Androgen metabolism in response to oestradiol‐17b and progesterone in human gingival fibroblasts (HGF) in culture

Abstract

The modulation of androgen metabolism by oestrogen and progesterone in HGF has been investigated, to elucidate hormone modulatory mechanisms, in periodontal disease presentation and healing responses. Duplicate incubations of HGF were performed in Eagle's MEM for 24 h with either 14C-testosterone/14C-4-androstenedione as substrate and serial concentrations of oestradiol-17beta, or progesterone (0.01-50 microg/ml). The effect of the anti- oestrogen tamoxifen on the action of oestradiol in HGF was also investigated. The medium was analysed and quantified for steroid metabolites. When 14C-testosterone was used as substrate, oestradiol stimulated the synthesis of 5alpha-dihydrotestosterone (DHT), 4- androstenedione (4-A) and the diols by 35%, 25% and 2-10-fold respectively (n=4; p<0.01), at optimal concentrations. Tamoxifen inhibited the stimulatory effects of oestradiol. Similarly, when 14C-4-androstenedione was used as substrate, there were 60% and 2-fold increases in the yields of DHT and testosterone respectively, with significant increases in the formation of the diols in response to oestradiol (n=4; p<0.001). Progesterone inhibited the formation of DHT and 4-A by 10-fold and 3-5-fold at effective inhibitory concentrations (n=4; p<0.001), when 14C- testosterone was used as substrate. Similarly, when 14C-4-androstenedione was used as substrate, progesterone decreased the yields of testosterone, DHT and the diols substantially. These results reinforce the potentially anabolic and catabolic roles of oestradiol and progesterone, respectively. This may partly explain the modulatory mechanisms involved, in periodontal disease presentation during altered hormonal states and healing responses in the inflamed periodontium.

Influence of sex hormones on the periodontium

“…Effects of estrogen in the Periodontium increased amount of plaque with no increase of gingival inflammation inhibit proinflammatory cytokines release by human marrow cells (Gordon et al 2001) reduce T-cell-mediated inflammation (Josefsson et al 1992) suppress leukocyte production from the bone marrow (Josefsson et al 1992, Cheleuitte et al 1998 inhibit PMN chemotaxis (Ito et al 1995) stimulate PMN phagocytosis (Hofmann et al 1986) Table 2. Effects of progesterone in the periodontium increase production of prostaglandins (self-limiting process) (ElAttar 1976b, Smith et al 1986 increase polymorphonuclear leukocytes and PGE2 in the GCF reduce glucocorticoid anti-inflammatory effect (Feldman et al 1975, Chen et al 1977 altered collagen and noncollageneous protein synthesis (Willershausen et al 1991) alter PDL fibroblast metabolism (Nanba et al 1989b, Sooriyamoorthy & Gower 1989b, Tilakaratne & Soory 1999a increase vascular permeability (Abraham-Inpijn et al 1996) were positively correlated with free testosterone index and free estradiol index. They concluded that age as well as androgen and estrogen status are significant positive determinants, whereas parathyroid hormone (PTH) is a negative determinant of OPG serum levels in men (Szulc et al 2001).…”

Testosterone stimulates proliferation and inhibits interleukin‐6 production of normal and hereditary gingival fibromatosis fibroblasts

“…In addition, castration prevents calcium channel blocker-induced gingival overgrowth in beagle dogs (11). Although the molecular basis of these interactions remains poorly understood, Parkar et al (36) have shown, using semiquantitative reverse transcriptase-polymerase chain reactions (RT-PCR), that the androgen receptors but not the estrogen receptors are expressed by gingival fibroblasts, and that sex hormones influence the metabolism of fibroblasts derived from periodontal tissues (31,46). Moreover, recent studies have documented that the expression and production of interleukin-6 (IL-6) is downregulated by dihydrotestosterone, a potent metabolite resulting from metabolism of testosterone (15,35).…”

Modulation of androgen metabolism by phenytoin, oestradiol and tamoxifen in human gingival fibroblasts

“…Effective stimulatory/inhibitory concentrations of phenytoin, oestradiol and tamoxifen were established previously. It was 1 μ g/ml for each of phenytoin (Soory & Suchak 2001), oestradiol (Tilakaratne & Soory 1999) and tamoxifen (Tilakaratne & Soory 1999).…”

“…Androgens and oestrogen have been shown to influence remodelling of the mandibular condyl in growing mice (Fujita et al 2001). Specific inhibition of androgen 5 α ‐reductase by the inhibitor finasteride in HGF (Soory & Virdi 1998) is suggestive of androgen target tissue activity in gingivae, which may be modulated by oestradiol (Tilakaratne & Soory 1999).…”