Correspondence

Hirsutism

N Engl J Med 2006; 354:1533-1535April 6, 2006

Article

To the Editor:

Rosenfield (Dec. 15 issue)1 states in his article on hirsutism that it is reasonable to forgo laboratory evaluation if hirsutism is mild and menses are regular and that routine testing for androgens other than testosterone is of little use. In addition, he states that testosterone arises also from androstenedione and dehydroepiandrosterone sulfate.

On the basis of our recent experience with more than 400 women who had been evaluated for hirsutism, we found that more than 80 percent fulfilled the diagnostic criteria for either adrenal enzyme deficiencies or the polycystic ovary syndrome. Since these conditions may necessitate further follow-up, such as genetic testing or evaluation of glucose metabolism or for hypertension, laboratory studies are justified. In addition, there is evidence that testosterone derives from androstenedione and dehydroepiandrosterone (not the sulfated derivative),2 both of which are weak androgens that have rarely been evaluated in the context of hirsutism.

Holger S. Willenberg, M.D.
Maryam Bahlo, M.D.
Werner A. Scherbaum, M.D.
University Hospital Düsseldorf, 40225 Düsseldorf, Germany
holger.willenberg@uni-duesseldorf.de

2 References

1. 1

   Rosenfield RL. Hirsutism. N Engl J Med 2005;353:2578-2588
   Full Text | Web of Science | Medline

2. 2

   Hammer F, Subtil S, Lux P, et al. No evidence for hepatic conversion of dehydroepiandrosterone (DHEA) sulfate to DHEA: in vivo and in vitro studies. J Clin Endocrinol Metab 2005;90:3600-3605
   CrossRef | Web of Science | Medline

To the Editor:

The article on hirsutism emphasizes treatment with oral contraceptives, high-dose antiandrogens, or both and mentions flutamide (250 to 500 mg per day) as “rarely used for hirsutism because of its expense and risk of hepatocellular toxicity.”

Hyperinsulinemic hyperandrogenism is a primary cause of hirsutism. Oral contraceptives reduce some manifestations of this disorder (such as hirsutism, acne, and irregular menses), but they leave underpinning mechanisms unaltered — or even make them worse. A combination of low-dose flutamide (approximately 1 mg per kilogram of body weight per day) with metformin may be useful in patients with hyperinsulinemic hyperandrogenism.1,2 Because of flutamide's embryotoxicity, it may be wise to add an oral or transdermal estrogen–progestagen to a flutamide–metformin combination. In such polytherapy, the efficacy of flutamide and metformin is maintained, apparently without there being hepatotoxic effects.3

Francis de Zegher, M.D., Ph.D.
University of Leuven, 3000 Leuven, Belgium
francis.dezegher@uz.kuleuven.ac.be

David B. Dunger, M.D., Ph.D.
University of Cambridge, Cambridge CB2 2QQ, United Kingdom

Lourdes Ibáñez, M.D., Ph.D.
University of Barcelona, 08950 Barcelona, Spain

3 References

1. 1

   Ibanez L, de Zegher F. Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and antiatherogenesis in young women with ovarian hyperandrogenism: the key role of metformin at the start and after more than one year of therapy. J Clin Endocrinol Metab 2005;90:39-43
   CrossRef | Web of Science | Medline

2. 2

   Ibanez L, Valls C, Cabre S, De Zegher F. Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and antiatherogenesis in young women with ovarian hyperandrogenism: the key role of early, low-dose flutamide. J Clin Endocrinol Metab 2004;89:4716-4720
   CrossRef | Web of Science | Medline

3. 3

   Ibanez L, Jaramillo A, Ferrer A, de Zegher F. Absence of hepatotoxicity after long-term, low-dose flutamide in hyperandrogenic girls and young women. Hum Reprod 2005;20:1833-1836
   CrossRef | Web of Science | Medline

Author/Editor Response

For the physician who lacks reliable subspecialty laboratory backup, endocrine evaluation of uncomplicated mild hirsutism is not recommended because the medical risk is low and androgen results may be misleading. However, I agree with Dr. Willenberg and colleagues that there should be screening for hyperandrogenism and its associated manifestations in patients in whom hirsutism is more severe or in whom there are already features of a metabolic syndrome — such as other risk factors related to obesity and insulin resistance — or if these features emerge on follow-up. An extensive literature supports screening by measuring testosterone or free testosterone alone in a specialty laboratory. Genetic testing is currently only feasible for congenital adrenal hyperplasia, the prevalence of which is less than 5 percent in most populations (there are extreme variations, such as some Alaskan Eskimos).

Classic studies indicate that trough levels of the testosterone precursor dehydroepiandrosterone arise from minuscule metabolism of plasma dehydroepiandrosterone sulfate — levels of which are 1000 times as high as those of dehydroepiandrosterone — with which it is in equilibrium.1 The recent evidence cited to the contrary is not convincing. The conclusions are confounded by the use of radioimmunoassays of uncertain specificity, the episodic nature of ongoing adrenal secretion, and the short-term, potentially saturating load design.

Dr. de Zegher and colleagues discuss adding metformin to combination therapy with an antiandrogen and a weakly antiandrogenic oral contraceptive containing drospirenone for treating hyperandrogenism, and they specifically propose low-dose flutamide as the antiandrogen of choice. I, too, prefer nonandrogenic or antiandrogenic oral contraceptives for their beneficial metabolic effects, although controlled studies — none with drospirenone — have shown no evidence that they are superior at improving hirsutism. I agree that metformin has a place in managing the metabolic aspects of the polycystic ovary syndrome. However, the data from the study by Ibáñez and de Zegher cited in their letter indicate that the addition of low-dose flutamide plus metformin to oral-contraceptive therapy was no more effective than oral contraceptives alone in improving hirsutism, contrary to standard antiandrogen regimens. When the cost of antiandrogens at the customary dosage is compared with that of flutamide, the latter is three times as great, and the frequency of hepatotoxicity is 10 times as high or frequent, with about 5 percent of these cases of hepatotoxicity being fatal.2,3 The deaths seem to be the result of idiosyncratically severe reactions.4 Since it is not clear that a low dosage will prevent these deaths, it seems advisable not to use flutamide for benign disorders.5

Robert L. Rosenfield, M.D.
University of Chicago Pritzker School of Medicine, Chicago, IL 60637
robros@peds.bsd.uchicago.edu

5 References

1. 1

   Rosenfeld RS, Rosenberg BJ, Fukushima DK, Hellman L. 24-Hour secretory pattern of dehydroisoandrosterone and dehydroisoandrosterone sulfate. J Clin Endocrinol Metab 1975;40:850-855
   CrossRef | Web of Science | Medline

2. 2

   Manso G, Thole Z, Salgueiro E, Revuelta P, Hidalgo A. Spontaneous reporting of hepatotoxicity associated with antiandrogens: data from the Spanish pharmacovigilance system. Pharmacoepidemiol Drug Saf (in press).
   

3. 3

   Renkes P, Gaucher P, Trechot P. Spironolactone and hepatic toxicity. JAMA 1995;273:376-377
   CrossRef | Web of Science | Medline

4. 4

   Wysowski DK, Fourcroy JL. Flutamide hepatotoxicity. J Urol 1996;155:209-212[Erratum, J Urol 1996;155:1396.]
   CrossRef | Web of Science | Medline

5. 5

   Wysowski DK, Freiman JP, Tourtelot JB, Horton ML III. Fatal and nonfatal hepatotoxicity associated with flutamide. Ann Intern Med 1993;118:860-864
   Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   K. K. Ong, F. de Zegher, A. Lopez-Bermejo, D. B. Dunger, L. Ibanez. (2007) Flutamide-metformin for post-menarcheal girls with preclinical ovarian androgen excess: evidence for differential response by androgen receptor genotype. European Journal of Endocrinology 157:5, 661-668
   CrossRef