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Endocrine Care: Didier Dewailly, Sophie Catteau-Jonard, Anne-Céline Reyss, Maryse Leroy, and Pascal Pigny Oligoanovulation with Polycystic Ovaries But Not Overt Hyperandrogenism J Clin Endocrinol Metab 2006; 91: 3922-3927 [Abstract] [Full text] [PDF]

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Does PCOS without hyperandrogenism exist?

Didier Dewailly   (28 December 2006)

E-Letter to the Editor: Oligoanovulation with polycystic ovaries but not overt hyperandrogenism

Robert L Rosenfield   (13 November 2006)

Does PCOS without hyperandrogenism exist? 28 December 2006
Didier Dewailly, MD Lille University Hospital Send letter to journal: Re: Does PCOS without hyperandrogenism exist? ddewailly{at}chru-lille.fr Didier Dewailly	In his letter about our article (1), Dr Rosenfield raises several concerns, principally that we have under-diagnosed hyperandrogenism in some of our patients. In response to his hypothesis that our patients with oligo-anovulation but no overt hyperandrogenemia was a mixture of subjects with and without PCOS, the distribution of individual total testosterone values in this group was not bimodal, but rather was a continuum to the upper normal limit of the assay. Dr Rosenfield also questioned whether the total testosterone assay was appropriate to rule out hyperandrogenemia, recognizing its high rate of false negative results in “classic” PCOS populations (2), particularly because we gave a short progestin treatment in oligo-anovulatory patients to induce a withdrawal bleeding and because he inferred we did not consider the diurnal rhythm of total testosterone. We have previously reported that didrogesterone use has only a mild LH suppressant effect and does not modify the total testosterone level (3). Second, all our patients were sampled between 8:00 and 9:00 AM. Dr. Rosenfield suggests that the free androgen index offers greater diagnostic sensitivity than the total testosterone assay, although it is still normal in 20-30% of patients with “classic” PCOS (2). However, we did not use this measure in our study because, in our opinion, it introduces an important bias. Because the measured sex hormone binding globulin (SHBG) is used to calculate the free endrogen index with the formula T/SHBGx100, and knowing that hyperinsulinism reduces hepatic production of this protein, one can appreciate that the metabolic status of a woman can influence the free androgen index independent of her ovarian androgen production. Nonetheless, we agree with Dr Rosenfield that hyperandrogenemia was not well defined in our study, but this is the case in every study regarding PCOS! As noted in our Discussion and suggested by the term “overt” in our title, we did not claim that PCOS can exist without hyperandrogenemia, but rather suggested that hyperandrogenemia is not always perceivable with our current means. Our message was, therefore, not to exclude the possibility of PCOS entirely in seemingly normo-androgenic woman with oligo-anovulation and polycystic ovaries on ultrasound, providing the latter are defined by stringent criteria (4). These include an excessive number of small follicles (>12/ovary), which could represent the best evidence that hyperandrogenemia exists, at least within the ovary, knowing the strong relationship between the follicle number and androgens in this setting (5). References 1. Dewailly D, Catteau-Jonard S, Reyss AC, Leroy M, Pigny P. 2006. Oligoanovulation with polycystic ovaries but not overt hyperandrogenism. J Clin Endocrinol Metab 91:3922-3927 2. Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF for the Androgen Excess Society. 2006. Positions statement: criteria for defining polycystic ovary syndrome as predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 91:4237-4245 3. Dewailly D, Jonard S, Pigny P, Robert Y. 2005. Influence of the Progestin Withdrawal Test on the Hormonal and Ultrasound Characteristics of Patients with PCOS. The Endocrine society’s 87th meeting, San Diego, Presentation P1-367 4. Balen AH, Laven JS, Tan SL, Dewailly D. 2003. Ultrasound assessment of the polycystic ovary: international consensus definitions. Hum Reprod Update 9:505-514 5. Jonard S, Dewailly D 2004 The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest. Hum Reprod Update 10:107-117
E-Letter to the Editor: Oligoanovulation with polycystic ovaries but not overt hyperandrogenism 13 November 2006
Robert L Rosenfield, pediatric endocrinologist University of Chicago Pritzker School of Medicine Send letter to journal: Re: E-Letter to the Editor: Oligoanovulation with polycystic ovaries but not overt hyperandrogenism robros{at}peds.bsd.uchicago.edu Robert L Rosenfield	Dewailly et al. (1) recently addressed the controversy posed by the Rotterdam criteria as to whether oligoovulation with a polycyctic ovary without hyperandrogenism is truly a form of polycystic ovary syndrome (PCOS) (2, 3). They report that their cohort of patients with oligo-anovulation and polycystic ovaries without hirsutism or elevated plasma androgens had mild features of PCOS (1). Thus, they conclude that this group has a mild form of PCOS. I remain unconvinced that PCOS exists without hyperandrogenism. I would argue that their group of oligo-ovulatory patients is a mixture of a sub-group with mild hyperandrogenemia that has PCOS and a sub-group without hyperandrogenemia that does not. Dewailly et al. do not appear to have excluded hyperandrogenemia in their patients. Although their patients had normal plasma total testosterone and androstenedione levels on days 2-5 of a progestin-induced cycle, they may have missed detecting hyperandrogenemia for three reasons. First, although all patients in this group had serum total testosterone and androstenedione levels that were within their historical normal range, they had significantly higher plasma mean testosterone and lower SHBG levels than the controls. This combination of findings suggests that among this group are a considerable number of patients with elevation of the plasma free testosterone level, which is the most sensitive single measure of hyperandrogenemia (4), and is not excluded by the absence of cutaneous manifestations (5). Second, they present no evidence that they controlled for diurnal rhythm in interpreting testosterone levels (4). Third, their progestin treatment regimen would be expected to transiently suppress ovarian function, particularly in a minimally hyperandrogenic state (6, 7). It would be important to learn whether oligomenorrheic patients with a polycystic ovary and no overt hyperandrogenic features have features of PCOS when hyperandrogenemia is more definitively excluded. References 1. Dewailly D, Catteau-Jonard S, Reyss AC, Leroy M, Pigny P. 2006. Oligoanovulation with polycystic ovaries but not overt hyperandrogenism. J Clin Endocrinol Metab 91:3922-3927 2. Azziz R. 2006. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab 91:781-785 3. Franks S. 2006. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: in defense of the Rotterdam criteria. J Clin Endocrinol Metab 91:786-789 4. Rosenfield RL. 2005. Clinical practice. Hirsutism. N Engl J Med 353:2578-2588 5. Hosseinian AH, Kim MH, Rosenfield RL. 1976. Obesity and oligomenorrhea are associated with hyperandrogenism independent of hirsutism. J Clin Endocrinol Metab 42:765-769 6. Taylor AE, McCourt B, Martin KA, Anderson EJ, Adams JM, Schoenfeld D, Hall JE. 1997. Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J Clin Endocrinol Metab 82:2248-2256 7. Eagleson CA, Gingrich MB, Pastor CL, Arora TK, Burt CM, Evans WS, Marshall JC. 2000. Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 85:4047-4052