Anovulation and The Polycystic Ovary

Who Should Be Tested for Hyperinsulinemia?

Do all anovulatory patients require testing for hyperinsulinemia? Both lean and obese women with polycystic ovaries can be found to have hyperinsulinemia, but not all hyperandrogenic women withpolycystic ovaries (lean and obese) have hyperinsulinemia.  However, it is more common and severe in overweight women and androgenic effects are more intense. Furthermore, lean women with hyperinsulinemia do not appear to have the same risk of future diabetes mellitus, although clinical follow-up may in time document an onset later in life of noninsulin-dependent diabetes mellitus compared to an earlier onset in obese women. It has been reported that anovulatory women with polycystic ovaries who have a parent with noninsulin-dependent diabetes mellitus are more likely to have impaired beta cell secretion of insulin in addition to insulin resistance.
Because of the probable inherited susceptibility for anovulation and insulin resistance, consideration should be given to a glucose tolerance and insulin evaluation for family members
of already diagnosed patients. Both brothers and sisters of anovulatory, hyperandrogenic women can be insulin resistant.

What about those women who are ovulatory and have no clinical complaints, yet supposedly have an underlying hyperinsulinemic disorder? In our view, if this is real, it is a homeostatic compensatory state, and until appropriate data reveal adverse outcomes in these women, diagnostic and therapeutic interventions are not indicated.
It would be ideal if all patients with android obesity were tested for hyperinsulinemia. The waist:hip ratio is a means of estimating the degree of upper to lower body obesity; the ratio ccurately predicts the amount of intra-abdominal fat (which is greater with android obesity). However, studies have demonstrated that the more easily determined circumference of the waist is a better predictor of central, android abdominal fat.  A waist circumference greater than 100 cm (about 40 inches) in men and 90 cm (about 35 inches) in women is predictive of abnormal endocrinologic and metabolic function and is associated with an increased risk of cardiovascular disease.

Teenagers who present with persistent anovulation would also be good candidates for hyperinsulinemia testing. During puberty, insulin resistance develops, probably because of the increase in sex steroids and growth hormone, resulting in a secondary increase in insulin and IGF-I.  The increase in insulin leads to a decrease in SHBG, which would allow greater sex steroid activity for pubertal developmentThere is reason to believe that some teenagers fail to normalize the hyperinsulinemia associated with the growth hormone increase in early puberty. It would be important to identify these teenagers who are at an increased risk for the development of diabetes mellitus and are destined to struggle with all of the problems associated with anovulation and polycystic ovaries. There is also reason to believe that many cases of premature adrenarche are due to hyperinsulinemia, and these patients go on to develop the full characteristics of anovulation, hyperandrogenism, and polycystic ovaries.

When clinical circumstances are encountered that do not seem to make sense, give consideration to the presence of hyperinsulinemia. We have experienced several examples where hyperinsulinemia proved to be the underlying answer. Several instances involved women in the reproductive age range, with significant hirsutism and very high testosterone levels. Evaluation failed to reveal an ovarian tumor or an adrenal lesion. The demonstration of hyperinsulinemia has avoided unnecessary surgical exploration for a “small tumor.” Another example was the onset of hirsutism in elderly women associated with testosterone levels greater than 200 ng/mL and normal imaging evaluations of the ovaries and adrenal glands. Again, hyperinsulinemia was the cause, not a hidden tumor.
Unfortunately, it is not certain what levels of insulin in the fasting state or in response to an oral glucose tolerance test are correlated with clinical outcome. However, in individuals with normal glucose tolerance, the fasting insulin level is strongly correlated with insulin resistance.247 In most laboratories, the upper limit of normal for a fasting insulin level is 10–20 U/mL. Because there is considerable overlap between normal women and patients with anovulation and polycystic ovaries, it is reasonable to assume that all overweight, anovulatory women with polycystic ovaries are hyperinsulinemic. Nevertheless we recommend the measurement of the ratio of fasting glucose to fasting insulin in order to provide evidence that lends credence and importance to counseling efforts. A ratio of less than 4.5 is consistent with insulin resistance.248

Based upon the information reviewed in this chapter, we offer the following recommendations:
All anovulatory women who are hyperandrogenic should be assessed for insulin resistance and glucose tolerance with measurements of:

1. The fasting glucose:insulin ratio, followed by
2. The 2-hour glucose level after a 75 g glucose load:

normal
less than 140 mg/dL
impaired
140–199 mg/dL
noninsulin-dependent diabetes mellitus
200 mg/dL and higher

Anovulory women who do not exhibit signs of hyperandrogenism should be evaluated for the presence of a metabolic abnormality by measuring the free testosterone level; if elevated, insulin resistance and glucose tolerance should be assessed. However, a fasting glucose:insulin ratio is about one-third the cost of a free testosterone level. It may be more economical to measure this ratio in all anovulatory women.

In women who continue to manifest this disorder, periodic surveillance is necessary. The frequency is uncertain, but annual assessment is appropriate in women who continue to be obese.

Conclusion

We are truly entering a new era in our understanding and management of women with polycystic ovaries and hyperandrogenism. In the past we have effectively treated the specific problems of infertility, dysfunctional uterine bleeding, nd hirsutism. We now have an opportunity to have an impact on the quality and quantity of life to be experienced by these patients. By creating and supporting a preventive health care attitude in anovulatory women, we can not only correct specific clinical consequences of anovulation, we can reduce major adverse effects on overall health.

Clinical Gynecologic Endocrinology and Infertility 6th ed: Leon Speroff, Robert H. Glass, Nathan G. Kase, 1999 Lippincott Williams & Wilkins