Hypopituitarism.

Hypopituitarism refers to deficiency of one or more hormones produced by the anterior pituitary or released from the posterior pituitary. Hypopituitarism is associated with excess mortality, a key risk factor being cortisol deficiency due to adrenocorticotropic hormone (ACTH) deficiency. Onset can be acute or insidious, and the most common cause in adulthood is a pituitary adenoma, or treatment with pituitary surgery or radiotherapy. Hypopituitarism is diagnosed based on baseline blood sampling for thyroid stimulating hormone, gonadotropin, and prolactin deficiencies, whereas for ACTH, growth hormone, and antidiuretic hormone deficiency dynamic stimulation tests are usually needed. Repeated pituitary function assessment at regular intervals is needed for diagnosis of the predictable but slowly evolving forms of hypopituitarism. Replacement treatment exists in the form of thyroxine, hydrocortisone, sex steroids, growth hormone, and desmopressin. If onset is acute, cortisol deficiency should be replaced first. Modifications in replacement treatment are needed during the transition from paediatric to adult endocrine care, and during pregnancy.

Hypothyroidism following childhood cancer therapy-an under diagnosed complication.

To determine the prevalence of hypothyroidism amongst most adult survivors of childhood cancer in Britain using the British Childhood Cancer Survivor Study (BCCSS). The BCCSS is a population based cohort of individuals diagnosed with childhood cancer between 1940 and 1991 and who survived at least 5 years from diagnosis (n = 17,981). 10483, 71% of those survivors aged at least 16 years, returned a completed questionnaire, which asked if hypothyroidism had been diagnosed. Of the whole cohort, 7.7% reported hypothyroidism with the highest risk among patients treated for Hodgkin's disease (HD) (19.9%), CNS neoplasms (15.3%), Non-Hodgkin's lymphoma (6.2%) and leukaemia (5.2%). Survivors were more likely to develop hypothyroidism if they had received radiotherapy for HD (p = 0.0001) or a CNS neoplasm (p < 0.00005) but not leukaemia (p = 0.3). In these three patient groups, the frequency of hypothyroidism was similar in men and women. Survivors of irradiated CNS tumours reported a prevalence of hypothyroidism, which was substantially lower if discharged to primary care compared with being on hospital follow-up and which declined substantially with increased follow-up in both primary care (p = 0.004) and hospital follow-up (p = 0.023) settings. Hypothyroidism is a common finding amongst adult survivors of childhood malignancy. The substantial differences in reported hypothyroidism prevalence after irradiated CNS neoplasms suggests substantial under-diagnosis, which increased with increased follow-up, and which increased among those followed-up in primary care compared with hospital settings.

The influence of growth hormone status on physical impairments, functional limitations, and health-related quality of life in adults.

The availability of recombinant human GH and somatostatin analogs has resulted in widespread treatment for adults with GH deficiency (GHD) and those with GH excess (acromegaly). Despite being at opposite ends of the spectrum in terms of their GH/IGF-I axis, both of these populations experience overlapping somatic impairments. Adults with untreated GHD have low circulating levels of IGF-I that manifest as altered body composition with increased fat and reduced lean body and skeletal muscle mass. At the other end of the spectrum, adults with GH excess, who have elevated levels of IGF-I, also have altered body composition. Impairments that result from disorders of either GHD or GH excess are both associated with increased functional limitations, such as reduced ability to walk quickly for prolonged periods, and poorer health-related quality of life (HR-QoL). Adults with untreated GHD and GH excess both commonly complain of excessive fatigue that seems to be associated more with impaired aerobic than muscular performance. Several studies have documented that administration of GH or somatostatin analogs to adults with GHD or GH excess, respectively, ameliorates abnormal biochemical profile and the associated somatic impairments. However, whether these improvements translate into improved physical function in adults with GHD or GH excess remains largely unknown, and their impact on HR-QoL controversial. Review of placebo-controlled trials to date suggests that GH and somatostatin analogs have greater effects on gas exchange and aerobic performance than as anabolic agents on skeletal muscle mass and function. Future investigations should include dose-response studies to establish the optimal combination of pharmacological agents plus exercise required to improve not only biochemical markers but also physical function and HR-QoL in adults with GHD or GH excess.

Partial growth hormone deficiency in adults; should we be looking for it?

Quantitatively, GH secretion exists as a continuum in states ranging from good health through to hypopituitarism. Currently, GH replacement is considered only for adults designated as being severely GH deficient (GHD). In clinical practice the gold standard, on which the biochemical diagnosis of severe GHD is based, centres on the presence of two or more additional anterior pituitary hormone deficits. Cohorts of adults with partial GHD (Growth Hormone Insufficiency [GHI]) have been reported with adverse body composition changes, dyslipidaemia, insulin resistance, altered cardiac performance and increased carotid intima-media thickness. The diagnosis of GHI in an individual patient, however, is extremely difficult because such patients rarely exhibit additional anterior pituitary hormone deficits, and the levels of GH-dependent proteins, including IGF-I, are normal in the majority. Currently, GH replacement therapy should only be considered in a patient characterized as GHI by dynamic GH testing in whom there is a plausible cause for hypopituitarism and in whom the IGF-I level is pathologically low.

Partial growth hormone deficiency is associated with an adverse cardiovascular risk profile and increased carotid intima-medial thickness.

OBJECTIVE: To quantify the relative prevalence of surrogate markers of vascular risk in adults with partial GH deficiency (GH insufficiency, GHI). CONTEXT: Hypopituitary adults with untreated GH deficiency (GHD) have an excess vascular mortality and demonstrate clustering of adverse vascular risk factors. The vascular risk profile of GHI adults has yet to be comprehensively studied. DESIGN: A cross-sectional case controlled study. PATIENTS: Thirty GHD adults, 24 GHI, and 30 age- and sex-matched controls. GHI adults were defined biochemically using two GH stimulation tests (peak GH 3-7 µg/l). MEASUREMENTS: Serum lipids and apolipoproteins, plasminogen activator inhibitor type-I (PAI-I), C-reactive protein (CRP), lipoprotein (a) [Lp(a)], fibrinogen, blood pressure and carotid intima-medial thickness (IMT). RESULTS: IGF-I levels of GHI adults were lower than controls (373 ± 123 vs 295 ± 104 µg/l; P < 0.001). Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) values were consistently between those of, but not significantly different from, GHD and control subjects. GHI adults showed significantly elevated PAI-I levels [80 (13-98) vs 50.5 (3-98) ng/ml; P = 0.01], although no there were differences in CRP, Lp(a), and fibrinogen levels compared with control subjects. No differences in systolic or diastolic blood pressure were shown between study groups. In parallel with the increased vascular risk profile of GH-insufficient adults, carotid IMT was significantly increased (0.503 ± 0.08 vs 0.578 ± 0.130 mm; P = 0.02). TC, LDL-C, Waist-Hip Ratio (WHR), truncal fat mass, and IMT correlated with IGF-I levels and GH status. TG, K(ITT), and PAI-I additionally correlated with GH status, but not with IGF-I levels. CONCLUSION: GHI adults are at elevated vascular risk, reflected by adverse surrogate markers and increased carotid IMT. The surrogate risk marker profile parallels GHD adults, but is less divergent from that observed in healthy individuals. No data are yet available as to whether these anomalies will be reflected in an increased vascular mortality in GHI adults.

Effect of aromatizable and unaromatizable androgen replacement in hypogonadal men on GH responsiveness.

OBJECTIVES: Although studies have clearly demonstrated that oestrogen replacement affects GH responsiveness by causing relative GH resistance, the effect of androgen replacement is unknown. Circumstantial evidence only suggests that androgen replacement may increase GH sensitivity and/or responsiveness. To examine the impact of androgens on GH responsiveness, hypogonadal men underwent the IGF-1 generation test in the unreplaced state, replaced with testosterone (T) and also replaced with dihydrotestosterone (DHT), its nonaromatizable metabolite. DESIGN AND PATIENTS: Twelve hypogonadal men with a normal GH axis were recruited. Each subject in random order had 4 weeks off T (NoRx), 4 weeks on T gel (TG) and 4 weeks on DHT gel (DHTG) applied daily, with 1 week washout between each preparation. An IGF-1 generation test using a subcutaneous injection of 7 mg of GH was performed at the end of each of these 4-week phases. MEASUREMENTS: Serum GHBP, total and free IGF-1, IGFBP-3 and acid-labile subunit (ALS) levels were measured at baseline and 24 h (peak) after GH administration. RESULTS: Despite a decrease in GHBP during the TG and DHTG phases, there were no observed differences in baseline, peak or increment (peak - baseline) total or free IGF-1 between the NoRx, TG or DHTG phases. CONCLUSIONS: There is no evidence of fluctuation in GH responsiveness in hypogonadal men, untreated or replaced with T or DHT alone. This implies that the increased level of oestradiol as a consequence of T replacement in hypogonadal men does not impact significantly on GH responsiveness, nor is there evidence of an androgen effect with elevated DHT levels as a consequence of either T or DHT replacement.

Cranially irradiated adult cancer survivors may have normal spontaneous GH secretion in the presence of discordant peak GH responses to stimulation tests (compensated GH deficiency).

CONTEXT: We have previously demonstrated that spontaneous (physiological) GH secretion was entirely normal in cranially irradiated patients who had normal individual peak GH responses to the insulin tolerance test (ITT) but reduced maximal somatotroph reserve as indicated by substantially reduced group GH responses to the GHRH + arginine stimulation test (AST). The normality of spontaneous GH secretion was attributed to a compensatory increase in hypothalamic stimulatory input within a partially damaged hypothalamic-pituitary (h-p) axis. It is unknown, however, if such compensatory stimulation can also maintain normality of GH secretion in those who fail the ITT but pass the GHRH + AST. STUDY SUBJECTS AND DESIGN: We studied 24-h spontaneous GH secretion by 20-min sampling both in the fed state (n = 11) and in the last 24 h of a 33-h fast (n = 9) in adult cancer survivors with subnormal peak GH responses to the ITT but either normal or relatively less attenuated peak GH responses to the GHRH + AST. The study was conducted 8.3 +/- 1.8 (range 2-23) years after cranial irradiation for nonpituitary brain tumours (n = 9) or leukaemia/lymphoma (n = 2) in comparison with 30 normal controls (fasting, 14). RESULTS: Previously published diagnostic thresholds for the ITT, GHRH + AST and spontaneous GH secretion were used to characterize GH secretion. Four of the 11 patients with impaired stimulated responses to both tests showed only minor discordancies between stimulated and spontaneous GH secretion. Two of the remaining seven patients had subnormal spontaneous GH secretion. However, spontaneous GH secretion, both individually and as a group, was entirely normal in the remaining five patients who had impaired GH responses to the ITT but normal individual responses to the GHRH + AST; in these five patients, IGF-I standard deviation scores (SDS; -2.7 to -0.8) were significantly reduced to a moderate degree compared with normals. CONCLUSIONS: In cranially irradiated adult cancer survivors, it cannot be assumed that failure to pass the ITT in isolation reflects severe GH deficiency (GHD). It appears that in some patients near-maximal compensatory overdrive of the partially damaged somatotroph axis may result in near-normal quantitative restoration of spontaneous GH secretion, thus limiting further stimulation with the ITT to the extent that impaired GH responses can be seen even before spontaneous GH secretion starts to decline in adults. However, IGF-I status continues to provide useful information about the adequacy of the compensatory process and therefore the degree of normality of GH secretion.

The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH Index.

BACKGROUND: TSH secretion in hypopituitary patients may be decreased due to TSH deficiency but it also remains under feedback inhibition by free thyroxine (fT4). We propose a TSH index (TSHI), as 'fT4-adjusted TSH', that corrects for any physiological TSH suppression, to provide a true estimate of pituitary thyrotroph function and any pathological pituitary suppression. METHODS: A total of 9519 thyroid function tests (TFTs) (Bayer Immuno-1) in 4064 patients of our institution were examined, including 444 patients investigated for hypopituitarism. Based on the physiological log-linear relationship between fT4 and TSH, we estimated the amount of feedback-induced change in log TSH per change in fT4, which allowed the extrapolation of log TSH to a fixed fT4 of 0, defining the TSHI. TSHIs were compared with other measures of pituitary function. RESULTS: Feedback inhibition was estimated to cause a 0.1345 decrease in log TSH (mU/l) for 1 pmol/l increase in fT4 concentration, therefore TSHI = log TSH + 0.1345 x fT4. Patients with lower peak-stimulated GH and cortisol concentrations had a significantly lower TSHI (P < 0.0001). TSHIs measured before pituitary stimulation tests predicted highly significantly the risk of test failure (P = 0.0002). Of all potential fT4-TSH combinations within the current reference ranges, 21.9% were identified as abnormal on the basis of the TSHI. CONCLUSION: The TSHI provides an accurate estimate of the severity of pituitary dysfunction in hypopituitary patients based on simple TFTs. It predicts the probability of pituitary stimulation test failure and extends the diagnosis of TSH deficiency into areas of the normal TFT reference ranges.

GH sensitivity of GH-deficient adults is dependent on gender but not timing of onset.

BACKGROUND: Females secrete 2-3 -fold greater amounts of GH compared with males despite maintaining similar IGF-I levels. IGF-I generation tests in healthy subjects suggest this discordancy results from relative resistance to GH in females. In GHD females the presumed relative insensitivity to GH is reflected by a lower basal IGF-I and the need for higher GH maintenance doses during replacement. Adults with severe GHD of childhood-onset (CO) have lower basal IGF-I SDS and require higher GH maintenance doses compared with adult-onset (AO) patients with GHD of equal severity. We hypothesised CO-GHD adults to be less sensitive to GH than AO-GHD patients. METHODOLOGY: In a single site study we analysed the incremental change in IGF-I (DeltaIGF-I) in 116 GHD adults following initiation of GH replacement. The data were corrected to provide DeltaIGF-I/mg GH because of slight variances in initial GH dose. RESULTS: Following GH replacement DeltaIGF-I was 230 +/- 245 and 356 +/- 278 ng/ml/mg GH in females and males, respectively (P = 0.01). In CO and AO patients DeltaIGF-I was 282 +/- 206 and 294 +/- 292 ng/ml/mg GH, respectively (P = 0.83). Further analysis after stratification by both gender and timing of onset of GHD showed DeltaIGF-I was 226 +/- 164, 324 +/- 228, 231 +/- 268, and 373 +/- 304 ng/ml/mg GH in the CO females, CO males, AO females, and AO males, respectively (AO males vs. AO females, P = 0.03; CO males vs. CO females, P = 0.17; AO males vs. CO males, P > 0.05; AO females vs. CO females, P > 0.05). Multiple linear regression with DeltaIGF-I as the dependent variable and age, gender, BMI, baseline IGF-I level, and timing of onset as independent variables showed DeltaIGF-I to be dependent on gender alone (R = 0.28, P = 0.004). Age (P = 0.44), BMI (P = 0.54), baseline IGF-I level (P = 0.63) and timing of onset (P = 0.61) had no effect on DeltaIGF-I. CONCLUSION: We have shown gender to have a significant impact on GH sensitivity in GHD adults, which, at least in part, explains differences in maintenance dosages during replacement. None of the additional variables impacted significantly on GH sensitivity. The lower basal IGF-I SDS and higher GH replacement requirement reported in CO compared with AO patients cannot be explained by differences in sensitivity to GH.

Normal testicular function and spermatogenesis.

The testis performs two basic functions, sperm production and testosterone secretion. Formation of the testis is genetically controlled; expression of the SRY gene directs the embryonic gonads into the pathway leading to the development of testes. By the fourth week of gestation in humans, the primordial germ cells derived from pluripotent cells of the embryonic epiblast proliferate and migrate from the endoderm of the yolk sac into the undifferentiated gonad, which becomes morphologically distinct during the seventh week of gestation in humans. Histological development of the testis is largely completed by the end of the third month of gestation.

Hypopituitarism following Radiotherapy Revisited.

Neuroendocrine disturbances in anterior pituitary hormone secretion are common following radiation damage to the hypothalamic-pituitary (H-P) axis, the severity and frequency of which correlate with the total radiation dose delivered to the H-P axis and the length of follow-up. The somatotropic axis is the most vulnerable to radiation damage and GH deficiency remains the most frequently seen endocrinopathy. Compensatory hyperstimulation of a partially damaged somatotropic axis may restore normality of spontaneous GH secretion in the context of reduced but normal stimulated responses in adults. At its extreme, endogenous hyperstimulation may limit further stimulation by insulin-induced hypoglycaemia resulting in subnormal GH responses despite the normality of spontaneous GH secretion. In children, failure of the hyper-stimulated partially damaged H-P axis to meet the increased demands for GH during growth and puberty may explain what has previously been described as radiation-induced GH neurosecretory dysfunction and, unlike in adults, the insulin tolerance test remains the gold standard for assessing H-P functional reserve. With low radiation doses (<30 Gy) GH deficiency usually occurs in isolation in about 30% of patients, while with radiation doses of 30-50 Gy, the incidence of GH deficiency can reach 50-100% and long-term gonadotropin, TSH and ACTH deficiencies occur in 20-30, 3-9 and 3-6% of patients, respectively. With higher dose cranial irradiation (>60 Gy) or following conventional irradiation for pituitary tumours (30-50 Gy), multiple hormonal deficiencies occur in 30-60% after 10 years of follow-up. Precocious puberty can occur after radiation doses of <30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Hyperprolactinaemia, due to hypothalamic damage is mostly seen in young women after high dose cranial irradiation and is usually subclinical. H-P dysfunction is progressive and irreversible and can have an adverse impact on growth, body image, sexual function and quality of life. Regular testing is advised to ensure timely diagnosis and early hormone replacement therapy.

Hypopituitarism following radiotherapy.

Deficiencies in anterior pituitary hormones secretion ranging from subtle to complete occur following radiation damage to the hypothalamic-pituitary (h-p) axis, the severity and frequency of which correlate with the total radiation dose delivered to the h-p axis and the length of follow up. Selective radiosensitivity of the neuroendocrine axes, with the GH axis being the most vulnerable, accounts for the high frequency of GH deficiency, which usually occurs in isolation following irradiation of the h-p axis with doses less than 30 Gy. With higher radiation doses (30-50 Gy), however, the frequency of GH insufficiency substantially increases and can be as high as 50-100%. Compensatory hyperstimulation of a partially damaged h-p axis may restore normality of spontaneous GH secretion in the context of reduced but normal stimulated responses; at its extreme, endogenous hyperstimulation may limit further stimulation by insulin-induced hypoglycaemia resulting in subnormal GH responses despite normality of spontaneous GH secretion in adults. In children, failure of the hyperstimulated partially damaged h-p axis to meet the increased demands for GH during growth and puberty may explain what has previously been described as radiation-induced GH neurosecretory dysfunction and, unlike in adults, the ITT remains the gold standard for assessing h-p functional reserve. Thyroid-stimulating hormone (TSH) and ACTH deficiency occur after intensive irradiation only (>50 Gy) with a long-term cumulative frequency of 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose less than 30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Gonadotrophin deficiency occurs infrequently and is usually a long-term complication following a minimum radiation dose of 30 Gy. Hyperprolactinemia, due to hypothalamic damage leading to reduced dopamine release, has been described in both sexes and all ages but is mostly seen in young women after intensive irradiation and is usually subclinical. A much higher incidence of gonadotrophin, ACTH and TSH deficiencies (30-60% after 10 years) occur after more intensive irradiation (>60 Gy) used for nasopharyngeal carcinomas and tumors of the skull base, and following conventional irradiation (30-50 Gy) for pituitary tumors. The frequency of hypopituitarism following stereotactic radiotherapy for pituitary tumors is mostly seen after long-term follow up and is similar to that following conventional irradiation. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy.

Iodothyronine deiodinase enzyme activities in bone.

Euthyroid status is essential for normal skeletal development and maintenance of the adult skeleton, but the mechanisms which control supply of thyroid hormone to bone cells are poorly understood. Thyroid hormones enter target cells via monocarboxylate transporter-8 (MCT8), which provides a functional link between thyroid hormone uptake and metabolism in the regulation of T3-action but has not been investigated in bone. Most circulating active thyroid hormone (T3) is derived from outer ring deiodination of thyroxine (T4) mediated by the type 1 deiodinase enzyme (D1). The D2 isozyme regulates intra-cellular T3 supply and determines saturation of the nuclear T3-receptor (TR), whereas a third enzyme (D3) inactivates T4 and T3 to prevent hormone availability and reduce TR-saturation. The aim of this study was to determine whether MCT8 is expressed in the skeleton and whether chondrocytes, osteoblasts and osteoclasts express functional deiodinases. Gene expression was analyzed by RT-PCR and D1, D2 and D3 function by sensitive and highly specific determination of enzyme activities. MCT8 mRNA was expressed in chondrocytes, osteoblasts and osteoclasts at all stages of cell differentiation. D1 activity was undetectable in all cell types, D2 activity was only present in mature osteoblasts whereas D3 activity was evident throughout chondrocyte, osteoblast and osteoclast differentiation in primary cell cultures. These data suggest that T3 availability especially during skeletal development may be limited by D3-mediated catabolism rather than by MCT8 mediated cellular uptake or D2-dependent T3 production.

GH replacement reduces increased lipid peroxidation in GH-deficient adults.

BACKGROUND: GH replacement improves numerous metabolic abnormalities in GH-deficient patients; increased lipid peroxidation (LPO) has been observed in GH-deficient patients; however, it is unknown if LPO is influenced by GH replacement. AIM AND METHODS: To evaluate the extent to which GH replacement might reverse the increased LPO in GH-deficient adults and to analyse if this phenomenon might be involved in the improvement of metabolic disturbances due to GH treatment. Serum concentrations of malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA), as an index of LPO, were measured at baseline, and after 12 and 24 months of GH replacement in 40 adult patients with severe GH deficiency (both in adult- and childhood-onset) and in 40 healthy volunteers, matched for sex, age and body mass index (BMI). Correlations were evaluated between LPO and lipids, IGF-I, metalloproteinase-2 and -9 (MMP-2, -9), vascular endothelial growth factor (VEGF), BMI and GH dose. RESULTS: LPO values in GH-deficient patients were several-fold higher than in controls [55.36 +/- 2.27 vs. 4.19 +/- 0.42 nmol/mg protein (mean +/- SEM), P < 0.0001] and decreased significantly over time with GH replacement to 38.61 +/- 2.15 nmol/mg protein (i.e. by approximately 30%), though still remaining markedly elevated compared with controls (P < 0.0001). The proatherogenic lipid profile parameters correlated positively with LPO in the childhood-onset subgroup before GH replacement. GH replacement restored the positive correlation between LPO and age in male patients (r = 0.57, P = 0.013; r = 0.8, P < 0.001, at 12 and 24 months of GH replacement, respectively). CONCLUSIONS: GH replacement partially reverses the grossly abnormal LPO in GH-deficient adults. It is highly probable, therefore, that oxidative mechanisms are involved in the overall improvement of metabolic changes due to GH replacement.

Do doctors discuss fertility issues before they treat young patients with cancer?

BACKGROUND: Many children treated for cancer are at risk of infertility, but for girls and prepubertal boys, all fertility preservation techniques remain experimental. We have assessed UK practice relating to information provision about the effects of cancer treatment on fertility and options for fertility preservation. METHODS: Paediatric oncologists prospectively completed a data form for each new patient registered over a 12 month period. RESULTS: Data were available on 1030 patients (68% of total registered). The effect of cancer treatment on fertility was discussed with 63% of patients. Of these, 61% were judged to be at high or medium risk of fertility problems. Discussions took place more commonly with boys than girls; the commonest reason for discussion not occurring was young age. The majority (83%) of post-pubertal boys assessed as high/medium risk of infertility were referred for semen cryopreservation. This rate fell to 39% of those in early puberty. Only 1% (n=4) of girls were referred to an assisted conception unit. CONCLUSIONS: These data indicate a high awareness of the potential adverse effects of therapy on fertility among UK paediatric oncologists. High referral rates for older boys indicate that current guidelines are followed, but there is a need for fertility preservation techniques for girls and younger boys.

Cranial irradiation and growth hormone neurosecretory dysfunction: a critical appraisal.

CONTEXT: It has been suggested that radiation-induced GH neurosecretory dysfunction exists in children; however, the pathophysiology is poorly understood, and it is unknown if such a phenomenon exists in adult life. STUDY SUBJECTS: Twenty-four-hour spontaneous GH secretion was studied by 20-min sampling both in the fed state (n = 16; six women) and the last 24 h of 33-h fast (n = 10; three women) in adult cancer survivors of normal GH status defined by two GH provocative tests, 13.1 +/- 1.6 (range, 3-28) yr after cranial irradiation (18-40 Gy) for nonpituitary brain tumors (n = 12) or leukemia (n = 4) in comparison with 30 (nine women) age- and body mass index-matched normal controls (fasting, 11 men and three women). RESULTS: Using previously published diagnostic thresholds, all patients had stimulated peak GH responses in the normal range to both the insulin tolerance test and the combined GHRH plus arginine stimulation test, as well as normal individual mean profile GH levels during the fed and fasting states. However, gender-specific comparisons revealed marked reduction (by 40%) in the overall peak GH responses to both provocative tests but similar GH secretory profiles; no differences were seen in the pulsatile attributes of GH secretion (cluster analysis) or the profile absolute and mean GH levels in the fed state or when the hypothalamic-pituitary axis was stimulated by fasting. CONCLUSIONS: Radiation-induced GH neurosecretory dysfunction either does not exist or is a very rare phenomenon in irradiated adult cancer survivors. The normality of physiological GH secretion in the context of reduced maximum somatotroph reserve suggests compensatory overdrive of the partially damaged somatotroph axis and constitutes a relative argument against somatotroph dysfunction being explained purely by hypothalamic damage with secondary atrophy due to GHRH deficiency. It is therefore possible that radiation in doses less than 40 Gy causes dual damage to both the pituitary and the hypothalamus.

The diagnosis of partial growth hormone deficiency in adults with a putative insult to the hypothalamo-pituitary axis.

CONTEXT: Similar to patients with severe GH deficiency (GHD), those with a more moderate impairment of GH secretion [GH insufficiency (GHI)] have abnormal body composition, dyslipidemia, and insulin resistance. Given the inherent problems in the diagnosis of severe GHD, the situation is likely to be even more difficult in individuals with GHI. OBJECTIVE: The objective of the study was to examine the utility of GH stimulation tests and GH-dependent proteins in the diagnosis of GHI. DESIGN: The study was a cross-sectional, case-controlled study. PATIENTS: The study included 31 patients with GHD, 23 with GHI [peak GH 3-7 microg/liter (9-21 mU/liter)], and 30 age- and sex-matched controls. MAIN OUTCOME MEASURES: Demographic and biochemical markers of GH status were measured. RESULTS: Nineteen of the patients with GHI (83%) had no additional anterior pituitary hormone deficits. Ten GHI patients showed discordant GH status based on the two GH stimulation tests performed. GH status was defined by the highest peak GH value achieved; in four this was to the insulin tolerance test (ITT), four the arginine test, and two the GHRH-arginine test. In five of the six patients in whom GH status was not defined by the ITT, peak GH levels to the ITT were in the range 2.4-2.9 microg/liter. IGF-I values for the GHI adults were significantly lower than the control subjects (121 +/- 48 vs. 162 +/- 75 microg/liter; P < 0.05); however, only six (26%) had values below the 10th percentile of levels seen in the control group. IGF binding protein-3 and acid labile subunit levels of the GHI adults were not significantly different from the controls. CONCLUSION: The diagnosis of GHI in an individual is extremely difficult because the patients rarely exhibit additional pituitary hormone deficits, and levels of GH-dependent proteins are normal in the majority. Diagnosis relies heavily on GH stimulation tests and requires two tests in all patients to define GHI; obesity when present is potentially a major confounder.

HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism.

CONTEXT: Mutations in the transcription factor HESX1 have previously been described in association with septooptic dysplasia (SOD) as well as isolated defects of the hypothalamic-pituitary axis. OBJECTIVE: Given that previous screening was carried out by SSCP detection alone and limited to coding regions, we performed an in-depth genetic analysis of HESX1 to establish the true contribution of HESX1 genetic defects to the etiology of hypopituitarism. DESIGN: Nonfamilial patients (724) with either SOD (n = 314) or isolated pituitary dysfunction, optic nerve hypoplasia, or midline neurological abnormalities (n = 410) originally screened by SSCP were rescreened by heteroduplex detection for mutations in the coding and regulatory regions of HESX1. In addition, direct sequencing of HESX1 was performed in 126 patients with familial hypopituitarism from 66 unrelated families and in 11 patients born to consanguineous parents. PATIENTS: All patients studied had at least one of the three classical features associated with SOD (optic nerve hypoplasia, hypopituitarism, midline forebrain defects). RESULTS: Novel sequence changes identified included a functionally significant heterozygous mutation at a highly conserved residue (E149K) in a patient with isolated GH deficiency and digital abnormalities. The overall incidence of coding region mutations within the cohort was less than 1%. CONCLUSIONS: Mutations within HESX1 are a rare cause of SOD and hypopituitarism. However, the large number of familial patients with SOD in whom no mutations were identified is suggestive of an etiological role for other genetic factors. Furthermore, we have found that within our cohort SOD is associated with a reduced maternal age compared with isolated defects of the hypothalamopituitary axis.

Growth hormone and the transition from puberty into adulthood.

With modern growth hormone (GH) replacement algorithms, children with a diagnosis of growth hormone deficiency achieve at the end of pediatric GH treatment an adult height that is on the average in the normal range. Recent experience with GH replacement in young adults with childhood-onset growth hormone deficiency, however, has shown that these patients present with variable degrees of somatic immaturity. As childhood GH treatment is discontinued when final height is attained, attention moves to the phase of somatic development that follows the end of longitudinal growth, called ''transition'', which had been excluded previously from consideration for either pediatric or adult GH replacement. This article reviews the changes taking place during this phase of development and their relevance for the attainment of adult body maturation. The critical role of GH in this process is described.

A new X-linked mental retardation (XLMR) syndrome with late-onset primary testicular failure, short stature and microcephaly maps to Xq25-q26.

X-linked mental retardation (XLMR) is a heterogeneous disorder with both syndromic and non-syndromic forms. Here we describe the clinical and molecular characterisation of a family with a syndromic form of XLMR with hypogonadism and short stature. We investigated a family in which four male members in two generations presented with hypergonadotrophic hypogonadism associated with development of small and abnormal testes. In two of the males, late-onset testicular ascent was noted. In addition, all affected males had short stature (<0.4th centile) and mild learning difficulties and three out of the four had microcephaly. Karyotypes were normal and endocrine investigations confirmed primary testicular failure. The phenotype segregated as an X-linked trait. Haplotype and genetic two-point linkage analysis with 22 microsatellites excluded the whole X chromosome except for a region on Xq25-Xq27 encompassing 13.7Mb with a maximum LOD score of 1.1 for marker DXS8038 at theta=0.05. One family previously described as having XLMR with hypogonadism and short stature maps to the same X chromosome region implicated in our family. However, the more severe mental retardation, muscle wasting and tremor described in this other family would suggest that our family is affected by a novel XLMR syndrome.