Growth hormone and glucose homeostasis

Patients with active acromegaly are insulin-resistant and glucose-intolerant, whereas children with growth hormone (GH) deficiency (GHD) are insulin-sensitive and may develop fasting hypoglycaemia. Surprisingly, however, hypopituitary adults with unsubstituted GHD tend to be insulin-resistant, which may worsen during GH substitution. During fasting, which may be considered the natural domain for the metabolic effects of GH, the induction of insulin resistance by GH is associated with enhanced lipid oxidation and protein conservation. In this particular context, insulin resistance appears to constitute a favourable metabolic adaptation. The problem is that GH substitution results in elevated circadian GH levels in non-fasting patients. The best way to address this challenge is to employ evening administration of GH and to tailor the dose. Insulin therapy may cause hypoglycaemia and GH substitution may cause hyperglycaemia. Such untoward effects should be minimized by carefully monitoring the individual patient.     

Effects of high-altitude hypoxia on the hormonal response to hypothalamic factors

Acute and chronic exposure to high altitude induces various physiological changes, including activation or inhibition of various hormonal systems. In response to activation processes, a desensitization of several pathways has been described, especially in the adrenergic system. In the present study, we aimed to assess whether the hypophyseal hormones are also subjected to a hypoxia-induced decrease in their response to hypothalamic factors. Basal levels of hormones and the responses of TSH, thyroid hormones, prolactin, sex hormones, and growth hormone to the injection of TRH, gonadotropin-releasing hormone, and growth hormone-releasing hormone (GHRH) were studied in eight men in normoxia and on prolonged exposure (3-4 days) to an altitude of 4,350 m. Thyroid hormones were elevated at altitude (+16 to +21%), while TSH levels were unchanged, and follicle-stimulating hormone and prolactin decreased, while leutinizing hormone was unchanged. Norepinephrine and cortisol levels were elevated, while no change was observed in levels of epinephrine, dopamine, growth hormone (GH), IGF-1, and IGFBP-3. The mean response to hypothalamic factors was similar in both altitudes for all studied hormones, although total T4 was lower in hypoxia during 45 to 60 min after injection. The effect of hypoxia on the hypophyseal response to hypothalamic factors was similar among subjects, except for the GH response to GHRH administration. We conclude that prolonged exposure to high-altitude hypoxia induces contrasted changes in hormonal levels, but the hypophyseal response to hypothalamic factors does not appear to be blunted.     

The phenotype of adults with partial growth hormone deficiency

The concept of partial growth hormone (GH) deficiency (GHD) is well established within the paediatric setting having been validated against height velocity. In hypopituitary adults, GHD is defined by a peak GH response <3 microg/l to stimulation. This cut-off is arbitrary due to the lack of a biological marker equivalent of height velocity. The majority of normal adults achieve peak GH levels several fold higher than this cut off during stimulation. It can be argued, therefore, that there is a cohort of hypopituitary adults with intermediate peak GH values (3-7 microg/l), who have relatively impaired GH secretion, and for whom the impact of this partial GHD (GH insufficiency, GHI) on biological endpoints is not known. Studies of GHI adults have demonstrated an abnormal body composition, adverse lipid profile, impaired cardiac performance, reduced exercise tolerance and insulin resistance. The severity of these abnormalities lies between GHD adults and normal subjects. Whether these anomalies translate into increased mortality, as observed in GHD hypopituitary adults, is not yet known. Given the presence of similar sequelae in GHI and GHD adults, and the improvements during GH replacement in GHD adults, a randomized placebo-controlled study of GH replacement in GHI patients is warranted.     

Ghrelin promotes slow-wave sleep in humans

Ghrelin, an endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor, stimulates GH release, appetite, and weight gain in humans and rodents. Synthetic GHSs modulate sleep electroencephalogram (EEG) and nocturnal hormone secretion. We studied the effect of 4 x 50 microg of ghrelin administered hourly as intravenous boluses between 2200 and 0100 on sleep EEG and the secretion of plasma GH, ACTH, cortisol, prolactin, and leptin in humans (n = 7). After ghrelin administration, slow-wave sleep was increased during the total night and accumulated delta-wave activity was enhanced during the second half of the night. Rapid-eye-movement (REM) sleep was reduced during the second third of the night, whereas all other sleep EEG variables remained unchanged. Furthermore, GH and prolactin plasma levels were enhanced throughout the night, and cortisol levels increased during the first part of the night (2200-0300). The response of GH to ghrelin was most distinct after the first injection and lowest after the fourth injection. In contrast, cortisol showed an inverse pattern of response. Leptin levels did not differ between groups. Our data show a distinct action of exogenous ghrelin on sleep EEG and nocturnal hormone secretion. We suggest that ghrelin is an endogenous sleep-promoting factor. This role appears to be complementary to the already described effects of the peptide in the regulation of energy balance. Furthermore, ghrelin appears to be a common stimulus of the somatotropic and hypothalamo-pituitary-adrenocortical systems. It appears that ghrelin is a sleep-promoting factor in humans.     

Effects of growth hormone administration on wool growth in merino sheep

The effects of daily administration of 10 mg of highly purified ovine growth hormone (GH) for a period of 4 weeks on wool growth have been measured in 12 Merino ewes fed either a calculated maintenance energy intake or 1.6 times this amount (six on each ration). Concentrations of hormones, glucose, urea, alpha-amino N and amino acids in the blood were monitored and faeces and urine collected for measurement of nitrogen balance. Wool growth rate decreased by 20% during the 4 weeks of GH treatment in sheep fed the high energy diet, largely because of reduced wool fibre diameter. This was followed by restoration of normal growth and then an increase of up to 20% above control levels, a response which persisted for 12 weeks following cessation of GH administration, and which was due to increases in both fibre length and diameter. GH administration caused marked increases in plasma concentrations of GH, insulin and somatomedin C, glucose and free fatty acids, all of which returned to basal levels following cessation of GH administration. No consistent changes in plasma concentration of T3, T4, cortisol, prolactin or alpha amino N were detected. Plasma urea and methionine levels decreased during GH treatment and returned to, or were raised above, basal levels after the GH treatment period. GH injection also resulted in a net retention of N during treatment, followed by a transient period of net N loss. The GH-induced changes in wool growth may be caused by a change in the partitioning of amino acids between the muscle mass and the skin. No other contributing factor(s) were identified.     

Responsiveness of cortisol and dehydroepiandrosterone to ACTH in children

In a total of 101 children, the dehydroepiandrosterone (DHA) and cortisol (F) levels were measured before and after ACTH (Synacten) administration. F responsiveness was unchanged during development, while DHA responsiveness in healthy children was highest during adrenarche. In hypopituitary patients DHA levels were lower than in the controls, but responsiveness to ACTH showed similar changes during development. Children with Turner's syndrome and hypergonadotrophic males had the response in elevated DHA levels while ACTH-induced DHA response related to bone-age matched controls. We conclude that regulation of adrenal androgens is mediated by both ACTH and another hypothalamo-pituitary hormone, perhaps independent of gonadal activation, but requiring gonadal integrity.     

Effects of growth hormone replacement therapy on bone markers and bone mineral density in growth hormone-deficient adults

During the 1990s, interest in the effects of growth hormone deficiency (GHD) in adults increased, and several studies were performed to evaluate the effects of growth hormone (GH) substitution therapy in these patients. Because adults with GHD have reduced bone mineral density (BMD) and an increased risk of fractures, the effects of GH replacement therapy on bone metabolism have been evaluated in long-term studies. A universal finding is that the serum and urinary levels of biochemical bone markers increase during GH substitution therapy, and these increases are dose dependent. After years of GH substitution therapy, the levels of biochemical bone markers remain elevated, according to some studies, whereas other studies report that these levels return to baseline. BMD of the spine, hip and forearm increase after 18-24 months of treatment. Bone mineral content (BMC) increases to a greater extent than BMD, because the areal projection of bone also increases. This difference could be caused by increased periosteal bone formation, but a measurement artefact resulting from the use of dual-energy X-ray absorptiometry cannot be excluded as a possible explanation. One study of GH-deficient adults found that, after 33 months of GH treatment, BMD and BMC increased to a greater extent in men with GHD than in women. There is also a gender difference in the increases in serum levels of insulin-like growth factor I and biochemical bone markers during GH treatment. The reason for these findings is unknown, and the role of sex steroids in determining the response to GH therapy remains to be fully elucidated.     

Effects of short-term oral salbutamol administration on exercise endurance and metabolism.

The present study examined whether oral short-term administration of salbutamol (Sal) modifies performance and selected hormonal and metabolic variables during submaximal exercise. Eight recreational male athletes completed two cycling trials at 80-85% peak O(2) consumption until exhaustion after either gelatin placebo (Pla) or oral Sal (12 mg/day for 3 wk) treatment, according to a double-blind and randomized protocol. Blood samples were collected at rest, after 5, 10, and 15 min, and at exhaustion to determine growth hormone (GH), cortisol, testosterone, triiodothyronine (T(3)), C peptide, free fatty acid (FFA), blood glucose, lactate, and blood urea values. Time of cycling was significantly increased after chronic Sal intake (Sal: 30.5 +/- 3.1 vs. Pla: 23.7 +/- 1.6 min, P < 0.05). No change in any variable was found before cycling except a decrease in blood urea concentration and an increase in T(3) after Sal that remained significant throughout the exercise test (P < 0.05). Compared with rest, exercise resulted in a significant increase in GH, cortisol, testosterone, T(3), FFAs, and lactate and a decrease in C peptide after both treatments with higher exercise FFA levels and exhaustion GH concentrations after Sal (P < 0.05). Sal but not Pla significantly decreased exercise blood glucose levels. From these data, short-term Sal intake did appear to improve performance during intense submaximal exercise with concomitant increase in substrate availability and utilization, but the exact mechanisms involved need further investigation.     

Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor alpha1 or beta

Thyroid hormone (T(3)) regulates bone turnover and mineralization in adults and is essential for skeletal development. Surprisingly, we identified a phenotype of skeletal thyrotoxicosis in T(3) receptor beta(PV) (TRbeta(PV)) mice in which a targeted frameshift mutation in TRbeta results in resistance to thyroid hormone. To characterize mechanisms underlying thyroid hormone action in bone, we analyzed skeletal development in TRalpha1(PV) mice in which the same PV mutation was targeted to TRalpha1. In contrast to TRbeta(PV) mice, TRalpha1(PV) mutants exhibited skeletal hypothyroidism with delayed endochondral and intramembranous ossification, severe postnatal growth retardation, diminished trabecular bone mineralization, reduced cortical bone deposition, and delayed closure of the skull sutures. Skeletal hypothyroidism in TRalpha1(PV) mutants was accompanied by impaired GH receptor and IGF-I receptor expression and signaling in the growth plate, whereas GH receptor and IGF-I receptor expression and signaling were increased in TRbeta(PV) mice. These data indicate that GH receptor and IGF-I receptor are physiological targets for T(3) action in bone in vivo. The divergent phenotypes observed in TRalpha1(PV) and TRbeta(PV) mice arise because the pituitary gland is a TRbeta-responsive tissue, whereas bone is TRalpha responsive. These studies provide a new understanding of the complex relationship between central and peripheral thyroid status.     

Long-term growth hormone treatment preserves GH-induced memory and mood improvements: a 10-year follow-up study in GH-deficient adult men

Growth hormone (GH) replacement therapy with duration of several years is known to be safe and beneficial in GH-deficient adult patients. However, long-term follow-up data on GH substitution, cognition, and well-being are scarce. The purpose of this study was to investigate whether the benefits of GH replacement in psychological functioning found in previous studies lasting up to 2 years are preserved over a 10-year follow-up period. Twenty-three men (mean age at baseline 28.6 years) with childhood-onset GH deficiency were studied during a 10-year period of GH substitution. Memory tasks, mood questionnaires, and IGF-I values were obtained at baseline and after 0.5, 1, 2, 3, 5, and 10 years of GH substitution. Both mood and memory improved during GH therapy. After 6 months of treatment, anxiety and tension were reduced and vigor had improved. Memory improved after 1 year of substitution. These improvements were maintained during the 10-year follow-up period. Higher intra-subject IGF-I levels were associated with better mood (anxiety, tension, vigor). This study shows that 10 years of GH therapy is beneficial in terms of well-being and cognitive functioning in childhood-onset GH-deficient men. It may be concluded that once the decision to start GH treatment has been taken, this may imply that GH therapy has to be continued for a long period to maintain the psychological improvements and to prevent a relapse.     

The effects of growth hormone on cortical and cancellous bone

Growth hormone (GH) has profound effects on linear bone growth, bone metabolism and bone mass. The GH receptor is found on the cell surface of osteoblasts and osteoclasts, but not on mature osteocytes. In vitro, GH stimulates proliferation, differentiation and extracellular matrix production in osteoblast-like cell lines. GH also stimulates recruitment and bone resorption activity in osteoclast-like cells. GH promotes autocrine/paracrine insulin-like growth factor 1 (IGF-I) production and endocrine (liver-derived) IGF-I production. Some of the GH-induced effects on bone cells can be blocked by IGF-I antibodies, while others cannot. In animal experiments, GH administration increases bone formation and resorption, and enhances cortical bone mass and mechanical strength. When GH induces linear growth, increased cancellous bone volume is seen, but an unaffected cancellous bone volume is found in the absence of linear growth. Patients with acromegaly have increased bone formation and resorption markers. Bone mass results are conflicting because many acromegalics have hypogonadism, but in acromegalics without hypogonadism, increased bone mineral density (BMD) is seen in predominantly cortical bone, and normal BMD in predominantly cancellous bone. Adult patients with growth hormone deficiency have decreased bone mineral content and BMD. GH therapy rapidly increases bone formation and resorption markers. During the first 6-12 months of therapy, declined or unchanged BMD is found in the femoral neck and lumbar spine. All GH trials with a duration of two years or more show enhanced femoral neck and lumbar spine BMD. In osteoporotic patients, GH treatment quickly increases markers for bone formation and resorption. During the first year of treatment, unchanged or decreased BMD values are found, whereas longer treatment periods report enhanced or unchanged BMD values. However, existing trials comprising relatively few patients and limited treatment periods do not allow final conclusions to be drawn regarding the effects of GH on osteoporosis during long-term treatment.     

Growth hormone - hormone replacement for the somatopause?

Twenty-four-hour growth hormone (GH) secretion reaches a peak at around puberty and by the age of 21 has begun to decrease. Thereafter the fall in GH secretion is progressive such that by the age of 60 most adults have total 24-hour secretion rates indistinguishable from those of hypopituitary patients with organic lesions in the pituitary gland. Patterns of GH secretion are similar to those in younger people but GH pulses are markedly reduced in amplitude. Sleep and exercise remain the major stimuli for GH secretion. The fall in GH secretion seen with ageing coincides with changes in body composition and lipid metabolism that are similar to those seen in adults with GH deficiency. In elderly subjects, although GH secretion is markedly reduced, remaining GH secretion correlates closely with body composition (particularly with lean body mass and inversely with central abdominal fat). Pioneering studies carried out by Rudman showed that GH administration to elderly subjects with low insulin-like growth factor-I levels resulted in reversal of many of the changes associated with GH deficiency, namely an increase in lean body mass and bone mineral density and a reduction in body fat and plasma cholesterol. These changes were remarkably similar to those shown a year earlier in adults with GH deficiency given GH replacement. Subsequent studies of GH replacement in elderly adults have confirmed Rudman's initial observations but have been dominated by side effects which have led to a high number of dropouts. It is now clear that the elderly are very sensitive to GH and the doses used need to be very low, increased very slowly and tailored to the individual needs of each patient. Using this more cautious approach, recent studies have been very positive. A series of papers from Blackman's group, presented at the US endocrine meeting in San Diego in 1999, investigated the effects of GH with or without testosterone supplements (in men) and oestrogen supplements (in women). Their results showed positive effects of GH on lean body mass, central fat, low-density lipoprotein cholesterol and aerobic capacity. In many instances there was a positive interaction between GH and hormone replacement with testosterone and oestrogen, but it appeared that GH showed the most potent anabolic effects. Clearly more studies are needed before GH replacement for the elderly becomes established. Safety issues will require close scrutiny, but the data available so far are sufficiently positive to undertake large multicentre, placebo-controlled trials, particularly looking at endpoints associated with prevention of frailty and loss of independence.     

Effect of human growth hormone on adrenal androgens in children with growth hormone deficiency

The effect of human growth hormone (hGH) on adrenal androgen secretion was assessed in 7 patients (5 males, 2 females) with GH deficiency but normal ACTH-cortisol function. Patients ranged in age from 9 5/12 to 14 8/12 years (median 12 years). Plasma concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and urinary excretion of 17-ketosteroids (17-KS) and free cortisol were determined before, during short-term (2 U/day X 3) and after long-term (6 months) treatment with hGH. No significant change was noted in the plasma concentration or urinary excretion of steroids during the short-term administration of hGH. Despite a significant increase in growth velocity during 6 months of hGH therapy (8.2 vs. 4.5 cm/year, p less than 0.01), the plasma concentrations of DHEA-S and the urinary 17-KS and free cortisol levels were unchanged. These results fail to substantiate a role for hGH in the physiologic control of adrenal androgen secretion. Thus, the low plasma levels of adrenal androgens sometimes seen in GH-deficient patients are not due to the absence of GH per se.     

Early diagnosis and early treatment of growth hormone deficiency

In the past, growth hormone (GH) deficiency has usually been diagnosed too late in dwarfed children, so that substitution therapy was not able to obtain a final height in the normal range for most of them. Complete catch-up of growth in hypopituitary patients needs early diagnosis and early treatment. This requires: (1) that full attention be paid to any insufficiency of length or height increment in infants and young children; (2) that evaluation of GH secretion be performed in spite of the practical difficulties encountered in small patients, and (3) that the interpretation of hormonal measurements be carefully discussed. Though the overall results obtained to date in treating very young GH-deficient children have not been completely satisfactory, it is certain that those whose height was within or near the limits of -2 SD at the onset of treatment maintained a normal height. The relationship of end results with the doses of GH used remains to be investigated. Future results will probably be improved more by earlier diagnosis and by using daily injections than by an increase in the annual dose of GH.     

Lower growth hormone and higher cortisol are associated with greater visceral adiposity, intramyocellular lipids, and insulin resistance in overweight girls

Although body composition, insulin sensitivity, and lipids are markedly altered in overweight adolescents, hormonal associations with these parameters have not been well characterized. Growth hormone (GH) deficiency and hypercortisolemia predispose to abdominal adiposity and insulin resistance, and GH secretion is decreased in obese adults. We hypothesized that low-peak GH on the GH-releasing hormone (GHRH)-arginine stimulation test and high cortisol in overweight adolescents would be associated with higher regional fat, insulin resistance, and lipids. We examined the following parameters in 15 overweight and 15 bone age-matched control 12- to 18-yr-old girls: 1) body composition using dual-energy X-ray absorptiometry and MR [visceral and subcutaneous adipose tissue at L(4)-L(5) and soleus intramyocellular lipid ((1)H-MR spectroscopy)], 2) peak GH on the GHRH-arginine stimulation test, 3) mean overnight GH and cortisol, 4) 24-h urinary free cortisol (UFC), 5) fasting lipids, and 6) an oral glucose tolerance test. Stepwise regression was the major tool employed to determine relationships between measured parameters. Log peak GH on the GHRH-arginine test was lower (P = 0.03) and log UFC was higher (P = 0.02) in overweight girls. Log mean cortisol (overnight sampling) was associated positively with subcutaneous adipose tissue and, with body mass index standard deviation score, accounted for 92% of its variability, whereas log peak GH and body mass index standard deviation score accounted for 88% of visceral adipose tissue variability and log peak GH for 34% of the intramyocellular lipid variability. Log mean cortisol was independently associated with log homeostasis model assessment of insulin resistance, LDL, and HDL and explained 49-59% of the variability. Our data indicate that lower peak GH and higher UFC in overweight girls are associated with visceral adiposity, insulin resistance, and lipids.     

Selective serotonin reuptake inhibitors and neuroendocrine function.

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are effective drugs for the treatment of several neuropsychiatric disorders associated with reduced serotonergic function. Serotonergic neurons play an important role in the regulation of neuroendocrine function. This review will discuss the acute and chronic effects of SSRIs on neuroendocrine function. Acute administration of SSRIs increases the secretion of several hormones, but chronic treatment with SSRIs does not alter basal blood levels of hormones. However, adaptive changes are induced by long-term treatment with SSRIs in serotonergic, noradrenergic and peptidergic neural function. These adaptive changes, particularly in the function of specific post-synaptic receptor systems, can be examined from altered adrenocorticotrophic hormone (ACTH), cortisol, oxytocin, vasopressin, prolactin, growth hormone (GH) and renin responses to challenges with specific agonists. Neuroendocrine challenge tests both in experimental animals and in humans indicate that chronic SSRIs produce an increase in serotonergic terminal function, accompanied by desensitization of post-synaptic 5-HT1A receptor-mediated ACTH, cortisol, GH and oxytocin responses, and by supersensitivity of post-synaptic 5-HT2A (and/or 5-HT2C) receptor-mediated secretion of hormones. Chronic exposure to SSRIs does not alter the neuroendocrine stress-response and produces inconsistent changes in alpha2 adrenoceptor-mediated GH secretion. Overall, the effects of SSRIs on neuroendocrine function are dependent on adaptive changes in specific neurotransmitter systems that regulate the secretion of specific hormones.     

Insulin hypoglycemia test and releasing hormone (corticotropin-releasing hormone and growth hormone-releasing hormone) stimulation in patients with pituitary failure of different origin

To investigate the efficacy of endocrine evaluation in diagnosing and localizing the cause of anterior pituitary failure, 17 patients with suprasellar space-occupying lesions, 4 patients with intrasellar tumors, 8 patients with no detectable anatomical lesion, 1 patient with posttraumatic failure and 1 patient with septooptical dysplasia were investigated. Endocrine evaluation consisted of measuring adrenocorticotropic hormone (ACTH), cortisol, and growth hormone (GH) levels during insulin hypoglycemia test (IHT) and after administration of corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GRH). In addition, basal prolactin levels, gonadal and thyroid function were evaluated. The results showed that 4 of 17 patients with suprasellar tumors had normal ACTH and GH responses during IHT and after releasing hormone (RH) administration. Five of these patients had a normal ACTH or cortisol rise but no GH response during IHT. All 5 had a normal ACTH and 3 had normal GH rise after RH. Seven patients with suprasellar tumors had no ACTH or GH response during IHT, but all had an ACTH response to CRH. Only 3 of this group had a GH response to GRH. There was one exception of a patient who showed a GH and ACTH rise during IHT but only a blunted ACTH and no GH rise after RH administration. Four patients with pituitary failure and no demonstrable lesion had an ACTH rise after CRH but no GH rise after GRH, whereas in 3 patients with isolated ACTH deficiency no ACTH rise after CRH was seen. In 4 patients with nonsecreting pituitary tumors normal ACTH responses to IHT and CRH were seen, whereas GH rose during IHT only in 1 patient.(ABSTRACT TRUNCATED AT 250 WORDS)     

Additive effects of cortisol and growth hormone on regional and systemic lipolysis in humans

Growth hormone (GH) and cortisol are important to ensure energy supplies during fasting and stress. In vitro experiments have raised the question whether GH and cortisol mutually potentiate lipolysis. In the present study, combined in vivo effects of GH and cortisol on adipose and muscle tissue were explored. Seven lean males were examined four times over 510 min. Microdialysis catheters were inserted in the vastus lateralis muscle and in the subcutaneous adipose tissue of the thigh and abdomen. A pancreatic-pituitary clamp was maintained with somatostatin infusion and replacement of GH, insulin, and glucagon at baseline levels. At t = 150 min, administration was performed of NaCl (I), a 2 microg.kg(-1).min(-1) hydrocortisone infusion (II), a 200-microg bolus of GH (III), or a combination of II and III (IV). Systemic free fatty acid (FFA) turnover was estimated by [9,10-3H]palmitate appearance. Circulating levels of glucose, insulin, and glucagon were comparable in I-IV. GH levels were similar in I and II (0.50 +/- 0.08 microg/l, mean +/- SE). Peak levels during III and IV were approximately 9 microg/l. Cortisol levels rose to approximately 900 nmol/l in II and IV. Systemic (i.e., palmitate fluxes, s-FFA, s-glycerol) and regional (interstitial adipose tissue and skeletal muscle) markers of lipolysis increased in response to both II and III. In IV, they were higher and equal to the isolated additive effects of the two hormones. In conclusion, we find that GH and cortisol stimulate systemic and regional lipolysis independently and in an additive manner when coadministered. On the basis of previous studies, we speculate that the mode of action is mediated though different pathways.     

Effects of sexual experience, season, and mating stimuli on endocrine concentrations in the adult ram.

Two behavioral trials were conducted to determine the endocrine response of cortisol (C), luteinizing hormone (LH), testosterone (T), prolactin (PRL), and growth hormone (GH) in adult rams during exposure to estrous ewes during the breeding and nonbreeding seasons. One-half of the rams in each season were sexually experienced (SE) and the remainder were sexually inexperienced (SI). All SE rams (100%) achieved at least one ejaculation, but only 33% (summer) and 67% (fall) SI rams achieved ejaculation. In the fall, mean C, T, and GH concentrations were elevated (P less than .001) compared to values measured in the summer, whereas LH and PRL levels were higher (P less than .01) in the summer. Overall levels of C, LH, T, and PRL were higher (P less than .05) in SE rams than in SI rams. Mean GH concentration was higher (P less than .10) in SI than in SE rams during restricted and complete access to estrous ewes. In general, LH, PRL, and GH responses were similar during restricted and complete access to females for both SE and SI rams. Cortisol levels were higher (P less than .06) during periods of mating and T levels were higher (P less than .001) during periods where activity was limited to courtship behavior (nasogenital investigation). Correlations of hormones to reproductive behaviors indicated that mounting and intromission were associated with elevations in C and PRL, whereas elevated LH and T tended to be associated with courtship behaviors. Correlations between GH and behaviors were inconsistent. However, there was an increased coincidence between time of female exposure and hormonal response that occurred in the fall; brief exposure to estrous ewes resulted in increases in concentrations of all hormones examined. The most consistent response was observed in sexually experienced rams during restricted access to females during the breeding season. These results provide new information on the effects of season and level of sexual experience upon hormonal and behavioral characteristics of the ram during mating activity.     

Pituitary-thyroid function of fetuses of hypothyroid and growth hormone treated hypothyroid rats.

Maternal hypothyroidism induced by surgical thyroidectomy (Tx) of the rat resulted in significantly higher fetal serum levels of thyroid stimulating hormone (TSH) and thyroxine (T4) on day 22 of gestation. Surprisingly, administration of growth hormone (GH) to hypothyroid mothers increased further the fetal serum T4 and TSH. The in vitro uptake of 131I-T4 by erythrocytes was elevated significantly when incubated with serum from fetuses of both hypothyroid and hypothyroid GH-treated mothers. Although the plasma protein levels of hypothyroid mothers and their fetuses are decreased significantly as compared to controls this is not true of hypothyroid GH-treated mothers and their fetuses. The T4 levels of both groups of Tx mothers were significantly below that of controls. However, as in the case of their fetuses, the serum T4 of GH-treated hypothyroid mothers was elevated from that of Tx only animals. It is concluded that the pituitary-thyroid system of fetuses of hypothyroid mothers is activated excessively during late gestation, that considerable T4 can be transported from the fetus to the mother during this period and that these fetuses are in fact born in a hyperthyroid state which is aggravated by maternal treatment with GH.