Testosterone in ageing men Gambineri, A; Pelusi, C; Vicennati, V ...
Expert opinion on investigational drugs,
03/2001, Letnik:
10, Številka:
3
Journal Article
Recenzirano
A progressive decline in androgen levels is a common finding in men after middle age. The resulting clinical picture may be characterised by alterations in the physical and psychological domains, ...which have been demonstrated to correlate positively with testosterone serum levels. This clinical picture closely resembles the features of primary or secondary hypogonadism. Testosterone is the more convenient hormone for substitution therapy in classic hypogonadism as well as in age-related hypoandrogenism. Different choices of testosterone preparations are currently available, which are characterised by different routes of administration and by various pharmacokinetic profiles. Two major achievements urgently need to be investigated in the near future: the ability of the new formulations to reach more physiological and sustained hormone levels with the concomitant amelioration of their tolerability and the evidence of long-term prospective studies aimed at demonstrating the benefits and the possible complications of this therapy.
Women with visceral obesity may have hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Since glucocorticoids are involved in the expression of the ob gene, this study was carried out to ...investigate the relationship between serum leptin and the activity of the HPA axis in women with different obesity phenotypes.
Cross sectional clinical study.
Fifteen obese (Body Mass Index BM128 kg/m2) women and ten normal weight control women (BM126 kg/m2) were included in the study.
Body fat distribution was defined by CT scan at the L4-L5 level. Baseline blood samples were obtained for hormone concentrations. The activity of the HPA axis was evaluated by measuring ACTH and cortisol blood levels after combined iv administration of corticotropin releasing factor (100 microg) + arginine-vasopressin (0.3 IU).
Baseline cortisol, ACTH, and androgen levels were similar in all groups, whereas leptin levels were significantly higher in the obese groups than in normal weight controls, without any significant difference between women with different obesity phenotypes. Incremental areas of ACTH and cortisol were significantly higher in women with visceral obesity than in those with subcutaneous obesity and controls. No significant correlation was found between the activity of the HPA axis and leptin concentrations. Leptin showed a highly significant correlation with BMI and subcutaneous fat and a weak but significant correlation with visceral fat and the visceral-to-subcutaneous fat ratio.
Women with different obesity phenotypes had similar serum leptin concentrations but different HPA axis activity, and there was no correlation between them.
To investigate the effects of weight loss on sex hormone-binding globulin (SHBG) in massively obese males and whether normal SHBG concentrations could be obtained regardless or not of the achievement ...of normal body weight values.
Sera were collected for SHBG determination from 63 massively obese men, partly before they underwent biliopancreatic diversion (pre-op group = 11) and partly during the post-surgical follow up (post-op group = 52), and twenty normal weight healthy control men.
Serum SHBG was measured using a noncompetitive liquid-phase immunoradiometric assay.
Baseline general characteristics were similar in both obese groups. Obese patients in the post-op group had lost 46.4 +/- 2.9 kg since they had undergone operation, namely during a mean period of 14.9 +/- 13.8 (range 1-58) months follow up. Obese groups had significantly lower SHBG than normal weight controls (66.2 +/- 18.6 nmol/l). However, pre-op obese (19.9 +/- 5.5 nmol/l) had significantly lower values than post-op obese subjects (45.5 +/- 24.8 nmol/l; P < 0.001). There were a highly significant correlation between SHBG and individual BMI values (r = -0.629; P < 0.001). Moreover, the post-op obese with BMI values lower or equal to 28 had significantly higher SHBG concentrations than those with BMI greater than 28 (62.8 +/- 22.2 nmol/l vs 32.1 +/- 19.6 nmol/l; P < 0.001), but not significantly different with respect to normal weight controls.
Massively obese men weight loss can completely reverse SHBG abnormalities, which can be restored to the normal range when near-normal body weight is achieved. Since reduced SHBG concentrations can be an independent risk factor for the development of diabetes and cardiovascular disease, this represents an additional benefit of weight loss program in massively obese individuals.
OBJECTIVE
Little is known about the natural history of polycystic ovary syndrome (PCOS), although preliminary data indicate that affected women are more susceptible than the general population to ...diabetes and cardiovascular diseases at post‐menopausal ages. The aim of this study was to follow‐up all main features of the metabolic syndrome in a group of young women with PCOS and to investigate the long‐term effects on metabolism and body composition of oestrogen–progestagen (OP) compounds, which are frequently used in these women to treat hyperandrogenism and related clinical features.
DESIGN
Long‐term follow‐up study.
SUBJECTS AND METHODS
Thirty‐seven women with PCOS were re‐evaluated 10.3 ± 0.8 years (range 6–18 years) after their first assessments (age: before 19.8 ± 4.9 years; after 29.9 ± 4.4 years). When first examined, women were instructed to follow a hypocaloric diet if they were obese plus OP, if they agreed to such treatment. Main anthropometric parameters, basal sex hormones and lipids, fasting and glucose‐stimulated glucose and insulin levels and several clinical data were recorded before and after follow‐up.
RESULTS
In the whole group of women with PCOS we found no changes in body weight and fat mass, whereas both the waist‐to‐hip ratio and the waist‐to‐thigh ratio were significantly reduced. No significant changes occurred in mean fasting and glucose‐ stimulated glucose and insulin concentrations, whereas a significant increase in high‐density lipoprotein– cholesterol was found. No significant changes occurred in testosterone levels. During the follow‐up period 16 women took OP for an average of 97 ± 18 months (range 12–180 months) (OP‐users) whereas 21 women never took OP (non‐OP‐users). All OP‐users were still taking OP when re‐evaluated at the follow‐up examination. With respect to baseline values, body mass index was higher in non‐OP‐users than in their counterparts. Waist circumference (P < 0.025), the waist‐to‐hip (P < 0.05) and the waist‐to‐thigh (P < 0.01) ratios decreased significantly only in the OP‐users. In addition, percentage changes in waist circumference (P < 0.05) and waist‐to‐hip ratio (P < 0.05) during the follow‐up period were significantly different between the groups. Glucose tolerance (as area under the curve (AUC)) improved (P < 0.05) in OP‐users but not in non‐OP‐users. Moreover, compared to baseline values, basal insulin levels were significantly (P < 0.01) reduced in OP‐users but not in non‐OP‐users. On the contrary, no significant change was found in insulinAUC in the former, whereas it significantly increased (P < 0.05) in the latter. Accordingly, fasting C‐peptide decreased (P < 0.05) in OP‐users, whereas both fasting (P < 0.01) and stimulated (P < 0.01) C‐ peptide significantly increased in non‐OP‐users. Changes in fasting or stimulated insulin and C‐peptide in non‐OP‐users were not associated with parallel changes in testosterone levels. Total cholesterol and triglycerides did not change in either group, but HDL‐cholesterol increased (P < 0.05) only in OP‐users. Sex hormone‐binding globulin concentrations increased significantly (P < 0.01) in OP‐users, without any significant change in non‐OP‐users. Testosterone concentrations did not change significantly in either group, but the testosterone : SHBG ratio significantly decreased in OP‐users (P < 0.05) but not in the non‐OP‐users. Among the clinical features, acanthosis nigricans significantly (P < 0.01) worsened in non‐OP‐users but not in the OP‐users, without any significant change in the hirsutism and acne scores. Pregnancy rates during the follow‐up were similar in both groups.
CONCLUSIONS
These data indicate that hyperinsulinaemia and insulin resistance tended to worsen spontaneously in women with PCOS, without any worsening of the hyperandrogenism. Long‐term oestrogen–progestagen treatment countered this tendency, probably because it improved the pattern of body fat distribution, by reducing abdominal fat depots.
This study analyses the relationships between body fat distribution and socioeconomic and psychological factors in a cohort of 426 healthy middle-aged women living in Virgilio, Mantua (Northern ...Italy). The information concerning their occupational, social and psychological conditions and smoking habits were obtained by means of questionnaires. Psychological factors were investigated using the Italian version of the Illness Behaviour Questionnaire and the Symptom Questionnaire. Anthropometric measurements, body mass index (BMI) (kg/m2), waist/hip ratio (WHR) and clinical/hormonal menopausal status were also collected for each subject. The women reported significantly higher or lower psychological factor scores (symptoms of conversion: p=0.005; perception of disease: p=-0.018; denial: p=0.021; hostility: p=0.57; and laxity: p=0.047) as their WHR increased, thus indicating some concern about their health. In a multiple regression model, their WHR and waist circumference (W) significantly correlated with symptoms of conversion (p=0.005 and p=0.029), and W was also significantly related to the perception of disease (p=0.043). There was a significant inverse correlation between the WHR and educational level (p<0.001). The prevalence of partners who were entrepreneurs or self-employed also decreased as WHR increased (p<0.001). Furthermore, the number of women living in the centre of town significantly diminished, whereas those living in the suburbs or in the country significantly increased (p=0.005). However, using age, BMI and menopausal status as covariates, only the partner's work significantly and negatively correlated with the WHR (p=0.029). These results are consistent with the hypothesis that psychological and socio-economic handicaps are associated with a higher prevalence of abdominal fatness in middle-aged women living in Northern Italy
To investigate whether obese female subjects with abdominal obesity may have adrenal androgen hypersecretion, we examined two groups of women with abdominal (n = 12) and peripheral (n = 13) obesity ...(defined by body mass index and waist-to-hip ratio) and a group of seven healthy normal-weight women. All subjects underwent the following protocol study that included a) baseline determination of major adrenal androgens, b) an ACTH test, performed by administering two boli of ACTH (Synacthen, 0.2 microg/Kg BW, e.v.), at 90 min intervals, with blood samples taken for cortisol and androgens, c) an oral glucose tolerance test, performed by administering glucose (75 gr), with blood samples taken for glucose and insulin determination. Each woman also underwent a control saline study. We then investigated the relationships between basal and stimulated androgen levels, body weight and fat distribution and fasting and stimulated insulin levels. Although basal cortisol levels were similar, their increase (as AUC) after the ACTH test was higher in women with abdominal obesity than in the other groups. On the contrary, there were no significant differences in basal and stimulated serum levels of dehydroepiandrosterone, androstenedione and 17-hydroxyprogesterone among the three groups. Fasting and stimulated (as AUC) insulin levels were significantly higher (p < 0.05) in women with abdominal obesity than in those with peripheral obesity and controls. No significant correlation was present between basal and stimulated androgen levels and body mass index, the waist-to-hip ratio or basal and stimulated cortisol values. Therefore, our data indicate that adrenal androgen secretion following low-dose ACTH administration in premenopausal women does not seem to be a function of body fat mass, fat distribution and insulin levels, nor does it correlate with the capacity of the adrenal glands to secrete cortisol in both basal and stimulated conditions.
There are no studies in vivo on the effects of insulin on androgens and sex hormone-binding globulin (SHBG) in men. We, therefore, investigated the effects of insulin suppression on testosterone and ...SHBG in two groups of eight nondiabetic adult obese men and six healthy normal weight men who underwent diazoxide treatment (100 mg, three times daily) for 7 days. Blood samples for hormone determination were obtained before the subjects had been selected for the study, immediately before diazoxide administration, and on the last day of treatment. A 24-h oral glucose tolerance test was also performed for glucose, insulin, and C-peptide determinations before and on the last day of treatment. Only one subject experienced significant side-effects, and no significant changes in mean body weight were found during the treatment. Diazoxide administration worsened glucose tolerance in several subjects and reduced fasting and glucose-stimulated insulin levels by approximately 50% in both control and obese subjects. No significant difference was present between historical and pretreatment hormone values in either group. Moreover, there were no differences in pretreatment gonadotropin and SHBG concentrations between the two groups, whereas testosterone (free and total) levels were lower in the obese than in the control subjects. After diazoxide administration, testosterone (free and total) decreased slightly, but significantly, whereas LH and SHBG significantly increased in both groups. Diazoxide treatment increased estradiol levels in controls, but not in obese men. In conclusion, these results indicate that in vivo, insulin is capable of stimulating testosterone production and, simultaneously, of inhibiting SHBG concentrations in both normal weight and obese men.
In a previous study, we demonstrated that premenopausal women with visceral obesity have hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, characterized by an exaggerated hormone ...response to corticotropin-releasing factor (CRF) and corticotropin (ACTH) stimulation. The hypothalamic peptide flow that stimulates the pituitary, particularly after a physiological stress challenge, involves not only CRF, but also arginine-vasopressin (AVP), which synergizes the CRF capacity to stimulate pituitary hormone secretion. Previous studies in humans have demonstrated that combining AVP with CRF permits maximal stimulation of the pituitary, providing a more appropriate method of assessing pituitary hormone reserve. We therefore investigated the response of the HPA axis to combined CRF and AVP stimuli in obese women with different obesity phenotypes. Moreover, we examined hormonal and cardiovascular responses to several mental stress tasks, according to previously standardized procedures. Two groups of age-matched premenopausal eumenorrheic obese women with visceral (V-BFD) or subcutaneous (S-BFD) body fat distribution and a group of normal-weight healthy controls were investigated. All women randomly underwent the following protocol: (1) a combined CRF/AVP test (100 μg plus 0.3 IU intravenously IV, respectively); (2) a standardized stress test, which consisted of completing two puzzles and a mental arithmetic test; and (3) a control saline test. Blood samples for ACTH and cortisol determinations were obtained before and during each test, and measurements of arterial blood pressure and pulse rate were made at regular intervals during the stress test. After combined CRF/AVP administration, ACTH and cortisol were significantly higher in V-BFD than in the other two groups. In contrast, no significant hormonal variation was found in either group during stress tasks. During the stress test, pulse rate (but not arterial blood pressure) significantly increased after 8 and 15 minutes in the V-BFD group, whereas no significant variation was found in S-BFD and control women. A significant correlation was present between the pulse rate and change in cortisol level during the stress test at minutes 8 (
r = .54,
P < .05) and 15 (
r = .57,
P < .01) in all women considered together. Subjective emotional involvement during stressful tasks was measured by a two-dimensional short verbal scale, which revealed that the stress section had a more significant impact in obese V-BFD than in S-BFD and control women. These data therefore confirm that women with visceral obesity have hyperactivity of the HPA axis, and that the combined CRF/AVP stimulation may offer a good tool for investigating pituitary reserve in this obesity phenotype. Moreover, the results indicate that these women probably have a hyperreactive sympathetic response to acute stress that seems interrelated to that of the HPA axis.
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