Chapter 28 - Uncertainties in endocrine substitution therapy for central endocrine insufficiencies: growth hormone deficiency

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Abstract

The growth hormone deficiency (GHD) syndrome is associated with several metabolic abnormalities and it has been postulated that the increased cardiovascular disease (CVD) morbidity and mortality in GHD patients may be related to the missing metabolic effects of GH. Many CVD risk factors show improvements after GH therapy. Reduced bone mineral density (BMD) has been recorded both in patients with isolated GHD and in those with multiple pituitary deficiencies, indicating that GHD per se is responsible for the low BMD in both types of patients.

These matters are, however, more complicated, as hypopituitary patients with GHD may have different phenotypes due to differences in underlying diagnoses. These phenotypes may not be clear-cut in individual patients. Moreover, patients may transit between different phenotypes over time due to extension of the pathology in the pituitary and/or the consequences of the treatment (surgery and/or radiotherapy). Three different phenotypes of hypopituitary patients will be discussed, with a focus on CVD risk and bone health: (1) patients with isolated GHD, e.g. due to prophylactic cranial radiotherapy for lymphoblastic leukaemia in childhood; (2) patients with GHD and multiple hormone deficiencies due to pituitary macroadenomas treated by surgery; (3) patients with GHD caused by craniopharyngiomas with multiple hormone deficiencies and hypothalamic involvement, where hypothalamic damage frequently dominates the positive metabolic effects of GH therapy. These phenotypes illustrate the differential impact of various pituitary pathologies on the phenotype of patients with GHD.

Introduction

The growth hormone (GH) deficiency syndrome is associated with several metabolic abnormalities (Cuneo et al., 1992, Carroll and Christ, 1998, Maison et al., 2004), and it has been postulated that the increased cardiovascular morbidity and mortality recorded in GH-deficient (GHD) patients may be related to the missing metabolic effects of GH (Rosén and Bengtsson, 1990, Bülow et al., 1997). In addition, it has been suggested that the adult GHD phenotype shares features of the metabolic syndrome, such as abdominal obesity, dyslipidemia, and insulin resistance, thus a cluster of risk factors for cardiovascular disease (CVD) and type 2 diabetes mellitus (Ford, 2005, Cornier et al., 2008). GH has a positive effect on body composition, with increased lean mass and reduced fat mass, and with a reduction particularly in waist measurements and a favorable effect on lipid levels (Maison et al., 2004). Many of the traditional CVD risk factors show improvements after GH therapy, which might decrease CVD risk in these patients and improve longevity. In particular, if patients with newly developed GHD received early GH replacement, the negative effects of GHD could possibly be avoided.

GH affects linear growth and is important for skeletal development in young adults and for bone turnover in adult skeletal tissue (Ohlsson et al., 1998). Reduced bone mineral density (BMD) has been recorded both in patients with isolated GHD and in those with multiple pituitary deficiencies, indicating that GHD per se is, at least in part, responsible for the low BMD in both types (De Boer et al., 1994, Holmes et al., 1994). There are, however, contradictory results from studies in adult onset GHD showing both normal BMD, particularly in older subjects (Toogood et al., 1997, Fernholm et al., 2000), and low BMD (Rosén et al., 1993, Degerblad et al., 1995). In contrast, in patients with childhood-onset GHD (Kaufman et al., 1992, O’Halloran et al., 1993, De Boer et al., 1994) there seems to be a clear reduction in BMD, which may illustrate the potential role of GH in the acquisition of peak bone mass (De Boer et al., 1994).

These matters are, however, more complicated, as hypopituitary patients with GHD appear in several phenotypes due to different background diagnoses. Furthermore, GHD is not the only risk factor for CVD or low BMD in these patients. This notion is based on the observation that the effect of complete hormone substitutions, including GH therapy, differs depending on the phenotypes of hypopituitary patients. However, these phenotypes are not clear-cut and not absolute in individual patients as patients may transit between the different phenotypes over time due to extension of the pathology and/or the effects of treatment (surgery and/or radiotherapy). Moreover, in clinical practice patients with similar pituitary diseases may fall into different categories of GHD and may even transit from one category (e. g., GHD only) to a second category (e.g., GHD with multiple hormone deficiencies).

The purpose of this chapter is to discuss three different phenotypes of hypopituitary patients with GHD, with a focus on CVD risk and bone health:

  • 1.

    Patients with isolated GHD, e.g., caused by prophylactic cranial radiotherapy for lymphoblastic leukemia in childhood

  • 2.

    Patients with GHD and multiple hormone deficiencies, caused by a pituitary macroadenoma, treated by surgery

  • 3.

    Patients with GHD and multiple hormone deficiencies and with hypothalamic involvement caused by a craniopharyngioma.

Section snippets

Cardiovascular risk after acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and constitutes 25% of all childhood cancers. The peak incidence is at the age of 2–4 years. The survival after ALL has improved dramatically during recent decades, and is currently about 85%, which emphasises the importance of long-term treatment complications (Oeffinger et al., 2000). GHD is common after long-term follow-up in survivors of childhood ALL treated with prophylactic cranial radiotherapy (Brennan et al.,

Cardiovascular risk in hypopituitary patients with nonsecreting pituitary macroadenomas

Epidemiologic studies have revealed increased cerebral and cardiovascular mortality in patients with hypopituitarism on conventional hormone treatment but without GH therapy. The greatest increase was seen in cerebrovascular disease (Bülow et al., 1997, Tomlinson et al., 2001), with a more pronounced risk in women (Bülow et al., 1997, Tomlinson et al., 2001), but without gender difference in cardiac mortality (Bülow et al., 1997). These epidemiologic studies included particularly patients with

Cardiovascular risk in patients with a craniopharyngioma

In cohort studies of patients with craniopharyngiomas (CP) the SMR varies from 2.88 to 9.28 (Bülow et al., 1998, Tomlinson et al., 2001, Pereira et al., 2005). In addition, CP patients have a particularly high CVD mortality in comparison to the general population (3–19-fold higher) (Bülow et al., 1998, Tomlinson et al., 2001, Pereira et al., 2005). Women with CP have an even higher risk (Bülow et al., 1998, Pereira et al., 2005).

Patients with hypothalamic involvement by a CP have significantly

General uncertainties of growth hormone therapy

GH therapy of adults has generally been regarded as quite a safe treatment, although concerns remain regarding the potential for cancer risk, as IGF-1 has mitogenic effects on both normal and cancerous cells (Maculty, 1992). In general, GH treatment is contraindicated in the presence of active malignancy. Although GH treatment reduces insulin sensitivity, the worsening of glycemic control has been minimal and transient, and low GH doses may even improve insulin sensitivity. However, GH

Conclusion

If GHD was an isolated entity the metabolic effects of GH therapy could be easily predicted. However, based on different background diagnoses, there are several phenotypes of the hypopituitary patient with GHD. In clinical practice these patients may even transit between the different phenotypes over time due to extension of the pathology and/or the effects of treatments (surgery and/or radiotherapy). Furthermore, hypothalamic involvement, but also hormone substitutions of other pituitary

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