Reversible thyrotroph hyperplasia with hyperprolactinemia: A rare presenting manifestation of primary hypothyroidism.

Pituitary thyrotroph hyperplasia with hyperprolactinemia has been described as a rare presentation of primary hypothyroidism. Premenopausal females with this disorder can present with features of hypothyroidism, menstrual disturbances, galactorrhea, and visual field defects because of enlarged pituitary. Here we describe a 32-year-old female presenting to her gynecologist primarily with galactorrhea and secondary amenorrhea. She was found to have raised serum prolactin, and MRI brain showed enlarged pituitary. She was referred for pituitary surgery when she came to us. Clinical examination and biochemistry were suggestive of primary hypothyroidism. She was prescribed levothyroxine replacement. At 6 weeks follow-up, serum prolactin came down to normal, galactorrhea subsided, and spontaneous menstrual cycles resumed. In 12 weeks, pituitary enlargement completely regressed and in another month after that, she conceived. Hence, primary hypothyroidism can present with thyrotroph hyperplasia, where correct diagnosis and levothyroxine therapy can prevent unnecessary pituitary surgery. Hyperprolactinemia in this setting is of no clinical significance.

INTRODUCTION

Hypothyroidism can affect all the organ systems of the body and can have varied manifestations. It can lead to hyperprolactinemia mainly because of pituitary thyrotroph hyperplasia. In Hashimoto's thyroiditis, the incidence of hyperprolactinemia has been reported to be 11.1% in subclinical and 42.4% in overt hypothyroid patients.[1] However, pituitary enlargement in this setting is rare. We report this case of Hashimoto's thyroiditis with hypothyroidism, pituitary enlargement, and hyperprolactinemia, presenting primarily with secondary amenorrhea.

CASE REPORT

A 32-year-old female, mother of two children 6 and 3 years old, presented to her gynecologist with a complaint of secondary amenorrhea of 3 months duration. Urine pregnancy test was negative. As part of evaluation of amenorrhea, the gynecologist found serum prolactin level to be high 101.8 ng/ml (normal 3.1–25 ng/ml). Because of hyperprolactinemia associated with amenorrhea, she was advised MRI brain which revealed pituitary size of 19×12.5×12 mm and a lesion of size 9×4 mm on the right-side hypointense on T1- and T2-weighted images and with enhancement on contrast and dynamic scan. The superior surface of the pituitary was convex while the posterior bright spot was normal. There was no cavernous sinus invasion [Figure 1a and b]. She was thus advised to seek endocrinology opinion for pituitary enlargement and its surgery when she came to our OPD.

Figure 1

(a) Coronal (contrast-enhanced) and (b) Sagittal (plain, T1 W) sections of MRI pituitary showing an enlarged pituitary measuring 19×12.5×12 mm showing convex upper border (a) and normal posterior bright spot (b)

There was no history of any previous drug intake, jaundice, or renal disease. On careful questioning, a history of hoarseness of voice, constipation, and weight gain was elicited. Her blood pressure was 120/86 mm Hg and pulse rate 62/min. Bilateral expressive galactorrhea was present. Although her skin was grossly normal and thyroid not palpable, her deep tendon reflexes were delayed. Visual field charting was bilaterally normal. Thyroid function test was consistent with hypothyroidism with a T3 of 0.38 ng/ ml (normal 0.60–1.81 ng/ml), T4 1.90 μg/dl (normal 5.5–13.5 μg/ dl), and TSH 660.18 mIU/ml (normal 0.35–5.5 mIU/ ml). Formal testing of other anterior pituitary hormones revealed serum cortisol 8.79 μg/ dl (normal 4.30–22.46 μg/dl), estradiol 58.85 pg/ ml (normal 20–150 pg/ ml), FSH 5.17 mIU/ ml (normal 2.5–16.20 mIU/ ml), and LH 3.97 mIU/ ml (normal 1.9–12.50 mIU/ml). Further, to elucidate the etiology of hypothyroidism, TPO antibody testing revealed a level of 4435.80 U/ml (normal <60.0 U/ml). Thus, a provisional diagnosis of Hashimoto's thyroiditis with hyperprolactinemia and pituitary thyrotroph hyperplasia likely due to uncontrolled hypothyroidism was made.

The patient was started on 100 μg/day of levothyroxine (L-T4), on empty stomach in the morning. On follow-up after 6 weeks, galactorrhea had subsided and spontaneous menstrual cycles resumed. Thyroid function tests revealed T3 1.23 ng/ ml, T4 14.40 μg/dl, and TSH 6.33 μIU/ml. Serum prolactin level had come down to normal 1.60 ng/ml. L-T4 dosage was reduced to 75 μg/day. On 12 weeks follow-up, both thyroid function tests and serum prolactin level were within normal range. A repeat MRI brain revealed a normal pituitary measuring 4.7×13×14.5 mm. The convexity of the superior surface and the lesion on the right side reported in the previous imaging had disappeared [Figure 2a and b]. Thus, a final diagnosis of reversible thyrotroph hyperplasia and hyperprolactinemia was made and she was advised to continue with 75 μg/day of L-T4. Four months after the commencement of therapy, she missed her menstrual bleed once again. Urine pregnancy test done at this time was positive. Thyroid function tests revealed free T3 2.50 pg/ml (normal 2.30–4.2 pg/ml), free T4 0.97 ng/dl (normal 0.70–1.51 ng/dl), and TSH 11.72 μIU/ml. In view of confirmed pregnancy, L-T4 dose was stepped up to 150 μg/day. On 1 month follow-up, thyroid function tests were within normal range. To date, she is asymptomatic, 7 months pregnant, and the gestation is progressing normally.

Figure 2

(a) Coronal (contrast-enhanced) and (b) Sagittal (plain, T1W) sections of MRI pituitary, after about 3 months of L-T4 therapy showing complete regression of the pituitary mass, with normalization of its size and contour, and no signs of bleeding or necrosis

DISCUSSION

Hyperprolactinemia is the most common pituitary hormonal abnormality, whereby there is an excess of circulating levels of the polypeptide hormone prolactin. It can have varied causes—physiological; drug intake particularly antipsychotics and antidopaminergics; and pathological and miscellaneous causes such as primary hypothyroidism, polycystic ovarian syndrome, hepatic, and renal failure.[2] Hence, a meticulous clinical assessment is indispensable to identify the etiology. A review of medical and psychiatric history, a history of drug intake, headache, visual disturbances, previous jaundice, or renal disease should be enquired. Detailed clinical examination should be performed to look for features of hypothyroidism and polycystic ovarian syndrome. Radiological imaging should be undertaken only once clinical and biochemical evidence suggests hypothalamopituitary pathology.[2] The treating gynecologist in the present case did not rule out secondary causes of hyperprolactinemia and advised MRI brain as the first investigation. Furthermore, the finding of pituitary enlargement with a localized lesion was also possibly misinterpreted as a prolactinoma and a dynamic MRI scan was done to look for cavernous sinus invasion and to exactly delineate the lesion before referring the patient for pituitary surgery.

In hypothyroidism, hyperprolactinemia is a common finding. Several mechanisms have been proposed to explain this.[3] First, hypothyroid state leads to compensatory increase in thyrotropin-releasing hormone discharge from central hypothalamus. This stimulates prolactin and TSH secretion from the pituitary. Second, anterior pituitary cells in hypothyroidism have decreased sensitivity to suppressant action of dopamine likely at receptor or post-receptor level. Third, prolactin clearance from circulation is decreased in hypothyroidism. Finally, 3,5,3’ triiodothyronine has been shown to decrease prolactin messenger RNA levels in pituitary cells. Reduced thyroid hormone level thus translates into more prolactin synthesis in the pituitary.

The clinical presentation of hyperprolactinemia in premenopausal females is variable and depends on the level of elevation of prolactin.[2] However, when hyperprolactinemia develops secondary to primary hypothyroidism, there are studies which have observed that menstrual abnormalities do not relate to prolactin excess questioning the clinical consequences of elevation of prolactin in this scenario.[45] Here, other than the features of hypothyroidism per se, the various modes of presentation reported include galactorrhea, oligo, or amenorrhea,[6] and even polymenorrhea despite documented hyperprolactinemia.[7] All these features such as polymenorrhea, oligomenorrhea, and galactorrea are known to occur in premenopausal females with primary hypothyroidism per se.[8] Hence, in our patient, presentation with secondary amenorrhea and galactorrhea which normalized completely on L-T4 therapy lead us to conclude that hyperprolactinemia was clinically of no significance in her.

Concomitant thyrotroph hyperplasia with hyperprolactinemia in the face of primary hypothyroidism has been rarely described in the literature, and this may[67] or may not regress completely[9] with levothyroxine therapy. Regression will not be seen if the pituitary enlargement is because of an adenoma or lymphocytic hypophysitis. Both these can produce mass effects in the form of visual field disturbances and pituitary hormonal dysfunction. The typical hormonal dysfunction seen in association with the latter is isolated ACTH deficiency with or without TSH deficiency, with normal gonadotropin levels. Diabetes insipidus can also be seen. The level of prolactin in such cases is variable ranging from low, normal, to high.[10] More so, lymphocytic hypophysitis can be differentiated from other causes of pituitary enlargement by the absence of posterior bright spot and by the finding of a thickened pituitary stalk. In our patient, none of these features was seen, hence we decided to put her on L-T4 therapy and regular follow-up with visual field charting. Pituitary enlargement completely regressed, her galactorrhea and amenorrhea resolved. and she conceived in a matter of 4 months. We thus finally concluded that the present patient had hyperprolactinemia and pituitary thyrotroph hyperplasia secondary to severe primary hypothyroidism.

To summarize, in any patient presenting with hyperprolactinemia with gonadal disturbances, the treating physician/endocrinologist should keep a high index of suspicion to rule out underlying secondary causes such as primary hypothyroidism. If pituitary enlargement is found in such a setting, then a judicious trial of L-T4 therapy can avoid unnecessary pituitary surgery.