madman
Super Moderator
ABSTRACT
Objective: To investigate the relationship between LH and T, which characteristics associated with the strength of this relationship, and their interrelationships with GH, TSH, cortisol, and ACTH.
Design: Hormones were measured in serum samples collected every 10 min for 24 h from 20 healthy men, comprising 10 offspring of long-lived families and 10 control subjects, with a mean (SD) age of 65.6 (5.3) years. We performed cross-correlation analyses to assess the relative strength between two time series for all possible time shifts.
Results: Mean (95% CI) maximal correlation was 0.21 (0.10–0.31) at lag time 60 min between LH and total T concentrations. Results were comparable for calculated free, bioavailable, or secretion rates of T. Men with strong LH-T cross-correlations had, compared to men with no cross-correlation, lower fat mass (18.5 (14.9–19.7) vs. 22.3 (18.4–29.4) kg), waist circumference (93.6 (5.7) vs. 103.1 (12.0) cm), hsCRP (0.7 (0.4–1.3) vs. 1.8 (0.8–12.3) mg/L), IL-6 (0.8 (0.6–1.0) vs. 1.2 (0.9–3.0) pg/mL), and 24-h mean LH (4.3 (2.0) vs. 6.1 (1.5) U/L), and stronger LH-T feedforward synchrony (1.5 (0.3) vs. 1.9 (0.2)). Furthermore, T was positively cross-correlated with TSH (0.32 (0.21–0.43)), cortisol (0.26 (0.19–0.33)), and ACTH (0.26 (0.19–0.32)).
Conclusions: LH is followed by T with a delay of 60 min in healthy older men. Men with a strong LH-T relationship had more favorable body composition, inflammatory markers, LH levels, and LH-T feedforward synchrony. We observed positive correlations between T and TSH, cortisol, and ACTH.
INTRODUCTION
Serum levels of several parameters from the hypothalamic-pituitary-gonadal (HPG) axis change with age in men, which has been reviewed by others (1,2). Total testosterone (T) levels decline moderately, but progressively with age, starting around the age of 30-40 years, while levels of sex hormone-binding globulin (SHBG) gradually increase with age, resulting in a steeper decline in serum levels of free T (2-5). The decline in T is a multifactorial process. Intervention studies have shown that aging in healthy men is accompanied by diminished gonadotropin-releasing hormone (GnRH) output, resulting in less luteinizing hormone (LH) drive on the Leydig cell, diminished testicular responsiveness to LH, while T feedback on the hypothalamus-pituitary unit is also decreased (6,7). The decline in T (free T) levels in males together with several sexual symptoms, when not caused by hypothalamus-pituitary disorders, including tumors, infections, and trauma, has been named late-onset hypogonadism (LOH) (8,9). Androgen deficiency is worsened by comorbidities, including diabetes mellitus, cardiac failure, renal disease, and chronic obstructive lung disease, obesity, medication, unhealthy lifestyle, and increased aromatase activity (1,9,10). Aside from age-related T decline, the increase of SHBG levels may mask a low serum-free T concentration. Factors influencing SHBG positively are thyroxine, estrogens, and anti-epileptic drugs, while insulin, IGF-1, prolactin, proinflammatory cytokines, and adiponectin decrease SHBG levels (11,12). With advancing age mean population LH levels increase, which can be attributed to diminished feedback on the gonadotrophic cells and hypothalamus centers involved in the secretion of GnRH. The diminished feedback is also revealed by amplified LH frequency and low amplitude pulses (13,14). It is worth noting that studies have shown that obesity, comorbidities, and lifestyle factors might be even better predictors for low T levels than age (3,5,15,16). In line, T levels were not lower in older men compared to younger men in a study with exceptionally healthy men nor in a study with men reporting themselves as having good or excellent health (17,18).
Although the underlying cellular mechanisms of the decline in T levels with age are not entirely clear, it is commonly thought that the age-related decline in T is a large contributor to many problems in older men (13). Therefore, T administration became a popular intervention in both hypogonadal and eugonadal men, and in both middle-aged and older men, especially in the USA (19,20). T administration might influence the secretion of hormones from other hypothalamic-pituitary-‘target gland’ axes. For example, one study in healthy older men showed that long-term low-dose T administration resulted in increased nocturnal growth hormone (GH) secretion (28), but not in spontaneous nocturnal cortisol secretion (29). Besides, with age, not only levels of LH and T change but levels of other pituitary hormones also change concomitantly with age. For example, elevated thyroid-stimulating hormone (TSH) levels and a decline in GH secretion have been observed with aging (30-32). It could be hypothesized that these hormonal changes are synchronized with each other, potentially because these endocrine systems share the ability to respond to changes in the environment in order to maintain homeostasis. In support of this hypothesis, anterior pituitary cells share the same embryonic origin, and there is evidence for crosstalk between pituitary cells (33-36). Recently, we observed interrelations between hormones from different hypothalamic-pituitary- ‘target gland’ axes, specifically between cortisol and TSH, GH and TSH, and between GH and cortisol concentrations, in healthy older men and women (37).
In a previous publication, we compared 24-h LH and T secretion parameters and the LH-T relationship between 10 healthy older male offspring of long-lived families to 10 healthy older male controls from the Leiden Longevity Study (38). We did not find an association between LH-T parameters and familial longevity. In the present study, we investigated the relationship between 24-h serum LH and T concentrations in the total population of 20 healthy older men from the Leiden Longevity Study and which health characteristics associated with the strength of this relationship. Furthermore, we aimed to determine the interrelationships between LH and T with GH, TSH, cortisol, and ACTH over 24 h. To this end, we performed cross-correlation analyses to assess the lative strength between two 24-h hormone concentration series at intervals of 10 min for all possible time shifts. Follicle-stimulating hormone (FSH) was not included in this study because its pulsatility is less pronounced due to its long half-life and low amplitude (39).
Summarizing, LH concentrations were followed by T concentrations/secretion with a delay of 60 min in healthy older men. The strength of an LH-T relationship was mainly associated with health factors, including body composition and inflammation markers, LH levels, and its feedforward drive, while chronological age and T levels were not associated with the strength of the LH-T relationship. Future research should aim to determine the role of the hypothalamus in this LH-T relationship and determine the importance of a strong LH-T relationship in aging men. Furthermore, we found that T concentrations were positively correlated with TSH, ACTH, and cortisol concentrations. These exploratory analyses could indicate that T and other hormones are driven by a common regulator or that there is crosstalk between these hormones. More research is needed to determine the biological meaning and clinical consequences of these interrelationships between T and other hormones.
Objective: To investigate the relationship between LH and T, which characteristics associated with the strength of this relationship, and their interrelationships with GH, TSH, cortisol, and ACTH.
Design: Hormones were measured in serum samples collected every 10 min for 24 h from 20 healthy men, comprising 10 offspring of long-lived families and 10 control subjects, with a mean (SD) age of 65.6 (5.3) years. We performed cross-correlation analyses to assess the relative strength between two time series for all possible time shifts.
Results: Mean (95% CI) maximal correlation was 0.21 (0.10–0.31) at lag time 60 min between LH and total T concentrations. Results were comparable for calculated free, bioavailable, or secretion rates of T. Men with strong LH-T cross-correlations had, compared to men with no cross-correlation, lower fat mass (18.5 (14.9–19.7) vs. 22.3 (18.4–29.4) kg), waist circumference (93.6 (5.7) vs. 103.1 (12.0) cm), hsCRP (0.7 (0.4–1.3) vs. 1.8 (0.8–12.3) mg/L), IL-6 (0.8 (0.6–1.0) vs. 1.2 (0.9–3.0) pg/mL), and 24-h mean LH (4.3 (2.0) vs. 6.1 (1.5) U/L), and stronger LH-T feedforward synchrony (1.5 (0.3) vs. 1.9 (0.2)). Furthermore, T was positively cross-correlated with TSH (0.32 (0.21–0.43)), cortisol (0.26 (0.19–0.33)), and ACTH (0.26 (0.19–0.32)).
Conclusions: LH is followed by T with a delay of 60 min in healthy older men. Men with a strong LH-T relationship had more favorable body composition, inflammatory markers, LH levels, and LH-T feedforward synchrony. We observed positive correlations between T and TSH, cortisol, and ACTH.
INTRODUCTION
Serum levels of several parameters from the hypothalamic-pituitary-gonadal (HPG) axis change with age in men, which has been reviewed by others (1,2). Total testosterone (T) levels decline moderately, but progressively with age, starting around the age of 30-40 years, while levels of sex hormone-binding globulin (SHBG) gradually increase with age, resulting in a steeper decline in serum levels of free T (2-5). The decline in T is a multifactorial process. Intervention studies have shown that aging in healthy men is accompanied by diminished gonadotropin-releasing hormone (GnRH) output, resulting in less luteinizing hormone (LH) drive on the Leydig cell, diminished testicular responsiveness to LH, while T feedback on the hypothalamus-pituitary unit is also decreased (6,7). The decline in T (free T) levels in males together with several sexual symptoms, when not caused by hypothalamus-pituitary disorders, including tumors, infections, and trauma, has been named late-onset hypogonadism (LOH) (8,9). Androgen deficiency is worsened by comorbidities, including diabetes mellitus, cardiac failure, renal disease, and chronic obstructive lung disease, obesity, medication, unhealthy lifestyle, and increased aromatase activity (1,9,10). Aside from age-related T decline, the increase of SHBG levels may mask a low serum-free T concentration. Factors influencing SHBG positively are thyroxine, estrogens, and anti-epileptic drugs, while insulin, IGF-1, prolactin, proinflammatory cytokines, and adiponectin decrease SHBG levels (11,12). With advancing age mean population LH levels increase, which can be attributed to diminished feedback on the gonadotrophic cells and hypothalamus centers involved in the secretion of GnRH. The diminished feedback is also revealed by amplified LH frequency and low amplitude pulses (13,14). It is worth noting that studies have shown that obesity, comorbidities, and lifestyle factors might be even better predictors for low T levels than age (3,5,15,16). In line, T levels were not lower in older men compared to younger men in a study with exceptionally healthy men nor in a study with men reporting themselves as having good or excellent health (17,18).
Although the underlying cellular mechanisms of the decline in T levels with age are not entirely clear, it is commonly thought that the age-related decline in T is a large contributor to many problems in older men (13). Therefore, T administration became a popular intervention in both hypogonadal and eugonadal men, and in both middle-aged and older men, especially in the USA (19,20). T administration might influence the secretion of hormones from other hypothalamic-pituitary-‘target gland’ axes. For example, one study in healthy older men showed that long-term low-dose T administration resulted in increased nocturnal growth hormone (GH) secretion (28), but not in spontaneous nocturnal cortisol secretion (29). Besides, with age, not only levels of LH and T change but levels of other pituitary hormones also change concomitantly with age. For example, elevated thyroid-stimulating hormone (TSH) levels and a decline in GH secretion have been observed with aging (30-32). It could be hypothesized that these hormonal changes are synchronized with each other, potentially because these endocrine systems share the ability to respond to changes in the environment in order to maintain homeostasis. In support of this hypothesis, anterior pituitary cells share the same embryonic origin, and there is evidence for crosstalk between pituitary cells (33-36). Recently, we observed interrelations between hormones from different hypothalamic-pituitary- ‘target gland’ axes, specifically between cortisol and TSH, GH and TSH, and between GH and cortisol concentrations, in healthy older men and women (37).
In a previous publication, we compared 24-h LH and T secretion parameters and the LH-T relationship between 10 healthy older male offspring of long-lived families to 10 healthy older male controls from the Leiden Longevity Study (38). We did not find an association between LH-T parameters and familial longevity. In the present study, we investigated the relationship between 24-h serum LH and T concentrations in the total population of 20 healthy older men from the Leiden Longevity Study and which health characteristics associated with the strength of this relationship. Furthermore, we aimed to determine the interrelationships between LH and T with GH, TSH, cortisol, and ACTH over 24 h. To this end, we performed cross-correlation analyses to assess the lative strength between two 24-h hormone concentration series at intervals of 10 min for all possible time shifts. Follicle-stimulating hormone (FSH) was not included in this study because its pulsatility is less pronounced due to its long half-life and low amplitude (39).
Summarizing, LH concentrations were followed by T concentrations/secretion with a delay of 60 min in healthy older men. The strength of an LH-T relationship was mainly associated with health factors, including body composition and inflammation markers, LH levels, and its feedforward drive, while chronological age and T levels were not associated with the strength of the LH-T relationship. Future research should aim to determine the role of the hypothalamus in this LH-T relationship and determine the importance of a strong LH-T relationship in aging men. Furthermore, we found that T concentrations were positively correlated with TSH, ACTH, and cortisol concentrations. These exploratory analyses could indicate that T and other hormones are driven by a common regulator or that there is crosstalk between these hormones. More research is needed to determine the biological meaning and clinical consequences of these interrelationships between T and other hormones.
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