought that estrogen alone increased VTE risk, however, it is now known that different progestins have varied VTE risk.

 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). 


	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)

 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;

 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. 


	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.

 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.

Multiple studies have evaluated use of the 52-mg LNG-IUS and VTE risk in a low-risk population.

 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.

 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).

 Two systematic reviews were conducted, one prior to and one including this article,

 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.


	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.

 Despite this increased relative risk, the baseline risk of VTE is 1 to 10 per 10,000 yearly in a young, healthy population,

 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.

 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,

 which is a greater risk compared to progestin-only agents.


	Injectable DMPA is FDA-approved for prevention of pregnancy at a dose of 150 mg IM every 3 months.

 Contraindications listed on the package insert include active VTE and history of VTE.

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).

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.

 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).


	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).

 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 AUB

 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.

 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.

Several large studies on norethindrone acetate 0.35 mg used for contraception conclude that there is no increased risk of VTE with this dose.

 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.

 Prior small studies had varied results, with one suggesting no clinically significant conversion,

 another suggesting significant conversion at higher doses of norethindrone acetate,

 and a third suggesting rates of conversation of 6 µg ethinyl estradiol per 1 mg norethindrone acetate which could be significant based on dose.

 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.

 Clearly, this is an area where more research is needed. 


	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.

 Regarding VTE risk, the FDA states that “thromboembolic phenomena including thrombophlebitis and pulmonary embolism (in some cases fatal) have been reported.”

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.

 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).

 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,

 a retrospective descriptive study in nursing home residents,

 a cohort study in 97 patients with advanced cancer receiving chemotherapy,

 and a randomized study of 179 patients with breast cancer patients whose disease failed to respond to tamoxifen.

 Three of these small studies suggest an increased risk of VTE with megestrol acetate use

 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.

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These four patient cases can help improve your decision-making about the best hormonal regimen for this population.

Emma Lawrence, MD

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