Use of combined hormonal contraceptives was found to reduce heavy menstrual bleeding in women with fibroids but has limited efficacy in its treatment [2]. Available data on the association between fibroids and OC appears too dispersed to allow precise risk quantification [3]. Evidence suggests that use of OC is associated with decreased risk of fibroids; however, in a prospective study with 3006 cases of women with fibroids, it has been found that if OC are started before ages 13–16 years, there was an elevated risk of fibroids [4]. Some authors have suggested that OC were contraindicated in fibroids; however, data suggest that OC are associated with reduction in the risk of fibroids and alleviated fibroid-associated symptoms. Other factors such as proportion of hormones in the preparation, the timing and duration of exposure, and different route of administration may play an important role. With the use of newer delivery methods of contraceptives, further studies are required.

Ulipristal acetate is a progesterone receptor modulator that has been studied for fibroid treatment and has been shown to reduce the volume of fibroid and symptoms associated with fibroids [5, 6]. Ulipristal acetate inhibits ovulation and also decreases estrogen release from ovary. The compound has been approved for 3 months for preoperative management of fibroids outside the United States. Recently, a randomized controlled trial compared three different doses of ulipristal acetate (oral, 5 mg or 10 mg once daily) for 13 weeks in 242 women with fibroid-associated menorrhagia, anemia, and ≤16 weeks’ size uterus. The authors reported significant reduction in menorrhagia, (5 mg, 91%; 10 mg, 92%; placebo, 19%), increase in hemoglobin (5 mg, 4.3 g/dL; 10 mg, 4.2 g/dL; placebo, 3.1 g/dL), and reduction in fibroid size (5 mg, −21%; 10 mg, −12%; placebo, +3%). Headache and the breast tenderness were the most common side effects noted with the use of ulipristal acetate [6]. However, effect on the endometrium after long term has spawned regimens with intermittent use. When compared with other medical treatment of fibroids, ulipristal acetate was found to be non-inferior to GnRH agonists with fewer severe side effects [7]. Oral administration and minimal side effects associated with these drugs make ulipristal acetate a suitable option. In the United States, ulipristal acetate is not currently approved for the treatment of fibroids. It is available only in a 30 mg dosage, as opposed to 5 and 10 mg that were studied for the treatment of fibroids. Also, long-term safety data after treatment with these agents are still lacking.

Mifepristone (RU-486) is an antiprogestin and has been studied for the treatment of fibroids. After treatment with 5–50 mg of mifepristone daily for 3–6 months, reduction in uterine and fibroid size was noted as 27–49% and 26–74%, respectively. This was accompanied by a reduction in severity of pressure symptoms, dysmenorrhea, and menorrhagia. Side effects were transient for transaminases in 4% of patients and endometrial hyperplasia in 28% of patients [8]. Simple endometrial hyperplasia was noted in 13.9% at 6 months and 4.8% at 12 months of its use with no patient had hyperplasia with atypia. After 5.7 months of posttreatment follow-up, most of the women had recurrence with average size of 42% less than the baseline [9]. Accumulating evidence suggests that mifepristone improves quality of life and reduces the size of the fibroid and fibroid-associated symptoms [10]. Like ulipristal acetate, mifepristone is not approved by FDA for the treatment of fibroids in the United States. Mifepristone is also available in single dose of 200 mg, not in 5–50 mg doses that have been studied for the treatment of fibroids.

This device is widely used and approved by the FDA for treatment of heavy menstrual bleeding. In a prospective study, after 12 months of use in women with fibroids, heavy menstrual bleeding was decreased from 97 to 16% (P < 0.001), and hemoglobin and hematocrit were improved in 95% of women [11]. The LNG -IUS also acts as a contraceptive for the women. After 3 years of LNG-IUS use in women with fibroids, the mean reduction in the uterine volume was noted to be 63.6 ± 19.0 (SD) cm³ (from 156.6 to 93 cm³, p = 0.014), and for the fibroids it was 5.2 ± 3.1 (SD) cm³ (from 12.8 to 7.6 cm³, P = NS). In addition, similar findings were noted with the reduction in menorrhagia and improvement in hematologic parameters but without any significant influence on the fibroid size [12]. Insertion of LNG-IUS is associated with an expulsion rate of 0–20% in women with fibroids, versus 0–3% in women without fibroids. However, women with submucosal fibroids were associated with a higher expulsion rate of 11% [13, 14]. The LNG-IUS is contraindicated in the presence of intracavitary fibroids that distort the uterine cavity.

GnRH agonists are among the most effective medical therapies for fibroids. These medications work primarily by downregulation of GnRH receptors to create a hypogonadotropic state that is clinically similar to menopause. These agents are used for the short-term use as a preoperative agent to reduce the uterine bleeding and symptoms of menometrorrhagia, concomitantly to improve hematologic parameters, and to reduce the uterine and fibroid size [15, 16]. GnRH agonists are approved for 3–6 months prior to fibroid-related surgery together with iron supplementation to correct anemia and facilitate a less invasive or a minimally invasive procedure [17]. After 6 months of GnRH therapy in women with fibroids, 48.3% of women had more than 36% mean reduction in fibroid volume [18]. In a randomized double-blind study, after 24 weeks of GnRH agonist therapy in women with fibroids, there were reductions in uterine size from 601 ± 62 to 294 ± 46 cm³ (P < 0.01).

GnRH agonists can result into severe hypoestrogenic symptoms, which include hot flashes, vaginal dryness, sleep disturbances, mood changes, and/or myalgias and arthralgias [19]. Osteoporosis caused by the long-term use of these drugs is the most serious side effects and limits therapy. In addition, discontinuation of GnRH agonists can lead to rapid resumption of the pretreatment uterine and/or fibroid volume. The side effects of GnRH agonists use can be reduced by “add-back” therapy with low-dose estrogen-progestin after the phase of downregulation. In a study of 51 patients with symptomatic uterine fibroids, estrogen-progestin add-back therapy for 21 months after 3 months of treatment with GnRH agonists showed no regrowth of the fibroids, thus sustaining the therapeutic role of GnRH agonists with reduction in the side effects [20]. These drugs can be used in perimenopausal women to provide short-term relief until they develop natural postmenopausal estrogen deficiency [21].

Similarly, GnRH antagonists can also be used in place of GnRH agonists to reduce the size of fibroids and associated symptoms [22]. The advantage is rapid onset of action without having the initial flare-up as observed with GnRH agonists. After a mean duration of 19 days (1–65 days) of treatment, there were maximum reductions in fibroid size. Noted was −42.7% (−77.0% to 14.1%) and −29.2% (−62.2% to 35.6%) with resolution of the hypoestrogenic side effects within 1 week after treatment [23]. Due to nonavailability of long-acting preparations, the treatment of fibroids is cumbersome with daily injections.

The efficacy of raloxifene for the treatment of fibroids or their symptoms is uncertain. After giving raloxifene with GnRH analog for six cycles of 28 days in premenopausal women, there was significant reduction in the size of fibroids. However, no difference was detected in fibroid-related symptoms [24]. A possible risk of venous thrombosis with high doses of raloxifene is a concern.

In perimenopausal woman, aromatase inhibitors can be used to reduce the size and alleviate the symptoms associated with fibroids [25]. Limited evidence is available to determine the duration of therapy, risks, and cost-effectiveness of aromatase inhibitors [26]. Danazol and gestrinone are androgenic steroids that may be effective in the improvement of the fibroid-associated symptoms [27]. Gestrinone is not available in the United States. Danazol inhibits pituitary gonadotropin secretion, thus inhibits ovarian estrogen production. It reduces the symptoms associated with fibroids, but no effect was found on the size of fibroid. Androgenic side effects are common with the use of androgenic steroids , which include acne, hirsutism, weight gain, muscle cramps, hot flashes, mood changes, and depression.

Nonsteroidal anti-inflammatory drugs reduce heavy menstrual bleeding and pain associated with fibroids but less effectively in comparison with the other medical therapies [28]. Antifibrinolytic agents , such as tranexamic acid , are useful in the management of heavy menstrual bleeding. It is FDA approved, and in one trial, approximately 35% of women were from the group of fibroid-associated heavy menstrual bleeding [29, 30].