Metabolic Lessons from the Study of Young Adolescents with Polycystic Ovary SyndromeIs Insulin, Indeed, the Culprit?
Sharon E. Oberfield
Department of Pediatric Endocrinology
Columbia University
New York, New York 10032
Address correspondence and requests for reprints to: Sharon E. Oberfield, M.D., Professor of Pediatrics, Department of Pediatric Endocrinology, Columbia University, 630 West 168th Street, PH-5 East Room 522, New York, New York 10032.
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Introduction
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The metabolic disturbances in type 2 diabetes
include both peripheral insulin resistance and impaired insulin
secretion (1). Polycystic ovary syndrome (PCOS), a
metabolic condition observed in
10% of reproductive age women, is
characterized by hyperandrogenism and chronic anovulation. It is often
associated with obesity, dyslipidemia, and acanthosis nigricans (AN).
Insulin resistance is a common comorbidity in women with PCOS and is
associated with increased risk for hypertension and cardiovascular
disease. Studies have shown that 2535% of obese women with PCOS, by
30 yr of age, will have either impaired glucose tolerance or type 2
diabetes (2). It has been suggested that PCOS should be
considered as another metabolic abnormality of "Syndrome X," which
includes dyslipidemia, hypertension, and insulin resistance
(3).
The actual role of insulin (hyperinsulinemic insulin resistance) in the
development and maintenance of hyperandrogenism in PCOS is a
controversial area in which consensus has not been reached. In
vitro and in vivo studies have shown that insulin acts
at multiple sites, often leading to increased androgen excess and
effect. Additionally, in women with PCOS, genetic factors, which may
modulate the response to insulin at the cellular level, are just
beginning to be described (for reviews see Refs. 4 and
5). An increase in serine/threonine phosphorylation of
P450c17 increases the enzymes 17,20 lyase activity, resulting in an
increase in androgen production, as seen in adrenarche
(6). Increased serine phosphorylation of the insulin
receptor ß chain causes insulin resistance by inhibiting tyrosine
phosphorylation (7). The contemporaneous reports of Miller
suggesting and Dunaif demonstrating that some women with PCOS have
hyperphosphorylated insulin receptors allowed for speculation of the
existence of a common molecular pathwayhyperactivity of a single
serine kinasefor the two major features of PCOS, namely
hyperandrogenism and insulin resistance (6, 7, 8). Recently,
however, this was not confirmed in analysis of 17,20 lyase activity in
cultured fibroblasts obtained from women with PCOS
(9).
Insulin has been shown to directly stimulate ovarian androgen secretion
through effects on steroidogenic enzymes (10). Nestler
et al. (11, 12) have shown that these effects
were partially reversed with use of metformin. It has been suggested
that insulin also augments adrenal androgen synthesis
(13). In vitro studies have demonstrated that
insulin may also stimulate LH release directly or enhance LH release
from pituicytes, thereby indirectly stimulating ovarian androgen
production (14). Insulin may increase ovarian LH receptors
(15). Insulin is known to decrease hepatic sex
hormone-binding globulin (SHBG) production, allowing for an increase in
the levels of circulating free androgens (16).
Additionally, insulin has been shown in vitro to decrease
insulin-like growth factor-binding protein I (IGFBP-I), which results
in an increase in IGF-I, which may then act locally at the ovary to
stimulate androgen synthesis (17). Thus, reduction of
serum insulin would be expected to decrease some of the
androgen-related symptomatology such as hirsutism. Decrease in insulin
itself should also result in a decrease or modification in risk factors
associated with hyperinsulinism and insulin resistance, including the
development of type 2 diabetes, dyslipidemias, hypertension, and
cardiovascular disease.
Most recently, insulin resistance has been demonstrated in girls with
premature adrenarche (PA) (18, 19). PA, defined by the
onset of pubic hair in girls before age 8 yr, is associated with
adrenal androgen levels higher than expected for age. It has been
suggested that PA may be an antecedent of PCOS (18, 20, 21). Indeed, although PA was once considered a benign condition,
it is now known to be associated with risk for many of the same
conditions as PCOS, including hirsutism, obesity, AN, hyperinsulinism,
and insulin resistance (22, 23, 24). Of relevance is the
hypothesis proposed by Barker et al. (25) that
lower birth weight or reduced fetal growth is related to the
development of type 2 diabetes mellitus, hypertension, and
hyperlipidemia, as well as "Syndrome X" in adult life
(26). Ibanez et al. (27, 28), a
major proponent of an extension of this theory, state in this issue of
the journal that a "constellation of hirsutism, hyperandrogenism,
oligomenorrhea, dyslipidemia and hyperinsulinism in lean, young women
may already be a late stage of a developmental disorder starting early
in life" (29). Germane to the current report is the
prior work by Apter et al. (30), in which
hyperinsulinemic insulin resistance and reduced IGFBP-I and SHBG levels
were associated with ovarian hyperandrogenism in young adolescent
girls, suggesting that peripubertally insulin plays a contributory role
to the development of the metabolic derangement ascribed to PCOS.
In the current report, Ibanez et al. (29) describe 10
"nonobese adolescents ... in whom the appearance of ovarian
hyperandrogenism was heralded by premature pubarche, hyperinsulinism
and dyslipidemia before puberty and, even earlier, by a low birth
weight," in whom treatment with metformin, an insulin sensitizing
agent, resulted in a decrease in hirsutism score, insulin response to
an oral glucose tolerance test (OGTT), free androgen index, and
androgen response to stimulation with GnRH. Serum triglyceride, total
cholesterol, and LDL cholesterol levels declined whereas HDL
cholesterol increased. Menses occurred within 4 months of treatment.
Perhaps the most important aspect of this study is that metformin use
was addressed in a young and lean population at risk for the
development of cardiovascular disease. If these findings are reproduced
in larger placebo and weight-controlled studies, significant
implications could be drawn including the encouragement of the use of
an insulin-sensitizing agent, like metformin, in young patients with
hyperinsulinemia, particularly those with a family history of type 2
diabetes and cardiovascular disease.
At the present time, few studies have addressed the use of metformin in
children as a treatment for either insulin resistance or obesity. The
action of metformin is not fully known. It inhibits hepatic glucose
production and increases peripheral tissue sensitivity to insulin. It
is thought to decrease insulin action on both the ovary and the
liver. In vitro, therapeutic concentrations of metformin
have been shown to simulate the tyrosine kinase activity of the
intracellular portion of the ß-subunit of the human insulin receptor,
but higher levels of metformin inhibited the tyrosine kinases
(31). The most common morbity associated with its use is
gastrointestinal distress, specifically diarrhea and abdominal pain,
which is often transient and seems to be lessened if the dose is
gradually increased. Although patients with renal insufficiency seem to
be most at risk of developing severe lactic acidosis after receiving
metformin, a recent case was observed in an elderly patient with normal
renal function (32).
Table 1 cites a limited number of recent
studies that have assessed the efficacy of metformin as an agent
capable of reversing metabolic and ovarian abnormalities often
associated with increased levels of insulin.
Although not reported by all investigators, metformin seems to cause a
decline in insulin levels, an increase in insulin sensitivity, and a
decrease in LH, androgens, and lipid levels and the ratio of
IGF-I/IGFBP-I. Many of these changes occur even in the absence of
changes in body mass index (BMI). It may not been effective in
profoundly obese women. It has been associated with modest declines in
weight and increases in normal menstrual cycling patterns and
ovulation. It has been used during pregnancy with safety. As seen in
Table 1, use of metformin in adolescents has been extremely limited
although its use seems to be safe in small pilot studies.
Comparison of the current study by Ibanez et al.
(29) with the reports above suggests that the dose
(1275 mg/day) and length of time (6 months) of metformin used is
similar to the previous studies. The young mean age of the girls was
16.8 yr (range, 1320; most were 1517 yr, with one only 20 yr of
age; personal communication) makes this of particular interest because
efforts aimed at preventing long-term cardiovascular complications of
hyperinsulinism and modifying effects of androgen excess in at-risk
adolescents and young women of child-bearing age may be speculated to
be more effective if begun at a younger age. Noteworthy is the fact
that these adolescents were all at least 3 yr postmenarche and had been
documented to have hyperinsulinemia8 of 10 prepubertally at diagnosis
of premature pubarcheand in early puberty, with mean serum insulin
levels 2 or more SD scores above the mean for
age. Thus, identification of an at-risk population would provide a
younger-aged population in whom potential benefit from targeted therapy
with insulin-sensitizing agents like metformin could be achieved.
Unlike the majority of women in the prior studies where metformin has
been effective, these adolescents were lean (mean BMI, 21.9
kg/m2) and not obese. Other efforts aimed at
reducing insulin levels in the Ibanez et al.
(29) cohort, such as weight reduction, were, thus, not a
real option. The significant decrease in hirsutism is noteworthy
because other agents such as birth control pills or antiandrogens,
which have been used to reduce the effects of hyperandrogenism in women
with hyperinsulism and PCOS, have often resulted in limited success
(52, 53). Although the skin findings of AN are frequently
observed in obese women with insulin resistance and obesity, only one
of these adolescents had mild AN (personal communication), perhaps
because of their lean BMI. However PAI-1, another marker known to be
associated with increased cardiovascular vascular events and
insulin-resistance in obese and type 2 diabetic patients, was elevated
and subsequently decreased with metformin use (54).
Furthermore, although her population was not small for gestational age
(i.e. weight less <10%), the mean birth weights were in
the lowest quartile for gestational age (55),
corroborating the previous reports linking low birth weight to insulin
resistance in adulthood (25, 27).
As in many small initial clinical drug studies, there was no placebo
control group; however, the reversal of improvements on withdrawal of
metformin was impressive. Indeed, although this report is of a very
small group of patients and may, in fact, represent a subgroup of girls
at risk because of low birth weight, it supports the hypothesis that
hyperinsulinemia may have an early critical role in the development of
PCOS and "Syndrome X" and challenges us to confirm and expand these
findings. Clearly, targeted treatment of a younger population of girls
at risk for cardiovascular disease and type 2 diabetes associated with
hyperinsulinism such as precocious pubarche may attenuate, decrease, or
even prevent progression to PCOS in the reproductive years.
The public health ramification of this report may be quite significant.
Currently, the incidence of type 2 diabetes in adolescents is
increasing at an alarming rate (56). In Tokyo, Japan, for
example, type 2 diabetes accounts for close to 80% of all childhood
diabetes [Dr. K. Kida (Ehime University, Matsuyama, Japan),
personal communication]. Is there sufficient safety and efficacy data
available for metformin to suggest it be used in young patients at-risk
for the development of type 2 diabetes?
As with any new therapeutic model, long-term safety issues need to be
addressed. In the current study, minimal transient gastrointestinal
discomfort was noted in three of the adolescents with no report of
hypoglycemia or lactic acidosis. Use of insulin sensitizers must be
carefully monitored as most recently evidenced by the Food and Drug
Administration withdrawal of the thiazolidinedione
troglitazone due to fatal liver toxicity associated with
its use. At the present time, given the lack of established long-term
efficacy and safety in either adults, adolescents, and certainly
children, until prospective large-scale clinical trials are performed,
it would seem prudent to limit the use of metformin to adolescents at
risk for the development of PCOS and type 2 diabetes to clinical
trials. The report by Ibanez et al. (29) should
encourage initiation of such studies.
Received August 10, 2000.
Accepted August 13, 2000.
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