RESUMEN
BACKGROUND: Opioid induced depression of sex hormones is a common finding in chronic pain patients receiving long-term opioids by oral, parenteral and even intrathecal routes of administration. The hypothalamic suppression by opioids leads to a hypogonadal state with low testosterone levels in males and subsequent low bone mineral density (BMD). METHODS: We have studied the effects of intrathecally administered opioids on BMD in a group of male chronic pain patients. In addition, we have studied the effects of supplementary testosterone on bone metabolism to see if the adverse effects of intrathecal opioids can be reversed. RESULTS: Eleven of the 27 patients were on supplementary testosterone having previously been diagnosed as hypogonadal with low serum testosterone. Duration of testosterone supplementation was greater than 2 years in all 11 patients. Both serum total and free testosterone levels were higher in patients on supplementary testosterone than in patients who did not receive this treatment. Of the 16 patients not on testosterone supplement, 14 (87%) had low serum testosterone levels (<10 nmol/L) and 11 (69%) had low or osteoporotic T scores. Within this group, low free testosterone was associated with low BMD scores, and this persisted after correcting for age. Eight of the patients on testosterone supplement had normal BMDT scores and three (27%) had low or osteoporotic T scores. T and age-corrected BMDZ scores were significantly greater in the 11 patients on testosterone supplements than BMD scores in the other 16 patients. CONCLUSION: Testosterone supplementation was found to largely correct the effects of intrathecal opioids on testosterone levels and BMD.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Densidad Ósea/efectos de los fármacos , Hipogonadismo/inducido químicamente , Hipogonadismo/tratamiento farmacológico , Testosterona/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Densidad Ósea/fisiología , Dolor Crónico/diagnóstico , Dolor Crónico/tratamiento farmacológico , Humanos , Hipogonadismo/diagnóstico , Inyecciones Espinales , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Phaeochromocytomas arising in adrenal or extra-adrenal sites and paragangliomas of the head and neck, in particular of the carotid bodies, occur sporadically and also in a familial setting. In addition to mutations in RET and VHL in familial disease, germline mutations in SDHD and SDHB genes that encode subunits of mitochondrial complex II have also been associated with the development of familial phaeochromocytomas. To further investigate the role of SDHD and SDHB in the development of these tumours we determined the occurrence of germline SDHD and SDHB mutations in four patients with a family history of phaeochromocytoma with associated head and neck paraganglioma, one patient with a family history of phaeochromocytoma only and two patients with apparently sporadic extra-adrenal phaeochromocytoma, one of whom had early onset disease. Secondly, we investigated whether somatic SDHB mutations correlated with loss of heterozygosity at 1p36 in a subgroup of 11 sporadic and three MEN 2-associated RET-mutation-positive phaeochromocytomas. Novel SDHB mutations were identified in the probands from four families and two apparently sporadic cases (six of seven probands studied), including two missense mutations, a single nonsense and frameshift mutation, as well as two splice site mutations, one of which was shown to have partial penetrance resulting in 'leaky' splicing. Further, five intronic polymorphisms in SDHB were found. No SDHD mutations were identified. In addition, no somatic SDHB mutations were found in the remaining allele of the 11 sporadic adrenal phaeochromocytomas with allelic loss at 1p36 or the three MEN 2-associated RET-mutation-positive phaeochromocytomas. Therefore, we conclude that SDHB has a major role in the pathogenesis of familial phaeochromocytomas, but the possible role of SDHB in sporadic tumours showing allelic loss at 1p36 has yet to be ascertained.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Proteínas de Neoplasias/genética , Paraganglioma/genética , Feocromocitoma/genética , Subunidades de Proteína/genética , Neoplasias Retroperitoneales/genética , Succinato Deshidrogenasa/genética , Adolescente , Neoplasias de las Glándulas Suprarrenales/enzimología , Adulto , Edad de Inicio , Australia/epidemiología , Niño , Cromosomas Humanos Par 1/genética , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Complejo II de Transporte de Electrones , Mutación del Sistema de Lectura , Mutación de Línea Germinal , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias de Cabeza y Cuello/genética , Humanos , Intrones/genética , Proteínas Hierro-Azufre , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Complejos Multienzimáticos/genética , Neoplasia Endocrina Múltiple/enzimología , Neoplasia Endocrina Múltiple/epidemiología , Neoplasia Endocrina Múltiple/genética , Mutación Missense , Proteínas de Neoplasias/fisiología , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/genética , Oxidorreductasas/genética , Paraganglioma/enzimología , Paraganglioma/epidemiología , Linaje , Feocromocitoma/enzimología , Feocromocitoma/epidemiología , Subunidades de Proteína/deficiencia , Subunidades de Proteína/fisiología , Sitios de Empalme de ARN/genética , Neoplasias Retroperitoneales/enzimología , Succinato Deshidrogenasa/deficiencia , Succinato Deshidrogenasa/fisiologíaRESUMEN
OBJECTIVE: Sexual dysfunction and low testosterone levels have been observed previously in males with chronic noncancer pain treated with intrathecal opioids. To investigate the hypothesis that intrathecal opioids suppress the hypothalamic-pituitary-gonadal axis, a prospective nonrandomized investigation of the function of this axis was undertaken. DESIGN: Ten males with chronic noncancer pain were evaluated for clinical and biochemical evidence of hypogonadism at baseline and during the first twelve weeks of intrathecal opioid therapy. RESULTS: Intrathecal opioid administration resulted in a significant (p <0.0001) reduction in serum testosterone, from 7.7 +/- 1.1 (mean +/- SEM) nmol/L at baseline to 2.0 +/- 0.7, 2.8 +/- 0.5, and 4.0 +/- 0.9 nmol/L at 1, 4, and 12 weeks, respectively. This was associated with a reduction in libido and potency. Luteinizing hormone and follicle-stimulating hormone levels remained within reference ranges, indicating central rather than peripheral suppression. CONCLUSIONS: Administration of intrathecal opioids may result in hypogonadotrophic hypogonadism. As part of the consent for therapy process, patients should be informed about this effect and its management. With long-term intrathecal opioid administration, the hypothalamic-pituitary-gonadal axis should be monitored. Where indicated, testosterone replacement should be undertaken to improve sexual function and prevent the potential metabolic effects of hypogonadism, in particular, osteoporosis.