Hypogonadism in male cancer patients

Basil O Burney, Jose M Garcia, Basil O Burney, Jose M Garcia

Abstract

Prevalence of hypogonadism in men with cancer has been reported between 40% and 90%, which is significantly higher than in the general population. Hypogonadism is likely to affect the quality of life in these patients by contributing to non-specific symptoms, including decreased energy, anorexia, sarcopenia, weight loss, depression, insomnia, fatigue, weakness, and sexual dysfunction. Pathogenesis of hypogonadism in cancer patients is thought to be multi-factorial. Inflammation may play an important role, but leptin, opioids, ghrelin, and high-dose chemotherapy through different mechanisms have all been implicated as the cause. Hypogonadism is also associated with poor survival in cancer patients. Data looking into the treatment of hypogonadal male cancer patients with testosterone are limited. However, improvements in body weight, muscle strength, lean body mass, and quality of life have been shown in hypogonadal men with other chronic diseases on testosterone replacement therapy. Prospective and interventional trials are needed to test the efficacy and safety of testosterone treatment in improving quality of life of these patients.

Figures

Fig. 1
Fig. 1
Illustration of pituitary–gonadal axis in healthy individuals (a) and in cancer patients (b). Increased ghrelin, decreased leptin, and medications (opioids and glucocorticoids) suppress LH production, thereby causing central hypogonadism. Increased inflammation, certain chemotherapeutic agents, and changes in ghrelin and leptin may also contribute to hypogonadism by downregulating testicular production of testosterone directly. Dashed lines indicate a decrease in the pathway

References

    1. Jemal A, Siegel R, Xu R, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300. doi: 10.3322/caac.20073.
    1. Ries LAG EM, Kosary CL, Hankey BF, Miller MBA, Clegg L,, al. e. SEER cancer statistics review, 197–2000. Bethesda, (MD): National Cancer Institute. 2003.
    1. Strasser F, Palmer JL, Schover LR, Yusuf SW, Pisters K, Vassilopoulou-Sellin R, et al. The impact of hypogonadism and autonomic dysfunction on fatigue, emotional function, and sexual desire in male patients with advanced cancer: a pilot study. Cancer. 2006;107:2949–2957. doi: 10.1002/cncr.22339.
    1. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86:724–731. doi: 10.1210/jc.86.2.724.
    1. Araujo AB, O’Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 2004;89:5920–5926. doi: 10.1210/jc.2003-031719.
    1. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60:762–769. doi: 10.1111/j.1742-1241.2006.00992.x.
    1. Garcia JM, Li H, Mann D, Epner D, Hayes TG, Marcelli M, et al. Hypogonadism in male patients with cancer. Cancer. 2006;106:2583–2591. doi: 10.1002/cncr.21889.
    1. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, Kaur G, Bruera E. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004;100:851–858. doi: 10.1002/cncr.20028.
    1. Todd BD. Pancreatic carcinoma and low serum testosterone; a correlation secondary to cancer cachexia? Eur J Surg Oncol. 1988;14:199–202.
    1. Chlebowski RT, Heber D. Hypogonadism in male patients with metastatic cancer prior to chemotherapy. Cancer Res. 1982;42:2495–2498.
    1. Fleishman SB, Khan H, Homel P, Suhail MF, Strebel-Amrhein R, Mohammad F, et al. Testosterone levels and quality of life in diverse male patients with cancers unrelated to androgens. J Clin Oncol. 2010;28:5054–5060. doi: 10.1200/JCO.2010.30.3818.
    1. Simons JP, Schols AM, Buurman WA, Wouters EF. Weight loss and low body cell mass in males with lung cancer: relationship with systemic inflammation, acute-phase response, resting energy expenditure, and catabolic and anabolic hormones. Clin Sci (Lond). 1999;97:215–223. doi: 10.1042/CS19990021.
    1. Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer. 2002;2:862–871. doi: 10.1038/nrc927.
    1. Pfitzenmaier J, Vessella R, Higano CS, Noteboom JL, Wallace D, Jr, Corey E. Elevation of cytokine levels in cachectic patients with prostate carcinoma. Cancer. 2003;97:1211–1216. doi: 10.1002/cncr.11178.
    1. Tsigos C, Papanicolaou DA, Kyrou I, Raptis SA, Chrousos GP. Dose-dependent effects of recombinant human interleukin-6 on the pituitary-testicular axis. J Interferon Cytokine Res. 1999;19:1271–1276. doi: 10.1089/107999099312948.
    1. Watson ME, Newman RJ, Payne AM, Abdelrahim M, Francis GL. The effect of macrophage conditioned media on Leydig cell function. Ann Clin Lab Sci. 1994;24:84–95.
    1. Afane M, Dubost JJ, Sauvezie B, Issoual D, Dosgilbert A, Grizard G, et al. Modulation of Leydig cell testosterone production by secretory products of macrophages. Andrologia. 1998;30:71–78. doi: 10.1111/j.1439-0272.1998.tb01149.x.
    1. Turnbull AV, Rivier C. Inhibition of gonadotropin-induced testosterone secretion by the intracerebroventricular injection of interleukin-1 beta in the male rat. Endocrinology. 1997;138:1008–1013. doi: 10.1210/en.138.3.1008.
    1. Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab. 2004;89:3313–3318. doi: 10.1210/jc.2003-031069.
    1. Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren LJ, Giltay EJ, Saad F. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol (Oxf).73:602-12.
    1. Cutolo M, Balleari E, Giusti M, Intra E, Accardo S. Androgen replacement therapy in male patients with rheumatoid arthritis. Arthritis Rheum. 1991;34:1–5. doi: 10.1002/art.1780340102.
    1. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382:250–252. doi: 10.1038/382250a0.
    1. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341:879–884. doi: 10.1056/NEJM199909163411204.
    1. Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest. 2003;111:1409–1421.
    1. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351:987–997. doi: 10.1056/NEJMoa040388.
    1. Smiechowska J, Utech A, Taffet G, Hayes T, Marcelli M, Garcia JM. Adipokines in patients with cancer anorexia and cachexia. J Investig Med. 2010;58:554–559.
    1. Furuta M, Funabashi T, Kimura F. Intracerebroventricular administration of ghrelin rapidly suppresses pulsatile luteinizing hormone secretion in ovariectomized rats. Biochem Biophys Res Commun. 2001;288:780–785. doi: 10.1006/bbrc.2001.5854.
    1. Fernandez-Fernandez R, Tena-Sempere M, Navarro VM, Barreiro ML, Castellano JM, Aguilar E, et al. Effects of ghrelin upon gonadotropin-releasing hormone and gonadotropin secretion in adult female rats: in vivo and in vitro studies. Neuroendocrinology. 2005;82:245–255. doi: 10.1159/000092753.
    1. Fernandez-Fernandez R, Tena-Sempere M, Aguilar E, Pinilla L. Ghrelin effects on gonadotropin secretion in male and female rats. Neurosci Lett. 2004;362:103–107. doi: 10.1016/j.neulet.2004.03.003.
    1. Sirotkin AV, Chrenkova M, Nitrayova S, Patras P, Darlak K, Valenzuela F, et al. Effects of chronic food restriction and treatments with leptin or ghrelin on different reproductive parameters of male rats. Peptides. 2008;29:1362–1368. doi: 10.1016/j.peptides.2008.03.011.
    1. Kluge M, Schussler P, Uhr M, Yassouridis A, Steiger A. Ghrelin suppresses secretion of luteinizing hormone in humans. J Clin Endocrinol Metab. 2007;92:3202–3205. doi: 10.1210/jc.2007-0593.
    1. Lanfranco F, Bonelli L, Baldi M, Me E, Broglio F, Ghigo E. Acylated ghrelin inhibits spontaneous luteinizing hormone pulsatility and responsiveness to naloxone but not that to gonadotropin-releasing hormone in young men: evidence for a central inhibitory action of ghrelin on the gonadal axis. J Clin Endocrinol Metab. 2008;93:3633–3639. doi: 10.1210/jc.2008-0049.
    1. Paice JA, Penn RD, Ryan WG. Altered sexual function and decreased testosterone in patients receiving intraspinal opioids. J Pain Symptom Manage. 1994;9:126–131. doi: 10.1016/0885-3924(94)90166-X.
    1. Abs R, Verhelst J, Maeyaert J, Van Buyten JP, Opsomer F, Adriaensen H, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000;85:2215–2222. doi: 10.1210/jc.85.6.2215.
    1. Finch PM, Roberts LJ, Price L, Hadlow NC, Pullan PT. Hypogonadism in patients treated with intrathecal morphine. Clin J Pain. 2000;16:251–254. doi: 10.1097/00002508-200009000-00011.
    1. Pimpinelli F, Parenti M, Guzzi F, Piva F, Hokfelt T, Maggi R. Presence of delta opioid receptors on a subset of hypothalamic gonadotropin releasing hormone (GnRH) neurons. Brain Res. 2006;1070:15–23. doi: 10.1016/j.brainres.2005.11.001.
    1. Delitala G, Grossman A, Besser GM. The participation of hypothalamic dopamine in morphine-induced prolactin release in man. Clin Endocrinol (Oxf). 1983;19:437–444. doi: 10.1111/j.1365-2265.1983.tb00017.x.
    1. Mendelson JH, Ellingboe J, Judson BA, Goldstein A. Plasma testosterone and luteinizing hormone levels during levo-alpha-acetylmethadol maintenance and withdrawal. Clin Pharmacol Ther. 1984;35:545–547. doi: 10.1038/clpt.1984.75.
    1. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377–384. doi: 10.1054/jpai.2002.126790.
    1. Fraser LA, Morrison D, Morley-Forster P, Paul TL, Tokmakejian S, Larry Nicholson R, et al. Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes. 2009;117:38–43. doi: 10.1055/s-2008-1076715.
    1. Howell SJ, Radford JA, Ryder WD, Shalet SM. Testicular function after cytotoxic chemotherapy: evidence of Leydig cell insufficiency. J Clin Oncol. 1999;17:1493–1498.
    1. Palmieri G, Lotrecchiano G, Ricci G, Spiezia R, Lombardi G, Bianco AR, et al. Gonadal function after multimodality treatment in men with testicular germ cell cancer. Eur J Endocrinol. 1996;134:431–436. doi: 10.1530/eje.0.1340431.
    1. Stuart NS, Woodroffe CM, Grundy R, Cullen MH. Long-term toxicity of chemotherapy for testicular cancer—the cost of cure. Br J Cancer. 1990;61:479–484. doi: 10.1038/bjc.1990.106.
    1. Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, et al. Cachexia: a new definition. Clin Nutr. 2008;27:793–799. doi: 10.1016/j.clnu.2008.06.013.
    1. Hijazi RA, Cunningham GR. Andropause: is androgen replacement therapy indicated for the aging male? Annu Rev Med. 2005;56:117–137. doi: 10.1146/annurev.med.56.082103.104518.
    1. Shores MM, Sloan KL, Matsumoto AM, Moceri VM, Felker B, Kivlahan DR. Increased incidence of diagnosed depressive illness in hypogonadal older men. Arch Gen Psychiatry. 2004;61:162–167. doi: 10.1001/archpsyc.61.2.162.
    1. Skipworth RJ, Moses AG, Sangster K, Sturgeon CM, Voss AC, Fallon MT et al. Interaction of gonadal status with systemic inflammation and opioid use in determining nutritional status and prognosis in advanced pancreatic cancer. Support Care Cancer.19:391–401.
    1. Greenfield DM, Walters SJ, Coleman RE, Hancock BW, Snowden JA, Shalet SM et al. Quality of life, self-esteem, fatigue, and sexual function in young men after cancer: a controlled cross-sectional study. Cancer.116:1592–601.
    1. Penson DF, McLerran D, Feng Z, Li L, Albertsen PC, Gilliland FD, et al. 5-year urinary and sexual outcomes after radical prostatectomy: results from the Prostate Cancer Outcomes Study. J Urol. 2008;179:S40–S44. doi: 10.1016/j.juro.2008.03.136.
    1. Deliveliotis C, Liakouras C, Delis A, Skolarikos A, Varkarakis J, Protogerou V. Prostate operations: long-term effects on sexual and urinary function and quality of life. Comparison with an age-matched control population. Urol Res. 2004;32:283–289. doi: 10.1007/s00240-004-0411-0.
    1. Del Fabbro E, Hui D, Nooruddin ZI, Dalal S, Dev R, Freer G, et al. Associations among hypogonadism, C-reactive protein, symptom burden, and survival in male cancer patients with cachexia: a preliminary report. J Pain Symptom Manage. 2010;39:1016–1024. doi: 10.1016/j.jpainsymman.2009.09.021.
    1. Taira AV, Merrick GS, Galbreath RW, Butler WM, Wallner KE, Allen ZA, et al. Pretreatment serum testosterone and androgen deprivation: effect on disease recurrence and overall survival in prostate cancer patients treated with brachytherapy. Int J Radiat Oncol Biol Phys. 2009;74:1143–1149. doi: 10.1016/j.ijrobp.2008.09.046.
    1. Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism. 2000;49:1239–1242. doi: 10.1053/meta.2000.8625.
    1. Svartberg J, Agledahl I, Figenschau Y, Sildnes T, Waterloo K, Jorde R. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res. 2008;20:378–387. doi: 10.1038/ijir.2008.19.
    1. Jockenhovel F, Minnemann T, Schubert M, Freude S, Hubler D, Schumann C, et al. Comparison of long-acting testosterone undecanoate formulation versus testosterone enanthate on sexual function and mood in hypogonadal men. Eur J Endocrinol. 2009;160:815–819. doi: 10.1530/EJE-08-0830.
    1. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89:2085–2098. doi: 10.1210/jc.2003-032006.
    1. Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab. 2003;88:2673–2681. doi: 10.1210/jc.2002-021058.
    1. Rabkin JG, Rabkin R, Wagner G. Testosterone replacement therapy in HIV illness. Gen Hosp Psychiatry. 1995;17:37–42. doi: 10.1016/0163-8343(94)00062-I.
    1. Coodley GO, Coodley MK. A trial of testosterone therapy for HIV-associated weight loss. AIDS. 1997;11:1347–1352. doi: 10.1097/00002030-199711000-00008.
    1. Corcoran C, Grinspoon S. Treatments for wasting in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1999;340:1740–1750. doi: 10.1056/NEJM199906033402207.
    1. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, Krook JE, Wilwerding MB, et al. Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. J Clin Oncol. 1999;17:3299–3306.
    1. Evans WJ, Smith M, Morley JE, et al. Ostarine increases lean body mass and improves physical performance in healthy elderly subjects: implications for cancer cachexia patients. J Clin Oncol. 2007;25:522S.
    1. von Haehling S, Morley JE, Coats AJ, Anker SD. Ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle. J Cachexia Sarcopenia Muscle. 2010;1:7–8.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren