The route of administration influences the effect of estrogen on insulin sensitivity in postmenopausal women.

Objective: To determine the effect of transdermal estrogen on insulin sensitivity in postmenopausal women and to compare this effect with changes observed with oral conjugated equine estrogens.

Design: Fourteen postmenopausal women were randomized to receive a transdermal E2 patch, 0.1 mg, for 25 days each month (n = 7) or transdermal E2 with added medroxyprogesterone acetate (MPA), 10 mg, from days 16 to 25 each month (n = 7). An insulin tolerance test (ITT) was performed at baseline and between days 23 and 25 during the 2nd month of treatment to assess insulin sensitivity. Values for the disappearance of glucose (K(itt)) were calculated and compared with values obtained from women receiving 1.25 mg of oral equine estrogens (n = 8).

Setting: University Clinical Research Center.

Patients: Healthy postmenopausal women not receiving hormonal replacement.

Intervention: Insulin tolerance tests before and after treatment.

Main Outcome Measure: Disappearance of glucose and insulin (K(itt)) before and after treatment.

Results: Women receiving transdermal E2 alone demonstrated improved insulin sensitivity. The K(itt) glucose values increased by 13.2%, compared with a 23.9% decrease in K(itt) values observed with 1.25 mg of conjugated equine estrogen. The group treated with transdermal E2 and MPA had a reduction in insulin sensitivity. Insulin clearance was enhanced only with transdermal estrogen and was significantly delayed (blunted clearance) with the addition of MPA to transdermal E2 and with oral estrogen.

Conclusion: We previously demonstrated a bimodal effect of oral equine estrogens on insulin sensitivity with an improvement occurring with the lower dose of 0.625 mg but with a deterioration with the dose of 1.25 mg. Here we suggest that this effect may be related to a first-pass hepatic-portal effect in that transdermal E2 (0.1 mg), which may be equated more closely with the larger dose of oral estrogen (1.25 mg), improved insulin sensitivity. Progestin, however, appeared to attenuate the beneficial effects of transdermal estrogen and may alter the clearance of insulin.