Fibroid uterin sudah menjadi masalah kesehatan sejak jaman purbakala namun sampai saat ini masih meninggalkan banyak masalah. Pada terbitan edisi minggu ini NEJM bagian editorialnya membahas masalah fibroid uterin. Judul yang dipilih pada editorial nejm tersebut adalah”Uterine Fibroids and Evidence-Based Medicine — Not an Oxymoron”. bagaimana paparan editorial ini? silakan kutipan selengkapnya sebagai berikut:
Elizabeth A. Stewart, M.D.
N Engl J Med 2012; 366:471-473February 2, 2012
The 2011 report from the Agency for Healthcare Research and Quality on comparative management of uterine fibroids noted, “Despite the prevalence and possible complications of uterine fibroids, few published studies examining the effectiveness of treatment strategies exist.”1 Few therapies are approved by the Food and Drug Administration (FDA) for fibroids; leuprolide acetate, a gonadotropin-releasing hormone (GnRH) agonist, was approved in 1995 for preoperative treatment of fibroids, with the addition of iron. In the past decade, uterine-artery embolization and magnetic-resonance–guided focused ultrasound surgery have also been therapeutic options. Surgeries for fibroids, especially hysterectomy, still predominate, and fibroids remain the leading cause of hysterectomy.2
Whereas estrogen was long considered to be the key factor in the pathogenesis of fibroids,3 it has been recognized more recently that progesterone also plays a critical role, as do inherited and somatic mutations, growth-factor dysregulation, and an active extracellular matrix.2 Several studies, including relatively small, randomized clinical trials, have supported the safety and efficacy of selective progesterone-receptor modulators in reducing uterine volume and controlling menstrual bleeding.4-6 However, this class of agent has not been approved for the treatment of fibroids, in part because of political issues surrounding the use of mifepristone.7
In this issue of the Journal, Donnez et al. report the results of two randomized clinical trials that support the efficacy of the progesterone-receptor modulator ulipristal acetate for preoperative treatment of symptomatic uterine fibroids.8,9 In one report, two doses of ulipristal acetate were compared with placebo among women with anemia; all the women in this trial also received iron supplementation.8 In the second, the same doses of ulipristal acetate were compared in a noninferiority trial with leuprolide acetate9; women in this trial received iron supplementation at the discretion of the treating physician. GnRH agonists are highly effective for the treatment of fibroids because they induce amenorrhea, resulting in cessation of heavy menstrual periods, and a reduction in fibroid volume, resulting in relief of symptoms related to leiomyoma bulk.3 However, GnRH agonists cause severe hypoestrogenic symptoms and long-term effects on bone density, thus limiting the safety and negatively affecting the side-effect profile of the drugs.
Ulipristal acetate was superior to placebo and noninferior to leuprolide acetate for the control of bleeding; more than 90% of the women treated with either dose of ulipristal acetate had a clinically significant decrease in bleeding, and approximately three fourths became amenorrheic. In addition, there was no initial steroidal flare with ulipristal acetate as there is with leuprolide acetate — an advantage for women with excessive menses and anemia. Ulipristal acetate induced amenorrhea more quickly than did leuprolide acetate and resulted in a greater increase in hemoglobin level than did placebo, although iron supplementation alone has been shown to be quite effective for the preoperative management of anemia.10
For symptoms related to leiomyoma bulk, leuprolide acetate appeared to be more effective than ulipristal acetate, resulting in a greater reduction in fibroid volume. However, data in the Supplementary Appendix (available with the full text of the article at NEJM.org) on the subset of women who did not undergo surgery support the results of prior studies that suggest that progesterone-receptor modulators provide more prolonged volume reduction after treatment is discontinued, as compared with the rapid regrowth seen after discontinuation of GnRH agonist therapy.4
There were no major safety concerns with ulipristal acetate in these short-term studies. Ulipristal acetate had a better side-effect profile than did leuprolide acetate, with less profound suppression of estradiol levels, significantly fewer hot flashes, and few substantial effects on markers of bone turnover.9
The trials also shed some light on the major potential safety issue with progesterone-receptor modulators — their effect on the endometrium. Since progestins protect against estrogen-induced proliferation of endometrium, the question remains whether long-term use of progesterone-receptor modulators might lead to endometrial hyperplasia or carcinoma. Therapy with progesterone-receptor modulators causes a unique nonphysiologic pattern of endometrial changes with glandular dilatation and dyssynchronous changes between the glands and stroma, which have some hallmarks of malignant change but which, on intensive study, appear to be benign.11
In approximately 60% of the women in these trials who were treated with ulipristal acetate, endometrial biopsy samples showed changes typically associated with progesterone-receptor modulators after 3 months of therapy, but these changes resolved after a 6-month drug-free period.8 If longer-term studies confirm a carryover effect of progesterone-receptor modulators on reduction of uterine volume, as well as resolution of endometrial changes, women with symptomatic fibroids may have the option of a unique intermittent therapy that maximizes efficacy while minimizing safety concerns.
Several limitations of the current studies, in addition to the short duration of treatment, should be noted. Few black women were included, yet black women have a greater risk of fibroids, a more severe phenotype, and an earlier age of onset than do white women.2 This lack of diversity is unfortunately common in clinical trials of treatments for fibroids.12 Participants in these trials also tended to be thinner than the general population of women with fibroids, and their uteri were only moderately enlarged as compared with the uteri in women in other trials of innovative fibroid therapies.13,14 Women were not screened for ovulatory function, and thus leiomyomas may not be the sole explanation for bleeding in the women.
Studies of progesterone-receptor modulators as treatment for fibroids date back almost two decades. Since that time, innovations in interventional therapies have provided effective, minimally invasive alternatives to hysterectomy. Unfortunately, the rate of hysterectomy continues to be high,15 and there remains substantial need for effective medical therapy.2 The present studies represent an important step in that direction.