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0013-7227/02/$15.00/0 Printed in U.S.A. The Journal of Clinical Endocrinology & Metabolism 87(12):5430 –5434 Copyright © 2002 by The Endocrine Society doi: 10.1210/jc.2002-020672 CLINICAL CASE SEMINAR A 43-Year-Old Male with Untreated Panhypopituitarism due to Absence of the Pituitary Stalk: From Dwarf to Giant D. T. DEN OUDEN, M. KROON, P. H. HOOGLAND, P. H. L. M. GEELHOED-DUIJVESTIJN, J. M. WIT AND Departments of Internal Medicine (D.T.d.O., P.H.L.M.G.-D.), Clinical Chemistry (M.K.), and Radiology (P.H.H.), MCH Westeinde Hospital, 2501 CK The Hague, The Netherlands; and Department of Pediatrics, Leiden University Medical Center (J.M.W.), 2300 RC Leiden, The Netherlands A 43-yr-old male was referred because of an x-ray made after a fall, which showed open epiphysis of the arm. The man had always been short for his age; during childhood he once consulted a pediatrician because of short stature, but thereafter he never sought medical attention. At age 18 yr he was not allowed to join the army because of his height of 147 cm. He continued to grow steadily and finally reached 193 cm. He had no complaints and considered himself reasonably fit. Physical examination showed a disproportional man with a body mass index of 29.3 kg/m2 and Tanner stage P1G1. Laboratory investigations showed hormone levels consistent with multiple pituitary deficiency, with dynamic tests consistent with hypo- C ONGENITAL HYPOPITUITARISM IS a rare disorder consisting of multiple deficiencies of hormones originating from the adenohypophysis (GH, TSH, ACTH, and gonadotropins). It is also called multiple pituitary deficiency (MPD). It may lead to clinical signs at birth (hypoglycemia, prolonged jaundice, and micropenis) and severe growth retardation. Therefore, it is usually diagnosed in infancy or childhood. In many cases magnetic resonance imaging (MRI) shows an absence or hypoplasia of the pituitary stalk, a small anterior pituitary remnant, and the presence of an ectopic posterior pituitary at or below the tuber cinereum (1– 6). Treatment consists of substitution doses of GH, T4, hydrocortisone, and (during adolescence) sex steroids. With timely and adequate therapy, rapid catch-up growth and normalization of serum T4, cortisol, and eventually sex hormones occur, and final height is often within the genetic target range (7). Due to the extreme symptoms and clinical signs, treatment is usually provided in infancy or early childhood, so there is little documentation about the natural history of untreated MPD. To date, seven case reports have been published (8 – 14). There is more information about the final height of patients with MPD who were treated with T4, hydrocortisone, and sex steroids, but not with GH. They showed a final height of –3.1 sd score (15). Abbreviations: BMI, Body mass index; MPD, multiple pituitary deficiency; MRI, magnetic resonance imaging. thalamic or pituitary stalk disease. Magnetic resonance scanning of the brain showed a small anterior pituitary remnant, no pituitary stalk, and an ectopic neurohypophysis. This case of untreated panhypopituitarism shows a particular growth curve with an average growth velocity of 2 cm/yr, resembling patients with estrogen receptor mutation or aromatase deficiency. A literature study of other adult patients with untreated panhypopituitarism shows a variable growth pattern. Some speculations about possible reasons for this variability in clinical characteristics are presented. (J Clin Endocrinol Metab 87: 5430 –5434, 2002) Here, we describe the case of a 43-yr-old man with untreated congenital hypopituitarism due to absence of the pituitary stalk, who accidentally came under our attention during a visit to a hospital for a fracture. Case Report The male patient, who was born in 1956, was 193 cm tall when he presented to the orthopedic surgeon with an upper arm fracture after a fall. The humerus x-ray showed an open epiphysis. He was then referred to the internist, who diagnosed hypothyroidism, hypogonadism, and hypocorticism. Laboratory findings are shown in Table 1. Treatment with T4 and low dose hydrocortisone was initiated, and the patient was referred to our center for further analysis. The patient’s medical history revealed that he was the child of healthy and unrelated parents. His father is 172 cm, and his mother is 158 cm, which results in a target height (midparental height corrected for sex and secular change of ⫹4.5 cm/generation) of 175.5 cm. He was born fullterm, with unknown birth weight. He was examined by a pediatrician at 9 yr of age because of short stature. Unfortunately, the exact data from this visit are no longer available, but in the letter to the general practitioner a height of “10 centimeters short for his age” (presumably 10 cm below the third percentile) was mentioned. He had normal intelligence and normal body proportions. His bone age was described as being slightly retarded, and the metabolic rate was slightly decreased, for which the patient received thyroid hormone. Because of side-effects, the patient discontinued the medication and did not return to the pediatrician. From then on he did not see a doctor concerning his short stature or any other complaints. At age 18 yr, he was not allowed to join the army because of his height of 147 cm. He reported that he had always been much shorter than other boys of his age until approximately 25 yr of age. Thereafter, he had gradually become taller than most of his contempo- 5430 den Ouden et al. • Clinical Case Seminar J Clin Endocrinol Metab, December 2002, 87(12):5430 –5434 5431 TABLE 1. Hormonal measurements at presentation and after treatment May 1999a Cortisol (nmol/ liter) ACTH (ng/liter) Aldosterone (pmol/liter) Renin (ng/liter) Androsteredione (nmol/liter) Testosterone (nmol/liter) SHBG (nmol/ liter) DHEA-S (mol/ liter) LH (U/liter) FSH (U/liter) Prolactin (mU/ liter) Estradiol (nmol/ liter) Progesterone (nmol/liter) GH (mU/liter) IGF-I (nmol/ liter) IGF BP-3 (mg/ liter) TSH (mU/liter) FT4 (pmol/liter) 70 Oct. 1999b 306 Reference 96 150–700 8.6 133 0–50 170– 610 2 2.4 5– 65 1.7–10.0 ⬍0.1 ⬍0.7 18 12 ⬍0.1 0.4 290 Oct. 2000c 9.8 16 10–70 2.3 ⬍0.8 2.2–15.7 ⬍0.7 0.2 140 ⬍0.7 0.1 1.8– 8.0 1.5– 6.0 100–300 FIG. 1. Patient’s growth curve compared with contemporary references. 0.07– 0.15 prompted the consulting internist to substitute T4 and hydrocortisone, and the results after more extensive testing during treatment with 50 g T4 and 10 mg hydrocortisone twice daily. Serum LH, FSH, GH, ACTH, cortisol, testosterone, and SHBG were measured by immunoassay using Immulite (Diagnostic Products, Los Angeles, CA). Aldosterone and androstenedione were measured by RIA (Diagnostic Products), TSH and free T4 were determined by immunoassay (Abbott Laboratories, Chicago, IL), renin was measured by RIA (Bio-Rad Laboratories, Inc., Hercules, CA), and 25-hydroxyvitamin D was determined by RIA (DiaSorin, Inc., Stillwater, MN). Serum gonadotropin levels, testosterone, free T4, IGF-I, and vitamin D were all low, whereas the serum PRL level was normal. Serum TSH was slightly elevated. The results are consistent with MPD (panhypopituitarism). Dynamic tests (Table 2) showed no reaction of serum FSH and LH to LHRH, and the TSH response to TRH was consistent with tertiary hypothyroidism, as observed in patients with absent pituitary stalk. The CRH test was performed after withdrawal of hydrocortisone for 1 d, and there were very small responses of ACTH and cortisol. The GHRH test showed a minimal response of serum GH with a peak of 0.7 mU/liter (0.3 mg/liter). ⬍0.07 0.08 ⬍0.6 0.0–2.0 ⬍0.1 4.5 0.0–13.0 13.0–39.0 1.90 7.35 6.1 8.0–35.0 1.6 8.3 2.08– 4.31 0.15 9.4 0.40– 4.0 10.0–21.0 DHEA-S, Dehydroepiandrosterone sulfate; IGFBP-3, IGF-binding protein 3; FT4, free T4. a First presentation elsewhere. b T4 and hydrocortisone suppletion; testosterone starting dose. c T4, hydrocortisone, and testosterone suppletion. raries. His estimated growth curve compared with the 1980 Dutch references (16) is shown in Fig. 1. He stated that he had no physical discomfort, no gynecomastia, no signs of orthostatic hypotension, and normal urine frequency, and he indicated no symptoms of hypothyroidism. He never had any facial, axillary, or pubic hair. He reported some erections, but no ejaculations. He considered himself reasonably fit and stated that he never used any medication, had stopped smoking 10 yr previously, and drank a maximum of one glass of alcohol per week. He disliked sunlight because he was easily sunburned. He had finished high school (A level) and worked in an administrative job in an office. At physical examination he looked young for his age (see Fig. 2). His height was 193 cm (1.64 sd score for the Dutch 1980 nationwide references) (16), 17.5 cm above target height. His sitting height was 91 cm (P25) (17), his leg length was 102 cm (3 cm above the 97th percentile) (17), his arm span was 200 cm, his weight was 109 kg, his blood pressure was 140/80 mm Hg, and his heart rate was 80 beats/min. His body mass index (BMI) was 29.3 kg/m2. His voice was high-pitched. He had Tanner stage P1G1. There was no gynecomastia. Thoracic kyphoscoliosis and flat feet were present. No abnormalities of heart, lungs, or abdomen were found. Laboratory investigations Erythrocyte sedimentation rate, hematological parameters, blood glucose, and serum sodium, potassium, calcium, phosphate, magnesium, and creatinine were normal. Serum alkaline phosphatase was slightly elevated (138 U/liter; reference range, ⬍120), as were alanine aminotransferase (78 U/liter; reference range, 15– 45), aspartate aminotransferase (73 U/liter; reference range, 11– 40), and ␥-glutamyltransferase (277 U/liter; reference range, 8 –50). Table 1 shows the hormonal levels at presentation previously, which Radiology The thoracic x-ray showed severe kyphosis. The x-ray of the left hand and wrist showed a bone age of 16 yr according to Greulich and Pyle (18) (Fig. 3). Bone densitometry of the lumbar spine showed a z-score of – 0.59; the femur head showed a z-score of – 0.16. MRI of the sella turcica showed a small anterior pituitary remnant on the sella floor, no pituitary stalk, and an ectopic neurohypophysis (Fig. 4). Echocardiography showed normal left ventricle function. At an exercise-electrocardiogram test (after substitution of T4, hydrocortisone, and testosterone), a maximum of predicted 225 watts was reached at a maximum heart rate of 158 beats/min and a maximum blood pressure of 176/60 mm Hg (normal). Discussion Agenesis of the pituitary stalk is a well described syndrome in pediatric literature, usually associated with MHD or, more rarely and probably in cases of partial stalk transsection, with isolated GH deficiency (1– 4). However, this case is remarkable for various reasons. In the first place it is the particular growth curve, showing severe growth retardation in childhood and adolescence, a very low height for age at 18 yr (147 cm), and continuing growth from 18 – 43 yr of age, with an average growth velocity of 2 cm/yr up to a height considerably taller than the target height calculated from midparental height. Such tall stature associated with 5432 J Clin Endocrinol Metab, December 2002, 87(12):5430 –5434 den Ouden et al. • Clinical Case Seminar FIG. 2. Patient at presentation: 43 yr old. TABLE 2. Dynamic hormonal tests Test performed CRH, 100 ga GHRH, 200 g LHRH, 100 g TRH, 200 gb Glucose, 75 g a b ACTH (ng/liter) Cortisol (nmol/liter) GH (mU/liter) FSH (U/liter) LH (U/liter) TSH (mU/liter) Prolactin (mU/liter) Glucose (mmol/liter) Insulin (mU/liter) T⫽0 T ⫽ 15 ⬍0.5 388 ⬍0.1 0.1 ⬍0.7 1.8 140 5.9 27.1 9.6 286 0.3 T ⫽ 20 T ⫽ 30 T ⫽ 60 T ⫽ 90 min ⬍5.0 273 0.5 ⬍5.0 370 0.7 0.4 ⬍0.7 6.7 278 7.7 ⬍5.0 217 0.5 0.1 ⬍0.7 5.6 337 7.0 58.5 5.0 No hydrocortisone 1 d before test. No T4 1 d before test. eunuchoid habitus and open epiphyses is strongly reminiscent of the findings in a previously reported patient with estrogen receptor mutation (19) and patients with aromatase deficiency (20, 21), except that those patients had normal growth during childhood. Indeed, our patient had immeasurable serum estradiol levels, which may explain the absence of final fusion of the epiphyses. However, our case shows that such continuing growth can even occur in a patient with GH deficiency and low serum T4 levels. This indicates that in the absence of estrogens, normal GH and T4 secretion are not necessary conditions for continuing growth. A second remarkable observation is that in an industrialized country a 43-yr-old man with a deficiency of GH and androgens and a partial deficiency of the pituitary-thyroid and pituitary-adrenal axis has not been in contact with the medical profession since the age of 10 yr. Usually growth retardation is detected at routine school examinations in childhood or adolescence, or anxiety of the child and the parents about short stature or pubertal delay lead to referral to a pediatrician. In addition, it is remarkable that he has been able to live a regular life without subjective complaints. There is little information on the natural history of MPD; to date, six adult untreated panhypopituitarism patients have been described, for whom the characteristics are summarized in Table 3. There is a variable presentation, which is clear from this table; the hormonal abnormalities are comparable, but the physical presentations seem to differ among patients. The patients are sorted in this table according to height. Based on this small group of adult panhypopituitarism patients, it is difficult to make a statement about the existence of subgroups that differ in growth pattern, but it seems that that there is a taller subgroup and a shorter one. The trend is that taller patients also seem to have higher BMIs than shorter patients (normal to high BMIs vs. BMIs well below 20). Although high BMIs with especially high body fat mass, as in our patient, are known in MPD patients (22), this does not seem to be the case in the other relatively tall patients. den Ouden et al. • Clinical Case Seminar J Clin Endocrinol Metab, December 2002, 87(12):5430 –5434 5433 FIG. 4. MRI of the sella turcica, showing a small anterior pituitary remnant (arrow) on the sella floor, no pituitary stalk, and an ectopic neurohypophysis. FIG. 3. X-Ray of the left hand/wrist: bone age 16 yr. TABLE 3. Patient characteristics of six adult patients in literature with untreated panhypopituitarism compared with our patient Age (yr), gender Height (cm) Weight (kg) BMI (kg/m2) Bone age (yr) MRI Cortisol (ng/ml) ACTH (ng/liter) LH (U/liter) FSH (U/liter) Prolactin (ng/ml) GH (ng/ml) IGF-I (ng/ml) TSH (mU/liter) CRH test (g given) ACTH (ng/liter) peak GHRH test (g given) GH (mU/liter) Insulin test (IU/kg) GH (mU/liter) peak LHRH test (g given) LH (U/liter) peak FSH (U/liter) peak TRH test (g given) TSH (mU/liter) peak prolactin (ng/ml) peak Our patient Kageyama (12) Wada (14) Badawy (10) Navarro (9) Arrigo (11) Pentimone (13) 43, M 193 109 29.3 16 Small ant. pit., no pit. stalk, ectopic post. lobe 2 Low N 2 2 High N 2 2 1 100 sign. 1 200 NS ND 37, M 185 84 24.5 15 Transected pit. stalk, ectopic post. lobe 23, M 175 79.2 26.0 14 Transected pit. stalk, ectopic post. lobe 21, F 163 63.3 23.8 14 Ectopic post. pit. 29, M 153 43.3 18.5 13 Absent post. lobe and pit. stalk 25, M 149 38 17.2 12.5 Pit. stalk interruption 2 Low N 2 2 High N 2 2 1 100 sign. 1 100 NS 0.05 NS 100 NS NS 500 sign. 1 60⬘ sign. 1 2 Low N 2 2 1 2 2 High N 100 sign. 1 100 NS 0.05 NS 100 NS NS 500 sign. 1 60⬘ sign. 1 2 ND N 2 1 2 2 2 2 2 1 2 2 1 100 sign. 1 65 sign. 1 0.15 NS 100 NS NS 200 sign. 1 45⬘ ND 2 ND 2 2 ND ND ND N ND 48, M 148 40 18.3 17 No pit. stalk, small ant. pit., ectopic post. lobe 2 2 2 2 ND 2 ND 1 100 NS ND 100 NS NS 200 sign. 1 60⬘ sign. 1 1 ND ND ND 200 Unclear sign. 1 500 sign. 1 30⬘ sign. 1 ND 0.1 NS 63 NS NS 200 sign. 1 120⬘ ND ND 100 NS NS 200 sign. 1 120⬘ sign. 1 ant., Anterior; pit., pituitary; post., posterior; N, normal; sign., significant; NS, not significant; ND, not done. We can only speculate about the reason for these differences between the clinical characteristics of these small groups of adult untreated panhypopituitarism patients. For our patient and the two others with similar growth patterns, one can postulate that because of the total absence of estra- diol, the epiphyses did not close, and the patient kept growing, possibly because of factors other than GH or IGF-I. A possible candidate for such a growth factor could be insulin, which in our rather obese patient may be secreted more than in the other cases. Insulin can act as a growth stimulus, 5434 J Clin Endocrinol Metab, December 2002, 87(12):5430 –5434 probably partially through activating the IGF-I receptor (23), and it has been suggested that elevated insulin secretion causes the continuing growth without GH in children with craniopharyngioma (24). However, we cannot prove this hypothesis, because insulin secretion was not measured before treatment. A second possible growth stimulus in patients with low GH secretion is PRL in high levels, which has been implicated in the pathophysiology of growth without GH in craniopharyngioma (24). However, in our patient serum PRL was not elevated. Another option is the existence of an unknown growth factor or abnormal serum concentrations of IGF-binding proteins, which could be responsible for the slow but steady growth in patients who are GH deficient. Alternatively, the observation by Wiedemann and Schwartz (25, 26) that estrogens have a slightly antagonistic effect on the bioactivity of GH could explain why in the absence of estrogens the low GH secretion present has a greater effect than expected. Finally, differences in insulin and/or sex steroid sensitivity could be postulated. Further research will be necessary to reach a better understanding of this subject. With respect to growth of patients with MPD, there are some data for patients only treated with T4, hydrocortisone, and (at a relatively late stage) sex steroids, but not with GH. They showed a mean height sd score of –3.1 (15), which was not much lower than the final heights of patients treated with GH in relatively low dosages and at low injection frequency, but was higher than the final heights of untreated patients with GH deficiency. The observation that these patients did not continue to grow can be explained by the treatment with sex steroids. The patient is now being treated with T4, hydrocortisone, and testosterone. Although he reported no physical problems before treatment, now he says that he has never felt as good, and that his sex life has improved. We expect that testosterone treatment will increase serum estradiol sufficiently to close the epiphyses and stop further growth. We believe that GH treatment would further improve his physical status and quality of life (27). This may also improve his cardiac performance, although there are no complaints or objective evidence of heart problems to date. In conclusion, this case shows the natural history of untreated panhypopituitarism due to congenital agenesis of the neural pituitary stalk and demonstrates that continuing growth is possible even without normal GH and T4 secretion. Acknowledgments Received April 30, 2002. Accepted September 7, 2002. Address all correspondence and requests for reprints to: Dr. D. T. den Ouden, Department of Internal Medicine, MCH Westeinde Hospital, P.O. Box 432, 2501 CK The Hague, The Netherlands. E-mail: [email protected]. den Ouden et al. • Clinical Case Seminar 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. References 26. 1. Hamilton J, Blaser S, Daneman D 1998 MR imaging in idiopathic growth hormone deficiency. Am J Neuroradiol 19:1609 –1615 2. Hamilton J, Chitayat D, Blaser S, Cohen LE, Phillips III JA, Daneman D 1998 27. Familial growth hormone deficiency associated with MRI abnormalities. Am J Med Genet 80:128 –132 Kaufman BA, Kaufman B, Mapstone TB 1988 Pituitary stalk agenesis: magnetic resonance imaging of ‘ectopic posterior lobe’ with surgical correlation. Pediatr Neurosci 14:140 –144 Takamura T, Ohsawa K, Nishimura Y, Yamagishi S, Komatsu Y, Iwata A, Osada S, Nagai Y, Miyakoshi H, Kobayashi K 1995 An adult case of neurohypophyseal ectopy presenting ACTH deficiency and partial GH deficiency. Endocr J 42:83– 88 Crottaz B, Uske A, Reymond MJ, Rey F, Temler E, Germond M, Gomez F 1996 Normogonadotropic primary amenorrhea in a growth hormone-deficient woman with ectopic posterior pituitary: gonadotropin pulsatility and folliclestimulating hormone bioactivity. J Endocrinol Invest 19:48 –53 Maghnie M, Genovese E, Villa A, Spagnolo L, Campan R, Severi F 1996 Dynamic MRI in the congenital agenesis of the neural pituitary stalk syndrome: the role of the vascular pituitary stalk in predicting residual anterior pituitary function. Clin Endocrinol (Oxf) 45:281–290 Wit JM, Kamp GA, Rikken B 1996 Spontaneous growth and response to growth hormone treatment in children with growth hormone deficiency and idiopathic short stature. Pediatr Res 39:295–302 Tolis G, Cruess S, Goldstein M, Friesen HG, Rochefort JG 1974 Survival and growth in a woman with untreated hypothalamic panhypopituitarism of 21 years’ duration. Can Med Assoc J 111:553–556 Navarro P, Halperin I, Rodriguez C, Gonzalez JM, Vidal J, Vilardell E 1994 Congenital panhypopituitarism of late onset. J Endocrinol Invest 17:347–350 Badawy SZ, Pisarska MD, Wasenko JJ, Buran JJ 1994 Congenital hypopituitarism as part of suprasellar dysplasia. A case report. J Reprod Med 39:643– 648 Arrigo T, Crisafulli G, Salamone A, Cucinotta D, De Luca F 1994 Adult height exceeding target height in a patient with congenital panhypopituitarism diagnosed after the age of 25 years. J Pediatr Endocrinol 7:269 –272 Kageyama K, Watanobe H, Nasushita R, Nishie M, Horiba N, Suda T 1998 A hypopituitary patient who attained tall stature without growth hormone. Intern Med 37:472– 475 Pentimone F, Riccioni S, Del Corso L 1999 Congenital hypopituitarism in a 48-year old adult. Natural course, hormonal study and MRI evidence. Panminerva Med 41:351–354 Wada S, Minagawa A, Imamaki K, Suda S, Yamanaka K, Iitaka M, Katayama S 2000 A patient of hypogonadotropic hypogonadism accompanied by growth hormone deficiency and decreased bone mineral density who attained normal growth. Intern Med 39:641– 645 van der Werff ten Bosch JJ, Bot A 1990 Growth of males with idiopathic hypopituitarism without growth hormone treatment. Clin Endocrinol (Oxf) 32:707–717 Roede MJ, van Wieringen JC 1985 Growth diagrams 1980. Netherlands third nationwide survey. Tijdschr Soc Gezondheidszorg 63(Suppl):1–34 Gerver WJ, de Bruin R 1996 Body composition in children based on anthropometric data. A presentation of normal values. Eur J Pediatr 155:870 – 876 Greulich WW, Pyle SI 1959 Radiographic atlas of skeletal development of the hand and wrist. Stanford, CA: Stanford University Press Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS 1994 Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331:1056 –1061 Conte FA, Grumbach MM, Ito Y, Fisher CR, Simpson ER 1994 A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). J Clin Endocrinol Metab 78:1287–1292 Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K 1995 Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 80:3689 –3698 Rosen T, Bosaeus I, Tolli J, Lindstedt G, Bengtsson BA 1993 Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency. Clin Endocrinol (Oxf) 38:63–71 Chernausek SD, Jacobs S, Van Wyk JJ 1981 Structural similarities between human receptors for somatomedin C and insulin: analysis by affinity labeling. Biochemistry 20:7345–7350 Bucher H, Zapf J, Torresani T, Prader A, Froesch ER, Illig R 1983 Insulin-like growth factors I and II, prolactin, and insulin in 19 growth hormone-deficient children with excessive, normal, or decreased longitudinal growth after operation for craniopharyngioma. N Engl J Med 309:1142–1146 Schwartz E, Wiedemann E, Simon S, Schiffer M 1969 Estrogenic antagonism of metabolic effects of administered growth hormone. J Clin Endocrinol Metab 29:1176 –1181 Wiedemann E, Schwartz E 1972 Suppression of growth hormone-dependent human serum sulfation factor by estrogen. J Clin Endocrinol Metab 34:51–58 Murray RD, Skillicorn CJ, Howell SJ, Lissett CA, Rahim A, Smethurst LE, Shalet SM 1999 Influences on quality of life in GH deficient adults and their effect on response to treatment. Clin Endocrinol (Oxf) 51:565–573