- Email: [email protected]
Endocrine and neuroanatomic features associated with weight gain and obesity in adult patients with hypothalamic damage
The American Journal of Medicine (2005) 118, 45-50
CLINICAL RESEARCH STUDY
Endocrine and neuroanatomic features associated with weight gain and obesity in adult patients with hypothalamic damage Christina Daousi, MBBS,a Andrew J. Dunn, MBBS,b Patrick M. Foy, MBBS,c Ian A. MacFarlane, MD,a Jonathan H. Pinkney, MDa a
From the Diabetes and Endocrinology Research Group, Department of Radiology, and c Department of Neurosurgery, The Walton Center for Neurology and Neurosurgery, University Hospital Aintree, Liverpool, United Kingdom. b
KEYWORDS: Obesity; Weight gain; Hypothalamus; Craniopharyngioma
Purpose: Obesity is a common consequence in patients with tumors of the hypothalamic region and of related treatment in children. Much less information is available on adult patients and long-term survivors. The aims of this study were to estimate the prevalence of obesity in adult patients with acquired structural hypothalamic damage and to define the characteristics of patients at greatest risk of obesity. Methods: A retrospective study was conducted of 52 patients (25 women; median age at diagnosis, 44 years; range, 17 to 78 years) with tumors involving the hypothalamic region. These included 22 craniopharyngiomas, 24 pituitary adenomas, and six other hypothalamic tumors. Changes in body mass index were determined, magnetic resonance imaging scans were scored by a radiologist for tumor size and the extent of involvement of the hypothalamus, and current hormone replacement therapy was recorded, to identify possible features associated with new or worsened obesity (defined as a body mass index ⱖ30 kg/m2 at the latest follow-up, which had increased by at least 2 kg/m2 since diagnosis of the tumor). Results: Serial body mass index data from diagnosis to the latest follow-up were available for 42 patients. After a median of 5 years (range, 1 to 19 years) of follow-up, most patients with hypothalamic damage were obese (52% [n ⫽ 22] vs. 24% [n ⫽ 10] at the time of diagnosis, P ⬍ 0.0001). In a multivariate model, use of desmopressin (odds ratio [OR] ⫽ 13; 95% confidence interval [CI]: 2.0 to 86; P ⫽ 0.007) and growth hormone replacement (OR ⫽ 7.6; 95% CI: 1.1 to 51; P ⫽ 0.04) were associated with new or worsened obesity during follow-up. No correlation was found between the initial size or location of the tumor and subsequent weight gain. Conclusion: Obesity is highly prevalent in adult survivors of hypothalamic tumors. Use of desmopressin and growth hormone therapy, but not size or location of the tumor, were associated with weight gain and obesity following diagnosis. These findings may be helpful in identifying patients at increased risk of obesity, to whom earlier intervention could be offered. © 2005 Elsevier Inc. All rights reserved.
Requests for reprints should be addressed to: Christina Daousi, MBBS, Diabetes and Endocrinology Research Group, University Hospital Aintree, Clinical Sciences Center, Third Floor, Lower Lane, Liverpool L9 7AL, United Kingdom. E-mail address: [email protected].
0002-9343/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2004.06.035
It has long been recognized that obesity complicates disorders of the hypothalamus and their treatment.1,2 The most common causes of acquired hypothalamic damage are space-occupying lesions, such as craniopharyngiomas and pituitary macroadenomas with suprasellar extension. Weight gain is a common and sometimes distressing long-
46 term consequence of hypothalamic damage in these patients, occurring because of the underlying tumor or its treatment with surgery or radiotherapy.3-6 Excessive weight gain as a manifestation of hypothalamic injury is generally underestimated because it often takes years to develop and the problem may be under-recognized by physicians.7 Most information to date has focused on the endocrine sequelas (including obesity) of treatment of childhood craniopharyngioma and on the identification of the risk factors for obesity in children surviving brain tumors.3-6,8,9 There are far fewer data on the prevalence of obesity following structural hypothalamic damage in adults. We conducted a retrospective study of 52 patients who had presented with tumors involving the hypothalamic region and were thereby at risk of hypothalamic dysfunction. The aims of the study were to estimate the prevalence of current obesity in this patient group, and to define the diagnoses and endocrine characteristics that were most associated with weight gain, relating these markers with anatomic findings from neuroimaging.
Methods Subjects A retrospective study was conducted of 52 adult patients with primary tumors involving the hypothalamic pituitary region. All patients were attending a combined surgical and medical neuroendocrine clinic at the Walton Center for Neurology and Neurosurgery in Liverpool, United Kingdom. Data were obtained from the medical records; permission was given by the Center Audit Department. All patients had undergone treatment for hypothalamic tumors, or adjacent tumors directly compressing or invading the hypothalamus. The data described here represent clinical data up until 2002. There were 28 patients with craniopharyngiomas, Rathke cleft cysts, or other midline tumors with hypothalamic involvement, and 24 with pituitary macroadenomas and suprasellar extension, all of whom had optic chiasmal compression and visual field defects (Figure 1). Neurosurgical procedures were recorded along with the anatomical approach and the need for a ventricular drainage procedure. The administration of conventional fractionated external beam radiotherapy for either residual tumor or recurrence was also recorded. Two patients were treated with radiotherapy alone.
Anthropometric assessment Patients’ height and weight at the time of diagnosis of the tumor were recorded. Body mass index (kg/m2) was calculated at diagnosis and at the most recent follow-up clinic visit. Changes in body mass index were determined to identify the development of new or worsened obesity (defined as a body mass index ⱖ30 kg/m2 at latest follow-up,
The American Journal of Medicine, Vol 118, No 1, January 2005 which had also increased by at least 2 kg/m2 since the diagnosis of the tumor).
Endocrine assessment All patients underwent serial endocrine assessment following treatment. The glucagon stimulation test (GlucaGen; Novo Nordisk Pharmaceuticals, Crawley, United Kingdom) was used to assess adrenocorticotropic hormone and growth hormone reserve.10 Basal levels of thyroid-stimulating hormone, free thyroxine, free triiodothyronine, prolactin, estradiol, testosterone, cortisol, and insulin-like growth factor 1 were also used to assess endocrine status.
Neuroimaging All available pre- and postoperative computed tomographic (CT) and magnetic resonance imaging (MRI) scans for each patient were reviewed and scored by the same radiologist who was blind to the clinical data. The following anatomic features were recorded pre- and postoperatively: primary site of tumor; maximum extent (mm) of the tumor from the midline (to the right and left) on coronal views; presence of suprasellar extension of pituitary tumors; encroachment of pituitary tumors on the optic chiasm; invasion or compression by extrahypothalamic tumors of adjacent hypothalamic tissue; distortion of the third ventricle on coronal images at the level of the infundibulum; any abnormalities of the floor of the third ventricle or breach of the tuber cinereum by the tumor; and infiltration by the tumor of other brain areas, including the thalamus and temporal lobes.
Statistical analysis The Wilcoxon signed-rank test was used to compare longitudinal changes in body mass index in the 42 patients in whom serial weight data (from the time of diagnosis to the most recent follow-up) were available. Categorical data were examined with the chi-squared test or the Fisher exact test, as appropriate. Continuous data were examined with the use of the t test for normally distributed data or the Mann-Whitney U test for non-normally distributed data. Multiple logistic regression analysis was used to identify features associated with weight gain. Variables that differed significantly in the univariate analysis for patients with new or worsened obesity at follow-up were entered into the original model, along with the patients’ current age and age at the time of diagnosis of the tumor, and subjected to forward stepwise logistic regression analysis. Correlations between tumor size and subsequent weight gain were examined using the Spearman rank correlation coefficient for non-normally distributed data. Statistical significance was defined as P ⬍ 0.05 (two-tailed). All analyses were performed using SPSS, version 10.0 (SPSS Inc., Chicago, Illinois).
Daousi et al
Obesity in Adults with Hypothalamic Damage
47
Figure 1 Representative T1-weighted, coronal, postgadolinium images of the patients studied. (A) Suprasellar craniopharyngioma with intense enhancement of the rim of the tumor and invasion of the right temporal lobe. (B) Primary hypothalamic glioma arising above the suprasellar cistern with extension down the infundibulum. (C) Massive, enhancing suprasellar macroprolactinoma encasing both internal carotid arteries, invading the hypothalamus, and causing distortion of the third ventricle. (D) Nonfunctioning pituitary macroadenoma with suprasellar extension compressing the third ventricle, invading the hypothalamus, and encroaching on to the mamillary bodies.
Results Prevalence of obesity At the time of diagnosis and treatment, height and weight measurements were available for 42 of the 52 patients. The mean (⫾SD) age of the 42 patients was 52 ⫾ 14.2 years; 23 (55%) were men (Table 1). Twenty-eight patients (67%) were overweight or heavier (body mass index ⱖ25 kg/m2), 10 (24%) were obese (body mass index ⱖ30 kg/m2), and 2 (5%) had a body mass index ⱖ35 kg/m2; no patients were morbidly obese (body mass index ⱖ40 kg/m2). At the most recent follow-up, a median of 5 years later, the prevalence of obesity had increased substantially among the 42 patients: 37 (88%) were overweight or heavier, 22 (52%) were obese, 10 (24%) had a body mass index ⱖ35 kg/m2, and 1 was morbidly obese (Figure 2). There was a highly significant increase in median body mass index, from 27.8 kg/m2 (interquartile range, 24.2 to 29.8 kg/m2) at baseline to 30.4
kg/m2 (interquartile range, 27.3 to 34.8 kg/m2) at the latest follow-up (P ⬍ 0.0001).
Endocrine replacement at follow-up In 2002, 47 (90%) of the 52 patients were receiving replacement therapy with one or more pituitary hormone replacements, including 14 who were receiving desmopressin for cranial diabetes insipidus. Postoperatively, 3 other patients developed transient cranial diabetes insipidus. Currently, patients attending this clinic who have severe growth hormone deficiency (defined as a peak growth hormone response ⬍9 mU/L to provocative testing), adequate replacement of other pituitary hormone deficiencies, and impaired quality of life are offered a trial of growth hormone replacement therapy; 34 patients in this group were receiving growth hormone replacement therapy. Three others with severe growth hormone deficiency declined this treatment.
48
The American Journal of Medicine, Vol 118, No 1, January 2005
Table 1
Characteristics of the patients, according to obesity status New or Worsened Obesity (n ⫽ 18)
No Weight Gain (n ⫽ 24)
Number (%) or Mean ⫾ SD
Characteristic Current age (years) Age at diagnosis (years) Male sex Years of follow-up Baseline body mass index (kg/m2) Current body mass index (kg/m2) Trans-sphenoidal surgery Transfrontal surgery Radiotherapy Ventriculoperitoneal shunt Hydrocortisone replacement Growth hormone replacement Thyroxine replacement Sex steroids Desmopressin Invasion of thalamus on MRI Invasion of temporal lobe on MRI Abnormalities of third ventricle
47.2 ⫾ 11.9 39.2 ⫾ 13.1 9 (50) 7.4 ⫾ 5.5 28.3 ⫾ 3.7 35.1 ⫾ 3.3 8 (44) 8 (44) 10 (55) 1 (5) 16 (89) 16 (89) 16 (89) 15 (83) 10 (55) 0 0 4 (22)
55.5 ⫾ 14.9 47.6 ⫾ 15.4 14 (58) 6.7 ⫾ 5.1 26.7 ⫾ 4.4 27.7 ⫾ 4.1 14 (58) 6 (25) 9 (37) 3 (12) 14 (58) 12 (50) 13 (54) 13 (54) 2 (8) 2 (8) 2 (8) 9 (37)
P Value 0.06 0.07 0.8 0.6 0.2 ⬍0.0001 0.5 0.3 0.4 0.6 0.04 0.01 0.02 0.06 0.001 1.00 1.00 0.6
MRI ⫽ magnetic resonance imaging.
Endocrine replacement associated with obesity and weight gain since diagnosis
P ⫽ 0.04) were associated with the development of new or worsened obesity during follow-up.
Patients with new or worsened obesity at follow-up were more likely to be receiving growth hormone replacement therapy (P ⫽ 0.01), hydrocortisone (P ⫽ 0.04), thyroxine (P ⫽ 0.02), or desmopressin (P ⫽ 0.001), or to have treated or untreated severe growth hormone deficiency (P ⫽ 0.04) (Table 1). In a multivariate model, use of desmopressin (odds ratio [OR] ⫽ 13; 95% confidence interval [CI]: 2.0 to 86; P ⫽ 0.007) and growth hormone (OR ⫽ 7.6; 95% CI: 1.1 to 51;
Neuroanatomic features associated with obesity and weight gain since diagnosis
50
2
Body Mass Index (kg/m )
45 40 35 30 25
Preoperative neuroimaging scans were available for 26 patients and postoperative scans were available for 39 patients. No correlation was found between the width of tumor from midline on preoperative or postoperative MRI/CT coronal views and change in body mass index (Spearman r ⫽ ⫺0.3, P ⫽ 0.3). Radiologic involvement of the thalamus or temporal lobe, distortion of the third ventricle on coronal images at the level of the infundibulum, abnormalities of the floor of the third ventricle, and breach of the tuber cinereum by the tumor were not associated with weight gain (Table 1). Similarly, neither a history of transfrontal surgery (implying the initial presence of more extensive tumor and greater likelihood of perioperative hypothalamic damage) nor insertion of a ventriculoperitoneal shunt was associated with increased weight gain following diagnosis.
20
Discussion
15 10
Baseline
Follow-up
Figure 2 Changes in body mass index among the 42 patients during a median follow-up of 5 years.
Few studies have investigated the neuroanatomic and endocrine features associated with weight gain and obesity in adults with hypothalamic damage. Weight gain and obesity have been studied in children treated for craniopharyngioma, in whom deficiencies of pituitary hormones are com-
Daousi et al
Obesity in Adults with Hypothalamic Damage
mon along with weight gain, which leads to obesity in up to 50% to 80% of children.3,4,11-15 Our data show that obesity is also a post-treatment complication in adults with hypothalamic injury. After a median follow-up of 5 years, 52% of patients with hypothalamic lesions were obese, compared with only 24% at the time of diagnosis. Data from the general U.K. population16 indicate that the prevalence of obesity (body mass index ⱖ30 kg/m2) in adults aged 45 to 54 years increased from 18% in 1993 to 27% in 2001. Therefore, the weight gain observed in the present study is clearly in excess of the weight gain expected from demographic trends over the same time period in the background population of similar age to our cohort. Hypothalamic obesity is thought to result from disruption of mechanisms that control satiety and hunger.17 The medial hypothalamus contains nuclear groups controlling energy balance, and damage to these structures, which include the arcuate, paraventricular, ventromedial, and dorsomedial nuclei, leads to weight gain.18 All of these nuclei are vulnerable to midline lesions of the hypothalamus and pituitary tumors with suprasellar extension. Interrupted responses to anorectic signals such as leptin and insulin, caused by hypothalamic damage, is one possible mechanism contributing to obesity.19 Autonomic nervous system imbalance and hyperinsulinemia may also be involved in the development of human hypothalamic obesity.7,20-24 We found no relation between neuroanatomic extent of the tumor and weight gain. However, the resolution of current MRI scanning is probably insufficient for this purpose. For example, the medial and lateral hypothalamic areas cannot be clearly demarcated on current MRI protocols. It is impossible therefore to determine whether even smaller structures, such as the arcuate or paraventricular nuclei, are functionally intact. Nevertheless, De Vile et al3 observed a relation between the extent of hypothalamic damage and severity of postoperative obesity in children with craniopharyngiomas. In contrast, Sorva et al4 found that size of the craniopharyngioma and mode of surgery were not indicative of subsequent obesity in 13 of 21 children followed for 1 year after surgery, although this follow-up was probably inadequate to study long-term weight change. In another series of children surviving brain tumors, the main predictors of weight gain were age at diagnosis, radiation dose, and the presence of any endocrine deficiency.9 It is possible that improved resolution and advances in functional MRI could allow noninvasive assessment of hypothalamic function. In contrast to the findings on MRI, we found that weight gain was associated with certain endocrine replacement requirements. Patients with cranial diabetes insipidus and a long-term requirement for desmopressin gained more weight, possibly because cranial diabetes insipidus may reflect bilateral damage to the paraventricular and supraoptic nuclei in some patients. It may also reflect greater extent of neurosurgical damage in an attempt to achieve radical excision of the tumor, since cranial diabetes insipidus is
49 very rarely a presenting manifestation of these tumors. The paraventricular nucleus not only contains magnocellular neurons that project to the neurohypophysis from where vasopressin is released, but is also an important part of the neuroendocrine circuitry that controls energy balance. It is unlikely therefore that these circuits would be completely intact following a hypothalamic insult that also leads to cranial diabetes insipidus. Treated growth hormone deficiency was also associated with weight gain and obesity in our study. The reduction of lipolytic tone on adipose tissue in adults with growth hormone deficiency results in excessive body fat that is generalized but has a prominent abdominal component.25 Adults with growth hormone deficiency also have a marked deficit in lean body mass,26 and growth hormone replacement consistently results in a sustained increase in lean body mass and a reduction in body fat.27-29 Body weight, however, was not altered in some studies of growth hormone replacement,27,28 although small reductions occurred in others.30,31 Growth hormone deficiency can result from pituitary damage in the absence of hypothalamic involvement, and thus growth hormone deficiency alone is probably not a major determinant of obesity in patients with hypothalamic damage. However, growth hormone deficiency can also reflect hypothalamic damage, which may explain the association in the present study. Indeed, the close proximity of the mechanisms controlling growth hormone release to those controlling energy balance may result in the concomitant impairment of both functions. An increased prevalence of obesity among patients with prolactinomas, and weight loss after reduction in serum prolactin levels, has been found by some investigators32,33 but not others.34 In our study, the diagnosis of prolactinoma was not a feature associated with weight gain. Although these numbers of patients were small, they suggest that prolactin probably does not contribute to weight gain in patients with “hypothalamic obesity.” Although the present study suffers from several obvious limitations, such as the heterogeneity of the study sample, the retrospective design, and the lack of a control group, it nevertheless contains a substantial collection of long-term data on adult as opposed to pediatric patients with this condition. Obesity is a common sequel to hypothalamic damage caused by space-occupying lesions, and clinicians should be aware of this outcome and its clinical importance. Requirements for longterm treatment with desmopressin and growth hormone replacement are associated with an increased risk of weight gain. Early identification of patients at risk could limit the severity of weight gain, through the provision of dietary and behavioral modification, encouragement of regular physical activity, and, perhaps, antiobesity medication. Further clarification of the mechanisms that control food intake and energy homeostasis, and how these are disturbed by damage to the hypothalamus, could lead to the development of new treatments for hypothalamic obesity.
50
References 1. Bray GA, Gallagher TF: Manifestations of hypothalamic obesity in man: a comprehensive investigation of eight patients and a review of the literature. Medicine 54:301–333, 1975 2. Killeffer FA, Stern WE: Chronic effects of hypothalamic injury. Report of a case of near total hypothalamic destruction resulting from removal of a craniopharyngioma. Arch Neurol 22:419 – 429, 1970 3. De Vile CJ, Grant DB, Hayward RD, et al: Obesity in childhood craniopharyngioma: relation to post-operative hypothalamic damage shown by magnetic resonance imaging. J Clin Endocrinol Metab 8:2734 –2737, 1996 4. Sorva R: Children with craniopharyngioma. Early growth failure and rapid postoperative weight gain. Acta Paediatr Scand 77:587–592, 1988 5. Kalapurakal JA, Goldman S, Hsieh YC, et al: Clinical outcome in children with craniopharyngioma treated with primary surgery and radiotherapy deferred until relapse. Med Pediatr Oncol 40:214 –218, 2003 6. Curtis J, Daneman D, Hoffman HJ, Ehrlich RM: The endocrine outcome after surgical removal of craniopharyngiomas. Pediatr Neurosurg 21:24 –27, 1994 7. Pinkney J, Wilding J, Williams G, MacFarlane I: Hypothalamic obesity in humans: what do we know and what can be done? Obes Rev 3:27–34, 2002 8. Hayward R: The present and future management of childhood craniopharyngioma. Childs Nerv Syst 15:764 –769, 1999 9. Lustig RH, Post SR, Srivannaboon K, et al: Risk factors for the development of obesity in children surviving brain tumors. J Clin Endocrinol Metab 88:611– 616, 2003 10. Leong KS, Walker AB, Martin I, et al: An audit of 500 subcutaneous glucagon stimulation tests to assess growth hormone and ACTH secretion in patients with hypothalamic-pituitary disease. Clin Endocrinol (Oxf) 54:463– 468, 2001 11. DeVile CJ, Grant DB, Hayward RD, Stanhope R: Growth and endocrine sequelae of craniopharyngioma. Arch Dis Child 75:108 –114, 1996 12. Sklar CA: Craniopharyngioma: endocrine sequelae of treatment. Pediatr Neurosurg 21:120 –123, 1994 13. Hoffman HJ, De Silva M, Humphreys RP, et al: Aggressive surgical management of craniopharyngiomas in children. J Neurosurg 76:47– 52, 1992 14. Blethen SL: Growth in children with a craniopharyngioma. Pediatrician 14:242–245, 1987 15. Stahnke N, Grubel G, Lagenstein I, Willig RP: Long-term follow-up of children with craniopharyngioma. Eur J Pediatr 142:179 –185, 1984 16. Department of Health: Health Survey for England. Body Mass Index (BMI), by survey year, age and sex (1993-2001). Available at: http:// www.doh.gov.uk/stats/tables/trendtab06.xls. Accessed April 20, 2003. 17. Bray GA: Syndromes of hypothalamic obesity in man. Pediatr Ann 13:525–536, 1984
The American Journal of Medicine, Vol 118, No 1, January 2005 18. Schwartz MW, Woods SC, Porte D Jr, et al: Central nervous system control of food intake. Nature 404:661– 671, 2000 19. Roth C, Wilken B, Hanefeld F, et al: Hyperphagia in children with craniopharyngioma is associated with hyperleptinaemia and a failure in the downregulation of appetite. Eur J Endocrinol 138:89 –91, 1998 20. Inoue S, Bray G: An autonomic hypothesis for hypothalamic obesity. Life Sci 25:561–566, 1979 21. Bray G, Inoue S, Nishizawa Y: Hypothalamic obesity: the autonomic hypothesis and the lateral hypothalamus. Diabetologia 20:366 –377, 1981 22. Jeanrenaud B: An hypothesis on the aetiology of obesity: dysfunction of the central nervous system as a primary cause. Diabetologia 28: 502–513, 1985 23. Lustig RH, Rose SR, Burghen GA, et al: Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist. J Pediatr 135:162–168, 1999 24. King BM, Frohman LA: The role of vagally-mediated hyperinsulinemia in hypothalamic obesity. Neurosci Biobehav Rev 6:205–214, 1982 25. Davidson MB: Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev 8:115–131, 1987 26. Russell-Jones DL, Weissberger AJ, Bowes SB, et al: The effects of growth hormone on protein metabolism in adult growth hormone deficient patients. Clin Endocrinol (Oxf) 38:427– 431, 1993 27. Bengtsson BA, Abs R, Bennmarker H, et al: The effects of treatment and the individual responsiveness to growth hormone (GH) replacement therapy in 665 GH-deficient adults. KIMS Study Group and the KIMS International Board. J Clin Endocrinol Metab 84:3929 –3935, 1999 28. Chrisoulidou A, Beshyah SA, Rutherford O, et al: Effects of 7 years of growth hormone replacement therapy in hypopituitary adults. J Clin Endocrinol Metab 85:3762–3769, 2000 29. Li Voon Chong JS, Groves T, Foy P, et al: Elderly people with hypothalamic-pituitary disease and untreated GH deficiency: clinical outcome, body composition, lipid profiles and quality of life after 2 years compared to controls. Clin Endocrinol (Oxf) 56:175–181, 2002 30. Gotherstrom G, Svensson J, Koranyi J, et al: A prospective study of 5 years of GH replacement therapy in GH-deficient adults: sustained effects on body composition, bone mass, and metabolic indices. J Clin Endocrinol Metab 86:4657– 4665, 2001 31. Hansen TB, Vahl N, Jorgensen JO, et al: Whole body and regional soft tissue changes in growth hormone deficient adults after one year of growth hormone treatment: a double-blind, randomized, placebo-controlled study. Clin Endocrinol (Oxf) 43:689 – 696, 1995 32. Greenman Y, Tordjman K, Stern N: Increased body weight associated with prolactin secreting pituitary adenomas: weight loss with normalization of prolactin levels. Clin Endocrinol (Oxf) 48:547–553, 1998 33. Creemers LB, Zelissen PM, ’t Verlaat JW, Koppeschaar HP: Prolactinoma and body weight: a retrospective study. Acta Endocrinol (Copenh) 125:392–396, 1991 34. Soran H, Wilding J, MacFarlane I: Body weight and prolactinoma: a retrospective study. Int J Obes Relat Metab Disord 28:183, 2004
CLINICAL RESEARCH STUDY
Endocrine and neuroanatomic features associated with weight gain and obesity in adult patients with hypothalamic damage Christina Daousi, MBBS,a Andrew J. Dunn, MBBS,b Patrick M. Foy, MBBS,c Ian A. MacFarlane, MD,a Jonathan H. Pinkney, MDa a
From the Diabetes and Endocrinology Research Group, Department of Radiology, and c Department of Neurosurgery, The Walton Center for Neurology and Neurosurgery, University Hospital Aintree, Liverpool, United Kingdom. b
KEYWORDS: Obesity; Weight gain; Hypothalamus; Craniopharyngioma
Purpose: Obesity is a common consequence in patients with tumors of the hypothalamic region and of related treatment in children. Much less information is available on adult patients and long-term survivors. The aims of this study were to estimate the prevalence of obesity in adult patients with acquired structural hypothalamic damage and to define the characteristics of patients at greatest risk of obesity. Methods: A retrospective study was conducted of 52 patients (25 women; median age at diagnosis, 44 years; range, 17 to 78 years) with tumors involving the hypothalamic region. These included 22 craniopharyngiomas, 24 pituitary adenomas, and six other hypothalamic tumors. Changes in body mass index were determined, magnetic resonance imaging scans were scored by a radiologist for tumor size and the extent of involvement of the hypothalamus, and current hormone replacement therapy was recorded, to identify possible features associated with new or worsened obesity (defined as a body mass index ⱖ30 kg/m2 at the latest follow-up, which had increased by at least 2 kg/m2 since diagnosis of the tumor). Results: Serial body mass index data from diagnosis to the latest follow-up were available for 42 patients. After a median of 5 years (range, 1 to 19 years) of follow-up, most patients with hypothalamic damage were obese (52% [n ⫽ 22] vs. 24% [n ⫽ 10] at the time of diagnosis, P ⬍ 0.0001). In a multivariate model, use of desmopressin (odds ratio [OR] ⫽ 13; 95% confidence interval [CI]: 2.0 to 86; P ⫽ 0.007) and growth hormone replacement (OR ⫽ 7.6; 95% CI: 1.1 to 51; P ⫽ 0.04) were associated with new or worsened obesity during follow-up. No correlation was found between the initial size or location of the tumor and subsequent weight gain. Conclusion: Obesity is highly prevalent in adult survivors of hypothalamic tumors. Use of desmopressin and growth hormone therapy, but not size or location of the tumor, were associated with weight gain and obesity following diagnosis. These findings may be helpful in identifying patients at increased risk of obesity, to whom earlier intervention could be offered. © 2005 Elsevier Inc. All rights reserved.
Requests for reprints should be addressed to: Christina Daousi, MBBS, Diabetes and Endocrinology Research Group, University Hospital Aintree, Clinical Sciences Center, Third Floor, Lower Lane, Liverpool L9 7AL, United Kingdom. E-mail address: [email protected].
0002-9343/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2004.06.035
It has long been recognized that obesity complicates disorders of the hypothalamus and their treatment.1,2 The most common causes of acquired hypothalamic damage are space-occupying lesions, such as craniopharyngiomas and pituitary macroadenomas with suprasellar extension. Weight gain is a common and sometimes distressing long-
46 term consequence of hypothalamic damage in these patients, occurring because of the underlying tumor or its treatment with surgery or radiotherapy.3-6 Excessive weight gain as a manifestation of hypothalamic injury is generally underestimated because it often takes years to develop and the problem may be under-recognized by physicians.7 Most information to date has focused on the endocrine sequelas (including obesity) of treatment of childhood craniopharyngioma and on the identification of the risk factors for obesity in children surviving brain tumors.3-6,8,9 There are far fewer data on the prevalence of obesity following structural hypothalamic damage in adults. We conducted a retrospective study of 52 patients who had presented with tumors involving the hypothalamic region and were thereby at risk of hypothalamic dysfunction. The aims of the study were to estimate the prevalence of current obesity in this patient group, and to define the diagnoses and endocrine characteristics that were most associated with weight gain, relating these markers with anatomic findings from neuroimaging.
Methods Subjects A retrospective study was conducted of 52 adult patients with primary tumors involving the hypothalamic pituitary region. All patients were attending a combined surgical and medical neuroendocrine clinic at the Walton Center for Neurology and Neurosurgery in Liverpool, United Kingdom. Data were obtained from the medical records; permission was given by the Center Audit Department. All patients had undergone treatment for hypothalamic tumors, or adjacent tumors directly compressing or invading the hypothalamus. The data described here represent clinical data up until 2002. There were 28 patients with craniopharyngiomas, Rathke cleft cysts, or other midline tumors with hypothalamic involvement, and 24 with pituitary macroadenomas and suprasellar extension, all of whom had optic chiasmal compression and visual field defects (Figure 1). Neurosurgical procedures were recorded along with the anatomical approach and the need for a ventricular drainage procedure. The administration of conventional fractionated external beam radiotherapy for either residual tumor or recurrence was also recorded. Two patients were treated with radiotherapy alone.
Anthropometric assessment Patients’ height and weight at the time of diagnosis of the tumor were recorded. Body mass index (kg/m2) was calculated at diagnosis and at the most recent follow-up clinic visit. Changes in body mass index were determined to identify the development of new or worsened obesity (defined as a body mass index ⱖ30 kg/m2 at latest follow-up,
The American Journal of Medicine, Vol 118, No 1, January 2005 which had also increased by at least 2 kg/m2 since the diagnosis of the tumor).
Endocrine assessment All patients underwent serial endocrine assessment following treatment. The glucagon stimulation test (GlucaGen; Novo Nordisk Pharmaceuticals, Crawley, United Kingdom) was used to assess adrenocorticotropic hormone and growth hormone reserve.10 Basal levels of thyroid-stimulating hormone, free thyroxine, free triiodothyronine, prolactin, estradiol, testosterone, cortisol, and insulin-like growth factor 1 were also used to assess endocrine status.
Neuroimaging All available pre- and postoperative computed tomographic (CT) and magnetic resonance imaging (MRI) scans for each patient were reviewed and scored by the same radiologist who was blind to the clinical data. The following anatomic features were recorded pre- and postoperatively: primary site of tumor; maximum extent (mm) of the tumor from the midline (to the right and left) on coronal views; presence of suprasellar extension of pituitary tumors; encroachment of pituitary tumors on the optic chiasm; invasion or compression by extrahypothalamic tumors of adjacent hypothalamic tissue; distortion of the third ventricle on coronal images at the level of the infundibulum; any abnormalities of the floor of the third ventricle or breach of the tuber cinereum by the tumor; and infiltration by the tumor of other brain areas, including the thalamus and temporal lobes.
Statistical analysis The Wilcoxon signed-rank test was used to compare longitudinal changes in body mass index in the 42 patients in whom serial weight data (from the time of diagnosis to the most recent follow-up) were available. Categorical data were examined with the chi-squared test or the Fisher exact test, as appropriate. Continuous data were examined with the use of the t test for normally distributed data or the Mann-Whitney U test for non-normally distributed data. Multiple logistic regression analysis was used to identify features associated with weight gain. Variables that differed significantly in the univariate analysis for patients with new or worsened obesity at follow-up were entered into the original model, along with the patients’ current age and age at the time of diagnosis of the tumor, and subjected to forward stepwise logistic regression analysis. Correlations between tumor size and subsequent weight gain were examined using the Spearman rank correlation coefficient for non-normally distributed data. Statistical significance was defined as P ⬍ 0.05 (two-tailed). All analyses were performed using SPSS, version 10.0 (SPSS Inc., Chicago, Illinois).
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Obesity in Adults with Hypothalamic Damage
47
Figure 1 Representative T1-weighted, coronal, postgadolinium images of the patients studied. (A) Suprasellar craniopharyngioma with intense enhancement of the rim of the tumor and invasion of the right temporal lobe. (B) Primary hypothalamic glioma arising above the suprasellar cistern with extension down the infundibulum. (C) Massive, enhancing suprasellar macroprolactinoma encasing both internal carotid arteries, invading the hypothalamus, and causing distortion of the third ventricle. (D) Nonfunctioning pituitary macroadenoma with suprasellar extension compressing the third ventricle, invading the hypothalamus, and encroaching on to the mamillary bodies.
Results Prevalence of obesity At the time of diagnosis and treatment, height and weight measurements were available for 42 of the 52 patients. The mean (⫾SD) age of the 42 patients was 52 ⫾ 14.2 years; 23 (55%) were men (Table 1). Twenty-eight patients (67%) were overweight or heavier (body mass index ⱖ25 kg/m2), 10 (24%) were obese (body mass index ⱖ30 kg/m2), and 2 (5%) had a body mass index ⱖ35 kg/m2; no patients were morbidly obese (body mass index ⱖ40 kg/m2). At the most recent follow-up, a median of 5 years later, the prevalence of obesity had increased substantially among the 42 patients: 37 (88%) were overweight or heavier, 22 (52%) were obese, 10 (24%) had a body mass index ⱖ35 kg/m2, and 1 was morbidly obese (Figure 2). There was a highly significant increase in median body mass index, from 27.8 kg/m2 (interquartile range, 24.2 to 29.8 kg/m2) at baseline to 30.4
kg/m2 (interquartile range, 27.3 to 34.8 kg/m2) at the latest follow-up (P ⬍ 0.0001).
Endocrine replacement at follow-up In 2002, 47 (90%) of the 52 patients were receiving replacement therapy with one or more pituitary hormone replacements, including 14 who were receiving desmopressin for cranial diabetes insipidus. Postoperatively, 3 other patients developed transient cranial diabetes insipidus. Currently, patients attending this clinic who have severe growth hormone deficiency (defined as a peak growth hormone response ⬍9 mU/L to provocative testing), adequate replacement of other pituitary hormone deficiencies, and impaired quality of life are offered a trial of growth hormone replacement therapy; 34 patients in this group were receiving growth hormone replacement therapy. Three others with severe growth hormone deficiency declined this treatment.
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The American Journal of Medicine, Vol 118, No 1, January 2005
Table 1
Characteristics of the patients, according to obesity status New or Worsened Obesity (n ⫽ 18)
No Weight Gain (n ⫽ 24)
Number (%) or Mean ⫾ SD
Characteristic Current age (years) Age at diagnosis (years) Male sex Years of follow-up Baseline body mass index (kg/m2) Current body mass index (kg/m2) Trans-sphenoidal surgery Transfrontal surgery Radiotherapy Ventriculoperitoneal shunt Hydrocortisone replacement Growth hormone replacement Thyroxine replacement Sex steroids Desmopressin Invasion of thalamus on MRI Invasion of temporal lobe on MRI Abnormalities of third ventricle
47.2 ⫾ 11.9 39.2 ⫾ 13.1 9 (50) 7.4 ⫾ 5.5 28.3 ⫾ 3.7 35.1 ⫾ 3.3 8 (44) 8 (44) 10 (55) 1 (5) 16 (89) 16 (89) 16 (89) 15 (83) 10 (55) 0 0 4 (22)
55.5 ⫾ 14.9 47.6 ⫾ 15.4 14 (58) 6.7 ⫾ 5.1 26.7 ⫾ 4.4 27.7 ⫾ 4.1 14 (58) 6 (25) 9 (37) 3 (12) 14 (58) 12 (50) 13 (54) 13 (54) 2 (8) 2 (8) 2 (8) 9 (37)
P Value 0.06 0.07 0.8 0.6 0.2 ⬍0.0001 0.5 0.3 0.4 0.6 0.04 0.01 0.02 0.06 0.001 1.00 1.00 0.6
MRI ⫽ magnetic resonance imaging.
Endocrine replacement associated with obesity and weight gain since diagnosis
P ⫽ 0.04) were associated with the development of new or worsened obesity during follow-up.
Patients with new or worsened obesity at follow-up were more likely to be receiving growth hormone replacement therapy (P ⫽ 0.01), hydrocortisone (P ⫽ 0.04), thyroxine (P ⫽ 0.02), or desmopressin (P ⫽ 0.001), or to have treated or untreated severe growth hormone deficiency (P ⫽ 0.04) (Table 1). In a multivariate model, use of desmopressin (odds ratio [OR] ⫽ 13; 95% confidence interval [CI]: 2.0 to 86; P ⫽ 0.007) and growth hormone (OR ⫽ 7.6; 95% CI: 1.1 to 51;
Neuroanatomic features associated with obesity and weight gain since diagnosis
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2
Body Mass Index (kg/m )
45 40 35 30 25
Preoperative neuroimaging scans were available for 26 patients and postoperative scans were available for 39 patients. No correlation was found between the width of tumor from midline on preoperative or postoperative MRI/CT coronal views and change in body mass index (Spearman r ⫽ ⫺0.3, P ⫽ 0.3). Radiologic involvement of the thalamus or temporal lobe, distortion of the third ventricle on coronal images at the level of the infundibulum, abnormalities of the floor of the third ventricle, and breach of the tuber cinereum by the tumor were not associated with weight gain (Table 1). Similarly, neither a history of transfrontal surgery (implying the initial presence of more extensive tumor and greater likelihood of perioperative hypothalamic damage) nor insertion of a ventriculoperitoneal shunt was associated with increased weight gain following diagnosis.
20
Discussion
15 10
Baseline
Follow-up
Figure 2 Changes in body mass index among the 42 patients during a median follow-up of 5 years.
Few studies have investigated the neuroanatomic and endocrine features associated with weight gain and obesity in adults with hypothalamic damage. Weight gain and obesity have been studied in children treated for craniopharyngioma, in whom deficiencies of pituitary hormones are com-
Daousi et al
Obesity in Adults with Hypothalamic Damage
mon along with weight gain, which leads to obesity in up to 50% to 80% of children.3,4,11-15 Our data show that obesity is also a post-treatment complication in adults with hypothalamic injury. After a median follow-up of 5 years, 52% of patients with hypothalamic lesions were obese, compared with only 24% at the time of diagnosis. Data from the general U.K. population16 indicate that the prevalence of obesity (body mass index ⱖ30 kg/m2) in adults aged 45 to 54 years increased from 18% in 1993 to 27% in 2001. Therefore, the weight gain observed in the present study is clearly in excess of the weight gain expected from demographic trends over the same time period in the background population of similar age to our cohort. Hypothalamic obesity is thought to result from disruption of mechanisms that control satiety and hunger.17 The medial hypothalamus contains nuclear groups controlling energy balance, and damage to these structures, which include the arcuate, paraventricular, ventromedial, and dorsomedial nuclei, leads to weight gain.18 All of these nuclei are vulnerable to midline lesions of the hypothalamus and pituitary tumors with suprasellar extension. Interrupted responses to anorectic signals such as leptin and insulin, caused by hypothalamic damage, is one possible mechanism contributing to obesity.19 Autonomic nervous system imbalance and hyperinsulinemia may also be involved in the development of human hypothalamic obesity.7,20-24 We found no relation between neuroanatomic extent of the tumor and weight gain. However, the resolution of current MRI scanning is probably insufficient for this purpose. For example, the medial and lateral hypothalamic areas cannot be clearly demarcated on current MRI protocols. It is impossible therefore to determine whether even smaller structures, such as the arcuate or paraventricular nuclei, are functionally intact. Nevertheless, De Vile et al3 observed a relation between the extent of hypothalamic damage and severity of postoperative obesity in children with craniopharyngiomas. In contrast, Sorva et al4 found that size of the craniopharyngioma and mode of surgery were not indicative of subsequent obesity in 13 of 21 children followed for 1 year after surgery, although this follow-up was probably inadequate to study long-term weight change. In another series of children surviving brain tumors, the main predictors of weight gain were age at diagnosis, radiation dose, and the presence of any endocrine deficiency.9 It is possible that improved resolution and advances in functional MRI could allow noninvasive assessment of hypothalamic function. In contrast to the findings on MRI, we found that weight gain was associated with certain endocrine replacement requirements. Patients with cranial diabetes insipidus and a long-term requirement for desmopressin gained more weight, possibly because cranial diabetes insipidus may reflect bilateral damage to the paraventricular and supraoptic nuclei in some patients. It may also reflect greater extent of neurosurgical damage in an attempt to achieve radical excision of the tumor, since cranial diabetes insipidus is
49 very rarely a presenting manifestation of these tumors. The paraventricular nucleus not only contains magnocellular neurons that project to the neurohypophysis from where vasopressin is released, but is also an important part of the neuroendocrine circuitry that controls energy balance. It is unlikely therefore that these circuits would be completely intact following a hypothalamic insult that also leads to cranial diabetes insipidus. Treated growth hormone deficiency was also associated with weight gain and obesity in our study. The reduction of lipolytic tone on adipose tissue in adults with growth hormone deficiency results in excessive body fat that is generalized but has a prominent abdominal component.25 Adults with growth hormone deficiency also have a marked deficit in lean body mass,26 and growth hormone replacement consistently results in a sustained increase in lean body mass and a reduction in body fat.27-29 Body weight, however, was not altered in some studies of growth hormone replacement,27,28 although small reductions occurred in others.30,31 Growth hormone deficiency can result from pituitary damage in the absence of hypothalamic involvement, and thus growth hormone deficiency alone is probably not a major determinant of obesity in patients with hypothalamic damage. However, growth hormone deficiency can also reflect hypothalamic damage, which may explain the association in the present study. Indeed, the close proximity of the mechanisms controlling growth hormone release to those controlling energy balance may result in the concomitant impairment of both functions. An increased prevalence of obesity among patients with prolactinomas, and weight loss after reduction in serum prolactin levels, has been found by some investigators32,33 but not others.34 In our study, the diagnosis of prolactinoma was not a feature associated with weight gain. Although these numbers of patients were small, they suggest that prolactin probably does not contribute to weight gain in patients with “hypothalamic obesity.” Although the present study suffers from several obvious limitations, such as the heterogeneity of the study sample, the retrospective design, and the lack of a control group, it nevertheless contains a substantial collection of long-term data on adult as opposed to pediatric patients with this condition. Obesity is a common sequel to hypothalamic damage caused by space-occupying lesions, and clinicians should be aware of this outcome and its clinical importance. Requirements for longterm treatment with desmopressin and growth hormone replacement are associated with an increased risk of weight gain. Early identification of patients at risk could limit the severity of weight gain, through the provision of dietary and behavioral modification, encouragement of regular physical activity, and, perhaps, antiobesity medication. Further clarification of the mechanisms that control food intake and energy homeostasis, and how these are disturbed by damage to the hypothalamus, could lead to the development of new treatments for hypothalamic obesity.
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