• Non ci sono risultati.

Management of GH treatment in adult GH deficiency

N/A
N/A
Protected

Academic year: 2021

Condividi "Management of GH treatment in adult GH deficiency"

Copied!
1
0
0

Testo completo

(1)

This is the author's final version of the contribution published as:

Gasco V, Caputo M, Lanfranco F, Ghigo E, Grottoli S. Management of GH treatment in adult GH deficiency. Best Pract Res Clin Endocrinol Metab. 2017 Feb;31(1):13-24. doi: 10.1016/j.beem.2017.03.001

The publisher's version is available at:

http://www.bprcem.com/article/S1521-690X%2817%2930007-6/fulltext

When citing, please refer to the published version.

Link to this full text:

http://hdl.handle.net/dx.doi.org/10.1016/j.beem.2017.03.001

(2)

MANAGEMENT OF GH TREATMENT IN ADULT GH DEFICIENCY

Valentina Gasco, Marina Caputo, Fabio Lanfranco, Ezio Ghigo, Silvia Grottoli

Division of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, Turin, Italy

Word count: 7153 Correspondence to

Valentina Gasco, MD

Division of Endocrinology, Diabetes and Metabolism Department of Medical Science

University of Turin c.so Dogliotti 14 10126 Torino, Italy E-mail: valentina.gasco@unito.it Tel. +390116709562 Fax. +390116647421

(3)

Abstract

Growth hormone (GH) replacement therapy in adults with GH deficiency is still a challenge for the clinical endocrinologist and its implementation has still numerous difficulties and uncertainties. The decision to treat GH deficient adults requires a thoughtful and individualized evaluation of risks and benefits. Benefits have been found in body composition, bone health, cardiovascular risk factors, and quality of life. However, evidences for a reduction in cardiovascular events and mortality are still lacking, and treatment costs remain high.

It is advisable to start treatment with low doses of GH, the goals being an appropriate clinical response, an avoidance of side effects, and IGF-I levels in the age-adjusted reference range.

Although treatment appears to be overall safe, certain areas continue to require long-term surveillance, such as risks of glucose intolerance, pituitary/hypothalamic tumor recurrence, and cancer.

(4)

Introduction

The adult growth hormone (GH) deficiency syndrome is a well-defined clinical entity that is characterized by decreased lean body mass and bone mineral density, increased fat mass, an abnormal lipid profile, cardiac dysfunction, decreased fibrinolysis and premature atherosclerosis, decreased muscle strength and exercise endurance, and diminished quality of life (QoL) (1). Furthermore, it is likely, although unproven, that GH deficiency (GHD) contributes to the increase in cardiovascular morbidity and mortality that is consistently observed in hypopituitary adults (2). The importance of GH replacement therapy in adults has been highlighted in recent guidelines issued by the Endocrine Society (ES) (3), which are broadly similar to the widely accepted guidelines previously issued by the Growth Hormone Research Society (GRS) (4) and the American Association of Clinical Endocrinologists (AACE) (5). The guidelines emphasize that the risks of GH therapy are low, and that GH replacement has beneficial effects on body composition, exercise capacity, skeletal integrity, several cardiovascular surrogate outcomes, including endothelial function, inflammatory cardiovascular biomarkers, lipoprotein metabolism, carotid intima-media thickness, some aspects of myocardial function, and quality of life, particularly in patients with more severe clinical and biochemical evidence of GHD (3-5). However, whether long-term GH treatment has implications for the incidence of stronger outcomes such as cardiovascular morbidity and fractures remains to be established (3-5).

Originally, GH doses in replacement regimes were determined by body weight and surface area and dose increases based on body composition outcomes in analogy with pediatric practice (6, 7). These regimens led to significant side effects related to GH excess and IGF-I levels above the upper limit

(5)

of the reference range (6-8). Newer treatment regimes therefore account for known factors affecting dose responsiveness (3-5, 9-23).

Therapeutic monitoring is via clinical symptoms combined with serum total IGF-I levels. This potentially avoids excessive GH exposure and allows monitoring of compliance and dose titration. There is a lack of data relating IGF-I to biological endpoints, but analysis suggests that dose titration of IGF-I to the upper half of the age and gender related reference range is acceptable. In this review we focus on general aspects of GH therapy in adult GHD, in particular we discuss dosing strategies, factors affecting dose responsiveness, treatment monitoring, and safety issues.

Dosing strategies

Early studies on GH replacement in adults were based on paediatric experience, and used GH doses that were clearly excessive, resulting in a high frequency of side-effects. We now know that there is great variability in individual responsiveness to GH, with dosing regimens based on body weight and surface area alone proving unsuitable for adult patients. For instance, by not taking into account age and adiposity, such regimens wrongly suggest high doses for elderly and obese subjects.

The observations that the same GH dose can be sub-optimal in one patient but leads to side effects of over-dosage in another, and that normalization of serum IGF-I can induce side effects in some patients (24), have prompted the development of individual dose titration. In this paradigm, the GH dose is titrated against both clinical features of GHD and evidence of over-treatment determined by serum IGF-I and the appearance of side effects.

A multi-centre randomized open-label trial in a large cohort of adult GHD patients comparing fixed, weight based regimens with an individualized dose titration strategy based on IGF-I levels and clinical response convincingly demonstrated an equivalent efficacy of both regimens with an improved tolerability in the individualized dosing scheme (25). Taken together this and other studies (26-29) provide evidence for the optimal approach to GH replacement therapy that should

(6)

be started at a low dose and then titrated upwards depending on the clinical and biochemical patient’s response. This individualized dose titration leads to similar beneficial effects, less side effects, and a lower stable GH dose than using a body weight based regime.

The guidelines (3-5) recommend to start therapy with low individualized doses (Table 1). GH doses, therefore, must be individually tailored, taking into consideration all of the factors that influence GH responsiveness.

Management of GH replacement as function of factors affecting dose responsiveness

The individual response to GH replacement is highly variable. The first attempt to understand which patients can be considered more sensitive to the effects of GH, was made by Holmes and Shalet (30). In 63 GHD adults they observed that side effects occurred more frequently in subjects who were older and more obese, had a greater GH response on provocative testing indicating some residual GH secretion, and in whom GHD onset occured during adult life. The second decade of GH replacement in GHD adults has therefore been characterized by attempts to understand what predicts individual responsiveness to GH, and to use this information to improve the efficacy and safety of GH replacement therapy.

Treatment guidelines now recognize the need to adjust the GH dose for certain categories of patients to reflect variations in physiological GH secretion.

Age

Current age and age of GHD onset are factors that may influence dose responsiveness. As the sensitivity to side effects of exogenous GH is greater in elderly patients with GHD, guidelines advise that the starting dose, size of dose adjustments and target serum IGF-I levels should be reduced when GH replacement is considered in elderly patients (3-5). Indeed, elderly GHD patients are sensitive to GH and need low daily dose to normalize their serum IGF-I levels (9). However, in

(7)

terms of anabolic effects and muscle performance, elderly patients are less responsive than younger ones (31).

On the other hand, guidelines for downward dose titration from a childhood to an adult dose are still lacking. Based on the age-related reduction in the spontaneous rate of GH production from puberty to young adulthood (32), it could be hypothesized that progressive titration of GH dose during the transition phase to mimic physiological changes would lead to a dose reduction of approximately 50% in 2–4 years. In the transition phase, it is important to identify safe regimens that can

maximize linear growth potential and final adult height; it is also important to investigate the impact of age-adjusted regimens on carbohydrate and lipid metabolism, bone accretion, attainment of peak bone mass, body composition, behaviour, psychosexual function, and QoL.

Gender

There is a well known gender difference in GH secretion rate. In particular, GH production in healthy women of reproductive age is about two-fold higher than in men, but IGF-I levels are similar, suggesting a lower responsiveness to GH in women (33). In contrast to healthy men and women, IGF-I levels in adults with GHD are lower in women than in men, and there is a gender difference in GH requirement, with women needing higher doses and a longer duration to achieve the same clinical effects and IGF-I levels. This gender difference is closely related to estrogen secretion and is possibly influenced by serum testosterone as well. Considering this gender difference, the guidelines state that women require higher initiation and maintenance doses than their male counterparts to achieve an equivalent clinical and biochemical response (3-5). Gender differences have been observed not only in dosing, but also in the response to GH, as reflected by more marked changes in body composition (34, 35), plasma lipid profile (36), bone metabolism (37, 38), and increase in protein anabolism and muscle strength (31) in males than in females. Even when men and women were matched to similar IGF-I responses, the effects of GH on clinical endpoints such as body fat, LDL cholesterol, and circulating markers of bone turnover were still

(8)

blunted in women (10). Obesity

Decreased basal and stimulated GH and basal IGF-I levels and increased responsiveness to GH treatment are frequently reported in obesity. The role of obesity in affecting hepatic IGF-I

generation in response to GH was explored by Yuen et al. (11)in a cohort of severely GH-deficient non-obese and obese adults treated with a fixed low GH dose (0.2 mg/day). Results demonstrated a larger increment and decreased individual variability of IGF-I to the low GH replacement dose in obese compared with non-obese GHD adults. A positive association of IGF-I increment with baseline BMI suggested that the increased hepatic responsiveness to GH stimulation was more dependent on the degree of obesity rather than the GHD itself.

Current guidelines give special consideration to patients who are obese, in stating that initiating and maintaining GH therapy using low doses (0.1–0.2 mg/day) may be more appropriate in GHD patients with concurrent diabetes or obesity, and in those with previous gestational and family history of diabetes so as not to increase blood glucose levels (5).

Interactions with other therapies

It is well established that oral estrogen administration markedly reduces GH responsiveness (12). It has been shown (13) that estrogen stimulates a specific non-competitive postreceptor inhibitor of GH actions, SOCS2, in the liver. Because more than 70% of circulating IGF-I is produced in the liver (39), oral estrogen has a much greater effect in suppressing the stimulation of IGF-I, and in general women require higher doses of GH to achieve the same response in term of IGF-I levels (10). Cook et al. attempted to quantify this affect, by comparing GH doses in women receiving oral or transdermal estrogen, using normalization of IGF-I as the treatment objective (14). They found that women receiving oral estrogen required a mean dose of 10.6 µg/kg/day, compared to 5.0 µg/kg/day in women not receiving oral estrogen. These findings were extended by Janssen et al., who observed that changing replacement with 17beta-estradiol from the oral (2 mg/day) to the

(9)

transdermal (50 μg/day) route of administration, lead to a marked increase in serum IGF-I levels in GHD women receiving long-term GH therapy (15).

Baseline disease characteristics

Adult GHD should not be considered as a single clinical entity, as there are marked differences in baseline data between adulthood onset (AO)- and childhood onset (CO)- GHD (40), with patients with AO-GHD often regarded as being more sensitive to GH and more prone to side-effects than patients with CO-GHD.

Differences in dose requirements and responses have been observed in patients with AO-GHD and CO-GHD. In the study by Chihara et al. (16), individualized GH dosing resulted in a lower mean dose for patients with AO- compared with CO-GHD (0.032 ± 0.019 vs 0.061 ± 0.023 mg/kg per week). Similarly, Murray et al. (17) noted that low dose individualized GH replacement, aimed at normalization of serum IGF-I levels, was associated with a significantly greater mean dose for CO- than AO-patients at 12 months (0.45 ± 0.18 vs 0.32 ± 0.16 mg/day respectively; p = 0.004) and at 24 months (0.53 ± 0.24 vs 0.33 ± 0.20 mg/day; p = 0.024)

It has also been investigated whether the severity of GHD defined as i) GH-peak on stimulation tests, ii) number of additional pituitary deficits, or iii) baseline IGF-I SDS had an impact on the response to GH replacement. IGF-I SDS was a strong predictor of the response to GH replacement, in some studies (18, 19), but not in others (41-43), while the extent of hypopituitarism indicated by the GH stimulation test peak and the number of additional hormone deficiencies did not have an independent impact on the response to GH (18).

Furthermore, the degree of improvement in many biological endpoints affected by GH therapy are proportional to the degree of deviation from normality at baseline. For instance, it has been reported that subjects with the greatest severity of bone mineral loss (Z score worse than -2) had the greatest improvement in response to treatment (44). Also the degree of improvement in QoL is generally proportional to the deviation from normality at the outset (45).

(10)

It should also be recognized that underlying disease and cause of hypopituitarism may affect the response to GH replacement as it has been seen in subjects with craniopharyngioma (20), cured Cushing’s disease (21) or acromegaly (22, 23).

Does the mode of administration of recombinant human GH (rhGH) influence its effects?

Some studies have explored the mode, frequency and timing of GH injections for the optimal treatment schedule in adult GHD.

The bioavailability of intravenously (iv) injected GH is greater than an equivalent subcutaneous (sc) injection, suggesting a possible local degradation of GH when injected subcutaneously (46). Moreover, several parameters influence sc GH absorption, such as the depth and site of injection and the sc blood flow (47-49). The peak GH concentration is obtained more rapidly after abdominal injection; indeed GH absorption is faster from an abdominal site than from the thigh. However, injections in both areas have a similar effect on serum IGF-I levels.

Pulsatile GH administration in rats is more effective than continuous delivery in term of linear growth and IGF-I generation (50). Indeed, constant GH exposure might, in theory, down-regulate the GH receptor. However, evidence in man suggests that there is no clinically relevant difference between continuous vs intermittent GH administration in terms of IGF-I, bone metabolism, body composition, insulin sensitivity and lipoproteins (49, 51).

Studies comparing daily injections vs less frequent dosing (i.e. alternate days or three injections per week) have demonstrated that the effects during less frequent regimens were comparable with those observed in patients treated with daily injections in term of normalization of IGF-I levels and improvement of lipid profile, body composition, bone metabolism and bone density, with few side effects and good compliance (52). Given that lifelong therapy might be necessary, compliance is an important issue in the treatment of GHD. Indeed, current guidelines (5) suggest that, for patients

(11)

with compliance issues, clinicians may consider administering injections on alternate days or three injections per week using the same total weekly dosage.

Whether the timing of GH administration had any impact on its action in adult GHD has been also studied: evening injections were more successful than morning injections in normalizing the circadian patterns of hormones and metabolites crucial for intermediary metabolism (53).

Treatment monitoring

Although GH replacement in GHD adults is now approved in many countries, some outstanding questions concerning the optimization and individualization of treatment still remain. There is no biological or clinical marker with which to assess the efficacy of GH replacement in adulthood that is equivalent to the linear growth observed in those treated during childhood. In the absence of a specific marker, it is proposed that a combination of clinical response and serum IGF-I levels should be used to monitor the dose, in order to maximize the clinical benefits, whilst minimizing side-effects.

It is unclear how long GH therapy should last. If benefits are being achieved, there is no particular reason to stop treatment. On the other hand, if there are no apparent or objective benefits of treatment after at least 1 year, discontinuing GH therapy may be appropriate (3-5).

Biochemical markers for monitoring GH replacement therapy

Although IGF-I is recognized as the most useful serum marker for GH dose titration in adults, it must be considered that the relationship between serum IGF-I response during GH treatment and other treatment effects such as metabolic endpoints and body composition is poor (31, 54). The serum IGF-I response and the achieved serum IGF-I levels cannot therefore be used as a surrogate marker for other efficacy variables. However, while serum IGF-I can no longer be assumed to reflect the GH effect in all tissues, it remains a useful and important marker to detect over-replacement with GH.

(12)

No data are available regarding dose titration to the ideal target serum IGF-I level (i.e. whether to target the middle or the upper half of the reference range for maximum benefit). The AACE guideline (5) recommend targeting IGF-I to the middle of the age and sex appropriate reference range quoted by the laboratory used (50th percentile or 0 SDS), unless side effects are significant; a trial of a higher dose may be considered to determine whether this provides further benefit,

provided that IGF-I levels remain within the normal range and that the patient does not experience side effects (Figure 1).

Persistence of low or unchanged IGF-I levels despite treatment with adequate rhGH doses is a good measure of poor compliance to the drug regimen and another indication for the use of IGF-I in treatment monitoring.

Adult patients with GHD but normal IGF-I levels remain a therapeutic challenge, as there are few data to help understand whether they benefit from GH therapy and how to monitor therapy in the clinical setting.

Clinical responses as markers for monitoring GH replacement therapy

Treatment guidelines recommend regular assessment of a number of efficacy measurements and safety variables known to be modulated by GH to monitor the effects of treatment. Unlike in pediatric GHD, where the outcome of

treatment is clearly visible (i.e. growth), there is no single optimal marker used to monitor efficacy in adult GHD. As each efficacy measurement is only a crude marker of GH status, the use of several markers is thought to extend the

dimension of normalization in the individual and therefore improve safety during long term replacement (28). In addition, there is no fixed treatment target to attain. Studies often assess efficacy by comparing parameters with pre-treatment values and look for a shift in the right direction, or by comparing values against those for a control group (usually healthy subjects matched for sex, age,

(13)

and BMI), with pretreatment values being significantly lower than in controls and normalizing following GH therapy.

Current guidelines recommend that, once maintenance doses are achieved, objective parameters such as body composition should be used to monitor the response. Body composition can be assessed by anthropometric measurements and also dual-energy X-ray absorptiometry (DXA), which provides a measure of lean mass and fat mass (and is also a tool for assessing bone density). Measurement of bone mineral content and density before starting therapy is also recommended due to the increased risk of patients with adult GHD to develop osteopaenia and osteoporosis. If the initial bone DXA scan is abnormal, repeated scans are recommended at 2–3 year intervals to assess the need for additional bone-treatment modalities (3-5).

In recognition of the increased risk of cardiovascular morbidity and mortality in hypopituitary patients, a number of cardiovascular risk markers may be considered for yearly monitoring, including fasting lipid profile, diastolic blood pressure, and electrocardiogram results. Echo-Doppler assessment of arterial intima-media thickness and heart morphology and function

may also be helpful. Fasting glucose levels should also be monitored yearly because of increased prevalence of obesity and the potential for GH replacement to affect insulin sensitivity in these patients (3-5).

Adults with GHD have diminished QoL, and therefore, it is recommended that a specific questionnaire is administered before the start of treatment and evaluated annually thereafter to ascertain whether there is a change or sustained effect of therapy on QoL (3-5).

Tolerability as a marker for monitoring GH replacement therapy

GH therapy causes an increase in tubular reabsorption of sodium in the distal nephron (54). This is accompanied by an increase in plasma renin activity and decreased brain natriuretic peptide levels (54). Because this change is dependent upon GH dose, higher doses of GH can cause peripheral edema. In one double-blinded, placebo-controlled study, 15% of patients developed edema during a

(14)

12-month treatment period, whereas 3.6% of placebo patients developed this complication (55). The increase in extracellular water observed during GH replacement therapy can also explain some other adverse effects like headache, myalgia, arthralgia, and carpal tunnel syndrome reported by patients treated with higher doses.

Benign intracranial hypertension has been linked to GH treatment in children (56), but only two cases have been reported in adults (56, 57).

Finally, it must be taken into account that GH replacement therapy can interfere with other pituitary deficits or other replacement therapies. In patients with central adrenal failure, initiation of GH treatment may require an increase in hydrocortisone dose (3-5). Furthermore, by accelerating the peripheral metabolism of cortisol, GH therapy may precipitate adrenal insufficiency in susceptible hypopituitary patients (33).

Porretti et al. (58) reported that low doses of GH may unmask the presence of a mild central

hypothyroid state or might even worsen a pre-existing central hypothyroidism, making it necessary to adjust replacement thyroid hormone doses in patients receiving thyroxine replacement.

Safety

rhGH has been in use for 30 years, and over that time its safety has been subject to considerable scrutiny. Regulatory approval of GH treatment for adult GHD was based on placebo-controlled clinical trials of 6 to 12 month duration, each with < 200 patients (59). Because uncommon adverse drug reactions cannot be reliably detected in studies of this size, postmarketing research programs with larger sample sizes have been conducted to expand the safety data for adult GH replacement (26, 60-63). Although such studies have been generally reassuring, usually they have not compared the outcomes of GH- treated and GH-untreated patients in a prospective observational cohort. Such comparison is needed because hypopituitarism itself may increase rates of myocardial infarction, cerebrovascular events, malignancies, and overall mortality (2). Scientific societies have

(15)

recommended additional surveillance for diabetes, tumor recurrence, de novo tumors, and potential unforeseen adverse effects (3-5). Moreover, a recent Position Statement from the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) (64) established that continued surveillance of those exposed to rhGH is essential both during and in the years after treatment and into old age in those who continue therapy.

Risk for tumor recurrence or de novo tumors

There has been theoretical concern that GH replacement therapy and its expected increase in IGF-I levels could lead to the development or regrowth of malignancies or pituitary tumor regrowth/recurrence, but it has been shown that substitution treatment with rhGH does not increase the risk of recurrence of pituitary tumors (63, 65-67), or induce significantly greater onset of de novo cancers (63, 66). Therefore, the presence of a stable remnant of a pituitary tumor is not a contraindication to the substitution treatment with rhGH. In these conditions, a control with appropriate examinations imaging of the pituitary region is recommended, initially after 6 months and yearly thereafter. However, despite the large number of studies that have found no evidence of an increased cancer risk in patients treated with GH, the treatment is contraindicated in the presence of an active malignancy (3-5), because of the serious potential consequences of exacerbating the progression of a malignancy, due to the evidence of an association between increased IGF-I levels and cancer risk in some epidemiological studies (68).

Risk for diabetes

GH may modify glucose metabolism directly or indirectly via induction of IGF-I. GH replacement lowers fat mass, and increasing IGF-I improves insulin sensitivity (69). However, GH also has direct insulin antagonistic effects in the liver and other tissues (70). Insulin clamp studies have shown that when high doses of GH are given, insulin sensitivity acutely deteriorates as a result of increased free fatty acid release and possibly leads to increased intramyocellular triglyceride accumulation (71, 72). Because individual patients have differential sensitivity in these parameters,

(16)

it is not surprising that some show a worsening of insulin sensitivity after administration of GH, whereas others show little changes. In a metaanalysis of blinded, randomized, placebo-controlled trials on the impact of GH treatment on cardiovascular risk factors in GHD adults (73) a significant increase in both insulin and glucose concentrations during GH treatment was observed. However, very few studies with a prolonged follow-up were included in the metaanalysis, and it must be pointed out that in one trial reporting the GH effect on this outcome, deleterious effects on insulin were not maintained at 12 and 18 months (74). An improvement in homeostasis model of

assessment (HOMA) index has been reported in 22 adult GHD patients treated with rhGH for 5 years in comparison with 13 adult GHD untreated subjects (75).

Although GH replacement therapy decreased insulin sensitivity, mild and often transient changes in glucose metabolism have been demonstrated to be associated with GH replacement therapy in adults with GHD when compared with untreated adults with GHD (76). Indeed, the risk of

hyperglycemia and diabetes mellitus in the population of treated GHD is not different from that of the general population and high risk may be present in obese patients only (60).

Mortality

In 2012 Carel et al. (77) reported the initial results of the French cohort of the Safety and

Appropriateness of GH treatments in Europe (SAGhE) study. The study, aimed at evaluating the GH therapy safety profile, examines patients treated with GH for a condition of isolated GHD, idiopathic short stature (ISS) or short stature in children born small for gestational age (SGA). The mortality rates were increased in this population of adults treated as children with recombinant GH, particularly in those who had received the highest doses. Specific effects were detected in terms of death due to bone tumors or cerebral hemorrhage but not for all cancers (77). However, the data was criticized because the expected mortality cases were extracted from the general French population, rather than from untreated short persons with similar diagnoses. This criticism is especially salient as persons born small for gestational age have other known morbidities, and

(17)

persons with idiopathic GHD may have other unknown morbidities. In a subsequent study, data from the SAGhE cohort from Belgium, The Netherlands, and Sweden, demonstrated that the majority of deaths (76%) were caused by accidents or suicides. Importantly, none of the patients died from cancer or from a cardiovascular disease (78). These results highlight the need for

additional studies of long-term mortality and morbidity after GH treatment in childhood. However, in a recent review, four studies investigating the effect of GH treatment on all-cause mortality were described, and no increased mortality was found in men compared to the general population. Women and patients from high-risk groups (i.e. previous craniopharyngioma, Cushing’s disease, malignant causes of hypopituitarism or aggressive tumours) still had a slightly increased risk, but probably lower than in untreated GHD seen in earlier studies. The main cause of increased mortality was cerebrovascular diseases. No risk increase of malignancies was recorded after GH therapy. There was a significant impact of young age at disease onset and of death from secondary brain tumors after conventional cranial radiotherapy (79).

Summary

GH therapy has been shown to be beneficial for many GHD adults. The demonstrated benefits include improvements in body composition, exercise capacity, skeletal integrity, lipid profile, and quality of life. Although it has been suggested that GH treatment may reverse the increased vascular mortality associated with hypopituitarism, this has not been proved yet. Moreover, it should be emphasized that long-term clinical outcome studies on hard endpoints such as fractures, clinical heart disease, cancer, and mortality are still lacking. Dosing should be individualized, with attention to avoidance of side effects. Periodic monitoring will be necessary for both adverse effects and physiological benefits.

(18)

Authors have nothing to declare

References

*1. de Boer H, Blok GJ, Van der Veen EA. Clinical aspects of growth hormone deficiency in adults.

Endocrine Review 1995; 16: 63-86.

*2. Sherlock M, Ayuk J, Tomlinson JW et al. Mortality in patients with pituitary disease. Endocrine

Review 2010; 31: 301-342

*3. Molitch ME, Clemmons DR, Malozowski S et al. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. The Journal of Clinical

Endocrinology and Metabolism 2011; 96: 1587-1609

*4. Ho KK; 2007 GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia.

European Journal of Endocrinology 2007; 157: 695-700

*5. Cook DM, Yuen KC, Biller BM et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients - 2009 update. Endocrine Practice 2009; 15: 1-29

6. Jørgensen JO, Pedersen SA, Thuesen L et al. Beneficial effects of growth hormone treatment in GH-deficient adults. The Lancet 1989; 1: 1221-1225.

7. Salomon F, Cuneo RC, Hesp R, Sönksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency.

(19)

8. Bengtsson BA, Edén S, Lönn L et al. Treatment of adults with growth hormone (GH)deficiency with recombinant human GH. The Journal of Clinical Endocrinology and Metabolism 1993; 76: 309-317

9. Toogood AA, Shalet SM. Growth hormone replacement therapy in the elderly with

hypothalamic-pituitary disease: a dose-finding study. The Journal of Clinical Endocrinology and

Metabolism 1999; 84: 131-136

10. Burman P, Johansson AG, Siegbahn A et al.. Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. The Journal of Clinical Endocrinology and

Metabolism 1997; 82: 550-555

11. Yuen KC, Cook DM, Rumbaugh EE et al. Individual igf-I responsiveness to a fixed regimen of low-dose growth hormone replacement is increased with less variability in obese compared to non-obese adults with severe growth hormone deficiency. Hormone Research 2006; 65: 6-13

12. Wolthers T, Hoffman DM, Nugent AG et al. Oral estrogen antagonizes the metabolic actions of growth hormone in growth hormone-deficient women. American Journal of Physiology

Endocrinology and Metabolism 2001; 281: E1191-1196

13. Birzniece V, Sata A, Ho KK. Growth hormone receptor modulators. Review in Endocrine and

Metabolic Disorder 2009; 10: 145-56

14. Cook DM, Ludlam WH, Cook MB. Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults. The Journal of Clinical Endocrinology

and Metabolism 1999; 84: 3956-3960

15. Janssen YJ, Helmerhorst F, Frölich M, Roelfsema F. A switch from oral (2 mg/day) to

transdermal (50 microg/day) 17beta-estradiol therapy increases serum insulin-like growth factor-I levels in recombinant human growth hormone (GH)-substituted women with GH deficiency. The

(20)

16. Chihara K, Koledova E, Shimatsu A et al. An individualized GH dose regimen for long-term GH treatment in Japanese patients with adult GH deficiency. European Journal of Endocrinology 2005; 153: 57-65

17. Murray RD, Wieringa GE, Lissett CA et al. Low-dose GH replacement improves the adverse lipid profile associated with the adult GH deficiency syndrome. Clinical Endocrinology (Oxf) 2002;

56: 525-532

18. Feldt-Rasmussen U, Brabant G, Maiter D et al. Response to GH treatment in adult GH deficiency is predicted by gender, age, and IGF1 SDS but not by stimulated GH-peak. European

Journal of Endocrinology 2013; 168: 733-743

19. Murray RD, Howell SJ, Lissett CA & Shalet SM. Pre-treatment IGF-I level is the major determinant of GH dosage in adult GH deficiency. Clinical Endocrinology 2000 52: 537–542 20. Verhelst J, Kendall-Taylor P, Erfurth EM et al. Baseline characteristics and response to 2 years of growth hormone (GH) replacement of hypopituitary patients with GH deficiency due to adult-onset craniopharyngioma in comparison with patients with nonfunctioning pituitary adenoma: data from KIMS (Pfizer International Metabolic Database). The Journal of Clinical Endocrinology and

Metabolism 2005; 90: 4636-4643

21. Johannsson G, Sunnerhagen KS, Svensson J. Baseline characteristics and the effects of two years of growth hormone replacement therapy in adults with growth hormone deficiency previously treated for Cushing's disease. Clinical Endocrinology(Oxf) 2004; 60: 550-559

22. Norrman LL, Johannsson G, Sunnerhagen KS, Svensson J. Baseline characteristics and the effects of two years of growth hormone (GH) replacement therapy in adults with GH deficiency previously treated for acromegaly. The Journal of Clinical Endocrinology and Metabolism 2008;

93: 2531-2538

23. van der Klaauw AA, Bax JJ, Roelfsema F et al. Limited effects of growth hormone replacement in patients with GH deficiency during long-term cure of acromegaly. Pituitary 2009; 12: 339-46

(21)

24. de Boer H, Blok GJ, Popp-Snijders C et al. Monitoring of growth hormone replacement therapy in adults, based on measurement of serum markers. The Journal of Clinical Endocrinology and

Metabolism 1996; 81: 1371-1377

25. Hoffman AR, Strasburger CJ, Zagar A et al. Efficacy and tolerability of an individualized dosing regimen for adult growth hormone replacement therapy in comparison with fixed body weight-based dosing. The Journal of Clinical Endocrinology and Metabolism 2004; 89: 3224-3233 26. Abs R, Bengtsson BA, Hernberg-Stâhl E et al. GH replacement in 1034 growth hormone deficient hypopituitary adults: demographic and clinical characteristics, dosing and safety. Clinical

Endocrinology (Oxf) 1999; 50: 703-713

27. Drake WM, Coyte D, Camacho-Hübner C et al. Optimizing growth hormone replacement therapy by dose titration in hypopituitary adults. The Journal of Clinical Endocrinology and

Metabolism 1998; 83: 3913-3919

28. Johannsson G, Rosén T, Bengtsson BA. Individualized dose titration of growth hormone (GH) during GH replacement in hypopituitary adults. Clinical Endocrinology (Oxf)1997; 47: 571-581 29. Janssen YJ, Frölich M, Roelfsema F. A low starting dose of genotropin in growth hormone-deficient adults. The Journal of Clinical Endocrinology and Metabolism 1997; 82: 129-135 30. Holmes SJ, Shalet SM. Which adults develop side-effects of growth hormone replacement?

Clinical Endocrinology (Oxf) 1995; 43: 143-149

31. Johannsson G, Grimby G, Sunnerhagen KS, Bengtsson BA. Two years of growth hormone (GH) treatment increase isometric and isokinetic muscle strength in GH-deficient adults. The

Journal of Clinical Endocrinology and Metabolism 1997; 82: 2877-2884

32. Zadik Z, Chalew SA, McCarter RJ Jr et al. The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. The Journal of Clinical Endocrinology and

(22)

33. Scaroni C, Ceccato F, Rizzati S, Mantero F. Concomitant terapie (glucocorticoids and sex hormones) in adult patients with growth hormone deficiency. Journal of Endocrinological

Investigation 2008; 31: 61-65

34. Mukherjee A, Adams JE, Smethurst L, Shalet SM. Interdependence of lean body mass and total body water, but not quality of life measures, during low dose GH replacement in GH-deficient adults. European Journal of Endocrinology 2005; 153: 661-668

35. Bell W, Davies JS, Evans WD et al. Somatic characteristics and cardiovascular risk factors in growth hormone deficiency: a randomized, double-blind, placebo-controlled study of the effect of treatment with recombinant human growth hormone. American Journal of Human Biology 2004;

16: 533-543

36. Johannsson G, Oscarsson J, Rosén T et al. Effects of 1 year of growth hormone therapy on serum lipoprotein levels in growth hormone-deficient adults. Influence of gender and Apo(a) and ApoE phenotypes. Arteriosclerosis, Thrombosis, and Vascular Biology 1995; 15: 2142-2150 37. Bex M, Abs R, Maiter D et al. The effects of growth hormone replacement therapy on bone metabolism in adult-onset growt hormone deficiency: a 2-year open randomized controlled multicenter trial. Journal of Bone and Mineral Research 2002; 17: 1081-1094

38. Drake WM, Rodríguez-Arnao J, Weaver JU et al. The influence of gender on the short and long-term effects of growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adults: a 5-year study. Clinical Endocrinology (Oxf) 2001; 54: 525-532

39. Sjögren K, Liu JL, Blad K et al. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice.

Proceedings of the National Academy of Sciences of the United States of America 1999; 96:

7088-7092

40. Attanasio AF, Lamberts SW, Matranga AM et al. Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during

(23)

human GH treatment. Adult Growth Hormone Deficiency Study Group. The Journal of Clinical

Endocrinology and Metabolism 1997; 82: 82-88

41. Barbosa EJ, Koranyi J, Filipsson H et al. Models to predict changes in serum IGF1 and body composition in response to GH replacement therapy in GH-deficient adults. European Journal of

Endocrinology 2010; 162: 869–878

42. De Vries WR, Koppeschaar HP, Bol E et al. Intersubject responsiveness of high-affinity growth hormone (GH)-binding protein (GHBP) to long-term GH replacement therapy. Journal of

Endocrinological Investigation 2000; 23: 449–456

43. Johansson AG. Gender difference in growth hormone response in adults. Journal of

Endocrinological Investigation 1999; 22: 58-60.

44. Johannsson G, Rosén T, Bosaeus I et al. Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency. The Journal of Clinical Endocrinology and Metabolism 1996; 81: 2865-2873

45. Murray RD, Skillicorn CJ, Howell SJ et al. Influences on quality of life in GH deficient adults and their effect on response to treatment. Clinical Endocrinology (Oxf)1999; 51: 565-573

46. Jørgensen JO. Human growth hormone replacement therapy: pharmacological and clinical aspects. Endocrine Review 1991; 12: 189-207

47. Laursen T, Jørgensen JO, Christiansen JS. Pharmacokinetics and metabolic effects of growth hormone injected subcutaneously in growth hormone deficient patients: thigh versus abdomen.

Clinical Endocrinology (Oxf) 1994; 40: 373-378.

48. Blok GJ, van der Veen EA, Susgaard S, Larsen F. Influence of concentration and injection volume on the bioavailability of subcutaneous growth hormone: comparison of administration by ordinary syringe and by injection pen. Pharmacology & Toxicology 1991; 68: 355-359

(24)

49. Laursen T, Jørgensen JO, Christiansen JS. Metabolic effects of growth hormone administered subcutaneously once or twice daily to growth hormone deficient adults. Clinical Endocrinology

(Oxf) 1994; 41: 337-343

50. Maiter D, Underwood LE, Maes M et al. Different effects of intermittent and continuous growth hormone (GH) administration on serum somatomedin-C/insulin-like growth factor I and liver GH receptors in hypophysectomized rats. Endocrinology 1988; 123: 1053-1059

51. Laursen T, Gravholt CH, Heickendorff L et al. Long-term effects of continuous subcutaneous infusion versus daily subcutaneous injections of growth hormone (GH) on the insulin-like growth factor system, insulin sensitivity, body composition, and bone and lipoprotein metabolism in GH-deficient adults. The Journal of Clinical Endocrinology and Metabolism 2001; 86: 1222-1228. 52. Amato G, Mazziotti G, Di Somma C et al. Recombinant growth hormone (GH) therapy in GH-deficient adults: a long-term controlled study on daily versus thrice weekly injections. The Journal

of Clinical Endocrinology and Metabolism 2000; 85: 3720-3725.

53. Jørgensen JO, Møller N, Lauritzen T et al. Evening versus morning injections of growth hormone (GH) in GH-deficient patients: effects on 24-hour patterns of circulating hormones and metabolites. The Journal of Clinical Endocrinology and Metabolism 1990; 70: 207-214

54. Johannsson G, Sverrisdóttir YB, Ellegård L et al. GH increases extracellular volume by stimulating sodium reabsorption in the distal nephron and preventing pressure natriuresis. The

Journal of Clinical Endocrinology and Metabolism 2002; 87: 1743-1749

55. Ezzat S, Fear S, Gaillard RC et al. Gender-specific responses of lean body composition and non-gender-specific cardiac function improvement after GH replacement in GH-deficient adults. The

Journal of Clinical Endocrinology and Metabolism 2002; 87: 2725-2733

56. Malozowski S, Tanner LA, Wysowski D, Fleming GA. Growth hormone, insulin-like growth factor I, and benign intracranial hypertension. The New England Journal of Medicine 1993; 329: 665-666

(25)

57. Conway GS, Szarras-Czapnik M, Racz K et al. Treatment for 24 months with recombinant human GH has a beneficial effect on bone mineral density in young adults with childhood-onset GH deficiency. European Journal of Endocrinology 2009; 160: 899-907

58. Porretti S, Giavoli C, Ronchi C et al. Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T(4) therapy become

mandatory? The Journal of Clinical Endocrinology and Metabolism 2002; 87: 2042-2045

59. Simpson H, Savine R, Sönksen P et al. Growth hormone replacement therapy for adults: into the new millennium. Growth Hormone & IGF Research 2002; 12: 1-33

60. Attanasio AF, Jung H, Mo D et al. Prevalence and incidence of diabetes mellitus in adult patients on growth hormone replacement for growth hormone deficiency: a surveillance database analysis. The Journal of Clinical Endocrinology and Metabolism 2011; 96: 2255-2261

61. Spielhagen C, Schwahn C, Möller K et al. The benefit of long-term growth hormone (GH) replacement therapy in hypopituitary adults with GH deficiency: results of the German KIMS database. Growth Hormone & IGF Research 2011; 21: 1-10

62. Child CJ, Zimmermann AG, Woodmansee WW et al. Assessment of primary cancers in GH-treated adult hypopituitary patients: an analysis from the Hypopituitary Control and Complications Study. European Journal of Endocrinology 2011; 165: 217-223

63. Hartman ML, Xu R, Crowe BJ et al. Prospective safety surveillance of GH-deficient adults: comparison of GH-treated vs untreated patients. The Journal of Clinical Endocrinology and

Metabolism 2013; 98: 980-988

*64. Allen DB, Backeljauw P, Bidlingmaier M et al. GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults. European Journal of

Endocrinology 2015; 174: P1-P9

*65. Shen L, Sun CM, Li XT et al. Growth hormone therapy and risk of recurrence/progression in intracranial tumors: a meta-analysis. Neurological Sciences 2015; 36: 1859-1867

(26)

*66. Child CJ, Conroy D, Zimmermann AG et al. Incidence of primary cancers and intracranial tumour recurrences in GH-treated and untreated adult hypopituitary patients: analyses from the Hypopituitary Control and Complications Study. European Journal of Endocrinology 2015; 172: 779-790.

67. van Varsseveld NC, van Bunderen CC, Franken AA et al. Tumor Recurrence or Regrowth in Adults With Nonfunctioning Pituitary Adenomas Using GH Replacement Therapy. The Journal of

Clinical Endocrinology and Metabolism 2015; 100: 3132-3139

68. Jenkins PJ, Mukherjee A, Shalet SM. Does growth hormone cause cancer? Clinical

Endocrinology (Oxf) 2006; 64: 115-121.

69. Clemmons DR. The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity. The Journal of Clinical Investigation 2004; 113: 25-27

70. Cutfield WS, Wilton P, Bennmarker H et al. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. The Lancet 2000; 355: 610-613.

71. Svensson J, Fowelin J, Landin K et al. Effects of seven years of GH-replacement therapy on insulin sensitivity in GH-deficient adults. The Journal of Clinical Endocrinology and Metabolism 2002; 87: 2121-2127.

72. Yuen K, Cook D, Ong K et al. The metabolic effects of short-term administration of

physiological versus high doses of GH therapy in GH deficient adults. Clinical Endocrinol (Oxf) 2002; 57: 333-341

73. Maison P, Griffin S, Nicoue-Beglah M et al. Metaanalysis of Blinded, Randomized, Placebo-Controlled Trials. Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a Metaanalysis of Blinded, Randomized, Placebo-Controlled Trials. The Journal of

(27)

74. Sesmilo G, Biller BM, Llevadot J et al. Effects of growth hormone administration on

inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Annals of Internal Medicine 2000; 133: 111-22

75. Colao A, Di Somma C, Spiezia S et al. Growth hormone treatment on atherosclerosis: results of a 5-year open, prospective, controlled study in male patients with severe growth hormone

deficiency. The Journal of Clinical Endocrinology and Metabolism 2008; 93: 3416-3424

76. Woodmansee WW, Hartman ML, Lamberts SW et al. Occurrence of impaired fasting glucose in GH-deficient adults receiving GH replacement compared with untreated subjects. Clinical

Endocrinology (Oxf) 2010; 72: 59-69

77. Carel JC, Ecosse E, Landier F et al. Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. The Journal of Clinical Endocrinology and Metabolism 2012; 97: 416-425.

78. Sävendahl L, Maes M, Albertsson-Wikland K et al. Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE study. The Journal of Clinical Endocrinology and Metabolism 2012; 97: E213-217

*79. Erfurth EM. Update in mortality in GH-treated patients. The Journal of Clinical

(28)

Practice Points

-GH dosing regimens should be individualized rather than weight-based, starting with low doses and titrating according to clinical response, side effects, and IGF-I levels.

-GH therapy in GHD adults offers significant clinical benefits in body composition and exercise capacity, skeletal integrity and QoL. Moreover GH therapy improves several cardiovascular surrogate outcomes, including endothelial function, inflammatory cardiovascular biomarkers, lipoprotein metabolism, carotid intima-media thickness, and aspects of myocardial function.

However, to date, rhGH therapy has not been shown to improve the increased mortality observed in patients with hypopituitarism and GHD.

-Treatment with rhGH in adults with GHD has generally been regarded as being quite safe,

although concerns regarding the potential for cancer risk and tumor regrowth remain. Although GH treatment decreases insulin sensitivity, the worsening of glycemic control has in general been minimal or transient.

Research agenda

-Large and thoroughly conducted observational studies are needed to inform the ongoing debate on health care costs, drug safety and clinical outcomes.

-Adult patients with GHD but normal IGF-I levels remain a therapeutic challenge. Studies are needed to clarify whether these patients benefit from GH therapy and how to monitor therapy in the clinical setting.

-Studies are needed to clarify the best dose titration in the transition age that can optimize not only linear growth potential and final adult height, but also improve peak bone mass, body composition, behavior, psychosexual function, and QoL

(29)

Table 1 Current guidelines on the starting dose of rhGH in adult GHD patients

Scientific Society (reference)

Recommended starting dose

GRS (4)  Young men and women: 0.2 and 0.3 mg/day respectively.  Older individuals: 0.1 mg/day

AACE (5)  Age < 30 years: 0.4–0.5 mg/day (may be higher for patients transitioning from pediatric treatment)

 Age 30–60 years: 0.2–0.3 mg/day  Age > 60 years: 0.1–0.2 mg/day

 Use lower GH doses (0.1–0.2 mg/day) in all patients with diabetes or who are susceptible to glucose intolerance

ES (3)  Age < 30 years: 0.4–0.5 mg/day (may be higher for patients transitioning from paediatric treatment)

 Age 30–60 years: 0.2–0.3 mg/day  Age > 60 years: 0.1–0.2 mg/day GRS: Growth Hormone Research Society

AACE: American Association of Clinical Endocrinologists ES: Endocrine Society

(30)

Riferimenti

Documenti correlati

In 2001, Read and co-workers reported the complex between hLDH5 and 1 [14]; in this structure, the ligand strongly interacted with R169; the enzyme showed a closed conformation,

Nel caso di una bad bank si potrebbe registrare una mala gestione delle attività deteriorate allo scopo di ottenere benefici privati, rischiando così di danneggiare non solo lo

maniera assoluta la dissociazione del vapore d’acqua e dell’anidride carbonica, non avendo cosi’ sottrazione di calore. Stessa premura si e’ avuta nella determinazione

Art. I minori stranieri non accompagnati sono titolari dei diritti in materia di protezione dei minori a parità di trattamento con i minori di cittadinanza italiana o dell'Unione

Obiettivi di questo studio: valutare il ruolo di TMZ negli ependimomi intracranici recidivanti dell'adulto, con particolare riferimento al response rate (RR), alla

Come  conciliare  queste  informazioni?  Do ori  sostiene  che  il  Diario Ordinario offre un «imprecise account», forse tra

B, Cyto-fluorimetric analysis of total erythroid precursors from the bone marrow of WT and Fyn −/− mice using the following surface markers: CD71 and Ter119 (see also the