Is there an undiscovered neurocircuit for regulating GH secretion? -Pitfalls of GHRP-2 and ITT as GH provocative tests-

GH secretion is mainly regulated at the hypothalamus by a dual interplay between growth hormone releasing hormone (GHRH) and somatostatin, which are modulated by various factors. We examined the regulatory mechanism of GH secretion in an apparently healthy young man without decreased IGF-1 concentration and nocturnal GH secretion, but who showed low responses to insulin tolerance (ITT) and to GHRP-2 tests. The patient also had no GH response to acute aerobic exercise. However, he had normal secretion of pituitary hormone based on hypothalamic releasing hormone tests combined with CRH, GRH as GHRH, LH-RH and TRH. In addition, he had a GH response without paradoxical secretion to TRH stimulation as well as an ACTH response to subcutaneous glucagon stimulation, and AVP secretion responded to 5% hypertonic saline infusion, though it was not adequately stimulated by ITT. MRI showed no structural abnormalities in the hypothalamus-pituitary gland. These findings indicate that this subject may have an undiscovered neurocircuit for regulating GH secretion, as well as other neurohormones, to maintain homeostasis, even though there were low responses of the hormones to ITT and GHRP-2 stimuli, probably via altered secretion of hypothalamic hormones.     

HYPOTHALAMIC HYPOPITUITARISM FOLLOWING CRANIAL IRRADIATION FOR NASOPHARYNGEAL CARCINOMA

Eight patients, one male and seven females, with no pre-existing hypothalamic-pituitary disease, who developed symptoms of hypopituitarism following cranial irradiation for nasopharyngeal carcinoma were studied 5 years or more after radiotherapy. All were GH deficient. Four of the patients with no GH response during insulin tolerance tests (ITT) showed increased GH in response to synthetic human growth hormone releasing factor (GRF-44). Four patients had impaired cortisol responses to ITT, and gradual but diminished cortisol responses to ovine corticotrophin releasing factor (CRF-41). There was no significant difference between mean peak increments in response to ITT and those in response to CRF-41. TSH responses to TRH were delayed in five and absent in two patients; four of these had low free T4 index. Prolactin was raised in all seven women and increased further in response to TRH. Two patients had impaired gonadotrophin responses to LHRH. None of the patients had clinical or biochemical evidence of diabetes insipidus. These data suggest that post-irradiation hypopituitarism in these patients results from radiation damage to the hypothalamus leading to varying degrees of deficiency of the hypothalamic releasing or inhibitory factors.     

Dopamine affects basal and augmented pituitary hormone secretion.

Although the role of the neurotransmitter, dopamine (DA), in the regulation of PRL has been well documented, controversy exists regarding its participation in the regulation of the other pituitary hormones. Consequently, we infused DA into six healthy male subjects (ages 19-32) and studied its effects on both basal pituitary hormone levels and augmented hormonal release induced by insulin hypoglycemia (ITT), TRH, and gonadotropin-releasing hormone (GnRH). DA alone produced a modest though significant increase in GH concentration from 2.2 +/- 0.5 to 11.9 +/- 3.7 ng/ml (P less than 0.05) by 60 min, but the peak incremental GH response to ITT was significantly inhibited by DA (43.5 +/- 5.0 vs. 16.3 +/- 3.3 ng/ml; P less than 0.01). PRL concentrations fell during the DA infusion (20.4 +/- 3.0 to 10.6 +/- 1.5 ng/ml; P less than 0.02) at 235 min, and the PRL responses to both ITT and TRH were completely abolished. Although the basal LH and FSH concentrations were unaffected by DA, the incremental LH response to GnRH was inhibited (45.5 +/- 10.6 to 24.4 +/- 5.4 mIU/ml; P less than 0.05), while the FSH response was unchanged. DA significantly reduced the basal TSH concentration from 3.9 +/- 0.2 to 2.5 +/- 0.2 micro U/ml (P less than 0.01) at 230 min and blunted the peak incremental TSH response to TRH (6.0 +/- 1.5 vs. 2.9 +/- 0.9 microU/ml; P less than 0.01). DA had no effect on basal cortisol levels, the cortisol response to ITT, basal plasma glucose, or the degree of hypoglycemia after ITT. Our data provide new evidence that DA has an inhibitory as well as a stimulatory role in the regulation of GH secretion in normal humans. It inhibits centrally as well as peripherally mediated PRL secretion and blunts the LH response to GnRH. In addition, DA lowers both basal and TRH-mediated TSH release, confirming the reports of other investigators.     

Pituitary-thyroid axis, prolactin and growth hormone in patients with acute stroke

The pituitary-thyroid axis, serum prolactin and growth hormone levels were studied in 29 patients within 9 d of onset of acute ischaemic stroke. When compared to a control group of 80-year-old volunteers (n = 33), stroke patients were found to have elevated free thyroxine indices (P = 0.008), after adjustment for age and sex. Seventeen (81%) of the stroke patients showed a paradoxical rise in growth hormone in response to thyrotropin releasing hormone (TRH). In a multiple regression model, disorientation was associated with a low thyrotropin response to TRH (P = 0.02 and P = 0.04; 20 and 60 min after TRH, respectively). Disorientation was also positively correlated with the prolactin response to TRH (P = 0.045 after 60 min). Growth hormone levels were predicted by extensive motor impairment (P = 0.02). In conclusion, changes in pituitary and thyroid hormones were commonly observed after stroke and were closely associated with cognitive and/or motor impairment.     

Mechanisms involved in the effects of TRH on GHRH-stimulated growth hormone release from ovine and bovine pituitary cells

Incubation of cultured ovine pituitary cells with growth hormone-releasing hormone (GHRH) (10(-12)-10(-7) M) stimulated growth hormone secretion up to 3-fold. At a maximal stimulatory concentration of GHRH (10(-10) M), thyrotropin-releasing hormone (TRH) (10(-7) M) caused an inhibition of growth hormone release to approx. 50% of the response obtained with GHRH alone (during a 15 min incubation period). TRH also caused a small inhibition of the GHRH-stimulated cellular cyclic AMP level but this effect was only significant at a relatively high concentration of GHRH (10(-9) M). Incubation of cultured bovine pituitary cells with GHRH (10(-11)-10(-8) M) plus TRH (10(-7) M) caused a significant stimulation of growth hormone release by up to 40%, compared with the response obtained with GHRH alone (at all concentrations of GHRH). TRH (10(-7) M) had no effect on GHRH (10(-8) M)-stimulated cellular cyclic AMP levels in a partially purified bovine pituitary cell preparation. The effects of varying extracellular [Ca2+] (0.1-10 mM) on intracellular [Ca2+] and on the responsiveness to releasing hormones were also determined using ovine pituitary cells. GHRH (10(-10) M)-stimulated growth hormone release was inhibited when cells were incubated at both high (10 mM) and low (0.1 mM) [Ca2+] (compared with 1 mM or 3 mM Ca2+) with or without TRH (10(-7) M). At 1 mM Ca2+, TRH produced a synergistic effect with GHRH to stimulate growth hormone release. However, at 3 mM Ca2+ TRH inhibited GHRH-stimulated growth hormone release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of histamine on basal and TRH/LH-RH-stimulated PRL and LH secretion during different phases of the menstrual cycle in normal women

The neurotransmitter histamine (HA) may participate in the regulation of some pituitary hormones. We, therefore, investigated the effect of HA (50 micrograms/kg body weight/h, infusion 0-240 min) on basal and thyrotropin-releasing hormone (TRH) and luteinizing hormone releasing hormone (LH-RH) stimulated prolactin (PRL) and LH secretion in 5 normal women during the early follicular and the luteal phases of the same menstrual cycle. HA had no effect on the basal secretion of the two hormones. However, the PRL response to 200 micrograms TRH during the HA infusion was significantly increased compared to the response to a saline control infusion during the early follicular phase (peak responses were 1,902 +/- 398 vs. 1,228 +/- 230 microIU/ml, p less than 0.025) and during the luteal phase (peak responses were 2,261 +/- 335 vs. 1,647 +/- 245 microIU/ml, p less than 0.05). HA potentiated the LH response to 100 micrograms LH-RH during the early follicular phase (peak responses were 37.1 +/- 4.9 vs. 26.9 +/- 4.5 mIU/ml, p less than 0.05) and during the luteal phase (peak responses were 79.3 +/- 22.5 vs. 50.7 +/- 11.4 mIU/ml, p less than 0.025). We, therefore, found HA to have a potentiating effect on TRH/LH-RH-stimulated PRL and LH secretion in women. The results are similar to our previous findings in men, although the potentiating effects of HA were higher in women.     

INTERACTION BETWEEN SECRETION OF THE GONADOTROPHINS, PROLACTIN, GROWTH HORMONE, THYROTROPHIN AND CORTICOSTEROIDS IN MAN: THE EFFECTS OF LH/FSH-RH, TRH AND HYPOGLYCAEMIA ALONE AND IN COMBINATION

The interaction between the mechanisms involved in the LH, FSH, growth hormone, prolactin, ACTH and TSH responses to the synthetic LH and FSH releasing hormone, thyrotrophin releasing hormone and insulin induced hypoglycaemia was studied in twelve normal male volunteers. Each subject acted as his own control and the test procedures were performed individually and in combination. The simultaneous administration of one releasing hormone with another or with insulin in no way modified the hormonal responses to either releasing hormone or to hypoglycaemia. Clinical testing with these procedures may therefore be performed simultaneously, so that the pituitary reserve for the five anterior pituitary hormones may be assessed together in under 2 hr. In addition it has been shown that TRH releases a small amount of FSH but not LH in male subjects.     

THE INTERACTION OF GROWTH HORMONE RELEASING HORMONE WITH OTHER HYPOTHALAMIC HORMONES ON THE RELEASE OF ANTERIOR PITUITARY HORMONES

To determine whether the 29 amino-acid fragment of growth hormone releasing hormone (GHRH) can be combined with other hypothalamic releasing hormones in a single test of anterior pituitary reserve, the responses of anterior pituitary hormones to combinations of an i.v. bolus of GHRH(1-29)NH2 or saline with an i.v. bolus of either LH releasing hormone (LHRH) plus TRH, ovine CRH(oCRH) or saline were studied. Each infusion of GHRH(1-29)NH2 resulted in a rapid increment of the plasma GH value. Infusion of GHRH(1-29)NH2 also caused a small and transient rise in plasma PRL, but no change in the integrated PRL response. The combination of GHRH(1-29)NH2 with LHRH plus TRH caused a larger increment of peak and integrated plasma TSH levels than LHRH plus TRH alone. GHRH(1-29)NH2 did not affect the release of other anterior pituitary hormones after infusion with oCRH or LHRH plus TRH. Because of the finding of potentiation of the TSH-releasing activity of LHRH plus TRH by GHRH(1-29)NH2, the study was extended to the investigation of TSH release after infusion of TRH in combination with either GHRH(1-29)NH2 or GHRH(1-40). In this study the combination of TRH with both GHRH preparations also caused a larger increment of the peak and integrated plasma TSH levels than TRH alone. It is concluded that GHRH(1-29)NH2 possesses moderate PRL-releasing activity apart from GH-releasing activity. In addition, GHRH potentiates the TSH-releasing activity of TRH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenylate cyclase of GH and ACTH producing tumors of human: activation by non-specific hormones and other bioactive substances.

The adenylate cyclase responses of the human GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors to TRH, LH-RH, biogenic amines, peptides hormones, PGE1 and rat median eminence extract (MEE) have been examined. Out of 4 GH producing pituitary adenomas obtained from patients with active acromegaly at hypophysectomy two were stimulated by TRH, two by LH-RH, three by norepinephrine, one by dopamine, four by PGE1 and none by serotonin. Glucagon stimulated the adenylate cyclase in one of three and MEE in both of two tested. The positive responses of paradoxical GH release after TRH and/or LH-RH before surgery in these patients coincidentally related to the response of adenylate cyclase of each pituitary adenoma. There seems, however, to be no consistent correlation between the adenylate cyclase responses to biogenic amines and the GH release after L-Dopa or 5-hydroxytroptophan tested. The adenylate cyclase of a pituitary adenoma from case of Cushing's disease was stimulated by LH-RH, norepinephrine glucagon and MEE but not by TRH. Plasma levels of ACTH, beta-MSH and cortisol increased after LH-RH but not after TRH in this patient before hypophysectomy. The adenylate cyclase of two ectopic ACTH producing tumors (gastric carcinoid and malignant thymoma) was activated by TRH, LH-RH, norepinephrine, epinephrine, serotonin, PGE1 and MEE. These results indicate the presence of multiple hormone receptors in GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors, and suggest that the paradoxical GH or ACTH release after TRH and/or LH-RH injection in acromegaly and Cushing's syndrome might be caused by an alteration of the cellular membrane receptors of the pituitary adenomas.     

Thyrotropin and prolactin response to intraspinal TRH administration in man.

The effect of intraspinal (i.s.) TRH administration of Prolactin (Prl) and thyrotropin stimulating hormone (TSH) serum levels was studied in order to verify the existence of a ventricular route in man for releasing factor delivery to the anterior pituitary, which has been previously reported in rats. Ten young male subjects were given 200 microgram thyrotropin releasing hormone (TRH) i.s. injections and Prl and TSH were measured by radioimmunoassay (RIA) before and at various times after TRH administration. In the same subjects, an i.v. TRH test was also performed. After i.s. TRH, a prompt Prl increase (peak values at 10-30 min and return to baseline within 150 min) and a delayed increase (3-5 h following TRH injection) were observed in 7 and 5 subjects respectively, while an early elevation in serum TSH occurred in 6 subjects and a late one in other 6. In two subjects, a biphasic response of both tropins was present. Prl and TSH response to i.v. TRH was within the normal range in all cases; no late rise of the 2 hormones was observed. A kinetic experiment with 125I-TRH was also carried out to elucidate the mode of i.s. vs i.v. TRH action. These results confirm in man data reported in animals which suggest that TRH can be transported from the cerebrospinal fluid (CSF) to the portal system and the hypophysis.     

TRH is a tonic secretagogue in growth hormone secreting but not in nonfunctioning pituitary tumors

In most patients with growth hormone (GH) secreting pituitary adenomas and clinically nonfunctioning pituitary tumors (NFPT) the intravenous injection of thyrotropin releasing hormone (TRH) augments the secretion of GH and subunits of gonadotropin hormones respectively. Similar hormone responses to TRH have been detected in rat pituitary cell lines and in primary human pituitary tumor cultures in vitro. Nevertheless the TRH effect on tumor hormonal secretion has not been well characterized. In the present study we examined TRH-induced hormone secretion in GH secreting tumors and in NFPT in vitro. Cultured cells secreted betaLH and betaFSH (NFPT) or GH (GH secreting adenomas) up to 14 days in culture. In NFPT TRH (10(-8) mol/l) elicited peak betaLH and betaFSH secretion at 60 to 90 min, with no further increase at 24 h. TRH-stimulated GH secretion peaked at 90-120 min, and decreased after 3 h, but a secondary rise occurred after 24 h of incubation. Chronic daily exposure to TRH followed by an acute TRH challenge resulted in a further increase of GH secretion after one hour. In contrast, acute TRH administration following chronic exposure did not elicit increased P-subunits secretion in NFPT. Coadministration of cycloheximide did not change TRH induced beta-subunits secretion in NFPT. However, when it was administered 24 h prior to TRH, it blocked both basal and TRH induced beta-subunits levels in NFPT. Cycloheximide had no effect on basal or stimulated GH secretion when administered concomitantly or 24 h before TRH. Incubation of cultured GH secreting tumors with cycloheximide during 5 days blocked both basal and TRH stimulated GH secretion, thus indicating dependency on protein synthesis during the chronic, secondary phase. Since the acute secretion was not affected by coadministration of cycloheximide, these early increases in hormone levels apparently reflect the release of stored hormone. In summary, GH secreting adenomas and NFPT differ significantly in their hormonal response to continuous exposure to TRH. The mechanisms underlying the sustained effect of TRH on GH secretion in vitro remain to be investigated. If endogenous TRH exerts a similar continuous effect it may contribute to the disregulated GH secretion in acromegaly.     

A retrospective audit of the combined pituitary function test, using the insulin stress test, TRH and GnRH in a district laboratory

OBJECTIVE: To assess the value of the combined insulin stress test (IST), thyrotrophin-releasing hormone (TRH) and gonadotrophin hormone-releasing hormone (GnRH) tests. DESIGN: A retrospective audit of 232 such tests performed between 1980 and 1989 inclusive. PATIENTS: One hundred and ninety-seven patients with known or suspected pituitary disease. MEASUREMENTS: IST, TRH and GnRH responses were retrieved from laboratory records. Case notes were surveyed for clinical data and additional results. RESULTS: A basal serum cortisol level of less than 100 nmol/l (or less than 200 nmol/l in patients who had recently received glucocorticoid replacement therapy) accurately predicted a subnormal response to hypoglycaemia. All patients with a basal cortisol level of greater than 400 nmol/l, except those who had recently received steroids, showed a normal cortisol response. In retrospect, by consideration of such basal values, 55% of ISTs could have been avoided if the only aim was to assess cortisol reserve. A deficient growth hormone (GH) response to hypoglycaemia was, however, common in patients with a normal cortisol response. Two-thirds of patients with GH deficiency would have been missed if an IST had been avoided on the basis either of basal cortisol levels alone, or of cortisol responses to an alternative test which did not test GH reserve. There was poor agreement between the pituitary response to TRH and GnRH and basal levels of thyroxine and gonadotrophins respectively, suggesting that these releasing hormone tests are misleading. CONCLUSIONS: The IST provides information regarding pituitary function not provided by other tests of the hypothalamic-pituitary-adrenal axis, so that the choice between the IST and alternative tests must depend on a critical assessment of what information is required. Routine TRH and GnRH testing appears to yield little information of practical clinical value.     

FENCLOFENAC-SECONDARY EFFECTS UPON THE PITUITARY THYROID AXIS

To elucidate the mechanism of suppression of TSH responsiveness to TRH induced by the initiation of fenclofenac therapy, the early period of drug administration was examined in detail and the effect of the drug during a thyrotrophin releasing hormone infusion was assessed. In addition, the effect of fenclofenac upon the response of ACTH, cortisol, growth hormone and prolactin to insulin-induced hypoglycaemia was examined. The effect of fenclofenac upon an equilibrium dialysis method for estimating free thyroid hormones was evaluated and was found to be insignificant within the therapeutic concentration range of the drug. A sharp, short-lived rise in free thyroxine (21.7 +/- 2.0 to 26.8 +/- 1.9 pmol/l; P less than 0.03) was observed 60 min after the first dose of fenclofenac. Repeated peaks of free thyroxine during chronic fenclofenac treatment, superimposed upon the previously described steady decline of free and total serum thyroxine, are postulated to cause the observed suppression of TSH release which is present only until free and total serum thyroxine levels reach their nadir. The time course of the changes seen during thyrotrophin releasing hormone infusion suggested that the pituitary suppression was secondary to a rise in free thyroxine. The responses to hypoglycaemia of those pituitary hormones examined were not affected by fenclofenac.     

Synthetic growth hormone secretagogues control growth hormone secretion in the chicken at pituitary and hypothalamic levels

In the chicken growth hormone (GH) secretion is predominantly controlled by two hormones, thyrotropin-releasing hormone (TRH) and somatostatin (SRIH), respectively stimulating and inhibiting GH release. In view of the hypothesis of a novel GH secretagogue (GHS) in mammals, this specific species was used to further assess the exact function of two nonpeptidyl GHSs-L-692,429 and L-163,255. Both synthetic products stimulate GH secretion directly at the level of the pituitary as shown in in vitro perifusion studies. Plasma GH levels increase within 10–15 min after a single challenge of L-692,429 or L-163,255. A SRIH pretreatment dimishes this GH response. Both GH-releasing peptide mimetics decrease hypothalamic TRH concentrations, whereas SRIH levels are not affected. The novel GHS may therefore control GH secretion both at the level of the pituitary and the hypothalamus. The present article shows that nonpeptidyl mimetics also control GH secretion in nonmammalian species suggesting that the endogenous hormone may be a conserved GH stimulator in several vertebrates. The GH response to GHS in birds may be regulated both directly at the level of the pituitary and by releasing another endogenous GH stimulator (TRH) from the hypothalamus     

Concentrations of triiodothyronine, growth hormone, and luteinizing hormone in the plasma of thyroidectomised fowl (Gallus domesticus)

Surgical thyroidectomy increased (P less than 0.05) the basal concentrations of growth hormone (GH) and luteinizing hormone (LH) in the plasma of 10- to 12-week-old domestic fowl. The administration of thyrotrophin releasing hormone (TRH) (100 micrograms, sc) increased (P less than 0.01) the GH concentration in both intact and thyroidectomised birds. The magnitude of the TRH-induced increase in GH level was greater (P less than 0.01) in thyroidectomised birds than in intact controls. Although TRH had no effect on LH secretion in the controls, it induced a small (P less than 0.05) rise in the plasma LH level in thyroidectomised birds. In both the intact and thyroidectomised birds the LH concentration was enhanced (P less than 0.05) following the administration of LH-releasing hormone (LH-RH) (20 micrograms, sc). The increase in the LH level by LH-RH in the thyroidectomised birds was greater (P less than 0.001) than that in the intact controls. Plasma GH concentrations were unaffected by LH-RH treatment. These results suggest that thyroid hormones inhibit the secretion of LH and GH in birds. In thyroidectomised birds low levels of immunoreactive triiodothyronine (T3)-like material were measurable in the circulation, despite the absence of regenerated thyroid tissue. The administration of TRH (100 micrograms, sc) did not enhance the plasma level of this material in thyroidectomised birds, whereas plasma T3 concentrations were enhanced in intact birds following TRH treatment. These results suggest that the T3 immunoreactive substance in thyroidectomised birds is extrathyroidal in origin.     

HYPOTHALAMIC HORMONE INTERACTION IN ACROMEGALY

The growth hormone response to the administration of the currently available synthetic hypothalamic hormones was assessed in eleven patients with acromegaly. Eight of them showed a positive GH response to thyrotrophin releasing hormone and three showed no response. The GH response to TRH was shown to be unrelated to the thyrotrophin response to TRH. The GH response to TRH was inhibited by the administration of growth hormone release inhibiting hormone. Luteinizing hormone/follicle stimulating hormone releasing hormone (LHRH) caused a positive GH response in four patients, but this was trivial in three. The TRH mediated GH release in acromegaly is not mediated via TSH and appears to be attributable to loss of specificity of the receptor sites on the somatotroph to the hypothalamic hormones.     

Oestrogen-induced changes in the secretion of luteinizing hormone caused by continuous infusions of luteinizing hormone releasing hormone in the long-term ovariectomized rat.

Oestrogen-induced changes in luteinizing hormone secretion, caused by continuous infusions of luteinizing hormone releasing hormone (LH-RH), appear to depend on the duration of exposure of the pituitary gland to the releasing hormone. The initial oestrogen-induced depression of the potential response of the pituitary gland to LH-RH, which always seems to occur, does not necessarily turn into an enhancement of this potential response. It is suggested that this may be due to the fact that the response of the pituitary gland to LH-RH infusions is a continuously changing parameter influenced by oestrogen.     

Development of growth hormone and adrenocorticotropic hormone deficiencies in patients with prenatal or perinatal-onset hypothalamic hypopituitarism having invisible or thin pituitary stalk on magnetic resonance imaging

A gradual loss of anterior pituitary hormones is suspected in patients treated with irradiation due to brain tumors. Development of growth hormone deficiency (GHD) with age has been documented in patients with idiopathic GHD. A gradual loss of adrenocorticotropic hormone (ACTH) secretion has been also shown in a patient with severe GHD and an invisible pituitary stalk on magnetic resonance imaging (MRI). The purpose of this longitudinal and cross-sectional study was to evaluate the gradual loss of growth hormone (GH) and ACTH in a homogeneous group of patients with hypopituitarism. Twenty-eight patients (23 males, 5 females) from four hospitals were diagnosed as having prenatal or perinatal-onset hypothalamic hypopituitarism. They had an abnormal pituitary stalk on MRI (invisible in 18 patients, thin in 10 patients) without any other organic disease of the brain. Each patient had GHD upon initial evaluation. Height (n=20) was analyzed as standard deviation score (SDS). Longitudinal (n=8) and cross-sectional (n=28) GH secretion capacity was evaluated by GH peaks, in response to insulin tolerance test (ITT) and growth hormone releasing factor test (GRF test). Longitudinal (n=10) and cross-sectional (n=28) ACTH secretion capacity was evaluated by cortisol peaks in response to ITT. Height SDS decreased each year in all the untreated patients after birth. GH peaks decreased gradually with age. Longitudinal data showed decreased GH peaks with age in seven out of eight patients using ITT and in all four patients using GRF tests. Cortisol peaks also decreased gradually together with signs and symptoms for adrenal deficiency such as general fatigue. Cortisol peaks of less than 414 nmol/L (15 microg/dl) in response to ITT were seen in 24% of the tests before age 10 and 56% before age 25. In conclusion, GHD and ACTH deficiency developed gradually in patients with prenatal or perinatal-onset hypothalamic hypopituitarism who had invisible or thin pituitary stalks examined by MRI.     

Aberrant luteinizing hormone-releasing hormone-stimulated adrenocorticotropic hormone secretion in a patient with pituitary hyperplasia due to primary hypothyroidism

We report a patient with primary hypothyroidism associated with an aberrant ACTH response to the LH-RH test. A 40-year-old woman was admitted to our hospital displaying headache, nausea, and numbness on the left side of her face, upper limbs, and tips of her toes. Computed tomography and magnetic resonance imaging revealed a mass-like lesion in the pituitary. A high serum TSH concentration with concomitant low thyroid hormone concentrations resulted in a diagnosis of primary hypothyroidism. To exclude the possibility of a coexisting pituitary tumor including a TSH-secreting tumor, we performed dynamic TSH secretion tests. TRH testing showed an excessive, delayed TSH response, typical of primary hypothyroidism. Serum TSH decreased not only after administration of CRH, octreotide, or L-DOPA, but also after administration of LH-RH. In this case, LH-RH testing induced ACTH secretion. To determine if aberrant ACTH secretion in response to LH-RH loading is a common phenomenon in severe primary hypothyroidism, we performed the LH-RH test on 4 additional patients with pituitary enlargement due to primary hypothyroidism. Two patients demonstrated aberrant ACTH secretion in response to LH-RH loading, but the others did not. To our knowledge, this is the first report of aberrant LH-RH-stimulated ACTH secretion in primary hypothyroidism.     

Infusion of beta-endorphin has no suppressive effect on the releasing hormone-stimulated pituitary-adrenal-axis of normal human subjects

The existence of a short-loop feedback inhibition of pituitary ACTH release by administration of beta-endorphin was postulated. However, data on the effect of peripherally administered beta-endorphin in humans are highly controversial. We infused human synthetic beta-endorphin at a constant rate of 1 microgram.kg-1.min-1 or normal saline to 7 normal volunteers for 90 min. Thirty min after starting the beta-endorphin or placebo infusion, releasing hormones were injected as a bolus iv (oCRH and GHRH 1 microgram/kg, GnRH 100 micrograms, TRH 200 micrograms) and blood was drawn for measurements of beta-endorphin immunoreactivity, all other pituitary hormones, and cortisol. Infusion of beta-endorphin resulted in high beta-endorphin plasma levels with a rapid decrease after the infusion was stopped. During the control infusion, beta-endorphin plasma levels rose in response to CRH. Plasma ACTH and serum cortisol levels in response to the releasing hormone were not different in subjects infused with beta-endorphin or placebo. The PRL response to TRH was significantly higher after beta-endorphin than after placebo (area under the stimulation curve 1209 +/- 183 vs 834 +/- 104 micrograms.l-1.h). There was no difference in the response of all other hormones measured. Our data on ACTH and cortisol secretion do not support the concept of a short-loop negative feedback of beta-endorphin acting at the site of the pituitary.