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.