t Funded by a grant from TAP Pharmaceuticals, Deerfield, Illinois.

Transcription

1 FERTILITY AND STERILITY Vol. 63, No.4, April 1995 Copyright 1995 American Society for Reproductive Medicine Printed on acid-free paper in U. S. A. Prolonged gonadotropin-releasing hormone agonist treatment of symptomatic endometriosis: the role of cyclic sodium etidronate and low-dose norethindrone "add-back" therapy*t Eric S. Surrey, M.D.:!: Barbara Voigt, R.N.P. Nicole Fournet, M.D. Howard L. Judd, M.D. Division of Reproductive Medicine, Department of Obstetrics-Gynecology, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California Objective: To examine the safety and efficacy of combining cyclic sodium etidronate and lowdose norethindrone with a long-acting GnRH agonist (GnRH-a) for prolonged therapy of symptomatic endometriosis. Design: Prospective randomized open label study. Setting: Tertiary care university-affiliated reproductive medicine program. Patients: Nineteen regularly cycling women with laparoscopically diagnosed symptomatic endometriosis and 18 regularly cycling untreated controls without endometriosis. Interventions: All patients received a depot preparation of the GnRH -a leuprolide acetate 1M monthly for 48 weeks. Group I patients (n = 10) received supplemental sodium etidronate cycled with calcium carbonate as well as.5 mg norethindrone daily. Group II patients (n = 9) received only supplemental 10 mg norethindrone daily. Group III volunteers (n = 18) were untreated and followed for bone density changes. Main Outcome Measures: Disease extent at follow-up laparoscopy; pain, vasomotor, and vaginal symptom scores; bone mineral density (serial dual-energy roentgenogram absorptiometry scans); serum estrogens, lipids, and glucose and insulin response to glucose challenge. Results: Painful symptoms and extent of endometriosis were reduced in both treatment groups. Despite maintenance of a chronically hypoestrogenic state for 48 weeks, no changes in bone density over time or in comparison to group III untreated controls were noted. Similarly, no evidence of significant vasomotor symptoms were reported in either treatment group. However, adverse changes over time in circulating low-density lipoprotein (LDL) cholesterol and apolipoprotein Al levels as well as the ratio of high-density lipoprotein to LDL were noted only in group II. Conclusions: The combination of cyclic sodium etidronate and low-dose norethindrone with a long-acting GnRH -a served to safely prolong medical therapy of symptomatic endometriosis. Clinical efficacy was preserved while prophylaxis against significant hypoestrogenic side effects was achieved. Fertil SteriI1995;63: Key Words: Endometriosis, GnRH agonist, sodium etidronate, norethindrone Received February 8, 1994: revised and accepted October 14, * Presented in part at the 40th Annual Meeting of the Society for Gynecologic Investigation, Toronto, Ontario, Canada, March 31 to April 3, t Funded by a grant from TAP Pharmaceuticals, Deerfield, Illinois. :j: Reprint requests and current address: Eric S. Surrey, M.D., Center for Reproductive Medicine and Surgery, 9675 Brighton Way, Suite 40, Beverly Hills, California 9010 (FAX: ). Current address: Nicole Fournet, M.D., Department of Obstetrics-Gynecology, University of Geneva School of Medicine 111, Geneva 14, Switzerland. Vol. 63, No.4, April 1995 Surrey et al. GnRH agonist and etidronate 747

2 By inducing a chronic hypoestrogenic state, long-acting GnRH agonists (GnRH-a) effectively reduce painful symptoms and extent of implants associated with endometriosis (1-3). Although most patients achieve prolonged symptom relief after completion of the 6-month course of therapy currently recommended, a more refractory subset will experience rapid symptom recurrence (1, 3). Such individuals pose a significant management problem and may derive additional relief from prolonged GnRH-a administration. However, the reversible bone mineral density loss and vasomotor symptoms that result may limit compliance and safety for extended use (, 4). Those patients with refractory pelvic pain requiring longer-term therapy must currently be treated with other modalities. In an effort to maintain the effectiveness of these agents while eliminating hypoestrogenic side effects, various steroidal "add-back" regimes have been proposed. Norethindrone, a 19-nortestosterone-derived progestin, has been shown to suppress vasomotor symptoms and bone mineral density loss when administered to postmenopausal women in the absence of estrogen replacement (5, 6). We demonstrated previously that patients with symptomatic endometriosis experienced reduction in pain and extent of implants when administered norethindrone in maximal mean daily doses of.04 mg in conjunction with a highly potent GnRH-a (7). Although only rare vasomotor symptoms were noted by these patients, lumbar spine bone mineral density reversibly decreased. When supplemental norethindrone doses were increased to 10 mg daily in a placebo-controlled 6-month randomized masked trial, not only was symptomatic disease suppressed but vasomotor symptoms and bone loss were significantly reduced in comparison to patients receiving agonist alone (8). Unfortunately, undesirable but reversible alterations in cholesterol sub fractions were noted. The organic bisphosphonate, sodium etidronate, inhibits osteoclast activity and decreases the incidence of osteoporotic fractures in postmenopausal women with minimal side effects when given in a cyclic fashion with calcium carbonate (9, 10). This agent has not been used previously in women of reproductive age as a prophylaxis against medically induced hypoestrogenic bone mineral density loss. We recently reported encouraging preliminary data on the effects of combining cyclic sodium etidronate with low-dose norethindrone from an interim analysis of 15 symptomatic endometriosis patients administered a long-acting GnRH-a during a 4- week trial (11). In an effort to prolong safe and effective medical management of endometriosis in patients with severe pelvic pain, the results of an enlarged prospective randomized clinical investigation of this "add-back" regime extended over 48 weeks are presented. MATERIALS AND METHODS Nineteen patients with laparoscopically documented symptomatic endometriosis were entered in this 48-week prospective clinical trial. All patients had undergone a diagnostic laparoscopy performed during the follicular phase within 3 months of entering the protocol to document the presence of endometriosis. No disease was resected or ablated during this procedure. The findings were recorded on videotape in a standardized fashion and coded for independent review. Patients with less than four visible implants or with ovarian endometriotic cysts> 3 cm were excluded. After giving informed consent as approved by the Institutional Review Board of Cedars-Sinai Medical Center, patients were randomized into one of two treatment groups. All were administered a depot preparation of 3.75 mg 1M of the GnRH-a leuprolide acetate (Lupron Depot; TAP Pharmaceuticals, Deerfield, IL) every 8 days for 48 weeks with injections initiated during the midluteal phase. Patients randomized to group I (n = 10) self-administered 400 mg/d oral sodium etidronate (Didronel; Norwich-Eaton, Norwich, NY) for 14 days alternating with 500 mg/d oral calcium carbonate (Os Cal; Marion Merrell Dow, Kansas City, MO) for 4 days. This cycle was repeated consecutively six times during the investigation. Patients also received.5 mg/d oral norethindrone (Norlutin; Parke-Davis, Morris Plains, NJ). Patients randomized to group II (n = 9) received only 10 mg/d norethindrone in combination with the agonist throughout the 48-week trial period. These protocols are summarized graphically in Figure 1. Eighteen regularly cycling women without endometriosis and receiving no medications served as controls for changes in bone mineral density (group III). These women were matched by age, race, body mass index, and tobacco use history to the patients in groups I and II. No calcium supplements were permitted to patients in groups II or III. Dietary calcium intake was not controlled. All subjects had a history of regular menstrual cycles and had re- 748 Surrey et al. GnRH agonist and etidronate Fertility and Sterility

3 Group I N=10 I GnRHa 3.75 mg 1M q 8 days I Nore1hlndrone.5 mg po qd le 1 Ca+ lei Ca lei Ca lei Ca lei Ca lei Ca Group II I GnRHa 3.75 mg 1M q 8 days N=9 I Norethindrone 10 mg po qd I I r!! I! I I I t I I I I!,!!!! I o Week Figure 1 Graphic display of therapeutic regimes for the two treatment groups. * E, oral sodium etidronate, 400 mg/d X 14 days; + Ca, oral calcium carbonate, 500 mg/d X 4 days. ceived no hormone preparations in the 30 days before entering the study. Baseline clinical data are presented in Table 1. Age and body mass indexes were similar among the three groups. The majority of patients in groups I and II previously had undergone conservative surgery and/or received oral contraceptives, danazol, progestins, or GnRH -a as medical therapy for their disease. Patients were not randomized based upon stage of endometriosis at baseline laparoscopy. A second-look laparoscopy was performed 4 weeks after completion of therapy with findings recorded. In an effort to eliminate observer bias, coded videotapes of before and after treatment laparoscopies were reviewed by two skilled reproductive surgeons not associated with the patients, study design, or the surgeries. The findings were scored by the revised American Fertility Society (AFS) endometriosis classification (1). Modified scores reflecting extent of implants alone were also obtained by subtracting values attributed to adhesions. Painful symptoms, rated in severity from 0 to 5, were recorded in daily diaries by patients in both treatment groups beginning 4 weeks before initiation of therapy and continuing for 8 weeks after completion of therapy. Cumulative lunar monthly scores were calculated allowing a maximal possible pain score of 140. In addition, patients reported hot flush frequency and intensity as well as vaginal symptoms such as dyspareunia and dryness in daily diaries. Lunar monthly scores for these parameters were calculated as described previously (8, 11). Subjective vasomotor symptoms were correlated with elevations in forefinger skin temperature ob- tained in a temperature-controlled environment during a 6-hour period at weeks 0, 4, 4, and 48 using previously reported techniques (8). Serum was obtained at 8:00 A.M. before administration of medications during visits at weeks 0, 4, 8, 1,4, 36, 48, and post-therapy week 8 (week 56) in both treatment groups and at weeks 0, 4, and 48 in untreated controls. Circulating estrone (E}) and E levels were measured using established RIA techniques (11). After an overnight fast, serum levels of total cholesterol and triglycerides as well as lipoprotein and apolipoprotein subfractions were assessed in treated patients at baseline, 1-week intervals during therapy, and 8 weeks post-therapy using previously reported methods (8, 1). In addition,.fasting glucose and insulin tolerances were assessed at weeks 0, 4, 48, and 56. Serum was obtained 0, 30, 60, and 90 minutes after administration of a 75 mg oral glucose load. Bone mineral density of the second through fourth lumbar vertebrae was measured in all subjects at weeks 0, 4, and 48 by dual-energy roentgenogram absorptiometry scanning using a Hologic QDR-1000 Densitometer (Hologic, Inc., Waltham, MA) (13). Scans were repeated 4 weeks after completion of therapy (week 7) in group I and II patients. All studies were performed in duplicate. The mean ± SD coefficient of variation for these measurements was calculated to be 0.5% ± 0.41%. Thus, a >1.34% change in bone density (mean ± SD) was considered to be of clinical significance. One patient assigned to group II dropped out of Table 1 Baseline Clinical Data Group I (n = 10) Group II (n = 9) Group III (n = 18) Age (y)* 3.8 ± ± ± 1. Body mass index* (kg/m ).5 ± ± 1..5 ± 0.9 No. of patients at baseline endometriosis staget I II III IV No. of prior therapies Surgery Progestins Oral contraceptives Danazol gnrh-a Values are means ± SEM. t Revised AFS endometriosis staging system (1) o Vol. 63, No.4, April 1995 Surrey et al. GnRH agonist and etidronate 749

4 l the study after week 4 as a result of progressive vaginal bleeding and localized uterine pain due to a degenerating uterine fundal leiomyoma. This patient was not replaced and data derived from her experience were included in the clinical data presented in Table 1 but were excluded from other statistical analyses. The data were analyzed using paired and grouped Student's t-tests, Mann-Whitney U-tests, repeated measures analyses of variance, and Wilcoxon signed rank tests where appropriate. Glucose and insulin tolerance was assessed by comparison of total areas under the curve. A P value < 0.05 was considered to be statistically significant unless otherwise stated. RESULTS The effect of 48 weeks of therapy on the extent of endometriotic implants is displayed for both treatment groups in Figure. As assessed by unbiased observers, total and modified endometriosis scores were reduced dramatically (P < 0.05) for patients receiving both "add-back" regimes. The extent of improvement from baseline in the absence of surgical ablation was similar between the two groups. This decrease in endometriotic implants also was reflected by significant improvement in monthly pain scores among patients in both groups (Fig. 3). These values were maximally suppressed by week 1 and remained depressed throughout the 48-week course of therapy as well as for ~8 weeks thereafter. The extent of these changes over time was similar between the two treatment groups (P = 0.49). Levels of circulating estrogens were suppressed to a castrate range within 4 weeks of initiation of 30 ~ (; ell 0 (f) u...: 10,, Pre Post Pre Post Modified (Implants Only) Group II Pre Post Pre Post Figure Total and modified revised AFS endometriosis scores (1) derived from independent observers' review of coded videotapes before and 4 weeks after completion of therapy for patients in both treatment groups. Modified scores represent points attributable to implants alone. * P < 0.05 versus prether apy; tpercent change in scores from pretherapy laparoscopies, :j:p > 0. versus Group 1. therapy in both treatment groups. Mean ± SEM serum EI levels measured after 4 weeks in the two treatment groups were 16 ± pg/ml (group I) and 19 ± 3 pg/ml (group II). Mean ± SEM E levels assessed at the same data point were 9 ± 1 pg/ml (group I) and 1 ± 1 pg/ml (conversion factor to SI units, 3.671) (group II). Throughout the 48 weeks of therapy, no escape to this suppression was noted among patients receiving either of the two add-back regimes (P < 0.01 change over time versus week 0 for groups I and II). Control subjects in group III maintained relatively constant circulating estrogen levels during the investigational period, which did not change significantly over time. Mean vasomotor symptom scores based upon perceived hot flush frequency and intensity were minimized among patients in both treatment arms (Fig. 4, top). No significant changes from baseline were noted over time. These findings were confirmed by serial objective hot flush monitoring. Of all patients studied, only one patient in group Idemonstrated any measurable signs of vasomotor instability (0.3 hot flushes per hour at week 48 only). Similarly, no changes in monthly vaginal symptom scores representing pain, dryness, or dyspareunia were noted for patients in either group during the 48-week trial (Fig. 4, bottom). The results of the effects of these add-back regimes on lumbar spine bone mineral density are presented in Table. No changes in bone density were noted among the untreated controls. Despite persistent suppression of ovarian function for 48 weeks, no clinically significant changes in bone density were noted within either of the two treatment groups during or after completion of treatment. Although a slight increase was noted after 4 weeks of therapy in group I patients receiving supplemental cyclic etidronate and low-dose norethindrone, changes in bone density among the treated groups were no different than those of matched controls. Changes in mean levels of circulating lipids, lipoproteins, as well as glucose and insulin responses to oral glucose challenge in the two treatment groups are displayed in Table 3. Patients receiving both doses of norethindrone experienced some depression of serum high-density lipoprotein (HDL) cholesterol subfractions over time, the extent of which was greater for group II patients receiving higher 10 mg daily doses. However, persistent increases in levels, increases in the LDL:HDL ratio, as well as decreases in apolipoprotein Al levels were noted over time only in group II patients. No changes in 750 Surrey et al. GnRH agonist and etidronate Fertility and Sterility

5 80~ ~ o to) en c 40 'iii a.. Group I Group II * p<0.01 change over time vs. Week t f>o~hhlmlpy:.11:<.q.()05.vii, \"IlIel<O.... T Post-therepy: p< vs. week 0 * Figure 3 Lunar monthly endometriosis painful symptom scores derived from daily diaries for both treatment groups at baseline, during therapy, and 8 weeks after therapy. 0 O~---,---,---,---,--~--,---,---,--,---,---,---,------~ o Week 56 (Post-Tharapy) serum glucose or insulin responses to oral glucose challenges were appreciated in either add-back group during the course of therapy. Patients in both add-back groups experienced some cumulative weight gain over the course oftherapy (group I, 3.4 ± 1.0 kg; group II, 7.7 ± 1.7 kg; P < 0.1 for each group versus week 0). However, the A ! <.> U) 500 S E ~ 00 B Grou.p _ _.... Change over time va Week 0: NS o Week 100'~ _. II 8 80 rj) E 60 ~,., E rj) 40 Cii c C. 0 ~... ~. (3roup.l (3rou~.I.1... ~ C;~!I!'.g~.ov~nl!l)~.vs.w!!~~.Q:N~.... t NS V8 Group II _----_.. ~t... O~~~~~~~~~~~~~ o Week Figure 4 Mean ± SEM vasomotor (A) and vaginal (B) symptom scores derived from daily diaries at baseline and throughout the course of therapy for patients in both treatment groups. As part of the references, peak mean ± SEM and vaginal symptom scores calculated in a similar fashion for 10 previously described women receiving the same GnRH-a alone were 1,056 ± 47 and 44.9 ± 11.3, respectively (8). extent of weight gain was significantly less in group I patients receiving.5 mg daily norethindrone doses than in group II patients receiving higher 10 mg supplemental daily doses (P < 0.05). Control patients in group III failed to demonstrate any significant gain in weight during a similar observation period (0.9 ± 0.5 kg; P > 0.05). Weight changes recorded in groups I and II were significantly greater than those in group III (P = 0.0 and P < , respectively), With the exception ofthe previously mentioned dropout from group II, no other untoward side effects were experienced. DISCUSSION In this investigation, we have demonstrated that GnRH -a therapy for symptomatic endometriosis can be safely extended to ~48 weeks with the addition of either of two add-back regimes. Suppression of endometriotic implants and associated painful symptoms was unaffected by the addition of either high-dose norethindrone or cyclic sodium etidronate and low-dose norethindrone. Despite maintenance of a chronic hypoestrogenic state without escape throughout the course of the clinical trial in both groups, vasomotor symptoms were ameliorated and bone density loss was virtually eliminated as a result of these add-back regimes. The primary difference between these two treatment regimes rests with the greater abnormal lipoprotein changes and weight gain associated with administration of higher norethindrone doses. These findings confirm our preliminary results reported in an interim analysis of a subset of these patients completing 4 weeks of therapy (11). The efficacy of GnRH-a alone and in combination with varying doses of norethindrone in sup- Vol. 63, No.4, April 1995 Surrey et al. GnRH agonist and etidronate 751

6 Table Bone Mineral Density of L-4 Vertebrae: Dual-Energy Roentgenogram Absorptiometry Scans* Group Week 0 Week 4 Week 48 Week 7 (post-therapy) ± II ± III ± ± 0.035t (-0.44 ± 0.79):j: 1.09 ± t (-0.45 ± 1.4) 1.07 ± 0.015t (-0. ± 0.86) glcm ± 0.33t (-0.76 ± 0.94) 1.03 ± 0.039t (-1.1 ± 1.3) ± 0.017t (-0.3 ± 0.77) 1.09 ± 0.033t (-0.81 ± 0.73) ± t (0.5 ± 0.75) * Values are means ± SEM. t Not significant versus week O. :j: Values in parentheses are percentage from week O. Not significant versus group III. pressing the extent and symptom severity of endometriosis has been reported previously in 6-month clinical trials (1-3, 7, 8). Although investigators generally have reported prolonged relief after discontinuation of therapy, a subset of patients will present with more rapid recurrence despite achieving adequate pain relief during GnRH-a administration. Patients with higher stages of disease before therapy appear to be more likely to experience early recurrence (1, 14). Those who are refractory to more conservative measures may benefit from prolongation of pain relief during extended agonist therapy. Both add-back regimes used in the current investigation allowed for a significant suppression of painful symptoms as well as endometriotic implants assessed laparoscopically at the end of a 48- week course of therapy. We previously described a mean decline in modified AFS scores ranging from Table 3 Lipoprotein and Carbohydrate Metabolism* Group I Week (post-therapy) Total cholesterolt (md/dl) HDL cholesterolt (mg/dl) LDL cholesterolt (mg/dl) LDL:HDL Apolipoprotein A, (mg/dl) Apolipoprotein Bt (mg/dl) Triglyceridest (mg/dl) Glucose tolerance Insulin (I'D min/ml)** Glucose (mg min/dl):j:tt 177 ± ± ± ± ± ± 8 84 ± 14 6,376 ± 1,918 9,051 ± ± 6 47 ± 3 110±6.5 ± ± 8 11 ± ± ± 5 49 ± 3 100±5.1 ± ± 7 98 ± ± 9.6 5,75 ± 96 9,030 ± ± 5 49 ± 3 1 ± 4.6 ± ± ± ± ± 9 50 ± 3:j: 11 ± 8.5 ± ± ± ± 6.4 8,86 ± 716 9,957 ±, ± 7 54 ± 4 117±7.3 ± ±11 105± ± 1. 6,343 ± 6 9,566 ± 615 Group II Week (post-therapy) Total cholesterolt (md/dl) HDL cholesterolt (mg/dl) LDL cholesterolt (mg/dl) LDL:HDL Apolipoprotein A, (mg/dl) Apolipoprotein Bt (mg/dl) Triglyceridest (mg/dl) Glucose tolerance Insulin (I'D min/ml)** Glucose (mg min/dl):j:tt 183 ± 9 60 ± 4 113±7 1.9 ± ± ± ± 6.6 4,56 ± 860 9,647 ± ± ± 16 ± ± ± 7 11 ± ± ± ± 4 37 ± 4 37 ± ± ± ± ± ± ± 10 1 ± ± ± ± 6 7,361 ± ,019 ± ± 13 38± ± 1 II 3.8 ± ± ± ± 5 7,008 ± 1,696 11,001 ± 1, ± 1 54 ± ± 11.1 ± ± ± ± ,71 ± 97 9,051 ± 679 * Values are means ± SEM. t Conversion factor to SI units, :j: P < 0.05 change over time. P < change over time. II P < versus group lover time. \! Conversion factor to SI unit, ** Conversion factor to SI units, tt Conversion factor to SI units, Surrey et al. GnRH agonist and etidronate Fertility and Sterility

7 56% to 58% in endometriosis patients administered GnRH-a with or without supplemental norethindrone during a 4-week therapeutic trial (7, 8). In the current investigation, the decline in endometriotic implants after nearly 1 year of therapy was similar (group I, 47.4% ± 9.8%; group II, 58.7% ± 10.8%; P = 0.1). One could therefore hypothesize that maximal reduction of disease induced by GnRH-a may occur within the first 6 months of therapy. Continued administration serves to maintain pain relief for those patients requiring prolongation of a hypoestrogenic state to delay symptom recurrence. We have demonstrated that despite maintenance of circulating estrogen levels well within a castrate range for 48 weeks, no change in lumbar spine bone density measured by serial dual-energy roentgenogram absorptiometry scans could be detected as a result of the add-back regimes used in this investigation (Table ). When administered in the absence of add-back therapy for only 4 weeks, this same GnRH -a alone has been shown to induce a 5.57% ± 0.66% loss in bone density of the lumbar spine as assessed by similar techniques, which only partially recovered 4 weeks after cessation of therapy (8). We believe that the findings in the current investigation effectively demonstrate the value of prolonged prophylactic use of sodium etidronate for bone loss prevention in healthy women experiencing a medically induced hypoestrogenic state. Sodium etidronate inhibits osteoclast-mediated bone resorption when administered in low doses. Its effectiveness in the management of Paget's disease has been documented (15, 16). When administered cyclically with calcium carbonate in doses similar to those used in this investigation, sodium etidronate decreased bone density loss and incidence of vertebral fractures secondary to osteoporosis in postmenopausal women treated for up to years in the absence of estrogen replacement (9, 10). More recently presented data from Storm and co-workers (Storm T, Thamsborg A, Kollerup A, Sorensen H, Genant H, Steiniche T, Melsen F, Sorensen 0, abstract) confirmed the safety and efficacy of this regime for up to 5 years of treatment, reporting increases in bone mass in such patients. This cyclic regime appears to suppress bone resorption at the level of both the osteoclast and parathyroid glands (9, 10). The role of norethindrone in prevention of bone mineral density loss has been described previously. Ten milligram daily oral doses have been reported to suppress bone loss in postmenopausal women in the absence of estrogen replacement (17). Surrey and Judd (8) recently reported that this same daily norethindrone dose produced a similar effect during a 6-month clinical trial when combined with a depot preparation of the GnRH -a leuprolide acetate administered to endometriosis patients. In the current investigation, this beneficial effect was maintained for 48 weeks in patients randomized to Group II (Table ). Proposed mechanisms by which progestins may act as bone trophic hormones have been reviewed elsewhere (18). These data are confirmed by those of Friedman and co-workers (19) who noted a similarly beneficial effect on bone density in patients with uterine leiomyomata administered 10 mg/d norethindrone in conjunction with the same GnRH-a during a prolonged trial. Lower norethindrone doses similar to those administered to patients in group I have been used previously in uncontrolled investigations yielding inconsistent results. Riis and co-workers (0) reported that 1. mg daily norethindrone doses combined with an intranasal preparation of the GnRH -a nafarelin resulted in no loss oflumbar spine bone density measured with dual-photon absorptiometry techniques in a 6-month trial. Using 1.41 mg mean daily doses in combination with subcutaneous daily administration of the GnRH-a histrelin, Surrey et al. (7) reported a significant but reversible mean bone density loss of 5.6% of the lumbar spine measured by quanitative computerized tomography after 4 weeks of therapy. More recently, in a 6-month randomized double-blind placebo controlled trial of several norethindrone doses combined with nafarelin acetate, Eldred and co-workers (1) noted a 4.04 % reversible mean bone density loss with daily doses as high as.45 mg determined by dual-photon absorptiometry of the lumbar spine. These data would therefore suggest that similar norethindrone doses used in group I would be insufficient to effectively prevent GnRH-a-induced bone loss alone during prolonged therapy. One cannot rule out a potential synergistic effect on bone between low norethindrone doses and sodium etidronate among patients receiving both agents. A similar effect on femoral bone density has been reported in osteoporotic postmenopausal women administered etidronate in conjunction with estrogen replacement (). We previously have demonstrated in a 6-month placebo controlled masked trial that the use of 10 mg norethindrone doses as an add-back therapy significantly reduced vasomotor symptoms induced by agonists alone (8). The addition of lower maximal mean daily doses of.04 mg resulted in a similar Vol. 63, No.4, April 1995 Surrey et al. GnRH agonist and etidronate 753

8 benefit in an uncontrolled series using historic controls (7). The current investigation demonstrates that this benefit can be extended successfully at these low doses for up to 48 weeks of continuous GnRH-a administration (Fig. 4, top). Given that it is highly unlikely that an organic bisphosphonate alone would ameliorate hypoestrogenic vasomotor instability induced by GnRH -a, no treatment group was included in this study to assess the role of sodium etidronate and calcium alone as an "addback" regime (8). It is interesting to note that vaginal symptoms were minimized in both treatment groups (Fig. 4, bottom). This beneficial effect appeared to be somewhat related to the dose of norethindrone used. Although consideration was not given to control for sexual activity in this analysis, these results are consistent with previously reported data from our 6-month clinical trial (8). Patients in group II receiving 10 mg daily doses of norethindrone experienced untoward increases in serum LDL cholesterol levels and the ratio of LDL:HDL with concomitant decreases in apolipoprotein Al levels (Table 3). In contrast, those receiving lower norethindrone doses in conjunction with cyclic sodium etidronate experienced only a slight decrease in mean HDL cholesterol levels, which was not reflected in any change in mean LDL:HDL ratios over time. It is encouraging to note that all abnormal perturbations returned to baseline within 8 weeks of completion of therapy in both groups. Previous investigators have reported that progestins derived from 19-nortestosterone such as norethindrone alter levels of circulating lipoproteins and carbohydrate metabolism (3). Although the clinical significance of these relatively short-term changes has not been well established, traditional teaching has held that minimizing iatrogenic abnormalities in lipoprotein levels over time only can be beneficial (4). Although diet was not controlled in this study, the extent of undesirable weight gain appeared to be minimized for patients receiving lower progestin doses. No adverse effects on lipid or carbohydrate metabolism attributable to GnRH -a alone have been noted in previous studies (8). A trend toward glucose intolerance in group II failed to reach statistical significance. This may be the result of a Type II error and would be more clearly demonstrated with larger sample sizes. In conclusion, supplementation of a long-acting GnRH-a with either low-dose norethindrone and sodium etidronate or high-dose norethindrone alone was effective in reducing painful symptoms and extent of implants associated with endometriosis during 48 weeks of therapy. Despite maintenance of a persistent hypoestrogenic state, no changes in bone mineral density were noted in either treatment group over time or in comparison to untreated matched controls. In addition, vasomotor symptoms were minimized to a similar extent with both add-back regimes. Adverse changes in lipid profiles and weight gain attributable to the progestin were minimized by using lower norethindrone doses. Thus, the addition of cyclic sodium etidronate and low-dose norethindrone to a longacting GnRH -a may represent an ideal approach for refractory patients requiring prolonged medical management of endometriosis, providing therapeutic efficacy while enhancing patient safety and compliance. Acknowledgments. Special thanks to John F. Kerin, M.D., Ph.D. and Mark W. Surrey, M.D. for videotape review; Peter Christensen, Ph.D. for statistical analysis; Jerrold Mink, M.D. and co workers for performance of bone density studies; Elisa Obnial, B.S. for laboratory assistance; Ronald Arzaga, B.A. for typographic assistance; and the attendings and housestaff of Ceo dars Sinai Medical Center for their support and patient referrals. REFERENCES 1. Dlugi AM, Miller JD, Knittle J, 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: Steingold KA, Cedars M, Lu JKH, Randle D, Judd HL, Meldrum DR. Treatment of endometriosis with a long-acting gonadotropin-releasing hormone agonist. Obstet Gynecol 1987;69: Shaw RW, Zoladex Endometriosis Study Team. An open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. 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