Services on Demand
Journal
Article
Indicators
-
Cited by SciELO
Related links
-
Similars in SciELO
Share
Revista argentina de endocrinología y metabolismo
On-line version ISSN 1851-3034
Rev. argent. endocrinol. metab. vol.46 no.2 Ciudad Autónoma de Buenos Aires Apr./June 2009
Correction of Cortisol Overreplacement Ameliorates Morbidities in Patients with Hypopituitarism: A pilot study
Karina Danilowicz1, Oscar Domingo Bruno1, Marcos Manavela1, Reynaldo Manuel Gomez1, 2 and Ariel Barkan3
Publicado con la autorización de Springer Science y Business Media. Pituitary (2008) 11:279-285
1Division of Endocrinology, Hospital de Clínicas, Buenos Aires, Argentina,
2 Diagnóstico Médico SRL, Buenos Aires, Argentina, and
3 Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, United States.
Correspondencia: Karina Danilowicz, MD Division of Endocrinology Hospital de Clínicas Av. Córdoba 2351, 5° piso 1120, Ciudad Autónoma de Buenos Aires Argentina Tel: 00541159508828 Fax: 00541159508828
Dirección Postal: kdanilowicz@hotmail.com
Disclosure informations: All authors have nothing to declare.
Abstract
Context: Hyporituitarism in adults is known to be associated with deleterious effects on body composition, lipid profile and quality of life (QoL). This was attributed to GH deficiency. The potential role of glucocorticoid overreplacement had never been investigated.
Objective: To investigate whether reduction in glucocorticoid replacement dose to more physiological one could ameliorate the "AO-GHD"-attributed symptomatology in patients with hypopituitarism. Design: Eleven patients with panhypopituitarism taking 20-30 mg/day of hydrocortisone, but on no GH replacement were switched to 10 to 15 mg of hydrocortisone daily. Both basally and 6-12 months later, their body mass index, body composition by dual-energy x-ray absorptiometry, lipid profile, and the score of quality of life, QOL-AGHDA were measured.
Results: Within 6-12 months of lower hydrocortisone dose, subjects lost an average of 7.1 kg of total body fat and 4.1 kg of abdominal fat. No changes were seen in lean body mass, bone mineral content and HOMA-IR Plasma total cholesterol and triglyceride concentrations decreased significantly (<0.05) and the QoL improved (p=0.018).
Conclusions: Our pilot study suggests that decreasing the glucocorticoid replacement dose to ~ 15 mg/ day is beneficial in terms of patients' body composition, lipid profile and quality of life.
Key Words: Hypopituitarism; Cortisol replacement; Growth hormone deficiency
Palabras clave: Hipopituitarismo; Reemplazo de cortisol; Deficiencia de hormona de crecimiento.
Introduction
Pituitary diseases or their treatment are often followed by the development of hypopituitarism. Early studies have shown that patients with hypopituitarism, despite an apparently full replacement with glucocorticoids, thyroxine and sex steroids, still had a multitude of somatic and psychological symptoms and signs (1). This was attributed to the unsubstituted GH deficiency (GHD) and the constellation of abnormal body composition (increased adiposity and decreased lean mass), hyperlipidemia, and decreased quality of life was called an Adult-Onset GHD Syndrome (AO-GHD). Administration of GH to this population led to the amelioration of some of the AO-GHD components (2), strengthening the potential role of GHD in their pathogenesis.
Traditionally, glucocorticoid replacement consisted of daily administration of 25-35 mg of hydrocortisone or its equivalents (3, 4). Indeed, many studies asserting the existence of AO-GHD used similar glucocorticoid replacement dosages (5-7). However, it had been shown that the actual cortisol secretion rates in healthy humans are substantially lower than what was previously thought (8). Thus, the replacement glucocorticoid regimens used in the past were, in fact, supraphysiological and led to a mild iatrogenic Cushing's syndrome, the clinical manifestations of which are very similar to the AO-GHD.
The purpose of this pilot study was to investigate whether reduction in glucocorticoid replacement to more physiological doses could ameliorate metabolic and psychological morbidities in patients with hypopituitarism.
Subjects
This was a pilot study conducted in an open label, placebo-uncontrolled design, since the limited number of eligible participants in a single centre did not allow for a double-blind, placebo controlled design. Eleven patients with panhypopituitarism (3 men, 8 women, 50 + 14 years old, mean + SD) took part in the study. They were selected from the total population of hypopituitary subjects attending our endocrine clinic on the basis of receiving more than 20 mg/day of hydrocortisone. Six patients had a history of nonfunctioning pituitary tumors and 3 had a history of acromegaly. These patients underwent 1 or more pituitary surgeries and all had standard external radiotherapy 2 - 18 years prior to the study. One patient had a history of Sheehan's syndrome and one had pituitary cyst/abscess. All had ACTH deficiency as shown by morning plasma cortisol < 5 μg/L and low ACTH concentrations and plasma cortisol response to insulin hypoglycemia or 250 μg iv Cortrosyn test to < 20 μg/dl. All had TSH deficiency as evidenced by subnormal free T4 concentrations in the presence of low TSH. All had gonadotropin deficiency with low testosterone/low LH/FSH levels in men, amenorrhea with low gonadotropins in premenopausal women, and inappropriately low gonadotropins in postmenopausal women. One patient had central DI and required DDAVP. Baseline characteristics of the 11 patients are shown in Table 1.
Table 1. Baseline characteristics of the 11 patients
GH deficiency was documented in all subjects by plasma IGF-1 concentrations that were below age/gender adjusted normal limits (34.0±6.8ng/ ml, range non-detectable to 59ng/ml). Three patients also underwent insulin hypoglycemia, and their maximal plasma GH concentrations were below 3 μg/L.
Patients with history of acromegaly had GH deficiency documented by low IGF1 for at least a year prior to the study.
Prior to the study, all patients received replacement therapy with L-thyroxine 0.075-0.15 mg/ day, testosterone enanthate in men 250 mg IM every 2 weeks or estrogen/progesterone in premenopausal women (started after the documentation of low IGF-1 levels), and DDAVP as needed in 1 subject. Glucocorticoid replacement was given as hydrocortisone 15-20 mg in the morning, 5-10 mg in the afternoon. The total daily dose was 20-30 mg/day. They never received GH replacement therapy.
Protocol
The study was approved by the Institutional Review Board and conducted after written consent by the subjects was obtained.
At baseline, patients' weight and height were recorded, morning (fasting) level of serum lipids, plasma glucose and insulin were measured, and a 24h urine collection for free cortisol (on the customary hydrocortisone replacement) was submitted.
Dual energy x-ray absorptiometry was conducted to calculate total regional fat mass, lean body mass and bone mineral content. A Spanish version of QoL-AGHDA questionnaire (9) was utilized to assess the subjects' quality of life. Control values for QoL-AGHDA were obtained in 23 healthy Argentinian subjects (10 men, 13 women, 23 -64 years of age). The mean + 2 SD in this group was 5.5 + 3.4.
The subjects were then instructed to decrease their hydrocortisone replacement dose to 10-15 mg/day (5-10 mg in the morning and 5 mg in the afternoon).They were told that this adjustment was done based on contemporary data regarding cortisol requirements and asked to contact the investigators in case of worsened health. The possibility of potential beneficial effects upon body composition and QoL was not discussed. The subjects were seen in the clinic at 3 month intervals. Eight subjects were followed for a year, and three were followed for 6 months. At the end of the protocol the studies conducted at baseline were repeated (DEXA scan was not done in one subject).
Assays
Urinary free cortisol was measured by RIA (Immunotech, Beckman, USA). Insulin was measured by chemiluminescent assay (Immulite, DPC, Diagnostic Product Corporation, USA). Plasma glucose and serum lipids were measured according to standard methods (Biosystems, Spain). Serum low-density lipoprotein (LDL) cholesterol was calculated. HOMA-IR was calculated as [insulin mIU/ml x glucose (mg/dl)]/22.5 x 18.
Statistical Analysis
Data were analyzed by paired Student's t-test. P values < 0.05 were regarded as statistically significant. Data are shown as mean + standard error of the mean, M + SE.
Results
The baseline and final (6 or 12 months) data are summarized in Table 2.
Table 2. The baseline and final (6 or 12 months) data of the studied patients
At baseline, 8 of 10 subjects had UFC above the upper limit of the normal range (90 μg/24h). In 5 subjects UFC was elevated 1.5 - 2.5 fold above the upper normal limit (141 to 259 μg/24h).
The decrease in cortisol replacement dose led to the normalization of UFC in all subjects, with the values ranging between 20 and 75% of the upper limit of the normal range.
A decrease in the hydrocortisone replacement was not accompanied by any symptoms or signs of adrenocortical failure. No subject reported fatigue, weakness, tiredness, low energy, or orthostatic lightheadedness. The blood pressure remained normal in 9/11. Two persisted with mild hypertension (baseline systolic BP 120 ±14.8 mmHg and diastolic BP 72.7±6.5; final systolic BP 113.6±11.2 and diastolic BP 70.9±11.4).
Within 6-12 months of initiation of lower hydrocortisone replacement dose, 10/11 subjects lost 1 to 9 kg of weight (Fig. 1).
Fig. 1. Body weight, total and central adipose tissue before (pre) and after (post) decrease in hydrocortisone dose.
This was accompanied by the loss of an average of 7.1 kg of total body fat and of 4.1 kg of abdominal fat (Fig. 1) in the 10 patients with complete sets of DEXA studies. The amount of lean body mass remained stable. No changes were observed in bone mineral content either in the hip or in the lumbar spine.
No changes were seen in plasma glucose and insulin concentrations and, consequently, in HOMA-IR.
Plasma total cholesterol and triglyceride concentrations decreased on the average by 27 mg/ dl and 100 mg/dl respectively (Fig. 2) but there were no statistically significant changes in LDL cholesterol or HDL cholesterol. The Quality of Life (QoL) as measured by QoL-AGDHA improved significantly overall (p=0.018) (Fig. 3). Most importantly, in the four out of six patients whose basal scores were above mean + 2 SD of the control population (the most severely affected ones) AGDHA scores decreased substantially and fell into the normal range in two of them.
Fig. 2. Total serum cholesterol (mg/dl) and triglycerides (mg/dl) before (pre) and after (post) decrease in hydrocortisone dose.
Fig 3. QoL-AGHDA score before (pre) and after (post) decrease in hydrocortisone dose.
Discussion
We show here that a decrease in the daily dose of hydrocortisone replacement in patients with hypopituitarism ameliorates their body composition, unfavorable lipid profile and improves their quality of life.
Patients with panhypopituitarism often exhibit unfavorable symptoms and signs despite being replaced by all other missing hormones. Since GH was the only unreplaced hormone in these patients, these abnormalities had been frequently ascribed to GH deficiency. They include abnormal body composition with increased adiposity, thin skin, osteopenia, hyperlipidemia, insulin resistance and diminished quality of life (10, 11). Some manifestations, such as the amount of body fat (12), were clearly improved by GH administration. Despite decrease in body fat, GH-replaced hypopituitary patients exhibit only trivial and temporary improvements in plasma lipids (12) or not at all (13).
Similarly, GH treatment either does not change insulin sensitivity (14) or actually worsens it (15). Also, whereas the improvement in QoL was repeatedly asserted in many open-label trials, no such finding was reported in large double-blind, placebocontrolled studies (13), even when only the patients with the most severe decrease in QoL were analyzed separately (16). Recent studies re-examined the issue of osteopenia in hypopituitarism, and it was shown that bone density in panhypopituitary patients who were replaced with gonadal steroids but not with GH was in fact identical to the age and sex-controlled population (17). The increase in the lean body mass after GH replacement is due mostly to water accumulation (18) and no improvement in muscle strength/endurance was seen in double-blind, placebo-controlled studies (13). Thus, abnormal body composition, neuropsychiatric abnormalities and, perhaps, abnormal lipid profile are the most reproducible components of panhypopituitarism that respond favourably to treatment.
Another potential explanation for the metabolic and neuropsychiatric morbidities in panhypopituitarism is the potentially supraphysiological dose of glucocorticoids administered to these patients. Indeed, increased body adiposity, muscle weakness, thinning of the skin, hyperlipidemia, decreased insulin sensitivity and neuropsychiatric abnormalities are well-known manifestations of Cushing's syndrome. Modern, more accurate, methodologies have found that the true cortisol secretion rates in humans (5-7mg/m2) are less than half of the older estimates (19). Indeed, we have found that the patients taking traditionally-accepted hydrocortisone doses had UFC, a crude measure of free circulating cortisol, substantially above the normal range. The relatively modest excess in glucocorticoid replacement may have biological consequences: subjective health status in patients with hypoadrenalism is inversely proportionate to their glucocorticoid replacement dosage (20), and the "metabolic" abnormalities (BMI, waist circumference and lipids) in panhypopituitary patients have been shown to be directly proportionate to glucocorticoid replacement dosage (6). However, neither of these studies investigated the potential influence of lowered glucocorticoid replacement dose upon psychological well-being or metabolic syndrome. Dunne et al (21) did not detect changes in body weight, glucose and insulin in patients with hypopituitarism switched from 30 to 15 mg of hydrocortisone per day. However, their follow-up was limited to 3 months only, whereas resolution of clinical manifestations of hypercortisolism may take significantly more time (22). Indeed, only a 3-week long decrease in the dose of hydrocortisone in hypopituitary patients increased plasma osteocalcin, a marker of bone accretion (23).
In our pilot study we evaluated the effects of lowering the dose of hydrocortisone replacement in patients with hypopituitarism. Deficiencies of TSH, ACTH and gonadotropins were documented using standard approaches. Hartman et al (24) have previously shown that the presence of 3 other pituitary deficiencies, especially when combined with low IGF-1 levels predicts concomitant GH deficiency with 96% certainty. This was the basis of establishing GH deficiency in 8 of the 11 patients, while the remaining 3 had, in addition, demonstrated grossly impaired GH response to insulin hypoglycemia. Patients with a history of acromegaly had been biochemically GH deficient for a long time prior to the study as evidenced by subnormal IGF-1 concentrations. Thus, the subjects involved in this study were a representative sample of patients with hypopituitarism and severe GHD.
Lowering hydrocortisone replacement dose in this group brought about many beneficial effects traditionally ascribed to GH replacement in patients with AO-GHD. The most striking finding was the amelioration of body composition with a loss of substantial amount of total and, especially, abdominal fat. This was followed by a significant decrease in total cholesterol and triglycerides, i.e. strong predictors of subsequent cardiovascular risk (25). We found an approximate 40 % decrease in plasma triglycerides, similar to what is observed in successfully-treated patients with Cushing's disease (26). Decreasing hydrocortisone dosage in our study did not improve insulin sensitivity as measured by HOMA. On the other hand, no patient in this cohort exhibited worsening of insulin sensitivity. Perhaps, the use of euglycemic hyperinsulinemic clamp technique might be more informative in future studies of that nature. Successful treatment of endogenous Cushing's syndrome reliably improves insulin sensitivity (27). In our study, the lean body mass did not change. Patients with Cushing's syndrome do not improve their muscle function before 6 months after hormonal cure (28).
We did not assess muscle strength and endurance in our patients and this might be an important parameter to investigate in the future studies. We did not see a change in bone density. Whether longer duration of lower hydrocortisone replacement results in bone accrual needs to be verified in additional studies.
In conclusion, our pilot study suggests that decreasing the glucocorticoid replacement dose to ~ 15 mg/day is not only safe, but beneficial in terms of patients' body composition, lipid profile and quality of life. The main shortcoming of this trial is obvious: it was conducted in an open label, placebo-uncontrolled design. However, the number of eligible patients in a single medical center is limited and most of our hypopituitary subjects were already receiving lower glucocorticoid replacement doses. Thus, the encouraging data obtained in this study justify a multicenter trial to address the issue in a double-blind, placebo controlled design. Since these benefits occurred in the absence of concomitant GH replacement therapy, one would be tempted to speculate that the metabolic and neuropsychiatric abnormalities of panhypituitarism may be due not only to GH deficiency as such, but rather to overzealous replacement of glucocorticoids.
1. Malik IA, Foy P, Wallymahmed M, Wilding JP, MacFarlane IA. (2003) Assessment of quality of life in adults receiving long-term growth hormone replacement compared to control subjects. Clin Endocrinol (Oxf), 59, 75-81. [ Links ]
2 Attanasio AF, Bates PC, Ho KK, Webb SM, Ross RJ, Strasburger CJ, Bouillon R, Crowe B, Selander K, Valle D, Lamberts SW. (2002) Hypoptiuitary Control and Complications Study International Advisory Board. Human growth hormone replacement in adult hypopituitary patients: long-term effects on body composition and lipid status-3- year results from the HypoCCS Database. J Clin Endocrinol Metab, 87(4), 1600-1606. [ Links ]
3. Besser GM, Jeffcoate WJ. Endocrine and metabolic diseases. Adrenal diseases. (1976) Br Med J, 1, 448-451. [ Links ]
4 Groves RW, Toms GC, Houghton BJ, Monson JP. (1988) Corticosteroid replacement therapy: twice or thrice daily? J R Soc Med, 81(9), 514-16. [ Links ]
5 Johannsson G, Rosén T, Bosaeus I, Sjöström L, Bengtsson BA. (1996) Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency. J Clin Endocrinol Metab, 81(8), 2865-73. [ Links ]
6 Filipsson H, Monson JP, Koltowska-Haggstrom M, Mattsson A, Johannsson G. J. (2006) The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J Clin Endocrinol Metab, 91, 3954-3961. [ Links ]
7 Colao A, Di Somma C, Rota F, Pivonello R, Savanelli MC, Spiezia S, Lombardi G. (2005) Short-term effects of growth hormone (GH) treatment or deprivation on cardiovascular risk parameters and intima-media thickness at carotid arteries in patients with severe GH deficiency. J Clin Endocrinol Metab, 90(4), 2056-62. [ Links ]
8 Esteban NV, Loughlin T, Yergey AZ, Zawadzki JK, Booth JD, Winterer JC, Loriaux DL. (1991) Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab, 72, 1698-1700. [ Links ]
9 McKenna SP, Doward LC, Alonso J, Kohlmann T, Niero M, Prieto L, Wiren L. (1999) The Qol- AGHDA: an instrument for the assessment of quality of life in adults with growth hormone deficiency. Qual Life Res, 4, 373-38. [ Links ]
10 Rosen T, Bengtsson BA. (1990) Premature mortality due to cardiovascular disease in hypopituitarism. Lancet, 336, 285-288. [ Links ]
11 Beshyah SA, Freemantle C, Thomas E, Rutherford O, Page B, Murphy M, Johnston DG. (1995) Abnormal body composition and reduced bone mass in growth hormone deficient hypopituitary adults. Clin Endocrinol (Oxf), 42, 179-189. [ Links ]
12 Hoffman AR, Kuntze JE, Baptista J, Baum HB, Baumann GP, Biller BM, Clark RV, Cook D, Inzucchi SE, Kleinberg D, Klibanski A, Phillips LS, Ridgway EC, Robbins RJ, Schlechte J, Sharma M, Thorner MO, Vance ML. (2004) Growth hormone (GH) replacement therapy in adultonset GH deficiency: effects on body composition in men and women in a doubleblind, randomized, placebo-controlled trial. J Clin Endocrinol Metab, 89(5), 2048-56. [ Links ]
13 Mauras N, Pescovitz OH, Allada V, Messig M, Wajnrajch MP, Lippe B; Transition Study Group. (2005) Limited efficacy of growth hormone (GH) during transition of GH-deficient patients from adolescence to adulthood: a phase III multicenter, double-blind, randomized two-year trial. J Clin Endocrinol Metab, 90(7), 3946-55. [ Links ]
14 Christopher M, Hew FL, Oakley M, Rantzau C, Alford F. (1998) Defects of insulin action and skeletal muscle glucose metabolism in growth hormone- deficient adults persist after 24 months of recombinant human growth hormone therapy. J Clin Endocrinol Metab, 83(5), 1668-81. [ Links ]
15 Sesmilo G, Biller BM, Llevadot J, Hayden D, Hanson G, Rifai N, Klibanski A. (2000) Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Ann Intern Med, 133, 111-22. [ Links ]
16 Cuneo RC, Judd S, Wallace JD, Perry-Keene D, Burger H, Lim-Tio S, Strauss B, Stockigt J, Topliss D, Alford F, Hew L, Bode H, Conway A, Handelsman D, Dunn S, Boyages S, Cheung NW, Hurley D. (1998) The Australian Multicenter Trial of Growth Hormone (GH) Treatment in GH-Deficient Adults. J Clin Endocrinol Metab, 83(1), 107-16. [ Links ]
17 Murray RD, Adams JE, Shalet SM. (2006) A densitometric and morphometric analysis of the skeleton in adults with varying degrees of growth hormone deficiency. J Clin Endocrinol Metab, 91(2), 432-8. [ Links ]
18 Ehrnborg C, Ellegard L, Bosaeus I, Bengtsson BA, Rosen T. (2005) Supraphysiological growth hormone: less fat, more extracellular fluid but uncertain effects on muscles in healthy, active young adults. Clin Endocrinol, 62, 449-457. [ Links ]
19 Kerrigan JR, Veldhuis JD, Leyo SA, Iranmanesh A, Rogol AD. (1993) Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis. J Clin Endocrinol Metab, 76(6), 1505-10. [ Links ]
20 Hahner S, Loeffler M, Fassnacht M, Weismann D, Koschker AC, Quinkler M, Decker O, Arlt W, Allolio B. (2007) Impaired subjective health status in 256 patients with adrenal insufficiency on standard therapy based on cross-sectional analysis. J Clin Endocrinol Metab, 92(10), 3912-22. [ Links ]
21 Dunne FP, Elliot P, Gammage MD, Stallard T, Ryan T, Sheppard MC, Stewart PM. (1995) Cardiovascular function and glucocorticoid replacement in patients with hypopituitarism. Clin Endocrinol (Oxf), 43(5), 623-9. [ Links ]
22 Zeiger MA, Fraker DL, Pass HI, Nieman LK, Cutler GB Jr, Chrousos GP, Norton JA. (1993) Effective reversibility of the signs and symptoms of hypercortisolism by bilateral adrenalectomy. Surgery, 114(6), 1138-43. [ Links ]
23 Peacey SR, Guo CY, Robinson AM, Price A, Giles MA, Eastell R, Weetman AP. (1997) Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin Endocrinol (Oxf), 46(3), 255-61. [ Links ]
24 Hartman ML, Crowe BJ, Biller BM, Ho KK, Clemmons DR, Chipman JJ; HyposCCS Advisory Board; U.S. HypoCCS Study Group. (2002) Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? J Clin Endocrinol Metab, 87(2), 477-85. [ Links ]
25 Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW, Cobbe SM; West of Scotland Coronary Prevention Study Group. (2007) Long-term follow- up of the West of Scotland Coronary Prevention Study. N Engl J Med, 357(15), 1477-86. [ Links ]
26 Taskinen MR, Nikkilä EA, Pelkonen R, Sane T. (1983) Plasma lipoproteins, lipolytic enzymes, and very low density lipoprotein triglyceride turnover in Cushing's syndrome. J Clin Endocrinol Metab, 57(3), 619-26. [ Links ]
27 Krsek M, Silha JV, Jezková J, Hána V, Marek J, Weiss V, Stepán JJ, Murphy LJ. (2004) Adipokine levels in Cushing's syndrome; elevated resistin levels in female patients with Cushing's syndrome. Clin Endocrinol (Oxf), 60(3), 350-7. [ Links ]
28 Pirlich M, Biering H, Gerl H, Ventz M, Schmidt B, Ertl S, Lochs H. (2002) Loss of body cell mass in Cushing's syndrome: effect of treatment. J Clin Endocrinol Metab, 87(3),1078-84. [ Links ]