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Effect of gonadectomy and exogenous sex hormone administration on the concentrations of hepatic oestrogen receptors and hepatic atypical sex hormone binding protein (HASP) in the rat.

The concentrations of hepatic oestrogen receptors and atypical sex hormone-binding protein are regulated by sex hormones in different manners. Ovariectomy of female rats leads to a significant increase in the concentration of hepatic oestrogen receptors, which can be reversed following administration of either androgens or oestrogens. No differences are observed between total binding site and unoccupied receptor concentrations. Intact male rats contain significantly lower total binding site concentrations and these are not affected by either testectomy or subsequent androgen administration. However, treatment of male castrates with oestradiol leads to the induction of typical female levels. It is not possible to determine the concentrations of unoccupied receptors in intact or gonadectomized males, or rats of either sex treated with androgens, due to masking by the moderate affinity, high capacity oestradiol binder (hepatic atypical sex hormone-binding protein, HASP). Oestradiol binding to this protein is not affected by testectomy nor subsequent androgen administration, but is reduced pressed following treatment with oestradiol. It is also induced in ovariectomized rats by androgens. Oestradiol binding to this protein can be prevented by inclusion of sodium thiocyanate in the assay buffer, thereby permitting unhindered measurement of the oestrogen receptor concentrations.

Animals↗

Role of sex-hormone-binding globulin and free sex steroid hormones in hyperandrogenic anovulation.

To clarify the mechanism of hyperandrogenic anovulation, the binding capacity of sex-hormone-binding globulin (SHBG-BC), the levels of free steroid hormones, and the levels of basal serum testosterone (T), estradiol (E2), estrone (E1) and gonadotropins were determined in 42 hyperandrogenic anovulatory women. The mean levels of basal T (0.74 +/- 0.04 ng/ml, p less than 0.001), free T (3.07 +/- 0.51 ng/dl, p less than 0.01) and free E2 (2.26 +/- 0.27 pg/ml, p less than 0.05), basal luteinizing hormone (LH) (33.4 +/- 2.7 mIU/ml, p less than 0.001), responsiveness of LH (180.7 +/- 21.5 mIU/ml, p less than 0.001) after luteinizing hormone releasing hormone (LHRH) administration, and the basal LH/basal follicle stimulating hormone (FSH) ratio (3.42 +/- 0.25, p less than 0.001) in the patients were significantly higher, the SHBG-BC level (1.76 +/- 0.33 micrograms DHT bound/dl, p less than 0.05) significantly reduced, and basal levels of E2 (38.0 +/- 3.2 pg/ml) and E1 (110 +/- 13 pg/ml) unchanged compared to the controls. These findings suggest that increased T in hyperandrogenic anovulatory women results in decreased SHBG-BC and increased free T and E2 which might be the cause of inappropriate gonadotropin secretion followed by chronic anovulation.

Acne Vulgaris↗

[Basic and clinical studies on sex hormone receptors].

Sex hormone, an essential hormone in reproduction, acts upon the tissues through binding to its receptors. Thus, the study on the receptors is essential for understanding the reproductive processes, physiologically or pathologically. With the advent of molecular biology, receptorology in our field has rapidly developed. In this lecture, we presented our recent findings on the receptor and its gene expression, together with some brief overview on the development of the receptor study, basically or clinically. I. Basic study. 1) Methology: A specific and highly sensitive quantitative RT-PCR assay for measurement of the steroid hormone receptor (SHR) mRNA was developed. 2) Rat progesterone receptor (PR) cDNA, especially PR-BcDNA, was partially cloned. Using primers designed upon the cloned cDNA, two distinct different promoters was found to exist in PR-A and B gene expression in the rat. 3) Tissue specificity of gene expression of the SHRs in the central and peripheral tissues: The synthesis of the receptor protein was regulated mostly on the level of transcription. In some tissues, however, the receptor synthesis was regulated posttranscriptionally. Gene expression of the SHRs was widely distributed even in non-target tissue, indicating the existence of 'basic action' of SH on the tissues. 4) Primate monkey studies: SHR, especially PR, was localized mostly in the preoptic hypothalamic region and hypophysis in contrast with its wide distribution in the rat brain, suggesting the more limited feedback site of progesterone in women. 5) Brain sex differentiation and acquisition of steroid sensitivity: Region-specific and dynamic appearance of SHRs during peri- and postnatal development seemed to a major determinant of sex differentiation and hormone sensitivity' acquisition in female rats. Based upon analysis of PR-A and B mRNAs, gene expression of PR-B was first 'turn on', followed by PR-B gene expression. Progesterone seemed to be associated with 'termination' of the critical period of sex differentiation in the brain. 6) Thyroid hormone may be a regulator of synthesis and gene expression of the PR in rat cerebral cortex. Arachidonic acid, released from cell membrane, regulated SHRs in a non-competitive way, indicating some 'second messenger' role. Cross-talk might exist between the membrane factor and SHR. 7) Antisense mRNA against GnRHmRNA, SH2RNA, was identified in rat brain. Most interestingly, there was a reciprocal relationship between GnRHmRNA and SH2RNA, suggesting some GnRHmRNA regulatory mechanism other than previously thought. 8) Depression of the GnRH receptor (GnRHR)mRNA level by GnRH agonist indicated another mechanism on down-regulation of GnRHR.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

[Sex hormones profile in women on dialysis program in treatment with erythropoietin].

OBJECTIVE: The end stage renal disease has accompaniments in body systems, including hormonal changes. The present study was designed to evaluate the pattern of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) and estradiol (E2) in 47 women with end stage renal disease (ESRD), on regular dialysis and receiving recombinant human erythropoietin (r-HuEPO). METHODS: One patient was on intermittent peritoneal dialysis, 4 on continuous ambulatory peritoneal dialysis and 42 on maintenance haemodialysis. They were divided into: Group I consisted of 10 women with regular menses, aged lesser than 48 years; Group II consisted of 15 women with amenorrhea, aged lesser than 48 years and; Group III, consisted of 22 women with amenorrhea, aged 48 years or more. Levels of FSH, LH, PRL and E2 were obtained by ELISA. RESULTS: All groups showed FSH, LH and E2 levels in the normal range for normal women without renal failure, and there was no statistical significance in the levels of these hormones between women with regular menses or women with amenorrhea aged lesser than 48 years. The serum concentrations of PRL were above the normal range in all groups. The patients aged 48 or more showed hormonal profile consistent with post-menopausal (i.e. high FSH, high LH and low estradiol). CONCLUSIONS: We conclude that ovarian function is intact on ESRD and we have to search for other causes for amenorrhea in women that do not have an abnormal hormonal sex profile.

Amenorrhea↗

Sex hormone binding globulin binding capacity, testosterone, 5alpha-dihydrotestosterone, oestradiol and prolactin in plasma of patients with prostatic carcinoma under various types of hormonal treatment.

Sex hormone binding globulin (SHBG) binding capacity, the concentrations of testosterone (T), of 5alpha-dihydrotestosterone (DHT), of oestradiol-17beta (Oe2), of oestrone (Oe1), of prolactin (hPr) and the percentual specific binding of T to SHBG (%TB) were measured in plasma of patients suffering from prostatic carcinoma and of a control group of similar age. No significant differences in any of the investigated parameters were found between the control group and the carcinoma patients before treatment although 15% of the latter showed distinctly elevated hPr values. Treatment of carcinoma patients with 1) Antiandrogen (cyproterone acetate, Androcur) resulted in a significant decrease of T, Oe2 and SHBG. The DHT/T-ratio increased. n=5. 2) Orchidectomy caused an even more pronounced fall in T, DHT, Oe1 and Oe2 blood levels. SHBG was not altered. DHT/T-ratio increased. n=32. 3) Cyproterone acetate after orchidectomy led to elevated hPr values. n=5. 4) Oestrogen (diethylstiboestrol-diphosphate, Honvan) after orchidectomy increased SHBG and hPr. n=6. 5) Corticosteroid (Prednisone, Decortin) after orchidectomy decreased T and SHBG below the levels found after orchidectomy alone. n=5. 6) Diureticum (Mefruside, Baycaron) (n=5) or 7) a placebo (n=7) did not alter any of the parameters measured. 8) Treatment with HCG (Primogonyl) of patients suffering from oligozoospermia resulted in a significant increase of T, DHT and Oe2. SHBG was not altered. DHT/T-ratio decreased. n=7.

Chorionic Gonadotropin↗

Exogenous estrogen and endogenous sex hormones.

Estrogen replacement therapy is widely used to treat menopausal symptoms and prevent osteoporosis. The mechanism of these and other estrogen effects is currently under investigation. We studied the plasma steroid hormone and sex hormone binding globulin levels in frozen plasma obtained from 977 women aged 50 to 79 years from 1972 to 1974. Almost all of the 301 women who reported current use of noncontraceptive estrogen were taking conjugated estrogen by mouth; none reported use of a progestin. Women taking estrogen were significantly younger, thinner, and more likely to smoke cigarettes than women not taking estrogen. Sex hormone binding globulin and all endogenous hormones except testosterone were negatively correlated with age; estradiol was positively and cortisol and sex hormone binding globulin were negatively associated with obesity. After adjusting for age and obesity, dehydroepiandrosterone sulfate, androstenedione, and free testosterone were significantly lower in women currently taking estrogen than in women not using estrogen. These differences were independent of cigarette smoking. As expected, estrogens (including free estradiol), sex hormone binding globulin, and cortisol levels were higher in treated than untreated women. The possibility that some of the benefits and risks of replacement estrogen are secondary to altered adrenal steroid metabolism and androgen levels needs further evaluation.

Aged↗

Sex hormones correlated with sex skin swelling and rectal temperature during the menstrual cycle of the pigtail macaque (Macaca nemestrina).

Daily measurement of serum luteinizing hormone, estradiol-17beta, and progesterone were made during the menstrual cycle in nine pigtail macaques (Macaca nemestrina). All data were normalized to the day of the luteinizing hormone peak. Serum estradiol-17beta increased from approximately 100 pg/ml during the early follicular phase to 442 +/- 156 pg/ml during the maximum midcycle concomitant with the luteinizing hormone peak, and a small increase in serum estradiol-17beta was observed during the luteal phase coincident with the progesterone peak. Serum progesterone values increased slightly at the time of the luteinizing hormone peak and increased from 0.2-0.3 ng/ml during the midfollicular phase to peak levels of 8.3 +/- 1.75 ng/ml 9 days after the luteinizing hormone surge. Serum luteinizing hormone remained low and relatively constant throughout the early and midcycle, then sharply increased approximately four-fold to peak values of 6.25 +/- 0.9 ng/ml. Sex skin swelling increased slowly during the follicular phase and declined slowly throughout the early luteal phase. Rectal temperature did not change significantly throughout the menstrual cycle. The similarity of plasma sex hormone changes during the menstrual cycle between women and the pigtail macaque suggested that this nonhuman primate should be a useful animal model for studying human reproduction.

Animals↗

Continuous subcutaneous infusion of low dose growth hormone decreases serum sex-hormone binding globulin and testosterone concentrations in moderately obese middle-aged men.

OBJECTIVE: Sex-hormone binding globulin (SHBG) is a liver derived protein whose concentration has been shown to be affected by a number of factors. The aim of the present study was to investigate the possible effect of increased basal GH concentrations on serum concentrations of SHBG, testosterone and thyroid hormones. DESIGNS: Recombinant human growth hormone (rhGH) was given as a continuous subcutaneous infusion in a low dose (0.02 U/kg/day) over a period of 14 days in an open study. PATIENTS: Eight middle-aged (42-59 years) overweight (body mass index 26.1-33.8 kg/m2) but otherwise healthy men were studied. MEASUREMENTS: Blood samples were obtained after an over-night fast before and after 2, 7 and 14 days of treatment. Serum was separated and stored at -20 degrees C until assay. RESULTS: Serum GH concentrations increased to a steady level of 2-4 mU/l. Serum SHBG concentration decreased between 2 and 7 days of treatment and serum testosterone concentration changed in parallel. There was no change in the ratio between serum SHBG and serum testosterone. Serum T4 and free T4 concentrations decreased, and that of T3 increased as a result of continuous GH infusion. Simple correlations between changes in SHBG concentrations and other hormonal changes showed positive significant correlations between changes of SHBG and of testosterone. CONCLUSIONS: Low dose continuously infused GH resulted in a parallel decrease in serum SHBG and testosterone concentrations. Thyroid hormone concentrations were affected in a similar way to that previously demonstrated following daily injections of GH.

Adult↗

Binding of testosterone and oestradiol to sex hormone binding globulin, human serum albumin and other plasma proteins: evidence for non-specific binding of oestradiol to sex hormone binding globulin.

1. The percentage binding of testosterone (T) and oestradiol (E2) to sex hormone binding globulin (SHBG) and human serum albumin (HSA) was determined over a range of SHBG concentrations of 16-250 nmol of dihydrotestosterone (DHT) bound/l. It was found that the binding of both T and E2 to HSA was a function of their binding to SHBG and bore an inverse relationship to it. After removal of both SHBG and HSA from plasma by affinity chromatography a 'residual' binding of about 11% for T and 12% for E2 was still apparent. In addition to the specific high-affinity, low capacity binding of E2 to SHBG, non-specific low-affinity binding of 7-12% was demonstrated after selective denaturation of the specific binding site of the latter. 2. Competition studies indicated that although at the relatively higher levels of SHBG found in the normal female the physiological concentrations of E2, T and DHT need not be taken into account in estimating the unbound fractions of steroids, at the relatively lower levels of SHBG found in normal men and hirsute women, the physiological concentrations of T and DHT are effective in causing statistically significant displacement of E2 from the common, specific binding site on SHBG. 3. A simple computerized technique is described for the determination of fractions of E2 and T respectively, that are unbound to SHBG, unbound to SHBG and HSA, and unbound to all plasma proteins, when the total plasma levels of E2, T, DHT and SHBG are known.

Binding, Competitive↗

Serum sex hormone levels and myocardial infarction in the Honolulu Heart Program. Pitfalls in prospective studies on sex hormones.

It has been hypothesized that hyperestrogenemia may underlie myocardial infarction. As a test of this hypothesis, the serum estradiol and testosterone levels were estimated in samples collected prospectively from 96 male patients aged 52-74 years [mean age 60.8 +/- 6.3 (SD)] who had had a myocardial infarction and from 96 matched control subjects in the Honolulu Heart Program. Established risk factors for myocardial infarction were measured prospectively. No significant difference between patients and control subjects in mean estradiol or testosterone level was observed. The only established risk factor that was significantly different was blood pressure, which was higher in the patients. Thus, the data did not confirm the hypothesis. However, two major pitfalls for prospective studies of estradiol in myocardial infarction, which might have affected the validity of the results, were observed, namely, deterioration of estradiol values with prolonged storage (8.5-12 years in this study) and intervention. The value of this study, therefore, may lie in pointing out difficulties in carrying out prospective studies on sex hormones.

Aged↗

Genetic variant of luteinizing hormone: impact on gonadal steroid sex hormones in women.

A common variant of the LHbeta subunit has a varying prevalence in various ethnic groups. The consequences of the presence of mutated luteinizing hormone (LH) concern borderline alterations in pituitary/gonadal function that could be mediated by an altered action of variant LH on gonadal steroidogenesis. A comparison of plasma concentrations of gonadal steroid sex hormones was completed in women heterozygous for variant LH and in women with the wild type of LH in three different age ranges. The sample was a randomly selected group of 177 normal women 16 to 72 years old. Variant LH was determined by immunofluorimetric methods using two combinations of monoclonal antibodies. The ratios of LH measured by the two assays indicated whether the subject was wild type homozygote, heterozygote or homozygote for the variant LHbeta allele. The carriers of the variant LH allele in the group of postmenopausal women showed higher serum testosterone levels than those with the wild type LH. This is in agreement with the clinical observations made previously showing a slightly higher androgenic action in the population with variant LH. No differences were detected in serum LH, FSH, epitestosterone and sex hormone binding globulin (SHBG).

Adolescent↗

The influence of sex hormones on the development of sex-specific cholesterol serum levels in rats.

1. The development of sex-specific cholesterol serum levels (under a fat-enriched diet) depends on the sex hormone status during the postpuberal activation phase. 2. The efficiency of postpuberal sex hormones seems to be influenced by the presence of definite sex hormone levels during the prepuberal/puberal maturation phase. 3. An influence of the perinatal sex-specific brain differentiation on the development of sex-typical cholesterol biosynthesis as reported by Carlson et al. was not demonstrable, possibly because of our special diet regimes (fat-enriched diet).

Animals↗