Prolactin was first identified as a product of the anterior pituitary in 1933 (225). It is found in nearly every vertebrate species. Its presence in humans was long inferred by the association of the syndrome of amenorrhea and galactorrhea in the presence of pituitary macroadenomas, though it was not definitively identified as a human hormone until 1971. The specific activities of human prolactin (hPRL) were defined by the separation of its activity from growth hormone and subsequently by the development of radioimmunoassays (226–228). Although the initiation and maintenance of lactation is the primary function of prolactin, many studies document roles for prolactin activity both within and beyond the reproductive system.
Prolactin Secretion There are 199 amino acids within human prolactin, with a molecular weight (MW) of 23,000 D (Fig. 31.8). Although human growth hormone and placental lactogen have significant lactogenic activity, they have only a 16% and 13% amino acid sequence homology with prolactin, respectively. In the human genome, a single gene on chromosome 6 encodes prolactin. The prolactin gene (10 kb) has five exons and four introns, and its transcription is regulated in the pituitary by a proximal promotor region and in extrapituitary locations by a more upstream promotor (229).
In the basal state three forms are released: a monomer, a dimer, and a multimeric species, called little, big, and big-big prolactin, respectively (230–232). The two larger species can be degraded to the monomeric form by reducing disulfide bonds (233). The proportions of each of these prolactin species vary with physiologic, pathologic, and hormonal stimulation (233–236). The heterogeneity of secreted forms remains an active area of research. Studies indicate that little
Figure 31.8 Amino acid sequence of prolactin. Three cysteine disulfide bands are located within the molecule. (From Bondy PK. Rosenberg leukocyte esterase: metabolic control and disease, 8th ed. Philadelphia: WB Saunders, 1980, with permission.) prolactin (MW 23,000 D) constitutes more than 50% of all combined prolactin production and is most responsive to extrapituitary stimulation or suppression (233,235,236). Clinical assays for prolactin measure the little prolactin, and in all but extremely rare circumstances, these measures are sufficient to assess diseases of abnormal pituitary production of the hormone.
Prolactin, and its relatives growth hormone and placental lactogen, do not require glycosylation for most of their primary activities, as is the case for the gonadotropins and TSH. Glycosylated forms are secreted, and glycosylation does affect the bioactivity and immunoreactivity of little prolactin (237–240). It appears that the glycosylated form is the predominant species secreted, but the most potent biologic form appears to be the 23,000-D nonglycosylated form of prolactin (239). Prolactin has over 300 known biological activities. Prolactin’s most recognized activities include those associated with reproduction (lactation, luteal function, reproductive behavior) and homeostasis (immune responsivity, osomoregulation, and angiogenesis) (241). Despite these many activities, the only recognized disorder associated with deficiency of prolactin secretion is inability to lactate.
To some degree, the physical heterogeneity of prolactin may explain the biologic heterogeneity of this hormone, and although this complicates the physiologic evaluation of prolactin’s myriad effects, it is of little import to the diagnosis and management of hyperprolactinemic states.