Characterization of endocrine features and genotype-phenotypes correlations in blepharophimosis-ptosis-epicanthus inversus syndrome type 1.

OBJECTIVE: Blepharophimosis syndrome (BPES) is an autosomal dominant genetic condition resulting from heterozygous mutations in the FOXL2 gene and clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure. The distinction between the two forms is critical for female patients, as it may allow to predict fertility and to plan an appropriate therapy. Identifying an underlying causative mutation is not always predictive of the clinical type of BPES since genotype-phenotype correlations are not yet fully delineated. Here, we describe the clinical and hormonal phenotypes of three female patients with BPES type 1 from two novel families, correlate their phenotypes with identified mutations, and investigate the effects of hormone replacement therapy (HRT). METHODS: Clinical, biochemical, and genetic evaluation were undertaken in all the patients and genotype-phenotype correlation was analyzed. The effects of substitutive hormonal therapy on secondary sexual characteristics development and induction of menarche were evaluated. RESULTS: All patients presented with primary amenorrhea or other signs of ovarian dysfunction. Two distinct mutations, a missense p.H104R change and an in-frame p.A222_A231dup10 duplication in the FOXL2 gene were identified. Observed phenotypes were not in accordance with the prediction based on the current genotype-phenotype correlations. HRT significantly improved secondary sexual characteristics development, as well as the induction of menarche. CONCLUSIONS: This study highlights the importance of early recognition of BPES and emphasizes the need of personalized therapy and follow-up in female patients carrying distinct FOXL2 mutations.

Total compared with partial pancreatectomy for pancreatic adenocarcinoma: assessment of resection margin, readmission rate, and survival from the U.S. National Cancer Database.

Introduction: Total pancreatectomy for pancreatic ductal adenocarcinoma has historically been associated with substantial patient morbidity and mortality. Given advancements in perioperative and postoperative care, evaluation of the surgical treatment options for pancreatic adenocarcinoma should consider patient outcomes and long-term survival for total pancreatectomy compared with partial pancreatectomy. Methods: The U.S. National Cancer Database was queried for patients undergoing total pancreatectomy or partial pancreatectomy for pancreatic adenocarcinoma during 1998-2006. Demographics, tumour characteristics, operative outcomes, 30-day mortality, 30-day readmission, additional treatment, and Kaplan-Meier survival curves were compared. Results: The database query returned 807 patients who underwent total pancreatectomy and 5840 who underwent partial pancreatectomy. More patients who underwent total pancreatectomy than a partial pancreatectomy had a margin-negative resection (p < 0.0001). Mortality and readmission rates were similar in the two groups, as was long-term survival on Kaplan-Meier curves (p = 0.377). A statistically significant difference in the rate of surgery only (without additional treatment) was observed for patients in the total pancreatectomy group (p = 0.0003). Conclusions: Although total compared with partial pancreatectomy was associated with a higher rate of margin-negative resection, median survival was not significantly different for patients undergoing either procedure. Patients who underwent total pancreatectomy were significantly less likely to receive adjuvant therapy.

The immune system in extreme longevity.

Recent observations indicate that immunosenescence is not accompanied by an unavoidable and progressive deterioration of the immune function, but is rather the result of a remodeling where some functions are reduced, others remain unchanged or even increased. In addition, it appears that the ancestral/innate compartment of the immune system is relatively preserved during aging in comparison to the more recent and sophisticated adaptive compartment that exhibit more profound modifications. The T-cell branch displays an age-dependent decline of the absolute number of total T-cells (CD3+), involving both CD4+ and CD8+ subsets, accompanied by an increase of NK cells with well-preserved cytotoxic function and by a reduction of B-cells. One of the main characteristics of the immune system during aging is a progressive, age-dependent decline of the virgin T-cells (CD95-), which is particularly profound at the level of the CD8+ subpopulation of the oldest old subjects. The progressive exhaustion of this important T-cell subpopulation dedicated primarily to the defense against new antigenic challenges (viral, neoplastic, bacterial ones), could be a consequence of both the thymic involution and the lifelong chronic antigenic stimulation. The immune function of the elderly, is therefore weakened by the exhaustion of CD95- virgin cells that are replaced by large clonal expansions of CD28- T-cells. The origin of CD28- cells has not been completely clarified yet, but it is assumed that they represent cells in the phase of replicative senescence characterized by shortening telomers and reduced proliferative capacity. A major characteristic of the immune system during aging is the up-regulation of the inflammatory responses which appears to be detrimental for longevity. In this regard, we have recently observed a progressive age-dependent increase of type 1(IL-2, IFN-gamma, TNF-alpha) and type 2 (IL-4, IL-6, IL-10) positive CD8+ T-cells; in particular, type 1 cytokine-positive cells significantly increased, with age, in all CD8+ subsets particularly among effector/cytotoxic and memory cells. A major force able to drive a chronic pro-inflammatory state during aging may be represented by persistent viral infections by EBV and CMV. Therefore, we have determined the frequency and the absolute number of viral antigen-specific CD8+ T-cells in subjects older than 85 years, who were serologically positive for CMV or EBV. In the majority of these subjects we detected the presence of T lymphocytes positive for epitopes of CMV or EBV. In all subjects the absolute number of CMV-positive CD8+ cells outnumbered that of EBV-positive ones. In addition, the majority of CMV+ T cells were included within the CD28- subpopulation, while EBV+ T cells belonged mainly to the CD28+ subset. These data indicate that the chronic antigenic stimulation induced by persistent viral infections during aging bring about important modifications among CD8+ subsets, which are particularly evident in the presence of CMV persistence. The age-dependent expansions of CD8+CD28- T-cells, mostly positive for pro-inflammatory cytokines and including the majority of CMV-epitope-specific cells, underlines the importance of chronic antigenic stimulation in the pathogenesis of the main immunological alterations of aging and may favour the appearance of several pathologies (arteriosclerosis, dementia, osteoporosis, cancer) all of which share an inflammatory pathogenesis.

Taking advantage of viral immune evasion: virus-derived proteins represent novel biopharmaceuticals.

In healthy individuals, natural and adaptive immune responses are able to control virus entry into the host. In particular, CD8(+)-mediated cytotoxicity, sustained by the intervention of CD4+ cells, represents the major key event leading to virus eradication. On the other hand, viruses are able to evade from host immune response via several mechanisms, and special emphasis will be placed on hepatitis C virus and chronic Epstein-Barr infections also in view of personal data. Virokines, viroreceptors, and serpins greatly contribute to viral immune escape, and, among virokines, interleukin (IL)-10 has been object of intensive studies. Finally, all these products have been used as biopharmaceuticals, and, for instance, viral IL-10, chemokine-binding proteins, and serpins exhibit in animal models immunosuppressive, anti-inflammatory, and antiatherogenic activities. As far as their use in human trials is concernded, many cautions are required in order to avoid deleterious side effects and, in particular, the purity of the product, its route and frequency of administration, as well as the immune status of the patient should be taken into serious account.

Ablation of T-helper 1 cell derived cytokines and of monocyte-derived tumor necrosis factor-alpha in hereditary hemorrhagic telangiectasia: immunological consequences and clinical considerations.

Experimental evidences on the adaptive immune response in patients with hereditary hemorragic telagiectasia (HHT) are lacking. Here, we report in 9 patients with HHT a multiple deficit involving the intracellular expression of T helper (h)1-derived cytokines [Interferon (IFN)-gamma, Interleukin (IL)-2 and Tumor Necrosis Factor (TNF)-alpha] and of monocyte-derived TNF-alpha. On the other hand, percentages of Th2-derived cytokines (IL-4, IL-5 and IL-10) were normal or, in some cases, above normality. Quite interestingly, monocyte-derived IL-10 was detectable in 5 out of 9 patients in a percentage of cells comparable to controls or exceeding normal levels. Taken together, these data point out, in HHT, an ablation of Th1-responses, while Th2-type cytokines are preserved, thus exerting either a suppressive effect on Th1-cells (via IL-4 and IL-10) or an antiinflammatory response on monocyte-derived TNF-alpha (via IL-10). Furthermore, monocyte-derived IL-10 may also contribute to the antiinflammatory activity seen in HHT. According to current literature even if patients with HHT do not exhibit certain diseases, such as autoimmune diseases, cancer and abnormal responses to pathogens, the observed immune deficits need to be diagnosed and therapeutically corrected.

High risk for microcarcinoma in thyroid benign diseases. Incidence in a one year period of total thyroidectomies.

Over the last few years, incidental thyroid microcarcinoma (TMC) has become a frequent disease and its incidence in some reports is considerable. The discovery of new cases depends on the progress of the diagnostics (US scan, fine needle biopsy and cytology, CT, MRI), on the extended indications to thyroidectomy for benign disease and on the attention in pathologic examination of the specimen. The clinical evolution of this disease is not well known: in spite of a high incidence reported in some autoptic series, suggesting that this tumour could have a good prognosis, some authors report an overall incidence of up to 11% of local recurrence, metastasis and mortality. For these reasons the treatment of TMC is still controversial today. Aim of this study was to estimate the incidence and the clinico-pathological findings of TMC over a one year period of total thyroidectomies for diffuse benign thyroid diseases, and to evaluate, on the basis of the frequency of incidental microcarcinoma, if the surgical procedure of complete removal of the gland should be adopted in any case. In this series no patient had pre-operative diagnosis or tentative diagnosis of carcinoma and the incidence of TMC at the final histologic examination was 27.4%. Total thyroidectomy confirmed to be the treatment of choice for diffuse benign diseases and appeared necessary to obtain both, diagnosis and treatment of incidental TMC.

Increased serum concentrations of interleukin-6 (IL-6) and soluble IL-6 receptor in patients with Graves' disease.

Increased serum interleukin-6 (IL-6) concentrations have been reported in patients with thyroid destructive processes. In the present study we measured IL-6 and soluble IL-6 receptor (sIL-6R) concentrations in the serum of normal subjects and patients with Graves' disease using a high sensitivity sandwich enzyme-linked immunoassay. We found increased serum IL-6 and sIL-6R concentrations (69.3 fmol/L, and 964 pmol/L, respectively) in 49 hyperthyroid patients with Graves' disease (GD) compared to those in controls [55.8 fmol/L (P = 0.019) and 772 pmol/L (P = 0.007), respectively]. In 31 newly diagnosed GD patients, serum concentrations of IL-6 and sIL-6R during the hyperthyroid phase were elevated, and after therapy with methimazole only, serum sIL-6R concentrations returned to normal (940 vs. 726 pmol/L; P < 0.001) but serum IL-6 did not. Serum sIL-6R concentrations (mean +/- 2 SD) were higher in GD patients with active inflammatory thyroid-associated ophthalmopathy than those in patients with inactive or absent thyroid-associated ophthalmopathy (P < 0.05). In conclusion, we have demonstrated activation of the IL-6 system in GD and, for the first time, have measured and found increased serum sIL-6R concentrations in hyperthyroid GD patients.

Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure. CoQ10 Drug Surveillance Investigators.

Digitalis, diuretics and vasodilators are considered the standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of Coenzyme Q10 (CoQ10) adjunctive treatment in congestive heart failure which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2664 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing study in 173 Italian centers. The daily dosage of CoQ10 was 50-150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two-to seven-point scales. The results show a low incidence of side effects: 38 adverse effects were reported in 36 patients (1.5%) of which 22 events were considered as correlated to the test treatment. After three months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 78.1%, oedema 78.6%, pulmonary rales 77.8%, enlargement of liver area 49.3%, jugular reflux 71.81%, dyspnoea 52.7%, palpitations 75.4%, sweating 79.8%, subjective arrhytmia 63.4%, insomnia 662.8%, vertigo 73.1% and nocturia 53.6%. Moreover we observed a contemporary improvement of at least three symptoms in 54% of patients; this could be interpreted as an index of improved quality of life.

T lymphocyte proliferative capability to defined stimuli and costimulatory CD28 pathway is not impaired in healthy centenarians.

It is generally assumed that T cell proliferation is impaired in aged individuals. We report data on the proliferative capability of peripheral blood mononuclear cells (PBMC) and T lymphocytes from 40 healthy people of different ages, (19-107 years), including 14 centenarians, to defined mitogenic stimuli. We observed no age-related proliferative impairment both in PBMC and in purified T cells stimulated by anti-CD3 mAb or phorbol myristate acetate (PMA). Furthermore, T cells stimulated by anti-CD3 mAb or PMA and costimulated by CD28 mAb did not proliferate differently among young, middle aged subjects and centenarians. Thus, short term T cell proliferation is not affected even at extreme age when well defined stimuli are used on cells deriving from carefully selected healthy subjects.

Seasonal variation in the incidence of hip fractures in Emilia-Romagna and Parma.

Though some reports suggest the existence of seasonal changes in hip fracture incidence, with a peak in winter months, other investigations have failed to confirm this finding. In this study we present data on the month-to-month variability of hip fractures in Emilia-Romagna, a region of Northern Italy with a population of approximately four million inhabitants, and in Parma, a province of Emilia-Romagna (population of approximately 400,000). Data on cervical and trochanteric fractures were obtained from two sources: a) records of all operative procedures in the five orthopaedic centres serving the area of the Parma province; and b) a computerised database of all hospital discharges from public and private hospitals of Emilia-Romagna. In both cases, the analysis gave similar results, with no evidence of a consistent seasonal pattern in hip fracture rates.

The comparative effect of ovarian hormone administration on bone mineral status in oophorectomized rats.

The effect of oophorectomy and hormone replacement therapy on cortical and trabecular bone mass was assessed in Sprague-Dawley rats. Bone mineral density (BMD) of the femur and the lumbar spine was determined by dual photon absorptiometry 4 months after surgery. Femoral mineral content was also determined. A significant decrease in bone density and in calcium content was observed after surgical castration. Bone mineral loss was prevented by either progesterone or estrogen, while the combination of progesterone and estrogen had no effect on the bone mineral content. The present study suggests the possibility that estrogen-progestin treatment may be less effective than a therapy with estrogen alone, and that further study on the effect of progesterone alone would be worthwhile.

Hip fracture in Italy: epidemiology and preventive efficacy of bone-active drugs.

In this paper we report the results on the epidemiology of hip fracture and the preventive efficacy of bone-active drugs in Italy, observed in men and women aged 50 years or over, recruited in the three Italian centres participating in the Mediterranean Osteoporosis Study (MEDOS), namely Parma, Rome, and Siena. The number of fractures observed was 1,437 in a catchment area population of 847,508 individuals, with a total incidence of 169.6/100,000--a female-to-male ratio of 3.5 and a doubling-time of about 5.5 years. The female excess becomes evident in the age groups over 60 years. The mean age of fractures was 77 years in females and 73 in males. From the data collected, the estimated number of fractures per year in the Italian population aged over 50 years is 32,000. The pattern of use and the preventive efficacy of bone-active drugs was examined in women. Calcitonin and calcium were the drugs mainly used; less than 3% had taken vitamin D or oestrogen and only a minor percentage had taken anabolic steroids. Fluorides were not used at all. As seen in the European sample, the protective effect of calcium and calcitonin is statistically significant even in Italy, while vitamin D is not. The use of anabolic steroids was associated with a decrease in risk. Oestrogen administration does not seem to reduce the relative risk of hip fracture in Italian women, probably due to the small sample size.

Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoporosis.

The main objective of this study was to determine the effect of daily oral alendronate treatment on bone mass in postmenopausal women affected by osteoporosis. The efficacy of intranasal salmon calcitonin was also examined. Nine centers in Italy enrolled 286 postmenopausal women between the ages of 48 and 76 with spinal bone mineral density > or = 2 SD below adult mean peak in the two-year, double-blind, randomized, placebo-controlled trial. Patients were randomized to one of four treatment arms: double-blind placebo, alendronate 10 mg/day, alendronate 20 mg/day, or open-label intranasal salmon calcitonin 100 IU/day; all patients received 500 mg Ca++ supplements. Bone mass was measured by dual-energy x-ray absorptiometry every six months for two years. Patients who received alendronate 10 or 20 mg experienced significant increases in bone mass at all sites measured. At the end of the second year, the mean percent changes, for alendronate 10 and 20 mg relative to placebo, were 5.2% and 7.3% at the lumbar spine, 3.8% and 4.6% at the femoral neck, and 7.1% and 7.5% at the trochanter, respectively. In contrast, intranasal salmon calcitonin failed to increase bone mineral mass significantly at any site. Both alendronate doses significantly decreased serum alkaline phosphatase, serum osteocalcin, and urinary pyridinolines, markers of bone turnover, whereas placebo and intranasal calcitonin did not. Alendronate was generally well tolerated and no serious adverse events were attributed to its use.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that multiple risk factors for coronary artery disease exist in persons with abnormal glucose tolerance.

Multiple risk factors for coronary artery disease were determined in 50 healthy, non-diabetic persons with an oral glucose tolerance test result that could not be classified as normal by current criteria and 50 sex-, age-, and weight-matched persons with normal oral glucose tolerance. The results indicated that persons with abnormal oral glucose tolerance were hyperinsulinemic, as well as hypercholesterolemic and hypertriglyceridemic. In addition, patients with abnormal results in glucose tolerance tests had significantly elevated systolic blood pressure and heart rates. These data suggest that a cluster of risk factors for coronary artery disease exists in non-diabetic persons with abnormal oral glucose tolerance.

Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes.

Growing evidence suggests that interleukin-6 (IL-6) may play a pathogenetic role in postmenopausal bone loss and in other age-related pathological conditions. In this study, we have examined the age-related changes in the serum levels of IL-6 and the soluble receptors that modulate its biological activity--soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130)--in 220 women (from 25 to 104yr old), including 22 centenarians. Serum IL-6 rose exponentially with age (r=0.74, p<0.0001). The median level of IL-6 increased almost ten-fold with age, from 1.16pg/ml in premenopausal women to 10.27pg/ml in centenarians. Serum sIL-6R and sgp130 showed an increase until the seventh decade and a progressive decrease in older ages (r=0.39, p<0.0001 and r=0.26, p=0.008, respectively). IL-6, sIL-6R and sgp130 were significantly higher in women within 10yr of menopause as compared to premenopausal subjects (1.51 vs. 1.16pg/ml, p=0.012; 41.9 vs. 35.7ng/ml, p=0.002; and 253.4 vs. 230.7ng/ml, p=0.008, respectively). In postmenopausal women, a negative correlation was found between sIL-6R and the lumbar bone mineral density (BMD) (r=-0.28, p=0.002) even after adjusting for age and weight. Furthermore, sIL-6R levels were higher in osteoporotic compared to normal women (47.9 vs. 39.5ng/ml, p=0.001). In conclusion, our results show that the serum levels of IL-6, sIL-6R and sgp130 exhibit different patterns of age- and menopause-related changes, and that the biological activity of IL-6 may be increased with age with potential implications in the age-related diseases such as osteoporosis.

Plasma prolactin response to gonadotropin-releasing hormone during benzodiazepine treatment.

Previously we observed that prolactin (PRL) is secreted in response to gonadotropin-releasing hormone (GnRH) in normal women during the periovulatory phase of the menstrual cycle. Because sedative drugs affect the neurotransmitters involved in the regulation of PRL secretion, we investigated PRL responsiveness to GnRH in pre- and postmenopausal female subjects during prolonged treatment with benzodiazepines (six-60 months). In both pre-and postmenopausal patients who were not on benzodiazepine treatment, GnRH infusion (0.2 micrograms/min for 3 hr) was ineffective in eliciting a PRL response. In six premenopausal women treated with benzodiazepines, basal PRL concentrations were not influenced by the drug in four subjects (range 4.0-15.7 ng/ml) and were slightly elevated in two subjects (23 and 30 ng/ml). In six treated postmenopausal women, basal PRL concentrations were in the normal range (7.5-11.0 ng/ml). GnRH infusion induced a progressive increase in PRL concentrations which reached a peak at 120 min in the premenopausal subjects (mean % SEM increase: 64 +/- 30.5%) and at 60-90 min in the postmenopausal subjects (mean % increase: 110.6 +/- 34.7%). A saline infusion, performed on a separate day during benzodiazepine treatment as a control, did not influence PRL.

Serotonergic control of TSH and PRL secretion in obese men.

To evaluate whether the inhibitory control of TSH and the stimulatory control of prolactin (PRL) secretion exerted by endogenous serotonin was altered in obesity, 22 obese men and 10 normal controls were tested with TRH (200 micrograms IV bolus) in the presence (experimental test) and absence (control test) of the serotonergic agonist fenfluramine (60 mg PO 90 min before TRH). Control and experimental tests were also performed in seven male patients with subclinical hypothyroidism and were repeated in the same obese subjects after substantial weight loss. Basal TSH levels were similar in control and obese men. Normal TSH responses to TRH (peak less than or equal to 14 mU/L) were observed in all normal controls (mean peak +/- SE 9.8 +/- 0.6 mU/L). In contrast, obese men were divided into two groups: nine in whom the TRH-induced TSH rise was higher than normal (group I: mean peak = 16.5 +/- 0.5 mU/L) and 13 in whom it was normal (group II: mean peak = 10.6 +/- 0.7 mU/L). The hypothyroid men all had elevated basal and TRH-stimulated TSH levels. Basal PRL concentrations were similar in the normal controls and both groups of obese subjects. The PRL response to TRH was lower in both group I and group II obese men than in normal controls and was similar between group I and group II.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of ipriflavone--a synthetic derivative of natural isoflavones--on bone mass loss in the early years after menopause.

OBJECTIVE: We studied whether oral administration of ipriflavone, a synthetic derivative of naturally occurring isoflavones, could prevent bone loss occurring shortly after menopause. DESIGN: Fifty-six women with low vertebral bone density and with postmenopausal age less than five years were randomly allocated to receive either ipriflavone, 200 mg three times daily, or placebo. All subjects also received 1,000 mg elemental calcium daily. RESULTS: Vertebral bone density declined after two years in women taking only calcium (4.9 +/- 1.1%, SEM, p = 0.001), but it did not change in those receiving ipriflavone (-0.4 +/- 1.1%, n.s.). A significant (p = 0.010) between-treatment difference was evidenced at both year 1 and year 2. At the end of the study, urine hydroxyproline/creatinine excretion was higher in the control group than in the ipriflavone group, as compared to no difference at baseline. Five patients taking ipriflavone and five taking placebo experienced gastrointestinal discomfort or other adverse reactions, but only one and four subjects, respectively, had to discontinue the study. CONCLUSIONS: Ipriflavone prevents the rapid bone loss following early menopause. This effect is associated with a reduction of bone turnover rate.

Abnormalities of insulin and lipid metabolism in Milan hypertensive rats.

Plasma glucose, insulin, triglyceride, and cholesterol concentrations were measured in male rats of the Milan hypertensive strain (MHS) and compared to the Milan normotensive strain (MNS) of the same body weight. Both blood pressure (P less than .001) and left ventricular weight (P less than .005) were higher in rats of the MHS. Although plasma glucose concentrations were similar in both groups, mean (+/- SEM) plasma insulin concentration were significantly higher (P less than .01) in MHS as compared to MNS rats (30 +/- 4 v. 13 +/- 5 microU/mL). In addition mean (+/- SEM) plasma triglyceride concentrations were higher (P less than .01) in MHS rats (112 +/- 9 mg/dL) than in MNS rats (81 +/- 6 mg/dL), as were plasma cholesterol concentrations (114 +/- 3 v 100 +/- 2 mg/dL, P less than .001). These data demonstrate the presence of hyperinsulinemia and hypertriglyceridemia in another genetic model of rat hypertension.

Sex-related naloxone influence on growth hormone-releasing hormone-induced growth hormone secretion in normal subjects.

The effect of opiate-receptor antagonist naloxone on growth hormone (GH) release after growth hormone-releasing hormone (GHRH) 1-44 administration was investigated in ten normal men and 18 normal women during different phases of their menstrual cycle. Naloxone was infused at a rate of 1.6 mg/h in women and 1.6- and 3.2 mg/h in men, starting one hour before GHRH administration (50 micrograms iv as a bolus). On different day sessions, naloxone, GHRH, or saline were administered as controls. Naloxone infusion reduced the GHRH-induced GH release in normal women. The mean % inhibition of peak GH response was 83% during follicular phase, 46.5% during periovulatory phase, and 77.6% during luteal phase. On the contrary, in normal men, both doses of naloxone infusion were ineffective in blunting the GH response to GHRH. Our studies indicate that naloxone infusion was capable of inhibiting GH release induced by direct stimulation with GHRH in normal women, suggesting an opiate-antagonist action at the anterior pituitary level. The absence of such an effect in normal men strongly indicates a sex dependence of naloxone effects and suggests a role of the sexual steroid environment in opioid modulation of pituitary hormone secretion.