Ping Patrick

Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men

Cross-sectional studies have demonstrated a decline in testosterone and free and bioavailable testosterone with age. This occurs in a majority of older persons without an increase in luteinizing hormone (LH), suggesting that a component of the testosterone decrease is due to secondary hypogonadism. To determine whether these findings could be duplicated in a longitudinal study, we measured testosterone, LH, follicle-stimulating hormone (FSH), and sex hormone-binding globulin (SHBG) levels in 77 men participating in the New Mexico Aging Process Study who had sera available in 1980 or 1981 and two or more serial samples in 1982, 1984, 1989, and/or 1994. Thirty-nine subjects had samples available from both 1980 and 1994. The age at entry into the study ranged from 61 to 87 years. Testosterone levels decreased over the 15 years of the study. In persons who were alive for the duration of the study, testosterone levels were significantly lower 5 years before termination of the study (P < .05). Testosterone levels did not differ at entry into the study among those who died and those who were alive at the end of the study period. Eight of 77 subjects (10%) had LH levels above the normal range at some time during the study. In contrast, 43% of subjects had elevated FSH levels. Both LH and FSH increased significantly with age. SHBG levels were measured in 1980 and 1994 and increased significantly with age (P < .0001). LH and FSH were highly correlated with one another, but neither correlated with testosterone. This study demonstrated a longitudinal decline in testosterone and an increase in LH and FSH in older men. The average rate of decrement in testosterone concentration was 110 ng/dL every decade.

The effects of miglitol on glucagon‐like peptide‐1 secretion and appetite sensations in obese type 2 diabetics

Background: Previous studies reported that administration of first generation α‐glucosidase inhibitors (AGIs), such as voglibose or acarbose, produced exaggerated and sustained postprandial responses of glucagon‐like peptide‐1 (GLP‐1), an incretin hormone from the enteroinsular axis, in healthy humans. Little is known about the postprandial release of GLP‐1 after AGI therapy in diabetics. GLP‐1 plays a role to mediate satiety. Any agent that substantially elevates GLP‐1 levels may theoretically reduce hunger, increase satiation and limit food intake.

Longitudinal changes in serum 25-hydroxyvitamin D in older people.

Cross-sectional studies have suggested that serum 25-hydroxyvitamin D (25OHD) levels decline with aging. We have examined this putative decline in a longitudinal study using participants in the New Mexico Aging Process Study. 25OHD levels were measured in participants in whom serum samples were available between 1980 to 1982 and 1989 to 1994 (37 men and 99 women). The available data for these visits included age, gender, and the date the sample was obtained. Questionnaires assessing physical activity and vitamin D intake were administered at the visits. A seasonal variation (r = .25, P < .05) in 25OHD was demonstrated in the whole group of subjects. In 25 subjects who were not receiving vitamin D supplementation at either time and had samples obtained in the same season, both serum 25OHD (P < .05) and physical activity (P < .05) decreased over a mean period of 11.4 years. In 23 subjects who had samples obtained in the same season but used vitamin D supplements at both times, there was no change in serum 25OHD. Mean summer 25OHD levels did not change with the duration of study. On the other hand, the mean serum 25OHD declined with the duration of study when measured from winter to winter or spring to spring. Multiple regression analysis demonstrated that the month, activity level, vitamin D supplementation, and gender (P < .001) were independent determinants of serum 25OHD levels. This study confirms that aging is associated with a reduction in serum 25OHD, and suggests that this decrease is a reflection of reduced sun exposure rather than aging per se. The reduction in serum 25OHD was the result of decreasing winter and spring 25OHD serum concentrations. It is clear that vitamin D supplementation can prevent the age-related decline in 25OHD levels.

Effect of testosterone on functional recovery in a castrate male rat stroke model

Both increased and decreased testosterone levels have been reported to correlate with poor outcome after acute ischemic stroke. The present study focused on the role of testosterone during recovery from neurological deficits in a rat focal ischemia model. Castrate male rats were subjected to behavioral tests after 90 min of middle cerebral artery occlusion (MCAO). On day 7 post-MCAO, neurological deficit-matched rats were assigned to a treatment group implanted with subcutaneous testosterone pellets or a control group implanted with sham cholesterol pellets. After 4 weeks post-MCAO, the average infarct volume was not significantly different between the two groups. Rats in the testosterone group demonstrated significantly earlier improvement in neurological deficits and shortened latency of adhesive tape removal compared with the control group as analyzed by Wilcoxon signed ranks test. Walking on parallel bars improved in both groups with a trend towards early recovery observed in the testosterone group. Biased left body swings persisted during the test period in both groups post-MCAO. Serum testosterone was within physiological levels in the treatment group but was not detectable in the control group by radioimmunoassay. GAP-43 and synaptophysin expression did not differ between groups. Less GFAP expression and reactive astrocyte hypertrophy were found around the infarct area in testosterone-treated rats compared with control rats. In conclusion, testosterone replacement post-MCAO accelerated functional recovery in castrate rats, suggesting a potential therapeutic role for testosterone replacement in stroke recovery.

The Effect of Aging on Bone Mineral Metabolism and Bone Mass in Native American Women

OBJECTIVE: To examine the effect of age on mineral metabolism and bone mineral density (BMD) of the hip and spine in Native American women.

Validation of salivary testosterone as a screening test for male hypogonadism

Background. Saliva collection is an easy, non-invasive method to measure hormones. Methods. Two studies were performed. In the first, a convenience sample of 1454 males who had submitted saliva for salivary testosterone measurements were studied. In the second study, we intensively studied symptoms and measurements of total testosterone, free testosterone symptoms and measurements of total testosterone, free testosterone and bioavailable testosterone in relationship to salivary testosterone in 127 men. A secondary endpoint was to examine the relationship of salivary testosterone to hypogonadal symptoms in the ADAM and AMS questionnaires. Results. In the first study, we have shown that salivary testosterone, measured in 1454 males aged 20 to 89 years, declines by 47% over the lifespan. In the second study, salivary testosterone was strongly correlated with bioavailable testosterone (p < 0.000001) calculated free testosterone (p < 0.00001) and total testosterone (p < 0.002). Salivary testosterone was significantly related to hypogonadal symptoms on the St. Louis University ADAM questionnaire and the Aging Male Survey. Conclusions. These studies support the use of salivary testosterone as an acceptable assay for screening for hypogonadism. Salivary testosterone is not a better assay than other measures to diagnose hypogonadism.

REGULATION OF GONADOTROPINS AND PARATHYROID HORMONE BY NITRIC OXIDE

Nitric oxide has been recently recognized as an intra- and inter-cellular messenger. Animal studies have suggested a role for nitric oxide in the regulation of gonadotropin secretion. In this study of 14 healthy, young males, nitroglycerine administered sublingually was demonstrated to inhibit GnRH stimulated LH secretion from the pituitary (p < 0.05). There was no significant effect on GnRH stimulated FSH secretion. Nitroglycerine increased basal PTH levels (< 0.02), but had no significant effect on basal LH, FSH, TSH, cortisol, calcium, or prolactin levels. This study presents evidence that nitric oxide modulates LH and PTH secretion in humans.

Predictors of serum testosterone and DHEAS in African-American men

There are few reported data on biochemical and functional correlates of androgen levels in African-American men. This study aimed at reporting physical and biochemical correlates of serum total testosterone (total T), bioavailable testosterone (BT) and dehydroepiandrosterone-sulphate (DHEAS) levels in community-dwelling, African-American men aged 50-65 years. Home-based physical examinations and health status questionnaires were administered to randomly sampled men. Body composition (dual-energy X-ray absorptiometry), lower limb and hand-grip muscle strength, and neuropsychological functions were assessed. Levels of serum total T, BT, DHEAS, oestradiol (E2), adiponectin, leptin, triglycerides and glucose were measured. Multiple linear regression models were constructed to identify factors independently associated with androgen levels. DHEAS levels declined from age 50 to 65 years (p < 0.0001), but total T and BT levels remained constant. Independent of other associated factors, higher total T levels were associated with lower serum triglyceride levels (beta = -0.142, p = 0.049); higher BT was associated with better performance on the trail-making tests (TMT-B:TMT-A ratio: beta = -0.118, p = 0.024) and higher DHEAS levels were associated with lower adiponectin (beta = -0.293, p = 0.047) and higher mini-mental state examination (MMSE) score (beta = 0.098, p = 0.008). Multiple regression models predicted 21, 18 and 29% of variance in total T, BT and DHEAS, respectively. Higher total T levels were associated with serum metabolic markers, particularly lower triglycerides, whereas higher BT was associated with better cognitive and muscle function and DHEAS with lower adiponectin and higher MMSE scores.

SAMP8 mice have altered hippocampal gene expression in long term potentiation, phosphatidylinositol signaling, and endocytosis pathways

The senescence-accelerated mouse (SAMP8) strain exhibits decreased learning and memory and increased amyloid beta (Aβ) peptide accumulation at 12 months. To detect differences in gene expression in SAMP8 mice, we used a control mouse that was a 50% cross between SAMP8 and CD-1 mice and which showed no memory deficits (50% SAMs). We then compared gene expression in the hippocampus of 4- and 12-month-old SAMP8 and control mice using Affymetrix gene arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the long term potentiation (6 genes), phosphatidylinositol signaling (6 genes), and endocytosis (10 genes) pathways. The changes in long term potentiation included mitogen-activated protein kinase (MAPK) signaling (N-ras, cAMP responsive element binding protein [CREB], protein phosphatase inhibitor 1) and Ca-dependent signaling (inositol triphosphate [ITP] receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through phosphatidylinositol-3-kinase, and Western blotting revealed phosphorylation changes in serine/threonine protein kinase AKT and 70S6K. Changes in the endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered gene expression in 3 SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways might provide new therapeutic targets in addition to targeting Aβ metabolism itself.

Antisense against Amyloid-β Protein Precursor Reverses Memory Deficits and Alters Gene Expression in Neurotropic and Insulin-Signaling Pathways in SAMP8 Mice

The senescence-accelerated mouse (SAMP8) strain exhibits an age-related decrease in memory accompanied by an increase in hippocampal amyloid-β protein precursor (AβPP) and amyloid-β peptide (Aβ). We have shown that administration of an antisense oligonucleotide against the Aβ region of AβPP (AβPP antisense) reverses the memory deficits. The purpose of this study was to determine the effect of peripheral (IV) administration of AβPP antisense on hippocampal gene expression. The AβPP antisense reversed the memory deficits and altered expression of 944 hippocampal genes. Pathway analysis showed significant gene expression changes in nine pathways. These include the MAPK signaling pathway (p = 0.0078) and the phosphatidylinositol signaling pathway (p = 0.043), which we have previously shown to be altered in SAMP8 mice. The changes in these pathways contributed to significant changes in the neurotropin (p = 0.0083) and insulin signaling (p = 0.015) pathways, which are known to be important in learning and memory. Changes in these pathways were accompanied by phosphorylation changes in the downstream target proteins p70S6K, GSK3β, ERK, and CREB. These changes in hippocampal gene expression and protein phosphorylation may suggest specific new targets for antisense therapy aimed at improving memory.