Diagnosing PCOS in women who menstruate regularly.(polycystic ovary syndrome)
Contemporary OB/GYN, July, 2003, by Enrico Carmina
When should a patient who menstruates normally be diagnosed as having polycystic ovary syndrome, and what clinical differences exist between these somewhat atypical women and those with classic PCOS?
Normal menstruation is common in women who have hyperandrogenism, hirsutism, or both. In fact, in several studies that looked at different populations, 50% to 70% of hirsute women had normal menses. (1-4) In our experience, for instance, 50.8% of 588 hirsute women had normal menstrual cycles. (4)
In the past, these menstruating women would have been diagnosed with idiopathic hirsutism, but there’s now general agreement that this label should be reserved for hirsute women with normal menses and normal circulating androgen levels. (5) When carefully evaluated, however, as many as 90% of hirsute women with normal menses have elevated androgen levels and therefore cannot be included in the group of women with idiopathic hirsutism. (3,4)
Some of these women may actually have polycystic ovary syndrome (PCOS). Of course, the main problem is that experts don’t completely agree on the clinical or biological characteristics needed to diagnose PCOS. In the past, most clinicians diagnosed PCOS on the basis of hyperandrogenism and chronic anovulation, provided that some uncommon, but clearly defined forms of hyperandrogenism (tumors, Cushing’s syndrome, and adrenal enzymatic deficiencies) had been excluded. (67) If we use this definition, the syndrome should only be diagnosed in hyperandrogenic women-with or without hirsutism-who have normal menses but are anovulatory. It is not uncommon-and several studies have reported-that anovulation may be present in women with normal menses. (3,4) And more recently, we and others have provided evidence that the diagnosis of PCOS can be reached in hyperandrogenic ovulatory women. (8-10)
It’s likely then that normal menses in PCOS is more common than we once believed. In this review, we’ll discuss when to diagnose PCOS in women with normal menses and what differences there are between these patients and those with classic PCOS, who have irregular menses.
PCOS in anovulatory women with normal menses
In our experience, 15% to 21% of hyperandrogenic women with normal menses are anovulatory and have to be considered as affected by PCOS. [4,8] In 1963, after reviewing 1,079 patients, Goldzieher and colleagues reported that 12% of women with PCOS menstruate normally. (11) Similar data from other large studies are reported in Table 1.
The diagnosis of PCOS in these women with normal menses is easy It is sufficient to show the presence of anovulation (by low-serum progesterone) and hyperandrogenism (increased serum levels of testosterone or DHEAS). Of course, a single anovulatory cycle isn’t enough to make the diagnosis; chronic anovulation should be ascertained. In clinical practice, we measure serum progesterone during day 22 to 23 of the cycle in all hyperandrogenic women with normal menses. If progesterone levels are below 3 ng/mL, one more cycle is studied and the diagnosis of PCOS is made if this cycle is also anovulatory. Most of these patients present polycystic ovaries at ultrasound as well, but pelvic sonography is not required for the diagnosis. Serum levels of 17-hydroxyprogesterone (17-OHP), measured during the follicular phase, should also be evaluated to exclude nonclassic 21-OH deficiency.
It is not clear why some women with PCOS also have normal menses, in spite of being anovulatory. In our study, hyperandrogenic anovulatory women with normal menses, compared to classic PCOS with irregular menses, had similar polycystic ovarian morphology and similarly increased response to a GnRH agonist acute test. Serum androgen levels were elevated and no different from those found in patients with irregular menses.8 Interestingly patients with anovulatory PCOS and normal menses seemed to be leaner and have lower insulin and gonadotropin levels than those with classic PCOS. Therefore, differences in gonadotropin and/or insulin secretion could be responsible for the varying length of the ovarian cycle in anovulatory women. However, a large study comparing anovulatory patients with normal and irregular menses is yet to be done, and, in our experience, there is a large overlap between gonadotropin and insulin levels in individual PCOS women with normal and irregular menses.
Treatment of infertility and hirsutism in these women is no different from that of women with classic PCOS, and of course, clinicians should take steps to reduce cardiovascular risks in all patients with insulin resistance and altered serum lipids.
Is anovulation needed for the diagnosis of PCOS?
As we mentioned previously, for many years most authors have been convinced that chronic anovulation is needed for the diagnosis of PCOS. However, many ovulatory hyperandrogenic women present with typical PCOS features. (8,10) In fact, 45% to 50% of ovulatory hyperandrogenic women have polycystic ovaries on ultrasound, increased ovarian 17-OHP, and androstenedione response to a GnRH-agonist, suggesting ovarian hyperandrogenism. Moreover, in our studies we found that the same patients had mild insulin resistance and altered lipid profiles, similar to patients with classic (anovulatory) PCOS. (7,10) So evidently some ovulatory hyperandrogenic women have the same clinical and endocrine characteristics as women with classic (anovulatory) PCOS and there is no reason to make the diagnosis of PCOS only in patients with chronic anovulation.
If we believe that the main characteristics of PCOS are hyperandrogenism and insulin resistance, both elements are not necessarily linked to anovulation. In fact, hyperandrogenism is often associated with normal ovulatory cycles. In our study, 40% of hirsute women had hyperandrogenism but were still ovulating. (4) Similar data have been presented by other investigators.’ Others have reported that ovulatory hyperandrogenic women have similar androgen levels as anovulatory hyperandrogenic patients. (14) While the prevalence of ovulation in different hyperandrogenic populations varies, it is clear that hyperandrogenism per se does not automatically cause anovulation.
Also keep in mind that hyperinsulinemia is not necessarily associated with anovulation. For example, while insulin resistance and hyperinsulinemia are well-known components of obesity, most obese women have normal ovulatory cycles and normal fertility. (15,16) Moreover, insulin resistance is also a common finding in lean apparently normal women and in insulin resistance syndrome or syndrome X. (17,18)
It’s possible that hyperinsulinemia induces anovulation only when hyperandrogenism is present. This hypothesis is supported by the finding that obese women who have altered menstrual patterns also have higher androgen levels than eumenorrheic obese women. (19) However, our data have shown that in this situation, anovulation is not a necessary consequence. In fact, our hyperandrogenic ovulatory patients with polycystic ovaries had insulin resistance as well. (10) This suggests that the association between insulin resistance and hyperandrogenism does not necessarily precipitate anovulation.
What does ovulatory PCOS look like?
Patients with ovulatory PCOS present clinicians with a few unique problems:
How does one make the diagnosis? You should base the diagnosis on the finding of ovulatory cycles in hyperandrogenic women who have polycystic ovaries. Therefore, in ovulatory hyperandrogenic women, it is particularly important to evaluate ovarian morphology with pelvic sonography. The existence of polycystic ovaries is sufficient for the diagnosis of PCOS in these women because we have previously shown that in ovulatory hyperandrogenic women, there is a correlation between ovarian response to a GnRH agonist test and ovarian morphology by pelvic sonography (10) The sonographic diagnosis should be based on the classic criteria of Adams and associates. (20) Figure 1 provides a scheme for diagnosing PCOS in hyperandrogenic women with normal menses.
What other tests should clinicians perform to arrive at the diagnosis of ovulatory PCOS? An evaluation of insulin sensitivity by a simple mathematical method based on insulin and glucose basal levels such as HOMA-IR or QUICKI should be performed. (21,22) Moreover, cardiovascular risk should be assessed. Therefore glucose tolerance (by oral glucose tolerance test) and serum lipids (total cholesterol, HDL and LDL cholesterol, and triglycerides) should be measured.
If any of these values are altered, the patient should be carefully treated with nutritional therapy and, if needed, with insulin sensitizing agents. Consider metformin if diet fails to resolve insulin resistance or to improve lipids. If all values are normal, on the other hand, the patient should not be treated but insulin sensitivity, glucose tolerance, and serum lipids should be measured every 2 years. (7) Is fertility normal in patients with ovulatory PCOS? We can’t offer a definitive answer to that question at the moment. We have regarded these patients as fertile but recent studies have shown that women with ovulatory PCOS have some alterations in their early luteal phase. (9) It’s unclear if this might impair fertility.
Polycystic ovaries in normoandrogenic ovulatory women
We have known for several years that many apparently normal, fertile women have polycystic ovaries. (23-25) Up to 20% of normal women from different countries have polycystic ovaries on ultrasound. We don’t know what causes the altered ovarian morphology in many of these apparently normal women, but their fertility is normal. In fact, studying women who were ovum donors and had proven fertility, we found that some of these women have polycystic ovaries. (26) Most of these women have normal serum androgens as well, although we have shown that they may have a slightly increased ovarian response to a GnRH agonist acute test. (27,28) These apparently normal women also have some signs of very mild insulin resistance. (27,28)
This is probably a third group of women who have a very mild defect of insulin sensitivity Because of their normal fertility and the absence of basal hyperandrogenism, however, we don’t believe these women should be labeled as having PCOS.
Reevaluating the pathogenesis of PCOS
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. (7,29,30) While both are needed for the syndrome to come about, differing seventies of these two defects may be present in individual patients.
These underlying defects are probably responsible for a wide spectrum of conditions that are all part of what we call PCOS, but each of which may have very different clinical and endocrine presentations. In this spectrum, ovulatory PCOS represents the milder form of PCOS but is still able to induce sub-fertility, hirsutism, and increased cardiovascular risk. The differences between these milder forms of PCOS and the classical disorder are summed up in Table 2.
Prevalence of normal menses in three large studies of women with PCOS
Goldzieher Labo and Balen
and Axelrod (11) Carmina (12) et al. (13)
Prevalence of 12% 15% 25%
PCOS diagnosis by Laparoscopy Hyperandrogenism Polycystic
and chronic ovaries
anovulation on ovarian
Difference between classic and mild forms of PCOS
Menses Ovulation androgens resistance
Classic PCOS Irregular – + +
Anovulatory PCOS Normal – + +
with normal menses
Ovulatory PCOS Normal + + +
Normoandrogenic Normal + – +/-
with polycystic ovaries
Classic PCOS + +
Anovulatory PCOS + +
with normal menses
Ovulatory PCOS + +
Normoandrogenic + +/-
with polycystic ovaries
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