Evidence That Parenteral Testosterone Therapy May Improve Endothelium-Dependent and -Independent Vasodilation in Postmenopausal Women Already Receiving Estrogen

Abstract

The gender difference in cardiovascular disease has been partly attributed to higher androgenic hormone levels. Although testosterone in women may not affect lipids, it remains unknown whether it negates favorable estrogenic effects on endothelial function. We have investigated the effects of testosterone implant therapy on arterial reactivity encompassing endothelial-dependent and -independent vasodilation in women using hormone replacement therapy (HRT). B-mode ultrasound measurements of resting brachial artery diameter, following reactive hyperemia [endothelium-dependent flowmediated dilation (FMD)] and following glyceryl trinitrate (GTN) (endothelium-independent dilation), were recorded in 33 postmenopausal women stabilized on HRT (Ͼ6 months), at baseline, and 6 weeks after a testosterone implant (50 mg), with 15 postmenopausal nonusers of HRT serving as controls. In the brachial artery, baseline resting diameter was similar (0.40 Ϯ 0.01 vs. 0.41 Ϯ 0.01 cm, P ϭ 0.5). In the treated group, testosterone levels increased (0.99 Ϯ 0.08 to 4.99 Ϯ 0.3 nmol/L, P Ͻ 0.001), associated with a mean 42% increase in FMD (6.4% Ϯ 0.7 to 9.1% Ϯ 1.1, P ϭ 0.03). The control group did not change (8.1% Ϯ 1.4 to 5.6% Ϯ 1.0, P ϭ 0.4). ANOVA of repeated measures (P ϭ 0.04) and mean change (P ϭ 0.02) in FMD both demonstrated significantly greater improvement with testosterone compared with controls. GTN induced vasodilation increased with testosterone treatment (14.9% Ϯ 0.9 to 17.8% Ϯ 1.2, P ϭ 0.03). Our preliminary data indicate that parenteral testosterone therapy improves both endothelial-dependent (flow-mediated) and endothelium-independent (GTN-mediated) brachial artery vasodilation in postmenopausal women using long-term estrogen therapy. The mechanisms underlying these potentially beneficial cardiovascular effects require further investigation. (J Clin Endocrinol Metab 86: 158 -161, 2001) T ESTOSTERONE LEVELS DECLINE with increasing age in women during the reproductive years (1) and acutely following bilateral ovariectomy (2). Increasingly, testosterone is used in hormone replacement regimens to restore libido in postmenopausal women (3-5), with testosterone implants now approved for this purpose in the United Kingdom. Postmenopausal estrogen modulates cardiovascular risk via several mechanisms (6). Whether coadministration of testosterone attenuates these cardioprotective effects or is, in fact, deleterious has not been established. We have previously demonstrated that long-term testosterone implant therapy does not adversely affect the improvements in lipoprotein lipids associated with postmenopausal estrogen use (3). Studies in animals (7, 8), and more recently in men with established coronary artery disease (9), indicate that parenteral testosterone does not adversely affect coronary artery vascular function. However, the effect of parenteral testosterone replacement on vascular reactivity in postmenopausal women has not been reported.Endothelial dysfunction, a putative early marker of vascular disease, can be ...

The influence of testosterone upon vascular reactivity

“…Similarly, testosterone therapy is reported by TatchumTalom et al (43) to increase acetylcholine (but not sodium nitroprusside)-mediated femoral arterial vasodilatation in vivo, in female spontaneously hypertensive rats. Both these studies mirror the previous female human studies (29), and are in agreement with the hypothesis that testosterone replacement has a beneficial effect upon the dilatory capability of vessels in cardiovascular disease, although at the level of the vascular endothelium rather than the smooth muscle. However, as discussed previously, these observations should be interpreted with caution since they were restricted to female animals.…”

“…Subcutaneous physiological testosterone therapy has also been shown to increase both flow-mediated and glycerol trinitrate-induced brachial artery vasodilatation levels in women already receiving long-term oestrogen replacement therapy (29). However, the issue of testosterone therapy in women is contentious since it has been demonstrated to increase atherosclerotic burden in female cholesterol-fed animal models (30).…”

“…Testosterone is readily converted into 17b-oestradiol by aromatase, which is expressed in vascular tissue (38,39), and 17b-oestradiol is known to improve vascular reactivity in women and men (40,41). In addition, the observation that physiological testosterone therapy also increases both flow-mediated and glycerol trinitrate-induced brachial artery vasodilatation in women (29) makes such an action a possibility. However, in contrast, the rapidity of the improvement in flow-mediated brachial artery vasodilatation in men following testosterone treatment (27) suggests that this arises as a direct action, rather than following enzymatic conversion to an alternative agent.…”

Low testosterone levels are associated with endothelial dysfunction in oophorectomized early postmenopausal women

“…Oophorectomized women have higher risk of cardiovascular events according to Women's Health Initiative study (23). Populational studies including menopausal women up to 69 years reported higher cardiovascular risk in those who underwent bilateral oophorectomy before 50 years (26), found increased endothelium-dependent and independent vasodilatation after using, associated with estrogen-progestin therapy, 50 mg subcutaneous testosterone implants for 6 weeks.…”

Síndrome de insuficiência androgênica: critérios diagnósticos e terapêuticos

“…Após seis semanas, nas usuárias de testosterona, observou-se uma melhora da vasodilatação arterial tanto dependente quanto não-dependente da função endotelial. Tais resultados, ainda que preliminares, acenam para um risco menor do que se imaginava, ou, quem sabe, contrariamente, até para um benefício cardiovascular da testosterona por via parenteral em mulheres na pós-menopausa apropriadamente estrogenizadas (Worboys et al, 2001).…”