Correspondence

Hyperandrogenism in Polycystic Ovary Syndrome

N Engl J Med 1994; 331:131-132July 14, 1994

Article

To the Editor:

Rodin et al. (Feb. 17 issue)1 postulate the dysregulation of 11β-hydroxysteroid dehydrogenase in some women with the polycystic ovary syndrome. The interconversion of cortisol and hormonally inactive cortisone is catalyzed by at least two isoforms of 11β-hydroxysteroid dehydrogenase, a nicotinamide-adenine dinucleotide-dependent, unidirectional dehydrogenase (type 2) found predominantly in the placenta and kidneys, and the type 1 enzyme, which has both NADP-dependent dehydrogenase and 11-oxo-reductase activity and is found predominantly in the liver and gonads. The contribution of each type of enzyme to the urinary ratios of 11-oxo to 11-hydroxy metabolites of cortisol and corticosterone used in this study as an index of total 11β-hydroxysteroid dehydrogenase activity is unknown. However, since reductase function (conversion of cortisone to cortisol) has been attributed only to the type 1 enzyme, we assume that the results reported by Rodin et al. reflect impaired conversion of cortisone to cortisol by this enzyme. The authors state, “Little is known about the regulation of the relative oxidoreductase activity of this enzyme in vivo.” In fact, hyperthyroidism increases the conversion of cortisol to cortisone,2 and in animals glycyrrhetinic acid, progesterone and its hydroxylated derivatives, and possibly insulin reduce this conversion. Furthermore, the type 1 enzyme in liver is expressed in a sexually dimorphic fashion and is inhibited by estradiol3.

Women with congenital 11-oxo-reductase deficiency have oligomenorrhea and hirsutism, which are thought to be secondary to an excess of corticotropin-stimulated adrenal androgen due to enhanced cortisol clearance. In a study of women with polycystic ovary syndrome that we conducted several years ago, we found no abnormality in the interconversion of cortisol to cortisone,4 in contrast to the results of Rodin et al. Could this discrepancy be due to adiposity? Cortisol is converted to cortisone in adipose tissue, and although both we and Rodin et al. controlled for body-mass index, the absolute amount of adipose tissue, or more important, its distribution in women with the polycystic ovary syndrome and normal women may have varied both within and between the two studies. Also, only 5 of the 34 obese women with polycystic ovary syndrome who were studied by Rodin et al. had a urinary ratio of 11-oxo to 11-hydroxy cortisol metabolites that was above the reference range for the obese normal women.

Finally, as the authors note, although partial adrenocortical enzyme defects can be associated with polycystic ovaries, serum corticotropin concentrations are normal in women with late-onset 21-hydroxylase deficiency and in women with the polycystic ovary syndrome5. We wonder about the relation in each woman between the urinary ratio of 11-oxo to 11-hydroxy cortisol metabolites and total urinary excretion of cortisol metabolites as an indicator of cortisol production. Did the women with increased urinary ratios of 11-oxo to 11-hydroxy cortisol metabolites have higher rates of cortisol production? Without this information, one has to conclude that the reported findings are a consequence of the clinical features of the polycystic ovary syndrome, such as adiposity or impaired androgen and estrogen profiles, instead of being causally related to the condition.

Paul M. Stewart, M.D.
University of Texas Southwestern Medical Center, Dallas, TX 75234

Christopher R.W. Edwards, F.R.C.P.
University of Edinburgh Medical School, Edinburgh EH8 9AG, Scotland

5 References

1. 1

   Rodin A, Thakkar H, Taylor N, Clayton R. Hyperandrogenism in polycystic ovary syndrome: evidence of dysregulation of 11β-hydroxysteroid dehydrogenase. N Engl J Med 1994;330:460-465
   Full Text | Web of Science | Medline

2. 2

   Hellman, L, Bradlow HL, Zumoff B, Gallagher TF. The influence of thyroid hormone on hydrocortisone production and metabolism. J Clin Endocrinol Metab 1961;21:1231-1247
   CrossRef | Web of Science | Medline

3. 3

   Low SC, Assaad SN, Rajan V, Chapman KE, Edwards CR, Seckl JR. Regulation of 11β-hydroxysteroid dehydrogenase by sex steroids in vivo: further evidence for the existence of a second dehydrogenase in rat kidney. J Endocrinol 1993;139:27-35
   CrossRef | Web of Science | Medline

4. 4

   Stewart PM, Shackleton CHL, Beastall GH, Edwards CRW. 5α-Reductase activity in polycystic ovary syndrome. Lancet 1990;335:431-433
   CrossRef | Web of Science | Medline

5. 5

   Stewart PM, Penn R, Holder R, Parton A, Ratcliffe JG, London DR. The hypothalamo-pituitary-adrenal axis across the normal menstrual cycle and in polycystic ovary syndrome. Clin Endocrinol (Oxf) 1993;38:387-391
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We suggested that dysregulation of 11β-hydroxysteroid dehydrogenase may contribute to hyperandrogenism in women with the polycystic ovary syndrome because a substantial proportion of the women with that syndrome whom we studied had urinary ratios of 11-oxo to 11-hydroxy metabolites of cortisol above the upper limit of the normal range. That this abnormality is not universal in women with the polycystic ovary syndrome does not lessen its importance, since this condition is almost certainly a heterogeneous disorder.

The discordance between our results and those of Stewart et al.1 is of interest, though the explanation is not readily apparent. We adjusted our urinary steroid results for lean body mass, using the urinary creatinine concentration, and then used the body-mass index to correct for the effects of peripheral fat. Thus, the ratios of the results in the women with the polycystic ovary syndrome and in normal women that we reported demonstrate the effect of the polycystic ovary syndrome adjusted for the body-mass index.

Stewart and Edwards speculate that the distribution of body fat may be an important determinant of the pattern of steroid-metabolite excretion, since this may be related to insulin resistance and hyperinsulinemia. More relevant, however, is the observation that a larger proportion of nonobese women with the polycystic ovary syndrome had a urinary ratio of 11-oxo to 11-hydroxy cortisol metabolites above the reference range, making it unlikely that the factors mentioned by Stewart and Edwards caused the increase. The question of hyperinsulinemia and insulin resistance in nonobese women with the polycystic ovary syndrome is still controversial, since we2 and others have not found that nonobese women with the polycystic ovary syndrome have insulin resistance. We were aware of the effect of hyperthyroidism on cortisol metabolism,3 and it was excluded in all the women in our study. We considered the possibility that the dysregulation of 11β-hydroxysteroid dehydrogenase was secondary to hyperandrogenism. However, we found no correlation between serum androgen concentrations or urinary excretion of androgen metabolites and the ratio of 11-oxo to 11-hydroxy metabolites of cortisol. Moreover, this ratio is normal in men.

Stewart and Edwards raise a valid point concerning evidence of increased rates of cortisol production in women with the polycystic ovary syndrome. Although there are differences in the urinary excretion of cortisol metabolites between women with the polycystic ovary syndrome and normal women, we did not find a correlation between total urinary excretion of cortisol metabolites or urinary cortisol excretion and the urinary ratio of 11-oxo to 11-hydroxy cortisol metabolites in either women with the polycystic ovary syndrome or normal women. Further work with the use of isotopic-turnover studies will be needed to demonstrate directly the altered activity of 11β-hydroxysteroid dehydrogenase in women with the polycystic ovary syndrome and to determine whether this phenomenon is secondary to another metabolic disturbance, such as hyperinsulinemia, or occurs as a primary event.

D. Andrew Rodin, M.D.
St. George's Hospital Medical School, London SW17 ORE, United Kingdom

Richard N. Clayton, M.D.
North Staffordshire Royal Infirmary, Stoke-on-Trent ST4 7LN, United Kingdom

3 References

1. 1

   Stewart PM, Shackleton CHL, Beastall GH, Edwards CRW. 5α-Reductase activity in polycystic ovary syndrome. Lancet 1990;335:431-433
   CrossRef | Web of Science | Medline

2. 2

   Rajkhowa M, Bicknell J, Jones M, Clayton RN. Insulin sensitivity in women with polycystic ovary syndrome: relationship to hyperandrogenemia. Fertil Steril 1994;61:605-612
   Web of Science | Medline

3. 3

   Gordon GG, Southren AL. Thyroid-hormone effects on steroid-hormone metabolism. Bull N Y Acad Med 1977;53:241-259
   Medline