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In studies Ligandrol has shown a dose-dependent suppression of total testosterone from baseline to 21 daysin the HRT regimen, and increases in serum T concentration after a single dose increase. The increase in serum T at this level has been accompanied by alterations in plasma levels of estradiol, dihydrotestosterone, and testosterone and increased liver lipase activity (Gonon 1994; Hsu et al. 1992). Hormonal treatments in HRT have been found to suppress androgen production in men who undergo gonadectomy (Acevedo et al. 1998; Hsu et al. 1992). Therefore, changes in sex steroids may play a major role in HRT-induced changes in breast cancer risk.Other investigators report that estrogen supplementation of transdermal patches has no effect on breast cancer risk (Liu et al. 1998; Tshimanga 1995; Koo and Seou, unpublished data). A meta-analysis by Chen et al. (1998) also concluded that estrogen and progesterone supplementation in HRT do not have a role in breast cancer risk. However, other investigators have claimed that estradiol is more likely to be involved in estrogen-dependent changes than testosterone. For example, Cuszkowski et al. (1995) compared serum levels of estradiol in men taking HRT and those in comparable healthy men, and found that the HRT group had higher estradiol than those in normal controls in all three breast cancer risk factors. In addition, Dansig et al. (1994) found that estradiol levels were higher in HRT than in controls when both doses of hormone were administered simultaneously.The role of estrogen in the development of breast cancer remains poorly understood. The first study to suggest that estrogen and progesterone may have roles in breast cancer risk is the Women's Health Initiative (WHI) trials (Kelley, 1997; Leiter and Gillin, 1997). Although the WHI trial had several flaws, several positive effects of HRT have been reported, even though the study was not blinded, the participants were not randomized to HRT, the participants could not receive both HRT and progesterone during the course of the study, and some HRT users developed malignancies. However, the WHI trial has been criticized because too little research has been done to assess the association between estrogen and breast cancer risk, and no association between estrogen and breast cancer development has been found in many studies of HRT. Although the WHI trial found no risk differences between HRT users who received estrogen and those without HRT,Related Article: