Thyroid Science 6(10):CR1-4, 2011	www.ThyroidScience.com
Case Reports

Primary Hypothyroidism Associated with

Hyperprolactinemia and Pituitary Macroadenoma

Dragana Jokic, MD and Xiangbing Wang, MD, PhD

Division of Endocrinology and Metabolism,

Robert Wood Johnson Medical School

University of Medicine and Dentistry

New Brunswick, New Jersey

Corresponding Author: Xiangbing Wang, MD, PhD, FACE

Division of Endocrinology, Metabolism & Nutrition

Robert Wood Johnson University Hospital-UMDNJ

MEB 384B, 1 RWJ Place, P.O. Box 19. New Brunswick, NJ 08903

Phone (732) 235-7751 Fax (732) 235-7069 E-mail: wangx9@umdnj.edu

Received: July 13, 2011

Accepted: July 27, 2011

Abstract. Objective: Our purpose is to report a case of primary hypothyroidism associated with hyperpro
lactinemia and pituitary macroadenoma. Background: We present the case report, including detailed lab
oratory and radiological findings in a 28-year-old woman. In primary hypothyroidism there is hyperplasia of both thyrotrophs and lactotrophs as a response to TRH hypersecretion. The hyperplasia can result in sig
nificant enlargement of the pituitary gland and can be mistaken for a prolactin-secreting tumor. Case: We report the case of a female patient who presented with amenorrhea of 7-months duration and was found by her gynecologist to have elevated prolactin. The initial MRI showed a 1.7 cm pituitary mass which was treat
ed initially by cabergoline. Due to the patient's noncompliance and lack of follow up, the patient remained on cabergoline for 6 months and did not do thyroid function tests. Finally, after 6 months, a follow up MRI showed no change in size of her pituitary mass. Also, blood tests showed profound hypothyroidism, and after 6 month of thyroid replacement therapy, the patient was euthyroid. A repeated MRI of the brain showed complete resolution of the pituitary mass. Result: This case emphasizes the importance of evaluation of thy
roid function in cases of elevated prolactin and gonadal dysfunction. Despite a lack of the typical clinical presentation of hypothyroidism, resolution of the patient's symptoms and disappearance of her pituitary mac
roadenoma confirms the diagnosis. Conclusion: This case illustrates that primary hypothyroidism can pre
sent with amenorrhea and pituitary mass.

Keywords • Amenorrhea • Hyperprolactinemia • Hypothyroidism • Pituitary macroadenoma • Prolactin

Introduction

Prolactin is a pituitary-derived hormone that plays a pivotal role in a variety of reproductive functions. Prolactin negatively modulates the secre
tion of pituitary hormones responsible for gonadal function, including luteinizing hormone and folli
cle-stimulating hormone. An excess of prolactin, or hyperprolactinemia, is a commonly encountered clin
ical condition and is most commonly secreted in ex
cess by pituitary adenoma. The patient usually pre
sents with galactorrhea and gonadal dysfunction.

It is important to measure prolactin levels in all patients with unexplained primary or secondary a
menorrhea. This was emphasized in some previous studies that showed that as many as 20% of patients with hyperprolactinemia did not have galactorrhea nor any signs of pituitary dysfunction. Vilar et al. reported on 1234 patients with different etiologies of hyperprolactinemia, as well as the response of 388 patients with prolactinomas to dopamine agonists.[1]

Vilar et al. found that 56.2% of patients had pro
lactinomas, 14.5% had drug-induced hyperprolacti
nemia, 9.3% had macroprolactinemia, 6.6% had non-
functioning pituitary adenomas, 6.3% had primary hypothyroidism, 3.6% had idiopathic hyperprolacti
nemia, and 3.2% had acromegaly.[1]

In men, the diagnosis of prolactin-secreting tu
mors is usually delayed until visual impairment or hypopituitarism appears. The reason is the male's ini
tial signs of gonadal dysfunction. These signs, de
creased libido and occasionally galactorrhea, are as
sociated with prolactin excess are usually ignored.

There are many conditions associated with hyper
prolactinemia. The most common causes are preg
nancy, hypotalamo-pituitary disorders, drugs, and primary hypothyroidism.

With the development of the third generation TSH assay and the inclusion of thyroid function testing in annual blood screenings, hyperprolactine
mia caused by primary hypothyroidism become less common. Primary hypothyroidism can be associated with diffuse pituitary enlargement, which reverses with appropriate thyroid hormone replacement ther
apy.[2,3] However, primary hypothyroidism associated with a pituitary adenoma is extremely rare. Here, we report one such case.

Case Presentation

A 28-year-old female presented at her gynecolo
gist's office with 7 months of amenorrhea in 2009. The patient initially complained also of occasional dizziness, but she did not have headaches, visual dis
turbances, or galactorrhea. The patient also denied diarrhea or constipation, as well as dry skin, hot and cold intolerance, weight change, and muscle cramps. She never had menstrual abnormalities prior to this episode. She had recently married. Her only medical history was knee surgery 10 years before. Her family history was positive for thyroid cancer, which her sis
ter had. She never smoked or abused alcohol and was exercising regularly.

The initial laboratory work done by her gynecolo
gist was negative for pregnancy, but it showed a prolactin level of 139 ng/mL. An MRI of the brain showed a 1.7 cm pituitary macro adenoma. The ade
noma extended into the suprasellar region with in
dentation of the optic chiasm. Thyroid studies were also ordered but the patient did not follow up for re
evaluation.

The gynecologist started the patient on 0.25 mg of cabergoline twice weekly. After 6 months, the patient came back with the same complaint of amenorrhea and a new symptom of "feeling cold all the time." Her prolactin level had decreased to 11.7 ng/mL and an MRI of the brain showed no change in the size of the pituitary adenoma. The patient was referred to an endocrinologist for possible surgery because of failure of the adenoma to shrink. Although no symptoms suggested hypothyroidism except cold intolerance, blood tests showed a TSH of 562.5 U/mL, a FT4 of 0.18 ng/dL, and a reference range IGF-1 level. Cabergoline was discontinued and the patient was started on levothyroxine. The dosage was titrated to 112 g daily.

The patient was closely followed afterwards and 6 months later, her prolactin level was 23.2 ng/mL and her periods were regular; TSH had decreased to 0.237 U/mL, her total T3 was 127 ng/dL, and her FT4 was 1.63 ng/dL. An MRI one year after she had start
ed levothyroxine showed complete resolution of the pituitary adenoma.

Discussion

The hyperprolactinemia of hypothyroidism is re
lated to several mechanisms. In response to the hy
pothyroid state, a compensatory increase in the dis
charge of TRH results in an increased stimulation of pituitary prolactin secretion. Hypothalamic thyro
tropin releasing hormone (TRH) is a potent prolactin releasing factor, and it can cause thyrotroph hyper
plasia.

The high level of TRH in severe primary hypo
thyroidism and the lack of T4 feedback from the thyroid gland might cause proliferation and hyper
trophy of both the pituitary gland's thyrotrophs and lactotrophs. The hypertrophy may mimic a pituitary adenoma. With proliferation of the thyrotrophs and lactotrophs in primary hypothyroidism, as illustrated in our case, there is a significant increase in TSH lev
els and only a moderate increase in the prolactin level.

In our patient, regression of her pituitary mac
roadenoma after treatment with levothyroxine con
firmed the hypothesis of pituitary hyperplasia sec
ondary to primary hypothyroidism. Cabergoline de
creased her prolactin levels, but it did not decrease the size of the adenoma. This observation also supports the diagnosis of pituitary macroadenoma that was likely secondary to hypothyroidism.

Furthermore, prolactin elimination from the sys
temic circulation is reduced in severe hypothyroid
ism; this contributes to increased circulating prolactin concentrations. Primary hypothyroidism can be associated with diffuse pituitary enlargement, which will reverse with appropriate thyroid hormone re
placement therapy.

In our case, primary hypothyroidism was not investigated and treated at the beginning of her care

Figure. A and B: Coronal and sagittal post-gadolinium images show a 1.7 cm pituitary macroadenoma extending into the suprasellar region with indentation of the optic chiasm.

C and D: Coronal and sagittal post-gadolinium images show no difference in size of pituitary macroadenoma after 6 months of therapy with cabergoline

E and F: Coronal and sagital post-gadolinium images show complete resolution of the pituitary mass after 6 months of thyroid hormone replacement therapy.

for three reasons: (1) the patient was relatively asymp
tomatic, (2) presented with a pituitary macroadenoma rather than a diffuse enlargement, and (3) was non
compliant.

This case illustrates the importance of doing thyroid function tests in patients with hyperprolac
tinemia and pituitary macro adenoma. Doing so can avoid unnecessary pituitary surgery. However, sur
gical resection of a pituitary adenoma in primary hypothyroidism might still be necessary. In rare cases, for example, paradoxical pressure symptoms and development of a visual field defect will occur in the first months of thyroid replacement therapy. These symptoms suggest that monitoring for pressure symptoms during the treatment is important.[9]

TSH secreting pituitary tumors caused by pri
mary hypothyroidism should be distinguished from true thyrotroph neoplasia that results in secondary hy
perthyroidism. The appropriate therapeutic approach is completely different. TSH-omas are usually inva
sive macroadenomas and are known to be difficult to treat.[6]

The timeline of growth and regression of pituitary adenomas in hypothyroidism after replacement ther
apy has been started has not been clearly established. Studies show that discontinuation of T4 replacement in preparation for 131I therapy for only 3 weeks can cause significant enlargement of the pituitary gland.[2] In one reported case, the patient had rapid regression of a pituitary adenoma after one week of T4 replace
ment.[7] In our case, the exact time course could not be established. However, regression of the pituitary mac
roadenoma after treatment with levothyroxine con
firmed the hypothesis of pituitary hyperplasia sec
ondary to primary hypothyroidism.

Conclusion

Patients with hypothyroidism do not always pre
sent with typical symptoms. Our case illustrates that primary hypothyroidism can present in amenorrhea and pituitary mass. This suggests the importance of thyroid function testing during the investigation of

hyperprolactinemia and pituitary adenoma in order to

avoid unnecessary surgery.

References

1.	Vilar, L., Freitas, M.C., Naves, L.A., at el.: Diagnosis and management of hyperprolactinemia: results of a Brazilian multicenter study with 1234 patients. J. Endocrinol. Invest., 31(5):436-44, 2008.

2.	Passeri, E. and Tufano, A.: Large pituitary hyper
plasia in severe primary hypothyroidism. J. Clin. Endocrinol. Metab., 96: 22-23, 2011.

3.	Alves, C. and Alves, A.C.: Primary hypothyroidism in a child simulating a prolactin secreting adenoma. Childs Nervous System, 24(12):1505-8, 2008.

4.	Shimono, T, et al.: Rapid progression of pituitary hy
perplasia in humans with hypothyroidism: demon
stration with MR imaging. Radiology, 213: 383-388, 1999.

5.	Beck-Peccoz, P. and Persany, L.: Tyrotropinomas. Endocrinology and Metab. Clinic North Amer., 37:123-134, 2008.

6.	Beck-Peccoz, P., Brucker-Davis, F., Persani, L., et al.: Thyrotropin-secreting pituitary tumors. Endo
crine Rev., 17(6):610, 1996.

7.	Sarlis, N.J., Brucker-Davis, F., Doppman, J.L., et al.: MRI-demonstrable regression of a Pituitary mass in a case of primary hypothyroidism after a week of acute thyroid hormone therapy. J. Clin. Endocrinol. Metab., 82(3):808-818, 1997.

8.	Klibanski, A.: Prolactinomas. N. Engl. J. Med., 362:1219-1226, 2010.

9.	Stockigt, J.R., Essex, W.B., West, R.H., et al.: Visual failure during replacement therapy in primary hypo
thyroidism with pituitary enlargement. J. Clin. Enocr. Metabol., 43(5):1094-1100, 1976.

10.	Wajchenberg, B.L., Tsanaclis, A.M., and Marino Jú
nior, R.: TSH-containing pituitary adenoma associat
ed with primary hypothyroidism manifested by amen
orrhoea and galactorrhoea. Acta Endocrinologica, 106(1): 61-66, 1984.