Endocrinol.Japon.
1975.22(3),
269∼273
NOTE Lack
of
TRH-Induced Klinefelter's
YASUNORI
OZAWA
TSH Secretion in a Patient Syndrome: a Case Report AND
YOSHIMASA
with
SHISHIBA
Division of Endocrinology, Department of Medicine, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Akasaka, Tokyo 107
Synopsis In a 41 year-old patient with Klinefelter's syndrome, a failure of TRH-induced TSH secretion was noticed. Low 131I-thyroid uptake, together with the elevation following exogenous TSH administration, indicates that the defective locus exists in the hypothalamus or pituitary resulting in an impaired secretion of TSH. Such a defect may underlie thyroid dysfunction often associated with Klinefelter's syndrome.
Since the initial report of Klinefelter et al. of male hypogonadism characterized by gynecomastia, small testes, azospermia, Leydig cell failure and elevated urinary excretion of gonadotropin, it has become apparent from numerous reports that Klinefelter's syndrome may be variously manifested, and that causative disorder is an increase in the number of X chromosome. Recent development of sensitive radioimmunoassay revealed that the serum gonadotropin levels are invariably increased and that there may be blunted response of HGH to insulin-induced hypoglycemia or to arginine infusion in the patients with Klinefelter's syndrome. Among other endocrine abnormalities than pituitary, the latent thyroid dysfunction has been described by a number of investigators (Burt, et al., 1954; Received for publication January 13, 1975. This study was presented at the 11th annual meeting of Eastern Section of the Japan Endocrinological Society, Tokyo, November, 1974. This study was supported in part by the Research Grant from the Ministry of Education, No. 948241, from the Hashimoto Disease Research Committee, Ministry of Health and Welfare, and also from Mitsui Life, Social and Welfare Association.
Burr, et al., 1960; Carr et al., 1961 and Davis et al., 1963). We have experienced a case of Klinefelter's syndrome presenting such thyroid dysfunction. The purpose of the present communication is to propose a possibility that a failure of TSH secretion underlies thyroid dysfunction in Klinefelter's syndrome.
Case
Report
A 41 year-old japanese male visited our hospital because of infertility and the lack of secondary sex characteristics. He was the product of non-consanguineous marriage. The pregnancy and the delivery were reported to be normal. The physical and mental development had been normal except for the lack of secondary sex characteristics. Remarks at school was in the middle class. On graduation from high school, he has worked as a governmental officer without difficulty. At the age of 38, he married with a healthy girl. But the frequency of the intercourse was very sparce and they could not bear a baby. He had not noticed
270
OZAWA
AND
malaise, cold intolerance or goiter. On physical examination, he was well nourished japanese male with an eunuchoidal structure as evidenced by the height 167.2 cm, span 183 cm, and foot-pubic length 87 cm (Fig 1.). Facial hair was thin and the shaving once a week was sufficient. Pubic and axillary hair was sparce when compared to normal japanese male at the same age. No gynecomastia was present. Phymotic phallus was small, being 4cm in length from the pubic synphysis. Both testes were
Endocrinol,Japon. Jane 1975
SHISHIBA
fully
descended,
cm,
and
normally
on
in
tendon
reflex
was
and
observed
on
On
was
completely On
somal
analysis
type.
Table
endocrine were
both
of
serum
100ƒÊg
both
of
to
somewhat
was
4.0ƒÊg/dl, cortisol
response
glycemia tion
of
17OHCS
9.1
mg/day,
thyroxine both
being
8.6ƒÊg/dl in
cell
clinical
picture
and indicated
24hr-thyroid
uptake for
abnormally of jects
15
low to
on
35% the
hypo-
Urinary
excre-
12.9mg/day
a
on
hormone state, after
7%,
compared
obtained
on iodine
tanned
thyroid
was
29%,
Although
euthyroid
week
serum was
Antithyro-
performed
when
similar
RT3U
test. serum
concentration
was Serum
induced
negative
hemagglutination
restriction
lowest
limits.
range.
was
value
Total
normal
antibody
red
the
was
and
was
highest
respectively.
was
globulin
the
17KS
The
cortisol
normal. or
re-
blunted.
insulin
also
levels the
hypoglycemia
normal
to
was
Basal
and
within
exagadmin-
serum but
the FSH
an
but
was of
13.6ƒÊg/dl
both
of
and
intravenous
infusion
deranged,
(3p.m.)
LH
induced
variation
karyo-
result
normal,
insulin
arginine
circadian
XXY
LH-RH.
were
to
47,
showed
the
body
Chromo-
the
and
HGH
sponse
cells.
Serum
to
line
Barr
the a
elevated
and
hand-X-ray film.
summarizes
response
istration
and
of
studies.
gerated
chest
preparation,
revealed 1
normal
the
Epiphyseal on
60%
blood
within of
normal.
smear in
liver
and
was
closed
present
includ-
electrolytes
was
was
urinalysis,
examination
buccal
was
disc
examination
measurements
turcica
hypo-
Neither
choked
counts,
serum
X-ray
of
disturbance
examination.
blood tests,
was
Physical sign
visual fields. nor
laboratory
sella
or
visual
funduscopic
routine
limits.
of
no
of
complete
sugar
any
2
was
Achilles
prolonged.
atrophy
by
gland
position.
reveal
has
narrowing nerve
ing
not
He
no
optic
in
not
1 skin
thyroid
and
did
thyroidism.
only The
The
size
examination
measured
palpation.
warm.
normal
function
Fig.1. Eunuchoidal structure characterized by increased span, lack of axillary hair, sparce public hair and premature external genitalia.
but
soft
that to
the
the
normal
restriction.
131Iiodine was value subBy
Vol.22,
TSH
No.3
TSH
stimulation,
bovine
TSH,
uptake
was
Serum
samples
with
the
limit ml,
the
of
the
intravenous dose, the
would than
8ƒÊU/ml
Table
Table
1.
our
age
sex
matched
the
response
Endocrine
2.
of
Endocrine
hands,
less
Serum and
in
and
1.25ƒÊU/
results. before
elicit
the
months whose
administration
to
was
6
than
same
detectable
This
24%.
of for
less
of
radioim-
sensitivity
frozen
was
not
subjects,
to by
radioimmunoassay
essentially
ministered
higher
limit
better
gave
TRH.
increased
stored
sensitivity
was
10U 131I-thyroid
Re-determination
of
TSH
days,
measured
4ƒÊU/ml.
KLINEFELTER'S
with
three
was
whose
than
same
for
obviously TSH
munoassay less
performed i.m.,
IN
after
500ƒÊg
of
when normal at
than
function
function
ad-
least
24ƒÊU/
tested
tested
before
after
271
SYNDROME
ml at the peak response, this being compatible with the published data by other investigators (Kumahara et al., 1971, Ohtsuki et al., 1973 and Snyder et al., 1972). As tabulated in Table 2, pituitary function tests repeated 3 months after the administration of 100mg of testosterone-propionate once in every two weeks, when the levels of LH were lowered near to normal range, still showed no response of TSH to TRH, although thyroid replacement therapy was not performed. The response of HGH to insulin or arginine loading was obviously normalized. In the course of androgen replacement therapy, a decrease in total thyroxine concentration was observed, e. g., 2.6, the
replacement
the replacement
of
testostereone-propionate.
of testosterone-propionate.
272
OZAWA
4.1
or
ured
5.7ƒÊg/dl, RT3U
Serum as
T3
by
ng/dl
on
This
decrease
men
2
zation In
testes.
of
As
the
at
least
was
of
140
shown,
complete
tubule
Leydig were with
inter-
androgen.
of
compatible
or
measurements.
effect
of
Discussion
normal,
150
histology
These findings
Klinefelter's
also
of
was
clumping
meas-
thyroxine
seminiferous
biguous. but
the the
Endocrinol.Japon. June1975
SHISHIBA
respectively.
was
interstitium, fibrosis
that
28%
value
total
reflect
of
or
consecutive of
shows
of
concurrently
29
the
two
to
Fig.
29,
concentration
evidenced
preted
while
was
AND
biopsy
specihyalini-
was so
observed. remarkable
cells not the
was
am-
typical, diagnosis
syndrome.
Fig.2. Histology of biopsied testes. Complete hyalinization of seminiferous tubule was noticed. In the interstitium, fibrosis was dominant and clumping of Leydig cells was ambiguous.
This patient was a Klinefelter's syndrome with a 47, XXY karyotype, presenting infertility as a result of the lack of spermatogenesis. Although he was clinically euthyroid, and serum thyroid hormone was within normal range, his 1311-thyroid uptake was low. The existense of response of 131Ithyroid uptake to TSH and the lack of TSH response to TRH indicate the origin of this thyroid dysfunction is not thyroid gland itself, but in the defect of pituitary or hypothalamus, resulting in the impaired TSH secretion from the pituitary. Although there was a notion that the lack of TRHinduced TSH release indicates pituitary failure because hypothalamic region often results in a exaggerated TSH-response to TRH, such a differentiation has been deemed to be erratic. The reason of this patient having remained euthyroid may be explained by the residual secretion of TSH from the pituitary. In this context, numbers of clinically euthyroid patients with pituitary or hypothalamic lesion presenting the absence of TSH response to TRH were described in the previous reports (Hall et al., 1972; Samaan et al., 1974). In the literature, the incidence of thyroid dysfunction in patients with Klinefelter's syndrome was reported to be high. For instance, Barr et al. reported low 131I-thyroid uptake in 8 among 10 cases of Klinefelter's syndrome (Barr et al., 1960). The incidence of similar thyroid abnormality reported by Carr et at was 2 of 2, and that by Davis et al. was 4 out of 5 cases of this syndrome (Carr et al., 1961 and Davis et al., 1963). In those reports, all the patients were reported to be clinically euthyroid. The responsiveness of the thyroid to exogenous TSH has been variously described. Barr and Carr emphasized the poor responsiveness, whereas Davis described normal respon-
Vol.22,
No.3
TSH
IN
KLINEFELTER'S
siveness in 3 out of 4 patients with such thyroid dysfunction. In our own patient, the response to TSH of 131I-thyroid uptake was rather blunted. This aspect, however, can be altered either by the impaired gland itself or else by the long-standing TSHdeficiency as often experienced in Sheehan's syndrome (Taunton et al., 1965). Thus, the poor responsiveness of thyroid gland to TSH does not necessarily preclude the pituitary as the possible site of abnormality in this disorder. In order to further locate the site of abnormality in this patient, measurement of serum TSH was of value. Our results, although only on a single patient, clearly demonstrate a failure of TRHinduced TSH secretion, indicating that the site of abnormality is at pituitary or hypothalamus, resulting in the impaired TSH secretion. In the previous series cited, TRH test was obviously not available. Since the introduction of TRH into clinical application, there has been one case record of Klinefelter's syndrome whose response of TSH to TRH was reported to be normal (Gaul, et al., 1972). Therefore, it is obvious that the refractoriness to TRH is not a common feature of this syndrome, but may well be a characteristic abnormality in patients whose thyroid function was more or less deranged. Whether causative factor of this abnormality is from chromosomal origin or from the long-standing deviation of endocrine function due either to hypersecretion of gonadotropin or to hypogonadism itself remains to be explored. Of them, testosterone deficiency as a causative factor seems to be less likely in view of the fact that testosterone replacement was not effective in restoring TRH responsiveness in this patient.
SYNDROME
273
Acknowledgements The chromosomal analysis of the patient reported in this paper was performed by courtesy of Professor Akira Tonomura, Institute of Medical Genetics, Tokyo Medical and Dental University, Yushima, Tokyo.
References
Barr, M. L., E. L. Shaver, D. H. Carr and E. R. Plunkett (1960). J. Ment. Deficiency Research 4, 89. Burt, A. G., L. Reiner, R. B. Cohen and R. C. Sniffen (1954). J. Clin. Endocr. 14, 719. Carr, D. H., M. L. Barr, E. R. Plunkett, M. M. Grumbach, A. Morishima and E. H. Y. Chin (1961). J. Clin. Endocr. 21, 491. Davis, T. E., C. J. Canfield, R. H. Herman and D. Goler (1963). New Eng. J. Med. 268, 178. Gaul, C., A. J. Kastin and A. V. Schalley (1972). Recent Prog. in Hormone Res. 28, 173. Hall, R., B. J. Ormston, G. M. Besser and R. J. Cryer (1972). Lancet 1, 759. Kumahara, Y., K. Miyai and M. Azukizawa (1971). Med. J. Osaka Univ. 22, 97. Ohtsuki, M., M. Tateiwa and S. Baba (1973). Endocrinol. Jap. 20, 149. Samaan, N. A., M. E. Leavens and R. H. Jesse, Jr. (1974). J. Clin. Endocr. 38, 957. Snyder, P. J. and R. D. Utiger (1972). J. Ibid. 34, 380. Taunton, O. D., H. G. McDaniel and J. A. Pittman (1956). Ibid. 25, 266.
1975.22(3),
269∼273
NOTE Lack
of
TRH-Induced Klinefelter's
YASUNORI
OZAWA
TSH Secretion in a Patient Syndrome: a Case Report AND
YOSHIMASA
with
SHISHIBA
Division of Endocrinology, Department of Medicine, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Akasaka, Tokyo 107
Synopsis In a 41 year-old patient with Klinefelter's syndrome, a failure of TRH-induced TSH secretion was noticed. Low 131I-thyroid uptake, together with the elevation following exogenous TSH administration, indicates that the defective locus exists in the hypothalamus or pituitary resulting in an impaired secretion of TSH. Such a defect may underlie thyroid dysfunction often associated with Klinefelter's syndrome.
Since the initial report of Klinefelter et al. of male hypogonadism characterized by gynecomastia, small testes, azospermia, Leydig cell failure and elevated urinary excretion of gonadotropin, it has become apparent from numerous reports that Klinefelter's syndrome may be variously manifested, and that causative disorder is an increase in the number of X chromosome. Recent development of sensitive radioimmunoassay revealed that the serum gonadotropin levels are invariably increased and that there may be blunted response of HGH to insulin-induced hypoglycemia or to arginine infusion in the patients with Klinefelter's syndrome. Among other endocrine abnormalities than pituitary, the latent thyroid dysfunction has been described by a number of investigators (Burt, et al., 1954; Received for publication January 13, 1975. This study was presented at the 11th annual meeting of Eastern Section of the Japan Endocrinological Society, Tokyo, November, 1974. This study was supported in part by the Research Grant from the Ministry of Education, No. 948241, from the Hashimoto Disease Research Committee, Ministry of Health and Welfare, and also from Mitsui Life, Social and Welfare Association.
Burr, et al., 1960; Carr et al., 1961 and Davis et al., 1963). We have experienced a case of Klinefelter's syndrome presenting such thyroid dysfunction. The purpose of the present communication is to propose a possibility that a failure of TSH secretion underlies thyroid dysfunction in Klinefelter's syndrome.
Case
Report
A 41 year-old japanese male visited our hospital because of infertility and the lack of secondary sex characteristics. He was the product of non-consanguineous marriage. The pregnancy and the delivery were reported to be normal. The physical and mental development had been normal except for the lack of secondary sex characteristics. Remarks at school was in the middle class. On graduation from high school, he has worked as a governmental officer without difficulty. At the age of 38, he married with a healthy girl. But the frequency of the intercourse was very sparce and they could not bear a baby. He had not noticed
270
OZAWA
AND
malaise, cold intolerance or goiter. On physical examination, he was well nourished japanese male with an eunuchoidal structure as evidenced by the height 167.2 cm, span 183 cm, and foot-pubic length 87 cm (Fig 1.). Facial hair was thin and the shaving once a week was sufficient. Pubic and axillary hair was sparce when compared to normal japanese male at the same age. No gynecomastia was present. Phymotic phallus was small, being 4cm in length from the pubic synphysis. Both testes were
Endocrinol,Japon. Jane 1975
SHISHIBA
fully
descended,
cm,
and
normally
on
in
tendon
reflex
was
and
observed
on
On
was
completely On
somal
analysis
type.
Table
endocrine were
both
of
serum
100ƒÊg
both
of
to
somewhat
was
4.0ƒÊg/dl, cortisol
response
glycemia tion
of
17OHCS
9.1
mg/day,
thyroxine both
being
8.6ƒÊg/dl in
cell
clinical
picture
and indicated
24hr-thyroid
uptake for
abnormally of jects
15
low to
on
35% the
hypo-
Urinary
excre-
12.9mg/day
a
on
hormone state, after
7%,
compared
obtained
on iodine
tanned
thyroid
was
29%,
Although
euthyroid
week
serum was
Antithyro-
performed
when
similar
RT3U
test. serum
concentration
was Serum
induced
negative
hemagglutination
restriction
lowest
limits.
range.
was
value
Total
normal
antibody
red
the
was
and
was
highest
respectively.
was
globulin
the
17KS
The
cortisol
normal. or
re-
blunted.
insulin
also
levels the
hypoglycemia
normal
to
was
Basal
and
within
exagadmin-
serum but
the FSH
an
but
was of
13.6ƒÊg/dl
both
of
and
intravenous
infusion
deranged,
(3p.m.)
LH
induced
variation
karyo-
result
normal,
insulin
arginine
circadian
XXY
LH-RH.
were
to
47,
showed
the
body
Chromo-
the
and
HGH
sponse
cells.
Serum
to
line
Barr
the a
elevated
and
hand-X-ray film.
summarizes
response
istration
and
of
studies.
gerated
chest
preparation,
revealed 1
normal
the
Epiphyseal on
60%
blood
within of
normal.
smear in
liver
and
was
closed
present
includ-
electrolytes
was
was
urinalysis,
examination
buccal
was
disc
examination
measurements
turcica
hypo-
Neither
choked
counts,
serum
X-ray
of
disturbance
examination.
blood tests,
was
Physical sign
visual fields. nor
laboratory
sella
or
visual
funduscopic
routine
limits.
of
no
of
complete
sugar
any
2
was
Achilles
prolonged.
atrophy
by
gland
position.
reveal
has
narrowing nerve
ing
not
He
no
optic
in
not
1 skin
thyroid
and
did
thyroidism.
only The
The
size
examination
measured
palpation.
warm.
normal
function
Fig.1. Eunuchoidal structure characterized by increased span, lack of axillary hair, sparce public hair and premature external genitalia.
but
soft
that to
the
the
normal
restriction.
131Iiodine was value subBy
Vol.22,
TSH
No.3
TSH
stimulation,
bovine
TSH,
uptake
was
Serum
samples
with
the
limit ml,
the
of
the
intravenous dose, the
would than
8ƒÊU/ml
Table
Table
1.
our
age
sex
matched
the
response
Endocrine
2.
of
Endocrine
hands,
less
Serum and
in
and
1.25ƒÊU/
results. before
elicit
the
months whose
administration
to
was
6
than
same
detectable
This
24%.
of for
less
of
radioim-
sensitivity
frozen
was
not
subjects,
to by
radioimmunoassay
essentially
ministered
higher
limit
better
gave
TRH.
increased
stored
sensitivity
was
10U 131I-thyroid
Re-determination
of
TSH
days,
measured
4ƒÊU/ml.
KLINEFELTER'S
with
three
was
whose
than
same
for
obviously TSH
munoassay less
performed i.m.,
IN
after
500ƒÊg
of
when normal at
than
function
function
ad-
least
24ƒÊU/
tested
tested
before
after
271
SYNDROME
ml at the peak response, this being compatible with the published data by other investigators (Kumahara et al., 1971, Ohtsuki et al., 1973 and Snyder et al., 1972). As tabulated in Table 2, pituitary function tests repeated 3 months after the administration of 100mg of testosterone-propionate once in every two weeks, when the levels of LH were lowered near to normal range, still showed no response of TSH to TRH, although thyroid replacement therapy was not performed. The response of HGH to insulin or arginine loading was obviously normalized. In the course of androgen replacement therapy, a decrease in total thyroxine concentration was observed, e. g., 2.6, the
replacement
the replacement
of
testostereone-propionate.
of testosterone-propionate.
272
OZAWA
4.1
or
ured
5.7ƒÊg/dl, RT3U
Serum as
T3
by
ng/dl
on
This
decrease
men
2
zation In
testes.
of
As
the
at
least
was
of
140
shown,
complete
tubule
Leydig were with
inter-
androgen.
of
compatible
or
measurements.
effect
of
Discussion
normal,
150
histology
These findings
Klinefelter's
also
of
was
clumping
meas-
thyroxine
seminiferous
biguous. but
the the
Endocrinol.Japon. June1975
SHISHIBA
respectively.
was
interstitium, fibrosis
that
28%
value
total
reflect
of
or
consecutive of
shows
of
concurrently
29
the
two
to
Fig.
29,
concentration
evidenced
preted
while
was
AND
biopsy
specihyalini-
was so
observed. remarkable
cells not the
was
am-
typical, diagnosis
syndrome.
Fig.2. Histology of biopsied testes. Complete hyalinization of seminiferous tubule was noticed. In the interstitium, fibrosis was dominant and clumping of Leydig cells was ambiguous.
This patient was a Klinefelter's syndrome with a 47, XXY karyotype, presenting infertility as a result of the lack of spermatogenesis. Although he was clinically euthyroid, and serum thyroid hormone was within normal range, his 1311-thyroid uptake was low. The existense of response of 131Ithyroid uptake to TSH and the lack of TSH response to TRH indicate the origin of this thyroid dysfunction is not thyroid gland itself, but in the defect of pituitary or hypothalamus, resulting in the impaired TSH secretion from the pituitary. Although there was a notion that the lack of TRHinduced TSH release indicates pituitary failure because hypothalamic region often results in a exaggerated TSH-response to TRH, such a differentiation has been deemed to be erratic. The reason of this patient having remained euthyroid may be explained by the residual secretion of TSH from the pituitary. In this context, numbers of clinically euthyroid patients with pituitary or hypothalamic lesion presenting the absence of TSH response to TRH were described in the previous reports (Hall et al., 1972; Samaan et al., 1974). In the literature, the incidence of thyroid dysfunction in patients with Klinefelter's syndrome was reported to be high. For instance, Barr et al. reported low 131I-thyroid uptake in 8 among 10 cases of Klinefelter's syndrome (Barr et al., 1960). The incidence of similar thyroid abnormality reported by Carr et at was 2 of 2, and that by Davis et al. was 4 out of 5 cases of this syndrome (Carr et al., 1961 and Davis et al., 1963). In those reports, all the patients were reported to be clinically euthyroid. The responsiveness of the thyroid to exogenous TSH has been variously described. Barr and Carr emphasized the poor responsiveness, whereas Davis described normal respon-
Vol.22,
No.3
TSH
IN
KLINEFELTER'S
siveness in 3 out of 4 patients with such thyroid dysfunction. In our own patient, the response to TSH of 131I-thyroid uptake was rather blunted. This aspect, however, can be altered either by the impaired gland itself or else by the long-standing TSHdeficiency as often experienced in Sheehan's syndrome (Taunton et al., 1965). Thus, the poor responsiveness of thyroid gland to TSH does not necessarily preclude the pituitary as the possible site of abnormality in this disorder. In order to further locate the site of abnormality in this patient, measurement of serum TSH was of value. Our results, although only on a single patient, clearly demonstrate a failure of TRHinduced TSH secretion, indicating that the site of abnormality is at pituitary or hypothalamus, resulting in the impaired TSH secretion. In the previous series cited, TRH test was obviously not available. Since the introduction of TRH into clinical application, there has been one case record of Klinefelter's syndrome whose response of TSH to TRH was reported to be normal (Gaul, et al., 1972). Therefore, it is obvious that the refractoriness to TRH is not a common feature of this syndrome, but may well be a characteristic abnormality in patients whose thyroid function was more or less deranged. Whether causative factor of this abnormality is from chromosomal origin or from the long-standing deviation of endocrine function due either to hypersecretion of gonadotropin or to hypogonadism itself remains to be explored. Of them, testosterone deficiency as a causative factor seems to be less likely in view of the fact that testosterone replacement was not effective in restoring TRH responsiveness in this patient.
SYNDROME
273
Acknowledgements The chromosomal analysis of the patient reported in this paper was performed by courtesy of Professor Akira Tonomura, Institute of Medical Genetics, Tokyo Medical and Dental University, Yushima, Tokyo.
References
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