Authors’ Response: DHEA Replacement in Adrenal Insufficiency

Kristian Løvås, Olle Kämpe and Eystein S. Husebye

Division of Endocrinology (K.L., E.S.H.), Institute of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway; and Department of Clinical Sciences (O.K.), Uppsala University, S-751 85 Uppsala, Sweden

Address correspondence to: Kristian Løvås, M.D., Division of Endocrinology, Institute of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway. E-mail: kristian.lovas{at}med.uib.no.

To the editor:

We recently published the results of a randomized parallel-group clinical trial of dehydroepiandrosterone (DHEA) replacement in adrenal failure, in which we found no benefit for subjective health status and sexuality (1). We agree with Arlt and Allolio (2) that low statistical power infers risk of excluding true benefit (type 2 statistical error). However, statistical power is not only a matter of study size. It also depends on treatment variability and definitions of clinically relevant treatment responses. The wide variation in treatment responses was not known or anticipated at the time of our trial. It seems reasonable that clinically relevant treatment responses should at least exceed the range of measurement variability. The confidence intervals of treatment effects illustrate that there may be true benefit of DHEA replacement, although we did not find any statistically significant difference in effects between DHEA and placebo in our study population (1). Information provided by confidence intervals overcomes the limitations of presenting trial results simply as positive or negative. In fact, our results are consistent with those of Johannsson et al. (3), who did not find significant effects on subjective health status or sexuality (confidence intervals not given). Moreover, if only studies demonstrating significant effects are published, the conclusion of benefit may be severely biased (publication bias). We do not agree with the use of crossover trials (1), because this design is very vulnerable to unblinding, particularly when psychological outcome measures are used (4). Such design is at high risk of reporting statistically significant effects that are not clinically relevant. For instance, we questioned the clinical relevance of negative placebo effects in the two previous crossover trials (5, 6). Taken together, we agree with Arlt and Allolio (2) that larger parallel group studies are required, and we await the conclusions of the larger clinical trial by Gurnell and co-workers (7).

Received April 15, 2003.

References

  1. Løvås K, Gebre-Medhin G, Trovik TS, Fougner KJ, Uhlving S, Nedrebø BG, Myking OL, Kämpe O, Husebye ES 2003 Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial. J Clin Endocrinol Metab 88:1112–1118[Abstract/Free Full Text]
  2. Arlt W, Allolio B 2003 Letter: DHEA replacement in adrenal insufficiency. J Clin Endocrinol Metab 88:4001[Free Full Text]
  3. Johannsson G, Burman P, Wiren L, Engstrøm BE, Nilsson AG, Ottosson M, Jonsson B, Bengtsson BA, Karlsson FA 2002 Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebo-controlled trial. J Clin Endocrinol Metab 87:2046–2052[Abstract/Free Full Text]
  4. Woods JR, Williams JG, Tavel M 1989 The two-period crossover design in medical research. Ann Intern Med 110:560–566[Medline]
  5. Arlt W, Callies F, van Vlijmen JC, Koehler I, Reincke M, Bidlingmaier M, Huebler D, Oettel M, Ernst M, Schulte HM, Allolio B 1999 Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 341:1013–1020[Abstract/Free Full Text]
  6. Hunt PJ, Gurnell EM, Huppert FA, Richards C, Prevost AT, Wass JA, Herbert J, Chatterjee VK 2000 Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison’s disease in a randomized, double blind trial. J Clin Endocrinol Metab 85:4650–4656[Abstract/Free Full Text]
  7. Gurnell EM, Hunt PJ, Curran SE, Conway CL, Huppert FA, Herbert J, Chatterjee VK, A long term trial of DHEA replacement in Addison’s disease. Program of the 84th Annual Meeting of The Endocrine Society, San Francisco, CA, 2002, p 33 (Abstract S19-2)