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Indian Pediatr 2010;47: 877-880 |
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Pituitary Hyperplasia in Children with Short
Stature and Primary Hypothyroidism |
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Xu Aijing and Li Tang
From the Department of Pediatrics, The Affiliated
Hospital of QingDao Medical College,
QingDao University, QingDao 266 003, China.
Correspondence to: Dr Tang Li, Department of Pediatrics,
The Affiliated Hospital of QingDao Medical College, QingDao
University,QingDao 266 003, China.
Email:
[email protected]
Received: August 6, 2009;
Initial review: August 21, 2009;
Accepted: November 11, 2009.
Published online: 2010 March 15.
PII: S097475590900544-2
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Abstract
We present eight cases with short stature, pituitary
hyperplasia, and hypothyroidism. Pituitary hyperplasia due to primary
hypothyroidism was diagnosed on the basis of clinical manifestations,
endocrine examination and MRI. After 2 to 6 months of L-thyroxine
replacement therapy, the signs of hypothyroidism disappeared; free
triiodothyronine, free thyroxine, thyrotropin and prolactin became
normal; and pituitary enlargement regressed. In two children, the growth
rate remained low when treated with L-thyroxine, but with additional
recombinant human growth hormone (rhGH), the height increased by 11 cm
per year. No recurrence of lesions was found on follow-up.
Key words: Child, China, Growth hormone, Pituitary
hyperplasia, Primary hypothyroidism, Short stature.
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P
ituitary enlargement secondary to
primary hypothyroidism (PH) is a known but uncommon occurrence, and is
also difficult to distinguish on CT and MRI from primary pituitary
tumors(1). Following adequate hormone replacement with L-thyroxine, both
symptoms and pituitary hyperplasia are reported to regress within a few
months(2). It is important to recognize this condition so as to avoid
unnecessary surgery. Previous reports have mainly focussed on CT and MRI
identifying pituitary hyperplasia in children with primary hypothyroidism,
whereas only a few reports focus on plasma GH levels(3,4). This study was
conducted to observe the therapeutic effect of thyroxine on growth, and GH
levels in these children.
Methods
This study was conducted from 2002 to 2005 in the
pediatric department of the Affiliated Hospital, Qingdao Medical College,
China. Ethical approval and verbal consent were obtained. During this
period, we encountered 8 patients who displayed a decreased growth rate,
without typical clinical features of hypothyroidism. Hormonal analyses –
which included GH stimulation tests (arginine, insulin), free
triiodothyronine(FT 3),
free thyroxine (FT4), thyrotropin (TSH) (RIA assay) and thyroid
antibody and prolactin (PRL), was conducted. 99 Tc-pertechnetate thyroid
scan and MRI scan of the pituitary were undertaken. To assess for Turner
syndrome, cytogenetic studies were conducted on every female subject.
Based on the MRI findings and clinical signs and symptoms;
endocrinological examinations were diagnostic for pituitary enlargement
due to PH in a given child. The patients had a trial of T4 hormone
replacement (levothyroxine sodium 5-10µg/kg/d) and continued until
serum TSH level was normalized. FT3, FT4 and TSH
levels were taken as a guideline to adjust the dose of the drug. Clinical
and biochemical evaluations, MRI and the GH stimulation test were repeated
bimonthly, 3 months and 6 months, respectively. Diagnostic criteria and
guidelines for treatment were on the basis of relevant literature(5,6).
Results
Initial endocrinological work-up revealed abnormal GH
provocative tests, low levels of thyroid hormones and markedly elevated
TSH and PRL (Table I and II). Thyroxine
binding globulin and antithyroid peroxidase (anti-TPO) antibodies were
positive in three children. Cytogenetic studies ruled out Turner syndrome
in all female children. Pituitary MRIs revealed symmetrical enlargement of
the pituitary gland, measuring 12-31 mm in size. The mean follow-up period
was 22.8 ± 4.7 months. Following adequate hormone replacement with L-thyroxine
symptoms, thyroid function and prolactin were normalized over 2-6 months.
MRI demonstrated a marked decrease in the size of the pituitary mass
within the sella turcica after 3 months of treatment and showed normal
dimensions after 6 months of treatment. The height increased by 11.6 ±
1.7cm/year in six children; while in the other two, it was 4.9 cm/year and
5.2 cm/year, respectively (Patient 2 and 5, Table II). GH
stimulation tests of these 2 patients remained abnormal. Thereafter, they
were treated with daily injections of recombinant human growth hormone (rhGH)
0.1 IU/kg/d, in addition to L-thyroxine; resulting in a growth gain rate
of approximately 11cm/year.
TABLE I
Data of Patients with Pituitary Enlargement Due to Primary Hypothyroidism,
Before and After 22 Months of Thyroxine Therapy
|
Pateint |
|
Values before starting
therapy |
Values after 22 months therapy |
|
no/sex |
CA |
BA |
Height |
Thyroid |
GV(cm/ |
Pituitary |
CA |
BA |
Height |
Thyroid |
GV (cm/ |
Pituitary |
| |
(y) |
(y) |
(cm)(SDS) |
scan |
year) |
size (mm) |
(years) |
(years) |
(SDS) |
scan |
year) |
size (mm) |
|
1/ F |
5.3 |
3.0 |
91.5(-3.3) |
irregular# |
2.8 |
13.0 |
7.1 |
6.0 |
111.5(-0.8) |
Normal |
12.6 |
6.1 |
|
2/F |
6.8 |
3.5 |
103.5(-3.1) |
hypoplasia |
2.3 |
15.0 |
8.6 |
7.5 |
119.0(-0.8) |
Normal |
11.3 |
5.8 |
|
3/F |
6.6 |
3.5 |
103.5(-3.1) |
irregular# |
3.8 |
16.0 |
9.3 |
7.5 |
123.5(-0.4) |
Normal |
12.6 |
5.9 |
|
4/M |
9.2 |
5.5 |
112.0(-3.0) |
irregular# |
3.4 |
22.0 |
11.0 |
10.5 |
132.5(-1.7) |
Normal |
12.1 |
5.8 |
|
5/M |
7.5 |
4.0 |
108.5(-3.0) |
irregular# |
3.1 |
14.0 |
8.4 |
8.0 |
125.0(-0.4) |
Normal |
11.7 |
5.5 |
|
6/M |
5.1 |
2.0 |
91.0(-3.2) |
hypoplasia |
2.6 |
31.0 |
6.9 |
5.5 |
111.5(-1.3) |
Normal |
12.9 |
5.3 |
|
7/M |
6.8 |
4.5 |
102.5(-3.1) |
hypoplasia |
3.5 |
15.0 |
8.6 |
7.5 |
121.5(-0.9) |
Normal |
11.6 |
5.4 |
|
8/M |
7.8 |
4.5 |
106.5(-3.0) |
irregular# |
3.4 |
17.0 |
9.6 |
8.0 |
125.5(-0.5) |
Normal |
11.7 |
5.3 |
|
Mean |
6.9±1.3 |
3.8±1.1 |
102.4±7.5 |
|
3.11±0.5 |
17.9±2.1 |
8.7±1.3 |
7.6±1.5* |
121.5±7.2* |
|
12.1±0.6* |
5.6±0.3* |
| |
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(-3.1±0.1) |
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(-0.9±0.5*) |
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# irregular distribution; CA: Chronological age; BA: bone age; GV:
growth velocity; *compared to before therapy, P<0.01. |
TABLE II
Results of Hormonal Evaluation Before and After Treatment
|
Pateint |
Thyroid profile at star |
|
|
Thyroid profile at followup |
|
|
| no/sex |
FT3 |
FT4 |
TSH |
PRL levelsat |
GH levels at |
FT3 |
FT4 |
TSH |
PRL at followup |
GH at followup |
| |
(pmol/L) |
(pmol/L) |
(mU/L) |
start (ug/L) |
start (ng/mL) |
(pmol/L) |
(pmol/L) |
(mU/L) |
(ug/L) |
(ng/mL) |
| 1/ F |
2.2 |
5.6 |
82.2 |
45.2 |
>10 |
4.3 |
20.5 |
0.42 |
10.9 |
>10 |
| 2/F |
1.8 |
7.8 |
75.4 |
56.7 |
<5 |
4.7 |
13.4 |
0.34 |
11.3 |
<5 |
| 3/F |
1.9 |
4.5 |
68.9 |
34.6 |
>10 |
3.9 |
15.6 |
0.37 |
9.3 |
>10 |
| 4/M |
2.9 |
10.1 |
89.2 |
38.9 |
>10 |
5.6 |
17.8 |
0.41 |
3.8 |
>10 |
| 5/M |
3.1 |
6.7 |
68.3 |
36.9 |
5-10 |
4.5 |
15.9 |
0.25 |
8.9 |
7.5 |
| 6/M |
3.0 |
4.4 |
54.2 |
43.2 |
>10 |
3.9 |
20.4 |
0.29 |
2.5 |
>10 |
| 7/M |
1.6 |
6.3 |
80.3 |
30.9 |
>10 |
6.2 |
16.7 |
0.36 |
4.5 |
>10 |
| 8/M |
2.4 |
7.2 |
68.7 |
28.5 |
>10 |
4.5 |
18.4 |
0.38 |
5.7 |
>10 |
| Median |
2.4±0.6 |
6.5±1.9 |
73.3±10.9 |
38.4±9.0 |
|
4.7±0.8* |
17.3±2.4* |
0.4±0.1* |
7.1±3.4* |
>10 |
| (ref
range) |
(3.6-6.8) |
(12-22) |
(0.27-0.42) |
(1.6-13.8) |
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*compared to before therapy, p<0.01; FT3: free triodothyronine;
FT4: free thyroxine; TSH: thyrotropin; PRL: prolactin. |
Discussion
With long-standing hypothyroidism, thyrotroph
hyperplasia can result in the expansion of the sella turcica and the
enlargement of the pituitary gland(7). Khawaja, et al.(6) report
that pituitary enlargement on MRI is found in 70% patients with primary
hypothyrodism. The pituitary mass may extend outside the sella turcica and
produce clinical symptoms(8). Radiana, et al.(9) suggest that the
greatly increased number of TSH-cells in methimazole-induced-hypothyroidism
is due, at least partially, to the transdifferentiation of somatotroph
into thyrotroph cells and a role for TRH stimulation in the
transdifferentiation process. Key transcription factors, such as Pit-1 and
Gata 2 are known to be involved in pituitary endocrine cell
differentiation(10). Depending on demand, somatotrophs can reversibly
transform into thyrotrophs.
In adults, pituitary hyperplasia with hypothyroidism
generally exhibit in various forms like features of hypothyroidism,
amenorrhea; galactorrhea; visual abnormalities and headaches(5). While
short stature or decreasing growth is a frequent reason for pediatric
consultations, clinical features of hypothyroidism are subtle and missed.
All over patients consulted for growth arrest but their clinical signs of
hypothyroidism were mild and their intellectual development was normal. We
found that these patients were hypothyroid and had pituitary enlargement
upto 12-31 mm in size. A common cause of hypothyroidism is autoimmune
destruction of the thyroid gland(11). Hashimoto’s thyroiditis was the
likely main cause in our patients; because antithyroid antibodies were
positive and radionuclide thyroid scans showed an asymmetrical thyroid
gland with irregular distribution of 99mTc. The other reason was
congenital hypothyroidism, which was caused by thyroid hypoplasia or
dyshormonogenesis. Although neonatal screening has been carried out for
years, hypothyroidism, and consequently pituitary hyper-plasia, continues
to occur in our country.
The recommended and appropriate replacement therapy for
hypothyroidism is levothyroxine sodium. After 6-12 months, all patients’
pituitary hyperplasia regressed with adequate levothyroxine replacement,
but 2 patients still have impaired growth hormone secretion and a low
growth rate. Since thyroxine is a stimulating factor for GH synthesis, GH
production may be reduced in hypothyroic children(3). This is a very
important phase of their height increase in pre-puberty; so after the
complete disappearance of enlargement in the pituitary, rhGH was given to
these 2 patients. The combination levothyroxine with GH can be highly
effective in increasing final height. No recurrence of pituitary
enlargement was found in the 8 follow-up cases.
Contributors: LT designed the study and revised the
manuscript for important intellectual content. XAJ collected data and
drafted the paper.
Funding: None.
Competing interests: None stated.
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What This Study Adds?
• After adequate thyroxine replacement treatment,
regression of the pituitary hyperplasia due to primary
hypothyroidism occurs in the majority and in its absence, growth
hormone deficiency should be considered.
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