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

      Mukherjee, Annice; Helbert, M; Ryder, W David J; Borrow, R; Davis, Julian R E; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, UK. annice.mukherjee@srht.nhs.uk (2009-05)
      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.
    • GH sensitivity of GH-deficient adults is dependent on gender but not timing of onset.

      Columb, Breeda; Smethurst, Linda E; Mukherjee, Annice; Jostel, Andreas; Shalet, Stephen M; Murray, Robert D; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK. (2009-02)
      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.
    • Immune function in hypopituitarism; time to reconsider?

      Mukherjee, Annice; Helbert, M; Davis, J R E; Shalet, Stephen M; Dept of Endocrinology, Christie Hospital, Manchester, UK. (2009-12-18)
      Abstract Hypopituitarism is not currently considered as a potential cause of immune disruption in humans. Accumulating data from in-vitro and animal models support a role for the pituitary gland in immune regulation. Furthermore the increased mortality risk noted in patients with adult hypopituitarism remains poorly explained and immune dysfunction could conceivably contribute to this observation. In a recent issue of Clinical & Experimental Immunology we presented new data relating to immune status in adults with treated, severe hypopituitarism. We observed humoral immune deficiency in a significant proportion, despite stable pituitary replacement, including growth hormone (GH). This was especially evident in those with low pre-treatment IGF-I levels and appeared independent of anticonvulsant use or corticosteroid replacement. These observations require substantiation with future studies. In this short review we summarise existing data relating to the effects of pituitary hormones on immune function, and discuss potential clinical implications surrounding the hypothesis of immune dysregulation in severe hypopituitarism.
    • Pharmacological treatment of hypercortisolism.

      Shalet, Stephen M; Mukherjee, Annice; Department of Endocrinology, Christie Hospital, Manchester, UK. stephen.m.shalet@man.ac.uk (2008-06)
      PURPOSE OF REVIEW: To consider the current status and types of drug therapy aimed at restoring eucortisolaemia in patients with Cushing's syndrome. RECENT FINDINGS: Advances such as laparoscopic adrenalectomy modify the exact placing of drug therapy among the wide variety of therapies available to treat patients with Cushing's syndrome because of different causes; nonetheless, it is now clear that hypercortisolism, per se, if present for any length of time, modifies the future prognosis of the patient, even after cure of the Cushing's syndrome. Thus, early diagnosis and restoration of eucortisolsm are critical. There are three main types of drug therapy: steroidogenesis inhibitors, glucocorticoid antagonists and neuromodulatory compounds. Currently, steroidogenesis inhibitors such as metyrapone and ketaconazole are most commonly the first choice if drug therapy is to be used, but at least for the most common form of Cushing's syndrome, Cushing's disease, the neuromodulatory compounds such as cabergoline show potential. SUMMARY: Pharmacological therapy for Cushing's syndrome remains critically important for normalizing cortisol levels while awaiting the impact of more definitive treatment.
    • The value of IGF1 estimation in adults with GH deficiency.

      Mukherjee, Annice; Shalet, Stephen M; Department of Endocrinology, Salford Royal NHS Foundation Trust, UK. annice.mukherjee@srft.nhs.uk (2009-11)
      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.