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Anti-Prolactin (PRL) Autoantibodies Cause Asymptomatic Hyperprolactinemia: Bioassay and Clearance Studies of PRL-Immunoglobulin G Complex¹

Department of Pharmacology, Kansai Medical University, Osaka 570, Japan

Address correspondence and requests for reprints to: Naoki Hattori, M.D., Department of Pharmacology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi-shi, Osaka 570, Japan.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The causes of hyperprolactinemia are varied, but some cases are classified as "idiopathic" because of unknown causes. We examined whether anti-prolactin (PRL) autoantibodies can cause hyperprolactinemia, especially the asymptomatic type.

Serum PRL in four women with anti-PRL autoantibodies and five control patients with prolactinoma was characterized by a sensitive enzyme immunoassay, Nb2-bioassay, gel chromatography, affinity chromatography for immunoglobulin G (IgG), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under nonreducing conditions, and clearance studies using anesthetized rats.

In four women with anti-PRL autoantibodies, serum immunoreactive PRL concentrations were elevated (326 ± 216 µg/L, normal < 30 µg/L), and PRL (84 ± 5.5%) mostly consisted of the large molecular form in which a significant amount of 23 kDa PRL (60.6 ± 14.7%) was noncovalently bound to IgG. Although three of the four women lacked clinical symptoms of hyperprolactinemia such as amenorrhea and galactorrhea, the IgG-bound PRL was fully bioactive in vitro. It was cleared more slowly from circulation than free PRL.

The data suggest that PRL forms a complex with IgG, and this probably results in delayed clearance of PRL and leads to hyperprolactinemia in women with anti-PRL autoantibodies. .

	Introduction

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THE CAUSES of hyperprolactinemia include pregnancy, prolactin (PRL)-secreting pituitary adenoma (prolactinoma), intracranial tumors compressing the pituitary stalk or hypothalamus, PRL stimulative drugs, hypothyroidism, chest wall diseases, and hepatorenal disorders. However, 8.5–40% of hyperprolactinemia is classified as "idiopathic hyperprolactinemia" because the causes are unknown (1, 2). Some cases of microadenoma that cannot be detected by computed tomography (CT) or magnetic resonance imaging (MRI) are believed to fall into this category.

We recently found anti-PRL autoantibodies in sera from 16% of patients with idiopathic hyperprolactinemia (3, 4), and subsequently, similar cases have been reported from several other countries (5, 6, 7). Interestingly, these patients generally lacked the clinical symptoms of hyperprolactinemia such as amenorrhea and galactorrhea, and spontaneous pregnancy was possible without bromocriptine treatment for hyperprolactinemia (4).

Autoantibodies to several hormones such as thyroid hormones (8), parathyroid hormones (9), glucagon (10), and insulin (11) have been reported, and some of them are known to interfere with double-antibody radioimmunoassay (RIA) causing spuriously high serum levels. We previously demonstrated that anti-PRL autoantibodies did not cause spurious high serum PRL concentrations, as determined by double-antibody RIA or immunoradiometric assay (IRMA), probably because of the multiple antigenicity of PRL, and the hyperprolactinemia was observed in women with anti-PRL autoantibodies (12).

The aim of this study was to elucidate 1) the mechanisms involved in the lack of symptoms despite having hyperprolactinemia, and 2) whether the presence of anti-PRL autoantibodies leads to an increase in the serum PRL concentrations and whether this is a newly found cause of hyper-prolactinemia.

	Subjects and Methods

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Subjects

Four women with anti-PRL autoantibodies ages between 28 and 67 yr were investigated (Table 1). Case 1 noticed galactorrhea for the first time when she was taking domperidone, an anti-dopaminergic drug, for gastritis, and endocrinological examination revealed hyperprolactinemia. The drug was discontinued on the suspicion of drug-induced hyperprolactinemia. Although the galactorrhea disappeared within a few days and she menstruated normally, hyperprolactinemia persisted. Anti-PRL autoantibodies were initially detected in this woman. Fifty-four serum samples with elevated PRL levels (above 30 µg/L) were screened for anti-PRL autoantibodies, and three women (cases 2–4) were diagnosed as having anti-PRL autoantibodies because binding of ¹²⁵I-PRL to the serum component exceeded 8.9% (mean + 2 SD in 20 healthy volunteers), and the binding was displaced by excess unlabeled PRL (50 µg/mL serum). The ratio of ¹²⁵I-PRL binding with the 4 women’s sera was 24.3 ± 9.0% (6.5 ± 1.2% in normal subjects), and the serum immunoreactive PRL concentration was 326 ± 216 µg/L (normal < 30 µg/L). The reasons why PRL levels were initially measured in cases 2–4 were endocrinological evaluations for papillary adenocarcinoma of the thyroid gland in case 2, oligomenorrhea and minimal galactorrhea in case 3, and hypermenorrhea in case 4. Of clinical interest was that cases 1 and 4 lacked clinical symptoms of hyperprolactinemia such as amenorrhea and galactorrhea despite the reproductive ages. All four women had children, and normal pregnancy without bromocriptine treatment for hyperprolactinemia was confirmed in case 4 after she was diagnosed as having anti-PRL autoantibodies. Each woman otherwise had normal pituitary functions and no evidence of a pituitary adenoma on MRI. No women had generalized autoimmune disorders.

Enzyme immunoassay (EIA) for prolactin

A sensitive enzyme immunoassay for human PRL was developed according to an EIA for growth hormone (13) to measure small amounts of PRL in the gel filtration and clearance studies. Human PRL (hPRL-SIAFP-B-3 and hPRL-RP-2) and antiserum to human PRL (anti-hPRL-IC-5) were kindly supplied from NIDDK. The minimal detectable quantity was 0.05 µg/L in the sample, and the intra- and interassay coefficients of variation were 5% and 7%, respectively. The autoantibody was found not to interfer with this EIA.

Bioassay for PRL

Nb2 node lymphoma cells were kindly provided from Dr. Toshiaki Tanaka (National Children’s Medical Research Center, Tokyo, Japan), and bioassay for PRL was performed according to his original report (14). The minimal detectable quantity was 1 µg/L in the sample, and the intra- and interassay coefficients of variation were 10% and 12%, respectively.

Chromatography

Gel filtration was performed at 4C in an Ultrogel AcA 44 minicolumn (1 x 30 cm, IBF, La Garenne, France) as previously described (4), and PRL immunoreactivity was determined by EIA. IgG in the serum was purified by a protein G column (Mab Trap G, Pharmacia LKB, Uppsala, Sweden) as previously described (4). IgG-bound PRL (%) was determined from the bound PRL to the column/total PRL. When the PRL standard was applied to the column, no PRL was bound to the column.

SDS-polyacrylamide gel electrophoresis (PAGE)

PRL was immunoprecipitated from protein G-purified IgG using antiserum to human pituitary PRL (anti-hPRL-IC-5 or our laboratory generated antiserum). The precipitates were solubilized in 0.125 mol/L Tris-HCl buffer (pH 8.3) containing 4 mol/L urea and 2% SDS, boiled for 3 min, and electrophoresed on a 12% polyacrylamide gel containing 0.1% SDS. 2-Mercaptoethanol was not used to examine whether the binding of PRL to IgG was caused by noncovalent bonds. The samples were then electrotransferred to a nitrocellulose membrane (Millipore, Nihon Millipore, Yonezawa, Japan) and incubated with anti-PRL antiserum (anti-hPRL IC 5 or our laboratory generated antiserum). After the incubation with goat antirabbit immunoglobulin-peroxidase conjugate (Cosmo Bio, Co., Tokyo, Japan), the bands were detected using a Western blot chemiluminescence reagent (DuPont, Boston, MA).

Metabolic clearance study

To examine the metabolic clearance of the PRL-IgG complex, anesthetized male Wistar rats (200–250 g BW) were used. Urethane (0.8 g/kg) was injected intraperitoneally, and the jugular veins were exposed on both sides. Protein G-purified IgG (64–140 ng PRL/500 µL) from women with anti-PRL autoantibodies and PRL standard (200 ng/500 µL) mixed with 5 mg of normal human IgG as a control (n = 5) was injected into the right jugular vein. Blood (0.2 mL) was withdrawn from the left jugular vein at 0, 2, 5, 10, 20, and 40 min after the injection. Rat PRL was shown not to interfere with the present EIA for human PRL.

Data were expressed as means ± SD and were analyzed using the Student’s t-test.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Gel chromatographic profiles of immunoreactive PRL in the sera from women with anti-PRL autoantibodies and those from patients with prolactinoma are shown in Fig. 1. Most PRL (84 ± 5.5%) was eluted at a molecular mass of 150–170 kDa in women with anti PRL autoantibodies, while almost all PRL (99.3 ± 0.2%) was eluted at the same position as the 23 kDa human PRL standard in patients with prolactinoma. When IgG was affinity-purified from sera using a protein G column, a significant amount of immunoreactive PRL (60.6 ± 14.7%) was co-eluted with the IgG in women with anti-PRL autoantibodies, while no PRL was contained in the IgG fraction in patients with prolactinoma or normal subjects (Table 1). When this IgG fraction was analyzed on SDS-PAGE under nonreducing condition, the IgG-bound PRL was dissociated and immunostained at the same position as the 23 kDa PRL standard in women with anti-PRL autoantibodies, whereas the band of the 23 kDa PRL was not observed when IgG from patients with prolactinoma was used (Fig. 2). The same results were obtained when a different PRL antibody (anti-hPRL IC 5 or our laboratory generated antiserum) was used.

View larger version (19K): [in this window] [in a new window]   Figure 1. Gel chromatographic profiles of immunoreactive PRL in sera from four women with anti-PRL autoantibodies (•) and from five patients with prolactinoma () from an Ultrogel AcA 44 minicolumn (1 x 30 cm). Mean ± SE values of the ratio of immunoreactive PRL in each fraction to that in the peak fraction are shown. PRL immunoreactivity was eluted at the position of 150–170 kDa in women with anti-PRL autoantibodies and at 23 kDa in patients with prolactinoma.

View larger version (24K): [in this window] [in a new window]   Figure 2. Electrophoretic patterns of immunoreactive PRL precipitated from IgG fractions. IgG was affinity-purified from sera using a protein G column, and PRL contained in the IgG fraction was immunoprecipitated with anti-human PRL antiserum. SDS-PAGE without 2-mercaptoethanol, followed by Western blotting using anti-human PRL antiserum, was performed. The bands were detected by chemiluminescence. PRL was dissociated from IgG under nonreducing conditions and immunostained at the same position as the 23 kDa PRL standard in women with anti-PRL autoantibodies. The 23 kDa PRL band was not observed when IgG from patients with prolactinoma was used. Lane 1: PRL standard, Lane 2: prolactinoma, Lanes 3–6: Cases 1–4.

Fig. 3 depicts the disappearance curves of immunoreactive PRL from circulation when IgG-bound PRL from women with anti-PRL autoantibodies or PRL standard mixed with normal IgG was injected intravenously into rats. The ratios of the PRL concentration at each time with that at the peak time are shown. Serum PRL levels after 10, 20, and 40 min were significantly higher (P < 0.05) when IgG-bound PRL was injected. It was evident that IgG-bound PRL was cleared more slowly than free PRL.

View larger version (16K): [in this window] [in a new window]   Figure 3. Disappearance curves of immunoreactive PRL from the plasma when IgG-bound PRL (•, n=4) or PRL standard mixed with normal IgG (, n=5) as a control was injected intravenously into anesthetized rats. Mean ± SE values of the ratio of immunoreactive PRL at each time to that at peak times are shown. The PRL levels between them were compared each time. The IgG-PRL complex was cleared more slowly than free PRL. * P < 0.05.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

These cases have many similarities to macroprolactinemia, which is characterized by sustained hyperprolactinemia, normal menses, minimal galactorrhea, and the predominant form of large molecular weight PRL, although the binding of PRL to IgG was not examined or detected in the previous reports (15, 16). Indeed, we also observed a woman with macroprolactinemia without anti-PRL autoantibodies (17). Several possible natures of macroprolactinemia other than anti-PRL autoantibodies have been reported; a polymer of PRL bound by disulfide bridges (18), noncovalently associated aggregates of PRL (19), or PRL-IgG complex bound by a disulfide bridge (20). In women with anti-PRL autoantibodies, PRL was immunostained at the same molecular weight as the 23 kDa PRL standard on SDS-PAGE of IgG under nonreducing conditions, suggesting that PRL was noncovalently bound to IgG. Because the immunostaining of PRL was not detected when IgG from patients with prolactinoma was applied, this phenomenon is not the result of some crossreactivity of antisera with immunoglobulins (21). Although the causes of anti-PRL autoantibodies are unknown, like autoantibodies of other hormones (8, 9, 10, 11) they may be naturally occurring because they were found in healthy women, and PRL bound to IgG had the same molecular weight as the 23 kDa PRL standard. More recently, a PRL-binding protein from pooled human sera has been identified as IgG by protein sequence analysis (7). These observations suggest that anti-PRL autoantibodies are partly involved in the pathogenesis of macroprolactinemia.

In this study, the proportions of the large form of PRL separated by different methods were different, that is, 24.3 ± 9.0%, as shown by ¹²⁵I-PRL binding, 60.6 ± 14.7% with a protein G column, and 84 ± 5.5% by gel filtration. These findings may be the result of methodological problems, that is, some IgG can bind to endogenous PRL but not to radioiodinated PRL, or PRL may be dissociated from IgG during affinity purification by a protein G column or during gel filtration, resulting in underestimation of IgG-bound PRL. However, the possibility that IgG-nonassociated components may be involved in large forms of PRL cannot be excluded.

As we reported previously, most patients with anti-PRL autoantibodies lacked the clinical symptoms of hyperprolactinemia such as amenorrhea and galactorrhea (4). We initially speculated that IgG-bound PRL would have lower biological activity because some large forms of PRL were shown to have reduced biological activity (18). However, IgG-bound PRL had the similar biological activity as free PRL. The autoantibodies appear not to mask the sites of PRL important for its biological activity. Then why do most patients with anti-PRL autoantibodies lack the clinical symptoms of hyperprolactinemia in vivo, although the IgG-bound PRL is fully bioactive in vitro? One possibility is an abnormality in the PRL receptor and/or postreceptor signal transduction pathways. This is unlikely, however, from a clinical point of view. We found that when anti-dopaminergic agents such as sulpiride or domperidone were administered, mainly free PRL levels increased in patients with anti-PRL autoantibodies, and the clinical symptoms of hyperprolactinemia such as galactorrhea were observed in case 1 on such an occasion. These findings suggest that an acute rise in free PRL caused the clinical symptoms of hyperprolactinemia, indicating that the binding of PRL to the receptor and the postreceptor mechanism are intact. Another possibility is that IgG-bound PRL cannot exert its full biological activity in vivo because the access of PRL to target cells through the capillary wall may be restricted because of the large molecular size and/or changes in net charge.

We previously demonstrated that in patients with anti-PRL autoantibodies a significant positive correlation existed between autoantibody titers and the serum PRL concentrations, and we speculated that the autoantibodies might be a cause of hyperprolactinemia (4). This clearance study using rats showed that IgG-bound PRL was cleared from circulation more slowly than free PRL. PRL may accumulate as an IgG-bound form probably because the bound PRL does not get through the capillary wall. It is assumed that the hypothalamic negative feedback mechanism by the high PRL levels does not work, because the complex does not gain access the hypothalamus. Therefore, anti-PRL autoantibodies can also be a cause of hyperprolactinemia.

	Footnotes

 
¹ This work was supported, in part, by a grant from the Ministry of Education, Science and Culture, Japan.

Received March 10, 1997.

Revised June 3, 1997.

Accepted June 9, 1997.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hattori, N. Articles by Inagaki, C. Search for Related Content PubMed PubMed Citation Articles by Hattori, N. Articles by Inagaki, C.