GnRH analogs for the treatment of symptomatic uterine leiomyomas

Abstract

Uterine leiomyomas are the most frequent benign disease of the female reproductive tract. To date, the standard treatment of uterine leiomyomas is laparotomic/laparoscopic excision in women who want to preserve their fertility, whereas the use of a more extensive surgery, such as hysterectomy, is reserved for disseminated uterine leiomyomatosis, usually in the perimenopausal period. Given the pathogenesis of uterine leiomyomas, it is clear that future treatments for leiomyomas may be medical. At present the only clinically relevant medical treatment of uterine leiomyoma is GnRH agonist administration in depot formulations. In this review, the use of GnRH agonists, with or without “add-back therapy,” and antagonists will be assessed.

Introduction

Uterine leiomyomas are the most frequent benign disease of the female reproductive tract. They are found in at least 20–25% of fertile women and in 50% of women studied postmortem [1]. Between 20% and 50% of cases of uterine leiomyomas cause clinical symptoms (menorrhagia, infertility, recurrent abortion, pelvic pain, and so on) requiring treatment [1]. Thus, this disease is one of the main causes of health expenditure in the field of gynecology [1]. In fact, symptomatic uterine leiomyomatosis is the surgical indication for about two-thirds of hysterectomies, and this statistic is even more relevant because hysterectomy is the most frequent major surgery in women [1].

However, the pathogenesis of uterine leiomyomas is still not well defined. Uterine leiomyomas have been demonstrated to be estrogen-dependent monoclonal tumors [2–4]. The primum movens is probably a genetic mutation and thus an alteration of the intratumoral estrogenic metabolism [5–8]. The transcription and the expressivity of the estrogen receptor, in fact, is increased in the myoma tissue when compared with healthy myometrium [6, 7]. A specific distribution of estrogen receptor subtypes has been demonstrated. Specifically, it seems that, despite high concentrations of mRNA for estrogen receptor alpha, there is not a relationship in concentrations in the same receptor. On the contrary, concentrations of the beta receptors twofold to threefold higher in comparison with normal myometrium have been detected [8]. The simple action of estrogens does not seem to be the only pathogenic cause. Progesterone could play a pivotal role in transforming normal myometrial cell to myomatous cells [9, 10]. High progesterone levels, such as those detected in the luteal phase of the menstrual cycle, or after medroxyprogesterone acetate (MPA) administration are related to an increase in mitotic activity of the myoma cells [11, 12]. Finally, in the myomatous tissue, similarly to the estrogen receptors, there is overexpression of progesterone receptors [3].

To date, the standard treatment for uterine leiomyomas is laparotomic/laparoscopic excision in women who want to preserve their fertility. The use of more extensive surgery is reserved for disseminated uterine leiomyomatosis, especially in the perimenopausal period. Given the pathogenesis of uterine leiomyomas (see below), it is clear that future treatment of leiomyomas will be essentially medical.

Medical treatments

Several medical therapies have been proposed for treating uterine leiomyomas (Table 1). In clinical practice it is very common to administer oral contraceptives to patients affected by uterine leiomyomas [13–15]. The rationale for their administration includes regulating menstrual bleeding and decreasing the length of bleeding and the severity of menorrhagia [13]. Some studies [14, 15] have defined oral contraceptive administration as a causal factor in tumoral growth. In these cases, oral contraceptives should be stopped [14, 15].

Table 1 Medical therapies for uterine leiomyomas

The use of mifepristone (RU486), a drug with weak antiprogestin actions, in a dosage of 10 mg/day induces the reduction of progesterone receptors and leiomyoma dimensions [16, 17]. Gestrinone at doses of 2.5 mg or 5 mg two to three times per week has also been proposed for treating uterine leiomyomas [18–20]. Recent data confirm that danazol administration is also effective for treating patients with uterine leiomyomas [21]. In particular, it has been demonstrated that 400 mg daily of danazol for 4 months decreases leiomyomas by 25% with an action due to hypoestrogenism and antiprogestin [21]. However, in both of the latter therapeutic regimens, the treatment has several side effects, such as weight gain, seborrhea, acne, and hirsutism, that are related to an androgenic action of the drugs.

New hypotheses for treatment have been recently published in the literature [22–24]. The use of GnRH analogs (GnRH-a) seems to be a real and valid therapeutic option.

GnRH analogs (GnRH-a)

The GnRH-a is a group of drugs with an agonist/antagonist action on the GnRH receptor. Their effects are related to the action on the GnRH receptor of the pituitary gland.

GnRH agonists

GnRH agonists induce a profound downregulation of the pituitary with a subsequent postreceptor message blockage for gonadotropin synthesis and secretion. After a rapid secretion of gonadotropins (“flare-up” effect) during the first 2 weeks of treatment, there is a weak inhibition of pituitary function with inhibition of follicular development, anovulation, and a reversible hypogonadotropic hypogonadism state [24–25].

The first agonist used in the conservative treatment of uterine leiomyomas was reported by Filicori et al. [25] in 1983. Specifically, they showed the effectiveness of GnRH agonist administration in women affected by symptomatic uterine leiomyomas.

The use of GnRH agonists induces a significant reduction in leiomyoma size within only 8–10 weeks, achieving the highest reduction after 14 weeks of treatment. After this period, the volume reduction achieves a steady state. After treatment withdrawn, estrogen levels return to the normal range within about 1 month, and leiomyoma size returns to pretreatment dimensions after about 3 months [26–29]. The disease will cause symptoms again due to the leiomyoma’s regrowth.

The efficacy of these drugs, after careful patient selection, is about 90%, and they are a valid alternative to surgical intervention.

GnRH agonists have wide variability in terms of clinical efficacy. For this reason it is necessary to study the possible clinical response to treatment before drug administration [30–34]. In 1992 Hackenberg et al. [33] showed that after only 1 month of treatment, it is possible to define the patient as a “poor responder.” In these cases the risk-benefit ratio cannot be considered acceptable. Our data [31, 32] demonstrated that an ultrasound assessment of the echographic pattern of leiomyomas is important to decide whether to treat or not. GnRH analogs seem to have a reduced efficacy in the presence of hypo- or hyperechoic leiomyomas [31, 32]. Also, the use of magnetic resonance imaging has shown its efficacy in detecting leiomyomas more or less susceptible to medical treatment [35].

Another important factor that probably plays a role in the effectiveness of GnRH agonists is patients’ age. In particular, efficacy is higher in women under 35 years than in older women. Leiomyoma volume did not influence the response to treatment, but the evaluation of leiomyoma size is an important tool in predicting the efficacy of GnRH agonists. In fact, the presence of histological (fat and calcific) degeneration and high vascularity in large leiomyomas is related to a lowered response to conservative therapy.

The significant decrease of uterine and leiomyoma volumes induced by GnRH agonist treatment [36] should be due to a relative vasoconstriction of myomatous vessels [37, 38] and/or to diminished nitric oxide production [39]. In fact, the average diameter of intramyomatous arteries was 24% smaller in patients treated with GnRH-a compared with those receiving placebo [38]. In addition, arteriosclerotic changes, including intimal and medial fibrosis, were seen more often in the subjects treated with GnRH agonists [38]. Finally, GnRH-a act directly on myomatous cells by specific GnRH receptors, inducing a suppression of cell proliferation and promoting the apoptosis [37, 40].

There are several protocols for analog administration [41]. GnRH-a are usually administered in the early follicular phase (day 2–3 of the menstrual cycle). They are used preoperatively for 2 or 3 months in short-term protocols both to reduce fibroid and uterine volume and to control bleeding, whereas long-term protocols (over 6 months) are used in perimenopausal women to induce an iatrogenic climacteric state in the long-term nonsurgical management of symptomatic leiomyomas [41]. This is one of the most important challenges of endocrinological gynecology.

In a recent systematic review [42] that included only randomized controlled trials, it was shown that GnRH agonist therapy prior to surgery significantly improves pre- and postoperative hemoglobin and hematocrit and reduces intraoperative blood loss. Hysterectomy appeared to be easier after pretreatment with GnRH analog therapy; operating time was reduced, and more hysterectomy patients were able to have vaginal rather than abdominal procedures. In addition, the presence of small myomas is not a limitation in the preoperative use of analogs [42].

A recent study [34] showed that intermittent courses of GnRH agonists could be used in the nonsurgical management of women with symptomatic leiomyomata uteri. Specifically, each month of GnRH agonist therapy produced an average of 3 months of symptom control; in other words, a 6-month course of a GnRH agonist could be expected on average to produce 18 months of symptom control.

Nevertheless these results were obtained for treatments of at least of 6 months and there is no evidence demonstrating beneficial effects after stopping treatment with shorter courses of agonists.

To date, it seems that the use of intermittent 6-month courses of GnRH agonists is effective in treating leiomyoma symptoms, avoiding the profound hypoestrogenic state, and limiting the climacteric-like symptoms. In fact, the response of the pituitary ovarian axis to GnRH agonists administration is highly subjective. It is possible that the same dose of analog is effective in some women and ineffective in others. For this reason, the dosage of GnRH agonist could be adjusted considering the clinical response in terms of estradiol levels and leiomyoma size.

Both short- and long-term treatments with GnRH agonists are associated with several side effects because of the profound hypoestrogenic state [43–45]. The hypoestrogenism induced by the use of GnRH agonists causes several climacteric-like symptoms such as hot flashes, vaginal dryness, reduced libido, metabolic alterations, cognitive deficits, and, above all, bone loss that varies from 0.8% to 7% after 12 months of GnRH agonist administration [41, 43–46]. Notwithstanding the metabolic alterations recently studied in women treated with GnRH agonists [47], at the present there is no clear evidence of cardiovascular risk related to GnRH agonist treatment [41, 43–46].

For GnRH agonist administration beyond 6 months, it has been postulated that the addition of low doses of steroids (“add-back therapy”) may avoid the adverse effects due to the prolonged hypoestrogenism state without reducing the efficacy of analog alone [41, 43–46].

Add-back therapy

Friedman et al. [45] described a pilot study in women with uterine leiomyomas treated with GnRH agonists [46]. They added small amounts of estrogen to increase circulating estrogens to levels high enough to maintain the integrity of some tissue with relief of vasomotor symptoms while causing other tissues to remain in a state of regression (“threshold hypothesis”) [45].

Several drugs have been proposed as add-back therapy in the treatment of uterine leiomyomas. The addition of progestins (MPA 20 mg/day) at the start of the GnRH agonist treatment induces a reduction in uterine volume compared with analog alone [48]. On the contrary, it seems to be more effective to start the treatment with the analog alone and to add the add-back therapy only after 3 months [41]. After this “window period” of 3 months, the estro-progestin addition (0.75 mg estropipate daily plus 0.7 mg norethisterone acetate [NETA] sequentially added) is more effective than only progestin coadministration (NETA, 10 mg/day) in terms of leiomyoma size reduction [43, 44]. Furthermore, the adverse effects of GnRH agonists were reduced in both add-back therapy regimens, with no difference between them. After a follow-up of 6 months, both add-back therapy regimens were similarly effective in reducing leiomyoma size. No difference in estro-progestin administration has been shown between continuous or cyclic regimens [41].

A recent study [49] carried out on a small number of subjects demonstrated that estradiol administration after 2 months of GnRH analog treatment alone is effective in reducing bone loss and vasomotor symptoms without compromising the efficacy of treatment with an analog alone.

Tibolone seems to be an ideal drug with steroid activity that may be administered in association with GnRH-a as add-back therapy. Tibolone is a synthetic compound structurally related to norethynodrel, with weak estrogenic, androgenic, and progestogenic properties. It has been successfully used to treat women with climacteric complaints and to prevent bone loss in postmenopausal women [50] without significant endometrium stimulation [51]. Several studies have demonstrated the efficacy of tibolone in association with GnRH-a in treating postmenopausal women with uterine leiomyomas [52–54].

Palomba et al. [55] have demonstrated in a randomized double-blind placebo-controlled study that GnRH agonists alone or a GnRH agonist plus tibolone administration at the standard dose of 2.5 mg/day is similarly effective in terms of reducing uterine leiomyoma volume and myoma-related symptoms. In addition, tibolone reduced the mean number of hot flashes per day and prevented bone loss due to agonist treatment [55–57].

After 2 years of observation, a lower mean number of hot flashes per day was observed when compared with placebo [57]. Women treated with tibolone showed bone metabolism and an incidence of vaginal bleeding similar to those of women treated with analog alone; the reduction of uterine and leiomyoma volume remained constant throughout the study period [57]. After 6 months of follow-up, when the GnRH agonist was stopped, some perimenopausal women began menstruating, and an increase in leiomyoma size similar to that in the pretreatment phase was observed.

Tibolone is effective not only in long-term protocols [56, 57] but also in short-term ones [55]. In particular, after 2 months of presurgical treatment, GnRH agonist plus tibolone administration significantly reduced the duration of laparoscopic myomectomy and intraoperative bleeding, as did GnRH agonist plus placebo administration [55].

A recent study by Somekawa [58] evaluated the efficacy of the addition of ipriflavone in women with uterine leiomyomas treated with a GnRH agonist. Ipriflavone effectively alleviated the adverse effects of estrogen deficiency without reducing the efficacy of the GnRH agonist. Specifically, GnRH agonist plus ipriflavone administration reduced bone loss, with a reduction rate of 3.70% after 6 months of treatment.

Preclinical [59–63] and clinical [23] data have suggested that raloxifene may have a beneficial effect on leiomyomas. In fact, in a recent clinical study [23], a significant reduction in leiomyoma size after 1 year of treatment with 60 mg of raloxifene daily was observed in postmenopausal women. In contrast, the administration of raloxifene at standard and high doses to premenopausal women affected by uterine leiomyomas did not induce any reduction in uterine or leiomyoma sizes [64].

Based on these findings, we studied the efficacy of raloxifene as add-back therapy in women with uterine leiomyomas treated with GnRH analogs [65, 66]. In this last study, we compared in a randomized single-blind placebo-controlled fashion the administration of GnRH analog plus raloxifene versus GnRH analog alone. A significant decrease in uterine, leiomyoma, and not-leiomyoma sizes was detected in both treatment groups compared with baseline. Leiomyoma sizes were not significantly lower in the GnRH-analog-plus-raloxifene group than in the GnRH-analog-alone group, but no difference was observed in leiomyoma-related symptoms between the groups throughout the study period [65]. No significant variation in bone metabolism was detected during treatment with GnRH analog plus raloxifene [66].

In a subanalysis of the study [47], we observed that GnRH analog altered serum lipoproteins and homocysteine levels and increased insulin resistance. But when raloxifene was added to the GnRH analog, these acute metabolic changes were prevented or reduced [47]. However, raloxifene did not reduce the cognitive deficits observed during GnRH analog administration [67].

Finally, GnRH analog plus raloxifene is a safe pharmacological association in long-term studies [68] and improves the patient’s mood and quality of life [67].

During our study period few side effects were detected, and raloxifene treatment was tolerated as well as placebo. Raloxifene administration did not reduce the vasomotor symptoms related to GnRH-analog. In contrast, a significant reduction in the mean number of hot flashes per day was observed when tibolone was added to GnRH-a treatment [55–57, 69].

Raloxifene and tibolone are two compounds that did not induce endometrial proliferation in postmenopausal women with a high percentage of “not bleeding” cycles [70]. Our data confirm these findings. In fact, the addition of tibolone [56] or raloxifene to GnRH-a treatment in women with uterine leiomyomas did not increase the percentage of women with uterine bleeding compared with analog alone.

GnRH antagonists

The GnRH antagonists bind to gonadotrope GnRH receptors and compete successfully with endogenous agonist GnRH molecules for receptor occupancy [71]. Within a few hours, GnRH antagonists link competitively with GnRH receptors with no activation or stimulation of these receptors. Thus, no flare-up effect is observed when the agonist is administered. Specifically, the GnRH antagonist desensitization of gonadotropes induces an immediate decrease in the concentration of gonadotropins and a subsequent reduction in estradiol levels [71].

Hypoestrogenism induced by GnRH antagonists rapidly leads to improvement in uterine bleeding and shrinkage in myoma dimensions [72, 73], particularly in submucosal ones [73]. In fact, the maximum reduction is achieved within 2 weeks of treatment, a shorter time in comparison with GnRH agonist use. These advantages have a clinical relevance in the preoperative treatment of uterine leiomyomas [74].

The local tolerance of GnRH antagonists is generally good, but the percentage of patients with moderate or severe local tolerance reaction is higher than with GnRH analog. [71].

In a randomized study, Felberbaum et al. [73] evaluated the effectiveness of a depot preparation of third-generation GnRH antagonist for preoperative treatment in premenopausal women with symptomatic uterine leiomyomas who were undergoing surgery. A mean leiomyoma volume shrinkage rate of 31.3% after 14 days of treatment was observed. More recently, Hara et al. [75] have experimented with a nonpeptide orally active GnRH antagonist in an animal model, suggesting its use also for reproductive disorders.

Conclusions

At the moment, the only medical treatment for uterine leiomyomas is GnRH agonist administration in depot formulations. To reduce the GnRH agonist side effects, we recommend the coadministration of raloxifene at the start of treatment to maximize the efficacy in reducing uterine and leiomyoma size.

Future studies should evaluate the efficacy and safety of new depot formulations of GnRH antagonists in reducing the size and the symptoms of leiomyomas.