Blog changes

Thanks to everyone who followed Training Because I Can! over the last nine years. This blog started with Addison's Disease, hypothyroidism and a crazy idea of doing an Ironman distance triathlon. My life has changed and so has this blog. I am using this blog strictly for Addison's Support topics from here on out. I hope to continue providing people with hints for living life well with adrenal insufficiency.

Thursday, March 13, 2008

Addison's: Why is the management of glucocorticoid deficiency still controversial: A review of the literature

Why is the management of glucocorticoid deficiency still controversial: A review of the literature
Anna Crown; Stafford Lightman
Clinical Endocrinology. 2005;63(5):483-492.

The above review can be accessed through MedScape. You need a free account to access it. Below you will find my review of the review from an Addisonian's realistic perspective. My comments will be in light pink. All quotes taken directly from the review will be in quotation marks.

The article is summarized by saying that doctors need to try to treat primary and secondary hypoadrenal patients by giving them hydrocortisone in as physiological way as possible. Quality of life for Addison's patients is better when doses are split up and the lowest possible hydrocortisone dose is achieved. Adverse effects of overreplacement such as effects on bone, blood sugar and heart function can be avoided with optimal dosing of hydrocortisone.

Normal Physiology: The article has an interesting discussion about glucocorticoid production by normal males in early and late puberty. The authors claim that cortisol production by these males is lower than previously thought. 90% of cortisol is bound to Cortisol Binding Globulin. Cortisone is converted to cortisol in fat tissue, liver, brain and bone. The mechanism by which it is converted is very complex.

The Normal Pattern of Glucocorticoid Secretion: Diurnal and Ultradian Rhythmicity: Cortisol is released by the human body in the greatest amount prior to awakening and the amount released decreases through out the day. The article suggests that prolonged, nonphysiological, continuous exposure could decrease the the number of glucocorticoid receptors. To me, this is a good argument for the short acting steroid of hydrocortisone vs. prednisone, medrol, dexamethasone. I also think this backs up the theory of taking 50 % of the hydrocortisone dose BEFORE GETTING OUT OF BED, 25% midday and 25% in the afternoon. Don't take my word for it, check out the journal abstracts in the sidebar!

Pregnancy: Nothing noteworthy

Implications for Our Understanding of the Normal Physiology for Glucocorticoid Replacement Therapy:

  • Because conversion of cortisone to cortisol in the liver is innefficient, "...very little orally administered cortisone reaches the systemic circulation. [6, 27, 28]
  • "Hydrocortisone probably remains the most physiological drug of choice."
  • "It is important to consider the metabolism of other synthetic glucocorticoids when considering their use as replacement therapy in adrenal insufficiency."
  • We must try to "avoid unphysiologically high glucocorticoid levels" through out the day "recommending that patients take their last dose of hydrocortisone in the afternoon rather than the evening....If patients take most of their hydrocortisone in the morning and their last dose of hydrocortisone early, there will at least be a period of low receptor occupancy overnight."
  • Methods of measurement of hydrocortisone (day curve and urinary free cortisol) are discussed.
  • Lowest possible dose to make the patient feel well is recommended.
  • ACTH measurement is not a reliable way to test glucorticoid replacement. [41]
The Effect of Different Glucocorticoid Replacement Regimens on Clinical Outcomes

Bone: "Overall, there is some evidence of a lower bone mineral density in hypoadrenal patients on glucocorticoid replacement therapy, perhaps particularly in postmenopausal women, although less evidence of a negative correlation between glucocorticoid dose and bone mineral density. Serum osteocalcin (a marker of osteoblast activity) does seem to correlate inversely with the glucocorticoid dose, although no trends are seen in other markers of bone formation or resorption: this may reflect a pharmacological effect of glucocorticoids on osteocalcin secretion per se, which is recognized to be very sensitive to glucocorticoid excess.[23,48]".

Glucose Metabolism and Cardiovascular Function: "
Thus there is some evidence that untreated hypoadrenal patients may start with relatively favourable cardiovascular risk profiles, such as lower insulin concentrations and lower blood pressures than controls. There is evidence that glucocorticoid replacement therapy increases postprandial glucose and insulin concentrations in hypoadrenal patients."

Quality of Life: "Thus, the available evidence suggests that patients may complain of an impaired quality of life even on relatively high doses of steroids. Although one study showed a correlation between plasma cortisol concentrations and well-being, a more rigorous study showed no correlation between hydrocortisone dose (and urinary free cortisol excretion) and quality of life. There is some evidence that the quality of life of hypoadrenal patients is better on a twice daily replacement regimen than a once daily regimen, and may be better on a thrice daily regimen (although as discussed this data is not strong). "

Mortality: No statistical difference between us and "normals".

Interactions With Other Hormone Replacement Therapy and Medication: "Hyperthyroidism increases the metabolism and clearance of cortisol.[5,7] Rifampicin and phenytoin also increase cortisol clearance:[5] adrenal crises have been reported in patients receiving corticosteroid replacement therapy for primary adrenal failure who were treated with rifampicin.[59]."
'Sick day Rules', 'Well Day Recommendations' and Pregnancy:
  • Double your dose if you have a fever.
  • Most patients, although they might consider themselves well informed, don't know how to treat themselves when sick.
  • The authors dropped the ball here: 'Well Day Recommendations'. They consider a test to be the same stress as running a marathon. They do not consider that running a marathon requires months of consistent training and stress on the body (10 - 15 hours a week). A marathon is not a one time event. NO ONE goes out and just runs 26.2 miles off the couch, even healthy people. The authors recommend that hydrocortisone NOT be increased for training based on a small study of teenage boys with CAH who were asked to fast and exercise to maximal capacity one day and then for 90 minutes the next [9]. A one time 2 hour burst of exercise by teenage boys can not be compared to a 40 year old woman running 40 - 50 miles a week. A ridiculous oversight in my opinion.
  • Pregnancy recommendations with respect to steroids are made. I won't go into the details.
  • Evidence exists that women have an improved quality of life when on DHEA [65].
References
  1. Esteban, N., Loughlin, T., Yergey, A., Zawadzki, J., Booth, J., Winterer, J. & Loriaux, D. (1991) Daily cortisol production rate in man determined by stable isotope dilution / mass spectrometry. Journal of Clinical Endocrinology and Metabolism, 71, 39-45.
  2. Kerrigan, J., Veldhuis, J., Leyo, S., Iranmanesh, A. & Rogol, A. (1993) Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis. Journal of Clinical Endocrinology and Metabolism, 76, 1505-1510.
  3. Veldhuis, J. (1997) How does one get at glandular secretion, when only hormone concentrations are measured? Clinical Endocrinology, 46, 397-400.
  4. Veldhuis, J. & Johnson, M. (1992) Deconvolution analysis of hormone data. Methods in Enzymology, 210, 539-575.
  5. Stewart, P. (2003) The adrenal cortex. In: P. Larsen, H. Kronenberg, S. Melmed, K. Polonsky eds. Williams Textbook of Endocrinology, 10th edn. Saunders, Philadelphia, USA, 491-551.
  6. Seckl, J. & Walker, B. (2001) Minireview: 11-beta-hydroxysteroid dehydrogenase type 1 - a tissue-specific amplifier of glucocorticoid action. Endocrinology, 142, 1371-1376.
  7. Tomlinson, J., Walker, E., Bujalska, I., Draper, N., Lavery, G., Cooper, M., Hewison, M. & Stewart, P. (2004) 11-beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocrine Reviews, 25, 831-866.
  8. Seckl, J. & Walker, B. (2004) 11-beta-hydroxysteroid dehydrogenase type 1 as a modulator of glucocorticoid action: from metabolism to memory. Trends in Endocrinology and Metabolism, 15, 418-424.
  9. Stewart, P. (2003) Tissue-specific Cushing's syndrome, 11-beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action. European Journal of Endocrinology, 149, 163-168.
  10. Sandeep, T., Yau, J., MacLullich, A., Noble, J., Deary, I., Walker, B. & Seckl, J. (2004) 11 beta-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proceedings of the National Academy of Sciences of the United States of America, 101, 6734-6739.
  11. Bergendahl, M., Iranmanesh, A., Mulligan, T. & Veldhuis, J. (2000) Impact of age on cortisol secretory dynamics basally and as driven by nutrient-withdrawal stress. Journal of Clinical Endocrinology and Metabolism, 85, 2203-2214.
  12. Chrousos, G. (1998) Ultradian, circadian, and stress-related hypothalamic-pituitary-adrenal axis activity - a dynamic digital-to-analog modulation. Endocrinology, 139, 437-439.
  13. Young, E., Abelson, J. & Lightman, S. (2004) Cortisol pulsatility and its role in stress regulation and health. Frontiers in Neuroendocrinology, 25, 69-76.
  14. Windle, R., Wood, S., Shanks, N., Lightman, S. & Ingram, C. (1998) Ultradian rhythm of basal corticosterone release in the female rat: dynamic interaction with the response to acute stress. Endocrinology, 139, 443-450.
  15. Sarnyai, Z., Veldhuis, J., Mello, N., Mendelson, J., Eros-Sarnyai, M., Mercer, G., Gelles, H. & Kelly, M. (1995) The concordance of pulsatile ultradian release of adrenocorticotrophin and cortisol in male rhesus monkeys. Journal of Clinical Endocrinology and Metabolism, 80, 54-59.
  16. Hartmann, A., Veldhuis, J., Deuschle, M., Standhardt, H. & Heuser, I. (1997) Twenty-four hour cortisol release profiles in patients with Alzheimer's and Parkinson's disease compared to normal controls: ultradian secretory pulsatility and diurnal variation. Neurobiology of Aging, 18, 285-289.
  17. Invitti, C., De Martin, M., Delitala, G., Veldhuis, J. & Cavagnini, F. (1998) Altered morning and nighttime pulsatile corticotrophin and cortisol release in polycystic ovary syndrome. Metabolism, 47, 143-148.
  18. Thompson, E., Tomkins, G. & Curran, J. (1966) Induction of tyrosine alpha-ketoglutarate transaminase by steroid hormones in a newly established tissue culture cell line. Proceedings of the National Academy of Sciences of the United States of America, 56, 296-303.
  19. Ramakrishnan, R., Dubois, D., Almon, R., Pyszczynski, N. & Jusko, W. (2002) Pharmacodynamics and pharmacogenomics of methylprednisolone during 7-day infusions in rats. Journal of Pharmacology and Experimental Therapeutics, 300, 245-256.
  20. Dekelbab, B., Witchel, S. & DeFranco, D. (2004) Continuous versus intermittent administration of glucocorticoids: ligand-dependent down-regulation of glucocorticoid receptor revisited. P2-131.
  21. Trainer, P. (2002) Corticosteroids and pregnancy. Seminars in Reproductive Medicine, 20, 375-380.
  22. Stewart, P., Rogerson, F. & Mason, J. (1995) Type 2 11-beta-hydroxysteroid dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal adrenal steroidogenesis. Journal of Clinical Endocrinology and Metabolism, 80, 885-890.
  23. Edwards, C., Benediktsson, R., Lindsay, R. & Seckl, J. (1996) 11-beta-hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects. Steroids, 61, 263-269.
  24. Seckl, J. & Chapman, K. (1997) The 11-beta-hydroxysteroid dehydrogenase system, a determinant of glucocorticoid and mineralocorticoid action. European Journal of Biochemistry, 249, 361-364.
  25. Benediktsson, R., Calder, A., Edwards, C. & Seckl, J. (1997) Placental 11-beta-hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure. Clinical Endocrinology, 46, 161-166.
  26. Barker, D. (1995) Fetal origins of coronary heart disease. British Medical Journal, 311, 171-174.
  27. Feek, C., Ratcliffe, J., Seth, J., Gray, C., Toft, A. & Irvine, W. (1981) Patterns of plasma cortisol and ACTH concentrations in patients with Addison's disease treated with conventional corticosteroid replacement. Clinical Endocrinology, 14, 451-458.
  28. Barbato, A. & Landau, R. (1977) Serum cortisol appearance-disappearance in adrenal insufficiency after oral cortisone acetate. Acta Endocrinologica, 84, 600-604.
  29. Diederich, S., Eigendorff, E., Burkhardt, P., Quinkler, M., Bumke-Vogt, C., Rochel, M., Seidelmann, D., Esperling, P., Oelkers, W. & Bahr, V. (2002) 11-beta-hydroxysteroid dehydrogenase types 1 and 2: an important pharmacokinetic determinant for the activity of synthetic mineralo- and glucocorticoids. Journal of Clinical Endocrinology and Metabolism, 87, 5695-5701.
  30. Addison, R., Maguire, D., Mortimer, R. & Cannell, G. (1991) Metabolism of prednisolone by the isolated perfused human placental lobule. Journal of Steroid Biochemistry and Molecular Biology, 39, 83-90.
  31. Addison, R., Maguire, D., Mortimer, R., Roberts, M. & Cannell, G. (1993) Pathway and kinetics of prednisolone metabolism in the human placenta. Journal of Steroid Biochemistry and Molecular Biology, 44, 315-320.
  32. Aanderud, S. & Myking, O. (1981) Plasma cortisol concentrations after oral substitution of cortisone in the fasting and non-fasting state. Acta Medica Scandinavica, 210, 157-161.
  33. Howlett, T. (1997) An assessment of optimal hydrocortisone replacement therapy. Clinical Endocrinology, 46, 263-268.
  34. Wong, V., Yan, T., Donald, A. & McLean, M. (2004) Saliva and bloodspot cortisol: novel sampling methods to assess hydrocortisone replacement therapy in hypoadrenal patients. Clinical Endocrinology, 61, 131-137.
  35. Mah, P., Jenkins, R., Rostami-Hodjegan, A., Newell-Price, J., Doane, A., Ibbotson, V., Tucker, G. & Ross, R. (2004) Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clinical Endocrinology, 61, 367-375.
  36. Trainer, P., McHardy, K., Harvey, R. & Reid, I. (1993) Urinary free cortisol in the assessment of hydrocortisone replacement therapy. Hormone and Metabolic Research, 25, 117-120.
  37. Agha, A., Liew, A., Finucane, F., Baker, L., O'Kelly, P., Tormey, W. & Thompson, C. (2004) Conventional glucocorticoid replacement overtreats adult hypopituitary patients with partial ACTH deficiency. Clinical Endocrinology, 60, 688-693.
  38. Laureti, S., Falorni, A. & Santeusanio, F. (2003) Improvement of treatment of primary adrenal insufficiency by administration of cortisone acetate in three daily doses. Journal of Endocrinological Investigation, 26, 1071-1075.
  39. Bliesener, N., Steckelbroeck, S., Redel, L. & Klingmuller, D. (2003) Dose distribution in hydrocortisone replacement therapy has a significant influence on urine free cortisol excretion. Experimental Clinical Endocrinology and Diabetes, 111, 443-446.
  40. Monson, J. (1997) The assessment of glucocorticoid replacement therapy. Clinical Endocrinology, 46, 269-270.
  41. Dallman, M. (1984) Control of adrenocortical growth in vivo. Endocrine Research, 10, 213-242.
  42. Valero, M.-A., Leon, M., Ruiz Valdepenas, M., Larrodera, L., Lopez, M., Papapietro, K., Jara, A. & Hawkins, F. (1994) Bone density and turnover in Addison's disease: effect of glucocorticoid treatment. Bone and Mineral, 26, 9-17.
  43. Zelissen, P., Croughs, R., van Rijk, P. & Raymakers, J. (1994) Effect of glucocorticoid replacement therapy on bone mineral density in patients with Addison disease. Annals of Internal Medicine, 120, 207-210.
  44. Florkowski, C., Holmes, S., Elliot, J., Donald, R. & Espiner, E. (1994) Bone mineral density if reduced in female but not male subjects with Addison's disease. New Zealand Medical Journal, 107, 52-53.
  45. Peacey, S., Guo, C.-Y., Robinson, A., Price, A., Giles, M., Eastell, R. & Weetman, A. (1997) Glucocorticoid replacement therapy: are patients overtreated and does it matter? Clinical Endocrinology, 46, 255-261.
  46. Wichers, M., Springer, W., Bidlingmaier, F. & Klingmuller, D. (1999) The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism. Clinical Endocrinology, 50, 759-765.
  47. Suliman, A., Freaney, R., Smith, T., McBrinn, Y., Murray, B. & McKenna, T. (2003) The impact of different glucocorticoid replacement schedules on bone turnover and insulin sensitivity in patients with adrenal insufficiency. Clinical Endocrinology, 59, 380-387.
  48. Jeffcoate, W. (1999) Assessment of corticosteroid replacement therapy in adults with adrenal insufficiency. Annals of Clinical Biochemistry, 36, 151-157.
  49. Malerbi, D., Liberman, B., Giurno-Filho, A., Giannella-Neto, D. & Wajchenberg, B. (1988) Glucocorticoids and glucose metabolism: hepatic glucose production in untreated Addisonian patients and on two different levels of glucocorticoid administration. Clinical Endocrinology, 28, 415-422.
  50. Al-Shoumer, K., Beshyah, S., Niththyananthan, R. & Johnston, D. (1995) Effect of glucocorticoid replacement therapy on glucose tolerance and intermediary metabolites in hypopituitary adults. Clinical Endocrinology, 42, 85-90.
  51. Dunne, F., Elliot, P., Gammage, M., Stallard, T., Ryan, T., Sheppard, M. & Stewart, P. (1995) Cardiovascular function and glucocorticoid replacement in patients with hypopituitarism. Clinical Endocrinology, 43, 623-629.
  52. McConnell, E., Bell, P., Ennis, C., Hadden, D., McCance, D., Sheridan, B. & Atkinson, A. (2002) Effects of low-dose oral hydrocortisone replacement versus short-term reproduction of physiological serum cortisol concentrations on insulin action in adult-onset hypopituitarism. Clinical Endocrinology, 56, 195-201.
  53. Lovas, K., Loge, J. & Husebye, E. (2002) Subjective health status in Norwegian patients with Addison's disease. Clinical Endocrinology, 56, 581-588.
  54. Groves, R., Toms, G., Houghton, B. & Monson, J. (1988) Corticosteroid replacement therapy: twice or thrice daily? Journal of the Royal Society of Medicine, 81, 514-516.
  55. Riedel, M., Wiese, A., Schurmeyer, T. & Brabant, G. (1993) Quality of life in patients with Addison's disease: effects of different cortisol replacement modes. Experimental and Clinical Endocrinology, 101, 106-111.
  56. Tomlinson, J., Holden, N., Hills, R., Wheatley, K., Clayton, R., Bates, A., Sheppard, M. & Stewart, P. (2001) Association between premature mortality and hypopituitarism. The Lancet, 357, 425-431.
  57. Weaver, J., Thaventhiran, L., Noonan, K., Burrin, J., Taylor, N., Norman, M. & Monson, J. (1994) The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults. Clinical Endocrinology, 41, 639-648.
  58. Moore, J., Monson, J., Kaltsas, G., Putignano, P., Wood, P., Sheppard, M., Besser, G., Taylor, N. & Stewart, P. (1999) Modulation of 11-beta-hydroxysteroid dehydrogenase isoenzymes by growth hormone and insulin-like growth factor: in vivo and in vitroJournal of Clinical Endocrinology and Metabolism, 84, 4172-4177. studies.
  59. Kyriazopoulou, V., Parparousi, O. & Vagenakis, A. (1984) Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. Journal of Clinical Endocrinology and Metabolism, 59, 1204-1206.
  60. Lamberts, S., Bruining, H. & de Jong, F. (1997) Corticosteroid therapy in severe illness. New England Journal of Medicine, 337, 1285-1292.
  61. Coursin, D. & Wood, K. (2002) Corticosteroid supplementation for adrenal insufficiency. Journal of the American Medical Association, 287, 236-240.
  62. Flemming, T. & Kristensen, L. (1999) Quality of self-care in patients on replacement therapy with hydrocortisone. Journal of Internal Medicine, 246, 497-501.
  63. Arlt, W. & Allolio, B. (2003) Adrenal insufficiency. Lancet, 361, 1881-1893.
  64. Weise, M., Drinkard, B., Mehlinger, S., Holzer, S., Eisenhofer, G., Charmandari, E., Chrousos, G. & Merke, D. (2004) Stress dose of hydrocortisone is not beneficial in patients with classic congenital adrenal hyperplasia undergoing short-term, high-intensity exercise. Journal of Clinical Endocrinology and Metabolism, 89, 3679-3684.
  65. Arlt, W., Callies, F., van Vlijmen, J., Koehler, I., Reincke, M., Bidlingmaier, M., Huebler, D., Oettel, M., Ernst, M., Schulte, H. & Allolio, B. (1999) Dehydroepiandrosterone replacement in women with adrenal insufficiency. New England Journal of Medicine, 341, 1013-1020.

Training: Miles, elevation and map from Sunday

Click if you want to enlarge

Monday, March 10, 2008

Training: Pictures from the last couple of weeks

Allison snowshoeing up a very steep hill in Pole Canyon.



Me up a steep hill in Pole Canyon



My lunch spread, I didn't want to be hungry! What if I got stuck out over night?! I wouldn't be lacking food.




Snowmobile tracks up a very steep hill. Allison and I hiked part of the way up this hill. This was our view from where we ate lunch. Gorgeous!



A snowmobile trail groomer. Interesting piece of machinery.




On the way back from the snowshoe in Pole Canyon were these gorgeous eagles. Their feathers were bright white and they were huge.



Close up of an eagle.



Sunday's sunset over the Big Hole Mountains.



Paul running up the Targhee road last weekend. The Tetons are behind the clouds somewhere.



Allison snowshoeing over a huge log on Aspen Trail. This picture is about 10 days old.



Allison and I at the Aspen Trail trail head. I will try to take pictures in this same spot every time I come up here. It always looks very different. Aspen Trail is one of my favorite trails ever!

Items found on the side of the road this weekend

A 22 caliber bullet



A roach



A black sock



A pumpkin



Yummy! Pringles!



Another roach!



A hat