Pituitary Hyperplasia in Primary Hypothyroidism

Etiology

In patients with primary hypothyroidism, the most common cause is chronic autoimmune thyroiditis or Hashimoto's thyroiditis, which results in a combination of cell and antibody-mediated thyroid destruction.[1] As a result of thyroid destruction, the low levels of circulating thyroid hormone lead to a lack of negative feedback on the hypothalamus resulting in elevated thyrotropin-releasing hormone (TRH). The elevated TRH levels lead to thyrotroph hyperplasia in the pituitary, which, in turn, results in elevated thyroid-stimulating hormone (TSH) production. The elevated TRH can also lead to lactotroph hyperplasia, which is the cause of increased prolactin in these patients.[2] 

The thyrotroph hyperplasia is what ultimately results in the enlargement of the pituitary gland.[3] Important to note is that thyrotroph cells in the anterior pituitary only comprise 5% to 10% of all cell types in the gland and yet can result in significant gland enlargement in those with primary hypothyroidism.[4] One postulated mechanism is that the number of thyrotroph cells can increase by up to 34% in patients with hypothyroidism.[5]

Epidemiology

Certain studies have demonstrated that the incidence of pituitary hyperplasia in primary hypothyroidism can range anywhere from 25%-81%.[5] These studies were based on skull x-ray findings showing increased sella turcica volume in those with primary hypothyroidism. Additional research has shown that a correlation may exist between the presence of pituitary hyperplasia as measured by the size of the sella turcica with how high the level of TSH value is.[6] One study showed that in those patients with TSH levels above 50 IU/mL, 70% had enlargement of their pituitary.[7]

History and Physical

History and physical examination can help tremendously to guide further work-up. The clinician needs to think in an organized fashion with regards to end-organ deficiencies or excess and their manifestations as well as local complications of an enlarged pituitary gland.

If a patient has hypothyroidism, they may experience symptoms such as weight gain, fatigue, cold intolerance, constipation, dry skin, and irregular menses in females.[8] Children may present with delayed growth, short stature, obesity, and rarely precocious puberty.[9] Since a TSH-producing adenoma is on the differential, hyperthyroid symptoms are always asked in tandem, such as unintentional weight loss, anxiety, experiencing tremors, sweating, heat intolerance, and palpitations. As prolactin levels are fairly commonly elevated in patients with pituitary hyperplasia as a result of primary hypothyroidism, the clinician should also ask about amenorrhea and galactorrhea in females as well as any issues with fertility. For structural concerns related to the enlarged pituitary gland, the clinician should ask about the presence of headaches or changes in vision that would be concerning for the mass abutting the optic chiasm.

The history should also include asking about prior diagnoses of endocrine conditions, including hypothyroidism. Current medical diagnoses and medication lists are important to enquire about as well. Especially in patients already on thyroxine treatment, enquiring about adherence is vital. Family history should be noted, including the presence of any autoimmune or endocrine conditions that run in the family.

The physical examination needs to include a head-to-toe approach. Starting with the head, inspect for typical facies such as a "peaches and cream" complexion or loss of the lateral third of the eyebrow in those with hypothyroidism. A comprehensive eye examination should be performed, inspecting for periorbital edema, including testing visual fields and performing fundoscopy. Neck examination should include examining the thyroid for goiter or palpable nodules. Examining the extremities should include looking for dry skin, nail changes such as onycholysis or brittle nails, proximal muscle weakness, and checking reflexes that can show a delayed relaxation in patients with hypothyroidism. Moving on to the chest, the clinician should evaluate for breast discharge, check the pulse for an irregularly irregular rhythm suggestive of atrial fibrillation, or bradycardia in severe hypothyroidism, evaluate for a very soft or inaudible heart sounds that may suggest the presence of a pericardial effusion and finally check for reduced breath sounds at the lung base with dullness to percussion that may suggest the presence of a pleural effusion. For children specifically, the clinician should include the height and weight growth charts, calculation of body mass index (BMI), and Tanner classification.

Evaluation

Once a comprehensive history and physical examination are obtained, the next step is to look at thyroid biochemistry. In primary hypothyroidism, elevated TSH levels and low free thyroxine 4 (T4) and thyroxine 3 (T3) are observed. One study evaluated patients with a TSH above 50 IU/mL; 70% of these patients had pituitary enlargement on MRI. Of these patients with pituitary enlargement, 84% had a TSH 100 IU/mL or higher, which shows there may be a correlation between TSH levels and the presence of pituitary enlargement.[7] In a TSH-secreting adenoma, TSH levels are elevated; however, free T4 and T3 levels would be elevated too. If central hypothyroidism was on the differential as a result of pituitary adenoma, the clinician would expect low or normal TSH and low free T4 and T3. If primary hypothyroidism is suspected, it may also be useful to test for thyroperoxidase (TPO) antibodies and thyroglobulin antibodies (TGAb). If a TSH-secreting adenoma is suspected, additional testing can be performed, including a TRH stimulation test to which the patient does not respond and would also have an increased alpha-subunit to TSH ratio.[10]

When a patient has a pituitary lesion, in general, all cell lines with their end-organ hormones should be checked. Therefore, an adrenocorticotropic hormone (ACTH) and morning cortisol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone in males, estradiol with additional menstrual history in females, insulin-like growth factor-1 (IGF-1), and prolactin should all be obtained. Prolactin levels are often elevated in those with primary hypothyroidism with pituitary hyperplasia due to TRH stimulating lactotroph hyperplasia in addition to thyrotroph hyperplasia.[2]

Imaging is important in the evaluation of these patients. MRI is generally the best test to look at pituitary anatomy. However, it is not easy to differentiate hyperplasia from an adenoma on imaging alone. In general, pituitary hyperplasia is described as homogeneously enhancing and the "nipple sign," which is when the pituitary gland has smooth contours, but a central protrusion of a pituitary mass is present.[11]

Treatment / Management

The primary treatment for pituitary hyperplasia secondary to primary hypothyroidism is to treat the hypothyroidism with thyroid hormone replacement.[12] Some literature, particularly in children, describes perhaps utilizing gradually increasing doses of thyroxine replacement in an attempt to try to negate the complications that are potentially related to treatment.[13](B2)

It is imperative to follow up with these patients closely for multiple reasons. Sometimes, after initiation of thyroxine therapy, there exists a rare phenomenon whereby patients develop pseudotumor cerebri, and they might complain about headaches and varied visual changes.[14] Additionally, there is this paradoxical phenomenon whereby their vision may deteriorate after starting treatment with thyroid hormone replacement. It is thought that this is a result of an imbalance between TSH production and release, which in turn causes further enlargement of the pituitary. However, even though this may occur, when the TSH levels start to normalize, these effects are usually reversible.[15](B3)

Follow up imaging is necessary and should include an MRI of the pituitary. To confirm the diagnosis of pituitary hyperplasia as a result of primary hypothyroidism, these should be a reduction in the pituitary size when thyroxine therapy has been initiated. Studies have shown that approximately 85% of those with pituitary hyperplasia due to primary hypothyroidism demonstrate decreased pituitary gland size after starting thyroxine replacement.[16] The timing by which this happens is variable, but a noticeable effect is usually present on average after 2  to 4 months.[17] Another reason for follow up imaging is that if there is no regression in the size of the pituitary with the treatment of the underlying hypothyroidism, the clinician should reconsider this diagnosis. There may sometimes actually be an underlying adenoma. A TSH-secreting adenoma should be suspected if pituitary mass and TSH levels do not improve with thyroxine treatment.[18](B3)

As for the role of surgery in pituitary hyperplasia in primary hypothyroidism, this is generally reserved for those who have visual field defects and necessitates decompression of the optic chasm to avoid permanent vision loss. In addition, if there is noted progression in the size of the pituitary despite initiation of thyroxine treatment, surgery may be required to establish a diagnosis by pathology.[19](B3)

Thus, close follow up should include evaluation of symptoms of hypothyroidism and any new symptoms such as headaches or new visual changes. A visual examination should be performed, including visual fields and fundoscopy, as well as neurologic examination and follow up thyroid biochemistry to assess treatment progress.

Differential Diagnosis

In general, the differential diagnosis of a sellar mass includes pituitary adenomas, pituitary hyperplasia, either physiologic (pregnancy) or pathologic (resulting from end-organ insufficiency), lymphocytic hypophysitis, and in children, craniopharyngiomas and intracranial germ cell tumors.[9] Knowing the clinical situation as well as the appropriate biochemistry, can be helpful in working through the differential diagnosis.

In a specific setting where the patient has elevated TSH and low thyroid hormone levels with a pituitary mass, the patient can either have pituitary hyperplasia as a result of the primary hypothyroidism, or they may have a non-functioning pituitary adenoma in addition to primary hypothyroidism. A TSH-secreting adenoma should not be discounted, as even though one would expect elevated thyroid hormones in addition to an elevated TSH, there may be concomitant primary hypothyroidism and thus follow up imaging and thyroid biochemistry becomes important to differentiate these entities.

Prognosis

Prognosis in these patients is usually good with improvement after thyroid hormone replacement therapy, and very few patients actually require surgery due to compressive symptoms or inappropriate response to thyroxine replacement therapy. In general, when these patients are followed up, literature shows a vast proportion (85%) have a decrease in the size of their pituitary on repeat MRI imaging.[16] The timing of this improvement does vary in the literature, generally ranging anywhere from one week to several months.[20][21][22][23][24]

Complications

If the pituitary becomes large enough, it may impinge on the optic chasm causing visual defects, including problems with visual fields and, ultimately, bilateral hemianopsia. In addition, as described above, patients may also get a paradoxical worsening of their vision with the initiation of treatment with thyroxine as a result of an imbalance of TSH production and release and increase in pituitary size.[25]

There are a few extremely rare complications related to treatment. Pseudotumor cerebri has been described as occurring with the initiation of levothyroxine in some case reports. This highlights the importance of being aware of such complications so that upon follow up of these patients, a neurologic examination and fundoscopic examination should be performed.[13][26] Empty sella is another rare complication thought to occur secondary to the rapid shrinkage of the lactotroph and thyrotroph cells when the negative feedback is restored, and TRH stimulation is removed with thyroid hormone replacement.[2][27][28]

If the pituitary hyperplasia is sufficiently long-standing, it can result in other hormonal deficiencies and, ultimately, hypopituitarism.[19][29] Long-standing hyperplasia of the thyrotroph cells can result in damage to adjacent cell types, including corticotrophs, gonadotrophs, and somatotrophs.[29]

Another extremely rare complication of pituitary hyperplasia due to primary hypothyroidism is spontaneous ovarian hyperstimulation syndrome. Patients with this condition can present in a varied manner depending on the severity with abdominal discomfort, ascites, electrolyte derangements, elevated creatinine, and respiratory distress.[30] The mechanism behind this is thought to be due to the fact that TSH also has weak FSH activity, thus there could be stimulation of the FSH receptor by TSH. Additionally, when a female has hypothyroidism, there is preferential production of estriol, which results in reduced suppression of the release of gonadotropins when compared with estradiol.[29]