Corticotropin-releasing hormone is not the sole factor mediating exercise-induced adrenocorticotropin release in humans.

To determine whether CRH is the sole mediator of ACTH release during exercise, five men and five women were given, in a subject-blinded random manner at separate visits, both a 6-h infusion of ovine CRH (1 microgram/kg.h) and a saline infusion as a placebo. After the fourth hour of each infusion, when plasma concentrations of ovine CRH were sufficiently elevated to saturate the capacity of the corticotroph to respond further to CRH, each subject completed a high intensity intermittent run. Plasma ACTH and cortisol levels increased significantly during the CRH infusion from 4.6 +/- 0.8 (mean +/- SE) to 8.6 +/- 1.6 pmol/L and from 361 +/- 39 to 662 +/- 70 nmol/L, respectively (P less than 0.05). Despite elevated preexercise cortisol levels during the CRH infusion, plasma ACTH rose to 32.0 +/- 8.5 pmol/L after exercise. During the saline infusion, plasma ACTH rose from 3.4 +/- 0.6 pmol/L before exercise to 18.1 +/- 4.2 after exercise. Time-integrated responses for postexercise values of ACTH and cortisol were higher during the CRH infusion than during the saline infusion (P less than 0.05). No significant exercise-induced differences in heart rate or plasma concentrations of lactate, epinephrine, and norepinephrine were observed between the two tests. The findings suggest that some factor(s) in addition to CRH causes ACTH release during exercise. Vasopressin, produced by the magnocellular and/or parvocellular neurons of the hypothalamus, is a likely candidate.     

Effect of hydration on exercise-induced growth hormone response

DESIGN: Growth hormone (GH) has demonstrated water-retaining effects in subjects at rest, whereas other research has indicated that GH may stimulate sweating. Thus, the aim of this study was to investigate the effect of fluid intake on the exercise-induced GH response. METHODS: Seven healthy male volunteers (age: 27.4+/-1.3 years, weight: 74.5+/-1.1 kg, height: 179.3+/-2.3 cm) performed a 40-min submaximal rectangular cycling exercise in two different sessions. The first session (Session 1) was performed without water intake, and the second (Session 2) involved the ingestion of spring water (four intakes) corresponding to the volume of water lost during the first session. RESULTS: In session 1, the water loss was 568+/-32 ml. In Session 2, the volume of water loss was not significantly different from the volume of fluid intake (524+/-16 versus 568+/-32 ml respectively). The decrease in plasma volume was significantly reduced in Session 2 (-6.69+/-1.59% versus -11.3+/-1.89%; P<0.05). In Session 1, the GH concentration was significantly lower than that during Session 2 after 25 min (3.04+/-1.05 versus 5.26+/-1.81; P<0.05) and after 40 min (13.7+/-3.55 versus 17.60+/-4.14 ng/ml; P<0.05) of exercise. The total GH response was significantly lower in Session 1 than in Session 2 (136.6+/-39.2 versus 202.4+/-58.9 ng/ml x min; P<0.05). CONCLUSIONS: We conclude that the exercise-induced GH response decreases when exercise is performed without fluid intake.     

Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women.

To investigate the contribution of hypothalamic gonadotropin-releasing hormone (GnRH) secretion to the midcycle gonadotropin surge in the human, the response of luteinizing hormone (LH) to competitive GnRH receptor blockade achieved by administration of a range of doses of a pure GnRH antagonist was used to provide a semiquantitative estimate of endogenous GnRH secretion. The LH response to 5, 15, 50, and 150 micrograms/kg s.c. of the NAL-GLU GnRH antagonist ([Ac-D-2Nal1,D-4ClPhe2,-D-Pal3,Arg5,D-4-p-met hoxybenzoyl-2-aminobutyric acid6,D-Ala10]GnRH, where 2Nal is 2-naphthylalanine, 4ClPhe is 4-chlorophenylalanine, and 3Pal is 3-pyridylalanine) was measured in normal women in the early and late follicular phases of the menstrual cycle, at the time of the midcycle LH surge and in the early luteal phase. LH decreased in a dose-response fashion after administration of the GnRH antagonist in all cycle phases (P < 0.0001). When this suppression was expressed as maximum percent inhibition, there was no difference in response during the early and late follicular and early luteal phases. However, at the midcycle surge, there was a leftward shift of the dose-response curve with significantly greater suppression of LH at the lower antagonist doses in comparison to the other cycle phases (P < 0.005), but no difference at the highest dose. Thus, we draw the following conclusions. (i) There is a consistently greater degree of LH inhibition by GnRH antagonism at the midcycle surge at submaximal degrees of GnRH receptor blockade than at other phases of the menstrual cycle in normal women. (ii) This leftward shift of the dose-response relationship to GnRH receptor blockade suggests that the overall amount of GnRH secreted at the midcycle surge is less than at other cycle stages. (iii) These data confirm the importance of pituitary augmentation of the GnRH signal at the time of the midcycle gonadotropin surge in the human.     

Growth hormone treatment affects plasma LH pulsatile release in women with secondary amenorrhoea

OBJECTIVE Since growth hormone (GH) is administered as a co-gonadotrophic factor in ovulation induction, this study aimed to assess the action of GH on the episodic pulsatile release of LH and FSH in amenorrhoeic patients. PATIENTS AND DESIGN Nineteen patients affected by hypothalamic amenorrhoea were enrolled for this study: group A, 9 patients with normal gonadotrophins; group B, 10 patients with low gonadotrophins. Both groups were studied during GH infusion (0015 IU/min for 4 hours) and after 7 days of GH administration (0 1 IU/kg/day). Patients underwent a 4-hour pulsatility study, with blood sampling every 10 minutes. A standard GnRH test (10 μ g i.v. bolus) was performed immediately after the pulsatility evaluation. MEASUREMENTS LH and FSH were assayed with an IFMA method; oestradiol and IGF-I were assayed by RIA and IRMA, respectively. PULSE DETECTION Time series were analysed with Detect program. RESULTS All patients showed similar LH and FSH pulsatile characteristics both under baseline conditions and during GH infusion. After 7 days of GH administration, episodic FSH release showed no change in either group. On the contrary, LH pulse frequency (mean ± SE) significantly increased in group A (4 0±0 2 peaks/4h, P&kt;0 05), while putse amplitude (baseline, 3.9± 0 6 IU/I; after 7 days, 2.9±0.3 IU/I, P<0 05), and integrated LH plasma concentrations (baseline, 7.6 ±1–1 IU/I; after 7 days, 5±0 8 IU/I, P<0 05) were significantly decreased. No significant changes were observed for LH pulse frequency, amplitude or integrated LH plasma concentrations in hypogonado-trophinaemic patients (group B). Plasma oestradiol levels were significantly increased only in group A (baseline, 154 18±23 8 pmoI/I; after 7 days, 380 3±110 1 pmoI/I, P < 005), while IGF-I levels were significantly increased in both groups after 7 days of GH administration (P<0 05). No significant differences were observed in the gonadotropin responses to GnRH test before and after GH administration. CONCLUSIONS The present study showed that the administration of GH in amenorrhoeic patients determines the significant changes in episodic LH release in those subjects with normal LH plasma levels and suggests that the action of GH may be dependent upon the ovarian-pituitary feedback action.     

Effect of thymosin alpha 1 on hypothalamic hormone release.

Thymosin alpha 1 (T alpha 1) is a well-characterized immunopotentiating polypeptide originally isolated from calf thymus. We have recently shown in vivo, probable hypothalamic effects of T alpha 1 to decrease the release of the pituitary hormones, TSH, PRL and ACTH from the pituitary gland. Therefore, in the present study we evaluated the effect of the peptide on the release of hypothalamic regulatory hormones: thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH), as well as somatostatin (SRIH), from medial basal hypothalamic (MBH) fragments incubated in vitro. After a preliminary time-course study indicated that a 30-min incubation period was optimal, it was used for all the other experiments. At the end of the incubation the tissue was still able to respond to a depolarizing K+ concentration for 15 min by a 4-fold increase of TRH concentration compared to control basal release during the preceding 30 min. T alpha 1 was shown to inhibit the release of TRH and CRH from MBH fragments incubated in vitro with a minimal effective dose (MED) of 10(-11) M. SRIH and CRH release was also inhibited but the MED for these peptides was 10(-9) M. The relative responsiveness to the action of T alpha 1 was TRH greater than CRH, which was greater than SRIH. This correlated with our previous in vivo results for pituitary hormone release, except in the case of SRIH since we previously did not detect any significant effect of the peptide on growth hormone release. Finally, we evaluated the possible involvement of other neurotransmitters in the effect of T alpha 1 on TRH release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulsatile secretion of luteinizing hormone and prolactin in lactating and nonlactating women and the response to naltrexone

To investigate the mechanisms responsible for the postpartum suppression of reproductive function, LH and PRL levels were determined at 10-min intervals for 8 h in 10 lactating women, in 10 nonlactating women treated with bromocriptine, and in 5 nonpuerperal women. The lactating women were studied on postpartum day 7 (n = 5) or between days 28 and 35 (n = 5). All nonlactating women were studied on day 7. Five of them were treated with the opioid antagonist naltrexone to evaluate the role of endogenous opioids. By using a specific LH assay which does not cross-react with hCG, we were able to measure pulsatile LH secretion in the early puerperium for the first time. On day 7, LH levels were below the detection limit in both lactating and nonlactating women, hence no pulses could be detected. Chronic opioid blockade in bromocriptine-treated non-lactating women did not result in increased LH levels. Pulsatile LH secretion was present between days 28 and 35 of lactation, although pulse amplitude (P less than 0.05) and mean LH level (P less than 0.05) were lower than in nonpuerperal women. Mean LH in lactating women was negatively correlated with mean PRL (-0.87, P less than 0.05). Deconvolution analysis of the PRL responses to suckling revealed that PRL was secreted in distinct bursts, separated by intervals of secretory quiescence. Mean duration of PRL bursts was 40 +/- 4 min and the maximum secretory rate was reached around the end of suckling. We conclude that pulsatile LH secretion is completely suppressed during early lactation and partially suppressed during late lactation. Because the duration of suckling was similar, the relatively strong suppression during the early puerperium must be due to additional inhibitory factors. It has been suggested that endogenous opioids are involved in this process, but our results in puerperal women do not support this hypothesis.     

Effect of in vivo treatment with estrogen on luteinizing hormone synthesis and release by rat pituitaries in vitro.

The influence of estrogen on uptake of [3H]glucosamine and [14C]alanine and their incorporation into LH and total protein was investigated. Ovariectomized rats were sacrificed 22 h after injection with either oil or estradiol benzoate (EB, 50 microng/rat). Quartered anterior pituitary glands were incubated for 4 h with radioactive precursors in the presence or absence of 3.6 X 10-8M synthetic gonadotropin-releasing hormone (GnRH). Labeled LH was isolated by immunoprecipitation with specific anti-LH-beta serum. Both EB and GnRH significantly elevated the amount of [3H]glucosamine-LH appearing in the medium, the tissue, and the total system (medium + tissue), but they increased the amount of [14C]alanine-LH only in the medium. There was a significant positive interaction between EB and GnRH on the amounts of [3H]glucosamine-LH and [14C]alanine-LH in the medium and of [3H]glucosamine-LH in the tissue and total system. EB enhanced [3H]glucosamine uptake and incorporation into total protein, but GnRH had little or no effect on these parameters. In time course studies rats were injected with either oil or EB at 22, 11, or 5.5 h prior to sacrifice. At all times EB significantly increased synthesis and release of [3H]-glucosamine-LH and release of total immunoreactive LH (IR-LH) by pituitaries incubated with GnRH. The amounts of labeled and IR-LH released into the medium increased linearly with time after EB injection, but the amount of labeled LH in the total system plateaued at 5.5 h after EB injection. In another study, estradiol (E2, 5 microng/rat) dissolved in 1% ethanol-saline was injected at 0.5, 1.0, 2.0, or 4 h prior to sacrifice. Incorporation of [3H]glucosamine into tissue protein and release of [3H]glucosamine-LH was stimulated within 2 h after E2 injection. However, incorporation of [3H]glucosamine into LH was not stimulated until 4 h after E2 injection. These results suggest that estrogen and GnRH regulate LH synthesis at different sites, and that the effect of estrogen is non-specific compared to that of GnRH. The synthesis of the carbohydrate moiety of LH appears to be subjected to hormonal regulation more readily than the synthesis of the polypeptide moiety.     

Pulsatile growth hormone release in normal women during the menstrual cycle

OBJECTIVE: We sought to characterize pulsatile growth hormone (GH) release in normal women during the menstrual cycle and to document possible relationships between such characteristics and concentrations of 17 beta-oestradiol and progesterone. SUBJECTS: Fifteen women with ostensibly normal menstrual function were studied during the early follicular phase, 15 during the late follicular phase and 15 during the mid-luteal phase of the menstrual cycle. DESIGN: The phase of the menstrual cycle having been documented, blood samples were obtained from each woman every 10 minutes for 24 hours. MEASUREMENTS: Serum GH was measured in each sample by immunoradiometric assay. Pulsatile GH release was appraised utilizing the objective, statistically-based pulse detection algorithm Cluster. RESULTS: The mean (+/- SEM) integrated serum GH concentration (mU/l min) in late follicular phase women (5335 +/- 848) was higher than that observed in early follicular phase women (3156 +/- 322; P = 0.032). The integrated GH concentration calculated for mid-luteal phase women (3853 +/- 788) was intermediate between but not statistically different from that observed in early follicular (P = 0.48) and late follicular (P = 0.14) phase women. No differences in GH pulse frequency (pulses/24 hours) were found among early follicular (8.27 +/- 0.55), late follicular (7.93 +/- 0.91) or mid-luteal (8.47 +/- 0.66) phase women. Mean maximal GH pulse amplitude (mU/l) was higher in late follicular phase (8.93 +/- 1.00) than early follicular phase (5.74 +/- 0.67; P = 0.008) and mid-luteal phase (5.76 +/- 0.74; P = 0.008) women. Similarly, incremental GH pulse amplitude (mU/l) was higher in late follicular phase (7.33 +/- 0.83) than early follicular phase (4.68 +/- 0.58; P = 0.005) and mid-luteal phase (4.36 +/- 0.39; P = 0.002) women. No differences in mean pulse widths or in the interpeak valley mean GH concentrations were found among the groups. Multiple regression of each pulse parameter against serum concentrations of testosterone, 17 beta-oestradiol and progesterone revealed a significant (P = 0.045) positive correlation between maximum GH pulse amplitude and oestradiol and a significant (P = 0.04) negative correlation between maximal GH pulse amplitude and progesterone (r = 0.41). CONCLUSION: These results suggest that late follicular phase concentrations of oestradiol may enhance circulating GH via an amplitude-modulated rather than a frequency-modulated effect on the endogenous GH pulse. Progesterone may blunt this oestrogen-associated effect, thus resulting in the observed mid-luteal phase concentrations of GH. Whether these gonadal hormones act primarily at the hypothalamus and/or anterior pituitary gland remains to be clarified, but the present observations indicate that pulsatile GH release throughout the normal menstrual cycle is significantly amplitude regulated.     

Gamma-amino-beta-hydroxy butyric acid stimulates prolactin and growth hormone release in normal women.

The influence of gamma-amino-beta-hydroxy butyric acid (GABOB) treatment on pituitary function has been investigated in this study. Different doses (50 x 100 mg) of GABOB were iv injected into three and six normal women, respectively. PRL and GH plasma levels were measured before and after the injection. The treatment with 150 mg GABOB, performed in another two normal women, was interrupted because of side-effects (loss of consciousness etc.) due to the treatment. The treatment with 50 mg GABOB did not induce significant variations of the two hormones; however, significant increases of PRL (P less than 0.05) and GH (P less than 0.01) plasma levels were observed after injection with 100 mg GABOB. The present data suggest that gamma-amino butyric acid (GABA) itself of GABAergic drugs might play an important role in the control of hypothalamic-pituitary function.     

Effect of losartan in treatment of exercise-induced myocardial ischemia

Because no controlled clinical studies are available about the possible role of angiotensin II receptor blockers in preventing effort myocardial ischemia, we evaluated the effect of angiotensin II receptor blocker/losartan in preventing exercise-induced myocardial ischemia in patients with coronary artery disease. Twenty-four sedentary patients with chronic stable ischemia were prospectively randomized to 28 days (double blind) of losartan 100 mg or losartan placebo in 2 divided doses. In each patient the treatment was crossed over to the alternative regimen (28 days, double blind) after a 1-week placebo period (single blind). At the end of each phase a new exercise stress test was performed. At baseline, systolic blood pressure was significantly decreased after losartan 100 mg compared with losartan placebo. At submaximal exercise, systolic blood pressure and rate-pressure product were lower after losartan 100 mg administration compared with losartan placebo, and these findings remained significant at 1-mm ST depression and at peak exercise. Losartan 100 mg administration versus losartan placebo significantly delayed the time to 1-mm ST-depression onset and decreased ST-segment depression at peak exercise and time to recovery of ST-segment depression. Losartan 100 mg administration compared with losartan placebo was able to significantly increase exercise duration and maximal workload during exercise stress testing. In conclusion, in our study, losartan decreased electrocardiographic parameters of myocardial ischemia in patients with coronary artery disease, suggesting a possible role of this drug in treatment of patients with effort myocardial ischemia.     

Assessment of peripheral artery tonometry in the detection of treadmill exercise-induced myocardial ischemia

OBJECTIVES: We sought to assess the added diagnostic value of peripheral artery tonometric (PAT) measurements, based on finger pulsatile arterial volume changes, to standard 12-lead stress electrocardiography (ECG), for detecting exercise-induced myocardial ischemia, using single-photon emission computed tomography (SPECT) as the standard of comparison in a double-blinded, multicenter protocol. METHODS: An automated algorithm for identifying myocardial ischemia from PAT was derived from 345 training cases. The PAT outcome was combined with the ECG result (ischemic, nonischemic, or equivocal), giving a PAT-enhanced value. A threshold of normality was determined to optimize agreement with the SPECT results in the training sample. The PAT-enhanced analysis was then validated in 616 subjects, only two of whom had technically unacceptable PAT studies. RESULTS: In the validation cohort, receiver operating characteristic curve analysis of the PAT-enhanced diagnosis yielded an area under the curve of 0.72, a sensitivity of 63.5%, compared with 44.7% for ECG alone (p < 0.0001), and a specificity of 67.8% common to both ECG and PAT-enhanced diagnoses. Similar results were found in the training sample. Although over 10% of validation subjects had equivocal ECG results, with the aid of PAT, it was possible to provide diagnostic information for all but one subject. CONCLUSIONS: Peripheral artery tonometry may be useful for improving the diagnosis of exercise-induced myocardial ischemia by both enhancing the sensitivity without impairing the specificity and increasing the percentage of definitive test results.     

Effect of the prokinetic drug cisapride on gastrointestinal hormone release

The influence of the prokinetic drug cisapride on the release of gastrointestinal hormones was studied in volunteers. First, acute effects of single doses of cisapride compared with saline were investigated. Cisapride at doses of 8 mg and 20 mg intravenously significantly increased plasma concentrations of pancreatic polypeptide (hPP) by 145% and 146%, respectively. Cholecystokinin (CCK) levels were increased by 176% at 8 mg cisapride, whereas gastrin and insulin levels remained unchanged. Enhancement of PP and CCK secretion was almost completely abolished by pretreatment with 1 mg atropine. Carbachol (250 micrograms subcutaneously) increased PP release by 62% but did not affect the other hormones. Second, the influence of a 1-week treatment (10 mg three times daily, given orally) on plasma hormone levels was studied. After 1 week the postprandial CCK release was diminished by 58%. Basal levels and postprandial responses of gastrin, PP, and insulin were not altered by prolonged cisapride administration. It is concluded that acute application of cisapride stimulates secretion of PP and CCK via atropine-sensitive mechanisms and that chronic treatment with cisapride diminishes CCK release by an unknown mechanism.     

Effect of cold exposure on the hypothalamic release of thyrotropin-releasing hormone and catecholamines.

The effects of cold exposure on the release of thyrotropin-releasing hormone (TRH) and catecholamines as estimated by push-pull perfusion of the mediobasal hypothalamus were studied. Before cold exposure, the male rats had been kept at room temperature or at 30 degrees C for 3 weeks. Transfer to 4 degrees C increased plasma levels of thyroid-stimulating hormone (TSH), but this cold-induced TSH response was more pronounced in animals which had been acclimatized to 30 degrees C. Exposure to 4 degrees C also increased plasma thyroid hormone levels, but had no effect on plasma prolactin. The hypothalamic content of TRH and dopamine remained similar after transfer to 4 degrees C, but after 6 h of cold, the content of noradrenaline and adrenaline had increased 1.6-fold and 3-fold, respectively. In vivo hypothalamic release of TRH, adrenaline and dopamine remained similar during a 2-hour period in control rats kept at room temperature or 30 degrees C. The hypothalamic release of TRH, dopamine and adrenaline did not change in rats transferred from room temperature to 4 degrees C. The amount of dopamine and adrenaline in push-pull perfusate also remained similar in rats acclimatized to 30 degrees C after transfer to low temperatures. However, in these rats kept at 30 degrees C for 3 weeks, exposure to 4 degrees C increased TRH release in perfusate from the mediobasal hypothalamus in the first 15 min of cold exposure (2-fold increase). Thus, exposure to cold stimulates the hypothalamo-pituitary-thyroid axis and increases the hypothalamic release of TRH in rats which had been acclimatized to 30 degrees C.     

Estrogen induces the release of luteinizing hormone-releasing hormone in normal cyclic women

The plasma concentrations of immunoreactive LRH, LH, and FSH were determined by RIA every 6 h until 72 h after iv administration of conjugated estrogens during the midfollicular phase. The percentage change in LH from the preinjection level showed a biphasic pattern after the injection of conjugated estrogens, i.e. significant suppression (-70%) from 6-42 h after the injection, followed by a rebound increase with a peak (+150%) at 56 h. Plasma FSH after the injection also showed a biphasic pattern. The plasma immunoreactive LRH levels were unchanged until 32 h after the injection, but then increased significantly (P less than 0.02) to 160% of the preinjection level at 42 h and then decreased rapidly. These data indicate that 1) estrogen administration results in increases in plasma immunoreactive LRH and LH, and the peak of plasma LRH precedes that of gonadotropin; and 2) the negative feedback effect of estrogen on gonadotropin secretion may not be mediated through LRH.     

Effect of estradiol-drospirenone hormone treatment on myocardial perfusion reserve in postmenopausal women with angina pectoris

Recent randomized clinical studies failed to show cardiovascular protection with postmenopausal hormone therapy (HT), instead raising widespread concerns about possible increased cardiovascular risk. However, these studies primarily assessed the combination of conjugated equine estrogen and medroxyprogesterone acetate, which is suspected to abolish the beneficial effects of estrogen on the microcirculation. This preliminary study evaluated the effects of HT combining 17beta-estradiol (E2) with a new progestin, drospirenone, on myocardial perfusion reserve, a surrogate marker of coronary function. In this double-blind randomized study, 56 postmenopausal women with angina pectoris received oral E2 1 mg plus drospirenone 2 mg or placebo for 6 weeks. Myocardial perfusion reserve was measured using radioactive oxygen-labeled water and positron emission tomography before and after therapy. Myocardial perfusion reserve increased significantly in the E2-drospirenone group after 6 weeks versus placebo (p<0.0008). Mean myocardial perfusion reserve increased from 4.83 at baseline to 5.13 after 6 weeks in the E2-drospirenone group (n=27), but decreased from 4.84 to 4.13 in the placebo group (n=29). No significant side effects were observed with E2-drospirenone. A larger trial is needed to investigate whether myocardial perfusion improvements will be sustained and translate into a clinical benefit in postmenopausal women at risk of coronary heart disease. In conclusion, E2-drospirenone HT for 6 weeks has favorable effects on myocardial function in postmenopausal women with angina pectoris. These data suggest that drospirenone has the desired progestin actions on the endometrium, but does not abolish the beneficial effects of estradiol on cardiac microcirculation.