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Long-term management of endometriosis: a case study and review of the literature.

This 2-part series reviews challenges facing clinicians who manage patients who have, or are suspected of having, endometriosis. This monograph focuses on issues of diagnosis and management, with special emphasis on chronic pelvic pain that has been unresponsive to management through generally accepted initial treatment protocols. Central to this discussion is the use of gonadoptropin-releasing hormone (GnRH) agonist agents and the importance of add-back therapy to prevent or alleviate symptoms that occur in a hypoestrogenic state.

CASE STUDY

D.S. is a 20-year-old nulligravida seeking relief from the pelvic pain that began in her early teens as severe urinary urgency, frequency, and dysuria. Diagnosed with interstitial cystitis, she failed multiple interventions, including bladder instillations, dietary modification, and medications. She also had severe dysmenorrhea. Diagnostic laparoscopy revealed endometriosis. Oral contraceptive (OC) use did not manage her symptoms. Ultimately, a transsacral neurostimulator improved her bladder symptoms. Despite use of long-acting, daily narcotic medications, incapacitating symptoms necessitated home schooling for her final high school years. She is unable to work, characterizing her pain as constant and, at times, increasing with movement. Severity varies from 3 to 10 on a visual analog pain scale. At this initial office visit, which lasts 1 hour, D.S. is accompanied by her fiance.

Women such as D.S. tend to be complex patients with a long history of unrelieved pain that greatly affects multiple quality-of-life domains (FIGURE 1). (1) An effective and proactive patient counseling strategy is essential. This time-consuming and challenging approach requires complex medical decision-making. Such visits may be appropriately coded as relatively high-level evaluation and management services.

* CASE STUDY

I feel that a critical piece of information is missing from D.S.'s story. What happened in her early teen years? How did she transform from a functional preteen into a chronically disabled 20-year-old? D.S. seems fearful and extremely anxious about the pelvic examination. I ask whether she has experienced an episode in which someone hurt her. She says "yes" but does not elaborate. She exhibits extreme muscle tension throughout the abdominal wall and pelvic floor. Our women's health physical therapist notes baseline muscle tension more than 10 times the normal level. D.S. is completely unaware of this chronic muscle rigidity.

[FIGURE 1 OMITTED]

D.S. and I discuss her history of pain and documented endometriosis. I know that it will take time to explain the treatment options and provide her with the information she needs to make an informed decision. I briefly review available treatment options, ask which treatments interest her, and suggest resources for more information. I tell her that she doesn't have to decide now: Patients often need at least 2 office visits to make an informed decision; during this time, we also build the framework in which we will collaboratively develop a strategy for long-term management and pain relief. Also, a clear understanding of medication and surgical effects typically leads to improved outcomes.

Patient counseling prior to treatment

With all patients, I systematically describe on- and off-label treatment options, and review their risks and benefits. These include:

* Lifestyle modifications and other simple, nonpharmacologic interventions

* Empiric medical treatments that may resolve symptoms

* Choices in diagnosis: Is the patient interested in obtaining a definitive diagnosis by laparoscopy? Or is her primary interest pain relief?

* Symptom management: Does she consider her symptoms tolerable? (For perimenopausal women, therapy may slow disease progression (2) but symptoms will likely decline with menopause.)

I provide reading material, such as ACOG handouts, and/or a list of reputable Web sites that offer additional information. Appropriate sites include www. rx.luprongyn.com, www.endofacts.com, and www. endometriosisassn.org.

D.S. also must be empowered to be the "squeaky wheel" and ask for relief rather than tolerate dysfunction. When she experiences pain, she needs to be comfortable about alerting her health care provider so that together they can work out new strategies. Although it is apparent that multiple factors contribute to her pain response, endometriosis likely plays an important role and should be a key focus of treatment.

* CASE STUDY

D.S. may need time to think about treatment options: Which side effects make her more nervous than others? What about their duration? Can they be controlled? D.S. is most interested in the use of a GnRH agonist to reduce her pelvic pain. We schedule a second visit in 1 month. I ask D.S. to keep a list of concerns and questions for discussion at the next visit.

Inducing a hypoestrogenic state

GnRH agonists induce a hypoestrogenic state and may be an effective strategy for relief of D.S.'s pain. Menopausal hypoestrogenism leads to lesion atrophy and reduced pain; hysterectomy and surgical castration via bilateral salpingo-oophorectomy (BSO) are highly effective for treatment of pelvic pain caused by endometriosis. (3-5) Reducing estrogen levels also helps to create a baseline for pain management by eliminating the fluctuations in ovarian steroid hormone levels during the menstrual cycle and their effects on pain levels. The use of a GnRH agonist with add-back therapy avoids the hypoestrogenic side effects that comprise the most common reason for patient noncompliance. (6) An empiric medical treatment with a GnRH agonist represents a reasonable initial treatment, prior to considering additional surgical intervention by laparoscopy (FIGURE 2). (7-9)

[FIGURE 2 OMITTED]

Hormones, pain, and endometriosis

To help D.S. understand the relationship between ovarian hormones and endometriosis, I focus on the pituitary gland. I draw a picture of the feedback loop to show how the pituitary functions as the master gland of the body. In the normal reproductive cycle, the pituitary stimulates the ovaries to produce hormones. It receives feedback through the blood supply about hormone levels in the blood. When the levels are high enough, the pituitary gland shuts off ovarian activity.

I describe the action of OCs, which temporarily suppress endometriosis. (10-12) These agents produce a consistent level of circulating hormones that is high enough to stop ovarian stimulation by the pituitary gland. (12) These effects may slow disease progression, although evidence is conflicting. (13-18) I review the well-established risks associated with exogenous estrogen administration, including pulmonary embolism, stroke, and deep vein thrombosis. I explain that these agents are not safe for women over age 35 who smoke, are obese, or who have heart disease, hypertension, or diabetes.

I describe how progesterone and synthetic progestins reduce the levels of hormones produced in the pituitary and the ovaries. They also cause atrophy of endometriotic tissue. These agents often reduce pelvic pain caused by endometriosis, leading to full or partial relief in as many as 80% of women. (19-20) I describe agents approved by the US Food and Drug Administration (FDA) for use in the treatment of endometriosis: medroxyprogesterone acetate and norethindrone acetate (NETA), as well as their potential side effects: weight gain, irregular uterine bleeding/spotting, and mood changes (eg, depression). Prolonged use may decrease bone mineral density (BMD).

As NETA is also the only agent approved by the FDA for use in add-back therapy with GnRH agonists, I review its properties. Norethindrone has been shown to reduce the pain and disease severity of endometriosis, as shown by laparoscopy, when used in combination with GnRH agonists. (21,22) It reduces the vasomotor symptoms and bone loss side effects of GnRH agonists, possibly because NETA is metabolized to an estrogen, ethinylestradiol. (23) It provides estrogenic activity to protect against side effects, but not enough to stimulate endometriosis and increase pain. (23,24) In effect, NETA has dual purposes: as a treatment and as a means to avoid the side effects of these agents.

D.S. is concerned about the safety of hormonally active products. I present the risks/benefits as they apply to her. It may interest her that use of a GnRH agonist with add-back therapy doesn't increase the levels of hormones circulating in her body; instead, the levels of circulating estrogen will be lower than typical pretreatment levels.

Danazol

I discuss danazol, a potent progestin with androgenic activity. It prevents ovulation and helps stop the growth of endometriotic lesions. Additionally, danazol, as well as leuprolide acetate, suppresses the local immune system. (25) More than 80% of patients experience relief or improvement of pain symptoms within 2 months of treatment with danazol. (26) Women treated with danazol experience a significant decrease in the level of pelvic pain, lower back pain, defecation pain, and total pain scores. (27) The improvement in pain scores persists 6 months after therapy discontinuation. Typical androgenic, dose-dependent side effects may affect treatment compliance (28); they include weight gain; edema; acne; hirsutism; myalgia; voice changes; increased circulating levels of serum aspartate aminotransferase and alanine aminotransferase; and decreased levels of high-density lipoprotein cholesterol. Vaginal administration of danazol may result in lower effective dosages and reduced side effects. (29) Such formulations are in phase II trials and are not FDA approved.

GnRH agonists

I return to my drawing of the pituitary feedback loop to show D.S. how GnRH agonists affect the pituitary gland by downregulating the gland's GnRH receptors. Their effects are not based on circulating hormone levels. Basically, they tell the pituitary to turn off. Ovarian activity ceases. The body stops producing substances required for the reproductive cycle--development of a follicle, ovulation, and endometrial shedding. Thus, a temporary hypoestrogenic state occurs. (30)

When GnRH agonist administration is stopped, the pituitary turns back on, and the body resumes normal function. Menses typically return 60 to 90 days after GnRH therapy is stopped. (30) Although use of GnRH agonists without add-back therapy results in bone loss, this condition shows a trend toward reversal with discontinuation (although using add-back therapy with calcium to retain bone mass is certainly a more appropriate strategy). (31)

Evidence suggests that GnRH agonists address symptoms of endometriosis more effectively than do estrogen/progestin agents. (6) Disease activity is reduced. (26,28,30,32,33) An empiric trial of a GnRH agonist is an established and valuable first-line treatment. These agents provide a safe option when use of estrogen products is contraindicated.

It's particularly important to discuss side effects--and that they can be effectively managed. Physicians report that side effects are the most common reason for patients to discontinue treatment. (6,23) Hot flushes, insomnia, and an enlarged abdomen are commonly reported symptoms (without add-back). (7) In one study, 78% of women treated with leuprolide depot reported vasomotor symptoms, 16% reported vaginal symptoms (eg, vaginitis), and 34% reported headaches. (32) Onset of amenorrhea and hot flushes occurred within the first 4 weeks of therapy in 75% of women receiving GnRH agonists; 98% were hypoestrogenic by 8 weeks. (30) Additionally, a study of Lupron Depot, 3.5 mg for 3 months, showed a decrease in mean vertebral trabecular BMD of 2.7% compared with baseline. Six months after therapy was discontinued, a trend toward recovery was observed. (31) Exogenous hormones alleviate hypoestrogenic symptoms. (34-40)

I counsel D.S. that estrogen depletion is associated with side effects most commonly associated with menopause, including vasomotor symptoms, bone loss, vaginal atrophy, memory disturbance, sleep issues, and cognitive dysfunction. If she selects a GnRH agent, she will need add-back therapy (with calcium supplementation) to avoid temporary side effects, but at a dosage low enough to avoid endometriotic tissue stimulation.

I review the GnRH products available. FDA-approved agents are goserelin (Zoladex), leuprolide depot (Lupron Depot), and nafarelin (Synarel). They are administered subcutaneously (goserelin), intramuscularly (leuprolide depot), or via nasal spray (nafarelin) and are appropriate for patients with moderate to severe pelvic pain. These agents are approved for 6 months of continuous use (without add-back therapy). Treatment duration limits stem from concern about significant bone loss. The use of goserelin with hormone therapy products is advised, although optimal drug, dose, or duration of use is not established. (41) The FDA has approved retreatment with leuprolide depot for an additional 6 months if add-back therapy is included. (31) Current data suggest a 2-year interval between the first 6-month course of treatment with nafarelin and retreatment. (42)

Importance of add-back therapy with use of GNRH agonists. The FDA has approved a regimen of leuprolide depot IM, 3.75 mg (monthly) or 11.25 mg (every 3 months), plus NETA, 5 mg/day, with calcium supplements, 1000 mg/day, to reduce hypoestrogenic symptoms and preserve BMD. (31,43) Although not FDA-approved, transdermal [E.sub.2] (25 mcg) with daily medroxyprogesterone acetate in combination with goserelin acetate effectively prevents symptoms of low estrogen and endometriosis. (34) However, increased pain symptoms in GnRH-treated patients have occurred when circulating [E.sub.2] levels exceed 40 pg/mL. (30) Medroxyprogesterone acetate has also been evaluated as add-back therapy but features a risk of bone loss. (44)

D.S. does not want surgery. However, it may still be valuable to talk about both surgery and the use of GnRH agonists as a "preview" of the effects of surgery (ie, BSO/hysterectomy). A 3-month trial of a GnRH agonist allows patients to live with the postsurgical symptoms and assess their tolerability. (8) If pain continues during this trial, surgery likely will be ineffective. Therefore, a trial helps determine the appropriateness of surgery for a given patient. Hysterectomy with BSO is highly effective for treatment of pelvic pain caused by endometriosis. (3-5) However, a recent retrospective study showed that in women aged 30 to 39, ovarian removal did not significantly improve the duration of time before further surgery was required. (4)

One benefit of leuprolide depot is that it can be administered IM at monthly intervals. This creates a rationale for D.S. to schedule additional visits to solidify our relationship. Starting with the 1-month injection also lets us see how she responds to it. If she does well, we'll continue at monthly intervals or switch to administration at 3-month intervals (FIGURE 2).

* CASE STUDY

At her second office visit, D.S. has decided on a trial of leuprolide acetate and add-back therapy. However, she has visited several Web sites that described leuprolide treatment as simulating menopause and she is concerned about becoming infertile. She is also worried about bone loss and vasomotor symptoms. I make sure D.S. knows that she may experience estrogen withdrawal symptoms: hot flushes; night sweats; sleep and memory disturbances; joint pain; and muscle aches and pain. Vaginal dryness may occur, although typically only after 3 to 4 months. I reiterate that the hypoestrogenic effects are fully reversible on discontinuation, and that her menstrual cycle and fertility would be fully restored. In addition, side effects can be effectively managed with add-back therapy.

We begin with a 1-month injection with add-back therapy. I reiterate that she can call me immediately if she experiences side effects. I want her to have the confidence that I won't make her suffer for weeks with hot flushes, memory disturbances, or moodiness. If she is bothered by symptoms, she needs to know that I'll respond, and together we'll work through the problem quickly.

We schedule follow-up appointments with the physical therapist for help with the muscle tension component of her pain as well as a follow-up appointment with me in 4 weeks to assess treatment.

Selecting a treatment option

As a clinician, I want to under-promise and overdeliver, making sure that the patient understands all of the ramifications and potential side effects of treatment--and that they can be managed. I want to be sure that D.S. knows that her job is to communicate with me so that I know what she's experiencing. My job is to respond to her, validate what she experiences, and recognize that these symptoms are likely related to treatment, even if they are not listed in the package insert as a most common side effect.

I find that when a patient understands the potential for side effects (and the physiologic reasons for which they might occur) and knows that we'll deal with a problem promptly, she tolerates treatment much better than someone who is frightened, believes that the pain will continue unabated for many months, or is concerned that the side effects will not be reversible.

I begin the dialogue by asking the patient if she would like to review her list of questions and concerns. I then ask if she has read the material provided and if she has done any additional research. I ask her:

* What are your thoughts on treatment, compared with your feelings at the last visit?

* What questions or concerns can I address to help you make your choice?

As clinicians, we should always keep in mind that we are providing a service to the patient. Our job is to be a source of information and advice. However, it is not our job to tell our patients what to do. Optimal outcomes for treatment of chronic pain due to endometriosis result from patient/physician partnership.

* CASE STUDY

For her third office visit, D.S. arrives alone. She reports significant pain relief. She says she has done some additional research on the Internet and has a few questions about side effects with varying doses of leuprolide depot. After discussing possible next steps in her treatment, D.S. chooses the 3-month injection of leuprolide depot to limit the frequency of office visits. The add-back regimen remains the same. I assure her that she can call with any questions or new or intensified side effects.

D.S. also discloses her history of violent sexual abuse by her first boyfriend. He raped her (her first sexual experience), then remained controlling for several years. The relationship ended when she left school due to her prolonged disability. D.S. had never told anyone about the rape or the ongoing abuse she had experienced.

Clearly this patient--despite her recognized disease processes of endometriosis and interstitial cystitis-also has some major psychological issues that required professional attention. We discuss the importance of coordinating her care in an effort to address all factors contributing

to her pain syndrome. She is enthusiastic about the treatment program but has a long road ahead to meet our mutual goals of pain management and improvement in the quality of her life.

What the patient needs to know

Throughout the process of diagnosis and treatment, I seek to educate the patient about the following key points:

* Chronic pelvic pain requires a lifelong management process in which both patient and health care provider collaborate to develop a plan for symptom relief; this plan may need to be modified over time.

* Definitive diagnosis and complete "cure" may be unrealistic expectations for many patients; the goal of therapy is to provide enduring symptom relief.

* Treatment decisions must be individualized based on each patient's needs and desires. Important factors include symptom severity, desire for pregnancy, age, concerns about medication side effects, past surgeries, attitudes toward surgery (now or in the future), and costs.

* Pain may be exacerbated by ovarian cycling. Therefore, relief may be most effectively obtained by inducing amenorrhea.

* In treatment selection, the role of the pituitary gland in regulating systemic estrogen and progestogen levels should be considered.

* Surgical interventions--particularly if repeated--may not be effective in attaining the goal of providing enduring relief of pain and improving quality of life.

* Pain may also stem from a nongynecologic source, such as interstitial cystitis, irritable bowel syndrome, or myofascial pain. These conditions can coexist with endometriosis and make diagnosis challenging.

Add-back therapy: Reports from the medical literature

Although this monograph focuses on patient counseling, clinicians may want to review the literature on add-back therapy.

A 1-year, multicenter, prospective trial assessed GnRH therapy (with or without add-back) on symptoms and bone marrow density (BMD). Patients received leuprolide acetate depot, 3.75 mg IM every 4 weeks plus add-back, with pain effects as shown in the TABLE. (1,2) Additionally, vasomotor symptoms were lower in the add-back groups: a median of 28 in group A vs 0 to 2 in the other groups. Increased bleeding occurred in groups C and D. Suppression of menses occurred for at least 60 consecutive days in 94% to 100% of patients. Estradiol levels were within or near the menopausal range for all groups. Endometrial biopsies of all women were normal. BMD was reduced less from baseline with estrogen-progestin or progestin-only add-back. Greater loss occurred in group A compared with the other groups.

Additionally, NETA plus GnRH agonists suppressed the symptoms of endometriosis and the extent of disease at laparoscopy; it also ameliorated symptoms and preserved bone mass. (3) The regimen was as effective as GnRH agonist-only therapy in significantly reducing circulating gonadotropin and estrogen levels (P<.01), extent of visible endometriotic implants (P<.01), and painful symptoms (P<.01). (3) Add-back therapy markedly reduced vasomotor and vaginal symptoms. Lumbar spine BMD loss was significantly reduced and more completely reversed with combination therapy (P<.05) (FIGURE). A reversible decrease in high-density lipoprotein-cholesterol and increase in low-density lipoprotein:high-density lipoprotein ratio were noted only in the combination therapy group.

Another study compared the efficacy of a GnRH agonist with and without add-back therapy in 133 patients who had surgery and relapsed with pain. Use of a GnRH agonist with or without add-back provided a higher reduction of pelvic pain, dysmenorrhea, and dyspareunia than did oral contraceptives (OCs). (4) Similarly, GnRH agonist and add-back therapy resulted in more significant quality-oflife improvements, as assessed by the Medical Outcomes Survey Short Form-36 (SF-36) questionnaire. Add-back therapy allowed a longer treatment duration, reduced BMD loss, and provided good control of pain symptoms and better patient quality of life compared with either a GnRH agonist alone or an OC. (4)

Noting the importance of the adolescent years for bone acquisition and attainment of peak bone mass, the National Institutes of Health will conduct a trial titled "The Effect of Hormonal Add-Back Therapy in Adolescents Treated With a GnRH Agonist for Endometriosis: A Randomized Trial." The study will assess preservation of skeletal health and quality of life in adolescents with endometriosis. (5)

Certainly, other agents improve BMD and prevent fractures, most importantly bisphosphonates.

Physiologically, these agents are released slowly from the bone, with effects that persist long after discontinuation of treatment. Although there are no data in humans, their use in reproductive-age women may theoretically have an adverse effect on subsequent fetal bone development. (6)

References

(1.) Hornstein MD, Surrey ES, Weisberg GW, et al, for the Lupron Add-Back Study Group. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Obstet Gynecol. 1998;91:16-24.

(2.) Olive DL. The role of add-back therapy in the United States. Drugs of Today. 2005;41 (suppl A):22-26.

(3.) Surrey ES, Judd HL. Reduction of vasomotor symptoms and bone mineral density loss with combined norethindrone and long-acting gonadotropin-releasing hormone agonist therapy of symptomatic endometriosis: a prospective randomized trial. J Clin Endocrinol Metab. 1992;75:558-563.

(4.) Zupi E, Marconi D, Sbracia M, et al. Add-back therapy in the treatment of endometriosis-associated pain. Fertil Steril. 2004;82:1303-1308.

(5.) US National Institutes of Health. The Effect of Hormonal Add-Back Therapy in Adolescents Treated With a GnRH Agonist for Endometriosis: A Randomized Trial [planned clinical trial]. NCT00474851. http://clinicaltrials. gov/ct2/show/NCT00474851?term= NCT00474851&rank=1. Accessed July 18, 2008.

(6.) Fosamax [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2008.

References

(1.) Marques A, Bahamondes L, Mdrighi IM, et al. Quality of life in Brazilian women with endometriosis assessed through a medical outcome questionnaire. J Reprod Med. 2004;49:115-120.

(2.) Mahmood TA, Templeton A. 1he impact of treatment on the natural history of endometriosis. Hum Reprod. 1990;5:965-978.

(3.) Ranney B. Endometriosis. 3. Complete operations. Reasons, sequelae, treatment. Am J Obstet Gynecol. 1971;109:1137-1144.

(4.) Shakiba K, Bena IF, McGill KM, et al. Surgical treatment of endometriosis: A 7-year follow-up on the requirement for further surgery. Obstet Gynecol. 2008;111:1285-1292.

(5.) Hammond CB, Rock IA, Parker RT. Conservative treatment of endometriosis: the effects of limited surgery and hormonal pseudopregnancy. Fertil Steril. 1976;27:756-766.

(6.) Olive DL. The role of add-back therapy in the United States. Drugs of Today. 2005;41(suppl A):22-26.

(7.) Ling FW, for the Pelvic Pain Study Group. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Obstet Gynecol. 1999;93:51-58.

(8.) ACOG Committee Opinion. Number 310, April 1995. Endometriosis in adolescents. Obstet Gynecol. 2005;105:921-927.

(9.) ACOG Practice Bulletin. Medical management of endometriosis. Number 11, December 1999 (Replaces Technical Bulletin Number 184, September 1993). Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet. 2000;71:183-196.

(10.) Vercellini P, Frontino G, De Giorgi O, et al. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorthea that does not respond to a cyclic pill regimen. Fertil Steril. 2003;80:560-563.

(11.) Vercellini P, Trespidi L, Colombo A, et al. A gonadotropin releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertil Stefil. 1993;68:75-79.

(12.) Proctor ML, Roberts H, Farquhar CM. Combined oral contraceptive pill (OCP) as treatmeut for primary dysmenorrhoea. Cochrane Database Syst Rev, 2001;CD002120.

(13.) Vessey MP, Villard-Mackintosh L, Painter R, Epidemiology of endometriosis in women attending family planning clinics. BMI. 1993;306: 182-184.

(14.) Buttram VC Jr, Cyclic use of combination oral contraceptives and the severity of endometriosis, Fertil Steril. 1979;31:347-348.

(15.) 8trathy Ill, Molgaard CA, Coulam CB, et al. Endometriosis and infertility: a laparoscopie study of endometriosis among fertile and infertile women, Fertil Steril, 1982;38:667-672,

(16.) Kirshon B, Poindexter AN 3rd. Contraception: a risk factor for endometriosis. Obstet Gynecol. 1988;71:829-831.

(17.) Mahmood TA, Templeton A. Prevalence and genesis of endometriosis. Hum Reprod. 1991;6:544-549.

(18.) Parazzini F, La Vecehia C, Franceschi S, et al. Risk factors for endometrioid, mueinous and serous benign ovarian cysts. Int 1 Epidemiol. 1989;18:108-112.

(19.) Luciano AA, Turksoy RN, Carleo I. Evaluation of oral medroxyprogesterone acetate in the treatment of endometriosis. Obstet Gynecol. 1988;72:323-327.

(20.) Crosiguani PG, Luciano A, Ray A, et al. Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain. Hum Reprod. 2006;21:248-256.

(21.) Surrey ES, Gambone IC, Lu IKH, et al. The effects of cmnbining norethindrone with a gonadotropin-releasing hormone agonist in the treatment of symptonmtic endometriosis. Fertil Steril. 1990;53:620-626.

(22.) Surrey ES, Voigt B, Fournet N, et al. Prolonged gonadotropin-releasing hormone agonist treatment of symptomatic endometriosis: 3he role of cyclic sodium etidronate and low-dose norethindrone "add-back" therapy. Fertil Steril. 1995;63:747-755.

(23.) Homstein MD, Surrey ES, Weisberg GW, et al, for the Lupron Add-Back Study Group. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Obstet Gynecol. 1998;91:16-24.

(24.) Barbieri RL. Hormone treatment of endometriosis. 3he estrogen threshold hypothesis. Am J Obstet Gynecol. 1992;166:740-745.

(25.) Matalliotakis JM, Neonaki MA, Koumantaki YG, et al. A randomized comparison of danazol and leuprolide acetate suppression of serumsoluble CD23 levels in endometriosis. Obstet Gynecol. 2000;95:810-813.

(26.) Henzl MR, Corson SL, Moghissi K, et al. Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter double-blind comparative clinical trial. N Engl J Med. 1988;318:485-489.

(27.) Telimaa S, Puolakka J, Ronnberg L, et al. Placebo-controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis. Gynecol Endocrinol. 1987;1:13-23.

(28.) Barbieri RE New therapy for endometriosis. N Engl J Med. 1888:318:512-514.

(29.) Razzi S, Luisi S, Calonaci E et al. Efficacy of vaginal danazol treatment in women with recurrent deeply infiltrating endometriosis. Fertil Steril. 2007;88:789-794.

(30.) Hornstein MD. Gonadotropin releasing hormone agonists for long term treatment of en dometriosis. Up to Date. January 31, 2008. www. uptodate.com. Accessed April 22, 2008.

(31.) Eupron, 3.75 mg [package insert]. Lake Forest, IL: TAP Pharmaceutical Products Inc.; 2004.

(32.) Dlugi AM, Miller IS, Knittle J, for the Lupron Study Group. Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized placebo controlled double blind study. Fertil Steril. 1990;54:419-427.

(33.) Shaw RW. Nafarelin in the treament of pelvic pain caused by endometriosis. Am J Obstet Gynecol. 1990;162:574-576.

(34.) Howell R, Edmonds DK, Dowsett M, et al. Gonadotropin releasing hormone analogue (guserelin) plus hormone replacement therapy for the treatment of endometriosis: a randomized controlled trial. Fertil Steril. 1995;64:474-481.

(35.) Moghissi KS, Schlaff WD, Olive DL, et al. Goserelin acetate (Zoladex) with or without hormone replacement therapy for the treatment of endometriosis. Fertil Steril. 1998;69:1056-1062.

(36.) Irahara M, Uemura H, Yasui T, et al. Efficacy of every-other-day administration of conjugated equine estrogen and medroxyprogesterone acetate on gonadotropin-releasing hormone agonists treatment in women with endometriosis. Gynecol Obstet Invest. 2001;52:217-222.

(37.) Pierce SJ, Gazvani MR, Farquharson RG. Long-term use of gonadotropin-releasing hormone analogs and hormone replacement therapy in the nmnagement of endometriosis: a randomized trial with a 6-year follow-up. Fertil Steril. 2000;74:964-968.

(38.) Kiilholma P, Tuimala R, Kivinen S, et al. Comparison of the gonadotropin-releasing hormone agonist goserelin acetate alone versus goserelin combined with estrogen-progestogen add-back therapy in the treatment of endometriosis. Fertil Steril. 1995;64:903-908.

(39.) Franke HR, van de Weijer PH, Pennings TM, et al. Gonadotropin-releasing hormone agonist plus "add-back" hormone replacement therapy for treatment of endometriosis: a prospective, randomized, placebo-controlled, double-blind trial. Fertil Steril. 2000;74:534-539.

(40.) Zupi E, Marconi D, Sbracia M, et al. Add-back therapy in the treatment of endometriosis-assoeiated pain. Fertil Steril. 2004;82:1303-1308.

(41.) Zoladex [package insert]. Cheshire, UK: AstraZeneca; 2003.

(42.) Synarel [package insert]. New York, NY: Pfizer Inc; 2005.

(43.) Lupron, 11.25 mg [package insert]. Lake Forest, IL: TAP Pharmaceutical Products Inc.; 2004.

(44.) Ryan PL Singh SP, Guillebaud J. Depot medroxyprogesterone and bone mineral density. 1 Faro Plann Health Care. 2002;28:12-15.

BARBARA S. LEVY, MD, MEDICAL DIRECTOR, WOMEN'S HEALTH CENTER, FRANCISCAN HEALTH SYSTEM, FEDERAL WAY, WASHINGTON

Disclosure: Dr Levy reports that she has no financial relationships to disclose.
TABLE. Mean changes from baseline in pain score averaged over the
treatment period (a)

                    Baseline
Variable             n (%)          Group A

Dysmenorrhea        199 (99)   -1.9 [+ or -] 0.9
Pelvic pain         195 (97)   -0.9 [+ or -] 0.8
Pelvic tenderness   182 (91)   -0.8 [+ or -] 0.8

Variable                        Group B

Dysmenorrhea        -1.9 [+ or -] 0.8 (-0.20, 0.20)
Pelvic pain         -0.8 [+ or -] 1.0 (-0.36, 0.21)
Pelvic tenderness   -0.8 [+ or -] 1.0 (-0.17, 0.25)

Variable                        Group C

Dysmenorrhea        -1.8 [+ or -] 0.8 (-0.29, 0.13)
Pelvic pain         -0.8 [+ or -] 0.8 (-0.45, 0.14)
Pelvic tenderness   -0.8 [+ or -] 0.7 (-0.23, 0.22)

Variable                        Group D

Dysmenorrhea        -1.7 [+ or -] 0.7 (-0.40, 0.02)
Pelvic pain         -0.6 [+ or -] 0.8 (-0.58, 0.01)
Pelvic tenderness   -0.7 [+ or -] 0.6 (-0.32, 0.12)

All groups received a GnRH agonist. Additionally, group A, placebo; B,
NETA 5 mg/d; C; NETA 5 mg/d + CEE.625 mg/d; D, NETA 5 mg/d + CEE 1.25
mg/d.

(a) Mean change [+ or -] standard deviation (95% confidence interval
for difference from group A).

No significant differences were detected between treatment groups. All
within-group changes from baseline were significant (P [less than or
equal to] .001; analysis of covariance).

Reprinted with permission from Hornstein IVID, et al. Leuprolide
acetate depot and hormonal add-back in endometriosis: a 12-month
study. Lupron Add-Back Study Group. Obstet Gynecol. 1998;91:16-24.
Copyright [c] 1998 Lippincott Williams & Wilkins.

FIGURE. Changes from baseline in BMD in 4
study groups

             Week 24   Week 52

Group A      n=41*     n=29*
Group B      n=42*     n=32*
Group C      n=41*     n=33*
Group D      n=38*     n=24*

* P<.001 compared with group A.
BMD, bone mineral density.

Source: Olive DL. Drugs of Today.
2005;41(suppl A):22-26

Note: Table made from bar graph.
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Title Annotation:ISSUES IN ENDOMETRIOSIS: PART 2 OF A 2-PART SERIES
Author:Levy, Barbara S.
Publication:OBG Management
Article Type:Case study
Geographic Code:1USA
Date:Oct 1, 2008
Words:5286
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