It is antifibrotic factor that inhibits growth and induces apoptosis in cultured human leiomyoma cells [1]. Recent studies have shown that 1,25 dihydroxyvitamin D3 and serum 25-hydroxyvitamin D3 are significantly lower in women with leiomyomas compared to normal healthy controls [1]. Also there are strong dose–response correlations between lower serum Vit D levels and increased severity of uterine leiomyomas [2]. From all of the above, Vit D or its potent analogues can be considered as novel treatment options or as a preventive measure for uterine fibroid; till now no clinical trial has been proven. So we recommend screening women with symptomatic uterine fibroids for serum level of 25-hydroxy vitamin D. If the level is deficient (≤20 ng/mL) or insufficient (20–30 ng/mL), we recommend treating the hypo-vitamin D by oral 50,000 IU/W × 12 weeks followed by retesting of the serum level, and retreat as needed. This dose is recommended by the Endocrine Society [3].

The main ingredient in green tea is Epigallocatechin gallate (EGCG) [4]. The results of the papers suggest that EGCG may be a potential antifibroid agent acting through multiple signal transduction pathways as it has potent antioxidant and anti-inflammation capacity, and promotes apoptosis [5]. From our previous study we show that by the end of 4 months of treatment with 800 mg/day of EGCG, we identified a significant decline in the average menstrual blood loss in the treatment group (a decrease from 71 to 45 mL/month), while mean hemoglobin levels increased in the treatment group from 11.7 to 12.4 g/dL in the same group. We also showed significant reduction in total fibroid volume (32.6%) compared to placebo. In addition, EGCG treatment significantly reduced fibroid-specific symptom severity (32.4%) and induced significant improvement in quality of life score by (18.53%) [6].

Studies have demonstrated that the ovarian steroids estradiol and progesterone stimulate leiomyoma growth [32, 33]. This has led to the advent of various forms of hormonal medical management to block the stimulatory effects of ovarian steroids, decrease fibroid growth, and alleviate symptoms in women with leiomyomas. COCs can be used to improve heavy menstrual bleeding associated with fibroids without expected reduction in the leiomyoma volume or uterine size [23, 34]. The advantages of COCs are the ease of accessibility, oral administration, low cost, and minimal side effect profile [24]. However, overall COCs are not recommended for the treatment of leiomyomas.

It effectively improves the menstrual bleeding and hemoglobin levels in women with leiomyomas, but they do not demonstrate any change in fibroid volume. It consists of a 32-mm T shaped polyethylene frame with reservoir containing 52 mg of levonorgestrel (LNG) coated with a silicone membrane. It releases LNG into the uterine cavity. After a few weeks, the plasma concentration of LNG reaches plateau level (150–200 pg/mL). LNG released from the device leads to atrophy of the endometrial gland and devascularization of the stroma that suppresses endometrial growth and desensitization of the endometrium to estrogen. Once inserted, the LNG-IUS is effective for up to 5 years, thus potentially providing women with a long-term treatment option [24]. In 2009, the FDA approved the levonorgestrel-intrauterine system (LNG-IUS) as a method of contraception in women with heavy menstrual bleeding [35]. Because it is not administered systemically, minimal side effects are reported, and patient compliance is not required after insertion. However, given the increased risk of expulsion, the LNG-IUS is contraindicated in patients with severe uterine cavity distortion [24, 25, 36].

It is an isoxazole derivative of 17α-ethinyl testosterone. It causes hypo-estrogenemia by inhibition of pituitary gonadotropin secretion and ovarian steroid production [25, 32]. When 100 mg of danazol per day for a 4:6-month duration was used it showed reduction in both fibroid size by 37.6% ± 10% and uterine volume by 29% ± 6.8% (p < 0.05 for both) alone with improvement in hemoglobin concentrations [37]. It has a lot of side effects, e.g., endometrial atrophy weight gain, muscle cramps, edema, hot flushes, headaches, depression, skin rash, acne, and/or androgenic effects, such as deepening of the voice and hirsutism [38]. Because danazol is less effective than GnRH agonists, and because of its many associated side effects, its use in women with symptomatic leiomyomas is generally discouraged.

Gestrinone is a synthetic steroid derived from ethinyl nortestosterone that has both antiestrogenic and antiprogestogenic properties in the endometrium [38, 39]. Women given gestrinone 2.5 mg twice a week for 6 months showed a 32% reduction in uterine volume. Also there was a relatively slow reactivation, i.e., benefits of treatment lasted 18 months following a 6-month treatment course [40]. The reported side effects include weight gain, edema, decreased breast size, hirsutism, hot flushes, acne, and/or headaches [32, 36, 38, 40]. This medication is not recommended until more data are obtained via larger, randomized controlled trials.

GnRH agonists are synthetic peptides that are structurally related to endogenous GnRH; however, they exhibit longer half-lives, greater receptor affinity, and greater potency [35, 38, 41]. GnRH agonists were one of the first medical therapies to be used in the treatment of leiomyomas (FDA approved in 1999) [35]. Continuous (not pulsatile as occurs with endogenous pituitary GnRh) administration of GnRH agonists causes downregulation of pituitary GnRH receptors resulting in a decrease in the production of FSH and LH and a hypoestrogenic state [24, 38, 41] (Table 15.1).

Within the first 3:6 months of treatment, most women show a 30:65% reduction in fibroid volume and significant improvement of their symptoms, while preserving the option for fertility [24, 35]. Also it had been used 3 months preoperatively before hysterectomy or myomectomy, which helps to reduce uterine volume and fibroid size, control intraoperative bleeding, and correct preoperative anemia [42–44].

The most commonly reported side effects of GnRH agonists are related to the hypoestrogenic state which include distressing hot flushes, mood changes, vaginal dryness, and bone demineralization [24, 36, 42, 45, 46]. Moreover, treatment is associated with changes within the leiomyoma that may complicate surgical intervention. Other disadvantages to treatment include the relatively high cost of therapy and rapid regrowth of leiomyomas within 3 months after cessation of treatment [21, 42].

GnRH antagonists act by competing with endogenous GnRH for pituitary-binding sites, resulting in suppression of the secretion of FSH and LH and creation of a hypo-estrogen state [36, 38]. The subsequent reduction in estradiol levels leads to improvement in bleeding patterns and reduction in leiomyoma size as early as 3 weeks after initiation of treatment. Because of its rapid onset of action, and avoidance of a gonadotropin flare phase, patients experience faster symptom relief [32]. In the United States, cetrorelix and ganirelix (the two available injectable GnRH antagonists) are US FDA approved, but they are rarely used to treat fibroids due to the cost of GnRH antagonists [47]. The requirement for daily injections is another major factor further limiting their use. Elagolix is the frontrunner among an emerging class of GnRH antagonists, which unlike their peptide predecessors has a nonpeptide structure resulting in its oral bioavailability [48]. Elagolix is a short-acting agent which is administered orally so that unlike injectable depot GnRH agonists and antagonists, produces a dose-dependent suppression of ovarian estrogen production (partial suppression at lower doses to full suppression at higher doses). These properties provide an opportunity to minimize the hypoestrogenic side effects that limit long-term treatment with GnRH agonists. In addition, oral administration and a short half-life (~6 h) allow for rapid elimination of elagolix from the body, if treatment needs to be stopped [49].