Growth hormone, IGF-I, gonadal steroids, and aging.
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Aging↗
Biomedical subjects
M R Blackman
Publications and source records attributed to M R Blackman.
Age-related changes in the mechanisms of LHRH-stimulated LH release from pituitary cells in vitro.
In vitro release of LH in response to LHRH, phorbol myristate acetate (PMA), the ionophore A23187, and nifedipine was evaluated in primary cultures of anterior pituitary cells from intact mature (6 to 7 month) and old (23 to 24 month) male Wistar rats. LH release from pituitary cells is reduced approximately 30% and 60% after 4 and 48 h of 10(-7) M LHRH stimulation in cells of old rats, respectively. This impairment may be secondary to a loss of LHRH receptors. LHRH-stimulated LH release from cells of mature rats was inhibited 70% by the voltage-gated calcium channel blocker, nifedipine (10(-6) M), whereas LHRH-stimulated LH release from cells of old rats was too low to detect the effects of this drug. Age changes can be partially reversed by A23187 and PMA during 4 h, but not 48 hrs of stimulation. It therefore appears that short- and long-term (4 h and 48 h, respectively) stimulation of LH release may proceed through separate mechanisms that are differentially affected by aging.
Aging↗
Serum IGF-binding protein-3 is related to IGF-I, but not to spontaneous GH release, in healthy old men.
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Adult↗
Glucose tolerance in women: the effects of age, body composition, and sex hormones.
OBJECTIVE: To determine the separate and interactive effects of age, phase of the menstrual cycle, menopausal hormone status, body fat mass, and regional fat distribution on glucose tolerance in healthy women. DESIGN: Retrospective study. SETTING: The Baltimore Longitudinal Study of Aging. PATIENTS: Two hundred sixty healthy women aged 22-89 years. MEASUREMENTS: Plasma levels of estradiol and progesterone, body mass index (BMI), waist-to-hip ratio (WHR), and plasma glucose values in the fasting state (FPG) as well as 120 minutes after 40 gm/m2 of oral glucose (G120) were measured for each participant. RESULTS: We found a progressive decline in oral glucose tolerance of 0.4 mM (6.7 mg/dL)/decade at G120) in women from early to late adult years, with no relationship to phase of the menstrual cycle and no abrupt change associated with the menopause. Multiple regression analysis revealed significant, independent effects of BMI and WHR on FPG and G120. The influence of age (P less than 0.01) on G120 was stronger than that of the BMI or WHR (P less than 0.05). There was no significant relationship between the levels of endogenous sex hormones and glucose tolerance after adjustments for age, BMI, and WHR. However, women taking oral contraceptives, but not those receiving postmenopausal replacement therapy, did exhibit mildly elevated G120 values. CONCLUSIONS: Age per se, and to a lesser extent BMI and WHR, but not levels of endogenous sex steroids, contribute to the physiological decline in glucose tolerance in older women.
Activities of Daily Living↗
Central hypothyroidism is associated with advanced age in male Fischer 344/N rats: in vivo and in vitro studies.
We investigated age-related alterations in hypothalamic-pituitary-thyroid function in a series of in vivo and in vitro studies in 2-, 8-, 18-, and 24-month-old male Fischer 344/N (F344/N) rats. Thyroid histology showed progressive follicular loss with advancing age; this was associated with significant and progressive decrements in plasma levels of free T4 and free T3, but not immunoreactive TSH, which remained unchanged with age. This was accompanied by a progressive age-dependent loss in in vivo responsivity of the thyrotroph to synthetic TRH and a paradoxically augmented response of GH to this peptide in the oldest rats. Steady state levels of prepro-TRH mRNA in the hypothalamic paraventricular nucleus were decreased with age, whereas TRH content in and in vitro secretion by whole hypothalami remained unchanged. Both anterior pituitary steady state TSH beta-subunit mRNA levels and TSH content were decreased with age. Taken together, these data suggest that aging in male F344/N rats is associated with a progressive, centrally mediated decrease in thyroid function. The relative contributions to this phenomenon of age-related alterations in supra-hypothalamic and/or hypothalamic vs. pituitary thyrotropic function remain to be determined, as do the relationships between changes in hypothalamic-pituitary-thyroid function and those in aging per se.
Aging↗
Growth hormone (GH)-releasing hormone-(1-29) twice daily reverses the decreased GH and insulin-like growth factor-I levels in old men.
Aging is associated with decreased GH and insulin-like growth factor-I (IGF-I) levels and lean body mass, and increased body fat. Recombinant human GH treatment of old men partially reverses body composition changes. Administration of GH-releasing hormone (GHRH) to GH-deficient children and young adults increases GH and IGF-I levels while preserving physiological GH release. We investigated whether GHRH injections restore GH and IGF-I levels in old men to the levels in young men. Healthy young (n = 9; 26.2 +/- 4.1 yr; mean +/- SD) and old (n = 10; 68.0 +/- 6.2 yr) nonobese men underwent baseline blood sampling for measurements of IGF-I and 24-h profiles of GH release, followed by iv bolus GHRH stimulation tests. Old men then took, randomly, both low (0.5 mg) and high (1 mg) dose GHRH-(1-29) sc injections twice daily for 14 days, with an intervening 14-day nontreatment period. The study protocol was repeated on day 14 of each treatment. At baseline, the mean peak duration of spontaneous GH release (P less than 0.005) and IGF-I levels (P less than 0.0001) were lower in the old men. GHRH treatment evoked dose-related increases in all parameters, with significant differences (vs. old basal values) in mean 24-h GH (P less than 0.001), area under peaks (P less than 0.001), peak amplitude (P less than 0.05), and IGF-I (P less than 0.005) only at the high dose. After high dose treatment, there were no significant differences in these parameters between age groups. Peak and integrated responses to iv GHRH stimulation tests did not differ between young and old men either before or during GHRH treatment. Baseline serum levels of both testosterone (P less than 0.01) and phosphate (P less than 0.05) were lower in the older men. Phosphate levels increased (P less than 0.05) during GHRH treatment. GHRH treatment did not affect fasting glucose, urinary C-peptide, blood pressure, or chemistry and hematology profiles. Thus, short term sc administration of GHRH to healthy old men reverses age-related decreases in GH and IGF-I, suggesting that prolonged treatment could improve age-related alterations in body composition.
Adipose Tissue↗
Transdermal estradiol with oral progestin: biological and clinical effects in younger and older postmenopausal women.
The purpose of this study was to compare the biochemical and clinical effects of transdermal estrogen replacement therapy (tERT) in younger and older postmenopausal women. We treated 15 younger (less than 60 y) and 13 older (greater than or equal to 60 y) healthy postmenopausal women (45-72 y) with four successive 8-week regimens of tERT at doses of 0 to 150 micrograms/day, combined with cyclic oral medroxyprogesterone acetate (MPA). In both age groups, there were similar (p = .0001) dose-responsive increases in plasma estrogen levels and decreases in LH and FSH levels, although LH values were lower in older women both before and after tERT (p less than .02). The addition of MPA further suppressed LH and, to a lesser extent, FSH in both younger and older women. The ratio of estrogenized to nonestrogenized vaginal cells increased with tERT (p less than .007) in both age groups, but significant symptomatic improvement of vaginal irritation was noted only at the highest tERT dose. Adverse effects unrelated to age included short-term nausea in 4/28 women, and skin irritation at the patch sites in 20/28 women. Vaginal bleeding was of shorter duration, but breast tenderness was more common in older women. Further studies of long-term tERT effects in elderly women are indicated.
Administration, Cutaneous↗
Effects of progestin-opposed transdermal estrogen administration on growth hormone and insulin-like growth factor-I in postmenopausal women of different ages.
Prior studies in women have shown a positive correlation of endogenous estrogen levels with spontaneous and stimulated GH secretion and basal insulin-like growth factor-I (IGF-I) levels. In postmenopausal women, estrogen replacement therapy (ERT) by the oral route increases basal and GHRH-stimulated GH secretion but decreases basal IGF-I levels. To assess the corresponding effects of transdermal ERT (tERT) on this axis, we administered four 8-week regimens of transdermal 17 beta-estradiol (Estraderm; 0, 50, 100, or 150 micrograms/day) combined with oral medroxyprogesterone acetate (10 mg each day) during weeks 3-4 and 7-8 of each 8-week regimen (except placebo) to 28 healthy nonobese postmenopausal women, aged 45.3-71.8 yr. Basal levels of estradiol (E2), GH, and IGF-I as well as GH responsivity to bolus iv administration of GH-releasing hormone-(1-44) (1 micrograms/kg), were measured before tERT and at weeks 6 and 8 of each regimen; estrone (E1) levels were measured before tERT and at week 6 of each regimen. Before tERT, age was inversely correlated with both the peak GH response to GHRH (r = -0.43; P less than 0.02) and basal IGF-I levels (r = -0.37; P less than 0.05), but not with basal E2, E1, or GH levels. There were progressive increases in plasma E2 and E1 levels with increasing doses of tERT (P = 0.0001), independent of age (P greater than 0.2) and body mass index (P greater than 0.2). Mean basal GH and IGF-I levels were not altered significantly by tERT or medroxyprogesterone acetate. Peak and integrated GH secretory responses to exogenous GHRH decreased with increasing tERT dose (P less than 0.01) in both younger and older postmenopausal women. Our findings suggest that the known effects of tERT on bone and other tissues are not mediated via increases in circulating levels of immunoreactive GH or IGF-I, but do not preclude the possibility of tERT-induced increases in the biological activity or paracrine action of IGF-I.
Aged↗
Spontaneous and glucocorticoid-inhibited adrenocorticotropic hormone and cortisol secretion are similar in healthy young and old men.
We investigated the effects of age on pituitary-adrenocortical function in healthy young (21-38 yr, n = 11) vs. old (66-78 yr, n = 11) men by drawing frequent serial basal blood samples from 2000-0800 h for measurement of ACTH and cortisol, followed by an iv ovine CRH (oCRH) stimulation test. Subjects were readmitted at intervals and given increasing doses of oral dexamethasone (0.15, 0.3, 0.6, 1 mg) at midnight, followed by repeat blood sampling from 0400-0800 h and oCRH testing. We compared mean hormone levels for the entire 12-h and three component 4-h periods of the basal visit, and for each 4-h dexamethasone visit using the Mann-Whitney U test and repeated measures analysis of variance. Pulsatile secretion was characterized using the Pulsar computer program. Basal mean 12-h and 4-h ACTH and cortisol values did not differ with age (P greater than 0.1). Pulse analysis revealed no age change in the corresponding values for peak frequency, amplitude, or duration for either hormone examined. Increasing doses of dexamethasone produced progressive inhibition of mean ACTH and cortisol levels (P less than 0.001) as well as decreased (P less than 0.01) pulse frequency, amplitude, and duration with no age differences (P greater than 0.1). ACTH and cortisol responses to oCRH were progressively suppressed by increasing doses of dexamethasone (P less than 0.02) and did not differ between age groups (P greater than 0.3) except for a slightly higher peak cortisol response (P = 0.05) in the older men at the 0.3 mg dexamethasone dose. We conclude that basal and oCRH-stimulated ACTH and cortisol secretion, as well as sensitivity of the ACTH-cortisol axis to glucocorticoid feedback suppression, are essentially unaltered with age in healthy men.
Adrenocorticotropic Hormone↗
Thyroid hormone elevations during acute psychiatric illness: relationship to severity and distinction from hyperthyroidism.
Acute psychiatric illness may be accompanied by transient hyperthyroxinemia. The mechanism of this phenomenon was examined by determining the role of thyrotropin (TSH) in the genesis of this state. Serial measurements of TSH, thyroxine (T4), free T4 index (FT4I), triiodothyronine (T3), and free T3 index (FT3I) were performed in 45 acutely hospitalized patients with major psychiatric disorders. Twenty-two (49%) patients exhibited significant elevations (greater than or equal to 2 SD above mean value of controls) of one or more thyroid hormone (or index) levels. Among depressed patients with elevated FT4I, TSH was higher (p less than .05) on the day of the peak FT4I than on the day of the FT4I nadir. There were significant positive correlations between psychiatric symptom severity and levels of FT4I among both depressed (p less than .01) and schizophrenic (p less than .025) patients. These data show that elevations of T4, FT4I, T3, and FT3I are common among psychiatric inpatients, especially early in their hospitalization, and that levels of thyroid hormones are correlated with severity of psychiatric symptomatology. TSH is higher early in the acute phase of illness and is not suppressed in the face of elevated thyroid hormone levels, a finding that distinguishes this phenomenon from ordinary hyperthyroidism. Elevations of peripheral thyroid hormone levels, particularly among depressed patients, may result from a centrally-mediated hypersecretion of TSH.
Adult↗
Discordant effects of aging on prolactin and luteinizing hormone-beta messenger ribonucleic acid levels in the female rat.
To examine the molecular genetic basis for the age-related increase in PRL secretion and decrease in LH production in the rat, we measured steady state levels of PRL and LH beta mRNA in pituitary homogenates and cell lysates from monolayer adenohypophyseal cultures. These mRNA levels were compared with the corresponding levels of immunoreactive PRL and LH in sera and culture media. Paired groups (n = 4-10/group) of intact and 4-week ovariectomized mature (6-7 months old) and old (23-25 months old) female Wistar rats were studied. Serum PRL levels were 550% higher in intact old vs. mature rats (P less than 0.001), whereas the corresponding pituitary homogenate levels of PRL mRNA were similar (P greater than 0.4). Medium PRL concentrations were 230% greater (P less than 0.006) whereas cell lysate concentrations of PRL mRNA were unaltered (P greater than 0.2) in monolayer cultures from intact old vs. mature rats. Serum PRL levels were 650% higher (P less than 0.003) and pituitary homogenate PRL mRNA levels were slightly increased (P less than 0.04) in ovariectomized old vs. mature rats. Neither serum LH values (P greater than 0.07) nor pituitary homogenate LH beta mRNA levels (P greater than 0.1) differed in intact old and mature rats, whereas the corresponding medium concentrations of LH were reduced (P less than 0.001). Ovariectomized old vs. mature rats exhibited reductions in serum (P less than 0.02) and medium (P less than 0.001) LH concentrations, as well as in pituitary homogenate (P less than 0.002) and cell lysate (P less than 0.006) LH beta mRNA levels. Thus, these data revealed coordinate decreases with age in LH beta mRNA and LH secretion, particularly in ovariectomized rats, suggesting an age-related alteration at or before LH beta gene transcription. These findings parallel observations on other genes whose products change with age. In contrast, the observation that the increased secretion of PRL in old rats is accompanied by little or no increase in PRL mRNA is novel and suggests that age-related alterations in PRL gene expression proceed through a posttranscriptional mechanism.
Aging↗
Reproductive hormones in aging men. III: Basal and LHRH-stimulated serum concentrations of the common alpha-subunit of the glycoprotein hormones.
In a previous study, we described unaltered basal serum levels of sex steroids, increased basal luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and diminished and/or delayed gonadotropin responses to exogenous luteinizing hormone releasing hormone (LHRH) in 69 healthy men, aged 25 to 89 years, in the Baltimore Longitudinal Study of Aging. Here we report basal and LHRH-stimulated serum concentrations of the common alpha-subunit of the glycoprotein hormones in 53 of these same men, divided into groups: A, 25 to 49 years, (n = 22); B, 50 to 69 years, (n = 18); and C, 70 to 89 years, (n = 13). There were no significant (p greater than .2) age-related alterations in basal serum concentrations of the alpha-subunit. Using repeated measures analysis of variance (ANOVA), we found a significant difference between basal levels and peak responses to LHRH for alpha-subunit in each group (p less than .001); however, age per se did not influence the magnitude of this response (p greater than .1). Frequency distribution analysis of the time of the peak alpha-subunit response across age groups demonstrated a significant age-related delay in the timing of the peak alpha response (p less than .03). These data, in conjunction with our prior observations, suggest that in healthy men there may be age-related alterations in the secretion and/or metabolic clearance of pituitary gonadotropins and their component subunits.
Adult↗
Decreased in vitro secretion of LH, FSH, and free alpha-subunits by pituitary cells from old male rats.
Various in vivo and in vitro pituitary-Leydig cell functions were examined in mature (5-8 mo) vs. old (22-25 mo) male Wistar rats. Old rats exhibited decreased serum concentrations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) (P less than 0.0025) but similar levels of prolactin (P less than 0.01) both before and 4 wk after castration. The in vitro release of LH, FSH, and free alpha-subunits was measured in primary cultures of dispersed anterior pituitary cells from both intact and castrated rats. During 48 h of incubation, basal secretion rates of the glycoproteins were decreased (P less than 0.001) from cells of both intact and castrated old rats. After stimulation with LH-releasing hormone (LRH) in single (10(-8) M) or multiple (10(-10) - 10(-7) M) doses, the total amounts of the glycoproteins secreted were also less from cells of both intact and castrated old rats. However, repeated measures analysis of variance revealed age-related hyporesponsivity to LRH stimulation only for LH secretion by cells from intact rats. The basal molar ratios of alpha/(LH + FSH) secreted by cells from intact but not castrated old rats were lower than those from cells of the corresponding mature rats. Moreover, after LRH stimulation (10(-10) - 10(-7) M), molar secretory ratios of alpha/(LH + FSH) decreased from cells of intact mature rats but increased from cells of intact old rats. These in vitro data suggest that the reduced serum LH and FSH levels in intact and castrated old male rats result in part from decreased secretion of these glycoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Excess production of free alpha subunits by mouse pituitary thyrotropic tumor cells in vitro.
Primary cultures from three serially transplanted mouse pituitary thyrotropic tumors, Furth 97A, 97B, and 97C, and one newly generated tumor, NIH 101A, were shown to secrete free alpha subunits and a beta subunit (TSH-beta) in addition to intact TSH. The three glycopeptides were measured in specific, heterologous radioimmunoassays. Basal secretion of alpha subunit was found to be in excess in all four thyrotropic tumor cultures, ranging from 5.7- to 8.9-fold higher than that of intact TSH and 30- to 35-fold higher than that of free TSH-beta. In cultures from 97A, TRH (10(-7) M) stimulated the secretion of TSH, alpha subunit, and TSH-beta by 175-185% and (T4, 10(-5) M) inhibited TSH to 19%, alpha subunit to 68%, and TSH-beta to 58% of control. Secretion of TSH and its subunits in cultures from 97B was not consistently affected by TRH or T4. In cultures from 97C, TSH and alpha secretion was inhibited in a dose-dependent fashion by T3 from 2.5 x10(-9) to 1.6x10(-7) M. Gel chromatography of incubation media from tumor 97A revealed elution volumes of TSH and alpha similar to those of purified rat glycopeptides and confirmed the excess secretion of free alpha subunit. In contrast, the alpha to TSH ratios in media from cultures of pituitary cells from normal and thyroidectomized rats were 1.6 and 0.8, respectively. The total production of TSH and its subunits was measured in cultures from tumor 97A and confirmed that alpha subunit was synthesized excessively. The ratio of the plasma concentrations of alpha to TSH in tumor-bearing mice was 1.6 compared to 1.3 in thyroidectomized mice, and 0.36 in thyroidectomized rats. The alpha to TSH ratios in extracts of the corresponding thyrotropic tissues (tumor or pituitary) were 2.7, 1.7, and 0.40, respectively. These data are analogous to those reported in humans with thyrotropic and certain other pituitary tumors, and support hypothesis that the subunits of glycoprotein hormones are independently synthesized.
Animals↗
Ectopic hormones.
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Adrenocorticotropic Hormone↗
Plasma levels of estradiol, testosterone, and DHEAS do not predict risk of coronary artery disease in men.
Prior studies have reported men with coronary artery disease (CAD) to have elevated plasma levels of estrogens and reduced concentrations of dehydroepiandrosterone (DHEA) or DHEA-sulfate (DHEAS). We investigated whether gonadal steroids or DHEAS are risk factors for CAD in men, using a prospective design, in a well characterized population studied at regular intervals. We studied 46 men (Cardiac group) who developed CAD and 124 men (Control group) who remained free of CAD (mean follow-up, 9.5 years). We measured testosterone (T), estradiol (E2), and DHEAS, as well as plasma binding of T and E2, in samples stored before the onset of CAD (Cardiac group) or at matched times (Control group). Body mass index, blood pressure, and total serum cholesterol were measured at each visit. Both systolic blood pressure (SBP; P less than 0.001) and cholesterol (P less than 0.001) were increased in the Cardiac group, but no significant differences were found in total or free T or E2, the ratio of E2/T, or DHEAS between the two groups. The difference in cholesterol was significant only in men less than or equal to 65 years old (P less than 0.001), and SBP only in men greater than 65 years old (P less than 0.005). Cholesterol (P less than 0.05) and E2 (P less than 0.001) appeared to decrease with age in the Cardiac, but not the Control, group. Moreover, total (P less than 0.01) and free E2 (P less than 0.05) were lower only in Cardiac men less than or equal to 55 years old.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗