Paul Bennett

Reduced androgen levels in adult Turner syndrome: influence of female sex steroids and growth hormone status

In girls with Turner syndrome androgen levels are reduced. In order to assess androgen status in women with Turner syndrome, we compared untreated adult women with Turner syndrome with a group of normal women. In addition, the effects of female sex hormone replacement therapy and GH status on the levels of circulating androgens in Turner syndrome was examined.

Serum steroid levels in intact and endocrine ablated BALB/C nude mice and their intact littermates

An investigation was made of the serum steroid levels found in intact and endocrine ablated nude mice of both sexes and in their intact homozygous littermates. The results showed that nude mice have a normal steroidogenesis, but with decreased levels of circulating steroids compared to those of the littermates. The efficacy of the endocrine ablations was confirmed by the reduction in serum oestrone following oophorectomy, and by the reduction in serum testosterone and progesterone following orchiectomy. The normal steroidogenesis in nude mice, and the similarities between mouse and man with regard to changes in serum steroids following oophorectomy and orchiectomy, support the usefulness of human tumor xenograft models for the study of hormone-tumor interactions.

Left ventricular dysfunction in Klinefelter syndrome is associated to insulin resistance, abdominal adiposity and hypogonadism

Objective  Epidemiological data suggest there is an increased risk of dying from heart disease among patients with Klinefelter syndrome (KS). Due to high prevalence of hypogonadism and metabolic syndrome, we speculated that patients with KS may have subclinical changes in the left ventricular function. Therefore, the aim was to assess left ventricular long axis function by tissue Doppler echocardiography in patients with KS and relate these findings to the metabolic status and testosterone levels.

Immunoreactive inhibin-production in post-menopausal women with malignant epithelial ovarian tumors

In post-menopausal women with a malignant epithelial ovarian tumor the follicle stimulating hormone (FSH) level was found to be significantly lower compared with healthy controls. We demonstrated immunoreactive (i.r.) inhibin in 20% of controls which was elevated to 60% of women with an ovarian tumor and correlating strongly to FSH in the tumor group (P = 0.0002). Steroid hormone levels were comparable in the two groups. In women with ovarian tumors the survival time for the i.r. inhibin-producing women was found to be 4.6 years compared with 0.9 year, or 5.1 times longer than in the non-producing women (P = 0.002). The site of i.r. inhibin production in these post-menopausal women is unknown, but i.r. inhibin production by the developing ovarian tumor or by the post-menopausal ovary may be regarded as a defense mechanism against an elevated gonadotrophin level (the gonadotrophin theory) which would promote further tumor growth. The recent suggestion that the alpha subunit of inhibin is a tumor suppressor gene is consistent with these results. The serum i.r. inhibin or alpha subunit concentrations might be used as an aid to diagnosis or as a prognostic indicator of survival in women with an ovarian carcinoma.

Dehydroepiandrosterone substitution in female adrenal failure: no impact on endothelial function and cardiovascular parameters despite normalization of androgen status.

Background  Female adrenal insufficiency implicates reduced production of the adrenal androgen precursor dehydroepiandrosterone (DHEA) and low androgen levels. Oral DHEA restores androgen deficit but the clinical implications and safety of substitution therapy is uncertain. A putative DHEA receptor in vascular endothelium has been described and in vitro studies have shown involvement of DHEA in NO dependent pathways.

A randomized placebo-controlled study on the effects of pioglitazone on cortisol metabolism in polycystic ovary syndrome

OBJECTIVE To investigate possible effects of insulin-sensitizing treatment on cortisol metabolism in insulin-resistant patients with polycystic ovary syndrome (PCOS). DESIGN Randomized placebo-controlled study. SETTING Academic tertiary care medical center. PATIENT(S) Thirty insulin-resistant PCOS patients. INTERVENTION(S) Sixteen weeks of pioglitazone (30 mg/day) or placebo treatment. MAIN OUTCOME MEASURE(S) Twenty-four-hour 20 min integrated blood sampling for measurement of cortisol and 24 h urinary excretion of steroid metabolites. Relative 5alpha-reductase activity was evaluated by allotetrahydrocortisol (alloTHF)/THF and androsterone/etiocholanolone (A/E) ratios. Delta values denoted changes during the treatment period (16 weeks--basal). Pyridostigmine growth hormone (GH) stimulation tests were performed, and testosterone (T), dihydrotestosterone (DHT), DHEA, DHEAS, adiponectin, and insulin-like growth factor I (IGF-I) were measured before and after intervention. RESULT(S) Insulin sensitivity, GH, adiponectin, and IGF-I significantly increased during pioglitazone treatment, whereas alloTHF/THF levels significantly decreased. Delta alloTHF/THF levels inversely correlated with Delta adiponectin levels. Delta A/E ratio inversely correlated with Delta IGF-I and Delta peak GH during GH stimulation tests. No significant changes were measured in T, DHT, DHEA, DHEAS, 24 h mean cortisol, or urinary excretion of steroid metabolites. CONCLUSION(S) Pioglitazone decreased relative 5alpha-reductase activity, whereas no significant changes were measured in cortisol levels or urinary cortisol excretion.

Effect of alcohol and glucose infusion on pituitary-gonadal hormones in normal females

During 1 h, median 976 mmol ethanol in 5.5% glucose was administered i.v. to six healthy female volunteers (aged 26-37 years) in the luteal phase of the menstrual cycle. The median maximal blood ethanol concentration was median 33.5 mmol/l and serum ethanol concentrations of 2 mmol/l were reached after 8 h. Four of the women participated in a control experiment with infusion of an equal volume of glucose 5.5%. Venous blood samples were drawn 5 times during the 24-h follow up period. Serum concentrations of sex steroids and pituitary hormones decreased in both ethanol and control experiments and the results did not differ significantly. The lowest hormone concentrations were observed 1-5 h after the start of infusion. Oestradiol, oestrone and oestrone-sulphate concentrations decreased 24-46% compared to basal values. 5 alpha-dihydro-testosterone levels decreased 23-31%, androstenedione and dehydroepiandrosterone-sulphate levels decreased 6-48%, while testosterone levels did not change significantly. Prolactin concentrations were reduced by 41-51% of basal values and luteinizing hormone concentrations by 37-68% Follicle stimulating hormone levels did not change significantly. Stress factors or haemodilution are not likely explanations of the observed changes in hormone concentrations. A circadian rhythm could not explain changes in hormones of non-adrenal origin.

Menopausal age and sex hormones in postmenopausal women with alcoholic and non-alcoholic liver disease

In order to evaluate age at menopause and serum sex hormone profiles in postmenopausal women with stable chronic liver disease, six non-cirrhotic alcoholics, 13 with alcoholic cirrhosis, eight with non-alcoholic cirrhosis, and 46 healthy controls were studied. In all three groups, patients were significantly (p less than 0.05) younger at the time of natural menopause than controls. Compared to controls, non-cirrhotic alcoholic women had significantly (p less than 0.05) reduced levels of DHAS, significantly (p less than 0.05) more alcoholic cirrhotic women had detectable oestradiol concentrations, elevated concentrations of oestrone and sex hormone binding globulin (SHBG) and reduced levels of 5 alpha-dihydrotestosterone (DHT), while women with non-alcoholic cirrhosis had significantly elevated concentrations of SHBG and reduced levels of oestrone sulphate, DHT, androstenedione and dehydroepiandrosterone sulphate (DHAS) (p less than 0.05). The observed changes may be a consequence of liver disease since similar changes were observed in patients with alcoholic and non-alcoholic liver disease, but an additional effect of alcohol cannot be excluded.

The post-operative gonadotropin level in post-menopausal women with epithelial ovarian cancer

Serial estimates of the post-operative hormone levels were made in 15 women subjected to oophorectomy because of ovarian carcinoma. All women were post-menopausal. Pre-operatively, they had significantly lower follicle stimulating hormone (FSH) levels compared with an age-matched control group. Blood samples were collected after a median time of 8 months (139-378 days). After oophorectomy, significantly higher FSH values were found (P = 0.0002), whereas the luteinizing hormone (LH) values were not significantly changed. The inhibin, estradiol and progesterone values were found to be significantly lowered compared with the pre-operative sample. Total and unbound testosterone levels were significantly lower while dehydroepiandrosterone sulphate (DHEAS) and androstenedione levels were unchanged compared with the original sample and compared with controls. Most likely, estradiol and progesterone are produced by the epithelial malignant tumors, as the post-operative values are completely comparable with the primarily included healthy controls. The FSH is suppressed by inhibin and only to a minor degree by the steroid hormones as indicated by the correlation coefficients. Of great interest is the question whether inhibin production is random, or defensive, lowering the gonadotropin levels or influencing tumor growth in some hitherto unknown fashion.

Comparison of the effect of cortisol on aromatase activity and androgen metabolism in two human fibroblast cell lines derived from the same individual

The effect of preincubation with cortisol on estrogen and androgen metabolism was investigated in human fibroblast monolayers grown from biopsies of genital and non-genital skin of the same person. The activity in the cells of aromatase, 5 alpha-reductase, 17 beta-hydroxysteroid oxidoreductase and 3 alpha-hydroxysteroid oxidoreductase was investigated by isolating estrone, estradiol, estriol, dihydrotestosterone, androstanedione, androsterone, 3 alpha-androstanediol, testosterone and androstenedione after incubation of the cells with [14C]testosterone or [14C]androstenedione. For experiments with 14C-labeled substrate the cells were incubated in medium, charcoal stripped of steroids without Phenol Red. Preincubation from 6 to 36 h with cortisol in concentrations of 10(-8) - 10(-6) M showed maximal stimulation of aromatase activity after 12 h preincubation with cortisol in concentrations of 0.5-1.0 x 10(-6) M in both cell lines. When preincubation with cortisol was omitted no estrogen synthesis was detected. The formation of androgen was not altered after preincubation with cortisol. Pronounced differences were found in estrogen and in androgen metabolism in the two cell lines suggesting a local regulation of the hormonal environment. The aromatase activity, which is low in many tissues could be stimulated by cortisol without altering the androgen metabolism was found to be a suitable system for investigations of the cellular interconversion of androgens and estrogens and for investigations of the in vitro regulation of the enzymes involved.