Trial Information

The Role of Insulin Resistance and Adiponectin in the Pathogenesis of Polycystic Ovary Syndrome

Because of the menstrual irregularity and the hirsutism/acne caused by hyperandrogenism, the
treatment of choice for PCOS in young teenagers is to given the oral contraceptive; however,
such oral contraceptives fail to correct the endocrinometabolic anomalies and the excess of
fat. Therefore, there are some alternative treatments as adding the novel progesterone,
which is claimed to have antimineralocorticoid and antiandrogenic activities, or giving an
insulin-sensitizing compound such as metformin. These treatments were reported to be
effective in changing the endocrinometabolic state and the adiposity of PCOS. Besides, they
were also reported to have efficacy in aiding ovulation induction.

PCOS is the main androgen disorder in women and has been suggested to be associated with a
high risk of developing cardiovascular disease and type-2 diabetes. In many PCOS patients,
overweight or central obesity is generally associated with increases in fasting insulin
levels, insulin resistance, and glucose intolerance, and has been identified as a target for
new therapeutic strategy, including early change in lifestyle.

The plasma concentrations of adiponectin were lower in men than in women but were not
different between pre- and postmenopausal women. It suggests that androgen act to reduce
plasma adiponectin concentration. In animal experiment, testosterone supplement reduced
plasma adiponectin concentration in male mice. In cultured 3T3-L1 adipocytes, testosterone
and 5α-DHT suppressed the secretion of adiponectin, suggesting that androgen decreased
plasma adiponectin concentration through its effect on adipocytes.

Clinical and/or biochemical signs of hyperandrogenism are one of the three diagnostic
criteria defining the PCOS. Hyperandrogenemia may cause hirsutism, alopecia, acne, and also
strongly affect the ovulatory function. Some hormone therapy such as ethinylestradiol
cyproterone and ethinlyestradiol drosipirenone were usually used to reduce the serum
androgen level and correct the amenorrhea/oligomenorrhea, while its effect in improving the
endocrine-metabolic state and the adiposity of PCOS was still undetermined. Obese women with
PCOS are known to have high serum concentrations of C-reactive protein (CRP), a marker of
inflammation and cardiovascular risk factor; metformin monotherapy reduces the CRP levels,
whereas combined treatment with ethinylestradiol and cyproterone-acetate raises CRP further.
Therefore, I am interesting about how do the metformin and ethinylestradiol/cyproterone
acetate influence the serum adiponectin level.

Insulin resistance, defined as decreased insulin-mediated glucose utilization, is commonly
(10-25%) found in the normal population. In women with PCOS, insulin resistance appears even
more common (up to 50%), in both obese and non-obese women. Criteria developed for defining
a metabolic syndrome in PCOS includes components associated with insulin resistance syndrome
including centripetal obesity, hypertension, fasting hyperglycemia and dyslipidemia. Since
serum adiponectin concentrations correlate inversely with the severity of insulin resistance
was well established, however, the adiponectin levels in women with PCOS is still
controversial and need further elucidation. Such as Orio et al. suggested that insulin
sensitivity does not play any pivotal role in the control of adiponectin in PCOS women and
Ducluzeau et al. mentioned that glucose-to-insulin level is better than adiponectin in
predicting insulin resistance in PCOS. Besides, adiponectin level reduced in obese women
with PCOS was reported. Currently only a clinical trial suggested that the oral
contraceptives plus metformin may reduce the adipocytokine imbalance.

Hyperinsulinemia appears to play a key pathogenic role in the ovarian androgen
overproduction, because of the stimulatory effect of insulin on ovarian steroid production.
The mechanism that allows the ovary to remain sensitive to insulin when classical target
organs for insulin action (liver, fat, and muscle) exhibit insulin resistance was supported
by the presence of phosphatidyl inositol 3 (PI-3) kinase independent insulin signaling
pathway in human ovarian cells (theca and granulosa cell). Insulin is proposed to directly
stimulate activity of cytochrome P450c17α, an enzyme involved in ovarian androgen synthesis
that is found in thecal cells.