Depot leuprolide acetate with estrogen and progestin add-back for long-term treatment of premenstrual syndrome*t

FERTILITY AND STERILITY Vol. 62, No. 5, November 1994 Copyright 1994 The American Fertility Society Printed on acid-free paper in U. S. A. Depot leuprolide acetate with estrogen and progestin add-back for long-term treatment of premenstrual syndrome*t Gail Mezrow, M.D.:j: Donna Shoupe, M.D. Darcy Spicer, M.D. II Rogerio Lobo, M.D. Belinda Leung, M.D. Malcolm Pike, M.D. University of Southern California School of Medicine, Los Angeles, California Objective: To test the effectiveness and safety of long-term depot leuprolide acetate (GnRH-a) plus estrogen and progestin add-back therapy in the treatment of moderate and severe premenstrual syndrome (PMS). Design: A prospective trial with each patient serving as her own control. Setting: University teaching hospital. Participants: Ten women with regular menstrual cycles complaining of moderate to severe PMS. Premenstrual syndrome was diagnosed when symptoms increased :2o25% during the luteal phase. Treatment: Four-week cycles of IM injections of placebo or GnRH -a with all patients receiving saline (placebo), the first cycle followed by 12 cycles of GnRH-a, 7.5 mg. Conjugated equine estrogen (0.625 mg/d) was started Monday through Saturday within the first cycle and increased as needed. Medroxyprogesterone acetate (MPA), 10 mg/d, was taken orally for 10 days after 4, 8, and 12 cycles of GnRH-a therapy. Main Outcome Measures: Changes in three symptom categories (water retention, pain, and psychological function), serum levels of total cholesterol and HDL, HDL-2, and LDL cholesterol, E 2, and estrone. Endometrial biopsy was obtained 1 day after the end of the 12th GnRH -a cycle, and bone density was assessed using quantitative computer tomography at the end of the 12th GnRH-a cycle. Results: During treatment, there was a significant decrease compared with baseline and placebo in all three symptom categories. There were no significant changes in lipids. Endometrial biopsies revealed progestational changes with no evidence of hyperplasia. Quantitative computer tomography bone density dropped 3. 7 on average compared with baseline after 12 months of treatment, but this was not statistically significant. Conclusion: Gnadotropin-releasing hormone agonist therapy with hormonal add-back therapy is effective in treating PMS symptoms with progressive improvement over a 12-month period. This therapy prevents changes in lipids and adequately protects the endometrium with the addition of MPA every 4th cycle. Quantitative computer tomography bone density dropped at 12 months; further examination of bone changes is necessary. Fertil Steril 1994;62:932-7 Key Words: Premenstrual syndrome (PMS), gonadotropin-releasing hormone agonist (GnRH-a), add-back therapy, depot leuprolide acetate, estrogen replacement therapy (ERT) Received November 17, 1994; revised and accepted June 3, 1994. :j: Reprint requests: Gail Mezrow, M.D., Women's Hospital, * Supported by TAP Pharmaceutical, Inc., North Chicago, Illinois. 90033. 1240 North Mission Road L-1009, Los Angeles, California t Presented at the 39th Annual Meeting of the Society for Department of Obstetrics and Gynecology. Gynecologic Investigation, San Antonio, Texas, March 18 to 22, II Department of Medicine. 1992. 11 Department of Preventive Medicine. 932 Mezrow et al. Long-term treatment of PMS with GnRH-a Fertility and Sterility

Premenstrual syndrome (PMS) can severely affect quality of life for those women who have debilitating symptoms beginning after ovulation and continuing until menses. Unfortunately, studies of E 2, P, PRL, gonadotropins, and thyroid hormone have not been helpful in the understanding of this disorder (1-6). There is sufficient evidence, however, to show that ovarian function is necessary for PMS, including the onset of PMS after puberty, the cessation of PMS after surgical or natural menopause, and the persistence after hysterectomy in premenopausal women whose ovaries are not removed (7-10). Suppression of ovulation with gonadotropinreleasing hormone agonists (GnRH-a), which induce a reversible medical menopause, results in remission of PMS symptoms (11, 12). However, treatment has been limited to 6 months because of a loss in bone density. When low dose E 2 and progestin add-back therapy was taken for 4 months after 2 months of GnRH-a alone, the alleviation of symptoms was maintained (13). The purpose ofthis study was to test the effectiveness and safety of long-term administration of GnRH -a plus hormone replacement for women with moderate to severe PMS over a 12-month period. MATERIAL AND METHODS Approval of the protocol was obtained from the local Institutional Review Board and written informed consent was obtained from each subject. The study was advertised in the newspaper. Approximately 200 women responded from varied socioeconomic backgrounds with a wide variety of complaints. Potential participants were screened by phone and mailed a daily symptom chart (diary) shown in Figure 1. Women qualified for inclusion if they had regular menstrual cycles between 25 and 32 days, no medical or psychiatric illnesses, no history of substance abuse, were nonsmokers, were not on medication, had not used steroid therapy within the last 3 months, and were within 20% of ideal body weight. Psychiatric illness was ruled out by history and oral questioning regarding lack of severe depression, suicidal tendency, current or past use of psychiatric medication, and psychiatric hospitalization. One hundred fifty women were mailed calendars of which 53 were returned. After one cycle (cycle 0), the diary was reviewed and subjects were chosen if they had moderate to severe PMS defined by the 25% increase in symptoms in two of the three symptom categories (water retention, pain, and psychological function) in the luteal (defined as the last 14 days of the menstrual cycle) versus the follicular phase. Subjects rated symptoms on an A-to-F scale, which was converted to a number system with A equal to 1, B equal to 2, C equal to 3, D equal to 4, E equal to 5, and F equal to 6 to allow computation. Ten subjects qualified for the study and wished to participate. They were between the ages of 24 and 45 years; two had two children and the other eight had never been pregnant. They underwent complete medical history, physical and pelvic exam. All subjects understood that they would receive 13 injections at 4-week intervals and that at least one injection would be saline (placebo). Each subject received a blinded IM injection of normal saline and was instructed to continue to fill out the daily diary for 4 weeks after receiving the placebo (cycle 1). The placebo treatment allowed for a normalized response, establishing a true baseline. On each of their four weekly clinic visits, subjects received 7.5 mg IM of GnRH -a (leuprolide acetate, Lupron; TAP Pharmaceuticals, Inc., North Chicago, IL). Conjugated equine estrogen (Premarin, 0.625 mg/d except Sunday; Wyeth-Ayerst, Philadelphia, PA) was administered when the patient began to complain of E 2 deficiency symptoms (hot flushes, fatigue, or vaginal dryness), which occurred between 3 and 4 weeks after the initial GnRH-a injection. Medroxyprogesterone acetate (MPA, 10 mg/d for 10 days, Provera; Upjohn, Kalamazoo, Ml) was given during cycles 5, 9, and 13. Fasting blood samples were taken at the end of cycles 1 (baseline), 2, 4, 7, and 13, and 4 weeks after the end of cycle 13 and were assayed for E 2, estrone (E 1), total cholesterol, and HDL, HDL-2, and LDL cholesterol by RIA (14). Four weeks after the final GnRH-a injection an endometrial biopsy was obtained. Bone density was assessed by quantitative computer tomography at baseline and 1 month after the final GnRH-a injection. Patients were controlled for diet and exercise. Barrier contraception was used throughout the study. Statistical analysis was done with the Statgraphics Computer Package (STSC, Inc., Rockville, MD) using one-way analysis of variance. Statistical significance levels quoted are two sided (2p). RESULTS During placebo treatment, there were no changes in the percentage of cycles with any water retention Vol. 62, No.5, November 1994 Mezrow et al. Long-term treatment of PMS with GnRH-a 933

I IIIIIAL A - (lot,.._tit (IINIJ porcopt1b1o) 111) c ILD (Cl rlr ll""'ll!t1b1o but not ti'oiiiil-l o -n (Dof1n1to1J ll""'ll!t1b1o IIIII ti'oiiiil-l E snm tyerr ti'oiiiil-l f DTIPE (lntolorllllo, INII1o to porlono di11j octh1t1oo) -M-T(-,.,-,-------,;;;;;;-;;;;;04 101/05 101/01 IDIID7 101/01 IDI/01 IDIIID 101/11 IOIIIZ!DillS I 1Fr1!Sot!Sun!Non!Tui lllod!till 1Fr1!Sot!SUn Ilion IT,. lllod!till I MDIIIIIIIAI. II.DATIII/FIA.I.IIOS I I I I I I I I I I I I I I I 1 -+ +- -+- -+- +- -+- -+- -+- -+- -+- 1 1 1 - AIID/DI FUT MLLIII& I I I I I I I I I I I I I I I 1 +- -+ -+- -+- +- -+- -+- -+- +- -+- -+- 1 1 1 Fmlll& Of IIEIIMT IAII I I I I I I I I I I I I I I I 1 -+- -+- -+ -+- -+- -+- -+- -+- +- -+- -+- 1 1 1 WAST MLLJIIII'AJII/TmllWSS, I I I I I I I I I I I I,_,_, I I I.-- I I I I I I I I I I I I I I I - 1 -+- -+- -+- + -+- -+- -+- -+- -+ -+- -+- 1 1 1 - I I I I I I I I I I I I I I I...,...-+------+-- --+------+------+------+------l------1------l.jdiiii'aiididiiiisci.ei'aii I I I I I I I I I I I I I I I......-+-----..._,......_,..._...-+---- -l- ----1------l -IIAI.I'AIIV- I, I I I I I I I I I I I,_,_, I I I IIOIDSmiUDILGIIIII.UEILDIEI' I I I I I I I I I I I I I I I - 1 -+- -+- -+- -+- -+- -+- -+- -+- -+- -+- +- 1 1 1 IDUSITDSUJmm/- I I I I I I I I I I I I I I I IMJTaU-/IlftTJUIY I I I I I I I I I I I I I I I statideimjdsdcjautrmnl I I I I I I I I I I I I I I - 1 -+- -+- -+- -+- -+- -+- -+- -+- -+- -+- -+- 1 1 1 -- I I I I I I I I I I I I I I I...,..._..,......-...-+------+------+------+------1- ----l------l APPETITE.. ICIAft- I I I I I I I I I I I I I I I - 1 -+- -+- -+- -+- -+- -+- -+- -+- -+- -+- -+- 1 1 1 TIIIIIUII EmiY/IIAPSIFATIM, I I I I I I I I I I I I,_,_, I I I - I I I I I I I I I I I I I I I C:.USICIIICM'T tikdtiate I I I I I I I I I I I I I I I NLPJTan I I I I I I I I I I I I I I I 1 -+- -+- -+- -+- -+- -+- -+- -+- +- +- 1 1 1 IIITFIUIIISIFUIIIES I I I I I I I I I I I I I I I...,... J... J... J MATIMIIIITMATS I I I I I I I I I I I I I I I... 1- -- -+--- -... ---- ----- I--... --1------1 WJIIAI.MTIIIIM111F1LJ-I I I I I I I I I I I I I I I... 1-- ---+- ---+-----... - ------ - --- ------ ------1- ----1------1 - a I I I I I I I I I I I I I I I 1 -+- -+- -+- -+- -+- -+ -+- + + + -+ 1 1 1 IIIITIDSDF.UTM I I I I I I I I I I I I I I I 1 +- -+- -+- -+ -+- -+- -+ + + 1 1 1 IIUIIUI I I I I I I I I I I I I I I I... am Ill. 11m1 tsl I I I I I I I I I I I I I I I ----------------------------- ----1----- -- - - -- - ------ ---- -+ - --- -- ---- + ----- ------ ------ ------1------1----- -I MDICATJ (t1'* 1f _, I I I I I I I I I I I I I I I...._...... Figure 1 Premenstrual syndrome symptom chart. symptoms (Fig. 2). There was a 50% reduction in the percentage of cycles with any symptoms in the pain and psychological categories. After treatment with depot GnRH-a and E 2-progestin add-back therapy, there was a significant reduction (P < 0.05, compared with baseline and placebo) of PMS symptoms after six cycles of depot GnRH-a as shown in Figure 2. The most striking improvement was in the decrease in water retention symptoms. During the 6th cycle of GnRH -a, a cycle without MP A, there were no symptoms reported in this category and only 17% of cycles with symptoms at the 12th cycle of GnRH-a, a cycle with MPA. The percentage of cycles with psychological symptoms decrease from 66% of cycles before therapy to 29% with placebo only and continued to diminish over the 12 months oftherapy with 15% of cycles at 6 months and only 5% of cycles associated with these symptoms at 12 months. The symptoms associated with pain improved from 38% of cycles during pretreatment to 18% on placebo, declining further to 10% of cycles at 6 months, and only 5% of cycles had such symptoms at the end of the trial. Both psychological symptoms and symptoms associated with pain progressively improved throughout the 12-month study period. Symptoms during MPA treatment included anxiety, fluid retention, bloating, and mood changes. 934 Mezrow et al. Long-term treatment of PMS with GnRH-a Fertility and Sterility

80 Ul :::& 60 :::& > Ul :c!:: Ul w 40 u u > 1&. 20 0 PRERX PLACEBO -------- 6 CYCLES GnRH-A WATER RETENT PAIN PSYCHOL 12 CYCLES GnRH-A Figure 2 Premenstrual syndrome symptoms at baseline and over the 13-cycle study period. Water retention category includes abdominal bloating, feeling of weight gain, and breast swelling. Pain category includes headache, backache, and muscle pain. Psychological category includes anxiety, depression, mood changes, and lack of concentrate. However, these symptoms were mild to moderate in intensity, occurred only during the treatment days, and were well tolerated by the subjects. The endometrial biopsies obtained at the completion of the study showed inactive, simple glands or progestin effect on the endometrium. Seven of the women had amenorrhea throughout the study period. One patient had irregular bleeding throughout the study, and one had withdrawal bleeding to 200 _, a 100 ::1 + +ddback Saline GnRH'-------- _, CJ Q. 160 Depot GnRH Saline 140 120 100 80 60 40 20 lr 0-3 0 3 6 9 1 2 CYCLES Figure 4 Estrone (D) and E 2 ( +) levels at baseline and over the 13 treatment cycles. Error bars, ±SE. * P < 0.05 from baseline. MP A except for the last MP A cycle. Lipoproteins studies including total cholesterol and HDL, HDL- 2, and LDL cholesterol showed no significant change (Fig. 3). Four of the 10 subjects had results <2 SDs below normal for baseline bone density studies with quantitative computer tomography. Bone density dropped by 3.7% ± 1.6% overall, but this was not statistically significant (95% confidence limits, 0.5% to 6.9%). Estradiol and E 1 levels are shown in Figure 4. All subjects had a decline in E 1 and E 2 levels to postmenopausal levels ( <40 pg/ml [conversion factor to 81 unit, 3.671]) during the first month after GnRH-a before hormone replacement. Estrogen and E 1 levels before treatment were 112.0 ± 39.5 and 74.2 ± 14.6 pg/ml, respectively. Conjugated equine estrogen add-back therapy resulted in E 2 levels at 6 months of 71.5 ± 9.6 pg/ml and at 12 months of 35.5 ± 7.7 pg/ml. Estrone levels with add-back were 56.7 ± 31.3 pg/ml at 6 months and 44.5 ± 16.6 pg/ml at 12 months. DISCUSSION 0 3 6 1 2 14 CYCLES Figure 3 HDL (D), LDL (t), and total cholesterol ( ) levels at baseline during the 13-cycle study period and 4 weeks after the end of the last cycle. Error bars, ±SE. It previously was shown that GnRH -a therapy with low dose E 2 and progestin add-back therapy is more effective than placebo in significantly reducing the symptoms of PMS over a 6-month period. Our study demonstrated the long-term efficacy (12 months) of this treatment with improvement of PMS symptoms in the categories of water reten- Vol. 62, No.5, November 1994 Mezrow et al. Long-term treatment of PMS with GnRH-a 935

tion, pain, and psychological function. Symptoms progressively improved over the 12 treatment cycles in the categories of pain and psychological function. The add-back regimen used in the study allowed for an equivalent exposure of conjugated equine estrogen as the commonly used regimen where conjugated equine estrogen is taken on days 1 through 25. The advantage of our regimen is that it allows for a more steady-state administration and eliminates a long period of E 2 deficiency where symptoms of hypoestrogenism may appear. The addition of MPA every 4 months limits the subject's exposure to progestin, which is often associated with adverse symptoms. The differences in protocol design may explain the disparity between our study results and those reported by Mortola et al. (13), where subjects were noted to have a significant reduction in PMS symptoms during 2 months of treatment with a daily injection of GnRH -a. Subjects then were treated in a double-blind cross-over fashion for 1 month on conjugated equine estrogen alone days 1 through 25, MPA alone on days 16 through 25, MP A plus conjugated equine estrogen, and placebo. The subjects were significantly improved only on placebo and conjugated equine estrogen plus MP A. A reverse placebo effect was reported after the addition of conjugated equine estrogen alone or MP A alone. Our results are similar to Mortola et al. (13), who reported continued alleviation of severe PMS symptoms after bilateral salpingo-oophorectomy and daily conjugated equine estrogen add-back (1.25 mg). However, our protocol alleviates the necessity of an invasive and expensive surgical procedure and allows the subject to retain her childbearing potential. The addition of progestin to E 2 replacement therapy in postmenopausal women results in symptoms identical to PMS that have been well documented (15, 16). Although we saw side effects related to MP A during treatment every 4th month, we found no overall reversal of the improvement of PMS symptoms induced by the GnRH-a. Furthermore, this regimen was sufficient in protecting the endometrium, with all subjects having endometrial biopsies that revealed inactive simple glands or progestin effect. This is an important finding because not only is progestin associated with PMSlike symptoms, it may also reverse some of the cardiovascular benefit obtained with E 2 replacement therapy for postmenopausal women. One of the concerns in treating women with long- term GnRH -a therapy is that a prolonged hypoestrogenic environment may increase their risk for cardiovascular disease, which occurs in women with premature ovarian failure and women who are surgically castrated (17-19). It is therefore important to implement an E 2 replacement regimen that would be the most cardioprotective. In our study, there were no changes in lipoproteins. Further studies are necessary to document any long-term effects of this protocol on the cardiovascular system. Long-term use of GnRH-a alone is contraindicated because of the risk of osteoporosis associated with the use of this agent (20). Estrogen replacement prevents the rapid bone loss seen in untreated oophorectomized women (21). Therefore, E 2 addback therapy should prevent the bone loss seen with GnRH -a therapy and allow for extended treatment. Although there were no significant changes in bone density in our study, one subject lost 4.5%, and the mean overall loss was 3.7% ± 1.6%. This result causes concern and needs further evaluation. Quantitative computer tomography was the method used to evaluate bone density because it was the most accurate test available at the beginning of this study. Dual electron roentgenographic absorptiometry (dexa)-quantitative digital radiography has a much higher precision rate and is preferable to quantitative computer tomography. Results of baseline bone density assessment were also of concern with 4 of the 10 subjects having <2 SDs below normal. quantitative computer tomography bone density. This suggests that chronically lower E 2 levels may be a factor in PMS and deserves further investigation. If this is true, these women may be at higher risk of bone loss with GnRH-a therapy than women treated for other conditions. Future studies are necessary to ensure that the proposed long-term regimen for women with PMS does not result in bone loss, and bone density should be assessed with dexa. Women with moderate to severe PMS symptoms who have not found effective treatment with other modalities are encouraged to undergo a trial of GnRH-a with E 2 and progestin add-back. Gonadotropin-releasing hormone agonist therapy with hormonal replacement consisting of conjugated equine estrogen 6 days/wk and MPA for 10 days every 4 months is a promising treatment for these women because it allows them to retain childbearing capacity and improves their quality of life. Acknowledgment. Lupron was kindly supplied by TAP Pharmaceuticals, Inc., North Chicago, Illinois. 936 Mezrow et al. Long-term treatment of PMS with GnRH-a Fertility and Sterility

REFERENCES 1. Hammarback S, Damber JE, Backstrom T. Relationship between symptom severity and hormone changes in women with premenstrual syndrome. J Clin Endocrinol Metab 1989;68:125-30. 2. Varma TR. Hormones and electrolytes in premenstrual syndrome. Int J Gynaecol Obstet 1984;22:51-8. 3. Watts FF, Butt WR, Logan ER, Holder G. Hormonal studies in women with premenstrual tension. Br J Obstet Gynaecol1985;92:247-55. 4. Rubinow DR, Hoban MC, Grover GN, et a!. Changes in plasma hormones across the menstrual cycle in patients with menstrual related mood disorders and in control subjects. Am J Obstet Gynecol1988;158:5-11. 5. Roy-Byrne PP, Rubinow DR, Hoban MC, Grover GN, Blank D. TSH and prolactin responses to TRH in patients with premenstrual syndrome. Am J Psychiatry 1987;144: 480-4. 6. Casper RF, Patel-Christopher A. Powell AM. Thyrotropin and prolactin responses to thyrotropin-releasing hormone in premenstrual syndrome. J Clin Endocrinol Metab 1989;68:608-12. 7. Casson P, Hahn PM, Van Vugt DA, Reid RL. Lasting response to ovariectomy in severe intractable premenstrual syndrome. Am J Obstet Gynecol1990;162:99-105. 8. Casper RF, Hearn MT. The effect of hysterectomy and bilateral oophorectomy in women with severe premenstrual syndrome. Am J Obstet Gynecol 1990;162:105-9. 9. Backstrom CT, Boyle H, Baird DT. Persistence of symptoms of premenstrual tension in hysterectomized women. Br J Obstet Gynaecol 1981;88:530-5. 10. Hammarback S, Ekholm UB, Backstrom T. Spontaneous anovulation causing disappearance of cyclic symptoms in women with the Premenstrual Syndrome. Acta Obstet Gynecol Scand 1991;125:132-7. 11. Muse KN, CetelNS, Futterman LA, Yen SSC. The premenstrual syndrome: effects of "medical ovariectomy." N Engl J Med 1984;311:1345-9. 12. Hammarback S, Backstrom T. Induced anovulation as a treatment of premenstrual tension syndrome: a doubleblind cross-over study with GnRH agonist versus placebo. Acta Obstet Gynecol Scand 1988;67:159-66. 13. Mortola JF, Girton L, Fischer U. Successful treatment of severe premenstrual syndrome by combined use of gonadotropin-releasing hormone agonist and estrogen/progestin. J Clin Endocrinol Metab 1991;72:252A-F. 14. Goebelsmann U, Bernstein GS, Gale JA, Kletzky OA, Nakamura RM, Coulson AH, et a!. Serum gonadotropin, testosterone, estradiol, estrone levels prior to and following bilateral vasectomy. In: Teprow IH, Crozior R, editors. Vasectomy: immunologic and pathophysiologic effects in animals and man. New York: Academic Press, 1979:165-81. 15. Magos AL, Brewster E, Singh R, O'Dowd T, Brincat M, Studd JW. The effects of norethisterone in postmenopausal women on oestrogen replacement therapy: a model for the premenstrual syndrome. Br J Obstet Gynaecol 1986;93: 1290-6. 16. Hammarback S, Backstrom T, Holst J, Von Schoultz B, Lyrenas S. Cyclical mood changes as in the premenstrual tension syndrome during sequential estrogen-progestogen postmenopausal replacement therapy. Acta Obstet Gynecol Scand 1985;64:393-7. 17. Snajderman M, Oliver MF. Spontaneous premature menopause, ischemic heart disease and serum lipids. Lancet 1963;i:962-4. 18. Oliver MF, Boyd GS. Effect of bilateral ovariectomy on coronary artery disease and serum lipid levels. Lancet 1959;ii:690-4. 19. Parris HM, Carr CA, Hall DG, King TM. Time interval from castration in premenopausal women to development of excessive coronary atherosclerosis. Am J Obstet Gynecol 1967;99:155-62. 20. Johansen JS, Riis BJ, Hassager C, et a!. The effect of a gonadotropin-releasing hormone agonist (Nafarelin) on bone metabolism. J Clin Endocrinol Metab 1988;67:701-4. 21. Aitken JM, Hart DM, Lindsay R. Oestrogen replacement therapy for prevention of osteoporosis after oophorectmy. Br Med J 1973;2:515-8. 22. Hammarback S, Damber JE, Backstrom T. Relationship between symptom severity and hormone changes in women with premenstrual syndrome. J Clin Endocrinol Metab 1989;68:125-30. Vol. 62, No. 5, November 1994 Mezrow et al. Long-term treatment of PMS with GnRH-a 937