{"paper_id":"38f9ad98-55ad-4c51-a839-f73dc3776698","body_text":"Gynecol Surg (2004) 1:107–109\nDOI 10.1007/s10397-004-0018-z\nORIGINAL ARTICLE\nNiki Baxter · Sean Duffy\nThe effects of a 3-month depot preparation of leuprorelin acetate\non pain symptoms, bone mineral density and hormone levels in women\nwith endometriosis—preliminary data analysis\nPublished online: 17 April 2004\n/C23 Springer-Verlag Berlin / Heidelberg 2004\nAbstract The purpose of this study was to determine the\neffectiveness of Prostap 3 M, a 3-month depot preparation\nof a gonadotrophin-releasing hormone agonist, in the re-\nlief of pelvic pain symptoms caused by endometriosis and\nto assess its effects on bone mineral density. A prospec-\ntive cohort study was carried out at St. James’s University\nHospital, Leeds, and included 13 women with laparo-\nscopically diagnosed endometriosis ( n=13). Baseline in-\nvestigations were performed to measure pain symptoms,\nbone mineral density and oestradiol levels. The women\nwere then treated with 7 months of Prostap 3 M. At the\nend of treatment, the investigations were repeated. After\nthe 7-month treatment phase, there was a statistically\nsignificant reduction in all the pain subset scores. The\ncontinuous GnRHa therapy resulted in a fall of serum\noestradiol levels into the post-menopausal range. After\ntreatment with Prostap 3 M, women with endometriosis\nshowed a mean decrease of 5.57% in BMD of the lumbar\nspine and of 3.47% in femoral BMD. Both these falls are\nstatistically significant. Prostap 3 M is effective in re-\nlieving the painful symptoms associated with endometri-\nosis, and the continuous therapy over 7 months does in-\ndeed induce a hypo-oestrogenic state. However, the ef-\nfects of Prostap 3 M on bone mineral density appear to be\nmore detrimental than seen with monthly preparations.\nKeywords Endometriosis · Pelvic pain · Gonadotrophin-\nreleasing hormone agonists\nIntroduction\nChronic pelvic pain (CPP) is defined as pain that has been\npresent for 6 months or longer and is a common cause of\nreferral to gynaecology clinics. The most common cause\nfound for the pain is endometriosis, which is characterised\nby ectopic endometrial tissue lying within the pelvis.\nThere are many theories about the cause of endometriosis,\nincluding Sampson’s theory of “retrograde menstruation”.\nDiagnostic laparoscopy is the ‘gold standard’ investiga-\ntion for endometriosis and the only way to make a de-\nfinitive diagnosis of the condition. Laparoscopy may re-\nveal the presence of endometrial deposits in the form of\nblack spots, red polyps, white scarring, adhesions, en-\ndometriomas, etc.\nEndometriosis may be treated medically or surgically.\nHormone treatment of endometriosis is based on the theory\nthat endometriotic lesions require oestradiol to continue\ngrowing as oestrogen receptors are present in endometriotic\ndeposits. Therefore, by inducing a hypooestrogenic state,\nregression of the disease should occur. Gonadotrophin-re-\nleasing hormone agonists (GnRHa) were discovered in the\nearly 1970s and first used clinically in the 1980s. Since\nthen they have become one of the mainstay treatments for\nendometriosis. They act at a pituitary level, causing a fall in\nserum FSH and LH levels that in turn leads to a decrease in\novarian oestrogen production. GnRHa have been proved to\nbe effective in the management of the painful symptoms\nassociated with endometriosis [1].\nLeuprorelin acetate is a widely used GnRHa in the\nmanagement of endometriosis pain. At present, in the UK,\nit is licensed to be used in gynaecology in its monthly\nform (3.75 mg, Prostap SR, Wyeth). Several trials have\nshown a 6-month treatment of Prostap SR (six doses)\nto be highly effective for endometriosis-related pain.\nWheeler et al. [2] reported that 55% of women with en-\ndometriosis (n=128) reported complete resolution of pain\nafter Prostap SR treatment over 24 weeks. However, at\nthe end of 6 months of therapy with a continuous GnRHa,\nreductions of 2.9 to 5.6% in the bone mineral density of\nthe lumbar spine have been reported [3, 4, 5].\nN. Baxter\nDepartment of Obstetrics and Gynaecology,\nJessop Wing,\nTree Root Walk, Sheffield, S10 2SF, UK\nS. Duffy\nDepartment of Obstetrics and Gynaecology,\nSt James’s University Hospital,\nBeckett Street, Leeds, LS9 7TF, UK\n12 Alexandra Gardens, Nether Edge, Sheffield, S11 9DQ, UK\nN. Baxter (\n))\ne-mail: nikibaxter@btinternet.co\n\nProstap 3 M is a new 3-monthly depot preparation\nof leuprorelin acetate, 11.25 mg. It is administered in a\nsimilar way to Prostap SR, either intramuscularly or sub-\ncutaneously. The advantages of this preparation over\nProstap SR are that during a 6-month treatment period,\nonly two injections would be needed, resulting in fewer\nvisits to hospital for the patient and therefore cutting\ndown on clinic waiting times. Our preliminary studies\nhave shown Prostap 3 M to be as effective as Prostap SR\nin reducing painful symptoms over a 6-month therapeutic\nphase. However, its possible adverse effects are as yet\nunknown. This preliminary trial investigates the effec-\ntiveness with regard to pain and the bone demineralisation\neffects of Prostap 3 M and considers the results in light of\navailable data on Prostap SR.\nMaterials and methods\nThirteen women were recruited into this trial. All had initially\npresented to the gynaecology out-patient clinic at St James’s Uni-\nversity Hospital, Leeds, Yorkshire, complaining of chronic pelvic\npain for at least 6 months. Each underwent a diagnostic laparoscopy\nunder a general anaesthetic and all were found to have mild en-\ndometriosis. After being fully informed about the trial and ob-\ntaining written consent, each woman had a Dual Energy X-ray\nAbsorptiometry (DEXA) scan to measure baseline bone mineral\ndensity in the lumbar spine vertebrae 2–4 and neck of the femur. A\nvenous blood sample was taken to measure serum oestradiol levels.\nAll of them then completed a simple 0–3 baseline questionnaire,\nwhereby they scored their symptoms of dysmenorrhoea, dyspare-\nunia and pelvic pain (where 0= no pain and 3= severe pain). The\nwomen were then treated with a 7-month course of Prostap (a\n1-month dose of 3.75 mg leuprorelin acetate to establish tolerance,\nfollowed by two 3-month injections of 11.25 mg). At the end of the\ntreatment phase, the pain questionnaire, DEXA scan and blood test\nwere repeated. Cross-calibration of the DEXA equipment was\nperformed to ensure quality control. All the results were entered\ninto a database and statistically analysed. Significance was assumed\nfor P values of less than 0.05.\nResults\nComplete data have been obtained on 13 white women.\nThe ages ranged form 22 to 46 years with a mean of\n32.7 years. All the women had grade I or II endometriosis\non laparoscopy, using the American Fertility Society\nclassification. The mean spine BMD at the start of the\nstudy was 1.261 g/cm\n2 and the mean femur BMD was\n1.043 g/cm 2. Baseline mean pain scores were as follows:\ndysmenorrhoea 2.31€1.11, dyspareunia 1.85€0.90 and\nnon-cyclical pelvic pain 2.08€0.76. All women had serum\noestradiol levels within the normal pre-menopausal range.\nWhen the group was subdivided into endometriosis\ngrades I or II, using the revised American Fertility Society\nclassification, there was no significant difference between\nthe two subsets with regard to the baseline characteristics\nof body mass index (BMI), age, spinal or femoral BMD,\nor serum oestradiol levels. Grade of endometriosis also\nhad no significant influence on baseline pain scores.\nAfter the 7-month treatment phase, there was a sta-\ntistically significant reduction in all the pain subset scores\n(Fig. 1). There was a mean decrease in score of 2.08 for\ndysmenorrhoea, 1.0 for dyspareunia and 1.23 for non-\nmenstrual pain (Fig. 1).\nThe mean spine BMD post-treatment was 1.19€0.15.\nThis was an overall 5.57% decrease. The mean neck of\nfemur BMD dropped to 1.04€0.15, indicating a percent-\nage loss of 3.47%. A paired t-test showed that the de-\ncreases in bone mineral density in both the spine and the\nneck of the femur after treatment with Prostap 3 M were\nstatistically significant (Fig. 2).\nThe decrease in serum oestradiol levels was also sta-\ntistically significant after treatment. At the start of the\nstudy, the mean serum oestradiol value was 226.5 pmol/l.\nAfter 7 months of Prostap 3 M, the mean fell to 94.3 pmol/\nl, which is in the post-menopausal range. The grade of\nendometriosis did not have any statistically significant in-\nfluence on the changes in pain score, BMD or oestradiol\nlevels.\nDiscussion\nIt has been suggested that endometriosis is associated\nwith reduced bone mass in the periphery [6], possibly\nsecondary to immune dysfunction. Other studies have\nshown that women with endometriosis have bone mineral\nFig. 1 Changes in mean pain scores after treatment with Prostap\n3M\nFig. 2 Changes in BMD after Prostap 3M\nTable 1 Differences in mean bone mineral density (g/cm 2) of the\nneck of femur between white women with and without endome-\ntriosis\nNo endometriosis\n(Looker et al. [11])\nEndometriosis\n(Our data)\n20–29 years 0.858 1.145\n30–39 years 0.825 1.002\n40–49 years 0.791 0.954\n108\n\ndensity levels within the range normal for age [7, 8, 9,\n10].\nLooker et al. [11] produced normal ranges of bone\nmineral density of the neck of femur based on their data\nfrom normal US adults. They took a nationally repre-\nsentative sample and produced tables divided into groups\nby sex, ethnicity and age. We compared our baseline\nmeasurement results of the mean BMD of the neck of\nfemur in white women with endometriosis to their figures\non normal healthy white women (Table 1).\nIn a similar way to normal healthy women, women\nwith endometriosis showed a decreasing femoral BMD\nwith age. However, we found that endometriosis sufferers\nappear to have an increased mean femoral BMD com-\npared with normal values, and these differences are sta-\ntistically different ( P=0.02). The grade of endometriosis\ndoes not significantly influence the BMD.\nOur preliminary data shows that Prostap 3 M is an\neffective treatment for the pain caused by endometriosis.\nThe Gestrinone Italian Study Group [12] looked at the\neffectiveness of the monthly preparation of leuprorelin\nacetate, Prostap SR, in similar patients and, comparing\nour results with their data, Prostap 3 M appears to be as\neffective as Prostap SR in terms of symptom relief\n(P>0.05; Table 2).\nAs expected, the continuous GnRHa therapy resulted in\na hypo-oestrogenic state, and this was reflected in the fall\nof serum oestradiol levels into the post-menopausal range.\nAfter treatment with Prostap 3 M, women with endo-\nmetriosis showed a mean decrease of 5.57% in BMD of\nthe lumbar spine and of 3.47% in femoral BMD. Both\nthese falls are statistically significant. Dlugi et al. [13]\nreported a mean loss of 3.6% in spinal bone mineral\ndensity in 15 women with endometriosis who had been\ntreated with Prostap SR for 6 months. Hornstein et al. [14]\nalso treated their endometriosis patients with Prostap SR\nand found a BMD fall of 3.2€1.8% in the lumbar spine at\n6 months. Our results show a mean lumbar spine BMD\ndecrease of 5.57%, which suggests that the use of Prostap\n3 M is more detrimental than Prostap SR in terms of bone\ndemineralisation.\nConclusion\nProstap 3 M appears to be as effective as Prostap SR in\nrelieving the painful symptoms associated with endo-\nmetriosis. As expected, the continuous therapy over\n7 months induced a hypo-oestrogenic state. The effects of\nProstap 3 M on bone mineral density seem to be more\ndetrimental than Prostap SR. A randomised controlled\ntrial to assess the benefits of concurrent hormone re-\nplacement therapy with Prostap 3 M is now in progress.\nReferences\n1. Henzl MR (1988) Gonadotrophin-releasing hormone (GnRH)\nagonists in the management of endometriosis: a review. Clin\nObstet Gynecol 31:840–856\n2. Wheeler JM, Knittle JD, Miller JD (1992) Depot leuprolide\nversus danazol in treatment of women with symptomatic en-\ndometriosis. I. Efficacy results. Am J Obstet Gynecol 167:\n1367–1371\n3. Scialli AR, Jestila KJ, Simon JA (1993) Leuprolide acetate and\nbone mineral density measured by quantitative digitized radi-\nography. Fertil Steril 59:674–676\n4. Surrey ES, Judd HL (1992) Reduction of vasomotor symptoms\nand bone mineral density loss with combined norethindrone and\nlong-acting gonadotrophin-releasing hormone agonist therapy\nof symptomatic endometriosis: a prospective randomised trial.\nJ Clin Endocrinol Metab 72:558–563\n5. Finkelstein JS, Klibanski A, Schaeffer EH, Hornstein MD,\nSchiff I, Neer RM (1994) Parathyroid hormone for the pre-\nvention of bone loss induced by estrogen deficiency. N Eng J\nMed 331:1618–1623\n6. Comite F, Delman M, Hutchinson-Williams K, DeCherney AH,\nJensen P (1989) Reduced bone mass in reproductive-aged\nwomen with endometriosis. J Clin Endocrinol Metab 69:837–\n842\n7. Ulrich U, Murano R, Skinner M, Yin H, Chestnut CH III (1998)\nWomen of reproductive age with endometriosis are not osteo-\npenic. Fertil Steril 69:821–825\n8. Lane N, Baptista J, Snow-Harter C (1991) Bone mineral density\nof the lumbar spine in endometriosis subjects compared to an\nage-similar control population. J Clin Endocrinol Metab\n72:510–514\n9. Lane N, Baptista J, Orwoll E (1991) Bone mineral density of\nthe lumbar spine in women with endometriosis. Fertil Steril\n55:537–542\n10. Dochi T, Lees B, Sidhu M, Stevenson JC (1994) Bone density\nand endometriosis. Fertil Steril 61:175–177\n11. Looker AC, Wahner HW, Dunn WL, Calvo MS, Harris TB,\nHeyse SP, Johnston CC, Lindsay R (1998) Updated data on\nproximal femur bone mineral levels of US adults. Osteoporos\nInt 8:468–489\n12. The Gestrinone Italian Study Group (1996) Gestrinone versus a\ngonadotropin-releasing hormone agonist for the treatment of\npelvic pain associated with endometriosis: a multicenter, ran-\ndomized, double-blind study. Fertil Steril 66:911–919\n13. Dlugi AM, Miller JD, Knittle J, Lupron Study Group (1990)\nLupron depot (leuprolide acetate for depot suspension) in the\ntreatment of endometriosis: a randomised, placebo-controlled,\ndouble-blind study. Fertil Steril 54:419–427\n14. Hornstein MD, Surrey ES, Weisberg GW, Casino LA (1998)\nLeuprolide acetate depot and hormonal add-back in endome-\ntriosis: a 12-month study. Lupron Add-Back Study Group.\nObstet Gynecol 91:16–24\n15. Blake GM, Fogelman I (2003) The reporting of DXA scans.\nOsteoporos Rev 11:4–6\nTable 2 A comparison of\nProstap SR and Prostap 3 M\nwith regard to reduction in pain\nas a percentage\n(Leuprorelin acetate, 3.75 mg [12])\nProstap SR\n(Leuprorelin acetate, 11.25 mg)\nProstap 3M\nDysmenorrhoea 98.2% 88.5%\nDyspareunia 70.5% 73.1%\nNon-menstrual pain 70.2% 55.1%\n109","source_license":"CC0","license_restricted":false}