J. Endocrinol. Invest 15: 53-57,1992
CASE REPORT
Isolated adrenocorticotropic hormone deficiency secondary to hypothalamic deficit of corticotropin releasing hormone A. Velardo*, M. Pantaleoni*, G. Zizzo*, G. Del Rio**, F. Coletta*, C. Carani*,
and P. Marrama*
*Cattedra di Endocrinologia e **Cattedra Malattie del Metabolismo Universita di Modena, Modena, Italy ABSTRACT, A 42-year-old man and a 51-year-old woman with a positive history of weakness and 9astrointestinal complaints were shown to have low basal plasma cortisol and ACTH levels, and low daily urinary excretion of free cortisol. An empty sella was found in patient no, 1, while patient no, 2 was hypothyroid, Both patients showed a normal plas-
ma cortisol response to ACTH and an increment in plasma ACTH and lipotropin levels after ovine CRH (oCRH), lysine vasopressin (LVP) and oCRH-LVP stimulation tests, These studies clearly report an isolated idiopathic ACTH deficiency due to a deficit in CRH in two adult subjects,
INTRODUCTION
throughout the day. He reported episodes of accentuated weakness with epigastralgia, postural hypotension and diffusely sweating that ameliorated with water assumption. The presence of insulinoma was excluded on the basis of normal plasma glucose and insulin levels and negative arteriography of the celiac artery. The patient was subsequently referred to our clinic. Physical evaluation revealed normal pigmentation of the skin and mucosal surfaces, depression, asthenia and postural hypotension. Laboratory evaluation revealed hyponatremia (serum sodium: 130 mmol/I; normal 135-140 mmol/I) and fasting serum glucose of 80 mg/dl (normal 55-110 mg/dl). During hospitalization the postprandial plasma glucose was between 55 and 60 mg/dl at several measurements. Urinary excretion of free cortisol (35 Ilg/24 h; normal 40160 Ilg/24 h) basal plasma cortisol (1.0 Ilg/dl; normal 7-20 Ilg/dl) and ACTH levels (6.0 pg/ml; normal 10-50 pg/ml) were abnormally low.
The idiopathic isolated ACTH deficiency is a rare cause of adrenal failure. It has been reported in less than 200 cases after the first observation (1) made in 1954. The etiology of the idiopathic isolated ACTH deficiency is stili not clarified. Although both a congenital deficit (2) and a post-partum necrosis (3) have been claimed as determinants of the disorder, the presence of an autoimmune injury of the pituitary seems more tenable (4). The deficiency in ACTH secretion could also result from an hypothalamic deficit of CRH (5), but the differential diagnosis between the hypothalamic deficit and the pituitary failure was possible only with the availability of the synthetic ovine CRH (oCRH) (6,7). In this work we describe two patients with hypoadrenalism determined by a CRH deficit. CASE REPORTS Case no. 1
Case no. 2
A 42-year-old man had a history of smoking and chronic alcohol abuse. At the time of evaluation he denied recent excessive alcohol consumption. Height was 179 cm, weight 86 kg. The patient presented with a 2-year history of asthenia and fatigue
A 51-year-old menopausal woman was evaluated for a 12-month history of generalized weakness at rising and paresthesia in the upper and lower limbs. On admission the patient was normotensive (i.e, 130/80 mm/Hg) at repeated measurements and without abnormal skin pigmentation. Laboratory findings revealed hypothyroidism (TSH 8.0 IlU/ml; normal 0.5-5.0 IlU/ml; free T4 : 5.3 pg/ml; normal 6.0-18.0 pg/ml) with high antithyroglobulin autoantibodies and antimicrosomial antibodies.
Key-words. ACTH, CRH, secondary hypoadrenalism. Correspondence· Prof. A. Velardo, Cattedra dl Endocrlnologia, Via del Pozzo 71. 41100 Modena, Italy.
Received June 20, 1991, accepted October 22. 1991
53
A Velardo, M Pantaleoni,
G, Zizzo, et. al.
ACTH 1-24, iv) while DHEAS and androstenedione did not change. A biphasic response of plasma ACTH was observed after oCRH administration (1 I1g/kg bw iv; Fig. 1a) while a rise in ACTH levels was observed only 90 min after lysine vasopressin administration (10 UI im; Fig. 1b). The plasma LPH, after oCRH, was found to increase concomitantly to plasma ACTH, with a first peak at 15 min (from 6.2 to 17.0 pg/ml) and a second peak at 90 min (24.2 pg/ml). The simultaneous administration of oCRH and LVP (1 I1g/kg bw oCRH, iv; 10 UI LVP, im) induced a rise in ACTH plasma levels at 60 min with a small increment at 180 min (Fig 1c) An increment in LH (6.3 mUI/ml) was observed after GnRH administration while FSH did not change. GHRH induced a rise in plasma GH levels to 3.2 ng/ml. TSH and PRL levels increased after TRH injection to 12.3I1UI/ml and 24.0 ng/ml respectively.
Urinary free cortisol (18 I1g/24 h; normal 40-160 I1g/24 h) basal plasma cortisol (6,3 I1g/dl; normal 7,0 - 20,0 I1g/dl) and ACTH levels (8,0 pg/ml; normal 10 -50 pg/ml) were abnormally low, Height was 178 cm, weight 86 kg. She had never smoked or consumed alcohol. ANALYTICAL METHODS Specific solid phase fluoroimmunometric assays were employed to measure serum levels of PRL, FSH, LH, free T4 (Wallac,Turku,Finland) and GH (Cyber Fluor, Toronto, Canada). Serum TSH was measured by an immunoradiometric assay (BioRad, Laboratories, Ca, USA). Plasma levels of antiTG-Ab and anti M-Ab were determined by a solid phase immunoradiometric assay (Ares Serono Diagnostici, Milan, Italy). Specific solid phase radioimmunoassays were employed to measure serum levels of androstenedione (Diagnostic Systems Laboratories, Webster,Texas), DHEA-S (Sclavo RIA Department, Milan, Italy), testosterone (Bio Rad, Laboratories, Ca, USA), free T3 (Becton Dickinson, New York, USA), estradiol (E 2 ) (Diagnostic Products Corporation, Ca, USA), cortisol and urinary cortisol (IFCI Clone System, Bologna, Italy). Plasma concentration of ACTH and LPH were determined by competitive liquid phase radioimmunoassay (Nichols Institute, San Juan Capistrano, CA, USA).
Case no. 2 ACTH administration induced a peak rise in cortisol levels to 20.1 I1g/dl, at 60 min and an increase in DHEAS levels to 1.2 I1UI/ml, while androstenedione did not change. A biphasic response of ACTH was Table 1 - Basal hormone levels in a man (case no. 1) and a woman (case no. 2) with CRH deciency Hormone
RESULTS The results of basal plasma hormone levels determinations in the patients are reported in Table 1. Magnetic resonance imaging of the sella turcica and of the hypothalamus revealed an empty sella in patient no. 1 and no alterations in patient no. 2. Provocative tests of the anterior pituitary function with GHRH (1 I1g/kg bw GHRH 1-44, iv), TRH (200 I1g iv) and for patient no. 1 also with GnRH (100 I1g iv) were performed. The hypothalamus-pituitary-adrenal axis function was further evaluated using circadian profile of cortisol and ACTH secretion and urinary free 24-h cortisol excretion. The circadian variation in plasma ACTH and cortisol levels were absent and showed abnormally low levels. A diagnosis of adrenal insufficiency of undetermined etiology was made for both patients and provocative tests for the evaluation of the hypothalamus-pituitary-adrenal axis were performed (Fig. 1).
Case no, 1
Case no. 2
ACTH
6,0
8.0
10-50 pg/ml
LPH
62
4,2
12-115 pg/rn I
Cortisol
1,0
6,3
7-20/lg/dl
Urinary Cortisol
34
18
40-160 /lg/24 h
DHEAS
0,1
0.7
1 1-2,8 /lg/ml
Androstenedione
36
134
30-310 ng/dl
FSH (men) (women)
2,3 38.2
1 7-69 mUI/ml > 3.0 mUI/ml
LH (men) (wornen)
2,0 15.5
14-8,9 mUI/ml > 5,0 mUliml
GH
1,3
3,3
0.6-5,0 nq/ml
PRL
16
12
2-20 ng/ml
TSH
2,0
8,0
0,5-4,5/lUI/ml
FT4
6,3
5.3
60-180 pg/rnl
3,9
2,9
2,8-6,4 pg/m I
Anti-TG Ab
absent
106
< 100 mUl/rnl
Anti-M Ab
absent
358
< 100 mUl/ml
FT3
Case no. 1 The patient showed a peak rise in cortisol levels to 11 I1g Idl 30 min after ACTH administration (025 mg
Testosterone
E2 (menopause)
54
Normal range
360-900 ng/ml
450 12
5-30 pg/m I
Isolated ACTH deficiency
25
oCRH
E ......
20
+
~
15
'"
:z:
a)
0 - 0 Pat. 1
I-
!;!
10 Ii
.'
..
0
......... , .... - ..•..
,-
0
3:1
'i ...... go
~
:z:
~
30 2Ii
20
I
I
15
30
..
-. "
'
.
I
LVP
0-0
•
120
10
50
,4ft.
Pat. 1 Pat. 2
mInute.
b)
15 10
5 0 0
.... ~
'"
20 15
I
I
I
I
30
50
10
120
110
C)
oCRH+LVP
Pat. , .......... Pat. 2
0-0
!
~ ::t:
~
10 .~
11
0
-0
0-
......
mln.....
..................
.............
I
I
0
30
I
50
10
120
110
Fig. 1 - Plasma ACTH levels after provocative stimuli in two patients with hypothalamic deficit of CRH a) Plasma ACTH levels after oCRH (1 J.1g/kg/ bw ivY administration, b) Plasma ACTH levels after LVP (10 UI im) administration; c) Plasma ACTH levels after oCRH (1 J.1g/kg/ bw ivY mln..... and LVP (10 UI im) administration.
chemical signs of chronic adrenal insufficiency (6). The two patients reported in this study showed unequivocally the biochemical and hormonal findings characteristic of the adrenal failure. The clinical presentation and the symptoms in the patient no. 1 herein described were similar to those observed in patients with insulinoma. In our case hypoglycemia was partly due to the previous chronic alcohol consumption as frequently reported in patients with secondary adrenal failure (8). Patient no. 2 on the contrary did not show clinical signs specific for hypoadrenalism since the asthenia was probably due to the hypothyroidism concomitantly present. The hormonal deficiency was not adrenal in origin as demonstrated in both the patients by the rise in serum cortisol after ACTH administration. The blunted peak of plasma cortisol after ACTH iv observed in patient no.1 suggested a longer duration of the disease than in patient no. 2. The results of the CRH test are consistent with an hypothalamic defect (9, 10). The above hypothesis was confirmed by the evaluation of the plasma ACTH responses to LVP administration, a stimulus known to induce ACTH release through a cellu-
observed after oCRH administration (Fig. 1a) with the two peaks occurring at 30 and 90 min. A similar trend was found for LPH levels that showed a small increase at 30 min ( (from 4.2 to 8.1 pg/ml) and a second peak at 90 min (10.0 pg/ml). A rise in ACTH levels was observed only at 60 min after lysine vasopressin administration (Fig. 1b). The simultaneous administration of oCRH and LVP induced a rise in ACTH plasma levels at 60 min (Fig. 1c). GHRH induced a rise in plasma GH levels to 6.4 ng/ml. PRL levels after TRH increased to 33.6 ng/ml; the TSH rise up to 32.0 /lUl/ml after TRH injection confirmed the presence of hypothyroidism in this patient. DISCUSSION The symptoms associated with isolated ACTH deficiency are variable and not specific. The clinical presentation can be similar to that of primary adrenal deficiency but is less severe than the latter and acute adrenal failure is usually absent. Hypoglycemia has been frequently reported to occur in patients with isolated ACTH deficiency and is one of the classical bio-
55
A Ve/ardo, M. Panta/eont, G. Zizzo, et. a/.
lar mechanism different from that of CRH acting directly at the pituitary level (11-13). A peak in ACTH level was observed in both patients 60 min after CRH-LVP administration with a second increment toward the end of curve in patient no. 1. Other authors (14,15) reported a single peak of ACTH after the CRH-LVP test the response was found to be higher than during separate administration of CRH and LVP. Our patients on the contrary did not demonstrate the sinergistic effect of CRH and LVP on ACTH release. The lack of the sinergistic effect of CRH and LVP may be considered as a biochemical characteristic of the patient with hypothalamic deficit of CRH or, more likely, as the result of a large intraindividual variation in the ACTH response to stimuli (16). These hypothesis should be retained with caution since the deficit of CRH is a very uncommon cause of hypoadrenalism and to our knowledge no cases were described with the ACTH response to separate and simultaneous administration of the two peptides. Additional unknown factors that potentiate the ACTH secretion after stimuli should also be considered (17). The radiological finding of an empty sella in patient no. 1 was not completely surprising since other authors were able to describe a similar finding in patients with isolated ACTH deficiency (18-20). The pathological significance of the above association need to be evaluated further. It is known that chronic cortisol deficiency determines functional alterations in pituitary secretion (21). This was observed also in our patients as demonstrated by the blunted GH response to GHRH and by the elevated responses to TRH. These effects were both corrected after cortisone therapy and, in patient no. 2, after thyroid replacement (data not shown). In previously reported cases of isolated ACTH deficiency, the association with other autoimmune endocrine disorders have suggested that an autoimmune injury is responsible for the syndrome (4,22). Our patient no. 2 showed evidence of autoimmune thyroid disease and this finding confirms other reports on isolated ACTH deficiency (23). The presence of anti-CRH antibody, not evaluated in this study, could therefore be responsible of the syndrome in a certain number of cases (4, 24) and could be involved in the absence of ACTH response to CRH observed in patient no. 2. Since CRH and LVP act with different intracellular mechanism to induce ACTH secretion, i.e. the former through a cAMP-dependent pathway while the latter through a cAMP-independent pathway (11, 13), it is also possible to hypothesize a defect in the cellular cAMP-generation. The isolated ACTH deficiency secondary to a CRH
deficit was described by Martin et al. (5) in three children; as far as we know however these are the first two cases described in adults in which the adrenocortical deficiency is secondary to a suprapituitary defect. In conclusion the isolated ACTH deficiency secondary to hypothalamic dysfunction is a heterogeneous disorder characterized by symptoms of adrenocortical insufficiency associated with stimulation of cortisol and ACTH secretion following vasopressin and/or CRH administration.
ACKNOWLEDGMENTS The expert technical support of Dorval Ganazzi is gratefully acknowledged.
REFERENCES 1. Steinberg A, Schecter F.R, Segal H.I. True pituitary Addlson's disease: A pituitary un itrophic deficiency; fifteen years follow-up. J. Clln. Endocrinol. Metab. 14. 1519. 1954. 2. KOlde Y. Yamashita N. Kurusu T. Association of isolated adrenocorticotropin deficiency With a variety of neuro-somatic abnormalities in congenital facial diplegia (Moebius) syndrome. Endocnnoi. Jpn. 30. 499, 1983. 3. Stacpoole PW, Kandell TW. Fisher W. R. Primary empty sella, hyperprolactinemia, and Isolated ACTH deficiency after postpartum hemorrhage. Am. J. Med. 74.905,1983. 4. Sauter N.P. Toni R, McLaughlin CD., Oyess EM. Kntzman J., Lechan R.M. Isolated adrenocorticotropin deficiency associated with an autoantlbody to a cortlcotroph antlgon that IS not adrenocorticotropin or other proopiomelanocortin-derived peptides J. Clin. Endocinol. Metab. 70. 1391, 1990. 5. Martin M.M., Martin M.SA Idiopathic hypoglycemia. A defect in hypothalamic ACTH releasing factor secretion. Pedlatr. Res. 5.396. 1971. 6. Stacpoole PW, Interland JW., Nlcholson W.E . Rabin 0 Isolated ACTH deficiency: A heterogenous disorder. Critical review and report of four new cases. Medicine 61." 13.1982. 7. Nowakowski KJ. Tuccl J.R. Idiopathic isolated ACTH deficiency and the response to CRF. J. Endocrinol. Invest. 12253, 1989. 8. Baba S, Takase S., Uenoyama R., Morita S.. Mlzoi Y, Hishida S Isolated corticotropin-deficiency found through alcohol-induced hypoglycemic coma. Horm. Metab. Res. 8. 274.1976
56
Isolated ACTH deficiency
9. Tsukada T., Nakai Y, Koh T., Tsujii S, Inada M., Nishikawa M., Shinoda H., Kawai I., Takezawa I.H., Imura H. Plasma adrenocortitropin and cortisol responses to ovine corticotropin- releasing factor in patients with adrenocortical insufficiency due to hypothalamic and pituitary disorders. J. Clin. Endocrinol. Metab. 58: 758,1984. 10. Chrousos G.P., Schuermeyer T.H., Doppman J. Clinical applications of corticotropin-releasing factor. Ann. Intern. Med. 102.344,1985.
16. Salata RA, Jarret D.B., Verbal is J.G .. Roblnson AG. Vasopressin stimulation of adrenocorticotropin hormone (ACTH) in humans. In vivo bioassay of corticotropin-releasing factor (CRF) which provides evidence for CRF mediation of the diurnal rhythm of ACTH. J. Clin. Invest. 81.' 766,1988. 17. Linton EA, Lowry PJ. Corticotrophin releasing factor in man and its measurement: a review. Clin. Endocrinol. (Ox!) 31. 225,1989.
11. Gaillard R.C., Schoenenberg P. Favrod-Coune A Properties of rat anterior pituitary vasopressin receptor: relation to adenylate cyclase and the effect of corticotropin-releasing factor. Proc. Natl. Acad. Sci. USA 81.' 2907.1984.
18. Nakagawa H., Nagasaka A, Koie K., Yuasa T., Sakabe Y., Kato 0, Suzuki T., Hattori K., Katada K. Isolated adrenocorticotropin deficiency associated with an empty sella. J. Clin. Endocrinol. Metab. 55. 795,1982.
12. Fukata J., Usui T. Tsukada T., Nakai Y., Koh T., Ishihara T., Tanaka I., Uchida K., Yoshimasa T., Nakano R., Nishikawa M., Imura H. Effects of repetitive administration of corticotropinreleasing hormone combined with lYSine vasopressin on plasma adrenocorticotropin and cortisol levels in secondary adrenocortical insufficiency. J. Clin. Endocrinol. Metab. 71.1624, 1990.
19. Stephens WP, Goddard K.J., Laing I . Adams J.E. Isolated adrenocorticotropin deficiency and empty sella associated with hypothyroidism. Clin. Endocrinol. (Oxf) 22. 771, 1985. 20. Orme S.M., Belchetz PE Isolated ACTH deficiency. Clin. Endocrinol. (Oxf.) 35. 213,1991. 21. Wehrenberg W.B., Baird A, Ling N. Potent interaction between glucocorticoids and growth hormone-releasing factor in vivo. Science 221. 556,1983. 22. Kamijo K., Kato T., Saito A, Kawasaki K., Suzuki M., Yachi A A case of isolated ACTH deficiency accompanying chronic thyroiditis. Endocrinol. Jpn. 29. 183, 1982.
13. Aguilera G., Harwood JP, Wilson J.X., Morell J., Brown J.H., Catt K.J. Mechanisms of action of corticotropin-releasing factor and other regulators of corticotropin release in rat pituitary cells. J. Bioi. Chem. 258. 8039, 1983. 14. Lamberts SWJ, Verleun T., Oosterom R., De Jong F., Hackeng W.H.L. Corticotropin-releasing factor (ovine) and vasopressin exert a synergistic effect on adrenocorticotropin release In man. J. Clin. Endocrinol. Metab. 58. 298,1984.
23. Horii K., Adachi Y, Aoki N., Yamamoto T. Isolated ACTH deficiency associated Hashimoto's thyroiditis report of a case. Jpn. J. Med. 23. 53, 1984.
15. De Bold CR., Sheldon W.R., De Cherney G.S. Arginine vasopressin potentiates adrenocorticotropin release induced by ovine corticotropin-releasing factor. J Clin. Invest. 73. 533, 1984.
with
24. Sugiura M., Hashimoto A, Shizawa M. Heterogeneity of anterior pituitary cell antibodies detected in insulin-dependent diabetes mellitus and adrenocorticotropic hormone deficiency Diabetes Res. 3. 111, 1986.
57
CASE REPORT
Isolated adrenocorticotropic hormone deficiency secondary to hypothalamic deficit of corticotropin releasing hormone A. Velardo*, M. Pantaleoni*, G. Zizzo*, G. Del Rio**, F. Coletta*, C. Carani*,
and P. Marrama*
*Cattedra di Endocrinologia e **Cattedra Malattie del Metabolismo Universita di Modena, Modena, Italy ABSTRACT, A 42-year-old man and a 51-year-old woman with a positive history of weakness and 9astrointestinal complaints were shown to have low basal plasma cortisol and ACTH levels, and low daily urinary excretion of free cortisol. An empty sella was found in patient no, 1, while patient no, 2 was hypothyroid, Both patients showed a normal plas-
ma cortisol response to ACTH and an increment in plasma ACTH and lipotropin levels after ovine CRH (oCRH), lysine vasopressin (LVP) and oCRH-LVP stimulation tests, These studies clearly report an isolated idiopathic ACTH deficiency due to a deficit in CRH in two adult subjects,
INTRODUCTION
throughout the day. He reported episodes of accentuated weakness with epigastralgia, postural hypotension and diffusely sweating that ameliorated with water assumption. The presence of insulinoma was excluded on the basis of normal plasma glucose and insulin levels and negative arteriography of the celiac artery. The patient was subsequently referred to our clinic. Physical evaluation revealed normal pigmentation of the skin and mucosal surfaces, depression, asthenia and postural hypotension. Laboratory evaluation revealed hyponatremia (serum sodium: 130 mmol/I; normal 135-140 mmol/I) and fasting serum glucose of 80 mg/dl (normal 55-110 mg/dl). During hospitalization the postprandial plasma glucose was between 55 and 60 mg/dl at several measurements. Urinary excretion of free cortisol (35 Ilg/24 h; normal 40160 Ilg/24 h) basal plasma cortisol (1.0 Ilg/dl; normal 7-20 Ilg/dl) and ACTH levels (6.0 pg/ml; normal 10-50 pg/ml) were abnormally low.
The idiopathic isolated ACTH deficiency is a rare cause of adrenal failure. It has been reported in less than 200 cases after the first observation (1) made in 1954. The etiology of the idiopathic isolated ACTH deficiency is stili not clarified. Although both a congenital deficit (2) and a post-partum necrosis (3) have been claimed as determinants of the disorder, the presence of an autoimmune injury of the pituitary seems more tenable (4). The deficiency in ACTH secretion could also result from an hypothalamic deficit of CRH (5), but the differential diagnosis between the hypothalamic deficit and the pituitary failure was possible only with the availability of the synthetic ovine CRH (oCRH) (6,7). In this work we describe two patients with hypoadrenalism determined by a CRH deficit. CASE REPORTS Case no. 1
Case no. 2
A 42-year-old man had a history of smoking and chronic alcohol abuse. At the time of evaluation he denied recent excessive alcohol consumption. Height was 179 cm, weight 86 kg. The patient presented with a 2-year history of asthenia and fatigue
A 51-year-old menopausal woman was evaluated for a 12-month history of generalized weakness at rising and paresthesia in the upper and lower limbs. On admission the patient was normotensive (i.e, 130/80 mm/Hg) at repeated measurements and without abnormal skin pigmentation. Laboratory findings revealed hypothyroidism (TSH 8.0 IlU/ml; normal 0.5-5.0 IlU/ml; free T4 : 5.3 pg/ml; normal 6.0-18.0 pg/ml) with high antithyroglobulin autoantibodies and antimicrosomial antibodies.
Key-words. ACTH, CRH, secondary hypoadrenalism. Correspondence· Prof. A. Velardo, Cattedra dl Endocrlnologia, Via del Pozzo 71. 41100 Modena, Italy.
Received June 20, 1991, accepted October 22. 1991
53
A Velardo, M Pantaleoni,
G, Zizzo, et. al.
ACTH 1-24, iv) while DHEAS and androstenedione did not change. A biphasic response of plasma ACTH was observed after oCRH administration (1 I1g/kg bw iv; Fig. 1a) while a rise in ACTH levels was observed only 90 min after lysine vasopressin administration (10 UI im; Fig. 1b). The plasma LPH, after oCRH, was found to increase concomitantly to plasma ACTH, with a first peak at 15 min (from 6.2 to 17.0 pg/ml) and a second peak at 90 min (24.2 pg/ml). The simultaneous administration of oCRH and LVP (1 I1g/kg bw oCRH, iv; 10 UI LVP, im) induced a rise in ACTH plasma levels at 60 min with a small increment at 180 min (Fig 1c) An increment in LH (6.3 mUI/ml) was observed after GnRH administration while FSH did not change. GHRH induced a rise in plasma GH levels to 3.2 ng/ml. TSH and PRL levels increased after TRH injection to 12.3I1UI/ml and 24.0 ng/ml respectively.
Urinary free cortisol (18 I1g/24 h; normal 40-160 I1g/24 h) basal plasma cortisol (6,3 I1g/dl; normal 7,0 - 20,0 I1g/dl) and ACTH levels (8,0 pg/ml; normal 10 -50 pg/ml) were abnormally low, Height was 178 cm, weight 86 kg. She had never smoked or consumed alcohol. ANALYTICAL METHODS Specific solid phase fluoroimmunometric assays were employed to measure serum levels of PRL, FSH, LH, free T4 (Wallac,Turku,Finland) and GH (Cyber Fluor, Toronto, Canada). Serum TSH was measured by an immunoradiometric assay (BioRad, Laboratories, Ca, USA). Plasma levels of antiTG-Ab and anti M-Ab were determined by a solid phase immunoradiometric assay (Ares Serono Diagnostici, Milan, Italy). Specific solid phase radioimmunoassays were employed to measure serum levels of androstenedione (Diagnostic Systems Laboratories, Webster,Texas), DHEA-S (Sclavo RIA Department, Milan, Italy), testosterone (Bio Rad, Laboratories, Ca, USA), free T3 (Becton Dickinson, New York, USA), estradiol (E 2 ) (Diagnostic Products Corporation, Ca, USA), cortisol and urinary cortisol (IFCI Clone System, Bologna, Italy). Plasma concentration of ACTH and LPH were determined by competitive liquid phase radioimmunoassay (Nichols Institute, San Juan Capistrano, CA, USA).
Case no. 2 ACTH administration induced a peak rise in cortisol levels to 20.1 I1g/dl, at 60 min and an increase in DHEAS levels to 1.2 I1UI/ml, while androstenedione did not change. A biphasic response of ACTH was Table 1 - Basal hormone levels in a man (case no. 1) and a woman (case no. 2) with CRH deciency Hormone
RESULTS The results of basal plasma hormone levels determinations in the patients are reported in Table 1. Magnetic resonance imaging of the sella turcica and of the hypothalamus revealed an empty sella in patient no. 1 and no alterations in patient no. 2. Provocative tests of the anterior pituitary function with GHRH (1 I1g/kg bw GHRH 1-44, iv), TRH (200 I1g iv) and for patient no. 1 also with GnRH (100 I1g iv) were performed. The hypothalamus-pituitary-adrenal axis function was further evaluated using circadian profile of cortisol and ACTH secretion and urinary free 24-h cortisol excretion. The circadian variation in plasma ACTH and cortisol levels were absent and showed abnormally low levels. A diagnosis of adrenal insufficiency of undetermined etiology was made for both patients and provocative tests for the evaluation of the hypothalamus-pituitary-adrenal axis were performed (Fig. 1).
Case no, 1
Case no. 2
ACTH
6,0
8.0
10-50 pg/ml
LPH
62
4,2
12-115 pg/rn I
Cortisol
1,0
6,3
7-20/lg/dl
Urinary Cortisol
34
18
40-160 /lg/24 h
DHEAS
0,1
0.7
1 1-2,8 /lg/ml
Androstenedione
36
134
30-310 ng/dl
FSH (men) (women)
2,3 38.2
1 7-69 mUI/ml > 3.0 mUI/ml
LH (men) (wornen)
2,0 15.5
14-8,9 mUI/ml > 5,0 mUliml
GH
1,3
3,3
0.6-5,0 nq/ml
PRL
16
12
2-20 ng/ml
TSH
2,0
8,0
0,5-4,5/lUI/ml
FT4
6,3
5.3
60-180 pg/rnl
3,9
2,9
2,8-6,4 pg/m I
Anti-TG Ab
absent
106
< 100 mUl/rnl
Anti-M Ab
absent
358
< 100 mUl/ml
FT3
Case no. 1 The patient showed a peak rise in cortisol levels to 11 I1g Idl 30 min after ACTH administration (025 mg
Testosterone
E2 (menopause)
54
Normal range
360-900 ng/ml
450 12
5-30 pg/m I
Isolated ACTH deficiency
25
oCRH
E ......
20
+
~
15
'"
:z:
a)
0 - 0 Pat. 1
I-
!;!
10 Ii
.'
..
0
......... , .... - ..•..
,-
0
3:1
'i ...... go
~
:z:
~
30 2Ii
20
I
I
15
30
..
-. "
'
.
I
LVP
0-0
•
120
10
50
,4ft.
Pat. 1 Pat. 2
mInute.
b)
15 10
5 0 0
.... ~
'"
20 15
I
I
I
I
30
50
10
120
110
C)
oCRH+LVP
Pat. , .......... Pat. 2
0-0
!
~ ::t:
~
10 .~
11
0
-0
0-
......
mln.....
..................
.............
I
I
0
30
I
50
10
120
110
Fig. 1 - Plasma ACTH levels after provocative stimuli in two patients with hypothalamic deficit of CRH a) Plasma ACTH levels after oCRH (1 J.1g/kg/ bw ivY administration, b) Plasma ACTH levels after LVP (10 UI im) administration; c) Plasma ACTH levels after oCRH (1 J.1g/kg/ bw ivY mln..... and LVP (10 UI im) administration.
chemical signs of chronic adrenal insufficiency (6). The two patients reported in this study showed unequivocally the biochemical and hormonal findings characteristic of the adrenal failure. The clinical presentation and the symptoms in the patient no. 1 herein described were similar to those observed in patients with insulinoma. In our case hypoglycemia was partly due to the previous chronic alcohol consumption as frequently reported in patients with secondary adrenal failure (8). Patient no. 2 on the contrary did not show clinical signs specific for hypoadrenalism since the asthenia was probably due to the hypothyroidism concomitantly present. The hormonal deficiency was not adrenal in origin as demonstrated in both the patients by the rise in serum cortisol after ACTH administration. The blunted peak of plasma cortisol after ACTH iv observed in patient no.1 suggested a longer duration of the disease than in patient no. 2. The results of the CRH test are consistent with an hypothalamic defect (9, 10). The above hypothesis was confirmed by the evaluation of the plasma ACTH responses to LVP administration, a stimulus known to induce ACTH release through a cellu-
observed after oCRH administration (Fig. 1a) with the two peaks occurring at 30 and 90 min. A similar trend was found for LPH levels that showed a small increase at 30 min ( (from 4.2 to 8.1 pg/ml) and a second peak at 90 min (10.0 pg/ml). A rise in ACTH levels was observed only at 60 min after lysine vasopressin administration (Fig. 1b). The simultaneous administration of oCRH and LVP induced a rise in ACTH plasma levels at 60 min (Fig. 1c). GHRH induced a rise in plasma GH levels to 6.4 ng/ml. PRL levels after TRH increased to 33.6 ng/ml; the TSH rise up to 32.0 /lUl/ml after TRH injection confirmed the presence of hypothyroidism in this patient. DISCUSSION The symptoms associated with isolated ACTH deficiency are variable and not specific. The clinical presentation can be similar to that of primary adrenal deficiency but is less severe than the latter and acute adrenal failure is usually absent. Hypoglycemia has been frequently reported to occur in patients with isolated ACTH deficiency and is one of the classical bio-
55
A Ve/ardo, M. Panta/eont, G. Zizzo, et. a/.
lar mechanism different from that of CRH acting directly at the pituitary level (11-13). A peak in ACTH level was observed in both patients 60 min after CRH-LVP administration with a second increment toward the end of curve in patient no. 1. Other authors (14,15) reported a single peak of ACTH after the CRH-LVP test the response was found to be higher than during separate administration of CRH and LVP. Our patients on the contrary did not demonstrate the sinergistic effect of CRH and LVP on ACTH release. The lack of the sinergistic effect of CRH and LVP may be considered as a biochemical characteristic of the patient with hypothalamic deficit of CRH or, more likely, as the result of a large intraindividual variation in the ACTH response to stimuli (16). These hypothesis should be retained with caution since the deficit of CRH is a very uncommon cause of hypoadrenalism and to our knowledge no cases were described with the ACTH response to separate and simultaneous administration of the two peptides. Additional unknown factors that potentiate the ACTH secretion after stimuli should also be considered (17). The radiological finding of an empty sella in patient no. 1 was not completely surprising since other authors were able to describe a similar finding in patients with isolated ACTH deficiency (18-20). The pathological significance of the above association need to be evaluated further. It is known that chronic cortisol deficiency determines functional alterations in pituitary secretion (21). This was observed also in our patients as demonstrated by the blunted GH response to GHRH and by the elevated responses to TRH. These effects were both corrected after cortisone therapy and, in patient no. 2, after thyroid replacement (data not shown). In previously reported cases of isolated ACTH deficiency, the association with other autoimmune endocrine disorders have suggested that an autoimmune injury is responsible for the syndrome (4,22). Our patient no. 2 showed evidence of autoimmune thyroid disease and this finding confirms other reports on isolated ACTH deficiency (23). The presence of anti-CRH antibody, not evaluated in this study, could therefore be responsible of the syndrome in a certain number of cases (4, 24) and could be involved in the absence of ACTH response to CRH observed in patient no. 2. Since CRH and LVP act with different intracellular mechanism to induce ACTH secretion, i.e. the former through a cAMP-dependent pathway while the latter through a cAMP-independent pathway (11, 13), it is also possible to hypothesize a defect in the cellular cAMP-generation. The isolated ACTH deficiency secondary to a CRH
deficit was described by Martin et al. (5) in three children; as far as we know however these are the first two cases described in adults in which the adrenocortical deficiency is secondary to a suprapituitary defect. In conclusion the isolated ACTH deficiency secondary to hypothalamic dysfunction is a heterogeneous disorder characterized by symptoms of adrenocortical insufficiency associated with stimulation of cortisol and ACTH secretion following vasopressin and/or CRH administration.
ACKNOWLEDGMENTS The expert technical support of Dorval Ganazzi is gratefully acknowledged.
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with
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