17beta-Hydroxysteroid dehydrogenase type 1 (17HSD type 1) catalyzes the reduction of estrone (E(1)) to biologically more active estradiol (E(2)). In the present study, the effect of activin, inhibin, and follistatin on 17HSD activity and 17HSD type 1 expression in cultured, unluteinized rat granulosa cells was examined. Furthermore, the effects of these hormones on 17HSD type 1 expression were compared with the expression of P450 aromatase (P450arom). Rat granulosa cells were pre-incubated in serum-free media for 3 days, followed by a 2-day treatment with activin, inhibin, follistatin and 8-Br-cAMP. Activin in increasing concentrations appeared to effect a dose-dependent increase in 17HSD activity. In addition, increasing concentrations of activin also increased 17HSD type 1 mRNA expression. Addition of 8-Br-cAMP at concentrations of 0.25 and 1.5 mmol/l together with activin significantly augmented the stimulatory effects of activin alone in the cultured cells. Neither inhibin, nor follistatin, either alone or in combination with 8-Br-cAMP, had any notable effects on 17HSD activity and 17HSD type 1 expression. Preincubation of activin with increasing concentrations of follistatin significantly diminished the stimulatory effect of activin. In the presence of follistatin, activin did not significantly increase the 8-Br-cAMP-induced 17HSD activity and 17HSD type 1 expression. The culturing of granulosa cells in the presence or the absence of inhibin or follistatin with or without 8-Br-cAMP did not alter the effect of these peptides on P450arom expression in rat granulosa cells as judged by Northern blot analysis of total RNA. However, cAMP-induced P450arom expression was enhanced by activin treatment, except when follistatin was present. This is in line with the suggested role of follistatin as an activin-binding protein, which limits the bioavailability of activin to its membrane receptors. Thus, the results support the notion of a paracrine/autocrine role of activin in follicular steroidogenesis of growing follicles.

8-Bromo Cyclic Adenosine Monophosphate↗

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Two 17beta-hydroxysteroid dehydrogenases (17HSDs) of estradiol biosynthesis: 17HSD type 1 and type 7.

Two 17beta-hydroxysteroid dehydrogenases (17HSDs), type 1 and type 7, are enzymes of estradiol biosynthesis, in addition to which rodent type 1 enzymes are also able to catalyze androgens. Both of the 17HSDs are abundantly expressed in ovaries, the type 1 enzyme in granulosa cells and type 7 in luteinized cells. The expression of 17HSD7, which has also been described as a prolactin receptor-associated protein (PRAP), is particularly up-regulated in corpus luteum during the second half of rodent pregnancy. A moderate or slight signal for mouse 17HSD7/PRAP mRNA has also been demonstrated in samples of placenta and mammary gland, for example. Human, but not rodent, 17HSD1 is expressed in placenta, breast epithelium and endometrium in addition to ovaries. A cell-specific enhancer, silencer and promoter in the hHSD17B1 gene participate in the regulation of type 1 enzyme expression. The enhancer consists of several subunits, including a retinoic acid response element, the silencer has a binding motif for GATA factors, and the proximal promoter contains adjacent and competing AP-2 and Sp binding sites.

17-Hydroxysteroid Dehydrogenases↗

PubMedDate not supplied

Androgenic-anabolic steroid effects on serum thyroid, pituitary and steroid hormones in athletes.

Endocrine responses in seven power athletes were investigated during a 12 week strength training period, when the athletes were taking high doses of androgenic-anabolic steroids, and during the 13 weeks following drug withdrawal. During the use of steroids significant decreases (P less than 0.05 to 0.001) in the serum concentrations of thyroid stimulating hormone, thyroxine, triidothyronine, free thyroxine, and thyroid hormone-binding globulin (TBG) were found, whereas the value of triidothyronine uptake increased (P less than 0.001). In relation to the changes in the thyroid function parameters measured, we suggest that the primary target of androgen action was TBG biosynthesis. In five of the seven subjects, serum concentrations of growth hormone increased at some point of the study 5 to 60-fold. Because of the use of exogenous testosterone, serum testosterone concentration tended to increase. This increase was associated with a corresponding increase (P less than 0.001) in serum estradiol. Furthermore, there were major decreases in serum LH (P less than 0.01) and FSH (P less than 0.01) concentrations, and testicular testosterone production was therefore decreased. This was characterized by a very low serum testosterone concentration (5.1 +/- 1.8 nmol/l) 4 weeks following drug withdrawal. Cessation of drug use resulted in return of all the variables measured to the initial values, except for serum testosterone, which was at a low level (14.6 +/- 8.8 nmol/l) 9 weeks after drug withdrawal, indicating prolonged impairment of testicular endocrine function. No consistent changes were found in the eight control athletes.

Adult↗

PubMedDate not supplied

Effect of conjugation on the biodistribution of 111In-labelled anti-PAP and anti-PSA monoclonal antibodies examined in nude mice with PC-82 human tumor xenografts.

The effect of conjugation on the biodistribution of 111In-labelled antibodies was studied in nude mice carrying human prostatic cancer xenografts (PC-82). Two monoclonal antibodies and their fragments raised against human prostate-specific acid phosphatase (PAP) and prostate-specific antigen (PSA) were used. We used the cyclic anhydride of DTPA (CA-DTPA) as a chelating agent, or, alternatively, 1-(p-aminobenzyl)diethylenetriaminepentaacetic acid (NH2-Bz-DTPA) was attached as a linker to the carbohydrate components of the parent molecules. The conjugation method, the amount of circulating antigen and the size of the antibody component affected the blood clearance of the labelled derivatives. F(ab')2 fragments displayed a faster blood clearance than the corresponding derivatives of intact IgG1s. Aminobenzyl derivatives of anti-PAP-IgG1 showed a faster blood clearance than the corresponding CA-DTPA derivatives, but, in the case of derivatives of anti-PSA-IgG1, this was less clear, possibly due to the high PSA concentrations in the mouse sera. All the derivatives studied accumulated in the liver independently of the size of the antibody derivative, most probably due to the formation of antigen-antibody complexes. All CA-DTPA derivatives showed a higher kidney accumulation than the corresponding aminobenzyl derivatives. CA-DTPA-anti-PAP-F(ab')2 fragments showed a higher kidney uptake than the corresponding anti-PSA-F(ab')2 derivatives, since a large fraction of the latter are complexed with circulating antigen, thereby slowing down its reabsorption by the kidney. In addition, the lower kidney accumulation for anti-PSA-F(ab')2 fragments might be, at least partly, due to the electronegative charge of the molecule.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗

PubMedDate not supplied

Effect of unlabelled monoclonal antibodies on the biodistribution of 111In-labelled anti-prostate-specific acid phosphatase monoclonal antibodies in the mouse model.

In order to optimize methods developed for the radioimaging of prostatic cancer, the effect of unlabelled monoclonal antibodies (MoAbs) on the biodistribution of 111In-labelled MoAbs was studied in nude mice carrying human prostatic cancer xenografts (PC-82). Since the intact IgG and its F(ab')2 fragment have different clearance patterns from the blood, we also studied which of these antibody forms is preferable for use as the unlabelled antibody, when injected prior to, simultaneously with, or following the injection of the labelled antibody. Due to their faster blood clearance, F(ab')2 fragments displayed higher tumour-to-blood ratios than the corresponding anti-prostate-specific acid phosphatase (anti-PAP) IgG1. However, tumour-to-blood ratios increased when the amount of the labelled anti-PAP-IgG1 was increased (from 10 micrograms to 25 micrograms) and the biodistribution measurements were carried out after a prolonged period (216 h). When a combination of labelled IgG1 (1, 10 micrograms) and unlabelled IgG1 (200 micrograms-300 micrograms) was used, tumour-to-blood ratios could not be improved. Contrary to what was observed with the intact IgG1, labelled F(ab')2 fragments did not display a dose-dependent accumulation in the tumour. A combination of labelled F(ab')2 fragments and unlabelled IgG1 resulted in a slight increase in tumour-to-blood ratios, but the administration of labelled F(ab')2 fragments with unlabelled F(ab')2 fragments resulted in a significant decrease (p = 0.04) in tumour-to-blood ratios. Liver-to-blood ratios could be decreased by using either a combination of unlabelled and labelled IgG1 (at ratios of 30:1, or 200:1), or a combination of unlabelled IgG1 and labelled F(ab')2 fragments (at ratios of 50:1, or 100:1), or a combination of the unlabelled and labelled F(ab')2 fragments (at a ratio of 50:1). The decrease of liver-to-blood ratios was independent of the mode of administration of the unlabelled substances. A "rinse" with an additional dose of unlabelled IgG1, 24 h before the sacrifice, resulted in even lower liver-to-blood ratios. The results obtained from this study suggest that, of the combinations investigated, to increase tumour-to-blood ratios and decrease liver-to-blood ratios thereby improving the radioimaging of prostatic cancer, the best one consists of 111In-labelled anti-PAP-F(ab')2 fragments and unlabelled anti-PAP-IgG1.

Acid Phosphatase↗

PubMedDate not supplied

Hepatic impairment during simultaneous administration of medroxyprogesterone acetate and tamoxifen in the treatment of endometrial and ovarian carcinoma.

Simultaneous administration of medroxyprogesterone acetate (MPA) and tamoxifen markedly elevated the serum alanine and aspartate aminotransferase activities in 4 out of 30 patients with endometrial or ovarian carcinoma; and also slightly increased the activities of gamma-glutamyl transferase in 2 of the patients. These pathological changes spontaneously returned to normal in 1 patient, and after the cessation of tamoxifen or tamoxifen plus MPA treatment in 3 patients. This kind of hepatic impairment was thought to be caused by reversible damage of liver cells possibly associated with slight intrahepatic cholestasis. It is suggested that special attention be paid to liver function during simultaneous MPA and tamoxifen administration; in case of adverse liver reaction during the combined treatment, a formula of sequential administration of the drugs could be implemented.

Aged↗

PubMedDate not supplied

Plasminogen activators and steroid receptor concentrations in normal, benign, and malignant breast and ovarian tissues.

The plasminogen activator (PA) activity and oestrogen and progestin receptor concentrations were determined in normal, benign and malignant tissues of human breast and ovary. The geometric mean of PA activity was significantly higher (p less than 0.05) in malignant than in normal breast tissue specimens. PA activity was also higher in benign breast tumours than in normal tissue, but lower than in malignant tumours. The geometric means of PA activity in normal, benign and malignant ovarian tissue specimens differed even more clearly (analysis of variance: p less than 0.001). There was no significant correlation between PA activity and cytosol oestrogen or progestin receptor concentrations in either breast or ovarian cancer tissues. Our data confirm the finding that increased tissue PA activity is associated with human malignant breast tumours, compared with normal tissue and benign mammary lesions, and show that a similar situation prevails in human ovarian tissues. In addition, they show that the possible female sex steroid dependency of PA activity in human breast and ovarian malignancies cannot be demonstrated by cytosol receptor assays alone.

Breast Neoplasms↗