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Impaired Adipocyte Lipolysis in Nonobese Women with the Polycystic Ovary Syndrome: A Possible Link to Insulin Resistance?¹

Departments of Medicine and Gynecology and Obstetrics, and the Research Center, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden

Address all correspondence and requests for reprints to: Hans Wahrenberg, M.D., Division of Endocrinology and Metabolism, Department of Medicine M63, Huddinge Hospital, Karolinska Institute, S-141 86 Huddinge, Sweden.

The polycystic ovary syndrome (PCOS) is the most common hyperandrogenic disorder among women and is characterized by metabolic and cardiovascular aberrations similar to those seen in the so-called insulin resistance syndrome. The regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 10 nonobese women with PCOS and in 11 age- and body mass index-matched healthy women. Eight PCOS women were reinvestigated after 3 months of treatment with combined oral contraceptives containing ethinyl estradiol and norethisterone, which normalized hyperandrogenicity. The PCOS women showed a marked resistance to the lipolytic effect of noradrenaline due to defects at two different levels in the lipolytic cascade: first, a 7-fold reduction in sensitivity to the ß₂-selective agonist terbutaline (P < 0.005), which could be ascribed to a 50% lower ß₂-adrenoceptor density (P < 0.02) as determined with radioligand binding; there was no difference with regard to dobutamine (ß₁) or clonidine (₂-sensitivity) or ß₁-adrenoceptor density; second, the maximum lipolytic response was also 35% lower (P < 0.02) in the PCOS women compared to that in the healthy women. This was seen with all ß-adrenergic agonists and the postreceptor-acting agents forskolin (activating adenylyl cyclase) and dibutyryl cAMP (activating protein kinase). Neither ß₂-adrenoceptor sensitivity or density nor the reduced lipolytic responsiveness was restored by 3 months of oral contraceptives treatment. The results indicate the existence of a marked impairment of catecholamine-induced lipolysis in nonobese PCOS women displaying early features of the insulin resistance syndrome due to multiple lipolysis defects as a lower ß₂-adrenoceptor density and reduced function of the protein kinase, hormone-sensitive lipase complex. These lipolysis defects are identical to those observed in the insulin resistance (metabolic) syndrome and could be a primary pathogenic mechanism for the development of these disorders.

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