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Post-traumatic hypopituitarism due to a hypothalamic lesion
Post-traumatic Hypopituitarism Due to a Hypothalamic Lesion
LUBOMIR
J. VALENTA,
M.D., Ph.D.
DON R. De FEO, M.D. Irvine, California
Two patients were studied who suffered from severe head trauma with skull fracture. Hypopituitarism developed in both. Because of elevated serum prolactin levels and because of preserved response of some of the pituitary hormones to exogenolis thyrotropin and gonadotropin-releasing hormones, the responsible lesion in both cases was most likely suprase!lar. Findings of interest included slightly elevated thyroid-stimulating hormone (TSH) levels in the presence of hypothyroidism in on6 of the patients, and dissociation of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responsiveness to both gonadotropin-releasing hormone and clomiphene c&ate in the other patient. It is suggested that the diagnosis of post-traumatic hypopituitarism be considered in patients with head trauma and that periodictilly appropriate laboratory testing be performed to confirm ihe diagnosis. Permanent diabetes insipidus is a relatively rare complication of head trauma and brain surgery [l]. Even less frequently, head trauma results in anterior pituitary deficiency. Thus far, only 20 ca&eshave been reported in the literature [l-7]. More frequbntly, necrosis of the anterior lobe of the pituitary gland has been found in patients who died from head trauma, and it has been suggested that rupture of the pituitary stalk or compromised blood supply might have been responsible for the pituitary lesion [8-lo]. Furthermore, ischemic or hemorrhagic lesions of the anterior hypothalamus were described in as many as 42.5 per cent of a total of 106 cases of closed head injury and were shown to be frequently associated with pituitary infarction Ill]. Recently, cases have been reported in which the diagnosis of a hypothalamic rather than a pituitary lesion was made also on clinical grounds [4,5,7]. It is important to think about post-traumatic hypopituitarism especially sinke cortisol deficiency can contribute to the pathology and prognosis of acute trauma, and panhypopituitarism can increase the morbidity of the patient later on. Described herein are two patients who suffered from severe head trauma and skull fracture. In one of them, panhypopituitarism developed subsequently. In the other, partial hypopituitarism manifested mainly as amenorrhea which responded to repeated courses of clomipherie citrate therapy. CASE REPORTS
Fromthe Departments of Medicine and Surgery, University of California at Irvine .Irvine, California. Requests for reprints should be addressed to Dr. Lubomir J. Valenta, P.O. Box 4157, Irvine, California 92716. Manuscript accepted July 5, 1979.
614
Patient 1. This 21 year old man was involved in a car accident and suffered a skull fracture. Within 12 months after the accident he had cold intolerance, dry skin, weakness, loss of skin pigmentation, loss of facial and body hair, and impotence; he lost about 20 kg of weight. An immediate consequence of the injury was blindness in the left eye. The patient was first seen 12 months after the accident. He measured 193 cm, and his weight was 76 kg. His body pro-
April 1960 The American Journal of Medicine
Volume 66
POST-TRAUMATIC
TABLE I
De FE0
Results of the Pituitary Reserve Test in Case 1
Wn)
GIU (g/100 ml)
cortisol (rs/iOO ml)
0 15 30 45 60
90 70 30 25 100
2 1 2 4 3
The
HYPOPITUITARISM-VALENTA,
(Illk2l)
9.2 12.5 12.8 13.3 13.1
FSH (mlU/ml)
TSH WlmJ)
3.4 4.1 4.3 4.7 5.7
10.7 15.2 21.8 22.9 20.5
PRL bWml) 40.7 40 41 42 40.7
NOTE: Glu = glucose, GH = growth hormone, LH = luteinizing hormone, FSH = follicle-stimulating hormone, TSH = thyroid-stimulating hormone, PRL = prolactin. All hormones were measured by specific radioimmunoassays using a double antibody technique.
portions were normal, the distance from crown to pubis was 95 cm, pubis to heels 98 cm, and his arm span was 4 cm shorter than his height. His blood pressure was 100/80 mmHg, showed moderate postural changes, and his pulse rate was 68/min. His mentation was slow. His skin tias pale, dry and cold in the acral parts. There were only traces of axillary and pubic hair, and thin light hair in the face which did not require shaving. The patient was blind in the left eye, and there was a slight asymmetry in the face with partial right facial nerve paralysis. His sense of smell was normal, the remaining cranial nerve functions were also intact, and the rest of the neurologic examination did not show any motor or sensory deficits. The patient admitted impotence, and the absence of erections and ejaculations. His penis was normal in size, but both testicles were soft and diminished in size, to a longest diameter of 1.5 cm. Past history revealed normal puberty which started at age 12 years: normal development of the secondary sex characteristics; facial hair which required daily shaving; heavy body hair; and a normal sex life. Skull films showed a healed fracture of the cranium. The sella turcica was intact. All results on the multichannel biochemical profile of the serum were within normal limits. The blood count showed slight anemia with a hematocrit value of 34 per cent and a hemoglobin level of 12.6 g/106 ml; the white blood cell count showed 4 per cent eosinophils and 42 per cent lymphocytes. The base line hormonal studies were as follows: serum thyroxine (Td) 4.7 pg/lOO ml (normal values 5 to 13 pg/lOO ml], triiodothyronine resin uptake (TsRU) 28 per cent (25 to 36). triiodothyronine by radioimmunoassay (T3 RIA) 54 ng/lOO ml (80 to 160 ng/lOO ml) and TSH 10.7 pU/ml, repeated 11.5 (normal is less than 8 pU/ml). Serum cortisol was 2 pg/lOO ml (normal 10 to 20 pg/loO ml in A.M.] and 1 pg/loO ml 8 hours after the oral administration of 3 g metopirone at midnight. At the same time, ll-deoxycortisol (compound S) was 1.8 ~g/lOO ml when normal response should be over 8 pg/lOO ml. Plasma ACTH was 22 pg/ml (normal A.M. values 20 to 80 pg/ml); serum testosterone was 4 ng/lOO ml (normal 400 to 1,000 mg/lOO ml]. Serum LH was 9.2 mIU/ml (normal values for males 5 to 22 mIU/ml), and FSH 3.4 mIU/ml (normal 3 to 17 mIU/ml). Thus, all these findings were compatible with panhypopituitarism with decreased levels of both pituitary and target gland hormones. The results of a pituitary reserve test are summarized in Table I. The test was performed by simultaneous administration of 506 pg thyrotropin-releasing hormone (TRH), 100 rg gonadotropin-releasing hormone (GnRH) and 0.15 U/kg body weight of regular insulin at time zero, after the blood was drawn for determination of base line hormone levels.
April
Significant hypoglycemia was achieved by the intravenous administration of insulin but without appropriate increase in serum cortisol and growth pormone. Base line levels of serum gonadotropins were in the low normal range, but inappropriately low for testosterone (4 ng/lOO ml). The response of the gonadotropins to GnRH was severely blunted. The base line TSH level was slightly elevated and the response to TRH was normal. [Our normal response is between 6 and 25 @J/ml.) The base line prolactin level was elevated. [Normal values for males are between 3 and 18 ng/ml.) There was no response of prolactin to TRH. The patient was treated with l-thyroxine and is currently taking 0.3 mg a day, he is also receiving hydrocortisone, 20 mg in the morning and 10 mg in the evening, and intramuscular injections of testosterone enanthate, 200 mg twice a month. With this therapy, the patient is asymptomatic. He gained about 25 kg of weight, mostly due to the increase in muscle mass without increased adiposity. He is shaving daily; there was a regrowth of the body hair, and he has a regular sex life. The pituitary reserve test was repeated during this therapeutic regimen, after the patient withheld his medications for 24 hours, and yielded the following data: T4 9.2 kg/loo ml, TsRU 31 per cent, T3RIA 84 ng/ml, serum testosterone [four days after the intramuscular administration of 200 mg testosterone enanthate) was 1,036ng/106 ml. The fasting A.M. serum cortisol level was 2 pg/lOO ml, and there was no increase after insulin-induced hypoglycemia (serum glucose of 19 mg/loO ml]. At the same time, plasma ACTH sightly increased from 14 pg/ml to 63 pg/ml. Fasting serum growth hormone was unmeasurable and did not increase in response to hypoglycemia. TSH, LH and FSH were all unmeasurable, and were not stimulated by TRH or GnRH, respectively. Serum prolactin was increased to 52 ng/ml. and there was no change during the test. These data indicate adequate hormonal replacement therapy and suggest again the presence of a suprasellar lesion resulting in growth hormone and partial ACTH deficiency, and in excess of prolactin. Case 2. This 16 year old girl, six months prior to admission, suffered a skull fracture with a head injury. She had retrograde amnesia for the accident and the circumstances leading to it. At the time of admission she still suffered from poor memory, loss of concentration ability and expressive aphasia. She also complained of slow mentation and tiredness. Since the accident she has had amenorrhea. Her medical history revealed that her menarche was at age 11. She had normal secondary sex characteristics, and her menses were always regular. She has never taken oral contraceptives or been pregnant.
1980
The American Journal of Medicine
VoIume 88
615
POST-TRAUMATIC HYPOPITUITARISM-VALENTA, De FE0
On physical examination the patient was slightly diffusely obese. Her blood pressure was 110/80 mm Hg, without postural changes, and the pulse rate was 66/min. She was clinically euthyroid. The body hair was of normal female type of distribution. She had small breasts without discharge, and there was generalized hyperreflexia of the deep tendon reflexes. The rest of the physical examination was within normal limits. The multichannel biochemical profile of the serum was normal and the complete blood count was within normal limits. A.M. serum cortisol was 9 pg/lOO ml, T4 5.2 rg/lOO ml, TsRU 30 per cent and TsRL4 110 ng/lOO ml, all borderline low. Serum TSH was inappropriately low for the T4 values, 2.9 /III/ml. A single dose (3 g) metopirone test result was normal with the increase of compound S to 12 &ldO ml. A.M. fasting serum growth hormone was below 1 ng/ml, and it failed to increase following insulin-induced hypoglycemia. Serum prolacfin was 35 ng/ml with normal values in females in fo% licular phase up to 30 ng/ml. A GnRH stimulation test was performed with the measurements of serum LH and FSH. Base line values were 11 and 12 mIU/ml, respectively. There was a normal response of LH with the increase up to 42 mIU/ml, whereas FSH increased to the maximum of only 16 mIU/ml at 45 minutes after the intravenous administration of the GnRH. Clomiphene citrate was given in a dose of 50 mg twice a day for five days. Serum LH and FSH were measured before and seven days after the patient started the medication. Serum LH increased from 15 to 38 mIU/ml, but serum FSH did not change at all. Thus, these data were compatible with borderline secondary hypothyroidism and with growth hormone deficiency. There was blunted response of FSH to the GnRH and absent response to clomiphene citrate, but the response of LH was normal. The pituitary-adrenal axis also seemed to function normally. The patient was treated with l-thyroxine, 0.2 mg daily, and her symptoms, namely, tiredness, slow mentation and tendency to weight gain, subsided substantially. Thus far she has not resumed spontaneous menstrual periods, but she has responded each time to a repeated course of clomiphene citrate therapy. After she had been treated, the patient’s serum prolactin remained in the range of 35 to 45 ng/ml. Her growth hormone deficiency was re-evaluated using the glucagon test. Glucagon (1 mg) was administered intravenously, and serum growth hormone, insulin and glucose were measured before and 5, l5,30,60,9O,l2O,l50 minutes after the injection. The growth hormone remained unmeasurable whereas there was a normal increase in serum insulin and glucose. COMMENTS
The case reports presented are compatible with panhypopituitarism in the male patient [Case 1) and partial hypopituitarism in the female patient [Case 2). A hypothalamic rather than a pituitary lesion was suggested in both by low or borderline low levels of serum pituitary hormones as well as target endocrine gland hormones, and by more or less normal responsiveness of the pituitary hormones to exogenous hypothalamic releasing hormones, namely, thyrotropin- and gonadotropin-releasing hormones. Blunted response of the
616
April 1966 The American Journal of Medicine
gonadotropins might have represented inadequate “priming” by the endogenous GnRH during the prolonged period of time between the injury and the time of examination. The failure of insulin-induced hypoglycemia, as well as of metopirone, to increase the responsiveness of the pituitary-adrenal axis was obviously due to the fact that normal responsiveness requires intact hypothalamic centers. Suprasellar origin of the disturbance was further suggested in both of our patients by elevated serum prolactin levels, and lack of response of prolactin to TRH in Case 1. These findings are compatible with an escape of the lactotrophs from the inhibitory influences of the hypothalamic centers. Several findings in our patients deserve a specific comment. In secondary hypothyroidism one would expect the levels of both T4 and TSH to be low. In our male patient instead, we have consistently observed mildly elevated TSH levels in the presence of low serum T4 levels as if he had suffered from primary hypothyroidism at the same time. However, the patient did not give any history of thyroid disease, goiter or any medication inhibiting thyroid function. Interestingly, borderline high. serum TSH levels and exaggerated response of TSH to TRH in the presence of low serum T4 was also reported by Dzur and Winternitz [7] in their case of post-traumatic hypopituitarism. Elevated basal TSH levels as well as normal or even exaggerated response of TSH to TRH have been reported in a number of patients with hypothalamic hypothyroidism. This was a subject of a recent review by Faglia et al. [12]. These investigators also presented data on biologic activity of the TSH in such conditions using a cytochemical assay, and demonstrated low or absent biologic activity. Thus, it appears that a hypothalamic lesion can result in hypothyroidism by two different mechanisms: (1) by an absolute lack of TSH or (21by a lack of biologically active TSH in the presence of normal or elevated immunoreactive TSH levels. Our patient [Case l] suggests that the latter situation may develop even after a head trauma. It is also interesting to note that in our female patient (Case 2) there was a dissociation in stimulation of the’ gonadotropins by both GnRH and clomiphene citrate. Although the LH response was normal, the FSH response was blunted or absent. It remains unresolved whether the decapeptide known as GnRH is the only hormone stimulating release of both gonadotropins or whether separate stimulators exist for LH and FSH. Our findings may speak in favor of the latter hypothesis and could be explainable by inadequate “priming” of the gonadotrophs by lacking endogenous FSH-releasing hormone. Furthermore, it is of interest that clomiphene citrate repeatedly induced ovulation and menstruation which did not occur spontaneously. The site of action of clomiphene citrate is presumably the hypothalamus, and its action involves stimulation of the secretion of GnRH. Thus, the absence of spontaneous menstrual cycles may be compatible with a lesion in a hypothetic,
Volume 66
POST-TRAUMATIC HYPOPITUITARISM-VALENTA.
anatomically separate area regulating cyclic secretion of the GnRH, or with a functional disturbance in the centers directly responsible for the GnRH secretion. The importance of measuring serum cortisol levels in patients after head trauma has been emphasized previously. We certainly do not want to diminish the importance of serial cortisol determination after head trauma. However, the diagnostic efforts should not concentrate on serum cortisol alone and should include other pituitary functions as well. Persistent elevation of serum prolactin is an important diagnostic feature of a suprasellar lesion. Most of the patients with severe head injury are receiving large doses of dexamethasone,
De FE0
which would prevent the adrenocortical crisis at the time of the trauma. The onset of the symptoms of posttraumatic hypopituitarism is insidious so that it may escape the attention of both the physician and the patient, or the symptoms are ascribed to post-traumatic neurosis. Therefore, it is important to think about the existence of this entity and to perform periodical laboratory hormonal studies in the early post-traumatic period. ACKNOWLEDGMENT
The synthetic GnRH (Factrel) was a gift of Ayerst Corporation.
REFERENCES 1. Porter RJ, Miller RA: Diabetes insipidus following closed head iniurv. I Neurol NeurosuraY Psvchiat 1948: 2:258” 262. ’ ” ’ 2. McCullanh EP. Schaffenburs CA: Teachinn Clinic. Anterior pituitary insufficiency folgwing.skull fracture. J Clin Endocrinol Metab 1953: 13:1283-1290. 3. Altman R. Pruzanski W Post-traumatic hypopituitarism. Ann Intern Med 1961; 55:149-154. 4. Klachko DM, Winer, N, Burns TW, White JE: Traumatic hypopituitarism occurring before puberty: survival 35 years untreated. J Clin Endocrinol Metab 1968; 28:17681772. 5. Woolf PD. Schalch DS: Hypopituitarism secondary to hypothalamic insufficiency. Ann Intern Med 1973; 78:8890. 6. Hollingsworth DR, Archer R: Massive virginal breast hypertrophy at puberty Am 1Dis Child 1973; i25:293-295.
Dzur J. Winternitz WW: Posttraumatic hypopituitarism: anterior uituitarv insufficiencv secondarv to head trauma. So Med J-1976; 69~1377-1379._ 8. Kornblum RN. Fisher RS: Pituitarv lesions in craniocerebral injuries. Arch Path01 1969; 88:242-248. 9. Daniel PM. Prichard MML. Trein CS: Traumatic infarction of the anterior lobe of the pituitary gland. Lancet 195% 2: 927-930. 10. Ceballos R: Pituitary changes in head trauma (analysis of 102 consecutive cases of head injury). Ala J Med Sci 1966; 3: 185-198. 11. Crompton MR: Hypothalamic lesions following closed head injury. Brain 1971; 94:165-172. 12. Faglia G. Bitenski L, Pinchera A, et al.: Thyrotropin secretion in patients with central hypothyroidism. Evidence for reduced biological activity of immunoreactive thyrotropin. J Clin Endocrinol Metab 1979: 48:989.
April 1980
7.
The American Journal of Medicine
Volume 68
617
LUBOMIR
J. VALENTA,
M.D., Ph.D.
DON R. De FEO, M.D. Irvine, California
Two patients were studied who suffered from severe head trauma with skull fracture. Hypopituitarism developed in both. Because of elevated serum prolactin levels and because of preserved response of some of the pituitary hormones to exogenolis thyrotropin and gonadotropin-releasing hormones, the responsible lesion in both cases was most likely suprase!lar. Findings of interest included slightly elevated thyroid-stimulating hormone (TSH) levels in the presence of hypothyroidism in on6 of the patients, and dissociation of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responsiveness to both gonadotropin-releasing hormone and clomiphene c&ate in the other patient. It is suggested that the diagnosis of post-traumatic hypopituitarism be considered in patients with head trauma and that periodictilly appropriate laboratory testing be performed to confirm ihe diagnosis. Permanent diabetes insipidus is a relatively rare complication of head trauma and brain surgery [l]. Even less frequently, head trauma results in anterior pituitary deficiency. Thus far, only 20 ca&eshave been reported in the literature [l-7]. More frequbntly, necrosis of the anterior lobe of the pituitary gland has been found in patients who died from head trauma, and it has been suggested that rupture of the pituitary stalk or compromised blood supply might have been responsible for the pituitary lesion [8-lo]. Furthermore, ischemic or hemorrhagic lesions of the anterior hypothalamus were described in as many as 42.5 per cent of a total of 106 cases of closed head injury and were shown to be frequently associated with pituitary infarction Ill]. Recently, cases have been reported in which the diagnosis of a hypothalamic rather than a pituitary lesion was made also on clinical grounds [4,5,7]. It is important to think about post-traumatic hypopituitarism especially sinke cortisol deficiency can contribute to the pathology and prognosis of acute trauma, and panhypopituitarism can increase the morbidity of the patient later on. Described herein are two patients who suffered from severe head trauma and skull fracture. In one of them, panhypopituitarism developed subsequently. In the other, partial hypopituitarism manifested mainly as amenorrhea which responded to repeated courses of clomipherie citrate therapy. CASE REPORTS
Fromthe Departments of Medicine and Surgery, University of California at Irvine .Irvine, California. Requests for reprints should be addressed to Dr. Lubomir J. Valenta, P.O. Box 4157, Irvine, California 92716. Manuscript accepted July 5, 1979.
614
Patient 1. This 21 year old man was involved in a car accident and suffered a skull fracture. Within 12 months after the accident he had cold intolerance, dry skin, weakness, loss of skin pigmentation, loss of facial and body hair, and impotence; he lost about 20 kg of weight. An immediate consequence of the injury was blindness in the left eye. The patient was first seen 12 months after the accident. He measured 193 cm, and his weight was 76 kg. His body pro-
April 1960 The American Journal of Medicine
Volume 66
POST-TRAUMATIC
TABLE I
De FE0
Results of the Pituitary Reserve Test in Case 1
Wn)
GIU (g/100 ml)
cortisol (rs/iOO ml)
0 15 30 45 60
90 70 30 25 100
2 1 2 4 3
The
HYPOPITUITARISM-VALENTA,
(Illk2l)
9.2 12.5 12.8 13.3 13.1
FSH (mlU/ml)
TSH WlmJ)
3.4 4.1 4.3 4.7 5.7
10.7 15.2 21.8 22.9 20.5
PRL bWml) 40.7 40 41 42 40.7
NOTE: Glu = glucose, GH = growth hormone, LH = luteinizing hormone, FSH = follicle-stimulating hormone, TSH = thyroid-stimulating hormone, PRL = prolactin. All hormones were measured by specific radioimmunoassays using a double antibody technique.
portions were normal, the distance from crown to pubis was 95 cm, pubis to heels 98 cm, and his arm span was 4 cm shorter than his height. His blood pressure was 100/80 mmHg, showed moderate postural changes, and his pulse rate was 68/min. His mentation was slow. His skin tias pale, dry and cold in the acral parts. There were only traces of axillary and pubic hair, and thin light hair in the face which did not require shaving. The patient was blind in the left eye, and there was a slight asymmetry in the face with partial right facial nerve paralysis. His sense of smell was normal, the remaining cranial nerve functions were also intact, and the rest of the neurologic examination did not show any motor or sensory deficits. The patient admitted impotence, and the absence of erections and ejaculations. His penis was normal in size, but both testicles were soft and diminished in size, to a longest diameter of 1.5 cm. Past history revealed normal puberty which started at age 12 years: normal development of the secondary sex characteristics; facial hair which required daily shaving; heavy body hair; and a normal sex life. Skull films showed a healed fracture of the cranium. The sella turcica was intact. All results on the multichannel biochemical profile of the serum were within normal limits. The blood count showed slight anemia with a hematocrit value of 34 per cent and a hemoglobin level of 12.6 g/106 ml; the white blood cell count showed 4 per cent eosinophils and 42 per cent lymphocytes. The base line hormonal studies were as follows: serum thyroxine (Td) 4.7 pg/lOO ml (normal values 5 to 13 pg/lOO ml], triiodothyronine resin uptake (TsRU) 28 per cent (25 to 36). triiodothyronine by radioimmunoassay (T3 RIA) 54 ng/lOO ml (80 to 160 ng/lOO ml) and TSH 10.7 pU/ml, repeated 11.5 (normal is less than 8 pU/ml). Serum cortisol was 2 pg/lOO ml (normal 10 to 20 pg/loO ml in A.M.] and 1 pg/loO ml 8 hours after the oral administration of 3 g metopirone at midnight. At the same time, ll-deoxycortisol (compound S) was 1.8 ~g/lOO ml when normal response should be over 8 pg/lOO ml. Plasma ACTH was 22 pg/ml (normal A.M. values 20 to 80 pg/ml); serum testosterone was 4 ng/lOO ml (normal 400 to 1,000 mg/lOO ml]. Serum LH was 9.2 mIU/ml (normal values for males 5 to 22 mIU/ml), and FSH 3.4 mIU/ml (normal 3 to 17 mIU/ml). Thus, all these findings were compatible with panhypopituitarism with decreased levels of both pituitary and target gland hormones. The results of a pituitary reserve test are summarized in Table I. The test was performed by simultaneous administration of 506 pg thyrotropin-releasing hormone (TRH), 100 rg gonadotropin-releasing hormone (GnRH) and 0.15 U/kg body weight of regular insulin at time zero, after the blood was drawn for determination of base line hormone levels.
April
Significant hypoglycemia was achieved by the intravenous administration of insulin but without appropriate increase in serum cortisol and growth pormone. Base line levels of serum gonadotropins were in the low normal range, but inappropriately low for testosterone (4 ng/lOO ml). The response of the gonadotropins to GnRH was severely blunted. The base line TSH level was slightly elevated and the response to TRH was normal. [Our normal response is between 6 and 25 @J/ml.) The base line prolactin level was elevated. [Normal values for males are between 3 and 18 ng/ml.) There was no response of prolactin to TRH. The patient was treated with l-thyroxine and is currently taking 0.3 mg a day, he is also receiving hydrocortisone, 20 mg in the morning and 10 mg in the evening, and intramuscular injections of testosterone enanthate, 200 mg twice a month. With this therapy, the patient is asymptomatic. He gained about 25 kg of weight, mostly due to the increase in muscle mass without increased adiposity. He is shaving daily; there was a regrowth of the body hair, and he has a regular sex life. The pituitary reserve test was repeated during this therapeutic regimen, after the patient withheld his medications for 24 hours, and yielded the following data: T4 9.2 kg/loo ml, TsRU 31 per cent, T3RIA 84 ng/ml, serum testosterone [four days after the intramuscular administration of 200 mg testosterone enanthate) was 1,036ng/106 ml. The fasting A.M. serum cortisol level was 2 pg/lOO ml, and there was no increase after insulin-induced hypoglycemia (serum glucose of 19 mg/loO ml]. At the same time, plasma ACTH sightly increased from 14 pg/ml to 63 pg/ml. Fasting serum growth hormone was unmeasurable and did not increase in response to hypoglycemia. TSH, LH and FSH were all unmeasurable, and were not stimulated by TRH or GnRH, respectively. Serum prolactin was increased to 52 ng/ml. and there was no change during the test. These data indicate adequate hormonal replacement therapy and suggest again the presence of a suprasellar lesion resulting in growth hormone and partial ACTH deficiency, and in excess of prolactin. Case 2. This 16 year old girl, six months prior to admission, suffered a skull fracture with a head injury. She had retrograde amnesia for the accident and the circumstances leading to it. At the time of admission she still suffered from poor memory, loss of concentration ability and expressive aphasia. She also complained of slow mentation and tiredness. Since the accident she has had amenorrhea. Her medical history revealed that her menarche was at age 11. She had normal secondary sex characteristics, and her menses were always regular. She has never taken oral contraceptives or been pregnant.
1980
The American Journal of Medicine
VoIume 88
615
POST-TRAUMATIC HYPOPITUITARISM-VALENTA, De FE0
On physical examination the patient was slightly diffusely obese. Her blood pressure was 110/80 mm Hg, without postural changes, and the pulse rate was 66/min. She was clinically euthyroid. The body hair was of normal female type of distribution. She had small breasts without discharge, and there was generalized hyperreflexia of the deep tendon reflexes. The rest of the physical examination was within normal limits. The multichannel biochemical profile of the serum was normal and the complete blood count was within normal limits. A.M. serum cortisol was 9 pg/lOO ml, T4 5.2 rg/lOO ml, TsRU 30 per cent and TsRL4 110 ng/lOO ml, all borderline low. Serum TSH was inappropriately low for the T4 values, 2.9 /III/ml. A single dose (3 g) metopirone test result was normal with the increase of compound S to 12 &ldO ml. A.M. fasting serum growth hormone was below 1 ng/ml, and it failed to increase following insulin-induced hypoglycemia. Serum prolacfin was 35 ng/ml with normal values in females in fo% licular phase up to 30 ng/ml. A GnRH stimulation test was performed with the measurements of serum LH and FSH. Base line values were 11 and 12 mIU/ml, respectively. There was a normal response of LH with the increase up to 42 mIU/ml, whereas FSH increased to the maximum of only 16 mIU/ml at 45 minutes after the intravenous administration of the GnRH. Clomiphene citrate was given in a dose of 50 mg twice a day for five days. Serum LH and FSH were measured before and seven days after the patient started the medication. Serum LH increased from 15 to 38 mIU/ml, but serum FSH did not change at all. Thus, these data were compatible with borderline secondary hypothyroidism and with growth hormone deficiency. There was blunted response of FSH to the GnRH and absent response to clomiphene citrate, but the response of LH was normal. The pituitary-adrenal axis also seemed to function normally. The patient was treated with l-thyroxine, 0.2 mg daily, and her symptoms, namely, tiredness, slow mentation and tendency to weight gain, subsided substantially. Thus far she has not resumed spontaneous menstrual periods, but she has responded each time to a repeated course of clomiphene citrate therapy. After she had been treated, the patient’s serum prolactin remained in the range of 35 to 45 ng/ml. Her growth hormone deficiency was re-evaluated using the glucagon test. Glucagon (1 mg) was administered intravenously, and serum growth hormone, insulin and glucose were measured before and 5, l5,30,60,9O,l2O,l50 minutes after the injection. The growth hormone remained unmeasurable whereas there was a normal increase in serum insulin and glucose. COMMENTS
The case reports presented are compatible with panhypopituitarism in the male patient [Case 1) and partial hypopituitarism in the female patient [Case 2). A hypothalamic rather than a pituitary lesion was suggested in both by low or borderline low levels of serum pituitary hormones as well as target endocrine gland hormones, and by more or less normal responsiveness of the pituitary hormones to exogenous hypothalamic releasing hormones, namely, thyrotropin- and gonadotropin-releasing hormones. Blunted response of the
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April 1966 The American Journal of Medicine
gonadotropins might have represented inadequate “priming” by the endogenous GnRH during the prolonged period of time between the injury and the time of examination. The failure of insulin-induced hypoglycemia, as well as of metopirone, to increase the responsiveness of the pituitary-adrenal axis was obviously due to the fact that normal responsiveness requires intact hypothalamic centers. Suprasellar origin of the disturbance was further suggested in both of our patients by elevated serum prolactin levels, and lack of response of prolactin to TRH in Case 1. These findings are compatible with an escape of the lactotrophs from the inhibitory influences of the hypothalamic centers. Several findings in our patients deserve a specific comment. In secondary hypothyroidism one would expect the levels of both T4 and TSH to be low. In our male patient instead, we have consistently observed mildly elevated TSH levels in the presence of low serum T4 levels as if he had suffered from primary hypothyroidism at the same time. However, the patient did not give any history of thyroid disease, goiter or any medication inhibiting thyroid function. Interestingly, borderline high. serum TSH levels and exaggerated response of TSH to TRH in the presence of low serum T4 was also reported by Dzur and Winternitz [7] in their case of post-traumatic hypopituitarism. Elevated basal TSH levels as well as normal or even exaggerated response of TSH to TRH have been reported in a number of patients with hypothalamic hypothyroidism. This was a subject of a recent review by Faglia et al. [12]. These investigators also presented data on biologic activity of the TSH in such conditions using a cytochemical assay, and demonstrated low or absent biologic activity. Thus, it appears that a hypothalamic lesion can result in hypothyroidism by two different mechanisms: (1) by an absolute lack of TSH or (21by a lack of biologically active TSH in the presence of normal or elevated immunoreactive TSH levels. Our patient [Case l] suggests that the latter situation may develop even after a head trauma. It is also interesting to note that in our female patient (Case 2) there was a dissociation in stimulation of the’ gonadotropins by both GnRH and clomiphene citrate. Although the LH response was normal, the FSH response was blunted or absent. It remains unresolved whether the decapeptide known as GnRH is the only hormone stimulating release of both gonadotropins or whether separate stimulators exist for LH and FSH. Our findings may speak in favor of the latter hypothesis and could be explainable by inadequate “priming” of the gonadotrophs by lacking endogenous FSH-releasing hormone. Furthermore, it is of interest that clomiphene citrate repeatedly induced ovulation and menstruation which did not occur spontaneously. The site of action of clomiphene citrate is presumably the hypothalamus, and its action involves stimulation of the secretion of GnRH. Thus, the absence of spontaneous menstrual cycles may be compatible with a lesion in a hypothetic,
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POST-TRAUMATIC HYPOPITUITARISM-VALENTA.
anatomically separate area regulating cyclic secretion of the GnRH, or with a functional disturbance in the centers directly responsible for the GnRH secretion. The importance of measuring serum cortisol levels in patients after head trauma has been emphasized previously. We certainly do not want to diminish the importance of serial cortisol determination after head trauma. However, the diagnostic efforts should not concentrate on serum cortisol alone and should include other pituitary functions as well. Persistent elevation of serum prolactin is an important diagnostic feature of a suprasellar lesion. Most of the patients with severe head injury are receiving large doses of dexamethasone,
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which would prevent the adrenocortical crisis at the time of the trauma. The onset of the symptoms of posttraumatic hypopituitarism is insidious so that it may escape the attention of both the physician and the patient, or the symptoms are ascribed to post-traumatic neurosis. Therefore, it is important to think about the existence of this entity and to perform periodical laboratory hormonal studies in the early post-traumatic period. ACKNOWLEDGMENT
The synthetic GnRH (Factrel) was a gift of Ayerst Corporation.
REFERENCES 1. Porter RJ, Miller RA: Diabetes insipidus following closed head iniurv. I Neurol NeurosuraY Psvchiat 1948: 2:258” 262. ’ ” ’ 2. McCullanh EP. Schaffenburs CA: Teachinn Clinic. Anterior pituitary insufficiency folgwing.skull fracture. J Clin Endocrinol Metab 1953: 13:1283-1290. 3. Altman R. Pruzanski W Post-traumatic hypopituitarism. Ann Intern Med 1961; 55:149-154. 4. Klachko DM, Winer, N, Burns TW, White JE: Traumatic hypopituitarism occurring before puberty: survival 35 years untreated. J Clin Endocrinol Metab 1968; 28:17681772. 5. Woolf PD. Schalch DS: Hypopituitarism secondary to hypothalamic insufficiency. Ann Intern Med 1973; 78:8890. 6. Hollingsworth DR, Archer R: Massive virginal breast hypertrophy at puberty Am 1Dis Child 1973; i25:293-295.
Dzur J. Winternitz WW: Posttraumatic hypopituitarism: anterior uituitarv insufficiencv secondarv to head trauma. So Med J-1976; 69~1377-1379._ 8. Kornblum RN. Fisher RS: Pituitarv lesions in craniocerebral injuries. Arch Path01 1969; 88:242-248. 9. Daniel PM. Prichard MML. Trein CS: Traumatic infarction of the anterior lobe of the pituitary gland. Lancet 195% 2: 927-930. 10. Ceballos R: Pituitary changes in head trauma (analysis of 102 consecutive cases of head injury). Ala J Med Sci 1966; 3: 185-198. 11. Crompton MR: Hypothalamic lesions following closed head injury. Brain 1971; 94:165-172. 12. Faglia G. Bitenski L, Pinchera A, et al.: Thyrotropin secretion in patients with central hypothyroidism. Evidence for reduced biological activity of immunoreactive thyrotropin. J Clin Endocrinol Metab 1979: 48:989.
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