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Biomedical subjects

A R Genazzani

Publications and source records attributed to A R Genazzani.

At least 91 records · Page 5Linked to original sources
PubMed2000

Allopregnanolone and dehydroepiandrosterone response to corticotropin-releasing factor in patients suffering from Alzheimer's disease and vascular dementia.

OBJECTIVE: Neurosteroids have been suggested to be involved in the regulation of cognitive performances. A major neurosteroid gamma-aminobutyric acid (GABA) agonist is allopregnanolone: the main source of circulating allopregnanolone is the adrenal cortex. Studies indicated that a disturbance of the central regulation of the hypothalamic-pituitary-adrenocortical axis occurs in both senile (Alzheimer's disease: AD) and vascular dementia (VD). DESIGN: The aim of the present study was to evaluate the levels of circulating allopregnanolone, dehydroepiandrosterone (DHEA) and cortisol and their response to corticotropin-releasing factor (CRF) test in AD and VD. METHODS: Three groups of 12 subjects were included in the study: AD, VD and age-matched control subjects. CRF test was performed in all subjects and allopregnanolone, DHEA and cortisol levels were measured every 15min for 2h. RESULTS: Mean +/- s.e.m. allopregnanolone and DHEA basal levels were significantly lower in AD and VD than in controls, while cortisol levels were significantly higher than in controls (P<0.01). Allopregnanolone and DHEA levels increase in response to CRF test in all subjects but the area under curve (AUC) in patients was significantly lower than in controls (P<0.01). Cortisol secretion appeared to be very sensitive in response to CRF stimulation: in fact, cortisol response to CRF test in AD and VD subjects was higher (both as AUC and as % max increase) than in controls (P<0.01). CONCLUSIONS: The present study firstly showed that allopregnanolone levels are reduced both in AD and in VD and that dementia has a preserved stimulated response of allopregnanolone to CRF. Overall, however, the total response of allopregnanolone to CRF remains reduced in respect to controls. Further studies are necessary for a better understanding of the role of neurosteroids in the regulation of cognitive function.

Aged↗
PubMed2000

Human GnRH-secreting cultured neurons express activin betaA subunit mRNA and secrete dimeric activin A.

OBJECTIVE: To evaluate the expression of activin betaA-subunit mRNA and the secretion of activin A in/from cultured GnRH-secreting neuronal cells cloned from human olfactory epithelium (FNC-B4), which showed biochemical and antigenic properties of GnRH-secreting neurons. DESIGN: FNC-B4 cells were cultured in basal and conditioned media. METHODS: Reverse transcription-polymerase chain reaction (RTR-PCR) evaluated the expression of activin betaA-subunit mRNA. By using a specific ELISA, dimeric activin A concentrations were measured in culture media, in the absence or presence of carvone or forskolin and with different doses of progesterone, GnRH, and estradiol. RESULTS: RT-PCR experiments performed on total RNA isolated from FNC-B4 cells, using specific primers for the activin betaA gene, showed a 787bp DNA band corresponding to the betaA gene. FNC-B4 cells secreted activin A, and the highest accumulation in conditioned medium was achieved after 3h culture: the addition of forskolin, but not of carvone, was able to stimulate the release of activin A from cultured neuronal cells (P<0.01). When progesterone or GnRH was added, a significant accumulation of activin A was observed (P<0.01), while estradiol administration did not significantly affect activin A secretion. CONCLUSION: To date, this is the only study, in an in vitro human model reporting, that GnRH-secreting neuronal cells expressed activin betaA-subunit mRNA, and released dimeric activin A in culture medium. The expression and secretion of activin suggests that in these cells activin A might exert its action by autocrine/paracrine mechanisms.

Activins↗
PubMed2000

Allergic reaction to a highly purified urinary follicle stimulating hormone preparation in controlled ovarian hyperstimulation for in vitro fertilization.

We report a case of general hypersensitivity-like allergic reactions to intramuscular injections of highly purified urinary follicle stimulating hormone (uFSH-HP) successfully managed by using intramuscular recombinant FSH (rFSH). The patient underwent a first cycle of in vitro fertilization (IVF) and controlled ovarian hyperstimulation (COH) was achieved with a combination of gonadotropin releasing hormone against (GnRH-a) and uFSH-HP. Because, after oocyte recovery, no fertilization occurred, the couple subsequently entered an intracytoplasmic sperm injection (ICSI) program. During the COH, the woman developed general hypersensitivity-like allergic reactions with itching, redness and swelling. Although there was regular follicular growth, the allergic symptoms worsened and, on day 8 of COH, the stimulation cycle was suspended. A few months later, the patient entered a new ICSI cycle. COH was achieved by using a combination of GnRH-a and rFSH. The cycle was completed and the patient did not report any allergic reaction. To avoid allergic reaction to the protein components of the urine-derived FSH preparations, the use of rFSH is suggested in those patients who present local and/or general hypersensitivity-like allergic reactions.

Adult↗
PubMed2000

Ovarian follicular fluid contains immunoreactive estriol: lack of correlation with estradiol concentrations.

Estradiol and estrone concentrations in ovarian follicular fluid change according to the ovulatory cycle, but no studies on the possible presence and/or changes of estriol are available. The aim of the present study was to evaluate whether estriol is measurable in follicular fluid and how its concentration changes according to the volume of ovarian follicles and to the maturational stage of oocytes. A group of women (n = 39) undergoing a program of induction of ovulation was included in this study and divided into three groups according to the causes of infertility: those with unexplained infertility (n = 11); those with endocrine disturbances (n = 5); and normal ovulatory women (n = 23) (controls). The follicles recruited (n = 116) on the basis of morphology and the appearance of the oocyte cumulus-corona complex were divided into: mature (n = 22); intermediate (n = 75); immature (n = 11); and atretic (n = 8). Ovarian follicles were also divided according to the diameter of each: < 1.5 cm (n = 38); 1.6-2.4 cm (n = 66); and > 2.5 cm (n = 12). Ovarian follicular fluids were aspirated under ultrasound guidance and a blood specimen was collected from each subject. Estriol and estradiol concentrations were evaluated by radioimmunoassay in serum and follicular fluid following an ether extraction. Estriol was found in high concentration in each sample of follicular fluid, significantly higher than in the respective serum sample (p < 0.01). Although the estradiol concentration was significantly lower in follicles containing immature and atretic oocytes than in intermediate or mature follicles (p < 0.01), the estriol concentration did not depend upon the maturational stage. In addition, the follicular fluid estriol concentration did not differ according to the causes of infertility. Follicular fluid and serum estradiol concentrations showed significant correlation (p < 0.01), whereas no significant correlation was observed between serum and follicular estriol concentrations. The present data show that follicular fluid contains a high concentration of estriol and that its changes are independent of the ovulatory cycle and estradiol concentrations, supporting an independent origin and suggesting a different function for estriol.

Estradiol↗
PubMed2000

Dose-response efficacy of a new estradiol transdermal matrix patch for 7-day application: a randomized, double-blind, placebo-controlled study. Italian Menopause Research Group.

New estradiol (E2) transdermal matrix patches developed for once-a-week application, releasing 25 micrograms E2 (7D-25) or 50 micrograms E2 (7D-50) daily, were investigated in comparison with a placebo patch and the twice-weekly parent patch releasing 50 micrograms E2 (Derm-50) daily. Three hundred and eleven postmenopausal patients suffering at least seven hot flushes daily were randomly assigned to the four parallel groups and treated continuously for 12 weeks without progestin opposition. The daily number of hot flushes significantly decreased in all groups. At the 12th week the decrease from a base-line average of eight to nine episodes per day was 78% with 7D-25, 93% and 97% respectively with 7D-50 and Derm-50, and significantly (p < 0.001) lower with placebo (59%). Comparable efficacy was observed in terms of severity of hot flushes, Kupperman Index and patient self-rated overall efficacy. Minor systemic adverse events occurred in 10.0%, 8.8%, 16.9% and 13.5% patients in the placebo, 7D-25, 7D-50 and Derm-50 groups respectively. Occasional mild and transient itching and/or erythema at the site of application was reported by a few patients, with no difference between groups or between once-weekly or twice-weekly application. In conclusion all E2 patches were significantly more effective than placebo in relieving climacteric symptoms in a dose-dependent fashion and all were well tolerated.

Administration, Cutaneous↗
PubMed2000

The use of a starting dose of recombinant follicle stimulating hormone for controlled ovarian hyperstimulation: a randomized pilot study.

The aim of this study was to compare the costs and effects of two different controlled ovarian hyperstimulation treatments: a starting dose of recombinant follicle stimulating hormone (FSH) followed by highly purified urinary FSH; or highly purified urinary FSH alone. Forty-six infertile patients, after being given luteal gonadotropin-releasing hormone (GnRH) agonist, were randomly assigned to the two stimulation protocols. During the ovarian stimulation regimen the patients underwent transvaginal ultrasonographic evaluation of follicular number and size. The retrieved oocytes were classified on the basis of the criteria of Acosta and colleagues. To study the impact of embryo quality on implantation, the embryos were graded morphologically before replacement. Pregnancy rates were ascertained and the costs of the two different protocols were analyzed. The number of days of FSH stimulation and the cost of gonadotropin treatment were similar in both groups. The number of follicles > 17 mm in size, the number of collected oocytes, and pregnancy rate per cycle were significantly higher in the group partially treated with recombinant gonadotropin. We conclude from these results that the use of recombinant FSH in the early phase of controlled ovarian hyperstimulation leads to significant improvements in pregnancy rate per cycle without increasing the costs of treatment.

Adult↗
PubMed2000

Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause.

The adrenal production of the delta 5-androgens, dehydroepiandrosterone (DHEA) and its sulfate ester dehydroepiandrosterone sulfate (DHEAS), declines linearly with aging. The evidence that DHEA or DHEAS administration may alleviate some of the problems related to aging has opened new perspectives for clinical research. The present study aims to investigate the effects of a 6-month DHEA supplementation in early and late postmenopausal women, with normal or overweight body mass index (BMI), on the level of circulating steroids, sex hormone binding globulin (SHBG), beta-endorphin and gonadotropins, and on the adrenal gland response to dexamethasone suppression and adrenocorticotropic hormone (ACTH) stimulation. Early postmenopausal women (50-55 years) both normal weight (BMI 20-24, n = 9) and overweight (BMI 26-30, n = 9) and late postmenopausal women (60-65 years) both of normal weight and overweight, were treated with oral DHEA (50 mg/day). Circulating DHEA, DHEAS, 17-OH pregnenolone, progesterone, 17-OH progesterone, allopregnenolone, androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, SHBG, cortisol, luteinizing hormone, follicle stimulating hormone and beta-endorphin levels were evaluated monthly and a Kupperman score was performed. The product/precursor ratios of adrenal steroid levels were used to assess the relative activities of the adrenal cortex enzymes. Before and after 3 and 6 months of therapy, each women underwent an ACTH stimulating test (10 micrograms i.v. in bolus) after dexamethasone administration (0.5 mg p.o.) to evaluate the response of cortisol, DHEA, DHEAS, androstenedione, 17-OH pregnenolone, allopregnanolone, progesterone and 17-OH progesterone. The between-group differences observed before treatment disappeared during DHEA administration. Levels of 17-OH pregnenolone remained constant during the 6 months. Levels of DHEA, DHEAS, androstenedione, testosterone and dihydrotestosterone increased progressively from the first month of treatment. Levels of estradiol and estrone significantly increased after the first/second month of treatment. Levels of SHBG significantly decreased from the second month of treatment only in overweight late postmenopausal women, while the other groups showed constant levels. Progesterone levels remained constant in all groups, while 17-OH progesterone levels showed a slight but significant increase in all groups. Allopregnanolone and plasma beta-endorphin levels increased progressively and significantly in the four groups, reaching values three times higher than baseline. Levels of cortisol and gonadotropins progressively decreased in all groups. The product/precursor ratios of adrenal steroid levels at the sixth month were used to assess the relative activities of the adrenal cortex enzymes and were compared to those found before therapy. The 17,20-desmolase, sulfatase and/or sulfotransferase, 17,20-lyase and 5 alpha-reductase activities significantly increased, while the 3 beta-hydroxysteroid-oxidoreductase activity did not vary. On the contrary, the 11-hydroxylase and/or 21-hydroxylase activities showed a significant decrease after 6 months of treatment. In basal conditions, dexamethasone significantly suppressed all the adrenal steroids and this suppression was greater after 3 and 6 months of treatment for DHEA, DHEAS and allopregnanolone, while it remained unchanged for other steroids. Before treatment, ACTH stimulus induced a significant response in all parameters; after the treatment, it prompted a greater response in delta 5- and delta 4-androgens, progesterone and 17-OH progesterone, while cortisol responded less in both younger and older normal-weight women. The endometrial thickness did not show significant modifications in any of the groups of postmenopausal women during the 6 months of treatment. Treatment with DHEA was associated with a progressive improvement of the Kupperman score in all groups, with major effects on the vasomotor symptoms in

Administration, Oral↗
PubMed2000

Polycystic ovary syndrome: a new ultrasonographic and color Doppler pattern.

The aim of this study was to evaluate whether patients with partial bilateral polycystic ovaries show different ovarian and uterine blood flow to those with complete bilateral polycystic ovaries, and to investigate whether there is a correlation between ultrasonographic and hormonal parameters. Fifteen patients with partial polycystic ovaries and eighteen patients with complete bilateral polycystic ovaries underwent clinical, biochemical, gray-scale and color Doppler ultrasonographic evaluation. Hormonal (luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH concentration ratio, estradiol, prolactin, androstenedione, testosterone), clinical (body mass index, Ferriman-Gallwey score), ultrasonographic (ovarian volume, number and distribution of subcapsular follicles, stromal score) and Doppler (uterine artery and intraparenchymal vessels pulsatility index, ovarian stromal vascularization) parameters were evaluated, in the early follicular phase (cycle day 3-5) in oligomenorrheic patients, or at random in amenorrheic patients. Significantly higher androstenedione plasma levels and LH/FSH concentration ratios were observed in complete bilateral polycystic ovaries. In partial polycystic ovaries, gray-scale and color Doppler ultrasonography showed different features in affected and unaffected areas of the ovary, similar to polycystic and normal ovary appearance respectively. In conclusion, PCOS does not predetermine a single ultrasonographic or Doppler pattern.

Adult↗
PubMed2000

Towards a molecular understanding of the atheroprotective effects of estrogens: a review of estrogen effects on endothelial activation.

Early phases of atherosclerosis are characterized by an increased adhesion of leukocytes to vascular endothelium, leading to a recruitment of white blood cells into the intima. Leukocyte adhesion is mediated by the expression of specific adhesion molecules on endothelial cells, dependent on a dysfunctional status of vascular endothelium (endothelial activation), potentially caused by the exposure to diverse atherogenic stimuli. Female sex steroid hormones regulate vascular function acting directly on vascular cells, and producing a net anti-inflammatory effect. Among the various mechanisms mediating the anti-atherogenic effects of estrogens, the inhibition of endothelial activation process and of leukocyte adhesion molecule expression are particularly important, for the strategic pathophysiological role played by these processes during atherogenesis. This brief review discusses recent discoveries on the molecular mechanisms of estrogens on endothelial activation, as well as pathophysiological and clinical implications of these effects.

Arteriosclerosis↗
PubMed1999

GH, IGFBP-1, and IGFBP-3 response to oral glucose tolerance test in perimenopausal women: no influence of body mass index.

OBJECTIVES: an increasing interest is being focused on the role of the somatotropic axis in the modulation of body weight and fat distribution, particularly in climacteric women. The influence of the glycometabolic state on the somatotropic axis in postmenopausal and in obese subjects has not been investigated. The aim of the present study is to evaluate whether menopause and body mass index (BMI) affect the response of growth hormone (GH), insulin-like growth factor-binding protein-1 (IGFBP-1) and -3 (IGFBP-3) to the oral glucose tolerance test (OGTT). METHODS: the study included 24 women, aged 45-55 years, categorized into 4 groups, premenopausal pre-obese (BMI = 28.5 +/- 0.8 Kg/m2) and normal body weight (BMI = 22.2 +/-1.1 Kg/m2), and postmenopausal pre-obese and normal body weight. All women underwent: (1) a biophysical evaluation with determination of waist/hip ratio; (2) an assessment of fat and lean tissue mass and body fat distribution by total body DEXA; and to (3) an OGTT. RESULTS: in response to OGTT plasma GH levels significantly decreased in all groups, but the relative decrease was more prominent in the lean subjects. A significant decrease of IGFBP-1 levels in response to OGTT was observed in all women, regardless of menopausal age and BMI, while IGFBP-3 levels did not significantly change in either group. CONCLUSIONS: in conclusion, the impact of both BMI and menopausal condition on GH, IGFBP-1, and -3 response to OGTT is limited to a blunted GH response in overweight women compared with normally-weighing ones. These findings appear to rule out the hypothesis that a common glycometabolic derangement may affect both the modifications of body weight and of the somatotropic axis observed in perimenopausal women.

Body Composition↗
PubMed1999

Hormone replacement therapy: the perspectives for the 21st century.

UNLABELLED: Nowadays different lines of evidence demonstrate the benefits of postmenopausal hormone replacement therapy (HRT). HRT is extremely effective in treating subjective symptoms and can really improve the quality of life of climacteric women. HRT and dementia: Estrogens are potentially relevant to the pathogenesis and treatment of Alzheimer's disease. The effects of different progestogens on cognitive functions and Alzheimer's disease are largely unknown. The prevention of Alzheimer disease might be a major indication to long term HRT. Large prospective, randomized trials will confirm these preliminary data. HRT and osteoporosis: HRT has been strongly correlated with higher bone mineral density and lower fracture incidence. Definite answers in terms of minimum effective dosages, timing and duration of HRT for fracture prevention are needed. HRT and cardiovascular disease: Different lines of evidence suggest that HRT can exert cardioprotective effects with substantial reduction of morbidity and mortality for cardiovascular disease in postmenopausal women. The effects and the role of progestogens in cardiovascular disease prevention are still debated. Prospective, randomized, controlled studies are needed to assess the impact of different HRT regimens on cardiovascular events. HRT and cancer: The major issue in the relationship between HRT and cancer is breast cancer. Long-term and current HRT use are followed by a slight, though significant increase in the risk of breast cancer. Progestogens can modify the cellular response of normal as well as cancer breasts. The possible protective effect of continuous progestogen addition is very interesting and needs further investigation. Alternative to classical HRT: Selective estrogen receptor modulators (SERM). SERMs such as raloxifene (RAL) are a new class of drugs that exert site specific estrogenic or antiestrogenic effects in different target tissues. RAL prevents bone loss and reduces serum cholesterol in postmenopausal women. In contrast to estrogen RAL does not stimulate breast or uterine tissues. In vitro RAL is highly effective at inhibiting the growth of estrogen-dependent breast adenocarcinoma cells. SERMs are expected to represent a major breakthrough for postmenopausal health. CONCLUSION: HRT can be offered either as a preventive tool or as individualized care on the basis of personal needs. New therapeutic options like the SERMs will offer a substantial medical advancement for the treatment of postmenopausal women.

Adult↗
PubMed1999

Menopause and the central nervous system: intervention options.

The central nervous system is an important target for sex steroid hormones. During the climateric period the rapid decline of gonadal steroids causes neuroendocrine changes in different areas of the brain. The failure of gonadal hormone production brings specific symptoms due to the central nervous system derangement. At the hypotalamic level estrogen withdrawal gives rise to vasomotor symptoms, eating behavior disorders and altered blood pressure control. Psychological disturbances such as depression, anxiety, irritability and mood fluctuation are related to estrogen-induced changes in the lymbic system. The hypothesis of specific neuroanatomical and neurophysiological effects of estrogen on the brain may also explain the correlation between estrogen deficiency and cognitive disturbances such as Alzheimer's type dementia (AD). The increasing interest in the influence of sex steroids on brain function has focused attention on hormonal replacement therapy. Clinical and epidemiological studies have demonstrated that estrogen therapy exerts a positive effect on vasomotor instability and improves psychological disturbances. The positive effects of estrogen on mood are probably related to its stimulatory action on adrenergic and serotoninergic tone. Estrogen may influence the cognitive function through different biological actions. Estrogen administration increases total cerebral and cerebellar blood flow, cerebral glucose administration and improves cholinergic tone, a key neurotransmitter in learning and memory. The evidence suggests that hormone replacement therapy may reduce the relative risk of developing AD. Progestagens and androgen may also have a role in the control of mood disorders. At present, few data are available regarding the influence that selective estrogen receptor modulators, a new class of compounds, can exert on the brain.

Alzheimer Disease↗
PubMed1999

Assessment of the prognostic relevance of serum anti-p53 antibodies in epithelial ovarian cancer.

The objective of this study was to assess the prognostic relevance of preoperative serum anti-p53 antibodies in epithelial ovarian cancer. These autoantibodies were detected with a new generation enzyme-linked immunosorbent assay in blood samples preoperatively drawn from 86 patients with this malignancy. Serum anti-p53 antibodies were found in 3 (10.0%) of the 30 patients with stage I-II and 15 (26.8%) of the 56 patients with stage III-IV epithelial ovarian cancer (P = 0.09). We assessed in detail 44 patients with stage III-IV disease who underwent six cycles of first-line platinum-based chemotherapy. A pathological complete response at second-look was achieved by none of the 15 patients with serum anti-p53 antibodies compared to 24.1% of the 29 patients without autoantibodies (P = 0.09). However, the preoperative serum anti-p53 antibody status had no prognostic relevance for progression-free survival and survival. In conclusion, the assessment of preoperative serum anti-p53 antibodies seems to have a limited clinical value in the management of patients with advanced epithelial ovarian cancer.

Autoantibodies↗
PubMed1999

Treatment of hirsutism: comparisons between different antiandrogens with central and peripheral effects.

OBJECTIVE: To compare the clinical and endocrinologic effects of cyproterone acetate (CPA), an antiandrogen with progestational activity; flutamide, a nonsteroidal antiandrogen, and finasteride, an inhibitor of 5alpha-reductase. DESIGN: Randomized, open, controlled clinical study. SETTING: Department of Obstetrics and Gynecology, University of Pisa, Pisa, Italy. PATIENT(S): Forty-five hirsute women were enrolled in the study: 29 were hyperandrogenic and 16 had idiopathic hirsutism. Three women dropped out of the study. INTERVENTION(S): Women were randomly treated with finasteride (5 mg/d; n = 14), CPA (25 mg plus ethinyl E2 (EE); n = 13), or flutamide (500 mg/d; n = 15) for 1 year. MAIN OUTCOME MEASURE(S): Hirsutism was assessed using the Ferriman-Gallwey method. Levels of total and free T, androstenedione (A), DHEAS, sex hormone-binding globulin, dihydrotestosterone, and 3alpha-androstanediol glucuronide were evaluated at the beginning of the study and every 3 months. RESULT(S): Treatment with finasteride, flutamide, and CPA significantly decreased the Ferriman-Gallwey score. The percent decreases in the hirsutism score induced by the different treatments were similar. Treatment with CPA plus EE significantly decreased levels of total and free T, A, dihydrotestosterone, and 3alpha-androstanediol glucuronide. These parameters were unchanged with flutamide therapy. Finasteride significantly increased total T levels but reduced dihydrotestosterone and 3alpha-androstanediol glucuronide concentrations. CONCLUSION(S): Finasteride, CPA, and flutamide are equally effective in decreasing hirsutism, despite different mechanisms of action.

Adolescent↗
PubMed1999

Antagonism by pivagabine of stress-induced changes in GABAA receptor function and corticotropin-releasing factor concentrations in rat brain.

Pivagabine [4-(2.2-dimethyl-l-oxopropylamino) butanoic acid] (PVG) is a hydrophobic 4-aminobutyric acid derivative with neuromodulatory activity. The effects of subchronic treatment with PVG on stress-induced changes both on brain concentrations of corticotropin-releasing factor (CRF) and neurosteroids and on the function of the gamma-aminobutyric acid type A (GABAA) receptor complex were investigated in male rats. Subchronic treatment with PVG (100-200 mg/kg, i.p.) resulted in a dose-dependent inhibition of the foot shock-induced increase in the binding of t-[35S]butylbicyclophosphorothionate to unwashed membranes prepared from the cerebral cortex of rats killed immediately after stress; PVG treatment alone had no effect on this parameter. This antagonistic action of PVG was also shown in adrenalectomized-orchietomized rats. Foot-shock stress decreased by 74% and increased by 125% the CRF concentration in the hypothalamus and cerebral cortex, respectively. PVG prevented these effects of stress on CRF concentration in both brain regions; this drug per se reduced hypothalamic CRF concentration by 52% but had no effect in the cortex. Moreover, intracerebroventricular injection of CRF, like stress, induced a dose-dependent increase of [35S]TBPS binding to cerebral cortical membranes: an effect not prevented by subchronic treatment of PVG. Finally, PVG did not antagonize the stress-induced increases in the concentrations of neuroactive steroids in brain or plasma. These results suggest that the marked antistress action of PVG is mediated by antagonizing the effects of stress on GABA(A) receptor function and CRF concentrations in the brain, but not by altering the stress-induced increase in neurosteroid concentrations.

Adrenalectomy↗
PubMed1999

Efficacy on climacteric symptoms of a new estradiol transdermal patch with active matrix in comparison with a reference reservoir patch. Two long-term randomized multicenter parallel-group studies.

METHODS: Two randomized prospective multicentre parallel group studies were performed (one in Germany and the other in Italy) in symptomatic postmenopausal women. The goal was to assess the efficacy on climacteric symptoms and the safety of a new estradiol (CAS 50-28-2) transdermal patch with solid active matrix (SAM) in comparison to a conventional liquid reservoir (LR) type estradiol transdermal patch. Both patches released 50 micrograms/day estradiol. One group of patients received the SAM patch and the other the LR patch in 4-week cycles, with a twice-weekly application of the patches for 3 weeks, followed by one week without patches. Progestin opposition was achieved with medroxyprogesterone acetate 5 mg/day orally in the last 11 days of patch application in the German study and with 10 mg/day in the last 12 days of patch application in the Italian study. Both studies were divided into two Parts: Part 1 with three 4-week cycles for a total of 12 weeks and Part 2 for other ten 4-weeks cycles in which the patches could be applied also continuously. The total duration of the study was therefore 52 weeks. RESULTS: Germany study. 133 patients resulted randomized to the SAM group and 129 to the LR group. Both estradiol patches quickly relieved climacteric symptoms already during the first 3 weeks of patch application, as shown by the rapid decrease of the Kupperman Index. At the end of Part 1, in the SAM group 91% and in the LR group 96% of patients reported relief from climacteric symptoms. At the end of Part 2 the percentages were 98% and 95%, respectively. The two patches were therapeutically equivalent with a power greater than 99.7%. Both patches were systemically fairly well tolerated. Only 4.5% of patients in the SAM group and 3.9% in the LR group discontinued prematurely for possible adverse reactions related to estradiol. There was no significant difference between the two patches with regard to systemic tolerability. Conversely, with regard to local skin reactions, the SAM patch was significantly (p < 0.01) better tolerated than the LR patch. The adhesion to the skin of the SAM patches was better than that of the LR patches. RESULTS. Italian study. 139 patients resulted randomized to the SAM patch and 128 to the LR patch. Also in this study both types of patches relieved the climacteric symptoms already during the first 3 weeks of patch application, as shown by the rapid decrease of the visual analogue scale (VAS) recordings of severity of hot flushes and of sweats. At the end of Part 1 both patches relieved 95% of patients from climacteric symptoms. At the end of Part 2, i.e. after 52 weeks, 100% of patients were relieved from climacteric symptoms. Of these, 72% in the SAM group and 78% in the LR group reported complete disappearance of symptoms. Also in the Italian study, therefore, the two patches were found therapeutically equivalent. Both patches stopped or even reversed bone mineral loss in L2-L4 and had some favorable effects on lipid metabolism. Both patches were systemically equally fairly well tolerated with premature discontinuations for systemic adverse drug reactions in only 5.0% of patients in the SAM group and 3.9% in the LR group. Conversely, as in the German study, the SAM patches were significantly better tolerated by the skin (p < 0.0001). CONCLUSIONS: The two types of estradiol transdermal patches were equivalent in providing an effective and rapid relief from climacteric symptoms. Systemically both patches were fairly well tolerated. The SAM patches were significantly better tolerated by the skin. The better local tolerability combined with better adhesion and cosmetic properties render the SAM patches very patient friendly and improve the compliance in the long term estrogen replacement therapy required to reduce osteoporosis and cardiovascular risks.

Adhesiveness↗
PubMed1999

Endocrine, neuroendocrine and behavioral effects of oral dehydroepiandrosterone sulfate supplementation in postmenopausal women.

Aging in women and men is characterized by a progressive decline of circulating dehydroepiandrosterone (DHEA) levels and its sulfate ester (DHEAS). The improvement of wellbeing described in postmenopausal women treated with DHEA suggests that this steroid may exert specific actions on the central nervous system (CNS). The postmenopausal period is associated with several neuroendocrine modifications. The decrease of circulating levels of beta-endorphin is considered a hormonal marker of those changes. The aim of the present study was to investigate neuroendocrine and behavioral effects of three months of DHEAS supplementation in postmenopausal women. Postmenopausal women (n = 22) were divided in three groups: the first group was treated with oral DHEAS (n = 8) (50 mg/day), the second treated with the same dose of oral DHEAS + transdermal estradiol (n = 8) (DHEAS) 50 mg/day, estradiol 50 micrograms/patch) and the third with transdermal estradiol alone (n = 6) (50 micrograms/day). Before and after 1, 2 and 3 months of therapy, the following circulating steroid and protein hormone levels were evaluated: DHEA, DHEAS, androstenedione, testosterone, estrone, estradiol, 17-hydroxyprogesterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinizing hormone (LH), beta-endorphin, growth hormone (GH) and cortisol, and a Kupperman score was performed. Before and after treatments, plasma beta-endorphin levels were evaluated in response to three neuroendocrine tests: (a) clonidine, an alpha 2-presynaptic adrenergic agonist (1.25 mg i.v.) (b) naloxone, an opioid receptor antagonist (4 mg i.v.) and (c) fluoxetine, a serotonin selective reuptake inhibitor (30 mg p.o.). In both groups of women treated with DHEAS, mean basal serum DHEA, DHEAS, androstenedione, and testosterone levels significantly increased after treatment, while no changes were shown in the group receiving estradiol alone. Serum estradiol, estrone, GH and plasma beta-endorphin levels significantly increased progressively for the three months of treatment, with higher levels for estrone and estradiol in subjects receiving estradiol alone or plus DHEAS. Serum SHBG, cortisol, and 17-hydroxyprogesterone did not show significant variations under any treatment. Serum LH and FSH levels showed a significant decrease in groups treated with estradiol alone or plus DHEAS at the second and third months. The Kupperman score showed that all treatments were associated with similar and progressive improvement. Before therapy clonidine, naloxone and fluoxetine stimuli failed to modify circulating beta-endorphin levels. After each of the treatments, the beta-endorphin response was completely restored and was similar, independent of the kind of therapy. Restoration of the beta-endorphin response to specific stimuli suggests that DHEAS and/or its active metabolites modulates the neuroendocrine control of pituitary beta-endorphin secretion, which may support the therapeutic efficacy of the DHEAS on behavioral symptoms.

Administration, Oral↗