Reijo Vihko

Pregnenolone and its sulfate ester in the rat brain

Pregnenolone (P) and its sulfate ester (PS) have been characterized in the brain of adult male rats. The concentration of P (38.4 +/- 6.9 and 22.1 +/- 2.9 ng/g, mean +/- S.D., in anterior and posterior brain, respectively) exceeded that of PS in brain (15.8 +/- 3.0 and 5.7 +/- 2.1 ng/g in the same fractions) and largely those of P and PS in plasma (1.3 +/- 0.2 and 1.4 +/- 0.3 ng/g, respectively). The level of P in brain was much larger than that of dehydroepiandrosterone sulfate (DS), characterized and measured previously (Corpéchot et al.). Brain P and PS levels did not seem to depend on steroidogenic gland secretion: no meaningful difference occurred in brain 15 days after adrenalectomy plus orchiectomy, compared with sham-operated controls. It is proposed that, as that of DS (ref. 5) P and PS formation or accumulation (or both) in the rat brain depend on in situ mechanisms unrelated to the peripheral endocrine gland system.

Complete amino acid sequence of human placental 17β‐hydroxysteroid dehydrogenase deduced from cDNA

CDNA clones for 17β‐hydroxysteroid dehydrogenase (17‐HSD; EC 1.1.1.62) were isolated from a placental λgt11 expression library using polyclonal antibodies against placental 17‐HSD. The largest cDNA contained 1325 nucleotides, consisting of a short 5′‐noncoding segment, a coding segment of 987 nucleotides terminated by a TAA codon, and a 329 nucleotide long 3′‐noncoding segment. The open reading frame encoded a polypeptide of 327 amino acid residues with a predicted M r of 34853. The amino acid sequence of 23 N‐terminal amino acids determined from purified 17‐HSD agreed with the sequence deduced from cDNA. The deduced amino acid sequence also contained two peptides previously characterized from the proposed catalytic area of placental 17‐HSD.

Estrogen and progestin receptors in endometriosis lesions: Comparison with endometrial tissue

Cytosol estrogen (ER) and progestin (PR) receptors were quantified in 47 endometriosis lesions from 41 patients and compared with receptor measurements in the endometrial tissue of nine of these patients. Half of the specimens of endometriosis tissue contained PR only, in concentrations that were significantly lower than in the endometrium. Only 30% of the specimens of endometriosis tissue contained the two receptors simultaneously, and levels of ER were very low compared with those in the endometrium. Levels of PR in the specimens of endometriosis tissue were highest at the periovulatory period, whereas concentrations of ER tended to be highest at the beginning and close to the end of the cycle. These results suggest that regulation of these receptors is dissimilar in endometriosis lesions and endometrium. It remains to be seen whether differences in receptor distribution in the lesions of individual patients could explain differences in the course of this disease, and have therapeutic implications. The presence of PR in the majority of the endometriosis lesions is in accord with the favorable therapeutic response often obtained with progestin treatment of this disease.

Serum FSH, LH and prolactin in normal males and patients with prostatic diseases.

Serum FSH, LH and prolactin were measured in fifty‐eight normal males between 30 and 80 years of age. At the same time, similar estimations were performed on samples taken from 232 patients with benign prostatic hypertrophy (BPH) and twenty‐six patients with prostatic carcinoma. The three groups were compared with respect to age, and it was observed that significant rises related to age occurred in the serum levels of FSH, LH and prolactin in normal men after the sixth decade. The patient groups did not differ significantly from each other, or from the normal age‐matched population in respect to prolactin and FSH levels. Serum LH in both the carcinoma and BPH patient groups, however, differed significantly from the controls, and remained at the level associated with younger normal males. It is suggested that testosterone metabolites from the prostate exert a negative feedback on pituitary LH secretion.

Serum Ferritin as a Measure of Iron Stores During and After Normal Pregnancy with and Without Iron Supplements

The iron stores of 32 healthy pregnant women were evaluated longitudinally during pregnancy and 6 months post partum by serum ferritin assay and by bone marrow iron content. Half of the women were receiving oral iron while the others were not given iron supplementation.

Role of 17β-hydroxysteroid dehydrogenase type 1 in endocrine and intracrine estradiol biosynthesis

Enzymes with 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity catalyse reactions between the low-active female sex steroid, estrone, and the more potent estradiol, for example. 17 beta-HSD activity is essential for glandular (endocrine) sex hormone biosynthesis, but it is also present in several extra-gonadal tissues. Hence, 17 beta-HSD enzymes also take part in local (intracrine) estradiol production in the target tissues of estrogen action. Four distinct 17 beta-HSD isozymes have been characterized so far, and the data strongly suggests that different 17 beta-HSD isozymes have distinct roles in endocrine and intracrine metabolism of sex steroids. Current data suggest that 17 beta-HSD type 1 is the principal isoenzyme involved in glandular estradiol production both in humans and rodents. During ovarian follicular development and luteinization, rat 17 beta-HSD type 1 is regulated by gonadotropins, and the effects of gonadotropins are modulated by steroid hormones and paracrine growth factors. Human 17 beta-HSD type 1 favors the reduction reaction, thereby converting estrone to estradiol both in vitro and in cultured cells. Hence, the enzymatic properties of the enzyme are also in line with its suggested role in estradiol biosynthesis. Interestingly, 17 beta-HSD type 1 is also expressed in certain target tissues of estrogen action such as normal and malignant human breast and endometrium. Hence, 17 beta-HSD type 1 could be one of the factors leading to a relatively high tissue/plasma ratio of estradiol in breast cancer tissues of postmenopausal women. We conclude that 17 beta-HSD type 1 has a central role in regulating the circulating estradiol concentration as well as its local production in estrogen target cells.

Significance of estrogen and progesterone receptors, disease-free interval, and site of first metastasis on survival of breast cancer patients.

Estrogen and progesterone receptors (ER/PR) were measured in primary tumors and metastases of 397 breast cancer patients. Survival following mastectomy was significantly longer in patients with ER and PR positive tumors, as was survival after first recurrence. The prognostic value of ER and PR was compared with such clinical factors as disease‐free interval (DFI) and the dominant site of first metastasis by Coxs regression analysis. With all the different therapy modalities long DFI was the best prognostic indicator. However, in the patient group treated with endocrine therapy, ER and PR positivity was the best prognostic indicator, suggesting that longer survival in receptor positive patients was related to the response to endocrine treatment. Cancer 56: 1696‐1700, 1985.

Steroidal regulation of endometriosis tissue: lack of induction of 17β-hydroxysteroid dehydrogenase activity by progesterone, medroxyprogesterone acetate, or danazol

Cytosol and nuclear estrogen receptors were detected in 73% and 89% of untreated endometriosis specimens, respectively. The corresponding figures for cytosol and nuclear progestin receptors were 94% and 100%, respectively. Compared with the endometrium, the concentrations in endometriosis tissue were low. The anatomic site, the severity of the disease, and the phase of the menstrual cycle had no significant influence on receptor concentrations in endometriosis tissue. The activities of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) did not increase during the luteal phase. Danazol for 1, 3, 7 to 11, and 18 to 30 days, or medroxyprogesterone acetate for 5 days, had no effect on receptor concentrations or 17 beta-HSD activity in endometriosis tissue. The frequent presence of the receptors suggests that endometriosis lesions are under the control of steroid hormones. The lack of effect by progesterone and progestins on 17 beta-HSD shows that this regulation is different in endometriosis tissue and in the endometrium.

SERUM STEROIDS IN NORMAL MALES AND PATIENTS WITH PROSTATIC DISEASES

The subjects investigated comprised 57 normal males between 30 and 80 years of age; 40 patients between 50 and 80 years of age suffering from benign prostatic hypertrophy (BPH), and 11 untreated prostatic carcinoma (Ca) patients aged between 57 and 79 years. Serum concentrations of oestradiol, pregnenolone, progesterone, 17α‐hydroxyprogesterone, androstenedione, testosterone, 5α‐dihydrotestosterone and androsterone were determined from a single serum sample (1.6 ml). Oestradiol was determined by an automated non‐chromatographic radioimmunoassay, while other steroids were determined by radioimmunoassays, after solvent extraction and chromatographic purification on Lipidex‐5000(tm) microcolumns. When patient groups were compared with the 25 normal males between 50 and 80 years of age, several conclusions could be drawn. Serum concentrations of 5α‐dihydrotestosterone (P < 0.01) and 17α‐hydroxyprogesterone (P < 0.001) were both significantly higher in the BPH patients when compared with the normal males. This trend was also apparent in the serum concentrations of progesterone and testosterone in the older BPH patients. Although the mean concentrations of 5α‐dihydrotestosterone and 17α‐hydroxyprogesterone were slightly higher in carcinoma patients than normal males, these differences were not statistically significant. No differences were seen in the concentrations of pregnenolone, androstenedione, androsterone and oestradiol between normal subjects and patients with BPH or prostatic Ca.

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 andro genic-anabolic steroids, and during the 13 weeks fol lowing drug withdrawal. During the use of steroids significant decreases (P < 0.05 to 0.001) in the serum concentrations of thyroid stimulating hormone, thyrox ine, triidothyronine, free thyroxine, and thyroid hor mone-binding globulin (TBG) were found, whereas the value of triidothyronine uptake increased (P < 0.001). In relation to the changes in the thyroid function param eters measured, we suggest that the primary target of androgen action was TBG biosynthesis. In five of the seven subjects, serum concentrations of growth hor mone 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 < 0.001) in serum estradiol. Furthermore, there were major decreases in serum LH (P < 0.01) and FSH (P < 0.01) concentrations, and testicular tes tosterone 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.