Preamble
This is an invited debate between the three authors, who present their opinions in two separate sections. The first section is authored by Jens O L Jorgensen and Gudmundur Johannsson both of whom recommend GH replacement (pro), whereas Ariel Barkan, who authors the second section, is against (contra).
Pro (J O L Jørgensen and G Johannsson)
‘Against stupidity, the gods themselves battle in vain.’ (From The Maid of Orleans, a tragedy by Friedrich Schiller)
‘My mind is made up. Don’t confuse me with the facts.’ (Uncertain origin)
Introduction
Pituitary human growth hormone (GH) was isolated 75 years ago (1), and its protein anabolic and fat catabolic effects were studied soon thereafter (2, 3, 4). Another significant leap forward was the development of a GH RIA that enabled characterization of the endogenous secretory pattern. Most of the underlying studies involved adolescent and adult subjects including patients with hypopituitarism, so the notion that GH plays a role beyond stimulation of longitudinal growth in children is that old. The supply of GH for therapeutic use was however extremely limited until the advent of biosynthetic GH in the mid-1980s, which prompted the first, randomized clinical trials of GH replacement in adult GH-deficiency (GHDA) (5, 6).
The pivotal trials and beyond
The first placebo-controlled trial was investigator-initiated and included adults with childhood-onset GHD and reported a GH-induced significant increase in muscle volume and reduction in fat volume accompanied by a significant increase in exercise capacity (5). Additional publications from the same trial revealed that GH replacement increased bone turnover (7, 8) and the extra-thyroidal conversion of T4 to T3 (9) and restored normal sweating capacity (10). The favorable changes in body composition and physical fitness prevailed during continued open GH replacement for 3 years (11, 12). The second placebo-controlled trial (6) comprised patients with adult-onset GHD and reported a significant increase in lean body mass (LBM) together with a significant reduction in fat mass. This was associated with an increase in resting energy expenditure, and data from the same study reported beneficial effects of GH replacement on exercise capacity and hyperlipidemia (13, 14, 15).
The term ‘syndrome’ was used to describe the emerging clinical picture of GHDA (16), which was substantiated by studies of the clinical features of the treatment-naïve patient (17, 18, 19). This accompanied numerous new treatment trials reporting reductions of almost 30% in visceral fat mass (20, 21, 22) and important cardiovascular effects such as reduced peripheral vascular resistance and increased cardiac output (23, 24, 25, 26, 27).
GH-untreated patients with hypopituitarism have an increased overall mortality (28, 29, 30, 31, 32). The annual incidence and prevalence of GHDA are approximately 15/million and 250/million, respectively (33). The symptoms and signs include fatigue, reduced muscle strength and exercise capacity, visceral obesity, hyperlipidemia, and premature cardiovascular disease (28, 34). Untreated GHDA is also accompanied by reduced extracellular fluid volume (17) that reverses by replacement (35, 36, 37, 38), and impaired thermoregulation (39, 40, 41) is also present and linked to reduced sweating capacity (10).
GH antagonizes the effects of insulin on glucose metabolism, and increased insulin sensitivity with fasting hypoglycemia is a salient feature of childhood GHD (42, 43). The opposite is true for active acromegaly (44). This effect of GH is rapidly reversible (45) and operates in normal physiology when insulin activity is low (4, 46). However, the prolonged biological half-life of daily subcutaneous GH injections do not resemble the endogenous GH pattern (47) and therefore induce moderate insulin resistance (46) despite favorable changes in body composition (48).
The annual number of GHDA publications increased exponentially from 2 in 1989 to >200 in 1999 (49) including dose-finding studies in different age groups (50, 51, 52), and it was confirmed that adult patients are highly sensitive to GH (53) and that male patients are more responsive to GH as compared to females (54, 55). Collectively, this translated into guidelines for the clinical management of GHDA issued by the Growth Hormone Research Society (56) and approval of the indication by the European Union in 1994. Subsequently, meta-analyses of published data on adult GH replacement have been published on outcomes such as cardiovascular risk factors (48), physical fitness (57, 58), bone mineral density (59, 60), body composition (61), and cardiac function (62). The meta-analyses confirm and substantiate both the numerous beneficial effects of GH replacement and the mild adverse effects attributable to fluid retention and insulin resistance (48, 61) (Fig. 1).
Body composition and exercise capacity in GH-deficient adults before (0) and after (12) 1-year GH replacement or placebo. An untreated group of age- and sex-matched healthy subjects (control) underwent assessment of visceral and subcutaneous fat (22). The figure is modifed from the original publication (Copyright 1996, John Wiley and Sons).
Citation: European Journal of Endocrinology 186, 1; 10.1530/EJE-21-0534
Body composition and exercise capacity in GH-deficient adults before (0) and after (12) 1-year GH replacement or placebo. An untreated group of age- and sex-matched healthy subjects (control) underwent assessment of visceral and subcutaneous fat (22). The figure is modifed from the original publication (Copyright 1996, John Wiley and Sons).
Citation: European Journal of Endocrinology 186, 1; 10.1530/EJE-21-0534
Body composition and exercise capacity in GH-deficient adults before (0) and after (12) 1-year GH replacement or placebo. An untreated group of age- and sex-matched healthy subjects (control) underwent assessment of visceral and subcutaneous fat (22). The figure is modifed from the original publication (Copyright 1996, John Wiley and Sons).
Citation: European Journal of Endocrinology 186, 1; 10.1530/EJE-21-0534
As regards bone health, data from placebo-controlled trials for up to 1 year recorded increased bone turnover but unchanged or even reduced bone mass was observed (63), whereas a study of 18 months observed a significant increase in bone mineral density (BMD) (64). GH replacement initially increases bone remodeling and thereby reduces BMD followed by a moderate but sustained increase in BMD (59). It is uncertain if this reduces the risk of osteoporotic fractures, but observational studies suggest this to be the case (65).
It is less certain if GH replacement therapy improves the quality of life (QoL), since neither original studies nor meta-analyses provide unambiguous answers (61, 66, 67, 68). Most QoL studies depend on questionnaires, which mainly record the patient’s remembrance and not day-to-day experiences in real time. Of note, the most convincing beneficial effects of adult GH replacement on QoL occurred in a placebo-controlled crossover study based on the response from the spouse of the patient (69). In addition, a double-blind placebo-controlled trial showed that discontinuation of long-term GH replacement reduces QoL (70). During GH replacement, both GH and insulin-like growth factor 1 (IGF-I) levels increase in the cerebrospinal fluid (71), and a placebo-controlled trial showed improved cognitive function after GH treatment (72). It is also noteworthy that the majority of the patients stay on GH replacement, which could indicate that the tools to measure quality of life and well-being do not capture the patient’s self-perceived effect of treatment (73, 74).
It has been hypothesized that the phenotype of adult GHDA largely is mainly accounted for by suboptimal glucocorticoid replacement of concomitant secondary adrenal insufficiency. A contributing effect may be that GHD is associated with increased activity of the enzyme that enhances the conversion of inactive cortisone to active cortisol and this activity is suppressed by GH and IGF-I (75). However, the phenotype of hydrocortisone-replaced patients with primary adrenal insufficiency differs markedly from that of hypopituitarism and does not include either obesity or hypertension (76). Along the same line, a large observational study of adult GH replacement therapy recorded comparable treatment response in patients with isolated GHD and patients with multiple pituitary deficits, respectively, which supports that the phenotype described in GHD hypopituitary patients relates to unreplaced GH (77).
Endogenous GH production and serum IGF-I levels decline with age (78) paralleled by the senescent changes in body composition and physical performance. Notwithstanding this, patients aged 60–80 years with documented pan hypopituitarism exhibit reduced age-corrected GH levels (79) and respond to GH replacement in much the same manner as younger patients (80, 81, 82). However, the GH dose requirement declines with age (Fig. 2).
Meta-analysis of published studies reporting mortality (SMR) in hypopituitary adults with and without GH replacement (97) (Copyright 2018, YS Medical Media Ltd). The analysis is an extension of a previous meta-analysis (83).
Citation: European Journal of Endocrinology 186, 1; 10.1530/EJE-21-0534
Meta-analysis of published studies reporting mortality (SMR) in hypopituitary adults with and without GH replacement (97) (Copyright 2018, YS Medical Media Ltd). The analysis is an extension of a previous meta-analysis (83).
Citation: European Journal of Endocrinology 186, 1; 10.1530/EJE-21-0534
Meta-analysis of published studies reporting mortality (SMR) in hypopituitary adults with and without GH replacement (97) (Copyright 2018, YS Medical Media Ltd). The analysis is an extension of a previous meta-analysis (83).
Citation: European Journal of Endocrinology 186, 1; 10.1530/EJE-21-0534
Mortality
Increased mortality in hypopituitary patients due to cardiovascular disease is undisputed but the role of GH in this is not (28, 83). Alternative or additional causes include the underlying disease and its treatment as well as suboptimal substitution of additional pituitary deficiencies. In addition, mortality and cancer incidence are increased in acromegaly (84, 85) and epidemiological studies reveal a U-shaped association between serum IGF-I levels and all-cause mortality in the general population (86). Randomized studies of GH replacement therapy with mortality as an endpoint do not exist for good reasons, but observational studies show that mortality is reduced in GH-replaced patients as compared to GH-untreated patients (83, 87, 88, 89, 90, 91) (Fig. 2).
Conclusion
GH replacement in GHDA is by a long chalk the most well-documented therapeutic indication in pituitary endocrinology in terms of placebo-controlled trials and post-marketing surveillance studies. The healthy change in body composition in terms of reduced fat mass, in particular abdominal fat, and increased LBM is perhaps the most robust effect. A proportion of the increase in LBM is due to increased hydration, but hydration-independent measurements such as total body potassium and total body nitrogen support an increase in protein content (20).
Most studies also record improvements in bone health, physical fitness and cardiac function. An improvement in QoL is shown in many but not in all studies, but QoL is inherently difficult to measure. The level of education is similar among GH-treated adult patients as compared to the background population, but a higher proportion of the patients are unemployed, retire earlier and are less likely to live with a partner (87, 92). These socioeconomic outcomes demonstrate that hypopituitarism remains a clinical challenge, and improved and optimized treatment options are needed for these patients.
Cancer risk is not increased with long-term GH replacement (93), and mortality is reduced (87, 88) (Fig. 2). The latter observation is very reassuring even though selection bias and overall improved care in specialized centers are likely contributors. Side effects in terms of fluid retention and impaired insulin sensitivity do occur, but they are benign, dose-dependent and rapidly reversible. Still, it is important to avoid overtreatment. The daily GH dose requirement to avoid supernormal IGF-I levels and side effects is 0.1 mg or lower in male patients aged above 70 years, which is only 10% of the dose used in the early adult trials. Careful dose titration guided by serum IGF-I concentration and clinical response is needed in order to obtain the best possible efficacy and to ensure long-term safety of treatment.
Taken together, not even the devil’s advocate should be able to turn the case around and persuade any sensible jury to disregard either the negative consequences of GHD or the positive effects of GH replacement in adult hypopituitary patients.
Is it necessary to argue for adult GH replacement 25 years after its approval? No, because the facts in favor of adult GH replacement are overwhelming, and yes, because barriers to the treatment still exist, as recently documented by the European Society of Endocrinology survey (94). The reasons for continued reluctance are probably manifold, of which lack of reimbursement is a major one. Another argument against adult GH replacement may be the risk of overtreatment because acromegaly is a serious disease with excess mortality. Should this line of argumentation then also apply to replacement therapy with hydrocortisone and levothyroxine? Finally, the fact that GH is administered as a daily injection rather than an (inexpensive) tablet is undoubtedly a treatment obstacle, which may be alleviated with long-acting GH preparations (95). The above-mentioned barriers to treatment therefore prevent many adult patients with hypopituitarism and severe GHD to receive GH replacement therapy.
The indication is not to be confused with the unlicensed use of GH as an antiaging treatment. The effect of GH in this regard is unproven and probably hazardous (96).
The first anecdotal report of GH treatment of a hypopituitary adult patient in 1962 concluded that ‘observations will be needed in more cases to indicate whether the favorable effect was more than coincidental’ (3). Today, it is safe to reply that observations from numerous placebo-controlled trials confirm beneficial effects and justify the treatment. We rest our case.
Contra (A Barkan)
‘… a beautiful hypothesis slain by an ugly fact’ (Thomas Henry Huxley)
GHD leads to short stature when it is of a congenital or a prepubertal nature. Treatment with exogenous GH improves final growth and is unquestionably indicated. However, GH impoverishment of aging or the use of GH for improvement of athletic performance is illegal, and GH administration is not approved for those indications.
In this short review, we shall concentrate on the indications for GH administration to adults with documented GHD as a consequence of hypothalamic-pituitary diseases.
The story begins with two papers from Sweden claiming GHD as a proximal cause of increased cardiovascular mortality in patients with hypopituitarism (28, 30). Subsequently, multiple studies have looked at other potential effects of GHD in adults and a new syndrome was described: adult-onset GHD (AO-GHD). It allegedly consisted of generalized weakness, fatigue, obesity, decreased muscle mass, strength and endurance, premature atherosclerosis, osteoporosis and diminished QoL. All these findings were automatically attributed to GHD since all other hormonal deficits were presumably correctly replaced, and treatment of GHD with exogenous GH was reported to have salutary effects on all of them.
In this short review, we shall critically discuss potential reasons for substituting GH in AO-GHD based on controlled studies.
Does GHD increase mortality?
In all animal models studied thus far, GHD was actually associated with the increased (by 20–70%) longevity (98). Increased cerebrovascular mortality was one of the most important arguments in favor of GH replacement in hypopituitary individuals (30) and was noticed in subsequent analyses by other groups. However, an autopsy study by Kaji et al. (99) in patients with hypopituitarism demonstrated an approximately two-fold increase in cerebrovascular disease (with four- to five-fold increase in cerebral hemorrhage) but paradoxically, a two- to four-fold decrease in all heart diseases and no difference in ischemic heart disease from the general population. The mechanism whereby GHD would differentially affect coronary and cerebral arteries is unknown and puzzling: it suggests that some other factor(s) might have been involved. The answer came from two large epidemiological studies involving large numbers of hypopituitary patients. In a study by Tomlinson et al. (29) involving 1014 hypopituitary patients from the West Midlands, increased mortality was associated with age, sex, diagnosis of craniopharyngioma, unsubstituted hypogonadism and history of cranial radiation. Jasim et al. (100) performed meta-analysis of 12 studies published between 1996 and 2015 that reported on a total of 23,515 patients with hypopituitarism. Risk factors for increased mortality fully confirmed conclusions by Tomlinson et al. (29) but revealed some additional connections (likely due to an ~23-fold higher number of patients): younger age at diagnosis, transcranial surgery and diabetes insipidus. Remarkably, neither of these reports found any connection between increased mortality and GHD as such. Cranial radiation is a known promoter of cerebrovascular morbidity and mortality (101, 102, 103), in particular cerebral hemorrhage, fully explaining the data of Kaji et al. (99). The meta-analysis by Pappachan et al. (83) has found improvement of mortality risk with GH replacement, but the authors openly admitted that it might have been due to the potential selection bias introduced by the post-marketing surveillance of commercial databases without an untreated control group. In a study by Lindholm et al. (104), mortality rates in patients with normal pituitary function and hypopituitarism after surgery for nonfunctioning pituitary adenomas were not different from those in the general population and treatment with GH of GH-deficient patients did not influence survival. Van Bunderen et al. (90) confirmed this conclusion. Then, we should necessarily ask a question: If it is not GHD that causes increased mortality in patients with hypopituitarism, what causes it? At least two studies provided an answer: excessive replacement with glucocorticoids. The study by Hammarstrand et al. (105), in which one of my opponents was a co-author, found that daily hydrocortisone equivalent dose > 20 mg increased mortality rate in patients with hypopituitarssm to 1.42 vs the expected 1, whereas daily doses < 20 mg maintained normal mortality rate of 0.88. In a more detailed study, Zueger et al. (106) had shown that patients on <20 mg hydrocortisone daily had a mortality rate of 1 vs those on no glucocorticoid replacement but did demonstrate increased mortality rates to 2.62 in those on 20–29 mg/daily and to 4.56 on >30 mg/daily. The case for glucocorticoid replacement seems to be clear. But does it mean that GHD or GH replacement does not play any role at all? That takes us into the relatively new field: metabolism of cortisol and its GH regulation. Hydrocortisone (cortisol) may exert its mineralocorticoid potential at the kidneys by inducing hypertension and hypokalemia in all of us. Luckily, kidneys express an enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta HSD- 2) that converts cortisol into the biologically inactive cortisone and protects the kidneys. Renal-generated cortisone reaches abdominal fat and liver and is regenerated there into active cortisol by 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD-1). GH inhibits and GHD stimulates the latter enzyme (107). Thus, hypopituitary GHD patients may be exposed to a double hit: overdose of glucocorticoid replacement (especially in the older studies) and increased 11-beta HSD-1 induced regeneration of inactive cortisone into cortisol, resulting in a ‘Cushing’s-like phenotype’: increased mortality, metabolic syndrome with hyperglycemia and insulin resistance, abdominal obesity, osteoporosis and neuropsychiatric abnormalities that so suspiciously overlap with the current description of AD-GHD (for detail see below). In those patients, administration of GH inhibits 11-beta-HSD-1 and mitigates at least partially the deleterious effects of glucocorticoid overdose (107).
What should any sane and non-biased physician choose: decrease the dose of glucocorticoids or add daily injections of expensive GH to mitigate the glucocorticoid-related side effects? In any other clinical situation involving other drugs, we sensibly choose the former approach. Why do some of us choose the ‘bass ackwards’ one is a mystery.
Recently, attention was drawn to the possibility that congenital IGF-1 deficiency, whether due to GH receptor defects (Laron’s syndrome) or to primary GH deficiency may confer protection from the development of malignant diseases (108). Indeed, no cases of any malignant diseases were found among homozygous patients with Laron’s syndrome (prevalence 0%), whereas 18 cases were found among their 218 first-degree relatives (prevalence 8.25%) and 25 among 113 further relatives (prevalence 22.1%). Among all patients with congenital GHD (isolated GHD, multiple hormone deficiencies, GHRH receptor mutations), cancers were found in 2.3%; in their first-degree relatives of comparable mean age, it was 7.4% and in further relatives 33% (108).
What about patients treated with GH? One study (109) did find an increased risk of second neoplasm in children treated with GH but that had not been confirmed by other reports (110). Child et al. (111) did not find an increased incidence of cancer in adults with GHD treated with GH.
In summary, hypopituitarism is associated with increased mortality rates, the causes of which are not associated with GHD but are due to age, sex, the diagnosis of primary illness (e.g. craniopharyngioma), glucocorticoid replacement dose and therapeutic interventions (e.g. cranial radiation). There is no convincing evidence that treatment of GHD improves mortality rates and this is not surprising: no abovementioned major causes of increased mortality (craniopharyngioma, radiation therapy etc.) can even theoretically be influenced by GH replacement. On the other hand, there is no evidence that treatment of GHD induces second malignancies, which is encouraging. However, vigilant follow up of treated cases needs to be continued: we may have not yet reached the point where such cases start showing up. In short, GH replacement in AO-GHD for the purpose of lowering mortality rate seems at the present time to be a reasonably benign but useless intervention that has neither negative nor positive influence on the mortality rate, the allegedly major consequence of hypopituitarism (28, 30).
Body composition and metabolic consequences
The most consistent effect of GH administration in patients with GHD is a decrease in fat mass (74), with a magnitude of about 2 kg after 6 months. Fat mass does not increase further over time and reverts to baseline with discontinuation of GH therapy (112). One would naturally expect it to be followed by an improvement in metabolic syndrome, hyperlipidemia and glucose handling.
In several trials (113, 114, 115), GH replacement did not improve the prevalence of metabolic syndrome but resulted in statistically significant increases in blood pressure and fasting blood glucose; ultimately, no change in metabolic syndrome was seen after 3 years of GH therapy (115).
Physiologically, GH causes insulin resistance (116) and is a ‘hyperglycemic’ hormone. Thus, it would be unexpected to see its administration to be accompanied by lowering plasma glucose. Indeed, all studies reported either elevation of glucose sometimes to the point of frank diabetes (117, 118) or just insulin resistance (70, 119). There are no data showing GH-induced loss of fat ameliorating insulin resistance and/or improving diabetes.
The data on plasma lipids are also inconsistent. Sesmilo et al. (119) reported rapid (3 months) improvements in plasma lipids after initiation of GH replacement in AO-GHD patients, but their levels returned to baseline from month 6 to month 18 of treatment. In a meta-analysis of 37 blinded, randomized, placebo-controlled studies, GH replacement was reported to reduce LDL and total cholesterol in half the studies and had no effect in the others (48). HypoCCS data showed an increased incidence of diabetes compared to background population in the GH-treated cohorts in the United States and Sweden but not in France or Germany (117). GH treatment decreased inflammatory markers (such as C-reactive protein, interleukin-6, TNF-α), as well as carotid intima-media thickness, a predictor of coronary disease (120). But GH replacement was also reported to increase plasma concentrations of lipoprotein A, an independent marker of cardiovascular risk (119). There are also data suggesting that the cause of abnormal body composition and metabolic abnormalities in AO-GHD patients and their improvement with GH therapy is ultimately related not to GHD or its correction but rather to overtreatment with glucocorticoids (107). Indeed, KIGS-KIMS database showed that all these parameters were proportionate to the dose of glucocorticoid replacement and that patients taking less than 20 mg of hydrocortisone daily had no manifestations of metabolic syndrome in excess of the ACTH-sufficient group (114). In addition, GHD has been shown to enhance regeneration of cortisol from cortisone by increasing 11β-HSD type 1 activity (107). The combination of supraphysiological glucocorticoid dosages and GHD-induced increased cortisol generation from cortisone results in excessive cortisol exposure in patients with hypopituitarism treated with what was considered in the past as appropriate doses of hydrocortisone (48). Swords et al. (121) showed that administration of GH to glucocorticoid-treated hypopituitary adults markedly lowered their plasma cortisol milieu. If this hypothesis is true, then just a decrease of hydrocortisone replacement dose from the previously used 25–35 mg/day to the currently employed one of 10–20 mg/day may be effective in improving metabolic parameters. Indeed, Danilowicz et al. (122) found that just a decrease of hydrocortisone dose from the supraphysiological 35 mg per day to the currently accepted 15 mg per day for 6–12 months resulted in major body fat loss (7.1 kg of total body fat, 4.1 kg of abdominal body fat), with a trend toward increased LBM, major declines in total cholesterol and triglycerides and improvement in the QoL in those with poor values. Additionally, if the goal of GH replacement is normalization of plasma lipid profiles, the use of widely available cheap oral medications might be sufficient. Monson et al. (123) had shown that even older statins (pravastatin, lovastatin, simvastatin, atorvastatin and fluvastatin) were equally or even more effective than GH in normalizing plasma lipids and had no ‘escape’ feature (119). There are no similar studies comparing GH with rosuvastatin, the most effective preparation from that group.
One may only wonder why should we give GH (with its diabetogenic property and other negative manifestations) to hypopituitary patients with metabolic syndrome rather than lower their inappropriately high hydrocortisone doses and/or add oral, equally or more effective, and infinitely cheaper HMG CoA reductase inhibitor (statin) therapy.
Muscle mass and function
GH therapy has been associated with a measured increase in LBM, but this is not due to an increase in muscle fiber mass but rather due to accumulation of water in extracellular fluid, as GH increases sodium reabsorption and plasma renin activity (124). Open-label studies found improvements in one muscle group strength but no improvement in others (125). In a randomized, placebo-controlled crossover trial, 60 patients who had received GH therapy for more than 3 years were assigned to continue GH or placebo for 4 months. The placebo group had decreased measured thigh muscle mass (likely due to water loss) but without change in muscle strength (126). A 2-year double-blind randomized trial in GHD adolescents transitioning to adulthood did not find a statistically significant change in treadmill exercise tolerance (70). Studies in other human models fully support lack of the GH effect on physical performance. GH administration to athletes increased their fat-free mass but had no influence on their physical performance (127, 128, 129). Similarly, in GH-impoverished elderly men, administration of GH decreased their body fat content and increased muscle mass but had no effect on their functional performance (130). In a GH excess model, acromegaly, muscle mass is increased, but muscle strength and endurance are diminished (131).
Thus, there is no convincing evidence that GH improves physical performance in humans across a wide spectrum of clinical situations. The GH-induced loss of subcutaneous fat allows water-swollen muscles to stand out in sharper relief. That may explain the popularity of GH among bodybuilders.
Bone health
Patients with hypopituitarism have an increased incidence of low bone density. However, in and by itself, low bone density becomes clinically important only when it leads to bone fractures that is the real marker of any therapeutic success or failure. It is uncertain, however, whether the rate of bone fractures is due to GH deficiency or improper replacement of other pituitary hormones such as undertreatment with gonadal steroids or overtreatment with glucocorticoids and/or thyroxine (132, 133, 134). Also, the etiology of hypopituitarism seems to play a role: in AO-GHD patients with previous acromegaly, treatment with GH inexplicably increased fracture rate after more than 6 years of therapy, while in those with previous diagnoses of nonfunctioning adenoma or Cushing disease, it remained stable (135). However, overall GH appears to increase bone density mildly to modestly and lowers fracture rate in patients without pre-existing osteoporosis and without radiological risk of fractures but was ineffective in patients with osteoporosis, that is, the group with a high risk of fractures, the very same group we worry about and treat with GH (65).
The question arises, whether standard therapy of osteoporosis with antiresorptive medications, denosumab or PTH analogs might be more effective than GH. Unfortunately, this information is by and large lacking. There are only two small studies in which alendronate was added to the GH regimen (136, 137). In both of them, alendronate significantly potentiated effects of GH, indicating that they work by separate mechanisms and that a study of alendronate alone and/or other anti-osteoporosis drugs may be justified.
Quality of Life (QoL)
QoL is a subjective and self-reported patient’s view of his/her general well-being. Multiple studies have claimed low QoL in hypopituitary patients and its improvement with GH replacement. However, most of them were done in an open-label fashion and thus were subject to a placebo effect. Therefore, we have performed a search for placebo-controlled studies. The only exclusion criteria were: duration of treatment < 6 months and the number of subjects involved being less than ten. Fourteen such studies were identified (20, 21, 53, 69, 112, 127, 138, 139, 140, 141, 142, 143, 144, 145), involving a total of 908 patients and employing a total of 25 psychological tests in different combinations. In ten studies, employing one to six different tests, the results of all tests were indistinguishable between GH and placebo. In four studies, six tests showed GH being better than placebo, five tests showed GH being equal to placebo and four tests showed that placebo was more effective than GH. In total, 37 tests showed that GH was equal to placebo, 6 that GH was better than placebo and 4 that placebo was better than GH. There were occasional disagreements between the studies on the outcomes of the same test. For example, NHP energy health domain favored GH in 2 studies involving 148 and 32 subjects, but no difference was found in 2 other studies, involving 36 and 40 subjects, and there was a better effect of placebo in the largest group with 163 patients.
Overall, these results obtained in a properly performed placebo-controlled fashion demonstrate convincingly that the administration of GH for the correction of abnormal QoL, the only approved indication for GH use by the British National Institute of Clinical Excellence (NICE) and by many medical insurance companies in the United States, differs from placebo in only one aspect: the price.
Well, that may not be exactly true: a large study involving 2737 hypopituitary patients based on Pfizer’s KIMS database (146) showed that there was a linear relation between higher daily hydrocortisone dose and decline in QoL. In a population of 194 patients with primary adrenal insufficiency and 140 patients with secondary adrenal insufficiency due to hypopituitarism, Bleicken et al. (147) showed the deleterious effects on QoL of hydrocortisone doses greater than 30 mg per day with no difference observed between the addisonian and hypopituitary groups. Normal QoL was observed in severely GH-deficient patients (two to four pituitary deficiencies and pathologically low IGF-1) who did not have pituitary radiation and took an average of 15 mg hydrocortisone daily (148). Swords et al. (121) have shown that GH administration to AO-GHD patients on hydrocortisone replacement lowers plasma cortisol milieu, a known predictor of neuropsychological distress.
Thus, again one can make a choice: to keep a hypopituitary patient with poor QoL on a high dose of hydrocortisone and add daily injections of GH to inhibit 11-β-HSD type 1 or just lower hydrocortisone to <20 mg/day. The answer appears to be certain.
The study by Miller et al. (149) stands apart: in a double-blinded placebo-controlled study, it has shown improved QoL in patients with GHD post-cure of acromegaly who were treated with GH. The mechanism of that is unknown, and van der Klaaw et al. (150) did not find any effects of GH replacement on QoL in patients with acromegaly rendered GH-deficient by surgery and radiation. The same group had previously shown that low physical and psychological QoL in patients with acromegaly depends on their osteoarthritic complaints and history of radiotherapy (150, 151, 152.).
Information for reflection
Congenital isolated GHD is the purest model to study effects of GH in adulthood. Such an opportunity was presented by the identification of a large group of GHD patients in a small Brazilian town Itabahianinya. They have a genetic form of GHD due to an inactivating mutation in the GHRH receptor. Their GH and IGF-1 levels are profoundly low, but all other hormonal systems function perfectly well.
The characteristic physical features of this isolated GHD population included short stature and truncal obesity. Compared to age- and gender-matched controls from the same area, they have normal longevity (153), normal QoL as evaluated by commonly used questionnaires (154), no increased risk of fractures and superior muscle strength (155). They have lower areal BMD due to smaller bone mass, but when BMD is corrected for bone size, the volumetric BMD is similar to controls (156). These individuals have higher total and LDL cholesterol throughout life (157, 158), but they do not have greater carotid intima-media thickness or coronary atherosclerosis (159); their cardiovascular mortality is no different from the control population (153). Oliveira et al. (160) treated 20 such adults with GH for 6 months. Lipid profile and body composition improved, but carotid intimal thickness increased and carotid atherosclerotic plaques developed within 6 months of treatment, with a 52-fold higher likelihood to have a carotid atherosclerotic plaque by 12 months even after discontinuation of GH therapy. Five years after cessation of GH therapy, intima-media thickness returned to normal, but the number of atherosclerotic plaques did not change (161). Some findings in that model may not be directly applicable to AO-GHD. Nevertheless, they provide us with valuable insights on the impact of long-term isolated GHD and the potential shortcomings of GH replacement on human health.
Summary and conclusions
GH cannot lower cerebrovascular morbidity and mortality in patients with AO-GHD, because neither is due to GHD but due to complications of radiotherapy in patients with pituitary tumors.
GH administration to patients with AO-GHD may be modestly capable of improving lipid profile and increasing bone density. However, there are other medications specifically designed for both of those problems that are infinitely cheaper, potentially more effective and definitely more convenient (a tablet vs an injection). Their use vs GH administration needs to be addressed in approved protocols.
GH administration to AO-GHD increases muscle mass at the expense of water accumulation but does not improve muscle strength and endurance.
Many patients are still treated with supraphysiological doses of glucocorticoids that have been shown to negatively affect metabolic processes, bone integrity with subsequent development of fractures and neuropsychiatric status (subjective perception of QoL). Lowering the daily dose of glucocorticoids improved the severity of what are believed to be manifestations of AO-GHD. In patients with no ACTH deficiency or on a lower dose of glucocorticoid replacement and without a history of radiotherapy the QoL is normal. GH by definition cannot correct impaired QoL due to physical impairments such as arthropathy, limitations and stress of a ‘chronic illness’ or the circumstances of life.
In short, the beautiful hypothesis of GH replacement being a panacea for all real and imagined ills of AO-GHD seems to be slain by a whole slew of ugly facts.
Declaration of interest
J O L J has received lecture fees from Novo Nordisk, Pfizer and Sandoz. A B has nothing to disclose. G J has received lecture fees from Novartis, Novo Nordisk, Pfizer, Sandoz, Merck Serono, and Otsuka as wells as consultancy fees from Astra Zeneca and Shire.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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