Utilisation of goals of care discussions and palliative care prior to image-guided procedures near the end of life.

AIM: To characterise image-guided procedures performed near the end of life and the use of goals of care discussions (GOC) and palliative care consultation (PCC) prior to these procedures. MATERIALS AND METHODS: Retrospective chart review of 3,714 consecutive inpatient procedures performed for 2,351 patients and 8,206 outpatient procedures performed for 5,225 patients within a suburban medical system. Data were collected on demographics, procedures performed, mortality, and use of GOC or PCC prior to the procedures. Procedures near the end of life were classified as emergent, elective, or palliative. Logistic regression was used to assess for demographic disparities in care. RESULTS: Nine percent of inpatients died within 30 days of their procedure, 57% of which were within the same hospitalisation. Of these patients, 59% had a documented GOC and 35% had a PCC. Similarly, 7% of outpatients died within 6 months of their procedure. A minority of these patients had a documented GOC (37%) or PCC (13%). There were few statistically significant demographic disparities in this care and the associated odds ratios were small. CONCLUSION: A wide array of image-guided procedures is performed near the end of life. GOC and PCC are underutilised prior to these procedures. Few demographic disparities exist in this care.

Lessons from KEEPS: the Kronos Early Estrogen Prevention Study.

The Kronos Early Estrogen Prevention Study (KEEPS) was a randomized, double-blind, placebo-controlled trial designed to determine the effects of hormone treatments (menopausal hormone treatments [MHTs]) on the progression of carotid intima-medial thickness (CIMT) in recently menopausal women. Participants less than 3 years from menopause and without a history of overt cardiovascular disease (CVD), defined as no clinical CVD events and coronary artery calcium < 50 Agatston units, received either oral conjugated equine estrogens (0.45 mg/day) or transdermal 17ß-estradiol (50 µg/day), both with progesterone (200 mg/day for 12 days/month), or placebo pills and patches for 4 years. Although MHT did not decrease the age-related increase in CIMT, KEEPS provided other important insights about MHT effects. Both MHTs versus placebo reduced the severity of menopausal symptoms and maintained bone density, but differed in efficacy regarding mood/anxiety, sleep, sexual function, and deposition of ß-amyloid in the brain. Additionally, genetic variants in enzymes for metabolism and uptake of estrogen affected the efficacy of MHT for some aspects of symptom relief. KEEPS provides important information for use of MHT in clinical practice, including type, dose, and mode of delivery of MHT recently after menopause, and how genetic variants in hormone metabolism may affect MHT efficacy on specific outcomes.

Endothelial function in women of the Kronos Early Estrogen Prevention Study.

OBJECTIVE: Endothelial dysfunction occurs early in the atherosclerotic disease process, often preceding clinical symptoms. Use of menopausal hormone treatment (MHT) to reduce cardiovascular risk is controversial. This study evaluated effects of 4 years of MHT on endothelial function in healthy, recently menopausal women. METHODS: Endothelial function was determined by pulse volume digital tonometry providing a reactive hyperemia index (RHI) in a subset of women enrolled in the Kronos Early Estrogen Prevention Study. RHI was measured before and annually after randomization to daily oral conjugated equine estrogen (oCEE, 0.45 mg), weekly transdermal 17ß-estradiol (tE2, 50 µg) each with intermittent progesterone (200 mg daily 12 days of the month) or placebo pills and patch. RESULTS: At baseline, RHI averaged 2.39 ± 0.69 (mean ± standard deviation; n = 83), and over follow-up did not differ significantly among groups: oCEE, 2.26 ± 0.48 (n = 26); tE2, 2.26 ± 0.45 (n = 24); and placebo, 2.37 ± 0.37 (n = 33). Changes in RHI did not correlate with changes in traditional cardiovascular risk factors, but may inversely correlate with carotid intima medial thickness (Spearman correlation coefficient ρ = -0.268, p = 0.012). CONCLUSION: In this 4-year prospective assessment of recently menopausal women, MHT did not significantly alter RHI when compared to placebo.

Human growth hormone and human aging.

In humans, both aging and GH deficiency are associated with reduced protein synthesis, decreased lean body and bone mass, and increased percent body fat. In healthy individuals, spontaneous and stimulated GH secretion, as well as circulating IGF-I and IGFBP-3 levels, are significantly decreased with advancing age. The extent to which these age-related changes in GH and IGF-I contribute to alterations in body composition and function remains to be elucidated. GH treatment of GH-deficient adults or old men with reduced IGF-I levels with exogenous GH increases plasma IGF-I, nitrogen retention, and lean body mass, decreases percent body fat, and exerts little effect on bone mineral density. Short-term adverse effects of GH therapy have been minimized by using low-dose regimens, but it is still uncertain whether long-term GH supplementation in adult life increases the risk of metabolic abnormalities or malignancy. Administration of GHRH, which has been shown to maintain the pattern of pulsatile GH secretion in old men, may represent another possible physiological approach to therapy. It may be justifiable initially to limit use of GH to certain elderly patients such as those suffering from catabolic illnesses, malnourishment, burns, cachexia, etc. A great deal more research will be necessary to determine whether normalization of GH and IGF-I levels in healthy older persons will lead to improvements in their physical and psychological functional capacity and quality of life.

The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men.

BACKGROUND: The observation that dehydroepiandrosterone (DHEA) concentrations decrease markedly with age has led to the hypothesis that declining DHEA concentrations may contribute to age-related changes in cognition. In the United States, DHEA is widely available as an over-the-counter supplement that individuals are using in an effort to ameliorate age-related cognitive and physical changes. OBJECTIVE: To investigate the relationship between age-associated decreases in endogenous DHEA sulfate (DHEA-S) concentrations and declines in neuropsychological performance in a prospective, longitudinal study. METHODS: The subjects were 883 men from a community-dwelling volunteer sample in the Baltimore Longitudinal Study of Aging. The men were aged 22 to 91 years at the initial visit, and they were followed up for as long as 31 years (mean, 11. 55 years), with biennial reassessments of multiple cognitive domains and contemporaneous measurement of serum DHEA-S concentrations. Outcome measures were the results of cognitive tests of verbal and visual memory, 2 tests of mental status, phonemic and semantic word fluency tests, and measures of visuomotor scanning and attention. Serum DHEA-S concentrations were determined by standard radioimmunoassay. RESULTS: Neither the rates of decline in mean DHEA-S concentrations nor the mean DHEA-S concentrations within individuals were related to cognitive status or cognitive decline. A comparison between the highest and lowest DHEA-S quartiles revealed no cognitive differences, despite the fact that these groups differed in endogenous DHEA-S concentration by more than a factor of 4 for a mean duration of 12 years. CONCLUSION: Our longitudinal results augment those of previous prospective studies by suggesting that the decline in endogenous DHEA-S concentration is independent of cognitive status and cognitive decline in healthy aging men.

Testosterone secretion in the rat in response to chorionic gonadotrophin: alterations with age.

It has been reported by others that both prevailing blood concentrations of testosterone and Leydig cell response to gonadotrophin (up to 1 h after injection) are reduced in the aged male rat. Although resting levels of plasma testosterone in our aged (24-26 months old) Sprague-Dawley rat are also depressed compared with young (3-4 months) or mature (12 months) animals of the same strain, subcutaneous injection with human chorionic gonadotrophin for 3 days restores secretory function, producing testosterone levels indistinguishable from those of similarly stimulated younger rats. In short term experiments, old rats did show a diminished testesterone secretory response to human chorionic gonadotrophin 1 h after a single intravenous injection, consistent with previous reports, but restoration of normal stimulated levels was observed by 2 h, and persisted up to 24 h. These findings differ from the demonstrated intrinsic testicular hyporesponsiveness to gonadotrophin of aged men, and probably represented a state of chronic understimulation of the aged rat Leydig cells, due to low prevailing levels of LH.

Inhibition of the ovarian augmentation reaction by a chemical antiestrogen.

Inhibition by antiestradiol serum of ovarian weight gain and follicular growth in hypophysectomized immature rats given FSH and hCG suggested that gonadotrophin induced endogenous estrogen secretion plays a role in the ovarian augmentation reaction. We have studied the effects of a chemical estrogen antagonist, cis-clomiphene, on ovarian weight response to gonadotrophins in hypophysectomized immature female rats. We found that this antiestrogen inhibits the ovarian response to FSH and hCG. To our knowledge, this is the first demonstration of a direct effect of a chemical antiestrogen on the ovary, a result consistent with a role for intraovarian estrogen in follicular growth.

Interaction of estrogen and gonadotrophins on follicular atresia.

We have investigated folluclar atresia by giving hypophysectomized immature female rats (HIFR) diethylstibestrol or gonadotrophins with and without the chemical antiestrogen CI-628, making total counts of normal and atretic follicles greater than 125 muM in diameter, and using a simple model to analyze data. Our results show an antiatretic effect of estrogen, independent of its well-documented mitogenic effect on preantral follicles. We have also shown that CI-628 acts as an anti-estrogen to block follicular proliferation, while acting as an estrogen to inhibit atresia. In addition, we have observed an increase in atresia caused by gonadotrophins, in opposition to their estrogen-mediated positive effect on follicular growth.

Effects of human chorionic gonadotropin, human interstitial cell stimulating hormone and human follicle-stimulating hormone on ovarian weights in estrogen-primed hypophysectomized immature female rats.

In connection with systematic studies of steroid and peptide hormone interactions during follicular growth, we have measured ovarian weight responses to graded doses of highly purified human chorionic gonadotropin (hCG), human interstitial cell stimulating hormone (hICSH)in hypophysectomized immature female rats (HIFR) treated with diethylstilbestrol in silastic capules (desc) implanted subcutaneously. Our results are consistent with earlier reports of enhancement of ovarian weight responses to hCG and FSH. Contrary to results of similar experiments reported by others, we have found that estrogen treatment of HIFR enhanced ovarian weight response to ICSH. In addition, we report for the first time that small doses of hCG and hICSH inhibit ovarian weight responses to estrogen in HIFR. Our observations on effects of small doses of hCG and hICSH and the long-known fact that ovarian interstitial cells are stimulated in HIFR given similar doses of these hormones lead us to hypothesize that ovarian interstitial cell stimulation is involved in the control of follicular maturation.

Follicle stimulating activity of human chorionic gonadotropin: effect of dissociation and recombination of subunits.

The follicle stimulating activity (FSA) and interstitial cell stimulating activity (ICSA) of highly purified human chorionic gonadotropin (hCG), its alpha and beta subunits, and hCG generated by subunit recombination were determined by ovarian weight and ventral prostate weight bioassays. Whereas highly purified hCG exhibited both FA and ICSA, its separated subunits were essentially devoid of both activities. ICSA and FSA, indistinguishable from that of the highly purified hCG, were restored by recombination of the hCG subunits. These observations are consistent with the hypothesis that the FSA and ICSA found in highly purified hCG preparations are properties of the hCG molecule.

Evidence of a role of adrogens in follicular maturation.

In hypophysectomized immature female rats (HIFR), the ovarian weight response to subcutaneously implanted diethylstilbestrol capsules (DESC) is inhibited by small doses of human chorionic gonadotropin (hCG). This effect, reproduced by equivalent doses of interstitial cell stimulating hormone (ICSH) but not by follicle-stimulating hormone (FSH), is inhibited by treatment with antiandrogens. These data implicate gonadotropic stimulation of interstitial cell androgen production in the control of follicular maturation in rats.

Reproductive hormones in aging men. I. Measurement of sex steroids, basal luteinizing hormone, and Leydig cell response to human chorionic gonadotropin.

Although alterations of circulating sex steroids have been reported in aging men, it is not known to what extent reported changes may represent effects of variables other than aging. We have measured sex hormone levels, serum binding, the testosterone (T) response to hCG, and basal LH levels in 69 male volunteers, aged 25-89 yr, without alcoholism, obesity, chronic illness, or severe prostatic disease, and not using potentially interfering medications. In our study there was no effect of age on serum T, 5 alpha-dihydrotestosterone, estrone, or estradiol. Binding of T to T-binding globulin increased slightly with age, but not enough to decrease the free T index (fraction free X T concentration). Basal serum LH rose significantly. The T response to hCG suggested a somewhat diminished Leydig cell reserve with age, a conclusion consistent with the LH elevation. Our failure to detect the decreased T and free T index or increased estrogens reported by others could reflect afternoon rather than morning sampling, but is more likely to be due to our use of exceptionally healthy volunteers. We suggest that factors other than aging might have influenceed the data previously reported, and that aging per se need not be associated with altered sex steroid levels in the human male.

Rapid measurement of an index of testosterone binding to serum binding globulin using ion exchange columns.

DEAE cellulose "mini" columns at pH 7.4 retain testosterone (T) bound to testosterone binding globulin (TeBG), which can be eluted at pH 2. Small 1:2 diluted serum or plasma samples are incubated with a tracer dose of tritiated T in pH 7.4 Tris buffer at 37 C then chilled and placed on columns at 4 C. Free and albumin bound T are washed off columns with pH 7.4 Tris buffer and columns are eluted with pH 2 Tris into vials for scintillation counting. After a simple mathematical correction for the small residual fraction of albumin bound T eluted at pH 2, we obtain a measure of TeBG binding of T which is highly correlated (r = .945) with that determined by dialysis. The method is quick, reproducible and applicable to serum or plasma volumes of 50 to 200 microliter. A single operator can process 100 samples in approximately 4 h.

Depressed plasma testosterone and fractional binding of testosterone in obese males.

Plasma testosterone (T), fractional binding of T to T-binding globulin (TeBG), LH, and FSH were evaluated in 22 obese men. Only 1 of 12 men weighing from 176-200% of ideal body weight (group I) had a low T concentration, while 9 of 10 men greater than 200% of ideal weight (group II) had plasma T concentrations 2 SD below the normal mean. The fractional binding of T to TeBG was equally and significantly decreased in both groups. As a result, the mean and individually calculated free T concentrations (free T index) were normal in group I. In contrast, the mean free T index in group II was significantly less than normal males and group I. Individually, 1 of 7 group II men had a free T index 2 SD below the normal mean. LH and FSH were normal in both groups. These studies indicate that in most obese males a low or low normal T is offset by decreased binding to TeBG, resulting in a normal free T index. However, some morbidly obese males are unable to alter their hypothalamic-hypophyseal-gonadal axis to maintain a normal free T index.

Pituitary-thyroid hormone economy in healthy aging men: basal indices of thyroid function and thyrotropin responses to constant infusions of thyrotropin releasing hormone.

In order to assess the effects of aging, as distinct from those of thyroid disease or extrathyroidal illness, on certain indices of thyroid function, we studied 74 healthy, ambulatory men recruited from the Baltimore Longitudinal Study on Aging. We determined basal serum values of T4, T3, rT3, thyroxine-binding globulin (TBG), and T3 resin uptake (T3RU) and calculated the free T4 index (FT4I = T4 X T3RU/100), free T3 index (FT3I = T3 X T3RU/100), and T4/TBG ratio for each subject. We used an ultrasensitive RIA to measure variations in basal concentrations of TSH within the normal range. We then infused TRH at a constant rate (0.4 microgram/min iv) for 240 min into 63 of the same men; serum samples, collected at 15-min intervals during the infusion, were analyzed for TSH by routine RIA. Subjects were divided into 3 groups according to age; A (n = 26, mean age = 39.4), B (n = 23, mean age = 60.0), and C (n = 25, mean age = 79.6). Analysis of variance with Duncan's multiple range test and regression analysis were used to evaluate data. There was no significant (P greater than 0.05) variation with age of basal serum values of T4, TBG, or T3RU. Comparison of groups A and C showed significant decreases of mean values of serum T3 (-11%, P less than 0.05), FT3I (-13%, P = 0.02), FT4I (-11%, P less than 0.01), and T4/TBG ratio (-12%, P less than 0.01) and an increase in serum TSH (+38%, P less than 0.05). For these variables, the mean values for group B were intermediate between, but not significantly different from, those of A and C. Regression analysis showed significant correlations of age with T3, FT3I, FT4I, T4/TBG, and TSH at P levels similar to those obtained by Duncan's test. No elderly individual exhibited a baseline elevation of TSH (greater than 7 microU/ml) or depression of T4 (less than 5 micrograms/dl), suggesting that primary hypothyroidism was not present in our old group. The basal TSH concentration did not correlate significantly with any index of thyroid function except with FT3I in group C (r = -0.43, P less than 0.05). In all age groups the TSH responses to TRH exhibited a biphasic pattern with early and late peaks.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-3, and prostate-specific antigen as predictors of clinical prostate cancer.

Insulin-like growth factors (IGFs) may play a role in prostate growth, hyperplasia, and malignancy. High plasma IGF-I has been associated with increased prostate cancer risk. In a prospective, cohort, case-control study in the Baltimore Longitudinal Study on Aging population, we examined prostate volume by magnetic resonance imaging, and prostate-specific antigen (PSA), IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in sera obtained approximately 9 yr before diagnosis of prostate cancer in cases (n = 72) or age-matched controls (n = 127) and in 76 additional Baltimore Longitudinal Study on Aging men (normal subjects) with measured prostate volumes and no prostate cancer. We calculated adjusted odds ratios (OR) by logistic regression, relative risks for significant ORs, and receiver operator curves for prostate cancer, using serum measures alone and in combination. Adjusted ORs for the high vs. low tertile were: for IGF-I, 3.1 [confidence interval (CI), 1.1-8.7]; for IGF-II, 0.2 (CI, 0.07-0.6); for IGFBP-3, 0.71 (CI, 0.3-1.7); and for PSA, 12.5 (CI, 3.8-40.9). For significant ORs, relative risk estimates remained significant at 2.0 for IGF-I, 0.3 for IGF-II, and 5.5 for PSA. Receiver operator curves showed PSA to be the most powerful predictor of prostate cancer. Adding IGF-II to PSA improved prediction. IGF-II was significantly and inversely related (r = -0.219; P < 0.01) and PSA was directly and significantly related (r = 0.461; P < 0.0001) to prostate volume, whereas IGF-I and IBFBP-3 were not. High IGF-I and low IGF-II are independently associated with increased risk of prostate cancer, but PSA level is a much stronger predictor of prostate cancer in the ensuing 10 yr than either IGF-I or IGF-II. The absence of a relationship of IGF-I to prostate size is inconsistent with increased ascertainment in men with large prostates as the source of greater prostate cancer risk associated with IGF-I. Our data suggest that IGF-II may inhibit both prostate growth and development of prostate cancer.

Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging.

Many studies have shown cross-sectional (and two small studies, longitudinal) declines in total and/or free testosterone (T) levels, with age, in men. The extent to which decline in T is the result of the aging process per se, as opposed to chronic illness, medication use, and other age-related factors, remains controversial. The frequency with which aging leads to T levels consistent with hypogonadism has also not been defined. These issues bear on the potential use of T replacement in aging men, because aging and hypogonadism have, in common, reduced bone and lean body mass and muscle strength and increased total and abdominal fat. We measured T and sex hormone-binding globulin (SHBG), by RIA, in stored samples from 890 men in the Baltimore Longitudinal Study on Aging. Using a mixed-effects model, we found independent effects of age and date of sampling to reduce T levels. After compensating for date effects, which investigation suggested was artifactual, we observed significant, independent, age-invariant, longitudinal effects of age on both T and free T index (free T index = T/SHBG), with an average change of -0.124 nmol/L.yr and -0.0049 nmol T/nmol SHBG.yr. T, but not free T index, also decreased with increasing body mass index. Use of beta-blocking drugs was associated with higher T and higher free T index levels. Using total T criteria, incidence of hypogonadal T levels increased to about 20% of men over 60, 30% over 70 and 50% over 80 yr of age, and even greater percentages when free T index criteria were employed. Our observations of health factor independent, age-related longitudinal decreases in T and free T, resulting in a high frequency of hypogonadal values, suggest that further investigation of T replacement in aged men, perhaps targeted to those with the lowest serum T concentrations, are justified.

Comparison of the effects of lung cancer, benign lung disease, and normal aging on pituitary-gonadal function in men.

We retrospectively determined serum total testosterone (T), fraction of T bound, free T index, LH, and FSH levels in 122 men with malignant lung disease, 32 men with benign lung disease, and 106 normal men. Men with malignant and, to a lesser extent, benign lung disease had decreased serum total T and free T index values at the 5th percentiles, with elevations of LH and FSH levels at the 95th percentiles. Linear regression analysis showed reductions in total T and free T index and increases in FSH, but not LH, levels with age in each group. Using multivariate analysis, we found stronger independent effects of disease than age on serum total T and fraction of T bound, but a greater influence of age on free T index. Serum LH values differed by diagnosis, whereas FSH differed by age. Relative to values in the normal men, mean serum total T levels were reduced in men with lung cancer; the fraction of T bound was decreased in the men with lung cancer and increased in the men with benign lung disease, the free T index was decreased in the men with both malignant and benign lung disease, and LH was increased in the men with lung cancer. The hormone and hormone binding results were similar in men with different types of lung cancer. Biochemical evidence of primary and secondary (or combined primary and secondary) hypogonadism was present in 50-59% and 28-32%, respectively, of the men with malignant and benign lung disease vs. 10% of the normal men. These data suggest that 1) there is an increased prevalence of both pituitary gonadotropic and testicular dysfunction in men with malignant and, to a lesser extent, benign chronic lung disease, and 2) the effects of illness are independent of, and quantitatively greater than, those due to age.

Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone to ovine corticotropin-releasing hormone in healthy aging men.

To assess the effects of age on both the pituitary ACTH response to corticotropin-releasing hormone (CRH) and the secretory responses of cortisol (F) and dehydroepiandrosterone (DHEA) to endogenous rises in ACTH, we measured evening basal and ovine CRH (oCRH; 1 mu/kg)-stimulated plasma concentrations of ACTH,F, and DHEA in 49 healthy men, aged 21-86 yr. By analysis of variance, we found no change with age in either the basal concentration of ACTH or the magnitude of the peak ACTH response to oCRH. Older men had higher basal F levels (P less than 0.05), while basal plasma levels of CBG and ratios of F to CBG did not vary significantly with age (P greater than 0.1). We also found no significant increase with age in the magnitude of the peak F response to oCRH (P greater than 0.2), although peak F responses occurred significantly earlier (P less than 0.03) in the older men. Basal plasma levels of DHEA decreased significantly with age (P less than 0.001), as did the magnitude of peak DHEA responses to endogenous ACTH rises (P less than 0.01). There was no alteration in the timing of the peak DHEA response with age (P greater than 0.7). We conclude that while ACTH and F responses to evening injections of oCRH are well maintained in healthy aging men, that of DHEA is discordantly decreased. The present findings are compatible with the hypotheses that there is a diminished sensitivity of ACTH secretion to negative feedback regulation by glucocorticoids in older men, and there is an ACTH-independent age-related diminution in adrenal androgen secretion.

Responses of growth hormone (GH) and somatomedin-C to GH-releasing hormone in healthy aging men.

Although controversy exists regarding the effects of aging on GH secretory responses to indirect stimulation, in the only prior study of GH-releasing hormone (GHRH)-mediated GH secretion decreased GH responsivity occurred in healthy men after age 40 yr. We measured serum GH before and up to 180 min after and somatomedin-C (SM-C) levels before and 24 h after single morning bolus iv injections of GHRH-(1-44)-NH2 (1 microgram/kg) in 50 healthy fasted men, aged 21-86 yr, from the Baltimore Longitudinal Study of Aging. Only subjects with a body mass index (BMI; kilograms per m2) between 20.0 and 29.0 were studied. Basal serum GH levels were undetectable (less than 0.7 ng/ml) in all but 2 men. Neither the frequency of GH responses (P greater than 0.8), the magnitude of response (P greater than 0.2), nor the timing (P greater than 0.05) of the peak GH responses to GHRH were significantly altered with age. Although BMI values did not vary significantly with age in our study group, there was a significant negative correlation (r = -0.37; P less than 0.01) of peak GH with BMI. Regression analysis revealed a slight but significant increase in the level of fasting blood sugar with age, but no significant correlation between fasting blood sugar and peak GH levels. Serum levels of SM-C were significantly lower in older men both before (P less than 0.001) and 24 h after (P less than 0.02) GHRH injection. Repeated measures analysis of variance revealed significant (P less than 0.001) responses of SM-C to endogenous GH elevations produced by GHRH at all ages, but no age-dependent alterations in the magnitudes of these responses (P greater than 0.7). Our findings suggest that increasing age in adult men has little effect on the secretory responsiveness of pituitary somatotropes to GHRH. However, the finding of lower serum levels of SM-C with intact SM-C responsivity to endogenous GH is compatible with prior observations of an age-related decrease in the total daily spontaneous secretion of GH.