Heterogeneity of Big-Big hPRL in Hyperprolactinemia

Tanaka, Tomoko; Yano, Hideki; Umezawa, Sachiko; Shishiba, Y; Okada, K.; Saito, T; Hibi, I

doi:10.1055/s-2007-1009157

Cited by 21 publications

(15 citation statements)

References 4 publications

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“…Several authors have claimed that accessible disulfide linkages may play a critical role in the maintenance of 1 50-170 kD PRL due to a shift in the molecular size after exposure to 2-mercaptoethanoI (6,8,16). On the other hand, a variety of biochemical studies have failed to show non-covalent aggregation of PRL or PRL bound to autoantibodies or binding proteins (6,8,9).…”

Section: Resultsmentioning

confidence: 99%

Different responses in little and bigbig prolactin to metoclopramide in subjects with hyperprolactinemia due to 150–170 kD (bigbig) prolactin

Bjøro

Johansen²,

Hh³

et al. 1993

Acta Endocrinologica

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We have studied in vivo induction of serum prolactin (PRL) levels in four females and one male, and regulation of PRL in the menstrual cycle in three females all with hyperprolactinemia with large amounts (72-92%) of bigbig PRL (MW 150-1 70 kD). Metoclopramide (MTC) iv induced a 4\p=n-\29-fold increase in little PRL (25 kD PRL) at 30 min, while the increase in 150-170 kD PRL was 1.1-2.2-fold. The maximal response in 150-170 kD PRL was seen after 2-6 h, and the decrease after the maximal PRL values for 1 50-1 70 kD PRL was delayed compared to the decrease in 25 kD PRL. The different kinetics for 25 kD PRL and 150-170 kD PRL was responsible for the prolonged increase in total PRL seen in the subjects with large amounts of 150-1 70 kD PRL compared to the controls. The percentage of 1 50-1 70 kD PRL decreased to 29-60% at 30 min and returned to unstimulated values after 6-24 h.In contrast, prolonged stimulation of PRL secretion, as in the luteal phase, did not change the percentage of 150-170 kD PRL. In a male subject secreting large amounts of 1 50-170 kD PRL the increase in PRL after MTC was less, while the temporal changes in the 25 kD PRL levels were almost the same as in the females.

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Section: Resultsmentioning

confidence: 99%

Different responses in little and bigbig prolactin to metoclopramide in subjects with hyperprolactinemia due to 150–170 kD (bigbig) prolactin

Bjøro

Johansen²,

Hh³

et al. 1993

Acta Endocrinologica

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“…Such forms are heterogeneous with molecular mass ranging up to approximately 500 kDa. They are incompletely characterized but are often composed of either covalent or noncovalent polymers of monomeric PRL, although some hyperglysolated variants have also been described 24,41–46 …”

Section: Nature Of Macroprolactinmentioning

confidence: 99%

“…They are incompletely characterized but are often composed of either covalent or noncovalent polymers of monomeric PRL, although some hyperglysolated variants have also been described. 24,[41][42][43][44][45][46] Although direct biochemical or structural evidence on the nature of macroprolactin is lacking, there is a considerable amount of indirect evidence that is consistent with the concept that macroprolactin is a PRL autoantibody complex. Such evidence includes the results of immunoadsorption and precipitation experiments using antihuman immunoglobulin G (IgG), protein A and protein G, 38,[47][48][49] together with Western blot anlysis.…”

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confidence: 99%

Clinical relevance of macroprolactin

Gibney

Smith

McKenna

2005

Clinical Endocrinology

128

108

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The anterior pituitary hormone PRL was identified in animal species as early as 1933 1 but only purified in humans in 1972. 2 Since then, the clinical syndrome of hyperprolactinaemia has been characterized extensively, the predominant symptoms being galactorrhoea, oligomenorrhoea or amenorrhoea and infertility in women and reduced libido, impotence and galactorrhoea in men. [3][4][5][6][7][8] Hyperprolactinaemia has an estimated prevalence of 15% in women with secondary amenorrhoea, 9,10 a condition that affects at least 3% of women of reproductive age. 11Pathological hyperprolactinaemia results from a lactotroph adenoma, conditions that increase TRH, such as hypothyroidism, conditions that decrease dopamine action at the lactotroph cell, such as hypothalamic or pituitary tumours, drugs such as dopamine D2 receptor antagonists, or conditions in which reduced clearance of PRL occurs, such as renal failure. By contrast, macroprolactinaemia, the presence of elevated levels of PRL of high molecular mass with little, if any, bioactivity, remains a largely under-recognized phenomenon and is not considered in the differential diagnosis of hyperprolactinaemia in current comprehensive endocrinology texts. 3,4,6 Recent studies have indicated that macroprolactinaemia accounts for up to 26% of biochemical hyperprolactinaemia depending on the immunoassay in use, [12][13][14][15][16][17][18] and thus macroprolactinaemia represents a common diagnostic pitfall, which is responsible for frequent misdiagnosis and mismanagement of hyperprolactinaemic patients. 19-23 Prolactin and macroprolactinProlactin, a globular protein consisting of 199 amino acids with three intramolecular disulfide bonds, is synthesized as a prehormone with a molecular weight of 26 kDa. 24 When the prehormone is proteolytically cleaved, the resulting mature polypeptide has a molecular weight of 23 kDa, and this monomeric form accounts for the majority of total PRL in the serum of normal subjects and most patients with hyperprolactinaemia. Prolactin is secreted episodically by the anterior pituitary and is primarily under tonic inhibitory control of the hypothalamus. 25 Physiological levels of PRL are higher during pregnancy and lactation than otherwise and mean serum levels are higher in women than in men. 26,27 In addition to monomeric PRL, which accounts for approximately 85% of the total circulating PRL in the majority of normal subjects and in those patients with hyperprolactinaemia, other molecular weight variants of PRL can be demonstrated in serum. 28,29 Big PRL, which has a molecular mass in the 50 kDa range and is thought to be a covalently bound dimer of PRL, accounts for approximately 10-15%. Big big PRL, or macroprolactin, which has a molecular mass of more than 150 kDa, usually contributes a small, though variable amount to circulating levels. 28,30Moreover, post-translational modification of pituitary PRL generates a variety of additional species, including glycosylated and phosphorylated variants, together with 14, 16 and 22 kDa proteolysed fo...

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“…Similarly, several groups of investigators have reported on a small number of patients with asymptomatic HPRL due to the nearly exclusive presence of big, big PRL (Ͼ100 kd) (10)(11)(12)(13)(14)(15)(16), termed macroprolactinemia. These cases were not related to the presence of the anti-PRL autoantibody.…”

mentioning

confidence: 96%

Biologic activity and plasma clearance of prolactin–IgG complex in patients with systemic lupus erythematosus

Leaños‐Miranda¹,

Chávez-Rueda²,

Blanco-Favéla³

2001

Arthritis & Rheumatism

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Objective. To characterize the clinical findings in hyperprolactinemic systemic lupus erythematosus (SLE) patients with or without macroprolactinemia (big, big prolactin [PRL]) due to anti-PRL autoantibodies (PRL-IgG complex), and to assess the bioactivity and structure of big, big PRL.Methods. Twenty-seven SLE patients with hyperprolactinemia (HPRL) were studied. Patients with (n ‫؍‬ 8) or without (n ‫؍‬ 19) big, big PRL were identified by gel filtration chromatography and affinity chromatography for IgG. PRL concentrations in serum and fractions by gel filtration chromatography and affinity chromatography were characterized by immunoradiometric assay (IRMA), Nb2 bioassay, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting, and clearance studies.Results. SLE patients without big, big PRL had significantly higher levels of disease activity, causeproven HPRL, and menstrual disturbances compared with patients with big, big PRL (P < 0.05). The big, big PRL fractions by Western blotting revealed a single 23-kd nonglycosylated PRL. The Nb2:IRMA ratio of the samples with big, big PRL was significantly higher than that of the samples without big, big PRL (P < 0.02). However, bioactivity of big, big PRL in the Nb2 cells was very similar to that of 23-kd nonglycosylated PRL.Clearance studies in rats demonstrated that the PRL-IgG complex was eliminated more slowly than monomeric PRL (little PRL).Conclusion. We demonstrated that the PRL-IgG complex was formed by 23-kd nonglycosylated PRL that was noncovalently bound to IgG and showed that the complex was fully active in vitro. This result suggests that the absence of symptoms of HPRL or lower levels of lupus activity in these patients is not explained by lower bioactivity of the complex. Instead, because of the large molecular size of the complex, the PRL does not easily cross the capillary walls. Delayed clearance of the PRL-IgG complex may account for increased serum levels of PRL in SLE patients with anti-PRL autoantibodies.

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Heterogeneity of Big-Big hPRL in Hyperprolactinemia

Cited by 21 publications

References 4 publications

Different responses in little and bigbig prolactin to metoclopramide in subjects with hyperprolactinemia due to 150–170 kD (bigbig) prolactin

Different responses in little and bigbig prolactin to metoclopramide in subjects with hyperprolactinemia due to 150–170 kD (bigbig) prolactin

Clinical relevance of macroprolactin

Biologic activity and plasma clearance of prolactin–IgG complex in patients with systemic lupus erythematosus

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