Volume 10 Number 2, 1997, Pages 185-190
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Menstrual Disorders in Insulin-Resistant
Richard S. Legro, MD, and Andrea Dunaif, MD
Menstrual disorders are common in insulin-resistant
states. In women with polycystic ovary syndrome, menstrual irregularity may be related to
underlying insulin resistance. Improving insulin sensitivity may therefore improve
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
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.
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
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).
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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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.
© 1997 American Diabetes Association
Last updated: 9/23/97
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