Multiple Symptomatic Intramural Fibroids in a Patient Who Desires Fertility

Figure 15.1
Transvaginal US showing three small intramural fibroid

Treatment Options

In this case we have a young patient with symptomatic multiple small intramural uterine fibroids who desires fertility preservation. The patient was counseled extensively regarding various treatment options ranging from medical, interventional radiology, and surgical treatment. In light of the patient’s desire for future pregnancy, she elected to proceed with complementary medicine approach [Epigallocatechin Gallate (EGCG) and vitamin D] plus iron supplementation for 6 months followed by reevaluation of treatment success and develop potential additional treatment plans.

Medical Treatment

The challenge in the field is to develop an inexpensive oral medical treatment with the ability to safely and effectively shrink fibroid size, with minimal or no side effects, and ideally without interfering with the ovulatory cycles or future fertility potential. In this chapter we will summarize the state of the art of various available and under development compounds for effective and safe treatment of symptomatic uterine fibroids.

Complementary and Alternative Medicine

We could start with a natural treatment like green tea and if she is vitamin D deficient, we treat her with vitamin D . If she responses well, she can try to get pregnant while using this treatment.

Vitamin D

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].

Epigallocatechin Gallate (Green Tea Extract)

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].

Hormonal Treatment

If these natural treatments show no benefit, and she is in a country where selective progesterone receptor modulators (SPRM) are available (e.g., ulipristal (UPA), she can use UPA until ready to attempt pregnancy. If she is in a country where UPA is not available, she can use Lupron for 3–6 months with add-back therapy until she is ready to pursue pregnancy.

Receptor Modulators

Selective Estrogen Receptor Modulator (SERMs)

They are nonsteroidal estrogen receptor ligands that display tissue-specific agonist-antagonist estrogenic actions which result in differential expression of specific estrogen-regulated genes in different tissues [7].

Tamoxifen is one of the oldest known SERMs . It showed a significant improvement in menstrual blood loss but no improvement in fibroid size or uterine volume after 6 months of treatment [8]. The study also reported many side effects, including hot flushes, dizziness, and benign endometrial thickening. This endometrial thickening occurs due to the ER agonist effect of tamoxifen on the endometrium; other studies have suggested that it actually increases leiomyoma growth [9]. Because of this side effect, its use is not recommended for the treatment of symptomatic leiomyomas. Raloxifene is a second-generation SERM, with no agonist effect on the endometrium and only subtle antiestrogenic effects on mammary tissue, so it was considered to be a candidate therapeutic option for uterine fibroids [10, 11]. Walker et al. showed that administration of SERMs over a 2- to 4-month course of treatment to Eker rats reduced tumor incidence by more than 50% [12]. Another prospective randomized single-blind placebo-controlled clinical trial was performed to evaluate the effects of raloxifene administration for 6 months on uterine and leiomyoma sizes in premenopausal women. It showed that raloxifene has no significant effect on uterine and leiomyoma size or on menstrual cycle in premenopausal women [13].

Selective Progesterone Receptor Modulators (SPRMS)

Progesterone is a major enhancer of fibroid growth and fibroids typically demonstrate overexpression of progesterone receptor A and B. SPRMs are effective in the treatment of fibroids by reducing uterine volume and fibroid size through blockage of progesterone receptor signaling causing tumor shrinking and control of bleeding [14, 15]. It also may block ovulation especially with continuous administration [16].

  1. 1.

    Mifepristone (RU-486)

    Mifepristone (RU-486) is an antiprogesterone agent. Although it was used as an abortifacient, it also exhibits inhibitory effects on myoma growth [17]. A systematic review of six trials demonstrated that daily treatment with mifepristone (5–50 mg/day) for 3–6 months resulted in a 26:75% reduction in leiomyoma volume with decreasing of the severity of dysmenorrhea, menorrhagia, and pelvic pain, as well as amenorrhea during the treatment period [14, 18]. It also reported side effects, e.g., hot flushes in approximately 38% of women, and endometrial hyperplasia in 28% of the women [14]. So the authors recommended treatment-free intervals to decrease the risk of these endometrial changes.


  2. 2.

    Asoprisnil (J-867)

    A randomized controlled trial that used asoprisnil in three doses (5, 10, or 25 mg) for 12 weeks showed a significant decrease in fibroid size, reduction in pressure symptoms, and decreased menstrual bleeding, and up to 80% of the women experienced amenorrhea in a dose-related manner [19]. As for the side effects, 10% of women reported vasomotor side effects but it was considered minimal. Also when asoprisnil was administered daily for longer than 3–4 months, significant endometrial thickening and unusual histological appearance of the endometrial glands occurred [20]. Potential deleterious effects of asoprisnil on the endometrium and safety concerns derailed further clinical development of this compound [21].


  3. 3.

    Telapristone (CDB-4124)

    It is a pure progesterone antagonist. It showed some adverse liver effects but it is still being evaluated at an adjusted dose regimen to address its safety and dose effectiveness in the treatment of uterine fibroids [22].


  4. 4.

    Ulipristal acetate (UPA, CDB-2914/VA2914)

    It is the most recent drug that had been studied for many years; these studies showed that it is the most effective drug in the treatment of the bleeding symptoms of uterine fibroids. It has recently been approved in Europe (2012) and Canada (2014) for the preoperative and short-term treatment of symptomatic fibroids [23, 2426]. However, in the USA, it is only approved by the FDA as an emergency contraceptive at a different dose range (30 mg). It has the advantages of oral availability, rapid onset of action, and minimal vasomotor symptoms with prolonged fibroid volume reduction after treatment discontinuation if compared to GnRH agonists [27]. The side effects of UPA treatment include headaches and breast tenderness; there have also been some reversible benign effects on the endometrium called progesterone receptor modulator-associated endometrial changes (PAECs) [15, 27, 28].

    In Europe, there have been multiple serial studies of UPA. In PERAL I and II [28, 29], they studied the short-term therapy of UPA (13 weeks). They concluded that 5 and 10 mg treatment was able to control myoma-associated bleeding in 90% of cases; patients developed amenorrhea in 5–7 days. They also reported 50% reduction in the fibroid volume in 50% of patients. Furthermore, this reduction is maintained for 6 months after stopping of the UPA in the patients that didn’t undergo surgery.

    In PERAL III [27], the trial was extended to show the efficacy of long-term intermittent treatment. They used four 3-month courses of UPA 10 mg daily, immediately followed by 10-day double-blind treatment with NETA (10 mg daily) or placebo. They demonstrated that more than one course of UPA is able to maximize its potential benefits in terms of control of bleeding and fibroid volume reduction. Seventy-nine percent of the females will develop amenorrhea with the rate increasing to 89%, 88%, and 90% in the next 2, 3, and 4 treatment cycles respectively. The reduction of the fibroid size was 49.9%, 63.2%, 67%, and 72.1% after 1, 2, 3, and 4 treatment courses respectively. And in PERAL IV [30], the safety profile of long-term ulipristal acetate was confirmed, and repeated treatment courses did not increase the occurrence of adverse reactions. The percentage of subjects with endometrial thickness >16 mm was 7.4% after the first treatment course, and returned to below screening levels (4.9%) in subsequent treatment courses. The frequency of nonphysiological changes did not increase with repeated treatment.

    Another paper reported the first pregnancies achieved after UPA treatment; they show that 21 patients attempted to get pregnant; among whom 15 (71%) succeeded. Twelve resulted in the birth of 13 healthy babies and three ended in early miscarriage. No regrowth of fibroids was observed during pregnancy. They also describe pregnancies obtained after UPA treatment for fibroids in women who did not undergo surgery. There were no maternal complications related to myomas during pregnancy. All the babies were healthy [31].


Combination Oral Contraceptive Pills

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.

Levonorgestrel Intrauterine System (LNG-IUS)

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

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).

Table 15.1
GnRh agonists, route of administration, and the dose regimen

Route of administration

Dose regimen

Leuprolide (Lupron)

Subcutaneous injection


Intramuscular depot

500–1000 mg/day

400 mg 4 days

3.75–7.5 mg/month

11.25 mg/3 months

Buserelin (Suprefact, CinnaFact)

Subcutaneous injection


200 mg/day

300–344 mg 4 days

Nafarelin (Synarel)


Intramuscular depot

3 mg/month

Depot2-4 mg/month

Goserelin (Zoladex)

Subcutaneous implant

3.6 mg/month

10.8 mg/3 months


(Decapeptyl, Diphereline, Gonapeptyl, Trelstar)

Intramuscular depot

3 mg/month

Histrelin (Vantas, Supprelin LA)

Subcutaneous injection

100 mg/day

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 [4244].

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

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].

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Feb 26, 2018 | Posted by in GYNECOLOGY | Comments Off on Multiple Symptomatic Intramural Fibroids in a Patient Who Desires Fertility

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