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R Santti

Publications and source records attributed to R Santti.

At least 37 records · Page 2Linked to original sources
PubMed1995

Phytoestrogens are partial estrogen agonists in the adult male mouse.

The intake, as well as serum and urinary concentrations, of phytoestrogens is high in countries where incidence of prostate cancer is low, suggesting a chemopreventive role for phytoestrogens. Their significance could be explained by the ability to antagonize the action of more potent endogenous estrogens in initiation or promotion of tumor formation. We have studied estrogenicity and antiestrogenicity of dietary soy and two phytoestrogens, coumestrol and daidzein, in our neoDES mouse model for the study or prostatic neoplasia. Soy was chosen because it is rich in phytoestrogens, is widely used in Oriental diets, and has antiestrogenic and anticarcinogenic properties in the neoDES mouse when given from fertilization onward. In short-term tests with adult animals, no evidence for estrogenicity or antiestrogenicity (capability to antagonize the action of 17 beta-estradiol) of soy was found when development of epithelial metaplasia and expression of c-fos protooncogene in prostate were used as end points of estrogen action. Estrogenic activity of coumestrol and daidzein on c-fos expression was subtle. Coumestrol, either given alone or in combination with 17 beta-estradiol, had no effect on development of epithelial metaplasia. These marginal or missing effects in adult males could be interpreted by assuming that the neonatal period is more critical for estrogenic or antiestrogenic action of soy and phytoestrogens. Once initiated, estrogen-related lesions would develop spontaneously. Alternatively, the chemopreventive action of soy is not due to antiestrogenicity of soy-derived phytoestrogens.

Animals↗
PubMed1995

Estrogen-specific 17 beta-hydroxysteroid oxidoreductase type 1 (E.C. 1.1.1.62) as a possible target for the action of phytoestrogens.

Several plant estrogens, especially coumestrol and genistein, were found to reduce the conversion of [3H]estrone to [3H] 17 beta-estradiol catalyzed by estrogen-specific 17 beta-hydroxysteroid oxidoreductase Type 1 (E.C. 1.1.1.62) in vitro. Coumestrol, the most potent inhibitor in our experiments, is the best inhibitor of the enzyme known to date. All compounds with inhibitory effects were also estrogenic. However, structural demands for 17 beta-HSOR Type 1 inhibition and estrogenicity of tested compounds in breast cancer cells (judged by increased cell proliferation) were not identical. Zearalenone and diethylstilbestrol, both potent estrogens, did not inhibit 17 beta-HSOR Type 1. Thus, changes in the estrogen molecule may discriminate between active sites of 17 beta-HSOR Type 1 and estrogen binding sites of the ER. The effects of these compounds in vivo cannot be predicted on the basis of these results. Inhibition of 17 beta-HSOR Type 1 enzyme could lead to a decrease in the availability of the highly active endogenous estrogen. However, these compounds are estrogenic per se, and they may thus replace endogenous estrogens. Additional studies are needed to further understand the role of these plant estrogens in the etiology of hormone-dependent cancers. It is not easily conceivable how the chemopreventive action of Asian diets, possibly mediated by phytoestrogens in soya products, can be based on the inhibition of estrone reduction at the target cells by phytoestrogens or related compounds, unless they are "incomplete estrogens" (i.e., unable to induce all effects typical of endogenous estrogens).

17-Hydroxysteroid Dehydrogenases↗
PubMed1994

Developmental estrogenization and prostatic neoplasia.

The association of estrogens with benign prostatic hyperplasia and prostatic cancer has been widely studied, but no conclusive evidence exists for a role of estrogens in prostatic disease. This paper reviews the literature and describes studies which have sought to show a correlation of estrogens and alterations in the prostates of humans and experimental animal models. Using the developmentally estrogenized mouse model, we propose an alternative role for estrogens as a predisposing factor for prostatic diseases: estrogen exposure during development may initiate cellular changes in the prostate which would require estrogens and/or androgens later in life for promotion to hyperplasia or neoplasia. Thus, the critical time for estrogen action would be during the development of the prostatic tissue. We further suggest that estrogen-sensitive cells may remain in the prostate and be more responsive to estrogens later in life or less responsive to the normal controlling mechanisms of prostatic growth.

Adult↗
PubMed1994

Immunohistochemical localization of estrogen-specific 17 beta-hydroxysteroid oxidoreductase in the human and mouse prostate.

The estrogen-specific 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR) enzyme protein was stained immunohistochemically in the newborn and adult human prostate as well as in the mouse prostate. In the newborn human prostate, ductal and urethral epithelia were faintly stained, whereas in the adult human prostate, intense staining for 17 beta-HSOR enzyme antigen could be detected in the epithelium of the collecting ducts and urethral epithelium as well as in the epithelium of the intraprostatic vas deferens and seminal vesicle epithelium. Immunostaining was weak in the prostatic tissues of both newborn and adult prostate. No positive cells were found in stroma. The activity of NADPH-dependent 3H-estrone reductase was detectable in cell-free homogenates prepared from human prostatic tissues. The activities showed a good correlation with immunocytochemical findings. In the mouse, neonatal estrogenization resulted in intensively stained epithelium of the collecting ducts at the age of 14 days. Moreover, when adult control and neonatally estrogenized mice were implanted with 17 beta-estradiol, the metaplastic epithelium of the periurethral collecting ducts of neonatally estrogenized mice was intensively stained with 17 beta-HSOR. These findings suggest that metaplastic epithelium rises from 17 beta-HSOR-positive cells. The similar distributions of 17 beta-HSOR-positive cells confirm the concept of homology in the posterior estrogen-responsive periurethral region (containing the periurethral ducts and periurethral glands) of the mouse and humans. Our findings further suggest that the 17 beta-HSOR-positive cells may have the same origin and hormonal control in both species.

Adult↗
PubMed1994

Dietary Estrogens Act through Estrogen Receptor-Mediated Processes and Show No Antiestrogenicity in Cultured Breast Cancer Cells.

Dietary estrogens are believed to exert their estrogenic or antiestrogenic (chemopreventive) action in estrogen responsive cells by interacting with the estrogen receptor (ER). The present study was undertaken to evaluate a direct role of ER in estrogenic or antiestrogenic activities of three dietary estrogens (coumestrol, genistein and zearalenone). HeLa cells were transiently co-transfected with an expression vector for ER and an estrogen-responsive reporter gene construct. Coumestrol, genistein, and zearalenone all increased the activity of the reporter gene, only in the presence of the ER, and the activation was blocked with the ER antagonist ICI 164,384, demonstrating an ER-specific, agonist response. In addition, in MCF-7 cells, coumestrol and zearalenone increased the expression of the estrogen-responsive pS2 gene. Coumestrol and genistein inhibited the purified estrogen-specific 17ß-hydroxysteroid oxidoreductase enzyme and the conversion of estrone to 17ß-estradiol in T-47D cells, which contain this enzyme. However, they did not inhibit the estrone-induced proliferation of T-47D cells. In conclusion, coumestrol, genistein, and zearalenone are all potent estrogens in vitro, and they act through ER mediated mechanism. Our findings give no evidence to support the idea that these compounds act as antiestrogens through competition for the binding sites of ER or by inhibition of the conversion of estrone to 17ß-estradiol in breast cancer cells, since this effect was nullified by their agonist action on cell proliferation. Therefore, their suggested chemopreventive action in estrogen-related cancers must be mediated through other mechanisms.

Journal Article↗
PubMed1993

Prostatic dysplasia associated with increased expression of c-myc in neonatally estrogenized mice.

Neonatal estrogenization of the mouse with diethylstilbestrol (DES; 2 micrograms./pup/day for days 1 to 3) or 17 beta-estradiol (200 micrograms./pup/day for days 1 to 3) resulted in epithelial dysplasia in the posterior periurethral region of the prostate at the age of 1 year. The dysplastic lesions ranged from mild to severe and, in addition to emergence of nuclear anaplasia, the architectural pattern of the glands was disturbed. Prenatal estrogenization (100 micrograms./kg. of maternal body weight on days 13 and 15 of gestation) only resulted in mild epithelial hyperplasia and occasional dysplasia in the ventral lobe of the prostate, but not in the posterior periurethral region. When neonatally estrogenized mice were allowed to grow until the age of 18 months, the degree and extent of the dysplasia of the posterior periurethral region was increased, but no frank invasion or metastases could be demonstrated. Combined estrogen and androgen treatment of neonatally estrogenized mice for 3 months (between 9 and 12 months of age) augmented nuclear dysplasia, but no invasive growth was seen in this group, either. Mild epithelial dysplasia was found in the dorsolateral lobes and coagulating glands of similarly treated control animals. A relation between the activation of certain proto-oncogenes and the development of several cancers has been shown in humans and experimental animals. In the present study, Northern blot analysis of total RNAs showed that the levels of c-myc mRNA were increased in the ventral and dorsolateral lobes, coagulating glands and prostatic urethra of neoDES mice at the age of 9 months. However, it remains to be determined whether the increase in c-myc expression is involved in the development of hyperplastic and dysplastic changes in the prostate of neoDES mice.

Animals↗
PubMed1992

Distribution of estradiol-17 beta hydroxysteroid oxidoreductase in the urogenital tract of control and neonatally estrogenized male mice: immunohistochemical, enzymehistochemical, and biochemical study.

The present study was conducted to investigate the regional distribution of the enzymes catalyzing the interconversion of the hydroxyl and carbonyl groups at C-17 of the estrogen molecule within the male urogenital tract of adult mouse and to test the hypothesis, whether regional differences in the distribution are critical for estrogen responses. The highest ratios of NADPH-dependent 3H-estrogen reduction to oxidation at C-17 of cell-free homogenates were obtained from coagulating gland and seminal vesicle as well as from the prostatic and lower intrapelvic urethra, which are considered the most estrogen-sensitive parts of the male urogenital tract. Both NADP- and NAD-dependent oxidation of 3H-17 beta-estradiol were low or nondetectable at these sites. The epithelium of the lower and prostatic urethra as well as the periurethral collecting ducts were stained with the antibody prepared against human placental 17 beta-hydroxysteroid oxidoreductase. The NAD-dependent 3H-estradiol-17 beta oxidase activity was highest in the bladder epithelium, and the activity declined sharply in the urinary tract from the bladder downward. The lowest detectable activities were found in vas deferens and prostate (combined ventral and dorsolateral lobes). The uneven distribution of estradiol-17 beta oxidase activity may provide additional explanation for the regional differences of estrogen responses. The NADPH-dependent 17 beta-reduction of estrone and the immunohistochemical staining of the human placental estradiol-17 beta oxidoreductase antigenicity were not significantly altered after neonatal estrogenization. These findings do not lend any support to the idea that the increased estrogen sensitivity observed after neonatal estrogenization is associated with changes in 17 beta-oxidoreduction. However, the possibility remains that there are specific sites (e.g., epithelium of prostatic urethra and collecting ducts) in which the changes in 17 beta-oxidoreduction of estrogen does play a role in the regulation of estrogen action.

17-Hydroxysteroid Dehydrogenases↗
PubMed1991

Regional differences in the prostate of the neonatally estrogenized mouse.

Neonatal estrogenization of the mouse with diethylstilbestrol resulted in time-of-exposure and dose-dependent inhibition of the growth of the prostatic lobes observed at the age of 2 mon. The critical time was the days 1-6 of postnatal life. In neonatally estrogenized (neoDES) mice, responses to 5 alpha-dihydrotestosterone in terms of nuclear 3H-thymidine labelling were altered concomitantly with the inhibition of growth and were in accordance with changes in the relative volumes of epithelium, glandular lumina, and interacinar stroma. Secondary estrogen treatment of neoDES mice with 17 beta-estradiol did not increase 3H-thymidine labelling in the prostate of control or neoDES mice. However, it induced squamous epithelial metaplasia in periurethral collecting ducts and proximal parts of coagulating glands of neoDES animals. In control mice only slight epithelial hyperplasia could be observed after similar treatment. Estrogen receptors, located immunocytochemically in nuclei of stromal cell, corresponded with the sites of increased estrogen sensitivity, observed as metaplastic transformation. When the neoDES animals aged, epithelial hyperplasia and dysplasia could be observed at distinct prostatic sites, ie, the periurethral collecting ducts and the coagulating glands and periurethral glands, and stromal inflammation become more extensive. Almost identical location of the epithelial changes and the altered estrogen response is suggestive of causal relationship.

Aging↗
PubMed1991

Testicular toxicity and mutagenicity of steroidal and non-steroidal estrogens in the male mouse.

The mutagenicity and toxicity of diethylstilbestrol (DES), 17 beta-estradiol and zeranol on the male mouse germ cells were investigated with meiotic micronucleus assays in vivo and in vitro, sperm-head abnormality test and morphometry. Further, the developmental effects of DES on testicular morphology were explored. Micronucleus induction was observed at 10(-7) M concentration of DES and 17 beta-estradiol in vitro, but other treatments yielded negative results. The micronucleus assay in vivo revealed a small number of micronuclei in early haploid spermatids 17 days after a single subcutaneous injection of DES 50 mg/kg, whereas estradiol and zeranol gave negative results. The sperm-head abnormality rates were significantly elevated 5 weeks after treatments with high doses of DES, 17 beta-estradiol and zeranol, and testicular morphometry revealed transient changes in the volume densities of testicular tissue components. Prenatal and neonatal estrogen administration resulted in permanent alterations in seminiferous epithelium and dilatation of the rete testis, but did not affect micronucleus or sperm-head abnormality rates. The mutagenicity and toxicity of hormones in the mouse testis paralleled the hormonal activity of these compounds. Early estrogenization was the most sensitive toxicity test, followed by in vitro meiotic micronucleus induction, whereas the sperm-head abnormality assay and morphological analysis did not reveal subtle changes.

Animals↗
PubMed1991

Androgen metabolism in control and neonatally estrogenized male mice.

Reduction, oxidation, and aromatization of androgens were studied in the male genital tract of untreated control and neonatally estrogenized mice. This study shows regional differences in 5 alpha-reductase and 17 beta-hydroxysteroid oxidoreductase activities in untreated male genital tract; 3 alpha/3 beta-hydroxysteroid oxidoreductase (3 alpha/3 beta-HSOR) activity varied little between tissues. Neonatal treatment with diethylstilbestrol (DES, 2 micrograms/pup/day on days 1 through 5) caused an alteration in the androgen metabolism of the male genital tract, resulting in apparent decreased net accumulation of dihydrotestosterone (DHT). This developmentally-induced 5 alpha-reductase deficiency may play a role in the long-term inhibitory effects of early estrogenization by DES in the growth and function of male sex accessory glands. No aromatase activity could be demonstrated in the male genital tract of control or neonatally estrogenized mice.

Androgens↗
PubMed1990

The influence of steroidal and nonsteroidal estrogens on the 5 alpha-reduction of testosterone by the ventral prostate of the rat.

The 5 alpha-reduction of testosterone to dihydrotestosterone (DHT) correlates with the androgen-mediated growth of the prostate under different experimental and clinical conditions. The aim was to study the regulation of the prostatic growth and enzyme activity by steroidal and nonsteroidal estrogens. Estrogens did not activate the androgen-dependent 5 alpha-reductase activity in cultured prostate of the rat. The direct inhibition of the enzyme activity by estrogens at the concentrations achievable in the male is not probable either. However, early estrogenization of the male rats in utero (on Day 17 of pregnancy) with diethylstilbestrol (DES) resulted in a persistent decrease of the enzyme activity and growth of the prostate indicating a critical estrogen-sensitive period in the regulation of the ultimate enzyme activity. The similar DES-like inhibitory effect on the growth of the prostate was achieved by keeping animals from fertilization throughout the pregnancy until weaning on diet containing soy, rich in environmental estrogens. Zearalenone (Zeranol) and coumestrol, two nonsteroidal estrogens found in human and animal food mimicked estradiol action in culture, but they were not estrogenic or antiestrogenic when administered to normal adults.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1989

Morphometric analysis of human epidermis treated with testosterone and dehydroepiandrosterone in organ culture.

The influence of testosterone and dehydroepiandrosterone (DHA) on human epidermal differentiation in skin organ culture were studied with quantitative light and electron microscopic morphometric methods. The hormones had equal effects on the general tissue architecture at the concentrations of 10(-7) mol/l: they had a negligible effect on the thickness of the vital and cornified layers of epidermis, and on the type of keratinization, but caused a significant increase in the number of granular cells. The electron microscopic stereologic analyses showed that testosterone did not alter the size of either vital or cornified epidermal cells. Neither did it influence the quantities of major keratinocyte organelles (keratin filaments, desmosomes, ribosomes, mitochondria) in the different epidermal strata. However, the amounts of keratohyalin granules and keratinosomes were significantly higher in testosterone-treated granular cells than in controls. Qualitative electron-microscopic analysis of DHA-treated skin showed a similar change in the amount of keratohyalin granules and keratinosomes. The present findings suggest that although androgenic hormones exert little or no direct anabolic effect on epidermis, they may modulate keratinocyte maturation.

Cell Differentiation↗
PubMed1987

Salivary testosterone in hirsutism: correlations with serum testosterone and the degree of hair growth.

Testosterone (T) concentrations in saliva and serum were measured in 53 women with various degrees of hirsutism and hyperandrogenism. The bioavailability of T was judged by comparing the correlations among the grade of hirsutism, salivary testosterone (SaT), and serum total and free T (fT) and sex hormone-binding globulin (SHBG) levels. The effect of body mass index on the correlations was also studied. The high SaT concentrations [mean, 237.6 +/- 66.7 (+/- SD) pmol/L] compared to the serum fT concentrations (mean, 29.1 +/- 11.8 pmol/L) in hirsute women may reflect the bioavailability of albumin-bound T or an ability of the salivary glands to metabolize steroids. SaT was more closely related to the T/SHBG ratio (mean, 82.5 X 10(-3) +/- 54.8), reflecting the non-SHBG-bound fraction of T, than to serum fT, which might support the former theory. SaT correlated better to the degree of hirsutism (rho = 0.45; P less than 0.01) than did any of the serum T parameters or SHBG. The correlation between SaT and hirsutism was partly dependent on the effect of body mass index. After eliminating this effect, SaT still correlated with hair growth on the total body area (rho = 0.36; P less than 0.05). On the basis of the results, SaT seems to relate to the bioavailable fraction of the hormone and, thus, appears to be an optimal method for studying hirsute women.

Adolescent↗
PubMed1985

The grade of hirsutism correlated to serum androgen levels and hormonal indices.

The degree of hair growth of 64 hirsute women was clinically graded. The patients were divided into two groups with respect to the ratio between the serum luteinizing hormone (LH) and the follicle-stimulating hormone (FSH). The two groups did not differ in terms of the grade of hirsutism, serum testosterone (T), calculated free testosterone (FTc), androstenedione (A), dehydroepiandrosterone sulphate (DHEAS), sex hormone binding globulin (SHBG), estradiol, or cortisol levels. In patients with a LH/FSH ratio of 3.0 or less (n = 49), FTc and A correlated well (rho 0.49, p less than 0.001) to the clinically graded hormonal hirsutism score, while SHBG showed an inverse correlation to it. By contrast, no correlations were found in patients with a serum LH/FSH ratio exceeding 3.0 (n = 15). Various indices for hyperandrogenism were calculated. In patients with lower LH/FSH ratio, T/SHBG, T/SHBG + A/100 and T/SHBG + A/100 + DHEAS/100 showed the best correlation with the clinically scored hair growth. These results show that correlations between hirsutism and hyperandrogenism can be demonstrated.

Adolescent↗
PubMed1984

Immunohistochemical characterization of the basement membranes of the human oral mucosa.

Type IV and V collagens, laminin and heparan sulphate proteoglycan were localized in vascular and subepithelial basement membranes. Fibronectin was distributed in a reticular pattern throughout the lamina propria under the oral epithelium. The uniform distribution of basement membrane components and type V collagen in different regions suggests a similar molecular composition for the basement membranes under functionally-different oral epithelia. The more intense reaction in the vascular than in the subepithelial basement membranes, with diluted antibodies to type IV collagen and laminin apparently reflects chemical differences in these basement membranes. Occasional discontinuities in the subepithelial basement membranes were seen in inflamed gingival sulci and in tonsillar crypts. The destruction responsible affected all basement membrane components, except fibronectin, which maintained a reticular distribution even in the deep tonsillar tissue. The immunohistochemical method is useful in demonstrating different degrees of destruction in basement membranes associated with inflammation.

Adolescent↗