Editorial Robert L. Barbieri, MD Editor in Chief

In a difficult-to-treat case Have you tried a progestin for your patient’s pelvic pain?

Progestins are highly effective for pelvic pain caused by endometriosis that’s refractory to other treatments

CASE Your patient is a 26-year-old G0 ndometriosis will be diag- adequate pain relief for your patient, woman who has a long history of pro- nosed in approximately 8% of you know that you should offer an alter- gressively worsening dysmenorrhea, E women of reproductive age.1 native to her. Taking into account that pelvic pain, and dyspareunia. In the re- Pelvic pain, dysmenorrhea, and deep progestins are significantly less costly cent past, she was treated with nonste- dyspareunia are common symptoms than a GnRH , a progestin for- roidal anti-inflammatory drugs, a cyclic of endometriosis that interfere with mulation might, for her, be considered -progestin contraceptive, and quality of life. a first-line postoperative treatment of a continuous estrogen-progestin con- Endometriosis is a chronic symptoms of endometriosis. traceptive—in that order, and without disease best managed by develop- appreciable relief of the pain. ing a life-long treatment plan. Fol- Recently, the woman underwent lowing laparoscopic diagnosis and Options when considering laparoscopy, which demonstrated treatment, many experts strongly a progestin Stage-II endometriosis, which was recommend postoperative - Norethindrone acetate ablated. suppressive therapy to reduce the This agent is available in a single for- What would you prescribe for her risk that severe pelvic pain will recur, mulation: a 5-mg ; however, postoperatively to alleviate symptoms? requiring re-operation. dosages ranging from 2.5 mg/d (half Options for postoperative hor- of a tablet) to 15 mg/d have been monal treatment of endometriosis reported to be effective for relieving Instant Poll include: pain caused by endometriosis. • an estrogen–progestin contraceptive What is it? NEA is an androgenic • a progestin (norethindrone ac- progestin that suppresses luteiniz- etate [NEA]; depot medroxypro- ing hormone and follicle-stimulating What is your preferred hormone gesterone acetate [DMPA]; oral hormone, thus reducing production treatment for women who have acetate; the of ovarian estrogen. In the absence endometriosis and pelvic pain, -releasing intrauter- of ovarian estrogen, endometriosis and whose symptoms have ine system [LNG-IUS; Mirena]; and lesions atrophy. In addition, NEA not been relieved by a cyclic or the progestin-releasing implant binds to, and stimulates, endome- continuous oral contraceptive? [Implanon]) trial progestin and recep- Send your nomination to me • a gonadotropin-releasing hormone tors, resulting in and at [email protected]. (GnRH) agonist (depot leuprolide atrophy of both eutopic and ectopic We’ll consider publishing it in [Depot Lupron]; nafarelin nasal endometrial tissue. an upcoming issue. spray [Synarel]). Importantly, NEA does not ap- pear to cause bone loss, a phenome- Please include your name and CASE Continued non that is common with agents such city and state. Considering that both cyclic and con- as the GnRH or DPMA.2–4 tinuous estrogen-progestin contracep- The research record. One random- tives have already failed to provide ized study, two pilot studies, and one

6 OBG Management | February 2012 | Vol. 24 No. 2 obgmanagement.com Editorial

large observational study have re- In another pilot study, women increase the dosage by 2.5 mg (half ported that NEA is effective for pelvic who had pelvic pain and recto­ of a tablet) daily every 4 weeks, to a pain caused by endometriosis. vaginal endometriosis were treat­ maximum dosage of 10 mg/d (two In the randomized trial, 90 ed with either an tablets). If that dosage is ineffective, I women who had moderate or severe inhibitor (letrozole, 2.5 mg/d) plus usually discontinue NEA and switch pelvic pain and rectovaginal endo- NEA (2.5 mg/d) or NEA (2.5 mg/d) to a GnRH agonist. metriosis, and who remained symp- alone for 6 months. Both treatments tomatic after conservative surgery, resulted in a significant improve- Depot medroxyprogesterone were randomized to receive NEA, ment in pelvic pain and deep dyspa- acetate; oral medroxy- 2.5 mg/d, or a low-dose estrogen- reunia. Improvement in pain scores acetate progestin contraceptive (ethinyl was greater with letrozole plus NEA; DMPA is available in two FDA- , 10 μg, plus patients were more satisfied with approved formulations: acetate, 3 mg) daily for 12 months.5 NEA monotherapy than with the • a 150-mg dose given by intramus- Both treatment groups reported combined letrozole-NEA treatment, cular every 3 months significant and similar decreases in however, because the former was as- • a 104-mg dose given by subcutane- dysmenorrhea, deep dyspareunia, sociated with fewer side effects.7 ous injection every 3 months. non-menstrual pain and dyschezia. In a large (n = 194) observa- Research. The results of two large In a small pilot study, 40 women tional study of the postoperative use clinical trials, comprising a total of who had pelvic pain and colorec- of NEA in young women with pel- more than 550 subjects, showed that tal endometriosis were treated with vic pain and endometriosis, NEA at DMPA (104 mg, SC, every 3 months) NEA 2.5 mg/d for 12 months. The dosages as high as 15 mg/d signifi- and depot leuprolide (11.25 mg, IM, drug produced significant improve- cantly diminished pelvic pain and every 3 months or 3.75 mg, monthly) ment in dysmenorrhea, pelvic pain, self-reported menstrual bleeding. were each equally effective in reliev- deep dyspareunia, dyschezia, and All subjects were started on a dos- ing dysmenorrhea, dyspareunia, cyclic rectal bleeding.6 age of 5 mg/d, which was increased pelvic pain, pelvic tenderness, and in 2.5-mg increments every 2 weeks pelvic induration in women who had to achieve the goals of endometriosis.9,10 Welcome, and a lessening of pelvic pain; the DMPA was associated with a Dr. Jennifer Gunter! maximum dosage administered was greater rate of episodes of irregular 15 mg/d. Mean duration of NEA use bleeding than depot leuprolide; con- The Editors of was 13 months; 75% of subjects took versely, depot leuprolide was associ- OBG Management the maximum prescribed dosage of ated with greater loss of bone density have appointed 15 mg at some point during treat- and a higher incidence of vasomotor Jennifer Gunter, MD, ment. The most commonly reported symptoms. Weight gain was in the to the publication’s side effects were weight gain (16% range of 0.6 kg in both groups. roster of Contributing of women); (10%); mood labil- Of note, DPMA is much less ex- Editors as an advisor ity (9%); and vasomotor symptoms pensive than depot leuprolide. on electronic communications, (8%).8 Another study showed that in- the Web, and social media. In summary. NEA is effective for creasing the dosage of DMPA did not treating pelvic pain caused by endo- improve efficacy over the standard Dr. Gunter is in ObGyn practice metriosis at dosages from 2.5 mg/d to dosage11: DMPA, 150 mg IM, month- in San Francisco. She is the 15 mg/d. An important goal of treat- ly, and DMPA, 150 mg IM, every author of The Preemie Primer: ment is a decrease in pain symptoms 3 months produced similar relief of A Complete Guide for Parents of and amenorrhea; a dosage of 2.5 mg pelvic pain. Premature Babies—from Birth is often insufficient to reliably achieve Oral medroxyprogesterone ac- through the Toddler Years and etate, Beyond (Da Capo Press, 2010) both of those objectives. prescribed at high dosages, is and of recent articles in In my practice I begin therapy also effective for pelvic pain caused OBG Management. She blogs at at a dosage of 5 mg/d; the drug is ef- by endometriosis. In a pilot study http://www.drjengunter.com fective for most patients at that dos- (n = 21), oral MPA, 50 mg/d for age. If 5 mg/d does not reduce pain, I 4 months, alleviated dysmenorrhea,

8 OBG Management | February 2012 | Vol. 24 No. 2 obgmanagement.com dyspareunia, pelvic pain, dyschezia, a trial of a progestin, such as NEA, 2006;21(1):248–256. 11. Cheewadhanaraks S, Peeyananjarassri K, Chok- and pelvic tenderness and decreased DMPA, or the LNG-IUS that I use in suchat C, Dhanaworavibul K, Choobun T, Bun- pelvic nodularity. Sixty percent of my practice. yapipat S. Interval of injections of intramuscular depot medroxyprogesterone acetate in the long- subjects reported weight gain— Progestins are, as I’ve described, term treatment of endometriosis-associated 1.5 kg, on average.12 effective for pelvic pain. They are also pain: a randomized . Gynecol Obstet Invest. 2009;68(2):116–121. relatively inexpensive and have a 12. Luciano AA, Turksoy RN, Carleo J. Evaluation Progestin-releasing devices: side-effect profile that most patients of oral medroxyprogesterone acetate in the treatment of endometriosis. Obstet Gynecol. Mirena and Implanon find acceptable. I recommend that 1988;72(3 Pt 1):323–327. Many pilot studies have reported you try a progestin for your patients 13. Wong AY, Tang LC, Chin RK. Levonorgestrel- releasing intrauterine system (Mirena) and depot that the levonorgestrel-releasing who have refractory pelvic pain. medroxyprogesterone acetate (Depoprovera) as intrauterine system (LNG-IUS) is long-term maintenance therapy for patients with moderate and severe endometriosis: a random- effective for pelvic pain caused by ized controlled trial. Aust N Z J Obstet Gynaecol. endometriosis.13-17 For example: 2010;50(3):273–279. Research. In a small clinical trial, 14. Lockhat FB, Emembolu JO, Konje JC. The effica- cy, side-effects and continuation rates in women 30 women who had pelvic pain and [email protected] with symptomatic endometriosis undergoing endometriosis were randomized treatment with an intrauterine administered References (levonorgestrel): a 3 year follow-up. to receive an LNG-IUS (Mirena) or Hum Reprod. 2005;20(3):789–793. 1. Missmer SA, Hankinson S, Spiegelman D, et al. 15. Petta CA, Ferriani RA, Abrao MS, et al. Random- DMPA, 150 mg IM, every 3 months The incidence of laparoscopically confirmed ized clinical trial of a levonorgestrel-releasing 13 endometriosis by demographic, anthropo- for 3 years. Both therapies were ef- intrauterine system and a depot GnRH ana- morphic and lifestyle factors. Am J Epidemiol. logue for the treatment of chronic pelvic pain fective at reducing pelvic pain. 2004;160(8):784–796. in women with endometriosis. Hum Reprod. 2. Abdalla HI, Hart DM, Lindsay R, Leggate I, Hooke At the conclusion of the study, 2005;20(7):1993–1998. A. Prevention of bone mineral loss in postmeno- 16. Vercellini P, Aimi G, Panazza S, De Giorgi O, Pe- more women opted to retain the pausal women by . Obstet Gyne- sole A, Crosignani PG. A levonorgestrel-releasing col. 1985;66(6):789–792 . LNG-IUS (87%) than to continue intrauterine system for the treatment of dysmen- 3. Riss BJ, Lehmann HJ, Christiansen C. Norethis- orrhea associated with endometriosis: a pilot DMPA injection (47%). Bone den- terone acetate in combination with estrogen: study. Fertil Steril. 1999;72(3):505–508. effects on the skeleton and other organs. Am J sity was maintained in women who 17. Vercellini P Frontino G, De Giorgi O, Aimi G, Zai- Obstet Gynecol. 2002;187(4):1101–1116. na B, Crosignani PG. Comparison of a levonorg- had the LNG-IUS placed but slight- 4. Hornstein MD, Surrey ES, Weisberg GW, Ca- estrel-releasing versus ex- sino LA. Leuprolide acetate depot and hormonal ly diminished in women receiving pectant management after conservative surgery add-back in endometriosis: a 12-month study. for symptomatic endometriosis: a pilot study. DMPA. Lupron Add-back Study Group. Obstet Gynecol. Fertil Steril. 2003;80(2):305–309. pilot study 1998;91(1):16–24. In a of an etonoges- 18. Walch K, Unfried G, Huber J, Kurz C, van Trot- 5. Vercellini P, Pietropauolo G, De Giorgi O, Pa- senburg M, Pernicka E, Wenzl R. Implanon trel releasing implant (Implanon), sin R, Chiodini A, Crosignani PG. Treatment of versus medroxyprogesterone acetate: effects 41 women who had pelvic pain and symptomatic rectovaginal endometriosis with on pain scores in patients with symptomatic an estrogen-progestogen combination versus endometriosis—a pilot study. Contraception. endometriosis were randomized low-dose norethindrone acetate. Fertil Steril. 2009;79(1):29–34. to receive the implant or DMPA, 2005;84(5):1375–1387. 150 mg IM, every 3 months for 6. Ferrero S, Camerini G, Ragni N, Venturini PL, Biscaldi E, Remorgida V. 18 1 year. Both therapies were similar- in the treatment of colorectal endometriosis: a ly effective at reducing pelvic pain. pilot study. Hum Reprod. 2010;25(1):94–100. Correction 7. Ferrero S, Camerini G, Seracchioli R, Ragni N, Reimbursement Adviser, Notably, irregular uterine bleed- Venturini PL, Remorgida V. Letrozole combined November 2011 ing is a common problem when the with norethisterone acetate compared with nor- ethisterone acetate alone in the treatment of pain -releasing implant is symptoms caused by endometriosis. Hum Re- The date of the changeover to used to treat endometriosis. Achiev- prod. 2009;24(12):3033–3341. the 10th revision of International 8. Kaser DJ, Missmer SA, Berry KF, Laufer MR. ing amenorrhea or oligomenorrhea Use of norethindrone acetate alone for postop- Classification of Diseases is an important goal for women who erative suppression of endometriosis symptoms (ICD-10-CM) codes is incorrectly [published online ahead of print December 9, stated on page 51. The date suffer from pelvic pain caused by 2011]. J Pediatr Adolesc Gynecol. doi:10.1016/j. endometriosis. jpag.2011.09.013. should be October 1, 2013. 9. Schlaff WD, Carson SA, Luciano A, Ross D, Bergqvist A. Subcutaneous injection of depot me- The corrected version of this My recommendation droxyprogesterone acetate compared with leup- rolide acetate in the treatment of endometriosis article appears at http://www. Most ObGyns see patients who are associated pain. Fertil Steril. 2006;85(2):314–325. obgmanagement.com/article_ suffering from difficult-to-treat pel- 10. Crosignani PG, Luciano A, Ray A, Bergqvist A. pages.asp?AID=10041&UID= Subcutaneous depot medroxyprogesterone ac- vic pain caused by endometriosis. etate versus leuprolide acetate in the treatment —The Editors Many of these patients have not had of endometriosis-associated pain. Hum Reprod.

obgmanagement.com Vol. 24 No. 2 | February 2012 | OBG Management 9