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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 12 5430-5434
Copyright © 2002 by The Endocrine Society

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 and J. M. Wit

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

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: denouden99{at}hotmail.com.

Abstract

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 hypothalamic 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.

CONGENITAL 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, 2, 3, 4, 5, 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, 9, 10, 11, 12, 13, 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).

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 1Go. Treatment with T4 and low dose hydrocortisone was initiated, and the patient was referred to our center for further analysis.


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  		Table 1. Hormonal measurements at presentation and after treatment

 
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 full-term, 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 contemporaries. His estimated growth curve compared with the 1980 Dutch references (16) is shown in Fig. 1Go.



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  		Figure 1. Patient’s growth curve compared with contemporary references.

 
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. 2Go). 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.



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  		Figure 2. Patient at presentation: 43 yr old.

 
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 {gamma}-glutamyltransferase (277 U/liter; reference range, 8–50).

Table 1Go shows the hormonal levels at presentation previously, which prompted the consulting internist to substitute T4 and hydrocortisone, and the results after more extensive testing during treatment with 50 µg 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 2Go) 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).


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  		Table 2. Dynamic hormonal tests

 
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. 3Go). 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. 4Go).



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  		Figure 3. X-Ray of the left hand/wrist: bone age 16 yr.

 


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  		Figure 4. MRI of the sella turcica, showing a small anterior pituitary remnant (arrow) on the sella floor, no pituitary stalk, and an ectopic neurohypophysis.

 
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, 2, 3, 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 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 3Go. 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.


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  		Table 3. Patient characteristics of six adult patients in literature with untreated panhypopituitarism compared with our patient

 
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 estradiol, 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, 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

Footnotes

Abbreviations: BMI, Body mass index; MPD, multiple pituitary deficiency; MRI, magnetic resonance imaging.

Received April 30, 2002.

Accepted September 7, 2002.

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