Severe GH deficiency (GHD) in adults has been described as a clinical entity. However, some of the features associated with GHD could be due to unphysiological and inadequate replacement of other pituitary hormone deficiencies. This may be true for glucocorticoid replacement that lacks a biomarker making dose titration and monitoring difficult. Moreover, oral estrogen replacement therapy decreases IGF1 levels compared with the transdermal route, which attenuates the responsiveness to GH replacement therapy in women. In addition, in untreated female hypogonadism, oral estrogen may augment the features associated with GHD in adult women. Important interactions between the hormones used for replacing pituitary hormone deficiency occur. Introducing GH replacement may unmask both an incipient adrenal insufficiency and central hypothyroidism. Therefore, awareness and proper monitoring of these hormonal interactions are important in order to reach an optimal replacement therapy. This review will focus on the complex hormonal interactions between GH and other pituitary hormones in GHD and in GH replacement.
Helena Filipsson and Gudmundur Johannsson
Oskar Ragnarsson and Gudmundur Johannsson
One hundred years have passed since Harvey Williams Cushing presented the first patient with the syndrome that bears his name. In patients with Cushing's syndrome (CS), body composition and lipid, carbohydrate and protein metabolism are dramatically affected and psychopathology and cognitive dysfunction are frequently observed. Untreated patients with CS have a grave prognosis with an estimated 5-year survival of only 50%. Remission can be achieved by surgery, radiotherapy and sometimes with medical therapy. Recent data indicate that the adverse metabolic consequences of CS are present for years after successful treatment. In addition, recent studies have demonstrated that health-related quality of life and cognitive function are impaired in patients with CS in long-term remission. The focus of specialised care should therefore be not only on the diagnostic work-up and the early postoperative management but also on the long-term follow-up. In this paper, we review the long-term consequences in patients with CS in remission with focus on the neuropsychological effects and discuss the importance of these findings for long-term management. We also discuss three different phases in the postoperative management of surgically-treated patients with CS, each phase distinguished by specific challenges: the immediate postoperative phase, the glucocorticoid dose tapering phase and the long-term management. The focus of the long-term specialised care should be to identify cognitive impairments and psychiatric disorders, evaluate cardiovascular risk, follow pituitary function and detect possible recurrence of CS.
Helena Filipsson, Ernst Nyström and Gudmundur Johannsson
The diagnosis of central hypothyroidism (CH) is often difficult to establish as serum TSH levels may be low, normal, or slightly increased.
To explore the use of recombinant human TSH (rhTSH) in the diagnosis of CH.
Randomized single-blind clinical trial.
Outpatient clinic of a tertiary care referral center.
A single intramuscular injection of 0.1 and 0.9 mg rhTSH in random order with 1-week interval.
Eighteen adult patients with pituitary insufficiency and six healthy age-, sex-, and body mass index-matched controls. Six patients had untreated CH (newCH), six had treated CH (CH), and six patients were TSH sufficient (nonCH). Five weeks before TSH stimulation, levothyroxine was replaced with tri-iodothyronine (T3) for 4 weeks. One week before stimulation, treatment was withdrawn.
Main outcome measures
Thyroid hormones and thyroglobulin (Tg) before and 2, 3½, 7, 24, 48, and 72 h after each injection.
In the newCH group, basal free thyroxine (FT4) levels were lower than in controls (P<0.05). After 0.9 mg rhTSH, the increases in FT4 and reverse T3 (rT3) were less marked in the newCH group than in controls (FT4±s.e.m. 9.2±0.5 to 19.7±1.2 vs 11.3±0.5 to 27.8.2±2.4 pmol/l, P<0.05). The CH group exhibited reduced basal and stimulated FT4 compared with the TSH-sufficient groups. Tg increased similarly among all study groups after rhTSH injection.
In this pilot study, patients with untreated CH had lower response to 0.9 mg rhTSH in FT4 and rT3 than controls. An rhTSH test may be useful in the diagnosis of CH, but further studies are required.
Gudmundur Johannsson, Hans Lennernäs, Claudio Marelli, Kevin Rockich and Stanko Skrtic
Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure−time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5–20mg and assess intrasubject variability.
Thirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20−55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3×5), and 20mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography−tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration−time profiles.
DR-HC 20mg provided higher than endogenous cortisol plasma concentrations 0−4h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (Cmax) was 82.0 and 178.1ng/mL, while mean area under the concentration−time curve (AUC)0−∞ was 562.8 and 1180.8h×ng/mL with DR-HC 5 and 20mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20mg. All exposure PK parameters were less than dose proportional (slope <1). PK differences between ethnicities were explained by body weight differences.
DR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional – an important consideration when managing intercurrent illness in patients with adrenal insufficiency.
Ashley Grossman, Gudmundur Johannsson, Marcus Quinkler and Pierre Zelissen
Conventional glucocorticoid (GC) replacement for patients with adrenal insufficiency (AI) is inadequate. Patients with AI continue to have increased mortality and morbidity and compromised quality of life despite treatment and monitoring.
i) To review current management of AI and the unmet medical need based on literature and treatment experience and ii) to offer practical advice for managing AI in specific clinical situations.
The review considers the most urgent questions endocrinologists face in managing AI and presents generalised patient cases with suggested strategies for treatment.
Optimisation and individualisation of GC replacement remain a challenge because available therapies do not mimic physiological cortisol patterns. While increased mortality and morbidity appear related to inadequate GC replacement, there are no objective measures to guide dose selection and optimisation. Physicians must rely on experience to recognise the clinical signs, which are not unique to AI, of inadequate treatment. The increased demand for corticosteroids during periods of stress can result in a life-threatening adrenal crisis (AC) in a patient with AI. Education is paramount for patients and their caregivers to anticipate, recognise and provide proper early treatment to prevent or reduce the occurrence of ACs.
This review highlights and offers suggestions to address the challenges endocrinologists encounter in treating patients with AI. New preparations are being developed to better mimic normal physiological cortisol levels with convenient, once-daily dosing which may improve treatment outcomes.
Mariam Elbornsson, Galina Götherström, Celina Franco, Bengt-Åke Bengtsson, Gudmundur Johannsson and Johan Svensson
Little is known of the effects of long-term GH replacement on bone mineral content (BMC) and bone mineral density (BMD) in elderly GH-deficient (GHD) adults.
In this prospective, single-center, open-label study, the effects of 3-year GH replacement were determined in 45 GHD patients >65 years and in 45 younger control GHD patients with a mean age of 39.5 (s.e.m. 1.1) years. All patients had adult-onset disease and both groups were comparable in terms of number of anterior pituitary hormonal deficiencies, gender, body mass index, and waist:hip ratio.
The mean maintenance dose of GH was 0.24 (0.02) mg/day in the elderly patients and 0.33 (0.02) mg/day in the younger GHD patients (P<0.01). The 3 years of GH replacement induced a marginal effect on total body BMC and BMD, whereas femur neck and lumbar (L2–L4) spine BMC and BMD increased in both the elderly and the younger patients. The treatment response in femur neck BMC was less marked in the elderly patients (P<0.05 vs younger group). However, this difference disappeared after correction for the lower dose of GH in the elderly patients using an analysis of covariance. There were no between-group differences in responsiveness in BMC or BMD at other skeletal locations.
This study shows that GH replacement increases lumbar (L2–L4) spine and femur neck BMD and BMC in younger as well as elderly GHD patients. This supports the notion that long-term GH replacement is also useful in elderly GHD patients.
Mariam Elbornsson, Galina Götherström, Ingvar Bosæus, Bengt-Åke Bengtsson, Gudmundur Johannsson and Johan Svensson
Few studies have determined the effects of more than 5–10 years of GH replacement in adults on bone mineral content (BMC) and bone mineral density (BMD).
In this prospective, single-centre, open-label study, the effects of 15 years of GH replacement on BMC and BMD, measured using dual-energy X-ray absorptiometry, were determined in 126 hypopituitary adults (72 men) with adult-onset GH deficiency (GHD). Mean age was 49.4 (range 22–74) years at the initiation of the study.
The mean initial GH dose of 0.63 (s.e.m. 0.03) mg/day was gradually lowered to 0.41 (0.01) mg/day after 15 years. The mean serum IGF1 SDS increased from −1.69 (0.11) at baseline to 0.63 (0.16) at the study end (P<0.001 vs baseline). The 15 years of GH replacement induced a sustained increase in total body BMC (+5%, P<0.001) and BMD (+2%, P<0.001). Lumbar (L2–L4) spine BMC increased by 9% (P<0.001) and BMD by 5% (P<0.001). In femur neck, a peak increase in BMC and BMD of 7 and 3%, respectively, was observed after 7 years (both P<0.001). After 15 years, femur neck BMC was 5% above the baseline value (P<0.01), whereas femur neck BMD had returned to the baseline level. In most variables, men had a more marked response to GH replacement than women.
Fifteen-year GH replacement in GHD adults induced a sustained increase in total body and lumbar (L2–L4) spine BMC and BMD. In femur neck, BMC and BMD peaked at 7 years and then decreased towards baseline values.
Helga Á Sigurjónsdóttir, Josef Koranyi, Magnus Axelson, Bengt-Åke Bengtsson and Gudmundur Johannsson
Objective: In the past years the interaction of GH and 11βhydroxysteroid dehydrogenase (11βHSD) in the pathogenesis of central obesity has been suggested.
Design: We studied the effects of 9 months of GH treatment on 11βHSD activity and its relationship with body composition and insulin sensitivity in 30 men with abdominal obesity, aged 48–66 years, in a randomised, double-blind, placebo-controlled trial.
Methods: Urinary steroid profile was used to estimate 11βHSD type 1 and 2 (11βHSD1 and 11βHSD2) activities. Abdominal s.c. and visceral adipose tissues were measured using computed tomography. Glucose disposal rate (GDR) obtained during a euglycaemic–hyperinsulinaemic glucose clamp was used to assess insulin sensitivity.
Results: In the GH-treated group the 11βHSD1 activity decreased transiently after 6 weeks (P < 0.01) whereas 11βHSD2 increased after 9 months of treatment (P < 0.05). Between 6 weeks and 9 months, GDR increased and visceral fat mass decreased. Changes in 11βHSD1 correlated with changes in visceral fat mass between baseline and 6 weeks. There were no significant correlations between 11βHSD1 and 11βHSD 2 and changes in GDR.
Discussion: The study demonstrates that short- and long-term GH treatment has different effects on 11βHSD1 and 11βHSD2 activity. Moreover, the data do not support that long-term metabolic effects of GH are mediated through its action on 11βHSD.
Mariam Elbornsson, Galina Götherström, Ingvar Bosæus, Bengt-Åke Bengtsson, Gudmundur Johannsson and Johan Svensson
Few studies have determined the effects of more than 5–10 years of GH replacement in adults on body composition and cardiovascular risk factors.
In this prospective, single-center, open-label study, the effects of 15 years of GH replacement on body composition and cardiovascular risk factors were determined in 156 hypopituitary adults (93 men) with adult-onset GH deficiency (GHD). Mean age was 50.5 (range 22–74) years at study start. Body composition was measured using dual-energy X-ray absorptiometry.
The mean initial GH dose of 0.55 (s.e.m. 0.03) mg/day was gradually lowered to 0.40 (0.01) mg/day after 15 years. The mean serum IGF1 SDS increased from −1.53 (0.10) at baseline to 0.74 (0.13) at study end (P<0.001 vs baseline). Lean soft tissue (LST) increased to 3% above the baseline level at study end (P<0.001). After a 9% decrease during the first year of treatment (P<0.001 vs baseline), body fat (BF) started to increase and had returned to the baseline level after 15 years. Serum levels of total cholesterol and LDL-cholesterol decreased and serum HDL-cholesterol level increased. Fasting plasma glucose increased from 4.4 (0.1) at baseline to 4.8 (0.1) mmol/l at study end (P<0.001). However, blood HbA1c decreased from 5.0 (0.1) to 4.6 (0.1) % (P<0.001).
Fifteen-year GH replacement in GHD adults induced a transient decrease in BF and sustained improvements of LST and serum lipid profile. Fasting plasma glucose increased whereas blood HbA1c was reduced.
Oskar Ragnarsson, Peter Berglund, Derek N Eder, Henrik Zetterberg, Max A Hietala, Kaj Blennow and Gudmundur Johannsson
Patients with Cushing's syndrome (CS) in long-term remission have impaired cognitive function. Cerebrospinal fluid (CSF) biomarkers are important diagnostic tools in the work-up of patients with cognitive impairment. The aim of this study was to analyze neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission.
A cross-sectional, single-center study.
Twelve women previously treated for CS and six healthy subjects.
Neurodegenerative CSF markers: total tau, hyperphosphorylated tau, amyloid beta peptides, soluble amyloid precursor protein alpha and beta, neurofilament light proteins, glial fibrillary acidic protein, and monocyte chemoattractant protein 1; and inflammatory CSF markers: interferon gamma, interleukin (IL) 1B, IL2, IL4, IL5, IL8, IL10, IL12p70, IL13, and tumor necrosis factor alpha.
The mean age (mean±s.d.) was similar in patients with CS in remission (44.9±14 years) and healthy subjects (42.3±15.7 years; P=0.726). No differences were observed in the concentrations of any neurodegenerative biomarkers between the patients and healthy subjects. Nor were the concentrations of inflammatory biomarkers different between the groups.
The pattern of neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission does not differ from that of the healthy subjects. The underlying mechanisms of the cognitive deficits in patients with CS in remission are different from those observed in patients with neurodegenerative disorders and remain to be explained.