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Menstrual Disorders in Insulin-Resistant States

Richard S. Legro, MD, and Andrea Dunaif, MD

Menstrual disorders are common in insulin-resistant states. They vary in presentation from amenorrhea to oligomenorrhea to menometrorrhagia. These conditions are the clinical consequence of anovulation, which appears to be another reproductive disturbance associated with insulin resistance independent of hyperandrogenism. There also appears to be a relationship between age of menarche and certain insulin-resistant states.

While theories abound about the links between menstrual disorders and insulin resistance, the exact causal mechanisms remain under investigation. This uncertainty in etiology makes treatment of these conditions problematic, as treatment with various hormonal manipulations often is empirical. Additionally, there is the concern that certain therapies may potentially worsen insulin resistance.

This review will focus largely on the most common insulin-resistant state in women, polycystic ovary syndrome (PCOS), with which we have had the most experience from both a clinical and a research standpoint.

PCOS is a common endocrine disorder of premenopausal women characterized by hyperandrogenism and chronic anovulation. The current recommended diagnostic criteria for PCOS, based on a 1990 National Institutes of Health/National Institute of Child Health and Human Devel-opment conference on PCOS¹ and reconfirmed in a 1995 Serono Symposium on PCOS,² are chronic anovulation and hyperandrogenism with exclusion of other etiologies (nonclassical congenital adrenal hyperplasia, hyperprolactinemia, Cushing's syndrome, and androgen- secreting tumors). In reviewing the literature, however, close attention must be paid to the diagnostic criteria utilized, for many researchers rely on their own definition of PCOS, and their findings may not be applicable to other subgroups of the disease.

Although there have been no specific population-based studies, we estimate that somewhere between 5 and 10% of women of reproductive age may be affected. This prevalence is derived from studies of polycystic ovaries finding that ~20% of self-selected normal women had polycystic ovarian morphology on ovarian ultrasound, although a substantial proportion had no identifiable endocrine abnormality.³

PCOS typically has a menarchal age of onset. There has been evidence that girls who enter puberty prematurely are more likely to develop hyperandrogenism,⁴ and the degree of androgen excess has been found to correlate with fasting insulin levels.⁵ Premature adrenarche may thus identify a subset of women with PCOS, but it is uncertain what percentage of all women with PCOS may have an early adrenarche. PCOS women of reproductive age have most commonly presented to their physicians with complaints of infertility, hirsutism, and menstrual irregularity.⁶ It is interesting to contrast the premature adrenarche of at least a subset of women with PCOS with the delayed menarche (0.8 year) that has been observed in women with prepubertal onset of diabetes.⁷ Whereas insulin resistance in an otherwise euglycemic patient may be central to the etiology of premature adrenarche, delayed menarche probably is due to insulin deficiency with corresponding poor glycemic control. Menstrual irregularities are twice as common among women with diabetes than among control women (21.6 vs. 10.8%) and are associated with elevated glycosylated hemoglobin levels and low body mass index.

Ovarian Morphology Is Not Necessary for the Diagnosis of PCOS
PCOS is unexplained hyperandrogenic chronic anovulation. The finding that has given the syndrome its moniker, polycystic ovaries, has become, however, a dispensable diagnostic criterion. Polycystic ovaries represent a final common phenotype with a wide variety of etiologies, or as Givens has so succinctly stated, they are "a sign, not a diagnosis."⁸ Nonetheless, many practitioners use ultrasound evidence of polycystic ovaries as a screening test for the syndrome. Indeed, the best evidence we have for the prevalence of the syndrome comes from ultrasound screening. Several studies have confirmed that about 25% of women have polycystic ovaries on ultrasound exam.^9,10 When a subset of these patients were evaluated endocrinologically, less than half had an abnormally elevated testosterone level.¹¹ These data suggest that the prevalence of PCOS among the population will vary according to the diagnostic criteria utilized and that polycystic ovaries are present in women with no apparent endocrinological abnormality. In summary, polycystic ovaries do not necessarily indicate the presence of the endocrine syndrome of hyperandrogenism and menstrual irregularity.

Women With PCOS: A Reservoir of Future Diabetes?
Although hyperinsulinemia reflecting some degree of peripheral insulin resistance was well-recognized in PCOS by the mid-1980s, glucose tolerance was not systematically assessed until our study in 1987.¹² We found that obese women with PCOS had significantly elevated glucose levels during an oral glucose tolerance test compared with age- and weight-matched ovulatory hyperandrogenic and control women. Twenty percent of the obese women with PCOS had im-paired glucose tolerance or frank type 2 diabetes by National Diabetes Data Group Criteria.

Subsequent retrospective studies in postmenopausal women with PCOS have found a significantly increased prevalence of type 2 diabetes as well as of hypertension (see below).¹³ We have continued to find prevalence rates of glucose intolerance as high as 40% in obese women with PCOS when the less stringent World Health Organization (WHO) criteria are used.¹⁴

The majority of affected women are in their third or fourth decade of life, but we have encountered adolescents with PCOS and impaired glucose tolerance or type 2 diabetes. These prevalence rates of 20-40% are substantially above prevalence rates for glucose intolerance reported in population-based studies of women of this age (5.3% by National Diabetes Data Group criteria and 10.3% by WHO criteria in women ages 20-44 years.¹⁵)

We have found that the prevalence of glucose intolerance is significantly higher in PCOS women (~30%) than in concurrently studied age-, ethnicity- and weight-matched ovulatory control women (~10%).¹⁴ Finally, based on the prevalence of glucose intolerance in women, the prevalence of glucose intolerance in PCOS, and a conservative estimate of the prevalence of PCOS (~5%), it can be extrapolated that PCOS-related insulin resistance contributes to ~10% of cases of glucose intolerance in premenopausal women. It is thus clear that PCOS is a major risk factor for type 2 diabetes in women.

Unfortunately, there are few studies with longitudinal follow-up of women with PCOS to confirm this increased risk. A recent large, case-control study of 206 women with PCOS found them to be more insulin resistant than were control subjects based on insulin levels.¹⁶

Insulin Resistance in PCOS
Except in rare instances of mutant insulins with decreased biological activity, hyperinsulinemia (basal and/or postglucose) indicates the presence of insulin resistance. How-ever, peripheral insulin levels are quite variable, and insulin sensitivity can be better quantified by direct measurement of insulin effects on glucose metabolism in target tissues, both in vivo and in vitro.

Hyperinsulinemic/euglycemic glucose clamp studies have demonstrated significant and substantial decreases in insulin-mediated glucose uptake in PCOS.¹⁷ This decrease (~35-40%) is of a similar magnitude to that seen in type 2 diabetes and is independent of obesity, glucose intolerance, increase in waist-hip girth ratio, and difference in muscle mass.¹⁸ This synergistic negative effect of obesity and PCOS on hepatic glucose production is an important factor in the pathogenesis of glucose intolerance in PCOS.

We have consistently found significant decreases in insulin-mediated glucose utilization in both lean and obese women with PCOS.¹⁹ Similarly, we have found significant decreases in insulin sensitivity determined by modified, frequently sampled intravenous glucose tolerance testing with minimal model analysis in such women with PCOS.²⁰ However, a Danish study of lean women with PCOS failed to find decreased glucose uptake using the euglycemic glucose clamp procedure.²¹ This may be related to ethnic differences in insulin sensitivity, which are preserved in PCOS.

We have also encountered both lean and obese women with PCOS who have normal insulin sensitivity, suggesting that there is some heterogeneity in the syndrome. Insulin resistance, however, has been found in women with PCOS of many racial and ethnic groups, including Japanese, Caribbean and Mexican Hispanics, nonHispanic whites, Asian Indians, and African Americans.^19,22-24

Does Insulin Resistance Cause Hyperandrogenism and Menstrual Irregularity?
The syndromes of extreme insulin resistance are commonly associated with hyperandrogenism when they occur in premenopausal women. Accordingly, it has been proposed that hyperinsulinemia causes hyperandrogenism. In the Pima Indians, an American Indian population with a high incidence of hyperinsulinemia and insulin resistance, menstrual irregularity has been correlated with elevated insulin levels.²⁵

Human studies of insulin action on gonadotropin secretion have yielded conflicting results. There is better evidence that insulin may work at the level of the ovary. Insulin can be shown experimentally to have a variety of direct actions on steroidogenesis in humans.²⁶ Insulin can stimulate ovarian estrogen, androgen, and progesterone secretion in vitro. It has been proposed that insulin mediates these changes via the IGF-1 receptor. This explains the preservation of insulin action at the ovary in the face of resistance to insulin action on glucose uptake.

Recent data from the Franks group suggest that physiological insulin levels enhance steroid production from granulosa cells of women with PCOS and significantly increase their subsequent response to leutinizing hormone.²⁷ Moreover, insulin has been shown to act on the ovary through its own receptor. There is accumulating evidence that reducing circulating insulin levels will lower androgen levels in women with PCOS.²⁸

Treatment of Menstrual Disorders in PCOS
In addition to the disabling effects of unpredictable and often heavy menstrual bleeding, the irregular cycles of women with PCOS hold medical risks. Menorrhagia places a woman at risk for iron deficiency anemia. Chronic anovulation places women with PCOS at increased risk for endometrial hyperplasia and endometrial cancer because of the long-term exposure to unopposed estrogen.^29-31

Several potential mechanisms explain this estrogen excess in women with chronic anovulation. Although these women may not produce large amounts of estradiol, there may be increases in unbound estradiol due to suppressed sex hormone binding globulin levels.³² Also, the large precursor pool of androgens may be aromatized peripherally, especially by fat tissue, into weak estrogens such as estrone. Regular withdrawal bleeding is a prerequisite for women with this type of chronic anovulation. The safe number of withdrawal bleeding episodes per year to minimize the risk for endometrial hyperplasia or carcinoma in women with PCOS is uncertain. A summary of treatments and their effects can be found in Table 1.

Table 1. Diagnostic Criteria for Major Depressive Disorder*
Pharmeceutical Agent	Menstrual Regularity	Ovulatory Function	Insulin Sensitivity
Diet/Activity
Weight loss
Cyclic Hormones
Oral contraceptive
Cyclic progestin	?	? No effect
Anti-Androgens
Spironolactone	/	/
Flutamide	/	/
Finasteride	/	/
Insulin-Sensitizing Agents
Metformin
Troglitazone
* No recommendation is being made to use any of the above agents other than weight loss for treatment of infertility, due to unknown possible teratogenic effects.

Weight loss. Weight loss in obese women with PCOS can improve the reproductive abnormalities associated with the syndrome. Weight loss frequently improves menstrual cyclicity and decreases circulating androgen levels.³³ Additionally, weight loss decreases serum insulin levels.³⁴ Thus, it is difficult to determine whether the improvement in menstrual function results from a reduction in circulating androgen levels or from an improvement in insulin sensitivity through weight loss. Weight loss should be a cornerstone of treatment intervention to improve menstrual cyclicity in obese women with PCOS.

Exercise. Unfortunately, there has been little research on the effects of exercise alone to improve insulin sensitivity. One small study of the effects of one brief episode on a bicycle ergometer in women with PCOS found no significant effects on glucose, insulin, or C-peptide levels compared to control subjects.³⁵ More research has been done on patients with type 2 diabetes, whose peripheral insulin resistance has been comparable with that of women with PCOS. Exercise has been found to improve insulin sensitivity in the case of patients with type 2 diabetes.³⁶ Even low-impact exercise has been found to dramatically improve insulin resistance.³⁷ This effect is independent of exercise-induced weight loss. If this were also true for women with PCOS, exercise would represent another treatment modality.

Diet. Although the popular literature and online discussion groups are filled with claims of the perfect diet to remedy menstrual disorders in PCOS, the scientific literature is less certain. Severely restrictive diets, such as a 421 kcal/day, protein-rich, very-low-calorie diet given to a small group of women with PCOS, result in significant decreases in body fat. Two of nine women in this group had restoration of menstrual cyclicity and became pregnant.³⁸ These types of diets do not produce sustainable weight loss over a longer period of time. When a subgroup of women from this study were continued on a more generous diet (1000-1500 kcal/day) for 24 weeks, insulin sensitivity remained improved, although the androgen levels rose to baseline.

A similar study with an initial very-low-calorie diet (330 kcal/day) followed by a larger 1000-kcal/day diet for 6 months showed similar results.³⁹ The greatest improvement in menstrual function was in the women who lost the most weight. Nine of eleven women with menstrual dysfunction who lost more than 5% of their body weight experienced an improvement in menstrual dysfunction.

Pharmacological interventions. Pharmacological interventions to improve menstrual function have traditionally utilized steroid hormones to regulate the menstrual cycle. A newer class of agents that improve insulin action is receiving a great deal of attention from both the lay public and researchers. Although initial results are promising and larger studies are ongoing, these agents currently do not have Food and Drug Administration approval for use in women with PCOS.

Hormonal treatment. Many women with PCOS are treated with oral contraceptives to induce regular menstrual bleeding, reduce the exposure of the endometrial lining to unopposed estrogen, and suppress ovarian androgen production. Because the progestins in oral contraceptives may have adverse effects on insulin action, there is concern about their use in PCOS women with confirmed insulin resistance.

There is evidence in both normal women and women with type 1 diabetes that oral contraceptive use may not worsen insulin resistance. A recent report from the Nurses Health Study II ( a prospective cohort study) did not find a noticeable increase in the risk of type 2 diabetes among current users of birth control pills (over a 4-year period), nor was there an increased risk among past users of the pill.⁴⁰ During 353,067 person-years of follow-up, there were only 185 incident cases of diabetes among the cohort aged 25-42 years. Of course, there may be a selection bias away from prescribing oral contraceptives for women with severe forms of PCOS, and the long-term follow-up of these women (into menopause) is lacking.

Short-term use (1 year) of a low-dose oral contraceptive with third generation progestin (gestodene/desogestrel) also does not worsen glucose metabolism in women with type 1 diabetes⁴¹ or in normal women.⁴² Of particular note in this latter study was the transient worsening in glucose tolerance noted at 3 months that resolved by 12 months.

The metabolic impact of oral contraceptive agents in women with PCOS has been minimally investigated. A worsening of glucose tolerance after a 12-month period was noted in a sample of 5 women with PCOS after 12 months on an oral contraceptive consisting of 35 µg of ethinyl estradiol and 2 mg of cyproterone acetate, a combination not available in the United States.⁴³ In a more sophisticated study of insulin action, a worsening of insulin sensitivity in women with PCOS was noted using a triphasic contraceptive.⁴⁴ A comparable decrease in insulin sensitivity was also noted in the control subjects, so the response did not appear to be unique to women with PCOS.

In women where the primary concern is to achieve menstrual cyclicity to decrease the risk for endometrial hyperplasia and cancer, intermittent medroxyprogesterone acetate administration may be the treatment of choice. Medroxyprogesterone acetate, at least in the injectable form, has been reported to slightly worsen glucose tolerance.⁴⁵ Other synthetic progestins may have different effects. Norethindrone alone, a component of the mini-pill, has been shown to have little effect on insulin sensitivity.⁴⁶

Long-acting gonadotropin-releasing hormone analogs can effectively suppress ovarian hyperandrogenism in insulin-resistant women with PCOS.1 This suppression also produces a hypoestrogenic state that may result in osteoporosis over prolonged periods of time. It is possible to add back low-dose estrogen replacement to prevent bone loss. A preliminary study has suggested that low-dose add-back estrogen replacement alone does not lower insulin sensitivity, although adding a progestin does.⁴⁷

The effects on insulin sensitivity of hormonal manipulations in PCOS, both to regulate the menstrual cycle and to suppress ovarian hyperandrogenism, is an area where future investigation may play a pivotal role in determining long-term therapy. If significant worsening of insulin action is noted, this may not be the standard of care, especially for obese women with PCOS.

Anti-androgen therapy. Other additional interventions in women with hyperandrogenism include the use of androgen antagonists. Spiro-nolactone, even at high doses, does not impair glucose tolerance.⁴⁸ Flutamide also has not been shown to affect insulin sensitivity in women with PCOS.⁴⁹ One study found a small but significant improvement in insulin sensitivity for both spironolactone and flutamide.⁵⁰ The effect of finasteride on insulin sensitivity in women with PCOS is unknown, although it has been reported to be equal to aldactone in interfering with the associated hirsutism.⁵¹ Anti-androgens must be used with caution in PCOS women of reproductive age given their potential for teratogenic effects in male fetuses. Thus, they are often given in conjunction with oral contraceptives, both to avoid this potential complication and to supress ovarian androgen production.

Insulin-sensitizing agents. The rationale for using agents that improve insulin action rests on the long-observed positive effect of weight loss on menstrual cyclicity and insulin resistance in women with PCOS (see above). This has also been supported by pharmacological manipulations of insulin action. Decreasing insulin levels using diazoxide⁵² or somatostatin⁵³ has resulted in decreased serum androgen levels in PCOS. These agents are not useful clinically, however, as they worsen glucose tolerance.

Many newer agents have been developed and are being studied that improve insulin sensitivity. Met-formin, a biguanide, reduces hepatic glucose production.⁵⁴ Metformin administration to women with PCOS has consistently resulted in decreased hyperandrogenism and restoration of menstrual cyclicity.^55-57 Insulin sensitivity is also improved, but in one of the studies, this appears to be secondary to weight reduction,⁵⁵ with no weight change noted in the other.⁵⁶ A recent, more sophisticated study of insulin action in PCOS women on metformin therapy involved frequently sampled intravenous glucose tolerance tests, graded IV glucose infusion, and insulin secretory responses to oscillatory glucose administration.⁵⁷ No effect of metformin on hyperinsulinemia or hyperandrogenemia could be found that was independent of weight loss.

The thiazolidinedione group is another family of agents that improves insulin sensitivity. We have examined an agent from this family, troglitazone, and our initial experience with this medication suggests that it also will significantly decrease insulin resistance, as well as improve hyperandrogenism.⁵⁸ This pilot study, however, needs confirmation in a larger, randomized, placebo-controlled trial before its use can be considered in women with PCOS for menstrual cycle complaints. Spon-taneous pregnancies have been reported on both troglitazone and metformin therapy. The human teratogenic potential of these drugs is uncertain at this point, although both are listed as Category B (animal studies negative without human studies or human studies negative despite positive animal studies).

Summary
PCOS is a disorder of unexplained hyperandrogenism and menstrual irregularity. The menstrual irregularity may be a marker for the insulin resistance that characterizes the syndrome. It is now clear that PCOS is often associated with substantial insulin resistance, as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important marker for type 2 diabetes in women. From a clinical standpoint, the early identification of a subset of high-risk women for the long-term sequelae of insulin resistance allows counseling of these risks, early identification of sequelae, and intervention to prevent long-term morbidity..

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⁵⁸Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R: The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 81:3299-3306, 1996.

Richard S. Legro, MD, is an assistant professor of obstetrics and gynecology at Pennsylvania State University College of Medicine, in Hershey. Andrea Dunaif, MD, is senior director for medical and scientific affairs at Parke Davis Medical research in Morris Plains, NJ.

Note of disclosure: Dr. Legro has received honoraria from the TAP, Wyeth-Ayerst, and Searle pharmaceutical companies, which make pharmacological agents that may be used for the treatment of women with PCOS. Dr. Dunaif is employed by Warner Lambert Parke-Davis, which is developing a drug for PCOS. She also holds stock in Warner Lambert, which manufactures drugs for the treatment of diabetes and is developing a drug for PCOS. Parke-Davis has provided funding to her laboratory for research into new pharmacological treatments for PCOS.

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