Peripheral arterial disease in a female using high-dose combined oral contraceptive pills.

The association between oral contraceptive (OC) pills and vascular diseases is well-known, although, the present generation of pills is considered to be relatively safer in this regard. Hormonal treatment for severe abnormal uterine bleeding is usually considered after ruling out malignancy, when such bleeding is resistant to all other forms of treatment. We report a case of severe peripheral arterial disease in a female, who had been on high-dose OC pills for an extended period of time for severe uterine bleeding.

Introduction

Women who use oral contraceptives (OCs) are at risk of development of peripheral arterial diseases. OCs act by increasing the plasma levels of prothrombin, the zymogen responsible for thrombin generation in the coagulation system.[1] While venous thrombosis, coronary, and cerebral vascular diseases have generally received more attention as adverse fallouts of OCs, peripheral arterial disease can also be of immense clinical significance. We report a case of severe peripheral arterial disease in a woman who had been on high-dose OC pills for a prolonged period of time, for control of abnormal uterine bleeding.

Case Report

A 40-year-old lady was admitted with complaint of heavy menstrual bleeding for the previous 6 years. Her menstrual cycles were regular lasting for 6-7 days and associated with passage of clots and there was no history of dysmenorrhea.

She had been prescribed Tab Ovral-G (Ethinyl estradiol 50 mcg and levonorgestrel 0.25 mg) for 2 months about 3 years ago for severe bleeding. However, the patient continued to take the high- dose OC pills on her own for the next 3 years. She had developed severe peripheral arterial disease of both lower limbs for which she had undergone a right common femoral to distal posterior tibial artery bypass grafting with saphenous vein, 7 months ago. However, arterial insufficiency progressed to gangrene of the right 1st, 2nd, and 3rd toes, which had to be amputated 5 months prior to presentation to our hospital. She also had a history of blurring of vision off and on. She was a known hypertensive on medications. She was also on Tab Clopidogrel 75 mg once daily. Throughout preceding 7-8 months, she had been advised several times to stop taking the OC pills, but never complied.

On admission, the blood pressure was 150/100 mm Hg. Gynecologic examination revealed no mass palpable per abdomen, a healthy cervix, and vagina with bleeding through cervical os, a bulky, mobile, non-tender, anteverted uterus with fornices free.

Routine hematological and biochemical workup was unremarkable except for hemoglobin of 7 g/dL. Lipid profile showed hypercholesterolemia, hypertriglyceridemia, reduced high-density lipoprotein (HDL) and elevated values of low-density and very low-density lipoproteins (LDL and VLDL). Test for coagulations were normal. Ultrasonography of abdomen and pelvis demonstrated uterus size 9.6 cm × 6.2 cm × 5.3 cm, with endometrial thickness of 1.4 cm. Ophthalmoscopic examination of the fundus revealed a high myopic fundus and Grade I hypertensive retinopathy without evidence of vascular occlusion. Echocardiography revealed normal left and right ventricular function with normal valves. Doppler mapping of both lower limb arterial systems revealed no flow in right popliteal, dorsalis pedis and posterior tibial and left dorsalis pedis and anterior tibial arteries. There was no evidence of deep vein thrombosis.

A diagnosis of perimenopausal dysfunctional uterine bleeding was made. Ovral-G, which the patient was continuing at that time was stopped. In consultation with the cardiologist, the patient was started on Tab Amlodipine 2.5 mg OD, statins and dual anti-platelet therapy (Aspirin-Clopidogrel) for peripheral arterial disease and on Tab Mefenamic acid 500 mg thrice daily. The bleeding reduced after 3-4 days and patient was discharged with instructions to come for pre-menstrual diagnostic curettage after stopping the anti-platelet drugs. Endometrial sampling carried out later revealed hyperplastic endometrium. Following dilatation and curettage (D and C) bleeding stopped. The patient was advised hysterectomy, but refused surgery and continues to be on follow-up with us.

Discussion

Peripheral arterial disease is associated with increased mortality. However, studies[2] demonstrate that incidentally occurring peripheral arterial disease is not independently associated with coronary, cardiovascular or total mortality.

Efforts to decrease the risk of arterial thrombosis associated with OC usage, led to the development of drugs containing <50 mcg ethinylestradiol and the development of other progestogens, i.e., levonorgestrel, which comprised the so-called second-generation OCs. OCs containing a third-generation progestogen like gestodene or desogestrel was introduced in the 1980s. They appeared to be less androgenic than older products, and they tended to increase HDL cholesterol levels. It was hypothesized that these OC pills might reduce the risk of arterial thrombosis. However, in 1995, several articles reported that users of third-generation OCs had an at least 2-fold increased risk of venousthrombosis. A similar increase was reported for venous sinus thrombosis.[3] All these findings led to the concerns about the safety of these pills. OCs can induce changes in lipid and carbohydrate metabolism similar to those associated with an increased risk of coronary heart disease, including, increased serum triglyceride, LDL, cholesterol, and insulin levels and decreased HDL levels, and it is conceivable that similar metabolic changes, along with alterations in plasma levels of prothrombin, referred to earlier, could pre-dispose to the development of peripheral arterial diseases as well. The appropriate dose and type of progestin may reduce the adverse effects of OCs on many metabolic markers of risk for coronary heart disease and peripheral arterial disease. Progestin-only formulations or combinations containing desogestrel or low-dose norethindrone were associated with the most favorable profiles in this regard.

The Risk of Arterial Thrombosis In relation to Oral Contraceptives (RATIO) study, a multicenter, population based case control study, consisted of three sub studies for vascular diseases (stroke, myocardial infarction, and peripheral arterial disease[4]) in relation to OC use among women 18-49 years of age in the Netherlands, and was the first study of its kind on OC use and peripheral arterial disease in humans. It concluded that all types of OCs were associated with an increased risk of peripheral arterial disease. Another meta-analysis[5] suggests that current use of low-dose OCs also significantly increases the risk of both cardiac and vascular arterial events, including a significant risk of vascular arterial complications with third-generation OCs.

Causality assessment

The high-dose combined OC pill was the possible cause of the peripheral arterial disease in the present case, as assessed by the Naranjo Causality criteria[6] with a score of 3. The causality assessment by WHO-UMC causality categorization[7] also showed that this adverse drug reaction had a “possible” association with high-dose combined OC pills.

Conclusion

This case clearly indicates the need for discretion in the use of OCs especially, when employed for non-contraceptive purposes. The drug should be reserved for severe bleeding or when other treatment fails. Caution must be exercised when using these drugs for long periods and patients of hypertension and abnormal lipid profile.