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Treatment with leuprolide acetate and hormonal add-back for up to 10 years in stage IV endometriosis patients with chronic pelvic pain

2006; Elsevier BV; Volume: 86; Issue: 1 Linguagem: Inglês

10.1016/j.fertnstert.2005.12.030

1556-5653

Mohamed A. Bedaiwy, Robert F. Casper,

Endometrial and Cervical Cancer Treatments

This pilot study examined the effect of a low-dose E and pulsed progestogen hormone therapy (HT) regimen for add-back during long-term GnRH-agonist therapy on bone mineral density (BMD) in five patients with stage IV endometriosis. Bone mineral density was stable after initiation of HT for the entire follow-up period (up to 10 years). One patient stopped her treatment on two occasions to conceive and was successful each time with delivery of a normal baby. No patient had return of pelvic pain after HT add-back. This pilot study examined the effect of a low-dose E and pulsed progestogen hormone therapy (HT) regimen for add-back during long-term GnRH-agonist therapy on bone mineral density (BMD) in five patients with stage IV endometriosis. Bone mineral density was stable after initiation of HT for the entire follow-up period (up to 10 years). One patient stopped her treatment on two occasions to conceive and was successful each time with delivery of a normal baby. No patient had return of pelvic pain after HT add-back. Among women being investigated for chronic abdominal pain, the incidence of endometriosis is estimated to be 15% (1Mahmood T.A. Templeton A. Prevalence and genesis of endometriosis.Hum Reprod. 1991; 6: 544-549PubMed Google Scholar). The aim of medical treatment for endometriosis is to induce atrophy in the ectopic endometrial tissue with the use of hormones. A recent Cochrane Review has shown that GnRH-agonists are a highly effective management option for endometriosis-associated pain with results comparable or superior to other available medications for short duration (2Prentice A D.A. Goldbeck-Wood S. Farquhar C. Smith S.K. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Review, no. 3. Update Software, Oxford1999Google Scholar). However, long-term use may lead to decreased BMD as a consequence of hypoestrogenism (3Casper R.F. Clinical uses of gonadotropin-releasing hormone analogues.CMAJ. 1991; 144: 153-158PubMed Google Scholar). It was estimated that up to 6% of bone mineral density might be lost in the first 6 months of GnRH therapy. However, the loss is restored almost completely 2 years after stopping treatment (4Paoletti A.M. Serra G.G. Cagnacci A. Vacca A.M. Guerriero S. Solla E. et al.Spontaneous reversibility of bone loss induced by gonadotropin-releasing hormone analog treatment.Fertil Steril. 1996; 65: 707-710Abstract Full Text PDF PubMed Google Scholar). On the other hand, irreversible loss of bone with pathological consequences may occur with prolonged (>6 months) treatment (5Pickersgill A. GnRH agonists and add-back therapy is there a perfect combination?.Br J Obstet Gynaecol. 1998; 105: 475-485Crossref PubMed Scopus (60) Google Scholar).Concomitant add-back HT during treatment with GnRH-agonists may prevent bone loss and other symptoms of E deficiency while keeping endometriotic implants quiescent (6Barbieri R.L. Gonadotropin-releasing hormone agonists and estrogen-progestogen replacement therapy.Am J Obstet Gynecol. 1990; 162: 593-595Abstract Full Text PDF PubMed Scopus (44) Google Scholar). We previously reported a novel regimen of continuous E with pulsed P as a unique HT (7Casper R.F. Estrogen with interrupted progestin HRT a review of experimental and clinical studies.Maturitas. 2000; 34: 97-108Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). We proved that this HT combination resulted in increased sensitivity to E and progestogen in E-responsive tissues. Consequently, lower doses of E and progestogen may be used for HT with excellent biological effects. We also proved that this combination is effective in maintaining BMD when combined with GnRH-agonist for up to 32 months in the treatment of endometriosis-associated pain and for up to 37 months for the treatment of premenstrual syndrome (8Mitwally M.F. Gotlieb L. Casper R.F. Prevention of bone loss and hypoestrogenic symptoms by estrogen and interrupted progestogen add-back in long-term GnRH-agonist down-regulated patients with endometriosis and premenstrual syndrome.Menopause. 2002; 9: 236-241Crossref PubMed Scopus (42) Google Scholar). The objective of the present study was to examine the effects of extended GnRH-agonist therapy (up to 10 years) coupled with the low-dose E and pulsed progestogen HT regimen for add-back in a group of young women with advanced endometriosis associated with severe chronic pelvic pain.All five patients with stage IV endometriosis included in this study sought medical treatment because of pelvic pain, dyspareunia, and dysmenorrhea associated with endometriosis, which was confirmed by laparoscopy and histopathology. All five patients had undergone multiple laparoscopic surgeries for management of endometriosis before medical management. Alternative therapies were discussed with the patients before starting the use of GnRH-agonist treatment, and the women were informed that GnRH agonist treatment for longer than 6 months was an off-label use of the drug. All patients were nonsmokers. The mean age ± SD of the patients at the beginning of the GnRH-agonist treatment was 30.33 ± 8.52 years. The age ranged from 20 to 40.5 years. The mean follow-up duration ± SD for the patients while on GnRH-agonist treatment was 8.5 ± 2.35 years.After exclusion of pregnancy by determination of a negative serum beta-hCG, GnRH-agonist treatment was started. Patients received leuprolide acetate depot 3.75 mg (Lupron, TAP Pharmaceuticals, Lake Forest, IL) IM monthly until their pelvic pain and dyspareunia had resolved to the point that the women considered themselves subjectively symptom-free (2–3 months). HT add-back was started along with the GnRH-agonist. In all patients, GnRH-agonist injections were started during the luteal phase of the menstrual cycle. The HT regimen consisted of oral administration of 1 mg micronized E2 (Estrace, Roberts Pharmaceutical, Mississauga, Ontario, Canada) daily and 0.35 mg norethindrone (Micronor, Ortho/MacNeil, Raritan, NJ) daily for 2 days alternating with 2 days without progestogen. The women were counseled to maintain adequate calcium intake by diet or calcium supplements.The primary outcome measure of this study was a change in BMD, calculated from measured bone mineral content, because a significant decline in BMD would necessitate a discontinuation of GnRH-agonist treatment. Bone density in the lumbar spine (L1–L4) and in the femoral neck and the total hip region was assessed by dual-energy x-ray absorptiometry (DEXA) (Hologic 1000, Hologic Corporation, Waltham, MA) at 12-month intervals for up to 10 years. The Hologic equipment was calibrated daily using a standard bone "phantom." The coefficient of variation for the BMD calculation was 1%. Secondary outcome measures were bleeding control and pain relief. The BMD results were compared between the start and end of GnRH-agonist treatment by paired two-tailed Student's t-test. The statistical tests were performed with GraphPad Prism Version 3 software (GraphPad Software, San Diego).All patients reported subjective resolution of their endometriosis-associated pain within 2–3 months of starting the GnRH-agonist injections. No patient had return of pelvic pain after HT add-back. After the first 3 months, all women in this study remained amenorrheic with the exception of occasional spotting. The one patient who stopped therapy to get pregnant conceived spontaneously, and both of her pregnancies were uneventful. She delivered spontaneously with normal neonatal outcome on both occasions.The BMD in the lumbar spine, the femoral neck, and the total hip region (Fig. 1) remained relatively stable throughout the follow-up period for each patient enrolled in the study. None of the patients lost a clinically significant percentage of BMD during the study (i.e., >3%). For the group as a whole, there was no significant difference between the mean (±SD) bone density in the lumbar spine, the femoral neck, and the total hip region at the end of treatment compared with the beginning (baseline BMD) of GnRH-agonist treatment. None reported any serious side effects or complaints regarding the treatment.Recurrence of symptoms is one of the cardinal features of endometriosis upon discontinuation of medical therapy. For instance, discontinuation of GnRH-agonist treatment is associated with up to a 75% recurrence of symptoms in women with advanced endometriosis within 6 months after stopping GnRH-agonist treatment (9Miller J.D. Shaw R.W. Casper R.F. Rock J.A. Thomas E.J. Dmowski W.P. et al.Historical prospective cohort study of the recurrence of pain after discontinuation of treatment with danazol or a gonadotropin-releasing hormone agonist.Fertil Steril. 1998; 70: 293-296Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Consequently, GnRH-agonist administration for longer periods might be needed to maintain the pain-free status. Loss of BMD that may be irreversible after 6 months of GnRH-agonist treatment is the main limitation for prolonged treatment strategy (5Pickersgill A. GnRH agonists and add-back therapy is there a perfect combination?.Br J Obstet Gynaecol. 1998; 105: 475-485Crossref PubMed Scopus (60) Google Scholar). In addition, other symptoms of hypoestrogenism associated with GnRH-agonist therapy such as hot flushes and vaginal dryness may be severe enough to be a cause of treatment discontinuation.Successful prevention of the hypoestrogenic symptoms induced by GnRH-agonist therapy was achieved without jeopardizing the clinical gains by means of HT add-back in symptomatic endometriosis and uterine leiomyomas as proved by several investigators (10Adashi E.Y. Long-term gonadotrophin-releasing hormone agonist therapy the evolving issue of steroidal "add-back" paradigms.Hum Reprod. 1994; 9: 1380-1397Crossref PubMed Scopus (58) Google Scholar, 11Surrey E.S. Steroidal and nonsteroidal "add-back" therapy extending safety and efficacy of gonadotropin-releasing hormone agonists in the gynecologic patient.Fertil Steril. 1995; 64: 673-685PubMed Google Scholar). However, these reports were for treatment durations 6 months) treatment (5Pickersgill A. GnRH agonists and add-back therapy is there a perfect combination?.Br J Obstet Gynaecol. 1998; 105: 475-485Crossref PubMed Scopus (60) Google Scholar). Concomitant add-back HT during treatment with GnRH-agonists may prevent bone loss and other symptoms of E deficiency while keeping endometriotic implants quiescent (6Barbieri R.L. Gonadotropin-releasing hormone agonists and estrogen-progestogen replacement therapy.Am J Obstet Gynecol. 1990; 162: 593-595Abstract Full Text PDF PubMed Scopus (44) Google Scholar). We previously reported a novel regimen of continuous E with pulsed P as a unique HT (7Casper R.F. Estrogen with interrupted progestin HRT a review of experimental and clinical studies.Maturitas. 2000; 34: 97-108Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). We proved that this HT combination resulted in increased sensitivity to E and progestogen in E-responsive tissues. Consequently, lower doses of E and progestogen may be used for HT with excellent biological effects. We also proved that this combination is effective in maintaining BMD when combined with GnRH-agonist for up to 32 months in the treatment of endometriosis-associated pain and for up to 37 months for the treatment of premenstrual syndrome (8Mitwally M.F. Gotlieb L. Casper R.F. Prevention of bone loss and hypoestrogenic symptoms by estrogen and interrupted progestogen add-back in long-term GnRH-agonist down-regulated patients with endometriosis and premenstrual syndrome.Menopause. 2002; 9: 236-241Crossref PubMed Scopus (42) Google Scholar). The objective of the present study was to examine the effects of extended GnRH-agonist therapy (up to 10 years) coupled with the low-dose E and pulsed progestogen HT regimen for add-back in a group of young women with advanced endometriosis associated with severe chronic pelvic pain. All five patients with stage IV endometriosis included in this study sought medical treatment because of pelvic pain, dyspareunia, and dysmenorrhea associated with endometriosis, which was confirmed by laparoscopy and histopathology. All five patients had undergone multiple laparoscopic surgeries for management of endometriosis before medical management. Alternative therapies were discussed with the patients before starting the use of GnRH-agonist treatment, and the women were informed that GnRH agonist treatment for longer than 6 months was an off-label use of the drug. All patients were nonsmokers. The mean age ± SD of the patients at the beginning of the GnRH-agonist treatment was 30.33 ± 8.52 years. The age ranged from 20 to 40.5 years. The mean follow-up duration ± SD for the patients while on GnRH-agonist treatment was 8.5 ± 2.35 years. After exclusion of pregnancy by determination of a negative serum beta-hCG, GnRH-agonist treatment was started. Patients received leuprolide acetate depot 3.75 mg (Lupron, TAP Pharmaceuticals, Lake Forest, IL) IM monthly until their pelvic pain and dyspareunia had resolved to the point that the women considered themselves subjectively symptom-free (2–3 months). HT add-back was started along with the GnRH-agonist. In all patients, GnRH-agonist injections were started during the luteal phase of the menstrual cycle. The HT regimen consisted of oral administration of 1 mg micronized E2 (Estrace, Roberts Pharmaceutical, Mississauga, Ontario, Canada) daily and 0.35 mg norethindrone (Micronor, Ortho/MacNeil, Raritan, NJ) daily for 2 days alternating with 2 days without progestogen. The women were counseled to maintain adequate calcium intake by diet or calcium supplements. The primary outcome measure of this study was a change in BMD, calculated from measured bone mineral content, because a significant decline in BMD would necessitate a discontinuation of GnRH-agonist treatment. Bone density in the lumbar spine (L1–L4) and in the femoral neck and the total hip region was assessed by dual-energy x-ray absorptiometry (DEXA) (Hologic 1000, Hologic Corporation, Waltham, MA) at 12-month intervals for up to 10 years. The Hologic equipment was calibrated daily using a standard bone "phantom." The coefficient of variation for the BMD calculation was 1%. Secondary outcome measures were bleeding control and pain relief. The BMD results were compared between the start and end of GnRH-agonist treatment by paired two-tailed Student's t-test. The statistical tests were performed with GraphPad Prism Version 3 software (GraphPad Software, San Diego). All patients reported subjective resolution of their endometriosis-associated pain within 2–3 months of starting the GnRH-agonist injections. No patient had return of pelvic pain after HT add-back. After the first 3 months, all women in this study remained amenorrheic with the exception of occasional spotting. The one patient who stopped therapy to get pregnant conceived spontaneously, and both of her pregnancies were uneventful. She delivered spontaneously with normal neonatal outcome on both occasions. The BMD in the lumbar spine, the femoral neck, and the total hip region (Fig. 1) remained relatively stable throughout the follow-up period for each patient enrolled in the study. None of the patients lost a clinically significant percentage of BMD during the study (i.e., >3%). For the group as a whole, there was no significant difference between the mean (±SD) bone density in the lumbar spine, the femoral neck, and the total hip region at the end of treatment compared with the beginning (baseline BMD) of GnRH-agonist treatment. None reported any serious side effects or complaints regarding the treatment. Recurrence of symptoms is one of the cardinal features of endometriosis upon discontinuation of medical therapy. For instance, discontinuation of GnRH-agonist treatment is associated with up to a 75% recurrence of symptoms in women with advanced endometriosis within 6 months after stopping GnRH-agonist treatment (9Miller J.D. Shaw R.W. Casper R.F. Rock J.A. Thomas E.J. Dmowski W.P. et al.Historical prospective cohort study of the recurrence of pain after discontinuation of treatment with danazol or a gonadotropin-releasing hormone agonist.Fertil Steril. 1998; 70: 293-296Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Consequently, GnRH-agonist administration for longer periods might be needed to maintain the pain-free status. Loss of BMD that may be irreversible after 6 months of GnRH-agonist treatment is the main limitation for prolonged treatment strategy (5Pickersgill A. GnRH agonists and add-back therapy is there a perfect combination?.Br J Obstet Gynaecol. 1998; 105: 475-485Crossref PubMed Scopus (60) Google Scholar). In addition, other symptoms of hypoestrogenism associated with GnRH-agonist therapy such as hot flushes and vaginal dryness may be severe enough to be a cause of treatment discontinuation. Successful prevention of the hypoestrogenic symptoms induced by GnRH-agonist therapy was achieved without jeopardizing the clinical gains by means of HT add-back in symptomatic endometriosis and uterine leiomyomas as proved by several investigators (10Adashi E.Y. Long-term gonadotrophin-releasing hormone agonist therapy the evolving issue of steroidal "add-back" paradigms.Hum Reprod. 1994; 9: 1380-1397Crossref PubMed Scopus (58) Google Scholar, 11Surrey E.S. Steroidal and nonsteroidal "add-back" therapy extending safety and efficacy of gonadotropin-releasing hormone agonists in the gynecologic patient.Fertil Steril. 1995; 64: 673-685PubMed Google Scholar). However, these reports were for treatment durations <12 months. Mitwally et al. reported much longer treatment durations without hypoestrogenic symptoms and with a stable BMD after adopting continuous E and pulsed P add-back therapy in patients with endometriosis (8Mitwally M.F. Gotlieb L. Casper R.F. Prevention of bone loss and hypoestrogenic symptoms by estrogen and interrupted progestogen add-back in long-term GnRH-agonist down-regulated patients with endometriosis and premenstrual syndrome.Menopause. 2002; 9: 236-241Crossref PubMed Scopus (42) Google Scholar). Here we report that stable BMD with HT add-back is reproducible for up to 10 years of continuous therapy. Continuous E with pulsed progestogen for add-back therapy may increase the efficacy of both components at low doses by using E and P receptor fluctuations. We have shown that the pulsed progestogen therapy maintained steroid receptors and improved their sensitivity to E in E-responsive tissues (7Casper R.F. Estrogen with interrupted progestin HRT a review of experimental and clinical studies.Maturitas. 2000; 34: 97-108Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). In this regimen, progestogen acts synergistically with E, resulting in a better impact on BMD than E alone (12Vanin C.M. MacLusky N.J. Grynpas M.D. Casper R.F. The effect of three hormone replacement regimens on bone density in the aged ovariectomized rat.Fertil Steril. 1995; 63: 643-651PubMed Google Scholar). Moreover, norethindrone (which has some androgenic activity) could have an independent positive impact on BMD as it was proven that androgens have a positive effect on BMD (13Lundon K.M. Jayo M.J. Register T.C. Dumitriu M. Grynpas M.D. The effect of androstenedione/estrone supplementation on cortical and cancellous bone in the young intact female monkey a model for the effects of polycystic ovarian disease on the skeleton?.Osteoporos Int. 2000; 11: 778-779Crossref PubMed Scopus (9) Google Scholar). The long-term use of HT could be argued against based on the results of the Women's Health Initiative (WHI) trial that was stopped prematurely after showing that the overall health risks exceeded benefits after the use of combined E plus progestin for an average 5.2 years (14Rossouw J.E. Anderson G.L. Prentice R.L. LaCroix A.Z. Kooperberg C. Stefanick M.L. et al.Risks and benefits of estrogen plus progestin in healthy postmenopausal women principal results From the Women's Health Initiative randomized controlled trial.JAMA. 2002; 288: 321-333Crossref PubMed Scopus (13852) Google Scholar). However, there are many differences between our proposed approach and that of the WHI trial. First, the patient population of the WHI trial was comprised of postmenopausal women aged 50–79 years, whereas our population is much younger, with an age range of 20–40.5 years at the initiation of therapy. Second, we used a very low dose hormonal combination, compared with the conjugated equine Es, 0.625 mg daily, plus medroxyprogesterone acetate, 2.5 mg daily, that was used in the WHI study. In fact, the women in our study, with ovarian function inhibited by GnRH-agonist, are exposed to less E with the HT add-back than they would be during spontaneous menstrual cycles, hence the quiescence of the endometriosis. We would therefore suggest that these women may actually have a lower risk of breast cancer than those in the general population of the same age because of lower overall exposure to E. In conclusion, a low-dose pulsed progestogen administered with continuous E for add-back therapy is effective when combined with GnRH-agonist for the treatment of chronic pelvic pain in patients with advanced endometriosis. Patients were followed for up to 10 years with maintained clinical improvement of chronic pelvic pain and maintained BMD and without major health risks.