Discussion:
This case series presents three patients with similar complaints and
radiological findings of pituitary lesions, yet with distinct underlying
causes and treatment outcomes. The cases highlight the need for a
thorough and systematic approach to diagnosis, incorporating clinical,
biochemical, and radiological findings. Comparison of the three has been
provided in the table 8.
The mechanism of secretion of thyroid hormones is basically controlled
by hypothalamus. Thyrotropin releasing hormone (TRH) from hypothalamus
stimulates thyrotrophs cells in anterior pituitary to release thyroid
stimulating hormone, which ultimately acts on TSH receptors on thyroid
gland and releases Thyroxine (T4) and triiodothyronine (T3) hormones.
This mechanism is controlled by a feedback response. Thyroid hormones
produced from thyroid glands give negative feedback to hypothalamus so
that TRH secretion can be reduced and vice versa. In primary
hypothyroidism, this negative feedback response is lost because thyroid
gland is not able to produce enough T3 and T4, as a result of which
hypothalamus keeps on producing TRH which stimulates thyrotropes of
pituitary gland, causing its hyperplasia and increasing TSH levels. This
TRH can also cause an increased rate of growth of lactotroph cells in
addition to thyrotropes cells which is the reason behind
hyperprolactinemia in primary hypothyroidism (6). It can be easily mis
diagnosed as a prolactinoma if we do not have the hormonal profile to
identify hypothyroidism.
The etiology of pituitary adenoma still needs to be clarified. It can be
sporadic or genetic. Sometimes, it is a part of a syndrome like MEN 1 or
a secondary effect of another condition like hypothyroidism, as in our
cases. Hypothyroidism itself is commonly due to iodine deficiency in
certain regions, while in developed countries, it is more often linked
to autoimmune diseases like Hashimoto’s thyroiditis. Other causes
include Medications (e.g., amiodarone, carbamazepine, lithium),
Post-thyroidectomy effects, Radioiodine ablation, Neck or chest
radiation, and Genetic factors.
Pituitary hyperplasia due to hypothyroidism was initially seen in 1851
when an autopsy of a cretin was done (5). It has been seen that the
incidence of pituitary hyperplasia with primary hypothyroidism has not
been apparent. Still, more literature is being done to understand the
etiology behind this relation more clearly. The risk of pituitary
hyperplasia with hypothyroidism can range from 25-81% (6), and features
of hyperprolactinemia are seen in 36% of people with primary
hypothyroidism (7). This is similar to our case number 1 presented
above, which presented with symptoms of hyperprolactinemia
(galactorrhea, menstrual irregularities), but it was due to primary
hypothyroidism.
Patients of hypothyroidism with pituitary involvement usually present
with galactorrhea, irregular menstrual cycle, infertility, weight gain,
fatigue, loss of appetite, dry skin, constipation, short stature, and
delayed puberty in children (8). The initial investigation should focus
on biochemical testing of pituitary hormones, including serum prolactin,
thyroid profile (TSH, T3, T4), cortisol, luteinizing hormone (LH),
follicle-stimulating hormone (FSH), and growth hormone levels. If the
hormonal profile does not indicate hypothyroidism but shows elevated
levels of another hormone, such as prolactin, brain imaging (MRI or CT)
should be considered. Importantly, radiological imaging alone cannot
reliably distinguish between pituitary adenoma and hyperplasia (8). Our
Case 2 illustrates a patient whose pituitary lesion, secondary to
hypothyroidism, comprised both hyperplasia and a persistent adenoma that
remained despite thyroxine treatment.
Medical management with thyroxine hormone supplementation is the
treatment for such patients. When thyroxine levels rise, they produce a
negative feedback response to the hypothalamus, reducing TRH and TSH
hormone levels. This treatment typically resolves pituitary hyperplasia
(7). Ongoing follow-up is crucial to assess treatment efficacy, and
repeat MRI imaging can help evaluate pituitary mass size. If the mass
does not respond to thyroxine therapy, a pituitary adenoma should be
considered.
TSH-secreting pituitary adenomas are a rare cause of hyperthyroidism,
accounting for less than 1% of all functioning pituitary adenomas
[3]. While the presence of a pituitary adenoma in a patient with
inappropriately elevated TSH levels can suggest TSHoma, this finding
alone is not diagnostic, as incidental pituitary tumors are detected in
up to 10% of normal subjects on MRI (10). Dynamic tests to diagnose
TSHoma include both stimulatory and inhibitory tests, including the TRH
stimulation and T3 inhibitory tests. The T3 suppression test (T3
inhibitory test), where failure to suppress TSH following T3
administration, alongside elevated levels of the serum glycoprotein
hormone alpha subunit (α-GSU), strongly supports a TSHoma diagnosis
(11). Elevated alpha subunit concentration or a high alpha subunit/TSH
molar ratio is typically present in patients with TSHoma.
Resistance to thyroid hormones (RTH) is most commonly caused by
mutations in the THRB gene on chromosome 3. The mutant thyroid hormone
receptor beta protein has either reduced affinity for T3 or abnormal
interaction with cofactors involved in thyroid hormone action, making
the target tissues refractory to thyroid hormones [12]. Patients
with THRB mutations have variable clinical presentation. They may be
clinically euthyroid or present with symptoms of hypothyroidism hy,
hyperthyroidism, or a combination of thyroid hormone excess and
deficiency, depending on the level of THRB and THRA gene expression in
the target tissue.
Peripheral metabolic markers, including sex hormone-binding globulin
(SHBG), bone-specific alkaline phosphatase (bs-ALP), carboxy-terminal
cross-linked telopeptides of type I collagen (ICTP), and ferritin, are
typically elevated in cases of TSHoma (13). The liver contains primarily
THR β1 THR β3. Raised levels of sex-hormone binding globulins favor
TSHoma as the likely etiology of inappropriate secretion of TSH. In case
of resistance to thyroid hormone, SHBG should be normal or low because
of end-organ resistance. Moreover, tachycardia and weight loss with low
BMI favored the diagnosis of TSHoma as these features might be absent in
case of resistance to thyroid hormone, depending on the level of gene
mutation. Additionally, average IQ is consistent with TSHoma, whereas
patients with RTH often experience learning disabilities due to
resistance in THR β receptors within the central nervous system. Despite
limited access to pituitary dynamic testing in this case, clinical
features and biochemical markers pointed to a diagnosis of TSH-secreting
pituitary tumor (TSHoma) in our third patient.
The first-line treatment is surgical resection of adenoma. Before
surgery, somatostatin analogs are started to optimize TFTs. In patients
who are not cured with surgical management, other available options are
medical treatment with somatostatin analogs and radiotherapy.
In summary, all three patients had elevated TSH and a pituitary lesion,
but their presentations and outcomes differed. Case 1 responded well to
medical treatment with thyroxine, whereas Case 2 had a residual adenoma
despite thyroxine therapy. In Case 3, a TSHoma was mismanaged initially
with thyroxine, delaying the necessary surgical intervention.