PCOS and normal menses: another point of view
Ricardo Azziz
Dr. Carmina presents a provocative and important argument on the relationship between PCOS and normal menses. While significant strides have been made in elucidating many of the associated features of polycystic ovary syndrome, much remains unclear.
Dr. Carmina alludes to an important fact that “normal menses” doesn’t exclude the presence of oligo-ovulation, particularly in the presence of other hyperandrogenic features like hirsutism and hyperandrogenemia. Up to 40% of hirsute women who menstruate regularly are anovulatory when evaluated more closely by luteal phase progesterone levels and basal body temperature charts. (1) Hence, it is important for the reader to always distinguish between “normal menses” and “normal ovulatory function”. As the author points out, we still don’t know why some women continue to have vaginal bleeding at regular intervals despite being anovulatory.
It is likely, however, that the presence of vaginal bleeding relates primarily to differences in endometrial factors, either intrinsic or in response to other extrauterine circulating factors. In the study by Carmina and Lobo, for instance, women who were having regular vaginal bleeding had lower circulating insulin levels than those who did not. (2) It is possible that insulin, directly or indirectly, alters endometrial integrity and growth in these women. Further studies are needed in this area, particularly in regards to the clinical implications of regular menstrual bleeding in the face of anovulation in women who otherwise have PCOS. The question of whether ovulatory dysfunction is required for the diagnosis of PCOS is an important one. The informal proceedings of a 1990 NICHD-sponsored conference on the subject noted that most participants in the conference felt that PCOS should be diagnosed by the presence of: (a) oligo-anovulation, (b) clinical and/or biochemical hyperandrogenism (e.g., hirsutism and/ or hyperandrogenemia), after (c) the exclusion of related disorders, such as nonclassic adrenal hyperplasia, Cushing’s syndrome, and androgen-secreting neoplasms. (3)
However, it is also very clear that this disorder is quite heterogeneous. For example, many women will have varying degrees of hirsutism and other dermatologic signs of androgen excess, despite having relatively similar circulating androgen levels. Likewise, many patients may not have “polycystic ovaries” on ultrasonography, nor will they have gross evidence of gonadotropic abnormalities on evaluation.
Finally, while up to 70% of women with PCOS demonstrate some degree of insulin resistance compared to weight-matched controls, up to a third of these patients may not have any evidence of insulin resistance whatsoever. (4, 5) Thus, it is conceivable that there is also considerable variation in the degree of hypothalamic-pituitary-ovarian axis abnormality. We have observed that approximately 16% of our patients with functional androgen excess have a phenotype similar to that described by Dr. Carmina; that is, the presence of hirsutism hyperandrogenernia, and normal menstrual and ovulatory function (at least in the cycles evaluated).
A greater problem arises when we begin to consider hyperandrogenic ovulatory women with polycystic ovaries as having PCOS. Carmina and Lobo indicate that on average their hyperandrogenic ovulatory patients with polycystic ovaries (labeled “ovulatory PCOS”) had higher circulating insulin levels, lower glucose-to-insulin ratios, and higher body mass compared to hirsute ovulatory women who had normal androgens; that is, ‘idiopathic hirsutism’, although ovarian morphology by ultrasound was not reported. (6) In a previous study these investigators reported that women with “ovulatory PCOS” generally had lesser degrees of hyperinsulinism than patients with frank PCOS. (7) Thus, it is unclear whether patients who have hyperandrogenism (i.e., hirsutism and/or hyperandrogenemia), polycystic ovaries, but regular ovulation and menstruation actually have PCOS. Do they represent an intermediate stable phenotype between idiopathic hirsutism and PCOS, or do they represent an early form of PCOS that will progress over time, o r is this an entirely different disorder? These questions remain unanswered and need to be investigated by performing long-term follow-up and genetic or familial studies.
Overall, it’s premature to begin to define a new disorder, namely “ovulatory PCOS”. While Dr. Carmina goes to great lengths to explain how this disorder may be diagnosed, it’s still unclear whether this is actually a disorder of similar concern as frank PCOS. Thus, we should be somewhat cautious before labeling these patients as having PCOS, particularly since the diagnosis has significant medical and reproductive implications.
Nonetheless, it is clear that this is an area that requires continued and aggressive study to elucidate the full spectrum of the disorder, its clinical implications, and potential preventive strategies. Dr. Carmina’s presentation provides significant “food for thought” in this regard. We should not forget that PCOS is the single most common endocrine disorder of reproductive-aged women, with significant reproductive and metabolic morbidity.
RELATED ARTICLE: Key points
* In our experience, 15% to 21% of hyperandrogenic women with normal menses are anovulatory and have to be considered as affected by PCOS.
* Treatment of infertility and hirsutism in these women is no different from that of women with classic PCOS.
* Many ovulatory hyperandrogenic women present with typical PCOS features, In fact, 45% to 50% of ovulatory hyperandrogenic women have polycystic ovaries on ultrasound.
* The most diffuse theory on the pathogenesis of PCOS is based on the presence of two different defects–hyperandrogenism and insulin resistance–both of which are probably inherited, While both are needed for the syndrome to come about, differing seventies of these two defects may be present in individual patients.
REFERENCES
(1.) Azziz R, Waggoner WT, Ochoa T, et al. Idiopathic hirsutism: an uncommon cause of hirsutism in Alabama. Fertil Steril. 1998;70:274-278.
(2.) Carmina E, Lobo RA. Do hyperandrogenic women with normal mucous have polycystic ovary syndrome? Fertil. Steril. 1999:71:319-322.
(3.) Zawdaki JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rationale approach. In: Dunaif A, Givens JR, Haseltine F, et al, eds. Polycystic Ovary Syndrome Boston, Mass: Blackwell Scientific Publications; 1992:377-384.
(4.) Dunaif A, Segal KR, Futterweit W, et al. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165-1174.
(5.) Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998:83:2694-2698.
(6.) Carmina E, Lobo RA. Polycystic ovaries in Hirsute women with normal menses. Am J Med. 2001;111:602-606.
(7.) Carmina E, Wong L, Chang J, of al. Endocrine abnormalit ins in ovalatory woman with polycystic ovaries on ultrasound. Hum Reprod. 1997;12:905-909.
Dr. Azziz is Chairman, Dept. of Obstetrics and Gynecology Cedars-Sinai Medical Center, and Executive Director, Androgen Excess Society, Los Angeles, Calif.
Dr. Carmina is Professor of Endocrinology, Department of Clinical Medicine, University of Palermo, Italy.
Series Editor: Richard Legro, MD, is Associate Professor, Department of Obstetrics and Gynecology, Penn State Milton S. Hershey Medical Center, Hershey, Pa.
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