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Context: Familial longevity is associated with higher circulating levels of thyrotropin (TSH), in the absence of differences in circulating thyroid hormones, and a lower thyroid responsivity to TSH, as previously observed in the Leiden Longevity Study (LLS). Further mechanisms underlying these observations remain unknown., Objective: We hypothesized that members from long-lived families (offspring) have higher thyroid hormone turnover or less negative feedback effect on TSH secretion compared to controls., Methods: In a case-control intervention study, 14 offspring and 13 similarly aged controls received 100 µg 3,5,3'-triiodothyronine (T3) orally. Their circulating T3, free T3 (fT3), and TSH levels were measured during 5 consecutive days. We compared profiles of circulating T3, fT3, and TSH between offspring and controls using general linear modeling (GLM) and calculated the percentage decline in TSH following T3 administration., Results: Circulating T3 and fT3 levels increased to supraphysiologic values and normalized over the course of 5 days. There were no serious adverse events. T3 and fT3 concentration profiles over 5 days were similar between offspring and controls (T3 GLM P = .11, fT3 GLM P = .46). TSH levels decreased in a biphasic manner and started returning to baseline by day 5. The TSH concentration profile over 5 days was similar between offspring and controls (GLM P = .08), as was the relative TSH decline (%)., Conclusions: Members of long-lived families have neither higher T3 turnover nor diminished negative feedback of T3 on TSH secretion. The cause and biological role of elevated TSH levels in familial longevity remain to be elucidated., (© Endocrine Society 2020.)

Context: Longevity is associated with higher circulating levels of TSH in the absence of differences in circulating thyroid hormones (TH), as previously observed in F2 members of long-lived families (F2-LLS) and their partners (F2-Con). The mechanism underlying this observed difference remains unknown., Objective: We hypothesized that the thyroid gland of members from long-lived families are less responsive to TSH stimulation, thereby requiring higher circulating TSH levels to maintain adequate TH levels., Methods: We performed a case-control intervention study with a single intramuscular (gluteal) injection with 0.1 mg recombinant human TSH in a subgroup of 14 F2-LLS and 15 similarly aged F2-Con. They were followed for 4 days. No serious adverse events were reported. For analyses, we compared time trajectories of TSH and TH, and the ratio of TH to TSH using area under the curve (AUC) calculations., Results: The AUC free T4/AUC TSH ratio was significantly lower in F2-LLS than in F2-Con (estimated mean [95% confidence interval] 1.6 [1.2-1.9] and 2.2 [1.9-2.6], respectively, P = 0.01). The AUC thyroglobulin/AUC TSH ratio was also lower in F2-LLS than in F2-Con (median [interquartile range] 2.1 [1.4-3.6] and 3.2 [2.7-7.4], respectively, P = 0.04). We observed the same trend with the AUC free T3/AUC TSH ratio, although the difference was not statistically significant (estimated mean [95% confidence interval] 0.6 [0.4-0.7] and 0.7 [0.6-0.8], respectively, P = 0.07)., Conclusions: The present findings show that members of long-living families have a lower thyroid responsivity to TSH compared with their partners., (© Endocrine Society 2020.)

Background: Interleukin-2 (IL-2), one of the proinflammatory cytokines, is used in the treatment of certain malignancies. In some studies, transient increases in cortisol and ACTH secretion occurred. Thus, this agent may be used as an experimental probe of adrenal cortisol secretion., Objective: This study quantifies the effects of low and moderate doses of IL-2 on cortisol secretion and assesses the modulation by age, dose and body composition., Site: Mayo Clinical Translational Research Unit., Subjects: Study comprised 35 healthy men, 17 young and 18 older., Methods: Randomized prospective double-blind saline-controlled study of IL-2 administration in two doses with concurrent 10-min blood sampling for 24 h., Outcome Measures: Deconvolution analysis and approximate entropy of cortisol secretion., Results: Low-dose IL-2 administration increased nocturnal pulsatile cortisol secretion from 1460 ± 160 to 2120 ± 220 nmol/L/8 h in young subjects and from 1680 ± 105 to 1960 ± 125 nmol/L/8 h (treatment P < 0.0001, but more in young than older, P = 0.02). Comparable results were obtained for total cortisol secretion (P treatment <0.0001, age effect P = 0.005). The higher IL-2 dose caused a large increase in young (P < 0.0001), but not in older (P = 0.90) subjects. This dose also increased approximate entropy from 0.877 ± 0.041 to 1.024 ± 0.049 (P = 0.008), pointing to reduced secretory orderliness. Incremental cortisol (nocturnal) secretion correlated negatively with visceral fat mass (R = -0.41, P = 0.019)., Conclusion: In healthy men, IL-2 injection drives pulsatile cortisol secretion in a dose-dependent way in young, but not older, individuals and erodes cortisol secretory orderliness at a higher dose in young subjects. Cortisol responses are diminished with increasing abdominal visceral fat mass.

Context: Patients with critical illness are thought to be at risk of adrenal insufficiency. There are no models of dynamic hypothalamic-pituitary-adrenal (HPA) axis function in this group of patients and thus current methods of diagnosis are based on aggregated, static models., Objective: To characterize the secretory dynamics of the HPA axis in the critically ill (CI) after cardiac surgery., Design: Mathematical modeling of cohorts., Setting: Cardiac critical care unit., Patients: 20 male patients CI at least 48 hours after cardiac surgery and 19 healthy (H) male volunteers., Interventions: None., Main Outcome Measures: Measures of hormone secretory dynamics were generated from serum adrenocorticotrophic hormone (ACTH) sampled every hour and total cortisol every 10 min for 24 h., Results: All CI patients had pulsatile ACTH and cortisol profiles. CI patients had similar ACTH secretion (1036.4 [737.6] pg/mL/24 h) compared to the H volunteers (1502.3 [1152.2] pg/mL/24 h; P = .20), but increased cortisol secretion (CI: 14 447.0 [5709.3] vs H: 5915.5 [1686.7)] nmol/L/24 h; P < .0001). This increase in cortisol was due to nonpulsatile (CI: 9253.4 [3348.8] vs H: 960 [589.0] nmol/L/24 h, P < .0001), rather than pulsatile cortisol secretion (CI: 5193.1 [3018.5] vs H: 4955.1 [1753.6] nmol/L/24 h; P = .43). Seven (35%) of the 20 CI patients had cortisol pulse nadirs below the current international guideline threshold for critical illness-related corticosteroid insufficiency, but an overall secretion that would not be considered deficient., Conclusions: This study supports the premise that current tests of HPA axis function are unhelpful in the diagnosis of adrenal insufficiency in the CI. The reduced ACTH and increase in nonpulsatile cortisol secretion imply that the secretion of cortisol is driven by factors outside the HPA axis in critical illness., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Hormones of the hypothalamic-pituitary-target gland axes are mostly investigated separately, whereas the interplay between hormones might be as important as each separate hormonal axis., Objective: Our aim is to determine the interrelationships between GH, TSH, ACTH, and cortisol in healthy older individuals., Design: We made use of 24-hour hormone serum concentrations assessed with intervals of 10 minutes from 38 healthy older individuals with a mean age (SD) of 65.1 (5.1) years from the Leiden Longevity Study. Cross-correlation analyses were performed to assess the relative strength between 2 24-hour hormone serum concentration series for all possible time shifts. Cross-approximate entropy was used to assess pattern synchronicity between 2 24-hour hormone serum concentration series., Results: Within an interlinked hormonal axis, ACTH and cortisol were positively correlated with a mean (95% confidence interval) correlation coefficient of 0.78 (0.74-0.81) with cortisol following ACTH concentrations with a delay of 10 minutes. Between different hormonal axes, we observed a negative correlation coefficient between cortisol and TSH of -0.30 (-0.36 to -0.25) with TSH following cortisol concentrations with a delay of 170 minutes. Furthermore, a positive mean (95% confidence interval) correlation coefficient of 0.29 (0.22-0.37) was found between TSH and GH concentrations without any delay. Moreover, cross-approximate entropy analyses showed that GH and cortisol exhibit synchronous serum concentration patterns., Conclusions: This study demonstrates that interrelations between hormones from interlinked as well as different hypothalamic-pituitary-target gland axes are observed in healthy older individuals. More research is needed to determine the biological meaning and clinical consequences of these observations., (© Endocrine Society 2019.)

Background: Aging is associated with diminished testosterone (Te) secretion, which may be attributed to Leydig cell dysfunction, decreased pituitary stimulation, and altered Te feedback., Objective: To study all regulatory nodes-gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and Leydig cell-in the same cohort of healthy men., Study Design: This was a placebo-controlled, blinded, prospectively randomized cross-over study in 40 men, age range 19 to 73 years, and body mass index (BMI) range 20 to 34.3 kg/m2. A submaximal dose of the GnRH antagonist ganirelix was used to assess outflow of GnRH, by calculating the difference between LH output during the control arm and ganirelix arm. Ketoconazole (a steroidogenic inhibitor) was used to estimate feedback, by the difference in LH output during the ketoconazole and control arm. High-dose ganirelix and repeated LH infusions were used to measure testicular responsivity. Blood sampling was performed at 10-minute intervals., Results: There were age-related, but not body composition-related decreases in estimated GnRH secretion, the feedback strength of Te on LH, and Leydig cell responsivity to LH, accompanied by changes in approximate entropy. Bioavailable Te levels were negatively related to both age and computed tomography (CT)-estimated abdominal visceral mass (AVF), without interaction between these variables. The LH response to a submaximal dose of GnRH was independent of age and AVF., Conclusion: Advancing age is associated with (1) attenuated bioavailable Te secretion caused by diminished GnRH outflow and not by decreased GnRH responsivity of the gonadotrope, (2) diminished testicular responsivity to infused LH pulses, and (3) partial compensation by diminished Te feedback on central gonadotropic regulation., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition., Objective: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function., Patients, Design, and Setting: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting., Main Outcome Measures: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates., Results: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels., Conclusions: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure., (© Endocrine Society 2019.)

The progesterone receptor (PR, encoded by Pgr) plays essential roles in reproduction. Female mice lacking the PR are infertile, due to the loss of the protein's functions in the brain, ovary, and uterus. PR is also expressed in pituitary gonadotrope cells, but its specific role therein has not been assessed in vivo. We therefore generated gonadotrope-specific Pgr conditional knockout mice (cKO) using the Cre-LoxP system. Overall, both female and male cKO mice appeared phenotypically normal. cKO females displayed regular estrous cycles (vaginal cytology) and normal fertility (litter size and frequency). Reproductive organ weights were comparable between wild-type and cKO mice of both sexes, as were production and secretion of the gonadotropins, LH and FSH, with one exception. On the afternoon of proestrus, the amplitude of the LH surge was blunted in cKO females relative to controls. Contrary to predictions of earlier models, this did not appear to derive from impaired GnRH self-priming. Collectively, these data indicate that PR function in gonadotropes may be limited to regulation of LH surge amplitude in female mice via a currently unknown mechanism.

Measurement errors commonly occur in 24-h hormonal data and may affect the outcomes of such studies. Measurement errors often appear as outliers in such data sets; however, no well-established method is available for their automatic detection. In this study, we aimed to compare performances of different methods for outlier detection in hormonal serial data. Hormones (glucose, insulin, thyroid-stimulating hormone, cortisol, and growth hormone) were measured in blood sampled every 10 min for 24 h in 38 participants of the Leiden Longevity Study. Four methods for detecting outliers were compared: (1) eyeballing, (2) Tukey's fences, (3) stepwise approach, and (4) the expectation-maximization (EM) algorithm. Eyeballing detects outliers based on experts' knowledge, and the stepwise approach incorporates physiological knowledge with a statistical algorithm. Tukey's fences and the EM algorithm are data-driven methods, using interquartile range and a mathematical algorithm to identify the underlying distribution, respectively. The performance of the methods was evaluated based on the number of outliers detected and the change in statistical outcomes after removing detected outliers. Eyeballing resulted in the lowest number of outliers detected (1.0% of all data points), followed by Tukey's fences (2.3%), the stepwise approach (2.7%), and the EM algorithm (11.0%). In all methods, the mean hormone levels did not change materially after removing outliers. However, their minima were affected by outlier removal. Although removing outliers affected the correlation between glucose and insulin on the individual level, when averaged over all participants, none of the 4 methods influenced the correlation. Based on our results, the EM algorithm is not recommended given the high number of outliers detected, even where data points are physiologically plausible. Since Tukey's fences is not suitable for all types of data and eyeballing is time-consuming, we recommend the stepwise approach for outlier detection, which combines physiological knowledge and an automated process.

Background: Oral administration of estradiol (E2) generally increases GH secretion in postmenopausal women. Oral administration of E2 is associated with a decrease in IGF-1, whereas parenteral or transdermally administered E2 may have no effect on GH. The effect of progesterone (P4) on GH secretion has rarely been studied. We hypothesized that moderately increased serum E2 levels stimulate GH and that P4 modulates E2-stimulated GH secretion., Study Design: Four parallel groups of randomly assigned postmenopausal women (n = 40). Treatments were saline placebo and oral placebo, saline placebo and oral micronized P4 (3 × 200 mg/d IM), E2 (5 mg IM) and oral placebo, and E2 IM and oral micronized P4. Outcome measures were overnight GH secretion (10 hours), stimulated (ghrelin, 0.3 µg/kg IV bolus) GH secretion, and CT-estimated visceral fat., Results: Intramuscular E2 administration did not alter nocturnal and ghrelin-stimulated GH secretion. Nocturnal GH secretion was not changed by P4 administration. However, P4 diminished ghrelin-stimulated pulsatile GH release with or without E2 (average, 7.20 ± 2.14 and 9.58 ± 1.97 µg/L/2 h, respectively; P = 0.045). Respective outcomes for mean GH concentrations and GH peak amplitudes were 0.97 ± 0.31 and 1.52 μg/L ± 0.29 (P = 0.025) and 2.76 ± 1.04 and 3.95 μg/L ± 0.90 (P = 0.031). Ghrelin-stimulated GH secretion correlated negatively with P4 concentration with or without correction for visceral fat area in the regression equation (R = 0.49, P = 0.04, β = -0.040 ± 0.016)., Conclusions: Low-range physiological E2 concentrations do not affect spontaneous or ghrelin-stimulated pulsatile GH secretion. Conversely, P4 inhibits ghrelin-stimulated GH secretion in a concentration-dependent fashion. The mechanistic aspects and physiological significance of natural P4's regulation of ghrelin-evoked GH secretion require further study., (Copyright © 2019 Endocrine Society.)

The process of bone turnover displays variations over 24 h, with C-terminal cross-linked telopeptide of type 1 collagen (CTX) and osteocalcin exhibiting a nadir in the afternoon and a peak in the night. In contrast, N-terminal propeptide of type 1 procollagen (P1NP) did not display an apparent 24-hour rhythm. Other emerging novel biomarkers of bone, sclerostin and Dickkopf-related protein 1 (DKK1), are markers of osteocyte activity with limited data available regarding their 24-hour profiles. In this study, we aimed to extend available data on 24-hour profiles of CTX, osteocalcin, and P1NP and to assess the 24-hour profiles of sclerostin and DKK1 in healthy older men and women and to compare these between men and women. We measured these five bone markers in EDTA plasma collected every 4 h during 24 h in 37 healthy older men and women (range 52-76 years). Differences between time points were determined using repeated measures ANOVA and cosinor analyses were performed to determine circadian rhythmicity. The circadian rhythm of CTX was confirmed by the cosinor model, with women showing larger amplitude compared to men. Osteocalcin showed higher levels during nighttime compared to daytime in both men and women. For P1NP levels we observed a small but significant increase in the night in men. Sclerostin and DKK1 did not show a circadian rhythm, but sclerostin levels differed between time points. Because of the large intraindividual variation, DKK1 as measured in this study cannot be considered a reliable marker for diagnostic or research purposes. In conclusion, when measuring CTX, osteocalcin, P1NP, or sclerostin either in clinical practice or in a research setting, one should consider the 24-hour profiles of these bone markers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Context: Testosterone (T) increases GH secretion in older men with a relative lack of T, in hypogonadal men of all ages, and in patients undergoing sex reassignment. The role of estradiol (E2) in men is less well defined., Objective: To assess the contribution of aromatization of T to spontaneous nocturnal and stimulated GH secretion., Participants: Four groups of healthy older men (N = 74, age range 57 to 77 years) were studied. The gonadotropic axis was clamped with the gonadotropin-releasing hormone antagonist degarelix. Three groups received T and one group placebo addback. Two T-replaced groups were treated with anastrozole (an aromatase inhibitor) and either placebo or E2 addback., Main Outcome Measures: Ten-minute GH concentration profiles were quantified by deconvolution analysis, after overnight (2200 to 0800 hours) sampling, and after combined IV injection of GHRH (0.3 µg/kg) and GHRH-2 (0.3 µg/kg) and withdrawal of a 2-hour somatostatin infusion (1 µg/kg/h)., Results: E2 addback during aromatase inhibition increased basal (P = 0.046), pulsatile (P = 0.020), and total (P = 0.018) GH secretion by 60% to 70%. E2 did not potentiate GH secretory stimuli. Logarithmically transformed pulsatile GH secretion correlated strongly and positively with concurrent E2 concentrations overall (P = 0.028) and under anastrozole treatment (P = 0.005)., Conclusion: E2 administration in older men transdermally stimulates overnight pulsatile GH secretion. The exact site of E2 action cannot be ascertained from these experiments but may include hypothalamic loci involved in GH regulation, especially because GH secretagogue effects on somatotrope pituitary cells were not affected.

Context: Quantitative studies of the short-term feedback of testosterone (T) on luteinizing hormone (LH) secretion in healthy men are relatively rare. Such studies require the shutting down of endogenous T secretion and the imposition of experimentally controlled IV T addback., Objective: To evaluate whether pulsatile and continuous T delivery confers equivalent negative feedback on LH secretion., Design: This was a placebo-controlled, blinded, and prospectively randomized crossover study comprising 16 healthy men [age range 23 to 54 years and a body mass index (BMI) between 22.3 and 34.2 kg/m 2 ]. Subjects received ketoconazole to block endogenous T secretion and received continuous or 90-minute pulses of IV T addback., Setting: The study was performed in a Clinical Translational Research Unit., Interventions: Subjects underwent 14 hours of blood sampling at 10-minute intervals, with a bolus IV injection of 33 ng/kg gonadotropin-releasing hormone (GnRH)., Main Outcome Measures: Log-transformed LH and T concentration ratios before and after GnRH administration., Results: Despite higher T concentrations during pulsatile T feedback, LH concentrations and secretion rates, whether driven by endogenous or exogenous GnRH, were similar to those during continuous T infusion, indicating diminished pulsatile T feedback. Feedback correlated negatively with BMI. Under controlled T feedback, basal but not pulsatile LH secretion correlated negatively with CT-estimated visceral fat mass., Conclusion: Feedback by pulsatile T delivery has diminished inhibitory strength compared with continuous infusion. Feedback is negatively correlated with BMI.

Background: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern., Methods: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice., Results: We found mutations in the insulin receptor substrate 4 ( IRS4 ) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutations (two novel) in three patients and one male sibling. All male carriers (n=8) had CeH with plasma free thyroxine concentrations below the reference interval. MRI of the hypothalamus and pituitary showed no structural abnormalities (n=12). 24-hour thyroid-stimulating hormone (TSH) secretion profiles in two adult male patients showed decreased basal, pulsatile and total TSH secretion . IRS4 mRNA was expressed in human hypothalamic nuclei, including the paraventricular nucleus, and in the pituitary gland. Female knockout mice showed decreased pituitary Tshb mRNA levels but had unchanged serum thyroid hormone concentrations., Conclusions: Mutations in IRS4 are associated with isolated CeH in male carriers. As IRS4 is involved in leptin signalling, the phenotype may be related to disrupted leptin signalling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Experimentally controlled studies of estrogenic regulation of lipid measures and inflammatory cytokines in men are rare., Objective: To delineate the effect of estradiol (E 2 ) on lipids and inflammatory markers., Design: This was a placebo-controlled, single-masked, prospectively randomized study comprising experimentally degarelix-downregulated healthy men [n = 74; age 65 years (range, 57 to 77)] assigned to four treatment groups: (1) IM saline and oral placebo; (2) IM testosterone and oral placebo; (3) IM testosterone and oral anastrozole (aromatase inhibitor); and (4) IM testosterone, oral anastrozole, and transdermal E 2 for 22 (±1) days., Results: Mean mass spectrometry-quantified serum E 2 concentrations ranged from 1.2 to 82 pg/mL in the four treatment groups. E 2 extremes did not alter total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol (HDL-C) , non-HDL-C, apolipoprotein B, lipoprotein (a), IL-6, or high-sensitivity C-reactive protein (hsCRP) concentrations. Higher E 2 concentrations elevated both sex hormone-binding globulin and prolactin as positive controls. LDL cholesterol, adiponectin, and leptin were higher in hypogonadal subjects without testosterone or E 2 addback ( P = 0.018, 0.039, and 0.023, respectively). Abdominal visceral fat area by CT (independent variable) correlated negatively with HDL-C ( P = 0.017), and positively with triglycerides ( P = 0.004), hsCRP ( P = 0.005), and leptin ( P < 0.0001)., Conclusion: In this placebo-controlled prospectively randomized study, wide variations in circulating E 2 did not influence lipid measures and inflammatory markers when testosterone concentrations were controlled experimentally. However, medically induced central hypogonadism in older men was accompanied by increased LDL cholesterol and metabolic cytokines, adiponectin and leptin. Abdominal visceral fat correlated strongly and positively with triglycerides, hsCRP, and leptin, but negatively with HDL.

Context: Controlled, blinded studies of sex-hormone replacement in postmenopausal women using natural estradiol (E 2 ) and native progesterone (P) are few., Objective: To delineate the effect of E 2 alone or with P on lipids and inflammatory markers., Design: A placebo-controlled, double-masked, prospectively randomized study of 40 healthy, postmenopausal volunteers assigned to four treatment groups: placebo, intramuscular E 2 , and/or micronized oral P for 23 (±2) days., Results: Treatment with E 2 alone compared with placebo lowered total cholesterol (TC; P = 0.006), non-high-density lipoprotein cholesterol (nonHDL-C; P = 0.004), low-density lipoprotein cholesterol (LDL-C; P = 0.012), and apolipoprotein B (Apo B; P = 0.02) levels, and raised HDL-C levels ( P = 0.03 vs the 3 other groups). Conversely, addition of P to E 2 reduced HDL-C levels ( P = 0.015). Triglyceride concentrations manifested no effect on E 2 or P. High-sensitivity C-reactive protein (hsCRP) level was highest in women with E 2 and P replacement ( P = 0.018 vs placebo). Leptin and IL-6 concentrations did not vary. P treatment decreased adiponectin levels ( P = 0.019). Serum E 2 levels correlated linearly with TC, LDL-C, nonHDL-C, Apo B (all negatively), and SHBG (positively) concentrations. P level correlated negatively with TC ( P = 0.029), HDL-C ( P = 0.002), and adiponectin ( P = 0.002) levels., Conclusion: In this study, there were individual and interactive effects of E 2 and P on key lipids in postmenopausal individuals.

Objective: In rare disease research, most randomized prospective clinical trials can only use limited number of patients and are comprised of highly heterogeneous populations. Therefore, it is crucial to report the results in such a manner that it allows for comparison of treatment effectiveness and biochemical control between studies. The aim of this review was to investigate the current methods that are being applied to measure and report growth hormone (GH) and insulin-like growth factor-1 (IGF-1) as markers for drug effectiveness in clinical acromegaly research., Search Strategy: A systematic search of recent prospective and retrospective studies, published between 2012 and 2017, that studied the effects of somatostatin analogues or dopamine agonists in acromegaly patients was performed. The markers of interest were GH, IGF-1, and the suppression of GH after an oral glucose tolerance test (OGTT). Additionally, the use of pharmacokinetic (PK) measurements in these studies was analyzed. The sampling design, cut-off for biochemical control, reported units, and used summary statistics were summarized., Results: A total of 49 articles were selected out of the 263 screened abstracts. IGF-1 concentrations were measured in all 49 studies, GH in 45 studies, and an OGTT was performed in 11 studies. A wide range of different cut-off values and sampling designs were used to determine biochemical control in acromegaly patients. The summary statistics were reported in various ways, with the percentage of biochemical control most frequently used. Nine studies sampled the PK at one or more time points. Non-compartmental analyses were commonly performed on the available PK data., Conclusions: The way GH and IGF-1 are measured and reported in acromegaly research varies considerably. A consensus on how to report study results would enable better comparisons between studies, thereby improving evidence based decision making to optimize treatment in acromegaly.

Context: Estrogens amplify spontaneous and stimulated growth hormone (GH) secretion, whereas they diminish GH-dependent insulin-like growth factor (IGF)-I in a dose-dependent manner. Selective estrogen receptor modulators (SERMs), including tamoxifen and toremifene, are widely adjunctively used in breast and prostate cancer. Although some endocrine effects of tamoxifen are known, few data are available for toremifene., Objective: To explore sex-dependent effects of toremifene on spontaneous 10-hour overnight GH secretion, followed by GH-releasing hormone-ghrelin stimulation. Additionally, effects on IGF-I, its binding proteins, and sex hormone-binding globulin (SHBG) were quantified., Participants and Design: Twenty men and 20 women, within an allowable age range of 50 to 80 years, volunteered for this double-blind, placebo-controlled prospective crossover study. Ten-minute blood sampling was done for 10 hours overnight and then for 2 hours after combined GH-releasing hormone-ghrelin injection., Main Outcome Measures: Pulsatile GH and stimulated GH secretion, and fasting levels of IGF-I, IGF-binding protein (IGFBP)1, IGFBP3, and SHBG., Results: Toremifene did not enhance pulsatile or stimulated GH secretion, but decreased IGF-I by 20% in men and women. IGFBP3 was unchanged, whereas while IGFBP1 and SHBG increased in both sexes to a similar extent., Conclusions: The expected rise in spontaneous and stimulated GH secretion under the diminished negative feedback restraint of powered IGF-I favors a central inhibitory antiestrogenic effect of toremifene. Estrogenic effects of toremifene on the liver were present, as evidenced by increased IGFBP1 and SHBG levels. Men and women responded to this SERM comparably.

Thyroid hormones are essential for growth, differentiation and metabolism during prenatal and postnatal life. The hypothalamus-pituitary-thyroid (HPT)-axis is optimized for these actions. Knowledge of this hormonal axis is derived from decades of experiments in animals and man, and more recently from spontaneous mutations in man and constructed mutations in mice. This review examines the HPT-axis in relation to 24 h TSH profiles in men in various physiological and pathophysiological conditions, including obesity, age, longevity, and primary as well as central hypothyroidism. Hormone rhythms can be analyzed by quantitative methods, e.g. operator-independent deconvolution, approximate entropy and fitting the 24-h component by Cosinor analysis or related procedures. These approaches have identified some of the regulatory components in (patho)physiological conditions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Context: Studies on 24-h cortisol secretion are rare. The impact of sex, age and adiposity on cortisol levels, often restricted to one or a few samples, are well recognized, but conflicting., Objective: To investigate cortisol dynamics in 143 healthy men and women, spanning 7 decades and with a 2-fold body mass index (BMI) range with different analytic tools., Setting: Clinical Research Unit., Design: Cortisol concentrations in 10-min samples collected for 24 h. Outcomes were mean levels, deconvolution parameters, approximate entropy (ApEn, regularity statistic) and 24-h rhythms., Results: Total 24-h cortisol secretion rates estimated by deconvolution analysis were sex, age and BMI independent. Mean 24-h cortisol concentrations were lower in premenopausal women than those in men of comparable age (176 ± 8.2 vs 217 ± 9.4 nmol/L, P  = 0.02), but not in subjects older than 50 years. This was due to lower daytime levels in women, albeit similar in the quiescent overnight period. Aging increased mean cortisol by 10 nmol/L per decade during the quiescent secretory phase and advanced the acrophase of the diurnal rhythm by 24 min/decade. However, total 24-h cortisol secretion rates estimated by deconvolution analysis were sex, age and BMI independent. ApEn of 24-h profiles was higher (more random) in premenopausal women than those in men (1.048 ± 0.025 vs 0.933 ± 0.023, P  = 0.001), but not in subjects older than 50 years. ApEn peaked during the daytime., Conclusion: Sex and age jointly determine the 24-h cortisol secretory profile. Sex effects are largely restricted to age <50 years, whereas age effects elevate concentrations in the late evening and early night and advance the timing of the peak diurnal rhythm., (© 2017 The authors.)

Background: Adrenocorticotropic hormone (ACTH) secretion is controlled by unobservable hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) pulses. Clamping exogenous CRH or AVP input could allow indirect quantification of the impact of the endogenous heterotypic hormone., Methods: We conducted a randomized, double-blind, placebo-controlled, crossover study in 28 healthy adults (16 men). Volunteers underwent a sex-steroid clamp and a cortisol clamp. ACTH was measured over 10 hours by 10-minute sampling during each of four randomized intravenous (IV) secretagogue clamps (i.e., continuous IV CRH, AVP, both peptides, or saline). Desensitization was tested by bolus injection of the noninfused peptide., Results: Mean ± standard error of the mean 10-hour ACTH concentrations (ng/L) in the sex-combined analysis were: saline, 32 ± 4.6; AVP, 29 ± 4.6; CRH, 67 ± 6.2; and CRH-AVP, 67 ± 8.8 (any CRH vs AVP or saline, P < 0.0001). CRH and AVP increased approximate entropy (relative randomness) of ACTH release (P < 0.0001). Bolus AVP injection after CRH infusion yielded a 2.5-hour ACTH concentration of 46 ± 4.3, exceeding that seen after bolus CRH or saline injection (26 ± 3.3 and 24 ± 3.6, respectively; P = 0.002 and 0.001). Sex hormone clamps did not influence ACTH levels., Conclusions: A CRH, but not AVP, clamp yields sustained pulsatile ACTH secretion with high ACTH secretory-burst mass and randomness. After 10-hour CRH infusion, bolus AVP but not CRH, evoked marked ACTH release, likely caused by heterotypic sensitization of corticotropes by CRH. Similar interactions might underlie chronic stress states., (Copyright © 2017 Endocrine Society)

Context: Exercise elicits incompletely defined adaptations of metabolic and endocrine milieu, including the gonadotropic and corticotropic axes., Objective: To quantify the impact of acute exercise on coordinate luteinizing hormone (LH) and testosterone (T) and adrenocorticotropic hormone (ACTH) and cortisol secretion in healthy men in relation to age., Participants and Design: Prospectively randomized, within-subject crossover study in 23 men aged 19 to 77 years old. Subjects underwent rest and 30 minutes of mixed exercise at 65% of maximal aerobic capacity with 10-minute blood sampling between 7:00 am and 1:00 pm, 2 weeks apart., Main Outcome Measures: Incremental changes in LH, T, ACTH, and cortisol concentrations, the feedforward and feedback strength between exercise and rest, quantified by approximate entropy (ApEn), and bihormonal synchrony, quantitated by cross-ApEn., Results: Mean hourly exercise-minus-rest LH and ACTH increments increased from -0.055 ± 0.187 to 0.755 ± 0.245 IU/L (P = 0.003) and from 2.9 ± 2.2 to 71.2 ± 16.1 ng/L (P < 0.0001), respectively, during exercise. T and cortisol increments increased concurrently from -9.6 ± 16.7 to 47.6 ± 17.1 ng/dL (P < 0.0001) and 0.45 ± 0.76 to 7.27 ± 0.64 µg/dL (P < 0.0001), respectively. During exercise, feedforward and feedback LH-T and ACTH-cortisol cross-ApEn decreased markedly quantifying enhanced hormonal coupling., Conclusions: Acute moderate mixed exercise in healthy men rapidly enhances feedforward LH-T and ACTH-cortisol coordination and reciprocal feedback within the gonadotropic and corticotropic axes. In principle, enhancement of both LH-T and ACTH-cortisol secretory synchrony by exercise could reflect augmented coupling between brain-testicular and brain-adrenal neural outflow., (Copyright © 2017 Endocrine Society)

Reduced growth hormone (GH) signaling has been consistently associated with increased health and lifespan in various mouse models. Here, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle-aged offspring of long-living families from the Leiden Longevity Study together with 18 of their partners as controls. Circulating GH concentrations were measured every 10 min and insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) every 4 h. Using deconvolution analysis, we found that 24-h total GH secretion was 28% lower (P = 0.04) in offspring [172 (128-216) mU L -1 ] compared with controls [238 (193-284) mU L -1 ]. We used approximate entropy (ApEn) to quantify the strength of feedback/feedforward control of GH secretion. ApEn was lower (P = 0.001) in offspring [0.45 (0.39-0.53)] compared with controls [0.66 (0.56-0.77)], indicating tighter control of GH secretion. No significant differences were observed in circulating levels of IGF-1 and IGFBP3 between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Context: A trade-off between fertility and longevity possibly exists. The association of the male hypothalamic-pituitary-gonadal (HPG) axis with familial longevity has not yet been investigated., Objective: To study 24-h hormone concentration profiles of the HPG axis in men enriched for familial longevity and controls., Design: We frequently sampled blood over 24 h in 10 healthy middle-aged male offspring of nonagenarian participants from the Leiden Longevity Study together with 10 male age-matched controls. Individual 24-h luteinizing hormone (LH) and testosterone concentration profiles were analyzed by deconvolution analyses to estimate secretion parameters. Furthermore, the temporal relationship between LH and testosterone was assessed by cross-correlation analysis. We used (cross-)approximate entropy to quantify the strength of feedback and/or feedforward control of LH and testosterone secretion., Results: Mean [95% confidence interval (CI)] total LH secretion of the offspring was 212 (156-268) U/L/24 h, which did not differ significantly ( p  = 0.51) from the total LH secretion of controls [186 (130-242) U/L/24 h]. Likewise, mean (95% CI) total testosterone secretion of the offspring [806 (671-941) nmol/L/24 h] and controls [811 (676-947) nmol/L/24 h] were similar ( p  = 0.95). Other parameters of LH and testosterone secretion were also not significantly different between offspring and controls. The temporal relationship between LH and testosterone and the strength of feedforward/feedback regulation within the HPG axis were similar between offspring of long-lived families and controls., Conclusion: This relatively small study suggests that in healthy male middle-aged participants, familial longevity is not associated with major differences in the HPG axis. Selection on both fertility and health may in part explain the results.

Context: Factors that regulate physiological feedback by pulses of glucocorticoids on the hypothalamic-pituitary unit are sparsely defined in humans in relation to gluco- or mineralocorticoid receptor pathways, gender, age, and the sex steroid milieu., Objective: The objective of the study was to test (the clinical hypothesis) that glucocorticoid (GR) and mineralocorticoid (MR) receptor-selective mechanisms differentially govern pulsatile cortisol-dependent negative feedback on ACTH output (by the hypothalamo-pituitary unit) in men and women studied under experimentally defined T and estradiol depletion and repletion, respectively., Setting: The study was conducted at the Mayo Center for Translational Science Activities., Subjects: Healthy middle-aged men (n = 16) and women (n = 25) participated in the study., Interventions: This was a randomized, prospective, double-blind, placebo- and saline-controlled study of pulsatile cortisol infusions in low cortisol-clamped volunteers with and without eplerenone (MR blocker) and mifepristone (GR blocker) administration under a low and normal T and estradiol clamp. During frequent sampling, a bolus of CRH-arginine vasopressin was infused to assess corticotrope responsiveness. Analytical Methods and Outcomes: Deconvolution and approximate entropy of ACTH profiles were measured., Results: Infusion of cortisol (but not saline) pulses diminished ACTH secretion. The GR antagonist, mifepristone, interfered with negative feedback on both ACTH burst mass and secretion regularity. Eplerenone, an MR antagonist, exerted no detectable effect on the same parameters. Despite feedback imposition, CRH-arginine vasopressin-stimulated ACTH secretion was also increased by mifepristone and not by eplerenone. Withdrawal vs addback of sex steroids had no effect on ACTH secretion parameters. Nonetheless, ACTH secretion was greater (P = .006) and more regular (P = .004) in men than women., Conclusion: Pulsatile cortisol feedback on ACTH secretion in this paradigm is mediated by the glucocorticoid receptor, in part acting at the level of the pituitary, and influenced by sex.

Context: Optimal blood sampling schemas of GH for the estimation of the 24-hour secretion rate have not been established in acromegalic patients., Objective: By censoring available 24-hour GH serum profiles, we investigated the reliability of such simplified schemas. Design, Subjects, and Methods: We used 24-hour serum GH concentration profiles obtained with 10-minute sampling in a large cohort of healthy subjects (n = 130; mean age, 42; range, 18-77 years) and acromegalic patients (n = 87; mean age, 48; range 18-72 years). Patient categories were active disease, surgically cured, and somatostatin analog-treated individuals. The regression coefficients of determination (R(2)) and the linear slopes (β) between 24-hour secretion rates or mean concentrations (144 samples) on the one hand and mean values with less frequent sampling on the other, decreased in controls and in patients a short (1-2 weeks) or long (2-5 years) time after successful surgery. By contrast, the regression parameters remained essentially unchanged in patients with active acromegaly and those under GH suppressive treatment. Excellent correlations (R(2) ≥ 0.90) without GH underestimation existed between mean GH of daytime profiles and mean GH of 24-hour profiles and GH secretion rates estimated by deconvolution in patients with active acromegaly and patients treated with somatostatin analogs., Conclusion: Simplified sampling schemes, particularly a day profile, can be used for the estimation of GH secretion in patients with active acromegaly and under medical treatment. However, in healthy controls and patients after successful surgery, prolonged and frequent sampling schemes, at least at 2-hour intervals, reliably reflect 24-hour secretion.

Context: In the experimental animal, inflammatory signals quench LH's feedforward drive of testosterone (T) secretion and appear to impair GnRH-LH output. The degree to which such suppressive effects operate in the human is not known., Objective: To test the hypothesis that IL-2 impairs LH's feedforward drive on T and T's feedback inhibition of LH secretion in healthy men., Setting: Mayo Center for Translational Science Activities., Patients or Other Participants: A total of 35 healthy men, 17 young and 18 older., Interventions: Randomized prospective double-blind saline-controlled study of IL-2 infusion in 2 doses with concurrent 10-minute blood sampling for 24 hours., Main Outcome Measures: Deconvolution analysis of LH and T secretion., Results: After saline injection, older compared with young men exhibited reduced LH feedforward drive on T secretion (P < .001), and decreased T feedback inhibition of LH secretion (P < .01). After IL-2 injection, LH's feedforward onto T secretion declined markedly especially in young subjects (P < .001). Concomitantly, IL-2 potentiated T's proportional feedback on LH secretion especially in older volunteers., Conclusion: This investigation confirms combined feedforward and feedback deficits in older relative to young men given saline and demonstrates 1) joint mechanisms by which IL-2 enforces biochemical hypogonadism, viz, combined feedforward block and feedback amplification; and 2) unequal absolute inhibition of T and LH secretion by IL-2 in young and older men. These outcomes establish that the male gonadal axis is susceptible to dual-site suppression by a prototypic inflammatory mediator. Thus, we postulate that selected ILs might also enforce male hypogonadism in chronic systemic inflammation.

Background: Loss-of-function mutations in immunoglobulin superfamily member 1 (IGSF1) cause an X-linked syndrome of central hypothyroidism, macroorchidism, delayed pubertal testosterone rise, variable prolactin deficiency and variable partial GH deficiency in childhood. The clinical features and gene expression pattern suggest a pivotal role for IGSF1 in the pituitary, but detailed knowledge on pituitary hormone secretion in this syndrome is lacking. We therefore aimed to study the 24-hour pituitary hormone secretion in male patients with IGSF1 deficiency., Methods: We collected blood samples every 10 min for 24 h in eight adult male IGSF1-deficient patients and measured circulating TSH, prolactin and gonadotropins. Deconvolution, modified cosinor and approximate entropy analyses were applied to quantify secretion rates, diurnal rhythmicity and regularity of hormone release. Results were compared to healthy controls matched for age and body mass index., Results: Compared to healthy controls, IGSF1-deficient patients showed decreased pulsatile secretion of TSH with decreased disorderliness and reduced diurnal variation. Basal and pulsatile secretion of FSH was increased by over 200%, while LH secretion did not differ from healthy controls. We observed a bimodal distribution of prolactin secretion, i.e. severe deficiency in three and increased basal and total secretion in the other five patients., Conclusion: The altered TSH secretion pattern is consistent with the previously hypothesized defect in thyrotropin-releasing hormone signaling in IGSF1 deficiency. However, the phenotype is more extensive and includes increased FSH secretion without altered LH secretion as well as either undetectable or increased prolactin secretion., (© 2015 S. Karger AG, Basel.)

Background: Studies on 24-hour growth hormone (GH) secretion are rare. The influences of sex, age, and adiposity are well recognized but generally derived from specific, selected subject groups, not spanning sexes, many age decades, and a range of body weights., Objective: Our goal was to investigate GH dynamics in a group of 130 healthy adult subjects, both men and women, across 5 age decades as well as a 2.5-fold range of body mass index (BMI) values., Methods: GH was measured by a sensitive immunofluorometric assay. Secretion parameters were quantified by automated deconvolution and relative pattern randomness by approximate entropy (ApEn)., Results: The median age was 40 years (range 20-77). The median BMI was 26 (range 18.3-49.8). Pulsatile 24-hour GH secretion was negatively correlated with age (p = 0.002) and BMI (p < 0.0001). Basal GH secretion negatively correlated with BMI (p = 0.003) but not with age. The sex- dependent GH secretion (greater in women) was no longer detectable after 50 years of age. Insulin-like growth factor (IGF)-1 levels were lower in women over 50 years of age compared with men of a similar age. ApEn showed an age-related increase in both sexes and was higher in premenopausal and postmenopausal women than in men of comparable age (p < 0.0001). A single fasting GH measurement is not informative of 24-hour GH secretion., Conclusions: BMI dominates the negative regulation of 24-hour GH secretion across 5 decades of age in this up till now largest cohort of healthy adults who underwent 24-hour blood sampling. Sex also impacts GH secretion before the age of 50 years as well as its regularity at all ages. Differences in serum IGF-1 partly depend on the pre- or postmenopausal state. Finally, a single GH measurement is not informative of 24-hour GH secretion., (© 2015 S. Karger AG, Basel.)

Acromegaly is an insidious disease of the pituitary caused by a growth hormone-secreting adenoma. Generally, the diagnosis is made rather late in the course of the disease. Currently, acromegaly can be cured in about half of the patients with the disease by expert surgery. The remainder of non-surgically cured patients often can be effectively treated with somatostatin analogs; either with the new generation of dopaminergic drugs or with Pegvisomant, a GH-receptor blocking agent. However, at the time of diagnosis many patients suffer from serious comorbidities, including hypertension, heart disease, arthrosis, sleep apnea and diabetes mellitus. Recent reports have shown that mortality risk can be normalized. Nevertheless, all efforts should be undertaken to treat comorbidities. New strategies for surgery and medical treatment are discussed.

Context: Longevity is associated with changes in circulating levels of thyroid hormone (TH) and/or TSH in animals and humans, but underlying mechanisms remain elusive., Objective: We explored in 38 offspring of nonagenarian participants from the Leiden Longevity Study, who are enriched for longevity and in their partners, ultradian and circadian rhythmicity of TSH, temporal relationship, and feedback and forward interplay between TSH and TH., Methods: We collected blood samples every 10 minutes for 24 hours for TSH and TH profiles. We used a deconvolution analysis to estimate basal (nonpulsatile), pulsatile, and other secretion parameters to characterize ultradian rhythmicity and locally weighted polynomial regression of TSH to assess circadian rhythmicity. A cross-correlation analysis was used to investigate the temporal relationship between TSH and TH and cross-approximate entropy to assess feedback and forward interplay between TSH and TH., Results: Compared with partners, offspring displayed higher mean (95% confidence interval [CI]) basal TSH secretion (34.3 [95% CI 27.2-43.1] mU/L per 24 hours vs 18.5 [95% CI 14.4-23.7] mU/L per 24 hours, P = .001) but no differences in ultradian or circadian properties of TSH. The temporal relationship between TSH and free T3 at zero delay was higher in offspring (0.48 ± 0.2) compared with partners (0.26 ± 0.4) (P = .05), but the feedback and forward interplay between TSH and TH did not differ., Conclusions: Familial longevity is associated with increased basal TSH secretion and a strong temporal relationship between TSH and free T3 but not with differences in ultradian or circadian TSH rhythmicity or feedback and forward interplay between TSH and TH.

Objective: The hypothalamic-pituitary-adrenal (HPA)-axis is the most important neuro-endocrine stress response system of our body which is of critical importance for survival. Disturbances in HPA-axis activity have been associated with adverse metabolic and cognitive changes. Humans enriched for longevity have less metabolic and cognitive disturbances and therefore diminished activity of the HPA axis may be a potential candidate mechanism underlying healthy familial longevity. Here, we compared 24-h plasma ACTH and serum cortisol concentration profiles and different aspects of the regulation of the HPA-axis in offspring from long-lived siblings, who are enriched for familial longevity and age-matched controls., Design: Case-control study within the Leiden Longevity study cohort consisting of 20 middle-aged offspring of nonagenarian siblings (offspring) together with 18 partners (controls)., Methods: During 24 h, venous blood was sampled every 10 minutes for determination of circulatory ACTH and cortisol concentrations. Deconvolution analysis, cross approximate entropy analysis and ACTH-cortisol-dose response modeling were used to assess, respectively, ACTH and cortisol secretion parameters, feedforward and feedback synchrony and adrenal gland ACTH responsivity., Results: Mean (95% Confidence Interval) basal ACTH secretion was higher in male offspring compared to male controls (645 (324-1286) ngl/L/24 h versus 240 (120-477) ng/L/24 h, P = 0.05). Other ACTH and cortisol secretion parameters did not differ between offspring and controls. In addition, no significant differences in feedforward and feedback synchrony and adrenal gland ACTH responsivity were observed between groups., Conclusions: These results suggest that familial longevity is not associated with major differences in HPA-axis activity under resting conditions, although modest, sex-specific differences may exist between groups that might be clinically relevant.

Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism.

Obesity impacts many hormonal systems, including pituitary hormones, as well as insulin and leptin. In this review we discuss articles which investigate the influence of obesity on the hypothalamic-pituitary-adrenal (HPA) axis. Different techniques have been used to assess the function of the HPA-axis in obesity, including measuring fasting and/or late evening levels of adrenocorticotropic hormone (ACTH) and (free) cortisol in plasma and saliva, studying feedback with dexamethasone or cortisol, and evaluating responsiveness of the system to corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) or ACTH 1-29. In addition, more elaborate studies investigated 24-h secretion patterns, analyzed with deconvolution techniques to quantitate pulsatile secretion rates of cortisol and less often ACTH. Other investigators used timed infusions of labeled cortisol for the estimation of the 24-h secretion rate, clearance rate and distribution volume. Many studies relied on the 24-h urinary excretion of free cortisol, but for quantitation of the 24-h secretion, measurement of all cortisol-derived metabolites is required. Several studies have applied modern liquid chromatography-tandem-mass spectrometry techniques to measure these metabolites. The picture emerging from all these studies is that, first, ACTH secretion is amplified, likely via enhanced forward drive; and, second, serum cortisol levels are normal or even low, associated with a normal 24-h cortisol secretion per liter distribution volume determined by deconvolution, but enhanced when based on the increased total distribution volume associated with obesity. Increased cortisol secretion was also established by isotope dilution studies and reports based on the measurement of all urinary cortisol metabolites. The responsiveness of the adrenal gland to ACTH is diminished. The studies do not address quantitative aspects of cortisol-cortisone metabolism on individual organs, including liver, central and peripheral fat, intestine, skin, and muscle.

Context: Hormone secretion by functioning pituitary tumors is characterized by increased basal (nonpulsatile) secretion, enhanced pulse frequency, amplified pulse mass, and increased disorderliness., Objective: The objective of the study was to quantify (subtle) abnormalities of hormone secretion by pituitary adenomas and the influence of selective pituitary surgery and suppressive medications on these parameters., Methods: Approximate entropy (ApEn) was quantified with a refined algorithm, spikiness by a new method to evaluate sudden short-lived increases in hormone levels, and pulsing regularity, determined with a fully automated deconvolution program. These 3 distinct measures of secretory disruption were compared in untreated and treated patients with acromegaly, prolactinoma, and Cushing's disease together with matching profiles in healthy controls., Results: ApEn and spikiness were markedly increased in all untreated patient groups and normalized after pituitary surgery in acromegaly and hypercortisolism. In contrast, hormone-suppressive medical treatment in acromegaly and prolactinoma did not normalize ApEn. Spikiness normalized in acromegalic patients but not in prolactinoma. GH and cortisol pulsing regularity was elevated in acromegaly and Cushing's disease, respectively, and normalized after surgery. Medical treatment caused normalization of pulsing regularity in acromegaly but not in prolactinoma patients., Conclusion: This study extends the understanding of disorganized hormone secretion by hyperfunctioning pituitary adenomas. The new findings are increased spikiness in all 3 tumor groups and increased pulsing regularity in GH- and ACTH-secreting adenomas. The mechanisms behind the marked pattern irregularity and the selective normalization by surgical and medical therapies are not established yet but may include diminished feedback signaling in addition to the anatomical and functional disorganization of intrapituitary cell networks.

Relations among hormone serum concentrations are complex and depend on various factors, including gender, age, body mass index, diurnal rhythms and secretion stochastics. Therefore, endocrine deviations from healthy homeostasis are not easily detected or understood. A generic method is presented for detecting regulatory relations between hormones. This is demonstrated with a cohort of obese women, who underwent blood sampling at 10 minute intervals for 24-hours. The cohort was treated with bromocriptine in an attempt to clarify how hormone relations change by treatment. The detected regulatory relations are summarized in a network graph and treatment-induced changes in the relations are determined. The proposed method identifies many relations, including well-known ones. Ultimately, the method provides ways to improve the description and understanding of normal hormonal relations and deviations caused by disease or treatment.

Context: Studies of the influence of sex, age, and body weight on TSH secretion are not unanimous. Most reports are based on a single TSH measurement; studies using frequent blood sampling are scarce and include a limited number of selected subjects., Objective: The goal was to investigate TSH dynamics in 117 healthy adults., Methods: TSH was measured by a sensitive immunofluorometric assay. Secretion parameters were quantified by automated deconvolution, approximate entropy [ApEn], spikiness, and diurnal properties., Results: Mean age was 43 years (range, 22-77 y). Mean body mass index (BMI) was 26.8 kg/m(2) (range, 18.3-39.4 kg/m(2)). Daily TSH secretion was 45.4 mU/L (range, 8.0-207 mU/L). There were no sex differences in secretion parameters, including pulse frequency; basal, pulsatile, and total secretion; pulse mode; half life; pulse regularity; ApEn; spikiness; and nycthemeral properties. BMI was positively related to basal secretion. Total secretion correlated negatively with free T₄ (R = 0.225; P = .018). The onset of the nocturnal surge was delayed by increasing BMI and advanced by increasing age. ApEn and spikiness correlated positively with age, especially in men. The 9 am sample correlated strongly with the total 24-hour secretion, explaining two-thirds of the variability., Conclusion: This study shows that the 24-hour TSH secretion in healthy volunteers is stable and robust and not influenced by sex, BMI, and age. ApEn in the elderly, especially men, is increased, pointing to a less tight feedback control. Furthermore, aging is associated with advance shifting of the TSH rhythm, which is a phenomenon also observed in other biological rhythms.

Background: C-type natriuretic peptide (CNP)/natriuretic peptide receptor 2 (NPR2) signaling is essential for long bone growth. Enhanced CNP production caused by chromosomal translocations results in tall stature, a Marfanoid phenotype, and skeletal abnormalities. A similar phenotype was described in a family with an activating NPR2 mutation within the guanylyl cyclase domain., Case: Here we describe an extremely tall male without skeletal deformities, with a novel NPR2 mutation (p.Arg655Cys) located in the kinase homology domain., Objectives: The objective of the study was to investigate the functional and structural effects of the NPR2 mutation., Methods: Guanylyl cyclase activities of wild-type vs mutant NPR2 were analyzed in transfected human embryonic kidney 293 cells and in skin fibroblasts. The former were also used to study possible interactions between both isoforms. Homology modeling was performed to understand the molecular impact of the mutation., Results: CNP-stimulated cGMP production by the mutant NPR2 was markedly increased in patient skin fibroblasts and transfected human embryonic kidney 293 cells. The stimulatory effects of ATP on CNP-dependent guanylyl cyclase activity were augmented, suggesting that this novel mutation enhances both the responsiveness of NPR2 to CNP and its allosteric modulation/stabilization by ATP. Coimmunoprecipitation showed that wild-type and mutant NPR2 can form stable heterodimers, suggesting a dominant-positive effect. In accordance with augmented endogenous receptor activity, plasma N-terminal pro-CNP (a marker of CNP production in tissues) was reduced in the proband., Conclusions: We report the first activating mutation within the kinase homology domain of NPR2, resulting in extremely tall stature. Our observations emphasize the important role of this domain in the regulation of guanylyl cyclase activity and bone growth in response to CNP.

Thyroid hormones are extremely important for metabolism, development, and growth during the lifetime. The hypothalamo-pituitary-thyroid axis is precisely regulated for these purposes. Much of our knowledge of this hormonal axis is derived from experiments in animals and mutations in man. This review examines the hypothalamo-pituitary-thyroid axis particularly in relation to the regulated 24-hour serum TSH concentration profiles in physiological and pathophysiological conditions, including obesity, primary hypothyroidism, pituitary diseases, psychiatric disorders, and selected neurological diseases. Diurnal TSH rhythms can be analyzed with novel and precise techniques, eg, operator-independent deconvolution and approximate entropy. These approaches provide indirect insight in the regulatory components in pathophysiological conditions.

Study Objectives: Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis. Here, we evaluated whether human hypocretin deficiency, or the narcolepsy therapeutic agent sodium oxybate, alter the levels of these hormones., Methods: Eight male, medication free, hypocretin deficient, narcolepsy with cataplexy patients, and 8 healthy controls matched for age, sex, body mass index (BMI), waisttohip ratio, and body fat percentage were assessed. Blood samples of total ghrelin and leptin were collected over 24 hours at 60 and 20-min intervals, respectively, during 2 study occasions: baseline, and during the last night of 5 consecutive nights of sodium oxybate administration (2 × 3.0 g/night)., Results: At baseline, mean 24-h total ghrelin (936 ± 142 vs. 949 ± 175 pg/mL, p = 0.873) and leptin (115 ± 5.0 vs. 79.0 ± 32 mg/L, p = 0.18) levels were not different between hypocretin deficient narcolepsy patients and controls. Furthermore, sodium oxybate did not significantly affect the plasma concentration of either one of these hormones., Conclusions: The increased BMI of narcolepsy patients is unlikely to be mediated by hypocretin deficiency-mediated alterations in total ghrelin or leptin levels. Thus, the effects of these hormones on hypocretin neurons may be mainly unidirectional. Although sodium oxybate may influence body weight, the underlying mechanism is unlikely to involve changes in total ghrelin or leptin secretion.

Tightly regulated output of glucocorticoids is critical to maintaining immune competence, the structure of neurons, muscle, and bone, blood pressure, glucose homeostasis, work capacity, and vitality in the human and experimental animal. Age, sex steroids, gender, stress, body composition, and disease govern glucocorticoid availability through incompletely understood mechanisms. According to an ensemble concept of neuroendocrine regulation, successful stress adaptations require repeated incremental signaling adjustments among hypothalamic corticotropin-releasing hormone and arginine vasopressin, pituitary adrenocorticotropic hormone, and adrenal corticosteroids. Signals are transduced via (positive) feedforward and (negative) feedback effects. Age and gonadal steroids strongly modulate stress-adaptive glucocorticoid secretion by such interlinked pathways., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The beneficial effects of recombinant human GH (rhGH) therapy in GH deficient (GHD) adults are well-established in the short term. However, data documenting the effects during prolonged follow-up are relatively scarce., Objective: To evaluate the reported effects of rhGH replacement (≥5 years) in GHD adults on biochemical and anthropometric parameters, quality of life (QoL), bone metabolism, muscle strength, serious adverse events and mortality., Methods: We conducted a systematic literature search. Quality assessment of retrieved papers was performed using a quality assessment based on the modified STROBE statement., Results: We included 23 prospective studies with a rhGH treatment duration ranging from 5 to 15 years. Overall, beneficial effects were reported on QoL, body composition, lipid profile, carotid intima media thickness and bone mineral density. In contrast, the prevalence of the metabolic syndrome, glucose levels, BMI and muscle strength were not, or negatively, influenced. Most of the studies were uncontrolled, lacked the presence of a control group (of non-treated GHD patients), and reported no data on lipid-lowering and anti-diabetic medication. Overall mortality was not increased., Conclusion: rhGH treatment in adult GHD patients is well-tolerated and positively affects QoL in the long term. However, the metabolic and cardiovascular effects during long-term treatment are variable. The low numbers of long-term studies and studied patients and lack of control data hamper definite statements on the efficacy of prolonged treatment. Therefore continuous monitoring of the effects of rhGH replacement to enable an adequate risk-benefit analysis that may justify prolonged, potentially life-long, treatment is advisable.

Background: The metabolic effects of recombinant human GH (rhGH) therapy in adults are well-documented in the short term. The effects of long-term rhGH therapy beyond 5 yr on metabolic parameters are presently unknown., Objective: The aim of the study was to evaluate the long-term effects of rhGH treatment on biochemical and anthropometric parameters in a large cohort of GH-deficient adults., Methods: Ninety-eight GH-deficient adult patients treated with rhGH for at least 10 yr were included (mean age, 59.4 yr; 50% female). Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, anthropometric parameters, IGF-I, and glucose were evaluated at baseline and after 5, 10, and 15 yr of treatment. In addition, the prevalence of the metabolic syndrome (MS) and the incidence of cardiovascular events were assessed., Results: Total cholesterol and low-density lipoprotein cholesterol concentrations were lower, and high-density lipoprotein cholesterol levels were significantly higher during long-term rhGH replacement when compared to baseline (all P < 0.001). Both waist circumference (P < 0.001) and body mass index (P = 0.018) were significantly higher after 10 yr, as were fasting plasma glucose levels (P < 0.001). No significant changes were observed in triglycerides, waist-to-hip ratio, and blood pressure during follow-up. In the subset of patients with 15-yr rhGH treatment (n = 43), generally similar metabolic effects were found. MS prevalence was increased after 10 yr of rhGH treatment (57.1 vs. 32.7%; P < 0.001), especially in males (69.4 vs. 32.7%; P < 0.001)., Conclusion: Despite improvement of several cardiovascular risk factors, MS prevalence increased significantly during rhGH treatment. The effect of long-term rhGH treatment on overall cardiovascular risk profile needs to be established in a larger cohort.

Background: Prolactin (PRL) has many effects in animals and man. For example, it regulates fat mass in fish, birds, and mammals. In particular, the timing of the serum PRL acrophase in relation to the light-dark cycle or to serum cortisol in constant light conditions determines whether the fat mass increases or decreases, as part of the adaptation to seasons. The role of PRL in this respect has been less well studied in man., Hypothesis: We hypothesized that the timing of the PRL acrophase (time point of peak amplitude of the rhythm) with respect to that of cortisol may be correlated with fat mass [or body mass index (BMI) as proxy] in the human, as observed in animals., Subjects: Seventy-four subjects were available [mean age, 43 (22-77) yr; mean BMI, 26.8 (18.7-38.4) kg/m(2)]., Measures: Immunofluorometric PRL assay and cortisol RIA of 10-min blood samples collected for 24 h were followed by cosinor analysis for the estimation of the acrophase., Results: The time difference between the cortisol and PRL acrophases was positively correlated with BMI (P = 0.002), but not with sex, age, or season., Conclusion: In various species, a wide gap between the serum cortisol acrophase and that of PRL leads to fat storage. Our finding is consistent with this observation, although we used BMI as proxy. If an advance shift of the PRL acrophase in relation to that of cortisol is indeed responsible for increased fat mass in man, manipulating the PRL phase may offer an alternative means to treat obesity.

Background: The ACTH-cortisol axis in women is activated and associated with decreased ACTH potency, estimated by relating ACTH and cortisol pulse masses. Recently, a new accurate method for constructing the endogenous dose-response relationship was introduced, which is based on the relation between ACTH concentrations and associated cortisol secretion rates within cortisol bursts., Hypothesis: The endogenous dose-response relation between ACTH and cortisol in obesity is changed, leading to diminished responsiveness., Subjects: Twenty-five obese premenopausal women and 16 normal weight premenopausal women were studied by 10-min blood sampling for 24 h., Outcomes: ACTH and cortisol secretion rates, analytical dose-response estimates of endogenous ACTH efficacy (maximal cortisol secretion), dynamic ACTH potency, and adrenal sensitivity (slope term) from 24-h ACTH-cortisol profiles were quantified., Results: The initial potency (negative logarithm) was -7.83 ± 0.75 (mean ± s.e.m.) in obese women and -10.14 ± 1.08 in lean women (P=0.10), and the corresponding values for the recovery phase were -26.62 ± 2.21 and -36.67 ± 1.66 (P=0.004). The sensitivity (curve slope) amounted to 0.468 ± 0.05 in obese women and 0.784 ± 0.09 in normal weight women (P=0.004). The efficacy (maximal value) was 17.6 ± 4.9 nmol/l per min in obese women and 26.3 ± 3.8 nmol/l per min in normal weight women (P=0.009). Basal secretion rate, inflection point, and EC(50) values were not different. Bromocriptine or acipimox did not change the dose-response curve., Conclusion: The ACTH-cortisol relation in obesity in women is characterized by decreased sensitivity and efficacy, thus explaining non-elevated serum cortisol concentrations despite increased plasma ACTH levels.

Transsphenoidal surgery (TS) is the treatment of choice for many pituitary tumors. Because TS may cause pituitary insufficiency in some of these patients, early postoperative assessment of pituitary function is essential for appropriate endocrine management. The aim of our study was to evaluate the clinical relevance of the CRH-stimulation test in assessing postoperative pituitary-adrenal function. We performed a retrospective analysis of 144 patients treated by TS between January 1990 and November 2009, in whom a CRH-test and a second stimulation test was performed to assess adrenal function during follow-up. Patients with Cushing's disease were excluded. Hydrocortisone substitution was started if peak cortisol levels were <550 nmol/L. The cortisol response was insufficient in 42(29%) and sufficient in 102 patients at the postoperative CRH-test. Thirteen of 42(30%) demonstrated a normal cortisol response during a second cortisol stimulation test. In 75 of the 102 patients with a sufficient response to CRH repeat testing revealed an insufficient cortisol response in 14 patients (14%). All but one had concomitant pituitary hormone deficits. There were no cases of adrenal crises during follow-up. Additional pituitary insufficiency was significantly more present (P < 0.001) in the group of patients with an abnormal response to CRH directly after surgery. In this study a substitution strategy of hydrocortisone guided by the postoperative cortisol response to CRH appeared safe and did not result in any case of adrenal crises. However, the early postoperative CRH-test does not reliably predict adrenal function after TS for pituitary adenomas in all patients and retesting is mandatory.

To study the currently available data of recurrence rates of functioning and nonfunctioning pituitary adenomas following surgical cure and to analyze associated predisposing factors, which are not well established. A systematic literature search was conducted using Medline, Embase, Web of Science and the Cochran Library for studies reporting data on recurrence of pituitary adenoma after surgery, in nonfunctioning adenoma (NF), prolactinoma (PRL) acromegaly (ACRO) and Cushing's disease (CUSH). Of 557 initially retrieved potential relevant studies 143 were selected. Recurrence in NFA was defined as reappearance of tumor on MRI or CT. Increase of hormone levels above normal limits as set by the authors after initial remission was used to indicate recurrence in the functioning tumor types. Remission percentage was lowest in NFA compared with other tumor types (P < 0.001). Surgery-related hypopituitarism was more frequent in CUSH than in the other tumors (P < 0.001). Recurrence, expressed as percentage of the cured population or as ratio of recurrence and total patient years of follow-up was highest in PRL (P < 0.001). The remission percentage did not improve over 3 decades of publications, but there was a modest decrease in recurrence rate (P = 0.04). Recurrences peaked between 1 and 5 years after surgery. Most of the studies with a sufficient number of recurrences did not apply multivariate statistics, and mentioned at best associated factors. Age, gender, tumor size and invasion were generally unrelated to recurrence. For functioning adenomas a low postoperative hormone concentration was a prognostically favorable factor. In NFA no specific factor predicted recurrence. Recurrence rate differs between pituitary adenomas, being highest in patients with prolactinoma, with the highest incidence of recurrence between 1 and 5 years after surgery in all adenomas. Patients with NFA have a lower chance of remission than patients with functioning adenomas. The postoperative basal hormone level is the most important predictor for recurrence in functioning adenomas, while in NFA no single convincing factor could be identified.