Gonadotrophin and testosterone suppression by 7alpha-methyl-19-nortestosterone acetate administered by subdermal implant to healthy men.
(9/824)
The synthetic androgen 7alpha-methyl-19-nortestosterone (MENT) is a potent suppressor of gonadotrophin that has several advantages for long term administration to normal or hypoandrogenic men. The aim of this study was to examine MENT serum concentrations following subdermal insertion of MENT acetate (MENT Ac) implants and their effects on gonadotrophins, testosterone, dihydrotestosterone (DHT), sex hormone-binding globulin, prostate specific antigen and insulin-like growth factor-1 serum concentrations in normal men. A total of 45 healthy men were recruited at three clinics. Each subject received one, two or four implants for 28 days. Serum samples were obtained before insertion and on days 8, 15, 22, 29, 36 and 43 after implant insertion. The average daily dose delivered in vivo by one implant was approximately 500 microg. One, two or four MENT Ac implants produced dose dependent and sustained serum MENT concentrations for the entire duration of treatment of 0.7 +/- 0.1, 1.2 +/- 0.1 and 2.0 +/- 0.1 nmol/l respectively. This treatment induced a dose dependent decrease in gonadotrophin and androgen serum levels. Two and four implants induced maximal suppression that was maintained throughout treatment and was completely reversed after removal of the implants. The mean decreases were 93 +/- 1% for testosterone, 80 +/- 3% for DHT, 97 +/- 1% for luteinizing hormone and 95 +/- 1% for follicle stimulating hormone. No serious adverse reactions were reported by the volunteers and no consistent changes in clinical chemistry and haematology were found. These results indicate that MENT Ac implants are an efficient way of MENT administration and confirm the potent gonadotrophin and androgen suppressive effect of this drug. (+info)
Investigation of female survival benefit in metastatic melanoma.
(10/824)
Epidemiological studies show female survival benefit in advanced metastatic melanoma. In investigating a possible mechanism for this female survival benefit, we have previously reported that the female steroid 17beta-oestradiol significantly reduces invasion of a human melanoma cell line (A375-SM cells) and ocular melanoma cells through fibronectin. Neither cell type was found to possess oestrogen receptor-alpha. The aim of the current study was to obtain further information on the extent to which progression of cutaneous melanoma might be sex steroid sensitive by (a) examining the relationship between circulating sex steroids, sex hormone binding globulin and disease progression; (b) examining the relationship between sex steroid structure and the ability of steroids to reduce invasion of a melanoma cell line in vitro; and (c) examining the effects of sex steroids on proliferation of these cells in vitro. We report a significant reduction in circulating oestrone with disease progression in male but not female patients. Examining steroids for their ability to inhibit invasion of A375-SM cells through fibronectin in vitro, oestrogenic compounds (17beta-oestradiol and oestrone) were found to inhibit invasion; in this respect, oestrone was approximately 50 times more potent than 17beta-oestradiol; steroids lacking the benzene ring structure did not inhibit invasion, indeed dehydroepiandrosterone (DHEA) which acts as a precursor to androgenic steroids significantly enhanced invasion. Proliferation of A375-SM cells was unaffected by 17beta-oestradiol, oestrone or dihydrotestosterone when cells were cultured on plastic; in contrast, all three steroids induced modest proliferation of cells when grown on fibronectin with dihydrotestosterone the most mitogenic of the three steroids. These data are consistent with sex steroids playing a role in melanoma progression. (+info)
Dehydroepiandrosterone replacement in women with adrenal insufficiency.
(11/824)
BACKGROUND: The physiologic role of dehydroepiandrosterone in humans is still unclear. Adrenal insufficiency leads to a deficiency of dehydroepiandrosterone; we therefore, investigated the effects of dehydroepiandrosterone replacement, in patients with adrenal insufficiency. METHODS: In a double-blind study, 24 women with adrenal insufficiency received in random order 50 mg of dehydroepiandrosterone orally each morning for four months and placebo daily for four months, with a one-month washout period. We measured serum steroid hormones, insulin-like growth factor I, lipids, and sex hormone-binding globulin, and we evaluated well-being and sexuality with the use of validated psychological questionnaires and visual-analogue scales, respectively. The women were assessed before treatment, after one and four months of treatment with dehydroepiandrosterone, after one and four months of placebo, and one month after the end of the second treatment period. RESULTS: Treatment with dehydroepiandrosterone raised the initially low serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone into the normal range; serum concentrations of sex hormone-binding globulin, total cholesterol, and high-density lipoprotein cholesterol decreased significantly. Dehydroepiandrosterone significantly improved overall well-being as well as scores for depression and anxiety. For the global severity index, the mean (+/-SD) change from base line was -0.18+/-0.29 after four months of dehydroepiandrosterone therapy, as compared with 0.03+/-0.29 after four months of placebo (P=0.02). As compared with placebo, dehydroepiandrosterone significantly increased the frequency of sexual thoughts (P=0.006), sexual interest (P=0.002), and satisfaction with both mental and physical aspects of sexuality (P=0.009 and P=0.02, respectively). CONCLUSIONS: Dehydroepiandrosterone improves well-being and sexuality in women with adrenal insufficiency. (+info)
Sex hormone-binding globulin levels in middle-aged premenopausal women. Associations with visceral obesity and metabolic profile.
(12/824)
OBJECTIVE: Low sex hormone-binding globulin (SHBG) levels in women are associated not only with hyperinsulinemia, increased risk for cardiovascular disease, and type 2 diabetes but also with excess body fatness and abdominal obesity. We tested the hypothesis that an elevated total or intra-abdominal adipose tissue accumulation mediates the relationship between low SHBG levels and an altered metabolic profile. RESEARCH DESIGN AND METHODS: We measured body composition (dual-energy X-ray absorptiometry [DEXA]) and body fat distribution (computed tomography) in 52 middle-aged (46.7 +/- 0.4, mean +/- SEM) premenopausal women. Insulin and glucose responses to a 75-g oral glucose load and plasma lipid-lipoprotein levels were also measured. RESULTS: Low plasma SHBG concentrations were associated with increased total body fat mass (r = -0.41, P < 0.005) and subcutaneous abdominal (r = -0.39, P < 0.005) and intra-abdominal (r = -0.37, P < 0.008) adipose tissue area. Low SHBG was also associated with a greater insulin response to oral glucose (r = -0.40, P < 0.005), higher triglyceride levels (r = -0.29, P < 0.05), higher cholesterol/HDL cholesterol ratio (r = -0.51, P < 0.005), but lower HDL cholesterol concentrations (r = 0.65, P < 0.005). When matched for intra-abdominal fat or total fat mass, subjects with either low or high SHBG showed no difference in the insulin response to an oral glucose challenge. Statistical adjustment for differences in intra-abdominal adipose tissue accumulation or total body fat mass also eliminated the associations between SHBG levels and metabolic variables, with the exception of the association between SHBG and HDL cholesterol levels (r = 0.52, P < 0.005). CONCLUSIONS: Our results suggest that the previously reported relationship between low SHBG levels and increased metabolic disease risk in women is mediated, to a large extent, by concomitant variation in body fatness and intra-abdominal adipose tissue accumulation. (+info)
Impact of gender and androgen status on IGF-I levels in normal and GH-deficient adults.
(13/824)
OBJECTIVE: The regulation of IGF-I levels is complex and not only dependent on GH status, as the diagnostic sensitivity of serum IGF-I levels for GH deficiency (GHD) in adults is low. Other GH-related parameters have so far not proven to be of additional diagnostic value in GHD adults. In the present study we evaluated the impact of gender and androgen status on IGF-I levels and the diagnostic value of IGF-I and GH-related parameters in a population of adult hypopituitary patients and age- and gender-matched healthy subjects. DESIGN: A cross-sectional study. SUBJECTS: Fifty-nine GHD patients (40 males, mean age 39.3+/-1.7 (s.e.m.) years, and 19 females, mean age 41.9+/-2.6 years) and 69 healthy subjects (42 males, mean age 36. 7+/-1.5 years, and 27 females, mean age 38.9+/-2.1 years). RESULTS: IGF-I levels were low in the GHD patients (91+/-7 vs 173+/-7 microgram/l, P<0.001), and lower in female patients than in male (68+/-10 vs 100+/-8 microgram/l, P=0.03). In the control group there was no gender-related difference in IGF-I levels (males: 178+/-8, females: 164+/-12 microgram/l, P=0.23). IGF-II and IGF-binding protein-3 (IGFBP-3) were also decreased in GHD without any gender-related differences. GH-binding protein (GHBP) levels were increased in the patient group. The diagnostic sensitivity (%) of IGF-I, IGF-I/GHBP, IGF-I/IGFBP-3, and of the combination of IGF-I plus IGF-II (both low or one normal and one low), was higher in female patients than in male (IGF-I: 57.8 vs 22.0, P<0.0001; IGF-I/GHBP: 84.2 vs 48.8, P=0. 002; IGF-I/IGFBP-3: 36.8 vs 7.3 P=0.001; IGF-I+IGF-II: 77.8 vs 52.6, P=0.01). Testosterone levels were reduced in the female patients compared with female controls (0.5+/-0.3 vs 2.1+/-0.2nmol/l, P<0.001). Forward regression analyses revealed that IGFBP-3 was a significant predictor of IGF-I levels in both patients and healthy subjects. In a combined analysis of both patients and controls, sex hormone-binding globulin (SHBG) level was the main contributor as an explanatory variable. Gender and prolactin also predicted IGF-I in patients, whereas SHBG and estradiol were significant predictors only in the control group. CONCLUSION: (i) Levels of IGF-I, and of IGF-I/IGFBP-3 and IGF-I/GHBP ratios are lower in females compared with male adult GHD patients. (ii) IGF-I/GHBP has a high diagnostic sensitivity of adult GHD, in particular in women. (iii) We hypothesize that the gender difference in IGF-I levels among adult GHD patients are causally related to the very low androgen levels observed among females. (+info)
Elevation of insulin-like growth factor-binding protein-1 mRNA expression following hormone replacement therapy.
(14/824)
The purpose of this study was to investigate the possible regulatory roles of insulin-like growth factors (IGF) and IGF binding protein-1 (IGFBP-1) on postmenopausal endometrium in women undergoing hormone replacement therapy (HRT). Endometrial tissues and blood samples were collected from 25 postmenopausal women with abnormal uterine bleeding before and after HRT. As a control, blood and endometrial samples were also obtained at mid-luteal phase (days 18-23 of the menstrual cycle) from 10 women with benign uterine leiomyoma during surgical intervention. Expression of mRNA for IGF-I, IGF-II, type 1-IGF receptor, IGFBP-1, oestrogen receptor (ER) and progesterone receptor (PR) in the endometrium was explored by a semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Serum concentrations of IGFBP-1, oestradiol, progesterone, follicle stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) were also determined. In the endometrium obtained from postmenopausal women with abnormal uterine bleeding (before HRT), expression of IGFBP-1 was undetectable, whereas PR expression was abundant. HRT significantly up-regulated expression of IGFBP-1 but down-regulated PR. Moderate expression of IGF-I, IGF-II, type 1-IGF receptor and ER was identified in the postmenopausal endometrium before HRT. HRT significantly down-regulated IGF-I, up-regulated IGF-II, but had no effects on expression of type 1-IGF receptor and ER. In conclusion, up-regulation of IGFBP-1 collaboratively with down-regulation of IGF-I may account for the protective effect of progesterone in HRT on the endometrium. (+info)
Sex hormone-binding globulin in non-cirrhotic alcoholic patients during early withdrawal and after longer abstinence.
(15/824)
In recently intoxicated non-cirrhotic male alcohol-misusing and -dependent patients, we studied, during early withdrawal and more prolonged abstinence, the rate of changes of sex hormones and their binding globulin (SHBG), the prevalence of hypo-androgenism and possible determinant factors of SHBG increase. Twenty-one alcoholics and 21 controls were studied. SHBG plasma levels, sex hormones (SH), cortisol, insulin and thyroid hormones were measured at admission and discharge. SHBG and SH were also determined on days 2, 4 and 7 after admission and on weeks 2, 6 and 12 after discharge. SHBG showed a 3-fold increase, decreasing slowly during the first 10 days, but remaining above control values. Luteinizing hormone was also increased. Free testosterone (Tf) was low at admission and correlated negatively with SHBG during the first 10 days. By day 10, Tf reached normal values, despite SHBG remaining elevated. The other sex hormones were normal. Neither insulin nor thyroid hormones correlated with SHBG. Cortisol was high at admission and then normalized. Clinical hypo-androgenism was found in 33-50% of patients, but did not correlate with SHBG or SH. During follow-up, nine patients relapsed. In those remaining abstinent, SHBG continued decreasing, reaching normal levels in the 12th week. In those who relapsed, SHBG remained high or even increased further. Gamma-glutamyltransferase showed similar but faster changes. We conclude that excessive alcohol ingestion is associated with marked increases of SHBG which slowly revert during abstinence. High SHBG does not fully explain the low Tf values or the presence of clinical hypo-androgenism in alcoholics. This SHBG response to ethanol makes it a potential marker of excessive alcohol intake. (+info)
Effects of intravenous administration of high dose-diethylstilbestrol diphosphate on serum hormonal levels in patients with hormone-refractory prostate cancer.
(16/824)
The objective of this study was to elucidate the mechanism underlying the further suppression of serum testosterone (T) by diethylstilbestrol diphosphate (DES-DP) in patients with prostate cancer refractory to hormonal treatment. These patients received an LHRH agonist with or without a non-steroidal androgen-receptor blocker or a gestagen before DES-DP. We measured serum levels of total and free T, dihydrotestosterone (DHT), estradiol (E2), dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione, cortisol, aldosterone before and during intravenous administration of high doses of DES-DP (500 or 1000 mg/day). DES-DP administration suppressed the serum levels of FSH (p=0.04) and total T (p=0.02), and eliminated free T (p=0.04) and E2 (p=0.04) from serum, while reducing serum DHEA-S to approximately two-thirds of the pretreatment level (p=0.03). In contrast, serum levels of SHBG (p=0.02) and cortisol (p=0.02) were markedly increased after DES-DP administration. The latter had no significant effect on serum levels of LH, DHT, ACTH, 17alpha-hydroxypregnenolone, 17alpha-hydroxyprogesterone, DHEA, androstenedione, or aldosterone. The results suggest that the potent suppression of circulating total T by DES-DP is caused, in part, by the inhibitory effect of DES-DP on serum DHEA-S level. In most patients, high-dose DES-DP treatment completely suppressed the serum level of free T, while possibly elevating serum SHBG and decreasing serum total T. The mechanisms that maintain the serum level of serum DHT during DES-DP treatment require further elucidation. (+info)