COMPASS - COpenhagen MenoPAuSe Study

Summary

During menopause, estrogen levels drop while the level of another hormone - LH (luteinizing hormone) substantially increases. This hormonal shift is linked to bone Loss and other complications. Estrogen therapy can help, but some women avoid it due to the increased risk of blood clots and cancer. This project will investigate whether blocking LH could offer a safe alternative to alleviate symptoms and complications of menopause since it is known from previous research that high LH levels contribute to both bone deterioration and metabolic issues. The goal is to explore new treatment options that can improve health and quality of life for women both during and after menopause. This randomized clinical trial is a single center, sponsor-investigator-initiated single-blinded 8 weeks clinical trial with four parallel groups comparing the effect of an gonadotropin releasing hormone(GnRH)-analog with placebo, and with two additional arms given estrogen or testosterone on change on bone health in postmenopausal women with moderate-to-severe symptoms.

Timeline

Start

2025-10-02

Primary completion

2027-12

Completion

2028-05

Publications

• Background Rosen HN, Moses AC, Garber J, Iloputaife ID, Ross DS, Lee SL, Greenspan SL. Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcif Tissue Int. 2000 Feb;66(2):100-3. doi: 10.1007/pl00005830.
• Background Langdahl B, Chung YS, Plebanski R, Czerwinski E, Dokoupilova E, Supronik J, Rosa J, Mydlak A, Rowinska-Osuch A, Baek KH, Urboniene A, Mordaka R, Ahn S, Rho YH, Ban J, Eastell R. Proposed Denosumab Biosimilar SB16 vs Reference Denosumab in Postmenopausal Osteoporosis: Phase 3 Results Up to Month 12. J Clin Endocrinol Metab. 2025 May 19;110(6):e1951-e1958. doi: 10.1210/clinem/dgae611.
• Background Kline GA, Holmes DT. Bone turnover markers for assessment of anti-resorptive effect in clinical practice: A good idea meets the problem of measurement uncertainty. Clin Biochem. 2023 Jun;116:100-104. doi: 10.1016/j.clinbiochem.2023.04.007. Epub 2023 Apr 19.
• Background Brown JP, Don-Wauchope A, Douville P, Albert C, Vasikaran SD. Current use of bone turnover markers in the management of osteoporosis. Clin Biochem. 2022 Nov-Dec;109-110:1-10. doi: 10.1016/j.clinbiochem.2022.09.002. Epub 2022 Sep 9.
• Background Migliorini F, Maffulli N, Spiezia F, Peretti GM, Tingart M, Giorgino R. Potential of biomarkers during pharmacological therapy setting for postmenopausal osteoporosis: a systematic review. J Orthop Surg Res. 2021 May 31;16(1):351. doi: 10.1186/s13018-021-02497-0.
• Background Everts-Graber J, Reichenbach S, Ziswiler HR, Studer U, Lehmann T. A Single Infusion of Zoledronate in Postmenopausal Women Following Denosumab Discontinuation Results in Partial Conservation of Bone Mass Gains. J Bone Miner Res. 2020 Jul;35(7):1207-1215. doi: 10.1002/jbmr.3962. Epub 2020 Feb 11.
• Background Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen EF, Guanabens N, Obermayer-Pietsch B, Ralston SH, Eastell R, Zillikens MC. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone. 2017 Dec;105:11-17. doi: 10.1016/j.bone.2017.08.003. Epub 2017 Aug 5.
• Background Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11.
• Background Yu L, Buysse DJ, Germain A, Moul DE, Stover A, Dodds NE, Johnston KL, Pilkonis PA. Development of short forms from the PROMIS sleep disturbance and Sleep-Related Impairment item banks. Behav Sleep Med. 2011 Dec 28;10(1):6-24. doi: 10.1080/15402002.2012.636266.
• Background Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006 May 22;166(10):1092-7. doi: 10.1001/archinte.166.10.1092.
• Background Greene JG. A factor analytic study of climacteric symptoms. J Psychosom Res. 1976;20(5):425-30. doi: 10.1016/0022-3999(76)90005-2. No abstract available.
• Background Derogatis LR, Rosen R, Leiblum S, Burnett A, Heiman J. The Female Sexual Distress Scale (FSDS): initial validation of a standardized scale for assessment of sexually related personal distress in women. J Sex Marital Ther. 2002 Jul-Sep;28(4):317-30. doi: 10.1080/00926230290001448.
• Background Rosen R, Brown C, Heiman J, Leiblum S, Meston C, Shabsigh R, Ferguson D, D'Agostino R Jr. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther. 2000 Apr-Jun;26(2):191-208. doi: 10.1080/009262300278597.
• Background Hilditch JR, Lewis J, Peter A, van Maris B, Ross A, Franssen E, Guyatt GH, Norton PG, Dunn E. A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas. 1996 Jul;24(3):161-75. doi: 10.1016/s0378-5122(96)82006-8.
• Background Radtke JV, Terhorst L, Cohen SM. The Menopause-Specific Quality of Life Questionnaire: psychometric evaluation among breast cancer survivors. Menopause. 2011 Mar;18(3):289-95. doi: 10.1097/gme.0b013e3181ef975a.
• Background Shieh A, Karlamangla AS, Gossiel F, Eastell R, Burnett-Bowie SA, Greendale GA. Estimating Net Bone Formation Relative to Resorption Using Reference Bone Turnover Markers. J Clin Endocrinol Metab. 2025 Jul 15;110(8):e2544-e2552. doi: 10.1210/clinem/dgae842.
• Background Nathorst-Boos J, Floter A, Jarkander-Rolff M, Carlstrom K, Schoultz Bv. Treatment with percutanous testosterone gel in postmenopausal women with decreased libido--effects on sexuality and psychological general well-being. Maturitas. 2006 Jan 10;53(1):11-8. doi: 10.1016/j.maturitas.2005.01.002. Epub 2005 Sep 23.
• Background Donovitz G, Cotten M. Breast Cancer Incidence Reduction in Women Treated with Subcutaneous Testosterone: Testosterone Therapy and Breast Cancer Incidence Study. Eur J Breast Health. 2021 Mar 31;17(2):150-156. doi: 10.4274/ejbh.galenos.2021.6213. eCollection 2021 Apr.
• Background Glaser RL, York AE, Dimitrakakis C. Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study. BMC Cancer. 2019 Dec 30;19(1):1271. doi: 10.1186/s12885-019-6457-8.
• Background Goldstat R, Briganti E, Tran J, Wolfe R, Davis SR. Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women. Menopause. 2003 Sep-Oct;10(5):390-8. doi: 10.1097/01.GME.0000060256.03945.20.
• Background El-Hage G, Eden JA, Manga RZ. A double-blind, randomized, placebo-controlled trial of the effect of testosterone cream on the sexual motivation of menopausal hysterectomized women with hypoactive sexual desire disorder. Climacteric. 2007 Aug;10(4):335-43. doi: 10.1080/13697130701364644.
• Background Simon J, Braunstein G, Nachtigall L, Utian W, Katz M, Miller S, Waldbaum A, Bouchard C, Derzko C, Buch A, Rodenberg C, Lucas J, Davis S. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab. 2005 Sep;90(9):5226-33. doi: 10.1210/jc.2004-1747. Epub 2005 Jul 12.
• Background Panay N, Al-Azzawi F, Bouchard C, Davis SR, Eden J, Lodhi I, Rees M, Rodenberg CA, Rymer J, Schwenkhagen A, Sturdee DW. Testosterone treatment of HSDD in naturally menopausal women: the ADORE study. Climacteric. 2010 Apr;13(2):121-31. doi: 10.3109/13697131003675922.
• Background Shifren JL, Davis SR, Moreau M, Waldbaum A, Bouchard C, DeRogatis L, Derzko C, Bearnson P, Kakos N, O'Neill S, Levine S, Wekselman K, Buch A, Rodenberg C, Kroll R. Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: results from the INTIMATE NM1 Study. Menopause. 2006 Sep-Oct;13(5):770-9. doi: 10.1097/01.gme.0000243567.32828.99.
• Background Hofling M, Lundstrom E, Azavedo E, Svane G, Hirschberg AL, von Schoultz B. Testosterone addition during menopausal hormone therapy: effects on mammographic breast density. Climacteric. 2007 Apr;10(2):155-63. doi: 10.1080/13697130701258812.
• Background Fooladi E, Bell RJ, Jane F, Robinson PJ, Kulkarni J, Davis SR. Testosterone improves antidepressant-emergent loss of libido in women: findings from a randomized, double-blind, placebo-controlled trial. J Sex Med. 2014 Mar;11(3):831-9. doi: 10.1111/jsm.12426. Epub 2014 Jan 16.
• Background Davis SR, Hirschberg AL, Wagner LK, Lodhi I, von Schoultz B. The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving systemic estrogen therapy. J Clin Endocrinol Metab. 2009 Dec;94(12):4907-13. doi: 10.1210/jc.2009-1523. Epub 2009 Oct 22.
• Background Davis SR, van der Mooren MJ, van Lunsen RH, Lopes P, Ribot C, Rees M, Moufarege A, Rodenberg C, Buch A, Purdie DW. Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Menopause. 2006 May-Jun;13(3):387-96. doi: 10.1097/01.gme.0000179049.08371.c7.
• Background Buster JE, Kingsberg SA, Aguirre O, Brown C, Breaux JG, Buch A, Rodenberg CA, Wekselman K, Casson P. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol. 2005 May;105(5 Pt 1):944-52. doi: 10.1097/01.AOG.0000158103.27672.0d.
• Background Kocoska-Maras L, Hirschberg AL, Bystrom B, Schoultz BV, Radestad AF. Testosterone addition to estrogen therapy - effects on inflammatory markers for cardiovascular disease. Gynecol Endocrinol. 2009 Dec;25(12):823-7. doi: 10.3109/09513590903056134.
• Background Floter A, Nathorst-Boos J, Carlstrom K, Ohlsson C, Ringertz H, Schoultz Bv. Effects of combined estrogen/testosterone therapy on bone and body composition in oophorectomized women. Gynecol Endocrinol. 2005 Mar;20(3):155-60. doi: 10.1080/09513590400021193.
• Background Floter A, Nathorst-Boos J, Carlstrom K, von Schoultz B. Addition of testosterone to estrogen replacement therapy in oophorectomized women: effects on sexuality and well-being. Climacteric. 2002 Dec;5(4):357-65.
• Background Moller MC, Bartfai AB, Radestad AF. Effects of testosterone and estrogen replacement on memory function. Menopause. 2010 Sep-Oct;17(5):983-9. doi: 10.1097/gme.0b013e3181dc2e40.
• Background Moller MC, Radestad AF, von Schoultz B, Bartfai A. Effect of estrogen and testosterone replacement therapy on cognitive fatigue. Gynecol Endocrinol. 2013 Feb;29(2):173-6. doi: 10.3109/09513590.2012.730568. Epub 2012 Oct 25.
• Background Dias RS, Kerr-Correa F, Moreno RA, Trinca LA, Pontes A, Halbe HW, Gianfaldoni A, Dalben IS. Efficacy of hormone therapy with and without methyltestosterone augmentation of venlafaxine in the treatment of postmenopausal depression: a double-blind controlled pilot study. Menopause. 2006 Mar-Apr;13(2):202-11. doi: 10.1097/01.gme.0000198491.34371.9c.
• Background Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, Burki RE, Ginsburg ES, Rosen RC, Leiblum SR, Caramelli KE, Mazer NA. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000 Sep 7;343(10):682-8. doi: 10.1056/NEJM200009073431002.
• Background Wisniewski AB, Nguyen TT, Dobs AS. Evaluation of high-dose estrogen and high-dose estrogen plus methyltestosterone treatment on cognitive task performance in postmenopausal women. Horm Res. 2002;58(3):150-5. doi: 10.1159/000064491.
• Background Penteado SR, Fonseca AM, Bagnoli VR, Abdo CH, Junior JM, Baracat EC. Effects of the addition of methyltestosterone to combined hormone therapy with estrogens and progestogens on sexual energy and on orgasm in postmenopausal women. Climacteric. 2008 Feb;11(1):17-25. doi: 10.1080/13697130701741932.
• Background Leao LM, Duarte MP, Silva DM, Bahia PR, Coeli CM, de Farias ML. Influence of methyltestosterone postmenopausal therapy on plasma lipids, inflammatory factors, glucose metabolism and visceral fat: a randomized study. Eur J Endocrinol. 2006 Jan;154(1):131-9. doi: 10.1530/eje.1.02065.
• Background de Paula FJ, Soares JM Jr, Haidar MA, de Lima GR, Baracat EC. The benefits of androgens combined with hormone replacement therapy regarding to patients with postmenopausal sexual symptoms. Maturitas. 2007 Jan 20;56(1):69-77. doi: 10.1016/j.maturitas.2006.06.005. Epub 2006 Jul 5.
• Background Basaria S, Nguyen T, Rosenson RS, Dobs AS. Effect of methyl testosterone administration on plasma viscosity in postmenopausal women. Clin Endocrinol (Oxf). 2002 Aug;57(2):209-14. doi: 10.1046/j.1365-2265.2002.01584.x.
• Background Islam RM, Bell RJ, Green S, Page MJ, Davis SR. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. Lancet Diabetes Endocrinol. 2019 Oct;7(10):754-766. doi: 10.1016/S2213-8587(19)30189-5. Epub 2019 Jul 25.
• Background Bowen RL, Perry G, Xiong C, Smith MA, Atwood CS. A clinical study of lupron depot in the treatment of women with Alzheimer's disease: preservation of cognitive function in patients taking an acetylcholinesterase inhibitor and treated with high dose lupron over 48 weeks. J Alzheimers Dis. 2015;44(2):549-60. doi: 10.3233/JAD-141626.
• Background Ludvigsson JF, Adolfsson J, Hoistad M, Rydelius PA, Kristrom B, Landen M. A systematic review of hormone treatment for children with gender dysphoria and recommendations for research. Acta Paediatr. 2023 Nov;112(11):2279-2292. doi: 10.1111/apa.16791. Epub 2023 May 1.
• Background Glaser R, York AE, Dimitrakakis C. Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS). Maturitas. 2011 Apr;68(4):355-61. doi: 10.1016/j.maturitas.2010.12.001. Epub 2010 Dec 21.
• Background Chidi-Ogbolu N, Baar K. Effect of Estrogen on Musculoskeletal Performance and Injury Risk. Front Physiol. 2019 Jan 15;9:1834. doi: 10.3389/fphys.2018.01834. eCollection 2018.
• Background Greendale GA, Sternfeld B, Huang M, Han W, Karvonen-Gutierrez C, Ruppert K, Cauley JA, Finkelstein JS, Jiang SF, Karlamangla AS. Changes in body composition and weight during the menopause transition. JCI Insight. 2019 Mar 7;4(5):e124865. doi: 10.1172/jci.insight.124865. eCollection 2019 Mar 7.
• Background Juel Mortensen L, Kooij I, Lorenzen M, Rye Jorgensen N, Roder A, Jorgensen A, Andersson AM, Juul A, Blomberg Jensen M. Injection of luteinizing hormone or human chorionic gonadotropin increases calcium excretion and serum PTH in males. Cell Calcium. 2024 Sep;122:102908. doi: 10.1016/j.ceca.2024.102908. Epub 2024 May 24.
• Background Neff LM, Hoffmann ME, Zeiss DM, Lowry K, Edwards M, Rodriguez SM, Wachsberg KN, Kushner R, Landsberg L. Core body temperature is lower in postmenopausal women than premenopausal women: potential implications for energy metabolism and midlife weight gain. Cardiovasc Endocrinol. 2016 Dec;5(4):151-154. doi: 10.1097/XCE.0000000000000078.
• Background van Gastel P, van der Zanden M, Telting D, Filius M, Bancsi L, de Boer H. Luteinizing hormone-releasing hormone receptor antagonist may reduce postmenopausal flushing. Menopause. 2012 Feb;19(2):178-85. doi: 10.1097/gme.0b013e31822542ca.
• Background Casper RF, Yen SS. Neuroendocrinology of menopausal flushes: an hypothesis of flush mechanism. Clin Endocrinol (Oxf). 1985 Mar;22(3):293-312. doi: 10.1111/j.1365-2265.1985.tb03243.x. No abstract available.
• Background Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ, Wactawski-Wende J, Jackson RD, Limacher M, Margolis KL, Wassertheil-Smoller S, Beresford SA, Cauley JA, Eaton CB, Gass M, Hsia J, Johnson KC, Kooperberg C, Kuller LH, Lewis CE, Liu S, Martin LW, Ockene JK, O'Sullivan MJ, Powell LH, Simon MS, Van Horn L, Vitolins MZ, Wallace RB. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013 Oct 2;310(13):1353-68. doi: 10.1001/jama.2013.278040.
• Background Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019 Sep 28;394(10204):1159-1168. doi: 10.1016/S0140-6736(19)31709-X. Epub 2019 Aug 29.
• Background Monteleone P, Mascagni G, Giannini A, Genazzani AR, Simoncini T. Symptoms of menopause - global prevalence, physiology and implications. Nat Rev Endocrinol. 2018 Apr;14(4):199-215. doi: 10.1038/nrendo.2017.180. Epub 2018 Feb 2.
• Background Vestergaard P, Rejnmark L, Mosekilde L. Increased mortality in patients with a hip fracture-effect of pre-morbid conditions and post-fracture complications. Osteoporos Int. 2007 Dec;18(12):1583-93. doi: 10.1007/s00198-007-0403-3. Epub 2007 Jun 14.
• Background Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet. 2019 Jan 26;393(10169):364-376. doi: 10.1016/S0140-6736(18)32112-3.
• Background Grey A, Bolland MJ. The effect of treatments for osteoporosis on mortality. Osteoporos Int. 2013 Jan;24(1):1-6. doi: 10.1007/s00198-012-2176-6. Epub 2012 Oct 18.
• Background Lee E, Anselmo M, Tahsin CT, Vanden Noven M, Stokes W, Carter JR, Keller-Ross ML. Vasomotor symptoms of menopause, autonomic dysfunction, and cardiovascular disease. Am J Physiol Heart Circ Physiol. 2022 Dec 1;323(6):H1270-H1280. doi: 10.1152/ajpheart.00477.2022. Epub 2022 Nov 11.
• Background Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, Dawson-Hughes B. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014 Nov;29(11):2520-6. doi: 10.1002/jbmr.2269.
• Background Knight MG, Anekwe C, Washington K, Akam EY, Wang E, Stanford FC. Weight regulation in menopause. Menopause. 2021 May 24;28(8):960-965. doi: 10.1097/GME.0000000000001792.
• Background Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women's lives. Am J Med. 2005 Dec 19;118 Suppl 12B:14-24. doi: 10.1016/j.amjmed.2005.09.031.
• Background Nelson HD. Menopause. Lancet. 2008 Mar 1;371(9614):760-70. doi: 10.1016/S0140-6736(08)60346-3.

Drugs

Indications