Evidence that androgens modulate human thymic T cell output

Abstract

Background: The thymus has long been recognized as a target for the actions of androgenic hormones, but it has only been recently recognized that alterations in circulating levels of gonadal steroids might affect thymic output of T cells. We had the opportunity to examine parameters of thymic cellular output in several hypogonadal men undergoing androgen replacement therapy.

Methods: Circulating naive (CD4+CD45RA+) T cells were quantitated by flow cytometric analysis of peripheral blood mononuclear cells. Cells bearing T-cell receptor excision circles were quantitated using real-time polymerase chain reaction amplification of DNA isolated from peripheral blood mononuclear cells from healthy men and from hypogonadal men before and after testosterone replacement therapy.

Results: CD4+CD45+ (naive) T cells comprised 10.5% of lymphocytes in healthy males; this proportion was greatly increased in 2 hypogonadal men (35.5% and 44.4%). One man was studied sequentially during treatment with physiologic doses of testosterone. CD4+CD45RA+ cells fell from 37.36% to 20.05% after 1 month and to 12.51% after 7 months of normalized androgen levels. In 2 hypogonadal patients, T-cell receptor excision circle levels fell by 83% and 78% after androgen replacement therapy.

Conclusions: Our observations indicate that the hypogonadal state is associated with increased thymic output of T cells and that this increase in recent thymic emigrants in peripheral blood is reversed by androgen replacement.

Figure 1

(A) CD4+CD45RA+ T cells (% of total cells) as a function of age in five normal males (closed symbols) and in five hypogonadal males (open symbols with subject numbers from Table 1). (B) Flow cytometric data showing staining for CD4 and CD45RA in two hypogonadal males (left panels; with subjects 4 and 5 from Table 1) and two normal control men (right panels). CD4+CD45RA+ cells are in the right upper quadrant of each panel. (C) T cell Receptor Excision Circle (TREC) quantitation as a function of age in three normal control males (closed symbols) and in two hypogonadal men (open symbols with subject numbers from Table 1).

Figure 2

(A) CD45RA+ cells (as percent of total) during androgen replacement therapy of subject 5 (Table 1) with hypogonadism. CD3+ cells are shown in closed symbols and CD4+ cells are shown in open symbols. (B) TREC quantitation in two men (subjects 5 and 6 from Table 1) in the hypogonadal state and after restoration of normal testosterone levels.