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Frequency of Macroprolactinemia Due to Autoantibodies against Prolactin in Pregnant Women

Autoimmunity Laboratory (D.P.-L., I.C.-H., L.M.-A., F.B.-F., A.L.-M.), Immunology Research Unit, Hospital de Pediatría; and Biochemistry Research Unit (G.D.-R.), Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México, D.F., México 06725

Address all correspondence and requests for reprints to: Dr. Alfredo Leaños-Miranda, Autoimmunity Laboratory, Immunology Research Unit, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Avenida Cuauhtémoc 330, Col. Doctores, CP 06725 México, D.F., México. E-mail: alfredo{at}intranet.com.mx

Abstract

The frequency of macroprolactinemia related to the presence of anti-PRL autoantibodies in the serum of 209 healthy women at different stages of pregnancy was studied. Measurements were taken of serum PRL concentrations before and after chromatographic separation (gel filtration and affinity with proteins A and G) and extraction of free PRL with polyethylene glycol (PEG). Sera from 8 of the 209 women (3.8%) were found to have a significantly high proportion of precipitated PRL by PEG (macroprolactinemia); in these patients, gel filtration showed that a substantial amount of big big PRL (molecular mass >100 kDa) was present (19.0–78.2% vs. 3.8–4.9%, P = 0.009 in normal pregnant women with a normal proportion of precipitated PRL by PEG). The presence of macroprolactinemia was attributable to anti-PRL autoantibodies in 5 of the 8 women. Comparison of serum levels of direct and free PRL between women with macroprolactinemia related to anti-PRL autoantibodies and women without macroprolactinemia showed significant differences (direct PRL: 270.2 ± 86.9 vs. 203.4 ± 69.0 µg/L, P = 0.04; and free PRL: 107.0 ± 75.9 vs. 173.3 ± 67.6 µg/L, P = 0.002). On the other hand, there was no difference between women with macroprolactinemia not related to anti-PRL autoantibodies and women with macroprolactinemia caused by anti-PRL autoantibodies, nor was there a difference between women with macroprolactinemia not related to anti-PRL autoantibodies and women without macroprolactinemia. There was a positive correlation between titers of the anti-PRL autoantibody and serum PRL levels (r = 0.82, P = 0.09). The presence of the anti-PRL autoantibody had no relation to the patient’s age, stage of gestation, or number of previous pregnancies. We concluded that the frequency of macroprolactinemia was 3.8% among healthy, pregnant women, which was caused by a anti-PRL autoantibodies in 62.5% of the cases. The autoantibodies were found in the bloodstream, forming a PRL-IgG complex, in accordance with the following observations: 1) immunoreactive PRL on gel filtration was eluted in the fractions corresponding to the molecular mass of IgG (150 kDa); 2) a significantly high proportion of immunoreactive PRL was retained on an affinity gel for IgG (proteins A and G); and 3) a significantly high proportion of serum PRL bound to IgG was precipitated by protein A. There was a positive correlation between titers of anti-PRL autoantibodies and serum PRL levels. Serum levels of total PRL were higher, and serum levels of free PRL were lower, in pregnant women with anti-PRL autoantibodies than in pregnant women without macroprolactinemia.

SEVERAL PRL ISOFORMS have been identified in serum and other biological fluids. The major circulating isoform of PRL is a 23-kDa single-chain polypeptide (little PRL), which comprises up to 80% of the total PRL in serum of normal subjects and most patients with hyperprolactinemia. In addition, there are two other isoforms with a higher molecular mass, big PRL (45–50 kDa), and big big PRL (>100 kDa) (1). These isoforms can be attributable to posttranslation modifications (aggregates of little PRL, and PRL bound to binding proteins). These modifications of PRL may affect biological properties differently from immunoreactivity (1, 2, 3, 4).

In a few individuals with hyperprolactinemia (mostly women), the predominant circulating isoform of PRL is the big big PRL, termed macroprolactinemia. Often, these women do not present the symptoms commonly associated with hyperprolactinemia, such as menstrual disturbances and/or galactorrhea (5, 6, 7, 8). Recently, macroprolactinemia has been detected in the serum of patients with idiopathic hyperprolactinemia, where big big PRL was shown to be caused by the covalent binding of little PRL to an IgG (9, 10, 11). In normoprolactinemic subjects, as in other hyperprolactinemic secondary states (prolactinomas, drugs, and others), the presence of anti-PRL autoantibodies has also been reported; however, their frequency is less than in idiopathic hyperprolactinemia (12).

During pregnancy, a great increment of serum PRL level occurs, and the presence of big big PRL has been reported in a range of 8–38% of total PRL (13, 14, 15). Jackson et al. (16) reported 2 women with persistent macroprolactinemia who became pregnant in spite of hyperprolactinemia, and macroprolactin was the predominant isoform during pregnancy. Hattori et al. (17) studied women during the third trimester of pregnancy and found a frequency of macroprolactinemia of 2.9% (3 of 105); in 2, this was attributable to the presence of anti-PRL autoantibodies and, in the other, to aggregates of glycosylated little PRL. However, all three women had a diagnosis of hyperprolactinemia previous to the pregnancy.

What the mechanism of production of the anti-PRL autoantibody is, or what the function or alteration that produces the presence of the anti-PRL autoantibody is, are still unclear; its presence, however, is associated with the hyperprolactinemic state and the lack of clinical manifestations of hyperprolactinemia. These data indicate that women without diagnosis of macroprolactinemia can become pregnant without a treatment to reduce PRL levels. At present, the frequency of macroprolactinemia has not been studied in large populations of healthy women at different stages of gestation without previous knowledge of the serum PRL status. The aim of the present work was to study macroprolactinemia frequency in different gestation stages and to investigate whether the presence of anti-PRL autoantibodies is involved in its etiology.

Subjects and Methods

The Human Ethical Committee and Medical Research of the Institute approved the study protocol, and informed written consent was obtained from all subjects who participated voluntarily in this study.

A group of 209 consecutive Mexican women were studied at different stages of pregnancy. None of the women had evidence of autoimmune or endocrine disorders or any other acute or chronic disease; their ages ranged from 19–35 yr. They were seen at Family Medicine Unit Number 4 and General Hospital 3-A of the Instituto Mexicano del Seguro Social, from April to October 1997. Clinical and demographic data were recorded. A venous blood sample was drawn between 0700 h and 0830 h, after an overnight fast or labor. The sera were separated and stored at -35 C until used.

Assay for PRL

PRL was measured directly in the serum samples by an immunoradiometric assay (ELSA-PRL, CIS-Bio International, Gif-sur-Yvette, France). This technique has shown reliability in detecting PRL independently of its isoform, and even the presence of anti-PRL autoantibodies does not interfere with test results (18, 19, 20). The limit of sensitivity of the assay was 0.09 µg/L, and the intra- and interassay coefficients of variation were 3.8% and 5.4%, respectively.

Macroprolactinemia screening

Free PRL was extracted from the serum, using polyethylene glycol (PEG), as previously described (21). The proportion of macroprolactinemia was determined using the following calculation: [(PRL in the serum - PRL in the supernatant) ÷ PRL in the serum] x 100. Serum samples were judged to contain significantly large amounts of macroprolactinemia when the result displayed a ratio that exceeded 45%. This value represented the mean + 2 SD of whole healthy, pregnant women (a proportion less than 45% was considered to be caused by nonspecific adsorption of PRL to the precipitates).

Chromatographic studies

Gel filtration and affinity chromatography, as previously described (21), were performed in all serum with macroprolactinemia, as well as in serum from five patients (paired by serum PRL levels, age, and weeks of gestation) without macroprolactinemia. Gel filtration was performed using a column (56 x 1.5 cm) of Sephadex G-200 Superfine (Pharmacia Biotech, Uppsala, Sweden); recovery of PRL was 108.2 ± 12.1%, on average. Affinity columns for IgG (proteins A and G) were used to confirm that the binding component in the serum was the immunoglobulin. Serum samples were judged to contain anti-PRL autoantibodies when the result displayed a proportion that exceeded 18.8% (this value represented the mean + 3 SD of serum without macroprolactinemia).

Determination of titers of the anti-PRL autoantibodies

The protein A-Sepharose CL-4B was used to immunoprecipitate the PRL-IgG complex as previously described (21). Serum samples were judged to contain anti-PRL autoantibody when the result displayed a ratio that exceeded 1.55%. This result represents the mean + 3 SD of 20 pregnant women without macroprolactinemia, in screening by PEG. For the purpose of this study, the proportion of PRL bound to IgG was useful to quantify the titers of the anti-PRL autoantibody in serum, to make a correlation with serum PRL levels.

Definition of trimesters of pregnancy

The first trimester was considered to be from conception until the 13th week of pregnancy; second trimester, from the 14th until the 27th weeks; and the third trimester, from the 28th week until delivery.

Statistical analysis

Data were expressed as mean ± SD or median (range). A nonpaired Student’s t test (or a Mann-Whitney U test for nonnormal distribution variable) was used to make comparisons between groups. Also, a paired Student’s t test was performed to control the influence of age, weeks of gestation, and number of previous pregnancies, on the concentration of PRL between the serum of pregnant women with or without macroprolactinemia. The linear relationship between the titers of anti-PRL autoantibody and serum PRL levels was assessed by Pearson’s correlation coefficient. A two-tailed P value less than 0.05 was considered to be statistically significant.

Results

A total of 209 healthy, pregnant women, in different stages of gestation, were studied (48 in the first trimester, 53 in the second trimester, and 108 in the third trimester). Mean age was 26.1 ± 4.5 yr. Figure 1 shows the screening for macroprolactinemia by PEG. Sera from 8 pregnant women were found to have macroprolactinemia [3.8%; confidence interval (CI), 95%, 1.2–6.4%]. Gel filtration profiles of immunoreactive PRL in the sera of the 8 pregnant women with macroprolactinemia, by PEG (>45%), showed a variable pattern (Fig. 2 and Table 1), whereas the presence of big big PRL in different proportions was present in all cases. In contrast, almost all PRL immunoreactivity was eluted at the position of little PRL in pregnant women without macroprolactinemia, determined by PEG (<45%). In 5 of 8 sera with macroprolactinemia, a significant amount of immunoreactive PRL was retained on the protein A-Sepharose column [44.8 ± 14.3% vs. 5.9 ± 4.3% (P = 0.001) in sera without macroprolactinemia]. In the 3 remaining sera with macroprolactinemia, almost all immunoreactive PRL passed through the protein A-Sepharose column; the amount of immunoreactive PRL retained was similar in sera without macroprolactinemia (10.1 ± 2.2%, P = 0.18) (Table 1). A similar result was obtained using a protein G column in the 5 sera [38.1 ± 15.1% vs. 7.8 ± 6.9% (P = 0.004) in sera without macroprolactinemia]. Then, anti-PRL autoantibodies were detected in 5 of the 8 pregnant women with macroprolactinemia (62.5%; CI, 95%, 29–96%). In the 5 cases of women with macroprolactinemia with anti-PRL autoantibodies, the mean of the titers of the anti-PRL autoantibody was 6.4% (range, 2.9–17.6%), higher than the mean + 3 SD (1.55%) of 20 pregnant women without macroprolactinemia. A positive, but not significant, correlation (r = 0.82, P = 0.09) was present between titers of anti-PRL autoantibody and serum PRL levels.

View larger version (12K): [in this window] [in a new window]   Figure 1. The proportion of PRL precipitated with 12.5% PEG in 209 serum samples collected during different stages of pregnancy. The ratio was determined by: (PRL in the serum - free PRL/PRL in the serum) x 100. The horizontal dotted line denotes mean + 2 SD from the total of pregnant women. Sera with a proportion ratio over this cut-off (45%) were considered to have macroprolactinemia.

View larger version (24K): [in this window] [in a new window]   Figure 2. Gel filtration profiles of immunoreactive PRL in the sera of (A, B, and C) five pregnant women with macroprolactinemia caused by anti-PRL autoantibodies at (A) first trimester (8 weeks of gestation), (B) second trimester (14 weeks of gestation, ; and 23 weeks of gestation, •), and C) third trimester (40 weeks of gestation); (D) three pregnant women with macroprolactinemia without anti-PRL autoantibodies (at 13 weeks of gestation, •; 17 weeks of gestation, ; and 40 weeks of gestation, ); and (E) pooled serum from pregnant women whose tests were negative for macroprolactinemia by PEG (at first trimester, •; second trimester, ; and third trimester, ). A Sephadex G-200 column (56 x 1.5 cm) was used. Samples (0.3–1.0 mL) were applied on the column, and fractions of 1.3 mL were collected.

When comparing the clinical variables between the 5 women with anti-PRL autoantibodies and the 204 women without autoantibodies, there was no difference related to age (28.8 ± 5.5 vs. 26.0 ± 4.4 yr, P = 0.2), weeks of gestation (21.6 ± 12.0 vs. 26.4 ± 11.6, P = 0.37), and the number of previous pregnancies (1.4 ± 0.5 vs. 2.0 ± 1.0, P = 0.2).

Finally, in three of the women with macroprolactinemia caused by anti-PRL autoantibodies from whom we took a new blood sample at 6, 8, and 12 months after delivery (without nursing), we found that the women persisted with hyperprolactinemia (43.8, 26.7, and 63.8 µg/L, respectively) and with macroprolactinemia (79.0%, 70.8%, and 51.0%, respectively).

Discussion

This study demonstrates that 3.8% of the healthy, pregnant women studied had significant macroprolactinemia; and protein A and G affinity chromatography showed that, in five of these eight cases (62.5%), the presence of macroprolactinemia was attributable to the binding of PRL with a specific autoantibody. These results are similar to those reported by Hattori (17), who studied 105 women during the third trimester of pregnancy. He found a frequency of macroprolactinemia of 2.9% caused by anti-PRL autoantibodies in 66.6% of the cases; however, these women, before the pregnancy, had a diagnosis of anti-PRL autoantibodies.

Several studies have reported that women with hyperprolactinemia caused by the presence of macroprolactinemia do not manifest the clinical symptoms commonly associated with hyperprolactinemia (such as galactorrhea and menstrual disturbances) and even that they are fertile. In contrast, women with hyperprolactinemia whose major circulating isoform is little PRL (23 kDa) present galactorrhea and amenorrhea and are infertile (4, 6, 7, 8). These data, together with the fact that the presence of anti-PRL autoantibodies was not related to age, weeks of gestation, or numbers of previous pregnancies, thus suggest that macroprolactinemia related to the presence of anti-PRL autoantibodies, in our patients, was present before pregnancy, as occurred with the pregnant women studied by Hattori. This observation can be supported by the results obtained in three of the women with macroprolactinemia caused by anti-PRL autoantibodies, from whom we took a new blood sample after delivery; these women persisted with hyperprolactinemia and macroprolactinemia. However, our study has the limitations inherent in a cross-sectional design (e.g. temporal ambiguity). The establishment of a temporal relationship between anti-PRL autoantibodies and pregnancy must be proven clearly in follow-up studies.

Matched analysis showed that the pregnant women with macroprolactinemia, independently of its cause, did not have a significant difference in the concentration of direct or total PRL but did have a smaller amount of free PRL, in comparison with pregnant women without macroprolactinemia. However, in comparing pregnant women with macroprolactinemia related to anti-PRL autoantibodies and pregnant women without macroprolactinemia, we found that total PRL concentration was higher and that free PRL was lower in pregnant women with macroprolactinemia anti-PRL autoantibody-positive. These data suggest that anti-PRL autoantibodies bound-PRL causes an alteration in feedback action on the hypothalamic-pituitary axis that, in turn, causes an increase in the secretion of PRL from the pituitary gland. This probable phenomenon is supported by the observation that there was a positive correlation between the titers of the anti-PRL autoantibody and serum PRL levels. On the other hand, clearance studies in rats showed that the PRL-IgG complex is eliminated more slowly from the bloodstream than free PRL (22, 23), postulating that this could be another mechanism in which PRL is retained in circulation for a long time (prolonged half-life).

When the etiology of macroprolactinemia was not attributable to anti-PRL autoantibodies, matched analysis with three pregnant women without macroprolactinemia did not show a significant difference in the concentrations of direct and free PRL, probably because of the reduced sample size, nor was there a significant difference in the concentrations of direct or free PRL when the subgroups with macroprolactinemia were compared. These data suggest that, independently of the etiology of macroprolactinemia, there exists an alteration in feedback action on the hypothalamic-pituitary axis and a delayed clearance of big big PRL.

Gel filtration showed that the proportion of little PRL was increased in all pregnant women with macroprolactinemia not related to anti-PRL autoantibodies. This was also the case for pregnant women without macroprolactinemia, consistent with previous studies in normal pregnancy and patients with macroprolactinemia (4, 24). On the other hand, if we observe together the patterns obtained by gel filtration of pregnant women with anti-PRL autoantibodies, we can see that, as pregnancy progressed, there were changes in the proportion of big big PRL. There existed a predominance of big big PRL during the early stages of pregnancy, moving toward variable patterns at pregnancy midpoint; and, at the end of pregnancy, a new change, with a predominance of little PRL (Fig. 2). Hattori found this same phenomenon in a woman with idiopathic hyperprolactinemia with autoantibodies against PRL during the pregnancy (17).

Recently, it has been suggested that the molecular heterogeneity of the PRL can explain the diverse biological activities and that, although there is little knowledge concerning these isoforms, big big PRL may not exert enough action, because it does not easily cross the capillary walls to reach their target tissues because of its high molecular weight. Nevertheless, it is of interest that isoforms of high molecular weight have lower affinity for the specific receptors; however, it has been found that they are able to stimulate the growth of Nb2 cells (11, 22). On the clinical side, an intriguing feature of hyperprolactinemia in pregnancy is the absence of clinical signs of hyperprolactinemia itself and, in particular, the lack of galactorrhea. This effect is usually ascribed to the action of high levels of circulating progesterone and estrogens (25, 26, 27). After parturition, there is an abrupt decline in circulating estrogens and progesterone caused by the expulsion of the placenta; it is this estrogen withdrawal that initiates the onset of lactation. Estrogens thus synergize with PRL in promoting breast growth and differentiation but antagonize PRL in inhibiting the actual secretion of milk. Nonetheless, a possible alternative explanation for the absence of galactorrhea would be the presence of high-molecular-weight isoforms of PRL, with their low binding affinity to PRL receptors. Interestingly, in pregnant women with anti-PRL autoantibodies, gel filtration profiles showed that, as pregnancy progressed, the relative proportion of little PRL increased. The release of little PRL from the pituitary gland may increase as the pregnancy progresses, and a part of little PRL binds to the anti-PRL autoantibody, leading to an increase in big big PRL. However, the increase in little PRL may exceed the binding capacity of the autoantibodies, leading to an increase until little PRL reaches its physiological level. These data suggest an important role of little PRL in preparation for nursing, as well as for childbirth labor, causing a hormonal imbalance among the different isoforms of PRL, estrogens, and progesterone. This, however, must be clearly proven experimentally.

Finally, there were no differences in the amount of big PRL among the three groups. Although there is no explanation for this, it is known that big PRL is a transition molecule between the little isoform and some big big PRL molecules, by which it probably contributes to the regulation of biological activity and/or delayed elimination of PRL, to maintain its physiological level.

In accordance with this, it is possible that the presence of different isoforms of PRL at different stages of pregnancy and their different interactions with the cellular receptors might be a mechanism to selectively elicit the different functions attributed to PRL (control of uterine motility, carbohydrate and lipid metabolism, hydroelectrolytic balance in the amnion, and the carrying out of fetal functions).

Received June 5, 2000.

Revised September 6, 2000.

Accepted October 8, 2000.

References

1. Fraser IS, Lun ZG. 1990 Polymers of prolactin and their clinical significance. Obstet Gynecol Surv. 45:515–520.[Medline]
2. Sinha YN. 1995 Structural variants of prolactin: occurrence and physiological significance. Endocr Rev. 16:354–369.[CrossRef][Medline]
3. Jackson D, Volpert OV, Bouck N, Linzer DIH. 1994 Stimulation and inhibition of angiogenesis by placental proliferin and proliferin-related protein. Science. 266:1581–1584.[Abstract/Free Full Text]
4. Carlson HE, Markoff E, Lee DW. 1992 On the nature of serum prolactin in two patients with macroprolactinemia. Fertil Steril. 58:78–87.[Medline]
5. Jackson RD, Wortsman J, Malarkey WB. 1985 Characterization of a large molecular weight prolactin in women with idiopathic hyperprolactinemia and normal menses. J Clin Endocrinol Metab. 61:258–264.[Abstract]
6. Whittaker PG, Wilcox T, Lind T. 1981 Maintained fertility in a patient with hyperprolactinemia due to big, big prolactin. J Clin Endocrinol Metab. 53:863–866.[Abstract]
7. Andersen AN, Pedersen H, Djursing H, Andersen BN, Friesen HG. 1982 Bioactivity of prolactin in a woman with an excess of large molecular size prolactin, persistent hyperprolactinemia, and spontaneous conception. Fertil Steril. 38:625–628.[Medline]
8. Larrea F, Villanueva C, Cravioto MC, Escorza A, Real O. 1985 Further evidence that big, big prolactin is preferentially secreted in women with hyperprolactinemia and normal ovarian function. Fertil Steril. 44:25–30.[Medline]
9. Cavaco B, Leite V, Santos MA, Arranhado E, Sobrinho LG. 1995 Some forms of big big prolactin behave as a complex of monomeric prolactin with an immunoglobulin G in patients with macroprolactinemia or prolactinoma. J Clin Endocrinol Metab. 80:2342–2346.[Abstract]
10. Hattori N, Ishihara T, Ikekubo K, Moridera K, Hino M, Kurahachi H. 1992 Autoantibody to human prolactin in patients with idiopathic hyperprolactinemia. J Clin Endocrinol Metab. 75:1226–1229.[Abstract]
11. Leite V, Cosby H, Sobrinho LG, Fresnoza A, Santos MA, Friesen HG. 1992 Characterization of big, big prolactin in patients with hyperprolactinaemia. Clin Endocrinology (Oxf). 37:365–372.[Medline]
12. Hattori N, Ikekubo K, Ishihara T, Moridera K, Hino M, Kurahachi H. 1994 Correlation of the antibody titers with serum prolactin levels and their clinical course in patients with anti-prolactin autoantibody. Eur J Endocrinol. 130:438–445.[Abstract]
13. Farkouh NH, Packer MG, Frantz AG. 1979 Large molecular size prolactin with reduced receptor activity in human serum: high proportion in basal state and reduction after thyrotropin-releasing hormone. J Clin Endocrinol Metab. 48:1026–1032.[Medline]
14. Suh HK, Frantz AG. 1974 Size heterogeneity of human prolactin in plasma and pituitary extracts. J Clin Endocrinol Metab. 39:928–935.[Medline]
15. Pansini F, Bergamini CM, Malfaccini M, et al. 1985 Multiple molecular forms of prolactin during pregnancy in women. J Endocrinol. 106:81–85.[Abstract]
16. Jackson RD, Wortsman J, Malarkey WB. 1989 Persistence of large molecular weight prolactin secretion during pregnancy in women with macroprolactinemia and its presence in fetal cord blood. J Clin Endocrinol Metab. 68:1046–1050.[Abstract]
17. Hattori N. 1996 The frequency of macroprolactinemia in pregnant women and the heterogeneity of its etiologies. J Clin Endocrinol Metab. 81:586–590.[Abstract]
18. Hattori N, Ikekubo K, Ishihara T, Moridera K, Hino M, Kurahachi H. 1994 Effects of anti-prolactin autoantibodies on serum prolactin measurements. Eur J Endocrinol. 130:434–437.[Abstract]
19. Leaños A, Bustos H, Fraga A, Blanco F, Pascoe D. 1998 Autoanticuerpos dirigidos contra prolactina en pacientes con lupus eritematoso sistémico e hiperprolactinemia. Ginecol Obstet Mex. 66:179–186.[Medline]
20. Leaños-Miranda A, Pascoe-Lira D, Blanco-Favela F. 1998 Prolactin and systemic lupus erythematosus (Letter). Br J Rheumatol. 37:1029–1030.[Free Full Text]
21. Leaños A, Pascoe D, Fraga A, Blanco-Favela F. 1998 Anti-prolactin autoantibodies in systemic lupus erythematosus patients with associated hyperprolactinemia. Lupus. 7:398–403.[Abstract/Free Full Text]
22. Hattori N, Inagaki CH. 1997 Anti-prolactin (PRL) autoantibodies cause asymptomatic hyperprolactinemia: bioassay and clearance studies of PRL-immunoglobulin G complex. J Clin Endocrinol Metab. 82:3107–3110.[Abstract/Free Full Text]
23. Sievertsen GD, Lim VS, Nakawatase C, Frohman LA. 1980 Metabolic clearance and secretion rates of human prolactin in normal subjects and in patients with chronic renal failure. J Clin Endocrinol Metab. 50:846–852.[Medline]
24. Carr B. 1992 Fertilization, implantation, and endocrinology of pregnancy. The fetal-placental-maternal unit. In: Griffin J, Ojeda S, eds. Textbook of endocrine physiology. Oxford: Oxford University Press; 189–209.
25. Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA. 1998 Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev. 19:225–268.[Abstract/Free Full Text]
26. Whitaker MD, Klee GG, Kao PC, Randall RV, Heser DW. 1984 Demonstration of biological activity of prolactin molecular weight variants in human sera. J Clin Endocrinol Metab. 58:826–830.[Abstract]
27. Shiu RPC, Friesen HG. 1980 Mechanism of action of prolactin in the control of mammary gland function. Annu Rev Physiol. 42:83–96.[CrossRef][Medline]

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