Ali Iranmanesh

Pathophysiology of hypercortisolism in depression

Objective:  The mechanisms mediating hypercortisolemia in depression remain controversial. Adopting the biomarker strategy, we studied adrenocorticotropin (ACTH) and cortisol dynamics in hypercortisolemic and non‐hypercortisolemic depressed in‐patients, and in normal volunteers.

Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men

OBJECTIVE Androgen replacement has been reported to increase bone mineral density (BMD) in hypogonadal men. We studied the effects of 6 months of treatment with a new transdermal testosterone (T) gel preparation on bone turnover markers and BMD.

The combined administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone

objective Central hyposomatotrophism, hypothyroidism and hypogonadism are present concomitantly in men with prolonged critical illness. This study evaluated the impact of combined treatment with GH‐releasing peptide‐2 (GHRP‐2), TRH and GnRH for 5 days compared with GHRP‐2 + TRH and with GHRP‐2 alone.

Increased Salivary cortisol concentrations during Chronic alcohol intoxication in a naturalistic clinical sample of men

BACKGROUND Cortisol, the primary glucocorticoid in humans, is intimately involved in the regulation of such varied and critical biological processes as emotion, cognition, reward, immune functioning, and energy utilization. A persistent increase in cortisol concentration as a result of chronic intoxication could therefore result in alcohol-related disorders such as sleep disruption, cognitive deficits, diabetes, and mood disturbances. Although moderate levels of acute alcohol ingestion are reported to produce an increase in cortisol levels, it is uncertain whether cortisol remains persistently increased during long-term chronic intoxication. METHODS Salivary cortisol and breath alcohol concentrations (BAC) were obtained on 73 subjects with primary alcohol dependence on initial presentation for treatment and 22 alcohol-dependent subjects participating in a residential treatment program. RESULTS Both intoxicated alcohol-dependent subjects (n = 38) and nonintoxicated subjects in acute alcohol withdrawal (n = 30) demonstrated significantly increased salivary cortisol concentrations compared with abstinent subjects (n = 27; p < 0.001). Nonintoxicated subjects in acute withdrawal demonstrated significantly increased salivary cortisol concentrations compared with highly intoxicated subjects (BAC >100 mg/dl) but were similar to subjects with lower levels of intoxication (BAC, 10-100 mg/dl). CONCLUSIONS Chronic alcohol-dependent subjects experience continuously increased concentrations of cortisol during both intoxication and withdrawal. Increased levels of cortisol during chronic intoxication seem to progressively increase with the onset of withdrawal. This suggests a daily cycle of hypercortisolemia during the active drinking phase, with further increases on the cessation of drinking and the emergence of withdrawal symptoms. Persistently increased levels of cortisol may extract a costly allostatic load, resulting in significant central nervous system and peripheral organ morbidity.

Elements in the pathophysiology of diminished growth hormone (GH) secretion in aging humans

Remarkable decreases in growth hormone (GH) secretion accompany healthy aging. The pathophysiology of this hyposomatotropism is confounded by concurrent changes in body composition (with increased visceral fat), physiological declines in estrogen and androgen concentrations, differences in gender responses to aging, and alterations not only in the quantity of GH secreted, but also (as more recently evident) in the orderliness or regularity of the GH release process (e.g., as assessed by approximate entropy). In addition, physical fitness or aerobic capacity also positively modulates GH secretion. Lastly, confounding variables such as altered sleep patterns and nutritional state may contribute to overall regulation of the GH axis in aging. Despite confounding variables, available human experiments suggest partial growth hormone-releasing hormone (GHRH) deficiency in healthy older individuals, presumptively combined with somatostatin excess, and disruption of the moment-to-moment pattern of coordinated and orderly GH release. Here, the authors review these selected facets of recent experimental evaluation of the human GH insulin-like growth factor-I (GH-IGF-1) feedback axis in aging humans.

NEUROPHYSIOLOGICAL REGULATION AND TARGET-TISSUE IMPACT OF THE PULSATILE MODE OF GROWTH HORMONE SECRETION IN THE HUMAN

Neuroendocrine axes function as an ensemble of regulatory loci which communicate and maintain homeostasis via time-delayed blood-borne signals. The growth hormone (GH)-insulin-like growth factor I (IGF-I) feedback axis sustains a vividly pulsatile mode of interglandular signalling. Pulsatility is driven jointly by hypothalamic GH-releasing hormone (GHRH) and GH-releasing peptide (GHRP), and modulated by somatostatinergic restraint. Paradoxically, intermittent somatostatin inputs also facilitate somatotrope-cell responses to recurrent secretagogue stimuli, thereby amplifying pulsatile GH secretion. A concurrent low basal (8-12% of normal total) rate of GH release is controlled positively by GHRH and GHRP and negatively by somatostatin. Sex-steroid hormones (such as oestradiol and aromatizable androgen) and normal female and male puberty augment GH secretory-burst mass 1.8- to 3.5-fold, whereas ageing, relative obesity, physical inactivity, hypogonadism, and hypopituitarism mute the amplitude/mass of pulsatile GH output. An abrupt rise in circulating GH concentration stimulates rapid internalization of the GH receptor in peripheral target tissues, and evokes second-messenger nuclear signalling via the STAT 5b pathway. Discrete GH peaks stimulate linear (skeletal) growth and drive muscle IGF-I gene expression more effectually than basal (time-invariant) GH exposure. A brief pulse of GH can saturate the plasma GH-binding protein system and achieve prolonged plasma GH concentrations by convolution with peripheral distribution and clearance mechanisms. A single burst of GH secretion also feeds back after a short latency on central nervous system (CNS) regulatory centres via specific brain GH receptors to activate somatostatinergic and reciprocally subdue GHRH outflow. This autoregulatory loop probably contributes to the time-dependent physiologically pulsatile dynamics of the GH axis. More slowly varying systemic IGF-I concentrations may also damp GH secretory pulse amplitude by delayed negative-feedback actions. According to this simplified construct, GH pulsatility emerges due to time-ordered multivalent interfaces among GHRH/GHRP feedforward and somatostatin, GH and IGF-I feedback signals. Resultant GH pulses trigger tissue-specific gene expression, thereby promoting skeletal and muscular growth, metabolic and body compositional adaptations, and CNS reactions that jointly maintain health and homeostasis.

Effects of age on the irregularity of LH and FSH serum concentrations in women and men

We evaluated an apparent distinction between follicle-stimulating hormone (FSH) and luteinizing hormone (LH) dynamics: visually, it appears that the pattern of serum concentrations of FSH is more irregular than that of LH in younger human females. We studied healthy humans, with LH and FSH serum samples obtained every 10 min for 24 h. Three groups were studied: 24 young females [8 early follicular (EFol), 8 late follicular (LFol), and 8 midluteal (MLut)]; 8 postmenopausal females; and 17 males 21-79 yr of age. To quantify serial irregularity, we utilized approximate entropy (ApEn), a scale- and model-independent statistic. For young females, FSH was consistently more irregular than LH per subject: among the younger subjects, ApEn(FSH) - ApEn(LH) = 0.342 +/- 0.270; ApEn(FSH) > ApEn(LH), P < 0.00001; ApEn(FSH) > ApEn(LH) for 23 of 24 subjects. For each cycle stage, pairwise ApEn(FSH) > ApEn(LH): P < 0.005 for both LFol and MLut, P < 0.01 for EFol. Notably, for the postmenopausal women, the irregularity difference vanished:ApEn(FSH) - ApEn(LH) = 0.008 +/- 0.205. Males exhibited qualitatively similar results: ApEn(FSH)- ApEn(LH) was significantly and negatively correlated with age (r = -0.75, P = 0.0006). The capability to quantify (the extent of) differences between FSH and LH release, beyond the general 1:1 correspondence between primary LH and FSH pulses, suggests a means to assess bihormonal changes as a clinical marker of altered reproductive status in a variety of settings, e.g., a perimenopausal milieu. Mechanistically, the erosion of unequal FSH-LH regularity with age is consistent with a loss of synchrony control within the integrated hypothalamo-pituitary-gonadal axis.

Aging alters feed-forward and feedback linkages between LH and testosterone in healthy men

To discern the effect of aging on coordinate luteinizing hormone (LH) and testosterone secretion, we sampled healthy older men (age 62-74 yr, n = 11) and young controls (age 21-34 yr, n = 13) every 2.5 min overnight. Deconvolution analysis and cross-correlation were used to relate serum LH concentrations to calculated testosterone secretion rates (feed-forward stimulation), as well as serum testosterone concentrations to computed LH secretion rates (feedback inhibition). Despite statistically similar mean serum LH and testosterone concentrations in the young and older men, older individuals had diminished feed-forward stimulation of LH concentrations on calculated testosterone secretion rates, as well as delayed feedback inhibition of testosterone concentrations on computed LH secretion rates.To discern the effect of aging on coordinate luteinizing hormone (LH) and testosterone secretion, we sampled healthy older men (age 62-74 yr, n = 11) and young controls (age 21-34 yr, n = 13) every 2.5 min overnight. Deconvolution analysis and cross-correlation were used to relate serum LH concentrations to calculated testosterone secretion rates (feed-forward stimulation), as well as serum testosterone concentrations to computed LH secretion rates (feedback inhibition). Despite statistically similar mean serum LH and testosterone concentrations in the young and older men, older individuals had diminished feed-forward stimulation of LH concentrations on calculated testosterone secretion rates, as well as delayed feedback inhibition of testosterone concentrations on computed LH secretion rates.

The aging male hypothalamic–pituitary–gonadal axis: Pulsatility and feedback

Aging results in insidious decremental changes in hypothalamic, pituitary and gonadal function. The foregoing three main anatomic loci of control are regulated by intermittent time-delayed signal exchange, principally via gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and testosterone/estradiol (Te/E(2)). A mathematical framework is required to embody these dynamics. The present review highlights integrative adaptations in the aging male hypothalamic-pituitary-gonadal axis, as assessed by recent objective ensemble models of the axis as a whole.

Basal, Pulsatile, Entropic (Patterned), and Spiky (Staccato-like) Properties of ACTH Secretion: Impact of Age, Gender, and Body Mass Index

BACKGROUND Age, gender, and BMI determine ultradian modes of LH and GH secretion, viz., pulsatile, basal, pattern-defined regularity [approximate entropy (ApEn)] and spikiness (sharp, brief excursions). Whether the same determinants apply to ACTH secretion is not known. SETTING The study was conducted at a tertiary medical center. SUBJECTS We studied normal women (n = 22) and men (n = 26) [ages, 23-77 yr; body mass index (BMI), 21-32 kg/m(2)]. METHODS Volunteers underwent 10-min blood sampling to create 24-h ACTH concentration profiles. OUTCOMES Dynamic measures of ACTH secretion were studied. RESULTS Mean ACTH concentrations (R(2) = 0.15; P = 0.006) and both pulsatile (R(2) = 0.12; P = 0.018) and basal (nonpulsatile) (R(2) = 0.16; P = 0.005) ACTH secretion correlated directly with BMI (n = 48). Men had greater basal (P = 0.047), pulsatile (P = 0.031), and total (P = 0.010) 24-h ACTH secretion than women, including when total secretion was normalized for BMI (P = 0.019). In men, both ACTH-cortisol feedforward and cortisol-ACTH feedback asynchrony (cross-ApEn) increased with age (R(2) = 0.20 and 0.22; P = 0.021 and 0.018). ACTH spikiness rose with age (P = 0.046), principally in women. Irregularity of cortisol secretion (ApEn) increased with age (n = 48; P = 0.010), especially in men. In both sexes, percentage pulsatile ACTH secretion predicted 24-h mean cortisol concentrations (R(2) = 0.14; P = 0.009). CONCLUSION Valid comparisons of ultradian ACTH dynamics will require cohorts matched for age, gender, and BMI, conditions hitherto not satisfied in most physiological studies of this axis.