Galactorrhea in Subclinical Hypothyroidism. Division of Endocrinology and Metabolism,

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1 Endocrinol. Japon. 1987, 34 (4), Galactorrhea in Subclinical Hypothyroidism TAKAJI TAKAI, KUNIHIRO YAMAMOTO, KOSHI SAITO, KAZUKO ANDO, TOSHIKAZU SAITO AND TAKESHI KUZUYA Division of Endocrinology and Metabolism, Jichi Medical School, Yakushiji , Minamikawachimachi, Tochigi , Japan Abstract Galactorrhea was found in 5 patients with subclinical hypothyroidism. The galactorrhea consisted of the discharge of a few drops of milk only under pressure. Serum T4 was in the lower level of the normal range, but serum T3 was normal (T4: 6.3 }1.2ƒÊg/dl, T3: 113 }7ng/dl). Basal serum TSH and PRL were slightly increased only in 2 and 1 cases, respectively. The PRL responses to TRH stimulation were exaggerated in all cases, although the basal levels were normal. An enlarged pituitary gland was observed in 1 patient by means of CT scanning. All patients were treated by T4 replacement. In serial TRH tests during the T4 replacement therapy, the PRL response was still increased even when the TSH response was normalized. Galactorrhea disappeared when the patients were treated with an increased dose of T4 ( ƒÊg/day). Recurrence of galactorrhea was not observed even though replacement dose of T4 was later decreased to 100ƒÊg/day in 4 cases. In patients with galactorrhea of unknown origin, subclinical hypothyroidism should not be ruled out even when their serum T4, T3, TSH and PRL are in the normal range. The TRH stimulation test is necessary to detect an exaggerated PRL response, as the cause of the galactorrhea. To differentiate this from pituitary microadenoma, observation of the effects of T4 replacement therapy on galactorrhea is essential. Recently, primary hypothyroidism has tended to be diagnosed in the disease's early stage, by a development of the radioimmunoassay system. It has been divided into several classes, from an asymptomatic type to full-blown myxedema, according to the Received November 11, 1986 Address all correspondence and requests for reprints to: Kunihiro Yamamoto, M. D., Division of Endocrinology and Metabolism, Jichi Medical School, Tochigi, , Japan levels of thyroid hormone and TSH (Evered et al., 1973, Bastenie et al., 1980). Since hypothyroidism is a graded phenomenon, it is possible that a mild complication of primary hypothyroidism may appear at a subclinical stage. Primary hypothyroidism during overt clinical stages is known to be one of the causes of galactorrhea and hyperprolactinemia (Onishi et al., 1977, Hombo et al., 1978, Kleinberg et al., 1977), but subclinical hypothyroidism has not been shown to be the cause of the symptoms.

2 540 TAKAI et al. Endocrinol. Japon. August 1987 In this study, the PRL response to TRH stimulation was examined in subclinical hypothyroid patients with galactorrhea, and was compared with those of subclinical hypothyroid patients without galactorrhea and of overt hypothyroid patients. The effects of T4 replacement therapy on galactorrhea and exaggerated PRL response to TRH stimulation are discussed. assay kits (Fuji-Rebio, Japan). The T4 replacement therapy for subclinical hypothyroidism was started with a dose of 100ƒÊg/day and increased 25 or 50ƒÊg/day when the replacement was judged to be insufficient. The judgement of the therapy's effects was based on the changes in galactorrhea, after at least 2 months of T4 replacement. The patients were given 500ƒÊg TRH i.v. serially during the T4 replacement therapy, to detect the pituitary reserves of TSH and PRL. Statistical analysis was performed by means of the Student's t-test. Materials and Methods Five patients with subclinical hypothyroidism and galactorrhea (females, age 28-40) were studied. None of the patients complained of any symptoms of hypothyroidism, except goiter and galactorrhea. Four patients showed a positive response to antithyroid antibody tests, and had small goiters, presumably due to autoimmune thyroiditis. One patient (case #5 in Table 1) with a negative response in the antithyroid antibody tests was in the recovery stage of subacute thyroiditis. During the follow-up study of thyroid function after subacute thyroiditis, she was found to be in the subclinical hypothyroid phase, due to thyroid destruction. Three subclinical hypothyroid patients without galactorrhea (females, aged 30-46), and 8 overt hypothyroid patients (females, aged 33-66) were compared for the pituitary reserves of TSH and PRL. They were chosen for this study because they had exaggerated PRL response to TRH stimulation. T4, T3, TSH and PRL were assessed by radioimmunoassay using commercially available kits. Antithyroid antibody tests for thyroid microsomal antigen (MCHA) and thyroglobulin (TGHA) were performed using hemagglutination Results The minimal degree of milk secretion was observed in 5 patients with subclinical hypothyroidism. The galactorrhea consisted of a few drops of milk, discharged only under pressure. In three of them galactorrhea failed to be noted until the physician manually expressed the milk. None of the patients was in puerperium or receiving oral contraceptive therapy prior to the oncet of the symptoms. It was ascertained that the patients were not taking any drugs known to cause galactorrhea or hyperprolactinemia. Despite the increased PRL response after TRH, basal levels of PRL were within the normal range (<20ng/ml) in 4 cases. Serum T4 was in the lower part of the normal range, but serum T3 was normal (Table 1). In the serial examinations of thyroid function before the start of T4 replacement therapy, transitory hypothyroxinemia was Table 1. Thyroid function and prolactin in subclinical hypothyroidism with galactorrhea. *: AIT denotes autoimmune thyroiditis; SAT, subacute thyroiditis; MCHA, antimicrosomal antibody; TGHA, antithyroglobulin antibody; Neg, negative.

3 Vol.34, No.4 GALACTORRHEA IN SUBCLINICAL HYPOTHYROIDISM 541 found in 3 patients (cases #2, 3, and 5). The T4 levels were 2.7, 3.7, and 3.8ƒÊg/dl, respectively. Serum TSH levels of the patients rose during the same periods while serum T3 did not change. The TSH levels of cases #2, 3, and 5 were 23.7, 11.8, and 51.0ƒÊU/ml, respectively. All patients except case #3 had increased TSH response to TRH stimulation. Case #3 showed an enlargement of the pituitary gland with an enhancement effect, with CT scanning. There were no differences in T4 and T3 levels in subclinical hypothyroid patients with or without galactorrhea. PRL and TSH levels (basal and peak after TRH) of the 2 groups, also did not differ with each other. Although the pituitary reserve of TSH was significantly increased in overt hypothyroidism, the PRL response to TRH was invariably increased in both the subclinical and overt phases of hypothyroidism (Table 2). In all patients, the exaggerated PRL response decreased and galactorrhea disappeared after 4 to 6 months of T4 replacement therapy. The peak PRL level after TRH stimulation fell to 42.8% (range; %) of the pretreatment value following T4 therapy. Although the peak PRL after TRH was suppressed by the treatment, the basal PRL remained at the same level as that before therapy (Table 3). In the patient with an enlarged pituitary gland (case #3), the enhancement effect observable with CT scanning was lost after T4 treatment. In 4 cases (cases #2-5), the replacement dose of T4 was reduced to 100 No recurrence of galactorrhea was observed under the ordinary replacement dose of T4. Case #1 had been prescribed the increased dose of T4 because the PRL response to TRH was still exaggerated. Discussion Hyperprolactinemia with or without galactorrhea and amenorrhea occurs in a wide

4 542 TAKAI et al. Endocrinol. Japon. August 1987 Table 3. Thyroid function and prolactin at the time galactorrhea disappeared. variety of endocrine and non-endocrine disorders (Kleinberg et al., 1977). Among the causes of hyperprolactinemia, primary hypothyroidism has the distinctive feature that the symptoms are correctable with thyroid hormone replacement therapy. Although primary hypothyroidism is well known as one of the causes, the existence of galactorrhea in subclinical hypothyroidism has not been reported, Bigos et al. (1978) reported that significant PRL level changes after TRH stimulation were observed only in overt hypothyroidism, though thyrotroph cells were readily augumented, even in mild thyroid impairment. Reports from Pelkomen et al. (1982) and Cooper et al. (1984) showed that the PRL response to TRH was markedly greater in the subclinical stage than in controls, though the response was within the normal range. In contrast to this, we found that some subclinical hypothyroid patients already had an exaggerated PRL response to TRH and galactorrhea when they otherwise had no symptoms of hypothyroidism. Pituitary PRL reserves were invariably increased in subclinical hypothyroid patients both with and without galactorrhea. The serum levels of thyroid hormone, TSH and PRL in both groups were similar. The factors which induce galactorrhea remain to be clarified. Pituitary PRL reserves in subclinical hypothyroidism were increased to the same extent as in overt hypothyroidism. It is possible that PRL secreting cells are more sensitive to TRH than thyrotroph cells. Jacobs et al. (1973) studied the effects of graded doses of TRH on TSH and PRL secretion in man. They found that smaller doses of TRH readily stimulated PRL secretion when they did not elicit the maximum TSH response. The prevalance of primary hypothyroidism as a cause of hyperprolactinemia is reported to be % (Hombo et al., 1978, Ferrari et al., 1983). On the other hand, hyperprolactinemia of unknown origin accounts for 50% (Ferrari et al., 1983). It is possible that the subjects of unknown origin may include some patients whose hyperprolactinemia is due to latent hypothyroidism. In the report of Ferrari et al. (1983), for example, 3 out of 19 cases of idiopathic hyperprolactinemia showed the presence of antithyroid antibodies and increased TSH secretion, and another 3 had antithyroid antibodies and diffuse goiter. The prevalence of galactorrhea and an exaggerated PRL response to TRH in subclinical hypothyroidism was not investigated in this study. We also have to be careful of the fact that autoimmune thyroiditis may be found coincidentally with prolactinoma. Ferrari et al. (1983) suggested that asymptomatic autoimmune thyroiditis occurs in hyperprolactinemic women with a prevalence far exceeding that observed in the general population. TRH-stimulated TSH levels were significantly higher in thyroid autoantibody positive subjects than in negative subjects. They also reported that the patients had diffuse or nodular goiter with 20% prevalence. Pelkonnen et al. (1982) reported that

5 Vol.34, No.4 GALACTORRHEA IN SUBCLINICAL HYPOTHYROIDISM 543 the TSH response to TRH was exaggerated in 4 out of 36 prolactinoma patients without any clinical evidence of autoimmune thyroiditis. In the prolactinoma patients, the mean TSH increase was higher than in controls. They suggested that TRH might be involved in the development of PRL secreting adenoma. In this study, 3 cases (cases #1.3, and 4) had serum levels of T4, T3 and TSH within the normal range, although they had galactorrhea and an exaggerated PRL response. In the follow-up study of these subjects before treatment, we observed transitory decreases in T4 and increases in TSH. It is supposed that the exaggerated PRL response to TRH stimulation might be initiated during the mild hypothyroid phase, and the increased PRL reserves in the pituitary remained increased even when the transient thyroid failure recovered spontaneously. Serum levels of thyroid hormone in the recovery phase may not be high enough to suppress the exaggerated PRL response, although serum T4 and T3 return to normal from subnormal. This assumption is based on the clinical course of the T4 replacement therapy. At a time when the dose of T4 was sufficient to suppress TSH to normal levels and render the patient clinically euthyroid, the PRL level continued to be slightly elevated. When TSH was suppressed to an undetectable level with an increased replacement dose of T4 ( ƒÊg/day), the PRL response to TRH stimulation normalized in 4 cases. One may hesitate to start T4 therapy for patients with transient hypothyroidism, but we urge patients with the transient hypothyroidism to undergo T4 treatment when they have galactorrhea and an exaggerated PRL response to TRH. Recently, the validity of T4 replacement therapy in subclinical hypothyroidism was assessed in a double blind trial (Cooper et al., 1984). Their findings suggested that T4 is of value in most subclinical hypothyroid patients with abnormal myocardial contractability or symptoms consistent with mild hypothyroidism, or both. They also reported that the exaggerated PRL response to TRH became normal with T4 treatment in 2 patients. Although we used increased T4 replacement doses, it was possible to reduce T4 to an ordinary replacement dose after the galactorrhea disappeared. Case #1 still had a high PRL response to TRH although the galactorrhea disappeared following T4 replacement (200ƒÊg/day). Barbarino et al. (1978) reported that PRL secretion failed to increase after TRH stimulation in patients with a PRL secreting adenoma. Since case #1 had a high PRL response to TRH, and T4 replacement improved the exaggerated PRL response and galactorrhea, we supposed that the galactorrhea in this patients was due to subclinical hypothyroidism rather than to microadenoma of the pituitary. An increased dose (200ƒÊg/day) of T4 to this patient had been continued and no evidence of pituitary adenoma had been found in radiographic examination. Attention should be paid on the following features in diagnosing subclinical hypothyroidism as a cause of galactorrhea and exaggerated PRL response to TRH. 1) The TRH stimulation test is necessary to find an exaggerated PRL response, since basal PRL and TSH levels are not necessarily elevated in these conditions. 2) To differentiate from pituitary microadenoma, observation of the effects of T4 replacement therapy on galactorrhea and an exaggerated PRL response to TRH stimulation is essential. References Barbarino, A., L. De Marinis, G. Maria, E. Menin and C. Anile Serum prolactin response to thyrotrophin-releasing hormone and metoclopramide in patients with prolactin-secreting tumors before and after transsphenoidal

6 544 TAKAI et al. Endocrinol. Japon. August 1987 surgery. J. Clin. Endocrinol. Metab. 47, Bastenie, P. A., M. Bonnyns and L. Vanhaelst Grades of subclinical hypothyroidism in asymptomatic autoimmune thyroiditis revealed by the thyrotropin-releasing hormone test. J. Clin. Endocrinol. Metab. 51, 163. Bigos, S. T., E. C. Ridgway, I. A. Kourides and F. Maloof Spectrum of pituitary alterations with mild and severe thyroid impairment. J. Clin. Endocrinol. Metab. 46, 317. Cooper, D. S., R. Halpern, L. C. Wood, A. A. Levin and E. C. Ridgway L-Thyroxine therapy in subclinical hypothyroidism. Ann. Intern. Med. 101, 18. Evered, D. C., B. J. Orston, P. A. Smith H. Hall and T. Bird Grades of hypothyroidism. Br. Med. J. 17, 657. Ferrari, C., M. Boghen, A. Paracchi, P. Rampini, F. Raiteri, R. Benco, M. Romussi, F. Codecasa, M. Mucci and M. Bianco Thyroid autoimmunity in hyperprolactinemic disorders. Acta Endocrinol. (Copenh) 104, 36. Hombo, K. S., A. J. Van Herle and K. A. Kellett Serum prolactin levels in untreated primary hypothyroidism. Am. J. Med. 64, 782. Jacobs, L. S., P. J. Snyder, R. D. Utiger and W. H. Daughaday Prolactin response to thyrotropin-releasing hormone in normal subjects. J. Clin. Endocrinol. Metab. 36, Kleinberg, D. L., G. L. Noel and A. G. Frantz Galactorrhea: A study of 235 cases, including 48 pituitary tumors. N. Engl. J. Med. 296, 589. Onishi, T., K. Miyai, T. Aono, T. Shioji, T. Yamamoto, Y. Okada and Y. Kumahara Primary hypothyroidism and galactorrhea. Am. J. Med. 63, 373. Pelkonnen, R., J. Salmi and B. A. Lamberg Interrelationship between TSH- and prolactin secretion in patients with prolactinoma and autoimmune thyroiditis. Acta Endocrinol. (Copenh) 100, 184.