Extensive expertise in endocrinology: UK stance on adult GH replacement: the economist vs the endocrinologist.

In the UK, through the use of a forced economic model, endocrinologists are in the curious position of offering GH replacement to some patients with severe GH deficiency (GHD) but withholding it from other patients with even more severe GHD. This approach is counter-intuitive to endocrine practice in treating endocrine deficiency states. For all other endocrine deficiencies, one would opt for treating those with the most severe biochemical evidence of deficiency first. If this endocrine approach was applied to adult GH replacement in an era of rationing, one would start with the GHD patients with a pathologically low IGF1 level. Given that the prevalence of subnormal IGF1 levels in a GHD population is age-dependent, this would result in GH replacement being offered to more young adult onset (AO) GHD and childhood onset GHD adults, and less often to middle-aged and elderly AO GHD adults. This in itself has the added advantage that the skeletal benefits appear more real in the former cohort of patients.

Long-term safety of growth hormone replacement after CNS irradiation.

CONTEXT: Radiotherapy is a central component in the treatment of many brain tumors, but long-term sequelae include GH deficiency and increased risk of secondary neoplasms. It is unclear whether replacement therapy with GH (GHRT) further increases this risk. OBJECTIVE: The objective of the study was to assess the effect of GHRT on the incidence of secondary tumors and tumor recurrence after cranial irradiation. DESIGN AND SETTING: We conducted a retrospective matched-pairs analysis of previously irradiated patients, with and without GHRT, attending a tertiary center between 1994 and 2009. PATIENTS: We reviewed the records for all patients undergoing GHRT at our institution over the study period. PATIENTS were included if they had received cranial irradiation, GHRT for at least 12 months, and records of serial magnetic resonance imaging data and data for dose and fractionation of irradiation were available. GH-naïve control patients were selected from a radiotherapy database of patients attending the same hospital. PATIENTS were matched for date of radiotherapy, age, site of primary diagnosis, radiation dose, and fractionation. MAIN OUTCOME MEASURE: The primary outcome measure was risk of tumor recurrence or secondary tumor. RESULTS: Matched controls were identified for 110 GH-treated patients. Median follow-up was 14.5 yr. No significant differences were apparent in the number of tumor recurrences (six vs. eight, GHRT vs. control group) or secondary tumors (five vs. three, respectively) between groups. CONCLUSIONS: Our study demonstrates no increased risk for recurrent or secondary neoplasms in patients receiving GHRT, thus supporting a high safety profile of GHRT after central nervous system irradiation.

The value of IGF1 estimation in adults with GH deficiency.

The GH/IGF1 system, like other endocrine systems, is dynamic and its activity changes with age and sexual maturation, and is influenced by body composition and other factors. A normal level of IGF1 does not exclude a diagnosis of GH deficiency (GHD) in adults, and the usefulness of IGF1 in the diagnosis of adult GHD has historically been confusing and contentious. The regulation of IGF1 secretion in adults is complex, and is not solely dependent on GH status with factors recognized to influence IGF1 status in patients with GHD including age, gender, exogenous estrogen therapy, prolactin status, and severity of GHD. The usefulness of IGF1 for monitoring treatment of GH disorders in adulthood is now widely accepted, especially as GH-dosing regimens for GHD have evolved from weight-based dosing (associated with overtreatment and side effects) to individualized dose-titration strategies, which maintain IGF1 within target limits. Sub-optimal replacement therapy may be associated with morbidity and mortality risk from a continuing state of functional GHD. Conversely, avoiding iatrogenic biochemical acromegaly is clearly important and other potential safety issues may be associated with a persistently high IGF1. Analysis and interpretation of IGF1 status therefore represent a useful diagnostic tool especially in the younger adult patients with severe GHD and an essential measurement for monitoring GH replacement in all adults with GHD. High-quality, method-specific reference ranges for IGF1 and a high degree of methodological consistency in the assay are essential for reliable comparison of results.

Failure of antibody response to polysaccharide antigen in treated panhypopituitary adults.

Although pituitary hormones are known to affect immune function, treated hypopituitarism is not a recognized cause of immune deficiency in humans. We set out to assess integrity of baseline and stimulated immune function in severely hypopituitary adults. Twenty-one panhypopituitary adults (group 1), on stable pituitary replacement including growth hormone, and 12 healthy volunteers (group 2) were studied. Lymphocyte subsets, pneumococcal antibody levels pre- and 1 month after polysaccharide vaccination, T cell numbers and in-vitro interferon (IFN)-gamma response were studied. There were no significant differences in T cell numbers or IFN-gamma secretion. B cell numbers were lower in group 1, especially those with low prolactin levels. Independent of this finding, nine of 21 patients in this group had low antibody response to polysaccharide antigen. This was most striking in those with low insulin-like growth factor 1 levels and appeared to be independent of the use of anti-convulsants or corticosteroid replacement. Significant humoral immune deficiency is seen in panhypopituitarism and may contribute to morbidity.

Use of a GH receptor antagonist (GHRA) to explore the relationship between GH and IGF-I in adults with severe GH deficiency (GHD).

OBJECTIVE: At diagnosis, approximately 50% of adults with severe GH deficiency (GHD) have an IGF-I within the reference range. It is unclear whether in such patients serum IGF-I levels are regulated by factors other than GH. DESIGN AND PATIENTS: We performed a double-blind, randomized, placebo-controlled, cross-over study to investigate the effect of the GH receptor antagonist - pegvisomant (20 mg daily for 14 days) on GH and IGF-I levels in three cohorts: patients with GHD and a normal IGF-I (NORMS); patients with GHD and a low IGF-I (LOWS) and healthy volunteers (CONS). RESULTS: Pegvisomant decreased IGF-I in CONS and NORMS [158.5 (101-206) vs. 103 (77-125) microg/l, P < 0.01; 124 (81-136) vs. 95 (51-113) microg/l, P < 0.01 respectively], but not in LOWS [31 (< 31-32) vs. 34.5 (< 31-38) microg/l], and this was associated with an increase in mean 24 h GH in CONS [0.49 (0.12-0.89) to 1.38 (0.22-2.45) microg/l (P = 0.03)] and in NORMS [69 (0-320)% from 0.1 (< 0.1-0.13) to 0.17 (0.11-0.42) microg/l (P = 0.03)], but not in the LOWS. The peak GH response to arginine was increased by pegvisomant in CONS and NORMS [6.1 (0.8-9) vs. 20.4 (13.1-28.8) microg/l, P = 0.03; 0.4 (0.1-0.5) vs. 0.5 (0.3-0.6) microg/l, respectively], but not in LOWS. CONCLUSIONS: These data indicate that patients with severe GHD with a normal IGF-I are able to increase GH secretion in response to a pegvisomant-induced fall in IGF-I, whereas those with low IGF-I levels are unable to increase GH secretion. Therefore circulating IGF-I appears to be GH-independent in GHD patients with a low IGF-I, but remains partially GH-dependent in GHD patients with a normal IGF-I.

Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels.

CONTEXT: TSH is known to have a circadian rhythm, but the relationship between this and any rhythm in T(4) and T(3) has not been clearly demonstrated. OBJECTIVE: With a view to optimizing thyroid hormone replacement therapy, we have used modern assays for free T(4) (FT4) and free T(3) (FT3) to investigate circadian rhythmicity. SETTING: The study was performed at a university hospital. DESIGN AND SUBJECTS: This was a cross-sectional study in 33 healthy individuals with 24-h blood sampling (TSH in 33 and FT4 and FT3 in 29 individuals) and cosinor analysis. RESULTS: Of the individuals, 100% showed a sinusoidal signal in TSH, for FT4 76%, and for FT3 86% (P < 0.05). For FT4 and FT3, the amplitude was low. For TSH the acrophase occurred at a clock time of 0240 h, and for FT3 approximately 90 minutes later at 0404 h. The group cosinor model predicts that TSH hormone levels remain above the mesor between 2020 and 0820 h, and for FT3 from 2200-1000 h. Cross correlation of FT3 with TSH showed that the peak correlation occurred with a delay of 0.5-2.5 h. When time-adjusted profiles of TSH and FT3 were compared, there was a strong correlation between FT3 and TSH levels (rho = 0.80; P < 0.0001). In contrast, cross correlation revealed no temporal relationship between FT4 and TSH. CONCLUSIONS: FT3 shows a circadian rhythm with a periodicity that lags behind TSH, suggesting that the periodic rhythm of FT3 is due to the proportion of T(3) derived from the thyroid. Optimizing thyroid hormone replacement may need to take these rhythms into account.

Modified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers.

BACKGROUND: All existing long-term glucocorticoid replacement therapy is suboptimal as the normal nocturnal rise and waking morning peak of serum cortisol is not reproduced. AIM: To test whether it is possible to reproduce the normal overnight rise and morning peak in serum cortisol using an oral delayed and sustained release preparation of hydrocortisone (Cortisol(ds)). SUBJECTS AND METHODS: Six healthy normal male volunteers attended on two occasions, in a single-dose, open-label, nonrandomized study. Endogenous cortisol secretion was suppressed by administration of dexamethasone. Cortisol(ds) (formulation A or B) was administered at 2200 h on day 1. Blood samples for measurement of cortisol were taken from 2200 h every 30 min until 0700 h, then hourly until 2200 h on day 2. Fifteen body mass index (BMI)-matched control subjects had serum cortisol levels measured at 20-min intervals for 24 h. Serum cortisol profiles and pharmacokinetics after Cortisol(ds) were compared with those in controls. RESULTS: Formulations A and B were associated with delayed drug release (by 2 h and 4 h, respectively), with median peak cortisol concentrations at 4.5 h (0245 h) and 10 h (0800 h), respectively, thereby reproducing the normal early morning rise in serum cortisol. Total cortisol exposure was not different from controls. CONCLUSIONS: For the first time we have shown that it is possible to mimic the normal circadian rhythm of circulating cortisol with an oral modified-release formulation of hydrocortisone, providing the basis for development of physiological circadian replacement therapy in patients with adrenal insufficiency.

Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study.

BACKGROUND: Testosterone replacement in hypogonadal males improves body composition, sexual function, and health-related quality of life. Male cancer survivors are at risk of androgen deficiency; however, when and in whom testosterone should be replaced remain unanswered questions. OBJECTIVE: The aim of our study was to define the prevalence of androgen deficiency in this patient group through assessment of testosterone levels and related measures. DESIGN: This was a cross-sectional, observational study of cases and controls. We recruited 176 cancer survivors and 213 controls, aged 25-45 yr. RESULTS: Of cancer survivors, 97% had received chemotherapy and 40% radiotherapy. Cancer survivors had lower total testosterone (tT) levels than controls (mean difference 2.67 nmol/liter; 95% confidence interval 1.58-3.76; P = 0.003), and 24 of 176 (13.6%; 95% confidence interval 9.3-19.5) had a tT less than 10 nmol/liter, which was less than 2.5% centile for controls. Cancer survivors had a greater fat mass, higher fasting insulin and glucose levels, increased fatigue, and reduced sexual function and health-related quality of life. In both cohorts, the tT correlated negatively with insulin levels and negatively with body fat mass; however, the difference in tT between them was independent of fat mass. We measured tT and SHBG and calculated bioavailable testosterone. The changes in calculated bioavailable testosterone were similar to tT. CONCLUSIONS: A significant proportion of young male cancer survivors had a frankly low tT associated with an increased fat mass and insulin level compared with controls. These factors would be predicted to improve in response to testosterone replacement therapy and provide a powerful argument for an interventional study of testosterone therapy in young male cancer survivors.

Defining growth hormone status in adults with hypopituitarism.

The identification of adults with severe growth hormone (GH) deficiency (GHD) is not straightforward. The insulin tolerance test remains the gold standard diagnostic test, although other stimuli such as GH-releasing hormone-arginine are gaining acceptance. Insulin-like growth factor-I has a poor diagnostic sensitivity in adult-onset GHD, but is more useful in the subgroup of adults with childhood-onset GHD. Therapeutic developments include increasing recognition of the need to continue GH therapy beyond final height in young adults with severe GHD on retesting. Consensus guidelines have provided a useful algorithm to identify individuals requiring retesting and the number of tests needed. The concept of partial GHD, recognized by paediatric endocrinologists for many years, is being examined in adults with hypothalamic-pituitary disease. Preliminary evidence suggests that this entity is associated with metabolic and anthropometric abnormalities intermediate between those in severe GHD and in healthy controls. It remains to be seen whether this subgroup will derive benefit from GH therapy. To date, therapeutic benefits of GH have been demonstrated only in adults with severe GHD. It is, therefore, imperative that these individuals are unequivocally identified; the diagnosis becomes more uncertain in the presence of obesity, increasing age, and in the absence of additional pituitary hormone deficits.

Aetiology, diagnosis, and management of hypopituitarism in adult life.

Hypopituitarism is a complex medical condition associated with increased morbidity and mortality, requires complicated treatment regimens, and necessitates lifelong follow up by the endocrinologist. The causes, clinical features, and the management of hypopituitarism including endocrine replacement therapy are considered in this review article.

Prolactin deficiency is independently associated with reduced insulin-like growth factor I status in severely growth hormone-deficient adults.

BACKGROUND: In adult life, considerable overlap in IGF-I status exists between normal and severely GH-deficient (GHD) subjects defined by conventional dynamic testing of GH secretion. IGF-I is not therefore widely viewed as a reliable diagnostic marker for GHD. Recognized factors influencing serum IGF-I level in GHD include age, gender, timing of onset of GHD, and exogenous estrogen therapy, but these do not fully explain GH/IGF-I discordance in severe GHD. The primary structures of prolactin and GH are closely related. Effects of hypoprolactinemia are not well described in humans, but laboratory studies suggest a role for prolactin in hepatic IGF-I release, possibly through a signal transducer and activator of transcription 5 (STAT5) pathway. The purpose of this study was to evaluate a potential contribution of prolactin to IGF-I status in severely GHD adults. PATIENTS AND METHODS: Using multiple regression analysis techniques, contributions of the following variables to age-adjusted IGF-I sd scores were evaluated in 162 (85 female) GHD adults: gender, timing of onset of GHD, presence or absence of prolactin deficiency, body mass index, number of additional pituitary deficits, and underlying pathology. RESULTS: Childhood onset GHD (P < 0.0001) and presence of prolactin deficiency (P < 0.0001) were independently associated with reduced IGF-I status. The contributions of these parameters to IGF-I sd scores were -2.55 and -2.67, respectively. Gender (P = 0.06), body mass index (P = 0.99), number of additional pituitary deficits (P = 0.64), and underlying pathology (P = 0.06) did not significantly influence IGF-I status. CONCLUSIONS: Prolactin deficiency is independently associated with reduced IGF-I status in hypopituitary adults. It is possible that prolactin deficiency is a surrogate for the degree of severity of GHD, implying a GHD paradigm undetected by conventional GH provocative tests; alternatively, it remains plausible that circulating prolactin contributes to IGF-I release in the absence of GH, possibly through a signal transducer and activator of transcription 5 (STAT5) pathway.

Does growth hormone cause cancer?

The ability of GH, via its mediator peptide IGF-1, to influence regulation of cellular growth has been the focus of much interest in recent years. In this review, we will explore the association between GH and cancer. Available experimental data support the suggestion that GH/IGF-1 status may influence neoplastic tissue growth. Extensive epidemiological data exist that also support a link between GH/IGF-1 status and cancer risk. Epidemiological studies of patients with acromegaly indicate an increased risk of colorectal cancer, although risk of other cancers is unproven, and a long-term follow-up study of children deficient in GH treated with pituitary-derived GH has indicated an increased risk of colorectal cancer. Conversely, extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk. However, given the experimental evidence that indicates GH/IGF-1 provides an anti-apoptotic environment that may favour survival of genetically damaged cells, longer-term surveillance is necessary; over many years, even a subtle alteration in the environmental milieu in this direction, although not inducing cancer, could result in acceleration of carcinogenesis. Finally, even if GH/IGF-1 therapy does result in a small increase in cancer risk compared to untreated patients with GH deficiency, it is likely that the eventual risk will be the same as the general population. Such a restoration to normality will need to be balanced against the known morbidity of untreated GH deficiency.

Hypopituitarism after cranial irradiation.

Radiation-induced damage to the hypothalamic-pituitary (h-p) axis is associated with a wide spectrum of subtle and frank abnormalities in anterior pituitary hormones secretion. While the rapidity of onset of these abnormalities is primarily radiation dose-dependent, their frequency and severity also depend on the length of follow-up. The GH axis is the most vulnerable to radiation damage, and GH deficiency is usually the only neuro-endocrine abnormality following irradiation of the h-p axis with doses <30 Gy. With higher radiation doses (30-50 Gy), the frequency of GH insufficiency can be as high as 50-100% and that of TSH and ACTH around 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose <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 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 yr) occurs after more intensive irradiation (>70 Gy) used for nasopharyngeal carcinomas and tumors of the skull base, and following conventional irradiation (30-50 Gy) for pituitary tumors. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy, to improve linear growth and prevent short stature in children cured from cancer, to preserve sexual function, prevent ill health and osteoporosis, and improve the quality of life.

Spermatogenesis after cancer treatment: damage and recovery.

Treatment with cytotoxic chemotherapy and radiotherapy is associated with significant gonadal damage in men, and alkylating agents are the most common agents implicated. The vast majority of men receiving procarbazine-containing regimens for the treatment of lymphomas are rendered permanently infertile, whereas treatment with doxorubicin hydrochloride (Adriamycin), bleomycin, vinblastine, and dacarbazine appears to have a significant advantage, with a return to normal fertility in the vast majority of patients. Cisplatin-based chemotherapy for testicular cancer results in temporary azoospermia in most men, with a recovery of spermatogenesis in about 50% of the patients after 2 years and 80% after 5 years. The germinal epithelium is very sensitive to radiation-induced damage, with changes to spermatogonia following as little as 0.2 Gy. Testicular doses of less than 0.2 Gy had no significant effect on FSH levels or sperm counts, whereas doses between 0.2 and 0.7 Gy caused a transient dose-dependent increase in FSH and reduction in sperm concentration, with a return to normal values within 12-24 months. No radiation dose threshold has been defined above which permanent azoospermia is inevitable; however, doses of 1.2 Gy and above are likely to be associated with a reduced risk of recovery of spermatogenesis; the time to recovery, if it is to occur, is also likely to be dose dependent.

Consensus statement on the management of the GH-treated adolescent in the transition to adult care.

The European Society for Paediatric Endocrinology held a consensus workshop in Manchester, UK in December 2003 to discuss issues relating to the care of GH-treated patients in the transition from paediatric to adult life. Clinicians experienced in the care of paediatric and adult patients on GH treatment, from a wide range of countries, as well as medical representatives from the pharmaceutical manufacturers of GH participated.

The characteristics of quality of life impairment in adult growth hormone (GH)-deficient survivors of cancer and their response to GH replacement therapy.

We studied 50 (27 women and 23 men) GH-deficient (GHD) cancer survivors and 47 (24 women and 23 men) GHD patients with pituitary pathologies. All GHD patients were considered for GH replacement on the basis of subjectively poor quality of life (QOL). Primary outcome measures were scores of QOL instruments psychological general well-being schedule (PGWB) and assessment of GH deficiency in adults (AGHDA) at baseline and early (6-13 months) and long-term (24-77 months) treatment follow-up. Of secondary interest were six PGWB domains. Linear mixed effect regression was used to model each QOL outcome. The groups differed with respect to three covariates: age, gender, and body mass index. These variables were included in all fitted models. Baseline scores for PGWB and AGHDA were not different between groups. Ranking of PGWB domains were similar between groups at baseline (lowest domain, vitality). The pattern of change in mean scores for all outcome measures from baseline did not differ between groups (P = 0.86). All QOL variables improved significantly with treatment [estimated mean change +/- se: PGWB, 16.2 +/- 1.7; AGHDA, -6.2 +/- 0.6; PGWB domains (transformed percentage scales): anxiety, 12.4 +/- 1.7; depression, 14.1 +/- 2.1; health, 12.4 +/- 1.7; self-control, 11.3 +/- 2.0; well-being, 15.2 +/- 1.7; vitality, 22.5 +/- 2.0 (vitality, greatest change)]. There was no evidence of group difference in early follow-up or long-term follow-up means for any outcome variable. The QOL in adult GHD cancer survivors was comparable to that in GHD adults with pituitary pathologies and improved with GH replacement in a similar manner. We conclude that QOL impairment in adult GHD cancer survivors appears mainly related to GHD rather than cancer diagnosis and treatment.

The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours.

Survival rates are improving following cancer therapy for childhood brain tumours. There is therefore a growing cohort of survivors at risk of late effects of cancer therapy. Endocrine problems are very common in these patients. The recognition and prompt management of these are essential to prevent further morbidity and impairment of quality of life. Cranial radiation can damage hypothalamic-pituitary function, most frequently affecting GH status; however, higher radiation doses may cause more widespread hypothalamic-pituitary damage. Early puberty secondary to cranial irradiation is now being managed with gonadotrophin-releasing hormone analogues to improve final height. Prompt diagnosis and management of GH deficiency may improve final height outcome; continued GH therapy beyond final height aids the achievement of adult body composition (lean body mass and bone mass) and GH therapy in adulthood improves quality of life. Both cranial irradiation alone and with spinal irradiation can result in radiation damage to the thyroid resulting in hypothyroidism and thyroid nodules, a high proportion of which are malignant. Gonadal damage secondary to spinal irradiation and adjuvant chemotherapy may have long-term consequences including infertility.

Stepping into adulthood: the transition period.

The period of growth from late puberty to full adult maturation, termed the transition period, is important for tissue maturation. Peak bone mass, muscle mass and strength are usually attained in this period. However, it is common clinical practice in children with growth hormone deficiency (GHD) to discontinue growth hormone (GH) treatment in adolescence after attainment of final height. Therefore, patients with childhood-onset GHD that continues into adulthood and who do not receive treatment as adults may experience more severe consequences than patients who acquire GHD as an adult. Recent studies indicate that bone and muscle maturation are attenuated if GH treatment is discontinued at final height. Furthermore, these patients will also develop cardiovascular risk factors that are normally associated with GHD in adults. Much debate surrounds when retesting for GHD should be carried out and when GH treatment should be restarted in adolescents; many of these patients will not have severe GHD according to the criteria set for adults. The transition period is an appropriate time to modify GH doses. Finally, registries exist that have recorded clinical treatment experiences for children and adults. Tools that collect and analyse data provide an important opportunity to investigate issues related to transition.

The effect of cigarette smoking use and cessation on serum insulin-like growth factors.

The patterns of risk association between circulating levels of insulin-like growth factor (IGF)-I, and its main binding protein, IGFBP-3, differ between smoking and nonsmoking-related cancers. To investigate this observation further, we measured serum IGF-I, IGF-II and IGF-binding protein-3 concentrations in 232 men and 210 women (aged 55-64 years), and related peptide levels to smoking characteristics. Current smoking was associated with significant reductions in mean IGFBP-3 levels in men assessed by the number of cigarettes smoked daily (P(trend)=0.007) and pack-years smoked (P(trend)=0.03). Mean IGF-I levels decreased with increasing cigarette use in men (P(trend)=0.11). There were no patterns of association between smoking and IGF peptides in women. For male former vs never smokers, there were no differences in mean IGF-I and IGFBP-3 concentrations, suggesting that smoking cessation is associated with normalisation of peptide concentrations.