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1 Gynecology-endocrinology FERTILITY AND STERILITY Vol. 64, No.3, September 1995 Copyright C> 1995 American Society for Reproductive Medicine Printed on acid-free paper in U. S. A. Gonadotropin-releasing hormone analogue (goserelin) plus hormone replacement therapy for the treatment of endometriosis: a randomized controlled trial* Rosemary Howell, M.B., B.S.t:j: D. Keith Edmonds, M.B., Ch.B.t Mitchell Dowsett, Ph.D.11 David Crook, Ph.D.~ Belinda Lees, B.Sc.~ John C. Stevenson, M.B., B.S. ~ Queen Charlotte's and Chelsea Hospital; Royal Marsden Hospital; and Wynn Institute for Metabolic Research, London, United Kingdom Objective: To determine whether treatment of endometriosis with a GnRH analogue (GnRHa; goserelin) combined with continuous estrogen and progestogen hormone replacement therapy (HRT) would prevent the hypoestrogenic effects, including loss of bone density, while maintaining efficacy for treatment of endometriosis. Design: Randomized controlled trial. Patients: Fifty premenopausal women with laparoscopically diagnosed endometriosis (revised American Fertility Score for endometriosis implants equal to four or greater) and significant symptoms of dysmenorrhoea, dyspareunia, and other pelvic pain. Intervention: Patients were randomized to receive either goserelin alone, 3.6 mg SC depot every 4 weeks for 24 weeks, or goserelin, 3.6 mg SC depot every 4 weeks for 24 weeks, plus HRT (25 J-lg trans dermal 17 (3 E2 daily and 5 mg medroxyprogesterone acetate orally daily) for 20 weeks commencing with the second goserelin injection. Results: There was a significant reduction in the extent of pelvic endometriosis in both groups, with no difference between the groups. Both groups experienced an improvement in symptoms and signs, again with no difference between groups. Hypoestrogenic side effects of hot flushes and loss of libido were significantly less in the group that received HRT. The amount of bone mineral density loss was significantly less in the HRT group at the lumbar spine, although it was not prevented completely. Conclusion: The addition of HRT to GnRH -a for the treatment of endometriosis did not reduce the efficacy of treatment, and adverse hypoestrogenic effects were decreased, although not abolished. Fertil Steril 1995;64: Key Words: Gonadotropin-releasing hormone analogue, endometriosis, hormone replacement therapy, bone mineral density Endometriosis, the clinical condition in which endometrial glands and stroma occur at ectopic sites, Received October 6,1994; revised and accepted March 15,1995. * Supported by Zeneca Pharmaceuticals, Macclesfield, United Kingdom. t Queen Charlotte's and Chelsea Hospital. * Present address: Queen Charlotte's and Chelsea Hospital, Goldhawk Road, London W6 OXG, United Kingdom. Reprint requests: Rosemary Howell, Queen Charlotte's and Chelsea Hospital, Goldhawk Road, London W6 OXG, United Kingdom. II Royal Marsden Hospital. ~ Wynn Institute for Metabolic Research. 474 Howell et at GnRH-a and hormone replacement therapy is estimated to affect 2% to 5% of women ofreproductive age (1). It generally is accepted to be an estrogen-dependent condition, although the exact relationship between the etiology of endometriosis and circulating E2 remains unclear. Endometriosis commonly recurs after medical or surgical treatment and, in the absence of a drug treatment that is safe for long-term use, recurrence can lead to hysterectomy and bilateral oophorectomy. Gonadotropin -releasing hormone analogues (GnRH-a) have an established place in the medical treatment of endometriosis. Gonadotropin-releasing hormone analogues act by down-regulating pituitary Fertility and Sterility

2 gonadotropins, resulting in suppression of gonadotropin production, with secondary ovarian suppression. Circulating E2 levels fall into the postmenopausal range, producing menopausal side effects, including hot flushes, vaginal dryness, and loss of libido. Importantly, GnRH-a cause a reduction in bone mineral density at the lumbar spine (2, 3) and proximal femur (4), which may not recover after ending treatment (2-4). This could increase the future risk of osteoporosis in these young women. Hormone replacement therapy (HRT) containing estrogen and progestogen has been proposed as a means of preventing the adverse effects of GnRH-a. The aim of this comparative study was to determine if the addition of continuous combined HRT to the GnRH-a goserelin (Zoladex; Zeneca Pharmaceuticals, Macclesfield, United Kingdom) could prevent clinical side effects and loss of bone density while maintaining efficacy for the treatment of endometriosis compared with goserelin alone. MATERIALS AND METHODS Study Design and Patients This was a prospective, open, randomized controlled trial. Fifty premenopausal women were recruited to the study after laparoscopic diagnosis of endometriosis. Endometriosis was diagnosed by inspection. A minimum revised American Fertility Score (revised AFS) (5) for endometriosis lesions (excluding adhesions) of four was required for entry to the study. All women complained of pelvic pain and a minimum Pelvic Pain Score (defined below) of 3 was required for entry. All women had a regular menstrual cycle (21 to 42 day cycles), had not used hormonal medication for the 2 months before study entry, and had not taken drugs known to affect bone metabolism, including GnRH-a, for the preceding 6 months. No patient suffered from a serious concomitant medical condition or condition likely to affect bone metabolism or assessment of bone mineral density. All patients had had a negative cervical smear within the preceding 12 months and were advised to use barrier contraception for the duration of the treatment period. Treatment Patients were randomized into two groups to receive 3.6 mg SC depot injection of goserelin (Zoladex) every 4 weeks for 24 weeks of treatment (group 1; n = 25) or 3.6 mg SC depot injection of goserelin every 4 weeks for 24 weeks treatment, plus transdermal 17,B-E2 25 I1g (Estraderm TTS patches changed twice weekly; Ciba Laboratories, Horsham, United Kingdom) daily and 5 mg oral medroxyprogesterone Vol. 64, No.3, September 1995 acetate (MPA, Provera; Upjohn Ltd., Crawley, United1Gngdom) daily for 20 weeks treatment, commencing with the second goserelin depot (group 2; n = 25). Goserelin was administered SC to the anterior abdominal wall. The first goserelin injection was administered within 7 days from the commencement of menstruation. Compliance with HRT was assessed by counting returned medication at each visit. Outcome Measures Endometriosis Response All patients underwent laparoscopy within 3 months before starting treatment and again had laparoscopy or laparotomy between 4 and 8 weeks after their final goserelin injection. This was timed to be performed before the first completed menstrual cycle after completion of treatment. Endometriosis was scored according to the revised AFS Score (5) and also as the additive diameter of implants, the sum of the average diameter of each endometriotic lesion (6). No operative procedures were undertaken at the pretreatment laparoscopy. Operative procedures were performed when clinically indicated at the post-treatment laparoscopy or laparotomy: laparoscopic laser ablation of endometriosis and/or adhesiolysis (group 1, n = 10; group 2, n = 9) or open adhesiolysis (group 1, n = 3; group 2, n = 0). Relief of Symptoms and Clinical Signs Symptoms of dysmenorrhoea, dyspareunia and other pelvic pain, and clinical signs of endometriosis, pelvic tenderness and pelvic induration on vaginal examination, were scored as mild, moderate, or severe before commencement of treatment and at each subsequent visit (7). The scores were added to produce the Pelvic Pain Score (range 0 to 15). Subjective Side Effects Patients were questioned at each visit as to the presence and severity (mild, moderate, or severe) of hot flushes, vaginal dryness, loss of libido, and headaches. Bone Mineral Density Bone mineral density measurements were made using dual-energy roentgenogram absorptiometry (Lunar DPX; Lunar Corp., Madison, WI) (8) at the following sites: lumbar spine (L2 to 4), femoral neck, and Ward's triangle. Measurements were made before treatment, at the completion of 6 months of treatment, and at 3 and 6 months after treatment. Our in vivo precision of dual-energy roentgenogram Howell et ai. GnRH-a and hormone replacement therapy 475

3 Table 1 Baseline Characteristics Group 1 (goserelin alone) Age (y)* Height (cm)* Weight (kg)* 29::t: ::t: ::t: 12 Pelvic pain score* 7.5 ::t: 1.7 Total revised AFS scoret 19.4 (4 to 119) Revised AFS score implantst 12.4 (4 to 66) Additive diameter of implantst (mm) 34.6 (10 to 120) Bone mineral density (g/cm 2 )* Lumbar spine* Femoral neck* Ward's triangle* Serum El (pg/ml)t+ Serum E2 (pg/ml)t+ Serum LH (miu/ml)t+ Serum FSH (miu/ml)tt ::t: ::t: ::t: (34.9 to 170.6) 74.2 (7.1 to 176.0) 3.55 (1.20 to 9.20) 7.10 (5.10 to 44.00) Group 2 (goserelin with HRT) 30::t: ::t: ::t: ::t: (4 to 57) 10.2 (4 to 42) 33.8 (10 to 74) ::t: ::t: ::t: (32.7 to 140.1) 74.4 (29.4 to 659.2) 3.40 (2.00 to 11.00) 6.50 (2.90 to 30.00) * Values are means ::t: SD. t Values are medians with ranges in parentheses. t Conversion factors to SI unit are as follows: E 1, 3.699; E 2, 3.671; LH and FSH, absorptiometry measurements is L2 to 4, 1.1% ± 0.5%; femoral neck, 1.6% ± 1.0%; Ward's triangle, 3.1 % ± 1.6% (mean ± SD) (9). Endocrinologic Effects Serum LH, FSH, estrone (E l ), and E2 were measured immediately before the first goserelin injection, at monthly intervals during treatment, and at 3 and 6 months after completion of treatment. Luteinizing hormone and FSH were assayed using direct double antibody immunoradiometric assay (LH MAIAclone and FSH MAIAclone; Serono Diagnostics, Woking, United Kingdom). According to the manufacturer's instructions, highest and lowest measurable levels of LH are 200 and 0.5 miu/ml (conversion factor to SI unit, 1.00), respectively, and are 150 and 0.3 miu/ml (conversion factor to SI unit, 1.00), respectively, for FSH. Interassay coefficients of variation for LH are between 5.6% and 8.8% and are between 2.0% and 5.4% for FSH; intra-assay coefficients of variation for LH are 2.5% and 8.3% and are 1.2% and 4.7% for FSH (23). Estrone and E2 were measured after organic extraction by methods described previously (10, 11). Serum Lipids and Lipoproteins Fasting blood samples were collected before treatment, at the completion of 6 months treatment, and at 3 and 6 months after treatment. Concentrations of serum and lipoprotein cholesterol and triglyceride were measured by fully enzymatic procedures. Highdensity lipoprotein (HDL) was measured by precipitation techniques as described previously (12). Lowdensity lipoprotein (LDL) was estimated using the Friedewald formula (13). 476 Howell et ai. GnRH-a and hormone replacement therapy Statistical Analysis Analysis of covariance (with pretreatment values as covariates) was used to compare endometriosis response, clinical symptoms and signs, and bone mineral density between groups. Paired Student's t tests were used to compare changes from baseline in endometriosis response, clinical symptoms and signs, bone mineral density, and lipids. Unpaired Student's t-tests were used to compare mean E2, Eb FSH, and LH during treatment between the groups. X 2 was used to compare frequency of side effects between groups. N onparametric analysis produced no substantive differences. RESULTS Of 50 patients randomized to commence treatment, all except 2 completed 24 weeks of treatment and underwent the second laparoscopic assessment. One from each group failed to complete the 6 months of treatment: one because of intolerable hot flushes (group 1) and the second because of the development of diarrhea. Thirteen patients did not complete the clinical and endocrinologic assessments at both follow-up visits either because of pregnancy (group 1, n = 3; group 2, n = 4) or failure to attend (group 1, n = 5; group 2, n = 1). Twenty patients did not complete all four bone mineral density assessments because of discontinuation of treatment (group 1, n = 1; group 2, n = 1), pregnancy (group 1, n = 3; group 2, n = 4), or failure to attend (group 1, n = 4; group 2, n = 7). There were no differences in baseline characteristics between the two groups (Table 1). Endometriosis Response The revised AFS score for implants and additive diameter of implants scores were reduced in both Fertility and Sterility

4 20, , GOSEREUN GOSEREUN + HRT GOSEREUN GOSEREUN + HRT i 30 ADI SCORE \ 20 \ \ 10 \ BEFORE AFTER BEFORE \ \ 0 AFTER Figure 1 Endometriosis response: revised AFS implant and additive diameter of implants scores. P < 0.01 compared with baseline revised AFS implant and additive diameter of implants scores both groups. Difference between groups is not significant. groups with no significant difference between the groups (P > 0.05) (Fig. 1). The total revised AFS score also was reduced in both groups. There was no significant change in the adhesion score in either group. The percentage of patients who had a reduction in their revised AFS score of ~50% was the same in the two groups (64%). Relief of Symptoms and Clinical Signs Both groups showed similar improvement in pelvic symptoms (dysmenorrhoea, dyspareunia, and other pelvic pain) and pelvic signs (tenderness and induration) during the course of treatment (Fig. 2) with no significant difference between the two groups (P > 0.05). There also was no difference between groups in the Pelvic Pain Score at 3 and 6 months after treatment. Subjective Side Effects Excluding the 4 weeks after the first goserelin injection, when an estrogen withdrawal bleed is ex- Vol. 64, No.3, September 1995 pected, there were four women in the goserelin alone group -who experienced vaginal bleeding during treatment. In two of these this was brief spotting only (1 and 2 days throughout the entire treatment period), whereas the other two described episodes of moderate loss (5 and 6 days) in addition to spotting (7 and 8 days total). In the HRT group, there was a significantly higher frequency of vaginal bleeding during treatment: 15 women reported vaginal bleeding (X 2 P < 0.01), with 8 reporting spotting only (mean number of days of spotting per 20 weeks treatment was 8.5 days, range 1 to 59 days) and 7 reporting moderate loss (mean number of days of moderate loss per 20 weeks treatment was 7.6 days, range 1 to 25). No women reported heavy bleeding during treatment, and no woman discontinued treatment because of bleeding. The incidence and severity of hot flushes was reduced significantly in the group that received HRT. Every woman in the goserelin alone group experienced some hot flushes during treatment compared with 21 of 24 (88%) ofthe HRT group (X2 P < 0.05), and nearly all (23/24) of the goserelin alone group complained of severe and/or frequent (more than three per 24 hours) hot flushes compared with 11 of 24 in the HRT group (X2 P < 0.01). One woman in the goserelin alone group was withdrawn from the study because of hot flushes. There was no difference in the proportion of women who complained of vaginal dryness during Pelvic Pain Score Fo110 wup 1+-~--~-.--'-~r--r~r-~ o Duration of treatment Follow up Figure 2 Endometriosis response: Pelvic Pain Score. P < 0.01 comparing pretreatment score with score at 6 months treatment for both groups. Difference between groups pretreatment compared with completion of 6 months treatment is not significant. group 1, goserelin alone; 0 group 2, goserelin with HRT. Howell et ai. GnRH-a and hormone replacement therapy 477

5 treatment (group 1, 10/24; group 2, 10/24; X 2 > 0.05). There was no difference in the proportion of patients who complained of headaches either developing or worsening during treatment (group 1, 11/24; group 2, 13/24; X2 > 0.05). Significantly fewer of the sexually active women in the goserelin plus HRT group (4/23) complained ofloss oflibido compared with the goserelin alone group (11/23) (X2 < 0.01). Bone Mineral Density At the completion of 6 months of treatment, the loss of bone mineral density at the lumbar spine was significantly less in the HRT group compared with the goserelin alone group, however, bone mineral density in both groups was reduced significantly compared with pretreatment levels (Fig. 3). The reduction in bone mineral density at the lumbar spine in group 1 was -4.1% compared with -2.3% in group 2. Bone density at the proximal femur also was reduced significantly at completion of treatment compared with pretreatment levels in both groups and there was no significant difference between the groups (Fig. 3). Three months after treatment, bone density at the lumbar spine had recovered partially in the HRT group but not in the goserelin alone group (group 1, -3.9%; group 2, -1.5%). Lumbar spine bone mineral density continued to be significantly higher in the goserelin plus HRT group than in the goserelin alone group. However, bone mineral density remained significantly less than baseline in both groups. Both groups also remained significantly reduced compared with baseline at the proximal femur and there was no significant difference between the groups. Six months after treatment, bone mineral density at the lumbar spine in the goserelin alone group had recovered toward baseline to a level that was similar to the HRT group, but both groups remained significantly lower than pretreatment levels (group 1, -1.9%; P < 0.05; group 2, -1.6%). At the proximal femur, there was no evidence of recovery of bone density, and both groups remained significantly less than baseline, with no significant difference between groups. Endocrinologic Effects Serum LH and FSH were suppressed in both groups (Fig. 4), although the goserelin alone group showed some recovery in FSH during the 6 months of treatment that was not present in the HRT group. Serum E2 was significantly higher in the HRT group than in the goserelin alone group (Fig. 4). Mean E2 was 14.0 ::!:: 13.9 pg/ml (conversion factor to SI unit, 3.671) in group 1 and 31.5 ::!:: 16.0 pg/ml (conversion factor to SI unit, 3.671) in group 2 (P < a..001). There 478 Howell et a1. GnRH-a and hormone replacement therapy LUMBAR SPINE 0 :-. BMD... (% change) Duration of treatment 6, 3, 6, ,** " t tt ns FEMORAL ~ ns~ nsl- ~ns NECK 0... BMD... (% change) * -2,** ~ _ WARD'S ns ns ns lrlangle 0 BMD... (% change) -1 0" ** *... * --~ ** '0'"--,,, ** 'b ** ** Figure 3 Bone mineral density. group 1, goserelin alone; 0 group 2, goserelin with HRT. *p < 0.05 compared with baseline; **p < 0.01 compared with baseline; tp < 0.05 difference between groups; ttp < 0.01 difference between groups; ns, not significant. was no correlation between the mean serum E2 and the reduction in additive diameter of implants. Serum El was suppressed in both groups. Serum Lipids and Lipoproteins Total cholesterol, triglycerides, and LDL remained unchanged at completion of treatment in both groups. There was an increase in HDL cholesterol in group 1 that was not seen in the HRT group (Table 2). DISCUSSION This study establishes that add-back HRT does not reduce the efficacy of GnRH-a for the treatment Fertility and Sterility

6 FSH (IUA.) LH (IUA.) (P:I'L) '"... A--o-~--o Duration oftreatment 5 "0 636 Figure 4 Endocrine response group 1, goserelin alone; 0 group 2, goserelin with HRT. of endometriosis, both in terms of relief of symptoms and reduction in the extent of endometriosis. The concept of add-back HRT to prevent the hypoestrogenic effects of GnRH-a treatment was first explored in the late 1980s for the treatment of a number of gynecological conditions. The first report used progestogen-only HRT in the treatment of fibroids and demonstrated partial relief of side effects (14). Gangar et al. (15) treated 21 women with chronic pelvic pain due to pelvic congestion with goserelin and combined estrogen-progestogen HRT (1 mg E2 valerate and 5 mg MPA daily continuously) for 4 months. Severe estrogen-deficiency side effects were abolished, although the pelvic pain was not relieved. However, all but two women were amenorrhoeic, suggesting that GnRH-a with HRT did not produce Vol. 64, No.3, September 1995 endometrial stimulation and thus providing encouragement that the combination could be used for endometriosis. There have been three reports of women with endometriosis treated with GnRH-a plus HRT. Reid et al. (16) reported a single patient with severe previously unresponsive endometriosis who maintained symptomatic improvement, with no loss of bone density, when treated with goserelin and combined continuous HRT (0.625 mg conjugated equine estrogens and 5 mg MPA daily) for 12 months. Friedman and Hornstein (17) treated eight women for 2 years in an uncontrolled retrospective 8tudy with leuprolide acetate plus mg daily conjugated equine estrogens and 2.5 mg MPA starting in the 3rd month. Six women completed 2 years of treatment. They found significant improvement in the endometriosis symptoms and extent of lesions at laparoscopy, with no loss of bone mineral density of the lumbar spine as measured by dual roentgenogram absorptiometry. Tuimala et al. (18) randomized 109 women to either goserelin alone or with 2 mg E2 and 1 mg norethisterone acetate continuously for 6 months. There was no difference in the efficacy of these two treatments as assessed laparoscopically. Hot flushes were reduced significantly and serum E2 levels were higher in the women receiving HRT. Bone density was not studied. Our finding that add-back HRT did not reduce the efficacy of GnRH-a therapy raises questions regarding the relationship between maintenance of endometriosis lesions and circulating levels of ovarian steroids. The traditional view of endometriosis as an estrogen-dependent condition that resolves on withdrawal of sex hormone support is the basis for the presumed mode of action of GnRH-a. Experimental evidence suggests that endometriosis does not respond in a consistent fashion to ovarian hormone stimulation when compared with the probable parent epithelium, endometrium, when examined either histologically (19), ultrastructurally (20), biochemically (21), or histochemically (22). Ovarian steroids have been demonstrated to be required for the maintenance but not implantation of surgically transplanted ectopic endometrium in the pelvis of monkeys (23). Alternative medical therapies for endometriosis, such as danazol and MPA, suppress ovarian steroid production but do not produce the profound hypoestrogenism seen with GnRH-a treatment. Their action is thought to be mediated by a direct suppressive effect on the endometriotic tissue and, for danazol, possibly by an immunosuppressive action, in addition to reduction on circulating estrogen. Gonadotropin-releasing hormone analogues do not appear to have any direct effect on the endometrium (24). Our study suggests, therefore, that pro- Howell et ai. GnRH-a and hormone replacement therapy 479

7 Table 2 Serum Lipids and Lipoproteins* Baseline 6 Months treatment 3 Months follow-up 6 Months follow-up Total cholesterol (mg/dl)t Group :!: :!: :!: :!: 37 Group :!: :!: :!: :!: 17 Triglycerides (mg/dl)* Group 1 73 :!: :!: :!: :!: 29 Group 2 81 :!: :!: :!: 22 66:!: 29 LDL cholesterol (mg/dl)t Group :!: :!: :!: :!: 37 Group 2 100:!: :!: :!: 19 95:!: 12 HDL cholesterol (mg/dl)t Group 1 51:!: 10 59:!: :!: 13 57:!: 14 Group 2 52:!: 11 53:!: 9 54:!: 9 53:!: 7 * Values are means:!: SD. t Conversion factor to SI unit, * Conversion factor to SI unit, P < 0.05 compared with baseline (paired t-test). lip < 0.01 compared with baseline (paired t-test). found hypoestrogenism in the absence of any direct endometrial effects is not required for the suppression of endometriosis. The etiology of endometriosis remains the subject of current research. It generally is accepted that the origin of the ectopic endometrial tissue in the pelvis is uterine endometrium and that the common method of transport is retrograde menstruation (1). Whether cyclic ovarian steroid production is important to the continuation of endometriosis by a direct effect on the ectopic endometrium or by the effect of maintaining continued retrograde menstruation remains unknown. Although more women in our HRT group experienced vaginal bleeding, GnRH-a with continuous combined HRT prevented regular cyclic shedding of the endometrium and avoided the normal cyclicity of endometrial stimulation. Suppression of endometriosis was not dependent on the level of circulating E 2 The HRT used in this study reduced the hypoestrogenic side effects of GnRH-a therapy and had no adverse effects on serum lipids and lipoproteins. However, we did not see complete prevention of loss of bone density, although bone mineral density loss at the lumbar spine at completion of treatment was less in the HRT group. Field et al. (25) compared three doses of transdermal 17,B-E2 with placebo and found that whereas mg/d 17,B-E2 retarded bone loss over a 2-year period, 0.05 mg/d 17,B-E2 was the minimum dose required for complete prevention of bone loss at the lumbar spine and also the proximal radius. Our findings that bone mineral density loss was not prevented by the HRT regimen used therefore is consistent with the conclusion that mg/d 17,B-E2 is not a bone-sparing dose. This dose of E2 was chosen for this study in the absence of any previous experience with add-back HRT therapy for endometriosis and based on concern that estrogen stimulation might 480 Howell et at. GnRH-a and hormone replacement therapy reduce the efficacy of treatment of endometriosis. Although bone loss was not prevented completely by this treatment regimen, our results together with the experience of Reid et al. (16) and Friedman and Hornstein (17) suggest that a higher dose of add-back estrogen may be effective in preventing bone mineral density loss without reducing efficacy for endometriosis treatment. We recommend that a bone-sparing dose of estrogen should be used. Add-back HRT will extend the role of GnRH-a therapy not only for endometriosis. Treatment with GnRH-a alone generally is restricted to 6 months duration because of concern over continuing loss of bone mineral density over longer treatment periods. The possibility oflong-term bone loss after GnRH-a therapy has restricted the use of GnRH-a treatment to one course. If a bone-sparing dose of HRT could be used in conjunction with GnRH -a therapy without reduction of efficacy, the combination could be used safely on a long-term basis and for repeated treatment courses. Currently in endometriosis therapy there is no medical treatment that is safe for longterm use, and hysterectomy with bilateral salpingoophorectomy remains the mainstay treatment in cases of recurrent and recalcitrant endometriosis. Danazol and high dose progestogen treatments are associated with potential adverse lipid effects and often are tolerated poorly. Although the continuous use of the combined oral contraceptive pill has been suggested as a means of prevention of recurrent endometriosis, appropriate data are lacking. Gonadotropin-releasing hormone analogue therapy with add-back HRT offers a reversible alternative to major sterilizing surgery, especially in relatively young women. Similarly, there is potential for the use of long-term GnRH-a therapy with add-back HRT in other gynecological conditions such as menstrual disorders, fibroids, or premenstrual syndrome and in nongynecological conditions such as breast cancer. Fertility and Sterility

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