By Robert W. Rebar, MD

Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo

Dr. Rebar reports no financial relationships relevant to this field of study.

SYNOPSIS: In a “before and after study,” the proportion of satisfied and very satisfied women did not change from the “before” period, during which women with endometriosis were treated with norethindrone acetate, to the “after” period during treatment with dienogest.

SOURCE: Vercellini P, Bracco B, Mosconi P, et al. Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: A before and after study. Fertil Steril 2016;105:734-743.

Progestins, with or without estrogens, are approved by the FDA and used frequently for treating women with symptomatic endometriosis.1 However, because therapy for endometriosis generally is long-term, there are still questions about which medications are best to use. In this unusual study, Italian investigators attempted to assess the effectiveness of norethindrone acetate (NETA), a 19-nortestosterone derivative progestin that has been available for many years, and dienogest, a semisynthetic 19-nortestosterone derivative progestin recently approved for the treatment of endometriosis in Europe, Australia, Malaysia, Singapore, and Japan. Before June 6, 2013, the group recommended treatment with NETA as the first-choice progestin; after that date, dienogest was recommended as highly effective and particularly well tolerated. The investigators compared the satisfaction of the last 90 patients with endometriosis between 18-40 years of age for whom treatment with NETA (2.5 mg/day) was initiated with the first 90 similar patients treated with dienogest (2 mg/day) at their academic medical center.

Three women in the NETA group and eight in the dienogest group discontinued therapy in less than six months, largely because of side effects or perceived ineffectiveness. After six months of therapy, 25 of 87 women treated with NETA discontinued treatment (side effects, n = 15; persistent pain, n = 6; desire for pregnancy, n = 4) compared with 31 of 82 treated with dienogest (side effects, n = 12; cost, n = 8; persistent pain, n = 5; desire for pregnancy, n = 6). In an intention-to-treat analysis of all 180 patients, 71% of women who received NETA were either very satisfied or satisfied with the therapy compared to 72% of those treated with dienogest. Dienogest was no more effective than NETA in improving health-related quality of life, sexual function, and psychological status, or in providing pain relief. Although there were no major adverse events, 55% of the women using NETA and 41% of those using dienogest reported side effects. The most frequently reported side effect was weight gain in 31% of NETA users and in 16% of dienogest users. Overall tolerability as assessed by a numeric rating scale was statistically significantly better in women using dienogest, and the proportion of women who reported that their medical treatment was well or very well tolerated was statistically significantly higher (80% vs. 58%) in the dienogest users as well. Despite the increased tolerability, the authors concluded that the high cost of the drug relative to the cost of NETA indicated that dienogest should be used selectively in women who do not tolerate NETA.

COMMENTARY

At first blush, this study may seem largely irrelevant to American readers because dienogest has not been approved by the FDA for the treatment of endometriosis in the United States. So why did I decide to review this particular study? This study documents, yet again, how difficult it is to provide adequate and appropriate therapy to young women suffering from endometriosis, and further emphasizes how common are the side effects of therapy. The most common complaints of women with endometriosis are chronic pelvic pain, dyspareunia, and infertility. Surgery only sometimes provides a definitive cure for those women desiring to preserve or improve their fertility, necessitating the use of medical therapy for symptomatic relief. All medical therapies commonly used, including progestins, combined oral contraceptives, and GnRH analogs, have side effects and are not entirely effective in alleviating all symptoms. This study also highlights the need for new drugs for use in the treatment of symptomatic endometriosis.

Today, endometriosis often is defined as “an estrogen-dependent inflammatory disease” and is thought to affect 5-10% of reproductive-aged women in the United States.2,3 The prevalence may be as high as 50% in infertile women4 and may be approximated as 75% in women with chronic pelvic pain.5 The recognized defining feature is the presence of endometrium-like tissue in sites outside the uterine cavity, primarily on the pelvic peritoneum and on the ovaries. The pathogenesis is complex and not yet completely understood.2 The attachment and implantation of endometrial glands and stroma on peritoneal surfaces is associated with the aberrant expression of endometrial genes and altered hormonal responses.2 The endometrial lesions produce a chronic inflammatory disorder with increased numbers of macrophages, proinflammatory cytokines, metalloproteinases, chemokines, and prostaglandins that cause the symptoms and findings associated with endometriosis. The altered inflammatory and immune responses associated with endometriosis, as well as estrogen, favor the survival and growth of endometriotic tissue. In contrast to the unfavorable role of estrogen in perpetuating endometriosis, the role of progesterone is less well defined. It appears that the eutopic endometrium in women with endometriosis exhibits progesterone resistance, which may account for the diminished fertility observed in many women with even mild endometriosis.

There is evidence that all the changes outlined originate from two distinct epigenetic changes that affect the transcription factors SF1 and estrogen receptor ß, both of which are found in extraordinarily high levels in endometriotic tissue. In response of the endometriotic cells to prostaglandin E2, SF1 binds to the promoters of several steroidogenic genes, including aromatase, and leads to the formation of large quantities of estradiol locally. The estradiol in turn stimulates COX-2 through activation of estrogen receptor ß and results in overproduction of prostaglandin E2. Thus, inflammation and estrogen are linked in a continuous feedback cycle that involves the overexpression of genes that encode the aromatase and COX-2 enzymes and formation of estradiol and prostaglandin E2. Moreover, estrogen receptor ß suppresses progesterone receptor levels, leading to progesterone resistance and disruption of a paracrine pathway that inactivates estradiol.

Based on this knowledge, what drugs can be used to treat endometriosis? Evidence indicates that the pain associated with endometriosis can be reduced with a variety of medications: nonsteroidal anti-inflammatory drugs (NSAIDs), progestins, combined oral contraceptives, GnRH agonists, androgens, aromatase inhibitors, and selective progesterone-receptor modulators.1,2 NSAIDs would be expected to have variable effectiveness, as they do. Progestins and combined OCs probably act by suppressing ovulation. In this regard, antiprogestins with a mix of agonist and antagonist properties might be expected to be more effective than progestins.6 Aromatase inhibitors7 and GnRH analogs might be at least as effective as other means of suppressing ovulation because they lower circulating estrogen levels even more than progestins and combined OCs. Androgens, such as danazol, also suppress estrogens and ovulation and are effective in treating the symptoms associated with endometriosis, but their side effect profile generally is more severe than that of other available drugs. No doubt NETA has more side effects than does dienogest because NETA is the more androgenic progestin. Drugs targeting COX-2, aromatase, estrogen receptor ß, and progesterone receptors will continue to be investigated for their ability to treat the symptoms associated with endometriosis.

What is clear from this discussion is that there is no magical medical bullet to treat symptomatic endometriosis at present. We will continue to need to use the multidisciplinary approach to pain, even as new drugs are developed and promoted for the symptomatic treatment of endometriosis.

REFERENCES

  1. American College of Obstetricians and Gynecologists. Practice Bulletin no. 114. Management of endometriosis. Obstet Gynecol 2010;116:223-236.
  2. Bulun SE. Endometriosis. N Engl J Med 2009;360:268-279.
  3. Giudice LC, Kao LC. Endometriosis. Lancet 2004;364:1789-1799.
  4. Rawson JM. Prevalence of endometriosis in asymptomatic women. J Reprod Med 1991;36513-36515.
  5. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol 1999;93:51-58.
  6. Chwalisz K, Perez MC, Demanno D, et al. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev 2005;26:423-38. [Erratum, Endocr Rev 2005;26:703.]
  7. Attar E, Bulun SE. Aromatase inhibitors: The next generation of therapeutics for endometriosis? Fertil Steril 2006;85:1307-1318.