Biomedical subjects

G A Laughlin

Publications and source records attributed to G A Laughlin.

At least 19 recordsLinked to original sources

PubMed2006

Sex-specific determinants of serum adiponectin in older adults: the role of endogenous sex hormones.

OBJECTIVE: To assess the sex-specific association of adiponectin with multiple factors thought to influence its levels, with a special emphasis on endogenous sex hormones. DESIGN AND METHODS: A cross-sectional study of determinants of serum adiponectin in 873 men and 673 postmenopausal women, ages 50-92. Factors evaluated include age, body size, fat distribution, lifestyle (exercise, smoking, alcohol intake), insulin resistance, renal function and endogenous sex hormone levels (total and bioavailable testosterone and estradiol). RESULTS: Median serum adiponectin was 50% higher in women than men (P<0.001). In unadjusted analyses, adiponectin was positively related to age, alcohol intake, high-density lipoprotein (HDL) and testosterone, and negatively related to waist girth, body mass index, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), triglycerides and bioavailable estradiol in both sexes (all P<0.01). Adiponectin was positively related to blood urea nitrogen, a measure of renal function, in men only (P<0.001). Sex-specific multivariate linear regressions adjusting for HDL and triglycerides showed that only age, HOMA-IR and sex hormones independently predicted circulating adiponectin for both men and women. Higher levels of endogenous testosterone and lower bioavailable estradiol concentrations each predicted higher adiponectin; this was true for both sexes, and was not explained by differences in age, adiposity, alcohol intake, insulin resistance or lipoprotein levels. CONCLUSIONS: The association of adiponectin with the factors studied here is strikingly similar for men and women. Sex differences in circulating adiponectin levels in older adults cannot be explained by sex hormone regulation.

Adiponectin↗

PubMed2003

Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.

BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

Aged↗

PubMed2001

A comparison of palatal adaptation in acrylic resin denture bases using conventional and anchored polymerization techniques.

PURPOSE: The study investigated the effects of palatal depth and a resin anchoring system on the adaptation of denture base resin to the master cast after compression molding and heat polymerization. MATERIALS AND METHODS: Forty-eight virtually identical polymethyl methacrylate dentures were fabricated on master casts with either a deep or shallow palatal vault. One half of the master casts of each palate type were altered by the addition of anchoring holes along the posterior land area, as well as perpendicularly in the midsaggital area. Anchoring holes were made with a #8 round bur to a depth of 5 mm. Twenty-four hours after polymerization, the bases on their casts were sectioned at the posterior border and evaluated for degree of adaptation using a traveling microscope. Maladaptation at the interface of the denture base and master cast was measured at predetermined mediolateral locations. A split-plot analysis of variance (alpha = 0.05) was performed followed by a post-hoc Dunn Multiple Comparison Test. RESULTS: In general, depth of the palatal vault did not significantly influence denture palatal discrepancy (p =.0780), but the use of the anchoring system significantly reduced mean gap distances (p =.000). At lateral and midpalate locations, gap distances between the denture bases and their casts were reduced from approximately 0.3 mm to approximately 0.1 mm when the anchoring system was used. CONCLUSIONS: Mean gap distances for steep palate dentures were significantly less than shallow palate dentures at vestibule and lateral palate locations, and anchoring holes placed in an edentulous master cast along the posterior land area and at the midline significantly improved the adaptation of denture bases.

Acrylic Resins↗

PubMed2000

Cortisol circadian rhythms during the menstrual cycle and with sleep deprivation in premenstrual dysphoric disorder and normal control subjects.

BACKGROUND: In this study we extended previous work by examining whether disturbances in the circadian rhythms of cortisol during the menstrual cycle distinguish patients with premenstrual dysphoric disorder (PMDD) from normal control (NC) subjects. In addition, we tested the differential response to the effects of early and late partial sleep deprivation on cortisol rhythms. METHODS: In 15 PMDD and 15 NC subjects we measured cortisol levels every 30 min from 6:00 PM to 9:00 AM during midfollicular (MF) and late luteal (LL) menstrual cycle phases and also during a randomized crossover trial of early (sleep 3:00 AM-7:00 AM) versus late (sleep 9:00 PM-1:00 AM) partial sleep deprivation administered in two subsequent and separate luteal phases. RESULTS: In follicular versus luteal menstrual cycle phases we observed altered timing but not quantitative measures of cortisol secretion in PMDD subjects, compared with NC subjects: in the LL versus MF phase the cortisol acrophase was a mean of 1 hour earlier in NC subjects, but not in PMDD subjects. The effect of sleep deprivation on cortisol timing measures also differed for PMDD versus NC subjects: during late partial sleep deprivation (when subjects' sleep was earlier), the cortisol acrophase was almost 2 hours earlier in PMDD subjects. CONCLUSIONS: Timing rather than quantitative measures of cortisol secretion differentiated PMDD subjects from NC subjects both during the menstrual cycle and in response to early versus late sleep deprivation interventions.

Adult↗

PubMed2000

Low levels of estradiol are associated with vertebral fractures in older men, but not women: the Rancho Bernardo Study.

This longitudinal study included 288 postmenopausal women without estrogen use (median age, 72 yr) and 352 men (median age, 66 yr). All were community-dwelling, ambulatory, and Caucasian. Blood for hormone assays (total and bioavailable estradiol and testosterone, estrone, androstenedione, dihydrotestosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate) was obtained in 1984-1987, and vertebral fractures were diagnosed from lateral spine radiographs obtained in 1992-1996. At least one vertebral fracture was found in 21% of women and 8% of men. Among men, age-adjusted hormone levels differed by fracture status only for total (64.1 vs. 75.4 pmol/L, P = 0.012) and bioavailable (43.0 vs. 51.4 pmol/L, P = 0.008) estradiol. There was a graded association between higher concentrations of total and bioavailable estradiol and lower fracture prevalence (trend P<0.01 for both hormones). Men with total testosterone levels compatible with hypogonadism (<7 nmol/L) were not more likely to have vertebral fractures. In women, none of the measured sex hormones was associated with vertebral fractures. There was also no increased prevalence of fractures in women with estradiol levels below the assay sensitivity (<11 pmol/L). These data suggest that estrogen plays a critical role in the skeletal health of older men and confirm other studies showing no association of postmenopausal endogenous estrogen levels with vertebral fractures in older women.

Age Factors↗

PubMed2000

Sexual dimorphism in the influence of advanced aging on adrenal hormone levels: the Rancho Bernardo Study.

In recent years, adrenal function and aging has been the subject of intense interest. This cross-sectional study examines age and gender differences in plasma levels of cortisol, dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS), and the molar ratio of cortisol/DHEAS in 50-89-yr-old community-dwelling adults. Plasma hormone levels were assayed in samples obtained between 0730 h and 1100 h from 857 men and 735 nonestrogen-using, postmenopausal women. Hormone levels were stratified by 10-yr age groups and compared by two-factor (gender and age) ANOVA. Overall, age and BMI-adjusted DHEA and DHEAS [collectively DHEA(S)] levels were 40% lower and cortisol levels 10% higher in women than men, resulting in a 1.7-fold higher cortisol/DHEAS molar ratio for women (both, P < 0.001). Cortisol levels increased progressively (20% overall) with age in both men and women (both, P < 0.01). Although DHEA(S) levels declined 60% and the cortisol/DHEAS ratio increased 3-fold across the 40-yr age range for both men and women (all P < 0.001), the pattern of the change differed (all P < 0.01 for interaction). For men, DHEA(S) fell in a curvilinear fashion, with the degree of change decreasing with each decade. In contrast, DHEA(S) levels in women fell 40% from the 50s to 60s, were unvarying from 60-80 yr of age, and declined an additional 18% in the 80s. The cortisol/DHEAS ratio increased in a linear fashion for men, but was flat during the 60-80-yr age range for women. Despite these differences in the effect of aging, levels of DHEA(S) remained lower and cortisol and the cortisol/DHEAS ratio higher, in women than men throughout the 50-89-yr age range. These results were independent of adiposity, smoking, and alcohol consumption. In summary, among older, healthy adults DHEA(S) levels are lower and cortisol levels higher in women than men. The age-related decline in adrenal androgens persists into advanced age for both men and women, but exhibits a sexually dimorphic pattern. In contrast, cortisol levels in men and women show a parallel, linear increase with aging. These findings may have important implications for a host of age-related processes that exhibit gender differences, including brain function, bone metabolism, and cardiovascular disease.

Adrenal Cortex Hormones↗

PubMed2000

Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study.

This study examines the cross-sectional association of hysterectomy and oophorectomy status, chronological age, and years since menopause with plasma levels of total and bioavailable testosterone and estradiol, androstenedione, estrone, and sex hormone-binding globulin (SHBG) in community-dwelling postmenopausal women who were not using estrogen replacement therapy. Six hundred and eighty-four women, aged 50-89 yr, were surveyed for hysterectomy and oophorectomy status and had plasma obtained between 1984-1987. Of these, 438 (67%) had not undergone hysterectomy or oophorectomy (intact), 123 (18%) reported hysterectomy with bilateral oophorectomy, and 123 (18%) reported hysterectomy with conservation of 1 or both ovaries. After adjustment for age and body mass index, both total and bioavailable testosterone levels were reduced by more than 40% (P < 0.001) in hysterectomized women with bilateral oophorectomy compared to those in intact women, with intermediate levels observed in hysterectomized women with ovarian conservation. Androstenedione levels were about 10% lower in hysterectomized women with or without ovarian conservation compared to those in intact women (P = 0.039). Total estradiol levels tended to be lower (P = 0.095) in bilaterally oophorectomized women. Levels of bioavailable estradiol, estrone, and SHBG did not differ by hysterectomy and oophorectomy status. Among intact women, total, but not bioavailable, testosterone levels increased with age (P = 0.015), reaching premenopausal levels for the 70-79 decade with relatively stable levels thereafter. Among oophorectomized women, total and bioavailable testosterone levels did not vary with age and were 40-50% lower than those in intact women throughout the 50-89 yr age range. Androstenedione levels decreased 27% and SHBG levels increased 30% (P < 0.001) with age in intact, but not oophorectomized, women. Levels of other hormones did not vary with age. Stratification by years since menopause or surgery yielded similar results. These results demonstrate that the postmenopausal ovary remains a critical source of androgen throughout the lifespan of older women. The clinical consequences of lower testosterone levels years after oophorectomy are unknown. Reconsideration of prophylactic oophorectomy and clinical trials to evaluate the effects of androgen replacement after oophorectomy are needed.

Aged↗

PubMed1999

Sleep EEG studies during early and late partial sleep deprivation in premenstrual dysphoric disorder and normal control subjects.

In this study of 23 patients with premenstrual dysphoric disorder (PMDD) and 18 normal comparison (NC) subjects, we examined sleep EEG measures during baseline midfollicular (MF) and late luteal (LL) menstrual cycle phases and after early sleep deprivation (ESD), in which subjects slept from 03.00 to 07.00 h, and late sleep deprivation (LSD), in which subjects slept from 21.00 to 01.00 h. Each sleep deprivation night was followed by a night of recovery sleep (ESD-R, LSD-R) (sleep 22.30-06.30 h) and was administered in the late luteal phase of separate menstrual cycles. During baseline studies, sleep EEG measures differed significantly by menstrual cycle phase, but not group. Both PMDD and NC groups showed longer REM latencies and less REM sleep (minutes and percent) during the luteal compared with the follicular menstrual cycle phase. PMDD subjects, however, did not show sleep architecture changes similar to those of patients with major depressive disorders. Sleep quality was better during recovery nights of sleep in PMDD compared with NC subjects. REM sleep measures changed in association with clinical improvement in responders to sleep deprivation. Both early and late sleep deprivation may help to correct underlying circadian rhythm disturbances during sleep in PMDD, although differential sleep changes during ESD vs. LSD did not correlate with clinical response. Further sleep studies addressing additional circadian variables may serve to elucidate mechanisms mediating the therapeutic effects of sleep deprivation in PMDD.

Affect↗

PubMed1999

Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study.

OBJECTIVE: The purpose of this study was to determine whether endogenous steroid hormone levels are associated with depressed mood in community-dwelling older women. DESIGN: A cross-sectional population-based study. SETTING: Rancho Bernardo, California PARTICIPANTS: A total of 699 non-estrogen using, community-dwelling, postmenopausal women (aged 50 to 90 years) from the Rancho Bernardo cohort who were screened for depressed mood and had plasma obtained for steroid hormone assays in 1984-1987. MEASUREMENTS: Plasma levels of total and bioavailable (non-SHBG-bound) estradiol and testosterone, estrone, androstenedione, cortisol, dehydroepiandrosterone, and (DHEA) and its sulfate (DHEAS) were measured by radioimmunoassay. Mood and depression were assessed using the Beck Depression Inventory. RESULTS: Only DHEAS levels were significantly and inversely associated with depressed mood, and the association was independent of age, physical activity, and weight change (P = .0002). Age, sedentary lifestyle, and weight loss were positively associated with depressed mood. Alcohol intake, cigarette smoking, marital status, type of menopause, and season of testing were unassociated with depressed mood. A subset of 31 women with categorically defined depression had lower DHEAS levels compared with 93 age-matched nondepressed women (1.17 +/- 1.08 vs 1.57 +/- .98 micromol/L; P = .01). CONCLUSIONS: These results add to the evidence that DHEA/S is a neuroactive steroid and point to the need for careful long-term clinical trials of DHEA therapy in older women with depressed mood.

Affect↗

PubMed1998

Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea.

The development of functional hypothalamic amenorrhea (FHA) in weight-stable, nonathletic women has long been thought to be psychogenic in origin. This study was designed to gain insight into the possibility that nutritional deficits and compensatory endocrine-metabolic adaptations contribute to the development and maintenance of FHA of the psychogenic type. Nutritional intake, insulin sensitivity, and 24-h dynamics of insulin/glucose, cortisol, leptin, somatotropic, and LH axes were simultaneously assessed in eight women with FHA not associated with exercise or weight loss and in eight age- and body mass index-matched regular cycling controls (NC). The percent fat body mass was lower and lean body mass was higher in FHA than in NC (P < 0.05). The FHA subjects scored higher (P < 0.05) on two Eating Disorder Inventory subscales and had a higher (P < 0.05) Beck depression rating than NC, although all were in the subclinical range. Although daily caloric intake did not differ, FHA consumed 50% less (P < 0.001) fat, twice (P < 0.05) as much fiber, and more carbohydrate (P < 0.05) compared to NC. During the feeding phase of the day, FHA exhibited lower glucose (P < 0.05) and insulin (P < 0.01) levels than NC, and the degree of hypoinsulinemia was directly related to relative dietary fat (r = 0.73). Although 24-h mean GH levels did not differ, the pattern of GH release in FHA was distinctly altered from that in NC. GH pulse amplitude was blunted, pulse frequency was accelerated 40% (P < 0.01), and interpulse GH concentrations were elevated 2-fold (P < 0.01) throughout the day for FHA compared to NC. This distorted pattern of GH pulses was associated with a 40% decrease (P < 0.01) in GH-binding protein levels. Levels of the insulin-dependent insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) were elevated (P < 0.001) during the feeding portion of the day in FHA and were inversely related to insulin (r = -0.50) and directly related to cortisol (r = 0.64) levels for FHA and NC groups together. Although levels of IGF-I and IGFBP-3 did not differ, the elevation of IGFBP-1 levels in FHA resulted in a reduced (P < 0.01) ratio of IGF-I/IGFBP-1, which may decrease the bioactivity and hypoglycemic effect of IGF-I. Twenty-four-hour mean leptin levels and the diurnal excursion of leptin in FHA did not differ from those in NC. LH pulse frequency was slowed 50% (P < 0.001) in FHA, with unaltered pulse amplitude, resulting in 45% lower (P < 0.01) 24-h mean LH levels for FHA compared to NC. LH pulse frequency for the two groups was related positively to insulin (r = 0.80) levels and the ratio of IGF-I/IGFBP-1 (r = 0.70) and negatively with cortisol (r = -0.61) and IGFBP-1 (r = -0.72) concentrations. In summary, we found evidence of subclinical eating disorders in weight-stable, nonathletic women with FHA accompanied by a severe restriction of dietary fat intake. Unbalanced nutrient intake in psychogenic FHA was associated with multiple endocrine-metabolic alterations. Among these, reduced levels of plasma glucose and serum GHBP, a decrease in the ratio of IGF-I/IGFBP-1, accelerated GH pulse frequency, and elevated interpulse GH levels are indicative of a hypometabolic state. In addition, the magnitude of glucoregulatory responses (increased cortisol secretion and decreased insulin/IGF-I action) were directly related to the degree of suppression of GnRH/LH pulse frequency. These results are remarkably similar to those seen in highly trained athletes with FHA(1). Thus, nutritional deficits may represent a common contributing factor to the development and maintenance of multiple neuroendocrine-metabolic aberrations underlying both psychogenic and exercise-related FHA.

Adult↗

PubMed1997

Altered binding of serum thyroid hormone to thyroxine-binding globulin in women with functional hypothalamic amenorrhea.

OBJECTIVE: To further characterize hypothyroidemia with decreased serum concentrations of total triiodothyronine and total T4 in women with functional hypothalamic amenorrhea. DESIGN: Cohort study. SETTING: University of California San Diego Clinical Research Center. PATIENT(S): 8 women with functional hypothalamic amenorrhea (hypogonadotropic or normogonadotropic amenorrhea of at least 6 months duration) and 9 normal cycling women in the early follicular phase of their cycles. INTERVENTION(S): 24-hour frequent blood sampling. MAIN OUTCOME MEASURE(S): Comparison of levels of thyroid hormones and binding proteins between functional hypothalamic amenorrhea and normal cycling women. Measurements of serum free T4, free triiodothyronine, total T4, total triiodothyronine, reverse triiodothyronine, thyroid-binding globulin, albumin, and prealbumin levels and determination of T4 binding and binding affinity to each of the three binding proteins. RESULT(S): The results confirmed reduced levels of total triiodothyronine and total T4, but revealed no significant difference in free triiodothyronine and free T4, as well as reverse triiodothyronine, levels between functional hypothalamic amenorrhea and normal cycling women. Although serum levels of thyroid hormone-binding proteins were similar between normal cycling women and functional hypothalamic amenorrhea, a significant decrease in T4 bound to thyroid-binding globulin along with a decrease in apparent affinity of thyroid-binding globulin for T4 was present in functional hypothalamic amenorrhea. No differences in prealbumin- or albumin-T4 interactions were found. CONCLUSION(S): In functional hypothalamic amenorrhea, a reduced thyroid-binding globulin binding affinity appears to explain the disparity between normal levels of free triiodothyronine, free T4, and binding proteins in the face of reduced levels of total triiodothyronine and total T4.

Adult↗

PubMed1997

Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea.

The possibility that chronic nutritional deficiency alters leptin regulation and its link to reproductive function was investigated by determining serum leptin levels during a 24-h period with controlled nutrient intake in highly trained athletes with and without menstrual cyclicity and in BMI-matched cycling sedentary controls (n = 8 per group). Our data show that 24th leptin levels were reduced equally (3-fold, P < 0.001) in both cyclic and amenorrheic athletes as compared to controls. Low leptin levels in the athletic groups were consistent with their reduction in body fat (r = 0.91, P < 0.0001) relative to BMI, but were also influenced by the presence of low insulin (r = 0.70, P < 0.001) and elevated cortisol (r = -0.65, P < 0.001) levels. A diurnal pattern of 24h leptin levels, with an approximate 50% rise (P < 0.001) from nadir (0900h) to peak (0100h), was present in normally cycling athletes and controls and was strikingly absent in amenorrheic athletes. The absolute increase in leptin levels from nadir to peak was directly related to insulin excursions in response to meals (r = 0.60, P = .002) and inversely related to the amplitude of the 24h cortisol rhythm (r = -0.70, P = .0002). These findings are consistent with a link between the functionality of adipocytes, nutritional status, and integrity of the reproductive axis in humans.

Adipose Tissue↗

PubMed1997

Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity.

In recent years, there has been uncertainty concerning the association of inappropriate gonadotropin secretion (high LH and normal FSH) and the polycystic ovary syndrome (PCOS). In the present study, we ascertained the influence of body composition on LH pulsatile parameters in 33 PCOS and 32 normal cycling (NC) women across a wide range of body mass index (BMI, 19-42 kg/m2). Twenty four-hour pulsatile parameters for serum LH (10-min sampling) and pituitary gonadotropin responses to i.v. bolus GnRH (10 micrograms) were evaluated. Fasting (0800 h) FSH and steroid hormone concentrations and 24-h mean insulin levels were determined. Insulin sensitivity (SI) was assessed by rapid i.v. glucose tolerance test in a subset of 28 PCOS and 29 NC subjects. Our results showed that BMI, an indicator of relative adiposity, had a significant negative impact on 24-h mean LH pulse amplitude (r = -0.63, P < 0.001) and the peak increment of LH in response to GnRH stimulation (r = -0.41; P = 0.02) for PCOS but not NC women. In contrast, 24-h LH pulse frequency was uniformly increased (40%) in PCOS as compared with NC women independent of BMI. In PCOS women, the blunting of pulse amplitude with increasing BMI resulted in a decline in 24-h mean LH levels (r = -0.63, P < 0.001) and the ratio of LH/FSH (r = -0.44, P = 0.02) not seen in NC. With BMI < 30 kg/m2, 24-h mean LH values for PCOS women were greater than the normal range for NC in 95% (18/19) of cases, whereas 24-h LH levels failed to discriminate PCOS from NC women in 43% (6/14) of obese (BMI > 30 kg/m2) PCOS women. Thus, the diagnostic value of LH determinations is retained for PCOS women with BMI < 30 kg/m2. For screening purposes, the mean of two LH values in samples collected at 30-min intervals was found to have a discriminatory power equal to that of the 24-h mean. These findings suggest that 1) BMI negatively influences LH pulse amplitude in PCOS women principally by an effect at the pituitary level; 2) accelerated LH pulse frequency in PCOS women is not influenced by BMI and represents a basic component of hypothalamic dysfunction in PCOS women; and 3) BMI does not influence gonadotropin secretion in normal cycling women. Thus assessments of basal LH levels and the LH/FSH ratio in hyperandrogenic anovulatory women are clinically meaningful when BMI is taken into account. Investigations to define the factor(s) that link adiposity and the attenuation of LH pulse amplitude in PCOS women would add further understanding of this complex neuroendocrine-metabolic disorder.

17-alpha-Hydroxyprogesterone↗

PubMed1997

Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women.

Attenuation of the GH and insulin-like growth factor I (IGF-I) axis in aging may be responsible for changes in body composition and metabolism. This relationship has been confirmed by studies of recombinant human GH replacement in aging men and women, but the adverse effects encountered limit its clinical utility. The use of GHRH or its analogs may be an alternative mode for restoring the GH-IGF-I axis in aging individuals. Here we report the endocrine-metabolic changes in response to a GHRH analog in age-advanced men and women. A single blind, randomized, placebo-controlled trial of 5 months duration was conducted. Ten women and 9 men between the ages of 55-71 yr self-injected placebo (saline) s.c. nightly for 4 weeks followed by 16 weeks of [Nle27]GHRH-(1-29)-NH2 at a dose of 10 microg/kg. Subjects underwent 12-h nocturnal (2000-0800 h) frequent blood sampling (10-min intervals) and 24-h urine collection at baseline, after 4 weeks of placebo injections, and after 16 weeks of GHRH analog administration. GH responses to GHRH analog and spontaneous GH pulsatility were assessed. Subjects were also monitored 2, 4, 8, and 12 weeks after commencement of GHRH analog treatment. Blood pressure, body weight, and fasting insulin and glucose levels were recorded at each visit. Serum concentrations of IGF-I, IGF binding protein-1 (IGFBP-1), IGFBP-3, GH-binding protein (GHBP), lipids, and safety laboratory tests (complete blood count and chemistry profile) were measured in fasting samples (0800-0900 h). Body composition was determined by dual energy x-ray absorptiometry scan, and skin thickness was measured at four sites, including the right and left hand and volar forearm, by Harpenden skin calipers. Insulin sensitivity was assessed by a frequently sampled i.v. glucose tolerance test. Quality of life parameters, including sleep, were evaluated through self-administered questionnaires. Nightly GHRH analog administration at 2100 h induced, within 10 min, an acute release of GH, which lasted for 2 h. The GH-releasing effect of GHRH analog was sustained during the course of the study. Compared with placebo, GHRH analog induced a significant increase in 12-h integrated nocturnal GH levels in women (P < 0.01) and men (P < 0.05). This was accompanied, within 2 weeks, by increased serum levels of IGF-I (P < 0.05) and IGFBP-3 (P < 0.001), but not IGFBP-1, which remained elevated for 12 weeks, returning toward baseline by 16 weeks in both genders. Within 4 weeks, GHBP concentrations were significantly increased (P < 0.01) in women, but not in men. Although blood pressure and body weight were unaffected, GHRH analog treatment resulted in a significant increase in skin thickness (P < 0.05) in both genders and increased lean body mass in men only (P < 0.05), with no other changes in body composition or bone mineral density in either gender. There was a trend for a positive nitrogen balance in both genders, which became significant (P = 0.03) when the data were combined. Fasting insulin and glucose levels were unaltered, but a significant increase in insulin sensitivity occurred in men (P < 0.05), but not in women. Assessment of quality of life parameters revealed a significant improvement in general well-being (P < 0.05) and libido (P < 0.01) in men, but not in women, and sleep quality was unaffected in both genders. The only adverse side-effect was transient hyperlipidemia, which resolved by the end of the study. We conclude that nightly administration of GHRH analog for 4 months in age-advanced men and women activated the somatotropic axis. Although an increase in skin thickness was found in both genders, increases in lean body mass, insulin sensitivity, general well-being, and libido occurred in men but not in women. These observations suggest that GHRH analog administration induced anabolic effects favoring men more than women. Further studies are needed to define the gender differences observed in response to GHRH analog administration.

Aged↗

PubMed1997

Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia.

Polycystic ovary syndrome (PCOS) is associated with chronic anovulation, hyperandrogenemia, insulin resistance (IR)/hyperinsulinemia, and a high incidence of obesity. Thus, PCOS serves as a useful model to assess the role of IR and chronic endogenous insulin excess on leptin levels. Thirty-three PCOS and 32 normally cycling (NC) women of similar body mass index (BMI) were studied. Insulin sensitivity (S(I)) was assessed by rapid ivGTT in a subset of 28 PCOS and 29 NC subjects; percent body fat was determined by dual-energy x-ray absorptiometry (DEXA) in 14 PCOS and 17 NC. Fasting (0800 h) and 24-h mean hourly insulin levels were 2-fold higher (P < 0.0001), and S(I) was 50% lower (P = 0.005) in PCOS than in NC, while serum androstenedione (A), testosterone (T), 17-alpha hydroxyprogesterone (17OHP), and estrone (E1) levels were elevated (P < 0.0001), and sex hormone-binding globulin (SHBG) levels were decreased (P < 0.01). Twenty-four hour LH pulse frequency, mean pulse amplitude, and mean LH levels were elevated in PCOS (P < 0.001) as compared with NC. Serum leptin levels for PCOS (24.1 +/- 2.6 ng/mL) did not differ from NC (21.5 +/- 3.5 ng/mL) and were positively correlated with BMI (r = 0.81) and percent body fat (r = 0.91) for the two groups (both P < 0.0001). Leptin levels for PCOS and NC correlated positively with fasting and 24-h mean insulin levels (r = 0.81, P < 0.0001 for both PCOS and NC) and negatively with S(I) and SHBG levels. Leptin concentrations for PCOS, but not NC, correlated positively with 24-h mean glucose levels and inversely with 24-h mean LH levels and 24-h mean LH pulse amplitude. Leptin levels were not correlated with estrogen or androgen levels for either PCOS or NC, although leptin levels were positively related to the ratios of E1/SHBG and E2/SHBG for both PCOS and NC and to the ratio of T/SHBG for PCOS only. In stepwise multivariate regression with forward selection, only 24-h mean insulin levels contributed significantly (P < 0.01) to leptin levels independent of BMI and percent body fat for both PCOS and NC. Given this relationship and the presence of 2-fold higher 24-h mean insulin levels in PCOS, the expected elevation of leptin levels in PCOS was not found. This paradox may be explained by the presence of adipocyte IR specific to PCOS, which may negate the stimulatory impact of hyperinsulinemia on leptin secretion, a proposition requiring further study.

Adipose Tissue↗

PubMed1996

Modification of circadian body temperature rhythm during the luteal menstrual phase: role of melatonin.

In women during early follicular phase (FP), the rise of melatonin at night accounts for 40% of the nocturnal core body temperature (Tc) decline. In seven normal-cycling women, the circadian rhythms of Tc and melatonin of the FP were compared with those of the luteal phase (LP). In addition, in both phases the Tc response to daytime melatonin administration was investigated. Melatonin levels were comparable during the two menstrual phases, but the nocturnal melatonin onset was delayed by 90 min in the LP (P < 0.01). This was accompanied by a delay of the nadir of the Tc circadian rhythm (P < 0.002), a 0.3 degrees C elevation (P < 0.005) of the mean 24-h value, and a 40% blunting (P < 0.002) of the amplitude. This attenuation of circadian Tc in LP women was replicated in two estrogen-treated hypogonadal women by the administration of medroxyprogesterone acetate. The daytime administration of melatonin (2.5 mg) decreased Tc during the FP (P < 0.01) but was ineffective in the LP. Present data indicate that in LP, in association with high progesterone levels, an attenuated and phase-delayed circadian Tc rhythm may, in part, be due to a reduced effect of melatonin.

Adult↗

PubMed1996

Nutritional and endocrine-metabolic aberrations in amenorrheic athletes.

Growing evidence suggests that menstrual disturbances in female athletes are related to the metabolic cost of high levels of energy expenditure without compensatory increases in dietary intake. However, the linkage(s) between nutritional deficits and reproductive impairments as a result of slowing of LH pulsatility has not been defined. This study was directed to simultaneously characterize nutritional intake, insulin sensitivity (by rapid iv glucose tolerance test), and 24-h dynamics of insulin/glucose, cortisol, somatotropic [GH/GH-binding protein (GHBP)/insulin-like growth factor I (IGF-I)/IGF-binding proteins (IGFBPs)], and LH axes in highly trained athletes with (cycling athletes; CA) and without (amenorrheic athletes; AA) menstrual cyclicity and in age- and body mass index-matched cycling sedentary controls (CS; n = 8/group). Although daily caloric intake did not differ among the three groups, athletes (CA and AA) consumed less fat and protein than CS. However, the restriction of fat was 50% greater (P < 0.01) in AA than CA and was accompanied by increased carbohydrate (P < 0.05) and fiber (P < 0.01) intake. Athletes, independent of menstrual status, had increased (P < 0.05) insulin sensitivity and reduced insulin levels during the feeding phase of the day. Hypoinsulinemia was more pronounced in AA (P < 0.05) than CA, extending throughout the day, and was accompanied by reduced glucose increments in response to meals (P < 0.05), not seen in CA. Levels of the insulin-dependent IGFBP-1 were markedly elevated (P < 0.001) throughout the diurnal pattern in AA, whereas in CA, a modest elevation (P < 0.001) of IGFBP-1 levels occurred only during the feeding portion of the day. IGFBP-1 levels for the three groups related inversely to 24-h insulin (r = -0.63) and directly to 24-h cortisol (r = 0.69) levels. A 70-80% augmentation (P < 0.001) of 24-h mean GH levels was seen in both groups of athletes, but with distinct pulsatile features. Although pulse amplitude was increased 60% in CA with no change in pulse number, AA displayed more frequent (P < 0.001) pulses, with an elevated (P < 0.01) baseline between pulses. The distorted pattern of GH pulses seen in AA was associated with a 35% decrease in GHBP levels, not seen in CA. Although levels of IGF-I and IGFBP-3 did not differ in either CA or AA, the 2- to 4-fold higher levels of IGFBP-1 in AA than in CA and CS resulted in a 3-fold reduced ratio of IGF-I/IGFBP-1 in AA, which may decrease the bioactivity and hypoglycemic effect of IGF-I. LH pulse frequency was progressively attenuated in the athletes, with a greater (P < 0.001) slowing in AA than CA, unaccompanied by alterations in pulse amplitude or 24-h levels. LH pulse frequency was related positively with insulin (r = 0.65) levels and the ratio of IGF-I/IGFBP-1 (r = 0.69), and negatively with cortisol (r = -0.70) and IGFBP-1 (r = -0.75) concentrations. Stepwise regression analysis suggested that negative influences associated with hypercortisolemia and elevated IGFBP-1 levels predominate in determining GnRH/LH pulsatile activity in these athletes. In sum, although neuroendocrine-metabolic adaptations to the energy cost of exercise training were evident in both groups of athletes, AA displayed alterations distinct from their cycling counterparts, with evidence of a hypometabolic state, including decreased basal body temperature and reduced levels of plasma glucose and serum GHBP, a decrease in the ratio of IGF-I/IGFBP-1, accelerated GH pulse frequency, and elevated interpulse GH levels. Thus, in AA, increased insulin sensitivity, decreased circulating insulin, and a reduced hypoglycemic effect of IGF-I together with elevated GH and cortisol concentrations may comprise a cascade of glucoregulatory adaptations to repartition metabolic fuels for conservation of protein. (ABSTRACT TRUNCATED)

Adolescent↗

PubMed1996

Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features.

The basic tenet of this investigation was that obesity is not a prerequisite in the development of polycystic ovary syndrome (PCOS), as indicated by the fact that 50% of PCOS women are not obese. Further, obesity itself is a disease entity with the common manifestation of insulin resistance/hyperinsulinemia with PCOS. Given recent evidence that insulin and GH may have gonadotropin-augmenting effects, we have determined the common and distinguishing features of neuroendocrine-metabolic dysfunctions of lean [body mass index (BMI), < 23 kg/m2] and obese (BMI, > 30 kg/m2) women with the classical form of PCOS. Insulin sensitivity, as determined by rapid i.v. glucose tolerance testing; 24-h dynamics of insulin/glucose levels, somatotropic [GH/GH-binding protein/insulin-like growth factor I (IGF-I)/IGF-binding proteins (IGFBP)], and LH axes; and their downstream effects on ovarian steroids were simultaneously assessed in eight lean PCOS and eight obese PCOS patients and an equal number of BMI-matched normal cycling controls. Our results show that insulin sensitivity was reduced 50% (P < 0.01) in lean PCOS from that in lean controls. There was a further decrease in obese controls (P < 0.01) and a 2-fold greater reduction (P < 0.001) in obese PCOS than in obese controls, suggesting that insulin resistance (IR) is a common lesion in PCOS, and that obesity contributes an additional component to IR in obese PCOS. Consistent with the degree of IR, the manifestation of compensatory hyperinsulinemia in lean PCOS was incipient, being evident only in response to meals (P < 0.05), and became overt during the 24-h fasting/feeding phases of the day in obese control (P < 0.001) with a 2- to 3-fold greater elevation (P < 0.001) in obese PCOS. An enhanced early insulin response to glucose occurs equally in obese control (P < 0.01) and obese PCOS (P < 0.05), but not in their lean counterparts. Considering the more profound IR and the associated hyperglycemia in obese PCOS, the magnitude of the early insulin release is inadequate, suggesting that beta-cell dysfunction exists in obese PCOS. Remarkable differences in the somatotropic axis were also observed; although 24-h GH pulse frequency and levels of IGF-I and IGFBP-3 were unaltered by either PCOS or obesity, the 24-h mean GH pulse amplitude was increased by 30% (P < 0.01) in lean PCOS in the presence of normal levels of high affinity GHBP and normal GH response to GHRH. In distinct contrast, the somatotropic axis in both obese control and obese PCOS was profoundly modified, with attenuation of GH pulse amplitude (P < 0.001) and GH response to GHRH (P < 0.001), resulting in a state of hyposomatotropinism with a more than 50% reduction (P < 0.001) of 24-h mean GH levels. In addition, GHBP levels were elevated 2-fold and were correlated inversely with GH (r = -0.81) and positively with insulin (r = 0.75) concentrations. IGFBP-I levels were suppressed in both obese groups, with a 4-fold greater reduction in obese PCOS than that in obese controls. Thus, the downstream effects of hyperinsulinemia on the somatotropic axis may include up-regulation of hepatic production of GHBP, suppression of IGFBP-1 (r = 0.82) and sex hormone-binding globulin (r = -0.69) levels, and a more than 3-fold increase in ratios of IGF-I/IGFBP-1 and estradiol-testosterone/sex hormone-binding globulin, thereby increasing their bioavailabilities. In contrast, LH pulsatility was unaffected by obesity alone. An accelerated LH pulse frequency was evident in both lean and obese PCOS (P < 0.001), whereas the mean 24-h LH pulse amplitude was increased in lean (P < 0.001), but not obese, PCOS patients. These events resulted in a 3-fold increase in 24-h mean LH levels in lean PCOS and a 2-fold increase in obese PCOS. Thus, increased LH pulse frequency and augmented LH response to GnRH are characteristic of PCOS, independent of obesity, and the presence of obesity in PCOS is associated with an attenuated LH pulse amplitude, not accounted f

Adolescent↗