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International Journal of Obesity (2000) 24, Suppl 2, S104±S108 ß 2000 Macmillan Publishers Ltd All rights reserved 0307±0565/00 $15.00 www.nature.com/ijo Physiopathology]> of prolactin secretion in obesity

PG Kopelman1*

1St Bartholomew's and the Royal School of Medicine and Dentistry, Queen Mary and West®eld College, University of London, London, UK

In many species prolactin is of biological importance and has a major role in determining the deposition and mobilization of fat. In human physiology, outside pregancy, prolactin secretion is altered by increasing body weight in both children and adults. Prolactin in this circumstance appears to be marker of hypothalamic ± pituitary function: the prolactin response to -hypoglycaemia, thyrotrophin releasing stimulation and other stimulatory factors may be diminished. In addition, obesity alters the 24 h spontaneous release of prolactin with a generalised dampening of release. A number of explanations have been given as possible causes for these alterations, but it seems likely that they re¯ect obesity per se and are associated with hyperinsulinaemia. Weight reduction, with accompany- ing decrease in plasma insulin levels, leads to a normalization of prolactin responses in most, but not all, circumstances. To date, no molecular basis has been identi®ed which links prolactin with increasing body fatness, weight and appetite: new data suggests a possible link in obese men between fasting plasma prolactin and concentrations. International Journal of Obesity (2000) 24, Suppl 2, S104±S108

Keywords: HPA; insulin; leptin; ; pituitary

Introduction partly explain prolactin's bewildering array of biolo- gical actions.2 Among the of the , pro- lactin, with more than 85 documented functions in various vertebrate species, is by far the most versatile. Prolactin was ®rst discovered in 1928 based on its Heterogeneity of prolactin isoforms ability to cause in pseudopregnant rabbits. The hormone was ®rst puri®ed in 1932, but it was not Human pituitary prolactin has been detected in a until 1971 that human prolactin was puri®ed and diversity of isoforms including a glycosylated shown to be distinct from human hormone. Human prolactin consists of 199 (HGH).1 In the early 1980s the cDNA and for residues and migrates on reducing gels at an apparent prolactin were cloned and sequenced and the prolactin molecular size of 23 kDa. A cleaved two-chain form gene de®ned as a member of a multigene family that has been detected in serum and pituitary preparations includes HGH and chorionic somato-mammotrophin in man. This isohormone is the product of speci®c hormone. In the late 1980s, the cloning and character- enzymatic cleavage resulting in 8 and 16 kDa chains ization of Pit-I as a tissue speci®c transcativator of held together with a single disulphide bond. Although prolactin gene transcription enhanced understanding the 16 kDa cleaved form can be produced in vitro as of pituitary cell development and prolactin gene an artefact, there is convincing evidence for it to be regulation. The cloning of several forms of the pro- physiologically signi®cant. Moreover, the 16 kDa has lactin receptor within the past few years has led to the reduced detectability in some radioimmunoassays.3 A recognition that the receptor is a member of a large glycosylated form of prolactin, which migrates at family of haemopoetic receptors. The diver- 25 kDa, has also been isolated from human pituitaries. sity of the isoforms and the struc- The glycosylated hormone represents between 13% tural overlap with other receptors in the family may and 25% of prolactin in the human pituitry gland.4 Fractionation of human serum by chromatography resolves prolactin into three immunoreactive peaks Ð 23 kDa, 48 ± 56 kDa and 150 kDa forms. 150 kDa prolactin demonstrates decreased receptor bind- *Correspondence: PG Kopelman, St Bartholomew's and the ing and biological activity: this may explain the Royal London School of Medicine, Turner Street, London E1 2AD, UK. phenomenon of sustained with E-mail: [email protected] minimal symptoms and normal menses. Prolactin and obesity PG Kopelman S105 stood, a number of prolactin-releasing factors (PRF) Hormone mediated regulation of and prolactin-inhibitory factors (PIF) have been iden- prolactin gene transcription (Table 1) ti®ed. The connections between the median eminence (ME) and the anterior pituitary are critical to the Steroids have both positive and negative effects. maintenance of physiological control over prolactin Injections of oestrogen into rats result in a rapid secretion. , a catecholamine present in the increase in prolactin gene transcription. By contrast, ME and the hypophyseal portal blood, acts as the glucocorticoids normally induce a negative transcrip- major physiological PIF via a direct action on the tional effect on the prolactin promoter. A variety of pituitary.8 The contains sev- other hormonal stimuli act indirectly on the prolactin eral pathways: the tuberoinfundibular- gene via intracellular second-messenger systems. dopaminergic (TIDA) system is the one that primarily Dopamine mediates its negative effect on prolactin regulates prolactin secretion. Its cell bodies are gene transcription via a decrease in intracellular located in the of the medial basal cAMP. Thyrotrophin releasing hormone (TRH) hypothalamus and their terminals project to the ME rapidly stimulates prolactin gene transcription through and pituitary stalk. Dopamine is transported to the increases in intracellular calcium.1 Physiological anterior pituitary lobe via the long hypophyseal portal doses of insulin appear to stimulate prolactin vessels; dopamine is present in high concentrations in secretion Ð the physiological signi®cance of this is the posterior lobe and this source of dopamine also uncertain. plays a role in inhibiting prolactin release. Dopamine has a series of speci®c isoreceptors but only the D2 receptor subtype is present on anterior pituitary cells. The cytoplasmic domain of the D2 receptor is linked Regulation of prolactin secretion to adenylate cyclase and dopamine binding results in a decreased adenylate cyclase activity. As with all pituitary hormones, prolactin is secreted TRH was the ®rst PRF to be identi®ed. TRH episodically with a distinctive 24 h pattern. In normal induces prolactin release by a direct action on the human subjects there are about 14 pulses of prolactin and TRH regulation of prolactin gene secretion in 24 h with approximately one every transcription.9 The role of TRH in the physiological 90 min. Superimposed on this pattern is a bimodal surges of prolactin is unclear. Vasoactive intestinal 24 h pattern of secretion with a major nocturnal peak (VIP) has also been shown to stimulate beginning after onset and peaking in mid-sleep.5 prolactin release in isolated pituitary glands by Prolactin levels are at their lowest around noon. Stress increasing prolactin mRNA, possibly by the induction is a potent releaser of prolactin with a signi®cantly of cAMP.10 Serotonin, or its precursor 5-hydroxytryp- greater increase observed in women compared with tophan, stimulates prolactin release by two possible men.6 This re¯ects the in¯uence of oestrogen on mechanisms either by reducing the activity of TIDA prolactin release both within lactotrophs and at the neurons or by stimulating the release of PRFs.11 level of the hypothalamus. The pathways mediating stress-related prolactin release are unclear but opioid , in particular b-, play a role.7 In contrast, melanocyte-stimulating hormone (MSH) Prolactin secretion in obesity appears to inhibit stress-induced increases. In many species prolactin secretion is associated with growth and . In the white-throated sparrow, for example, prolactin appears to be one of the factors controlling migration and fat deposition.12 Neuroendocrine regulation of Fat deposition is promoted or inhibited depending on prolactin secretion the relation between the peak release of prolactin and that of corticosterone during the day. This, in turn, is Although the exact molecular mechanisms controlling dependent on day length. In the Syrian hamster, prolactin release are presently incompletely under- appropriately timed injections of prolactin and corti- costerone during the day and night produce marked reductions in obesity and insulin resistance.13 In man, Table 1 Summary of the hormonal regulators of prolactin gene an increase in maternal plasma prolactin is seen in transcription. Hormones with positive effects increase prolactin girls following at a time of fat deposition.14 transcription; those with negative effects decrease transcription Furthermore, the circadian rhythm of pulsatile prolac- ) Positive effects ) Negative effects tin release is altered in adult obesity with a delay in 15 u Oestrogen u Glucocorticoids the nocturnal rise being reversed by weight loss. u TRH via increase in ic calcium u Dopamine via decrease in Evidence for an abnormality in the hypothalamic ± ic cyclic AMP pituitary regulation of prolactin secretion comes from u insulin the ®nding of impaired responses to a variety of

International Journal of Obesity Prolactin and obesity PG Kopelman S106 pharmacological stimuli. Two distinct patterns of system. Some investigators report a normal prolactin release to insulin-induced hypoglycaemia may be response to intravenous TRH, which suggests normal seen in obesity (Figure 1).16 In some obese subjects anterior pituitary reserves, while others have reported there is no prolactin response to symptomatic hypo- impaired prolactin release suggestive of a broader glycaemia (prolactin `non-responders'), while in other abnormality of hypothalamic regulation.16,20 The pro- equally obese subjects a normal response is seen lactin response to TRH stimulation is impaired in pre- (prolactin `responders'). It has been suggested that pubertal obese children.21 the impaired prolactin response results from a primary Drugs which antagonize the action of dopamine disorder of hypothalamic function because an cause a release of prolactin in man. Of these, meto- impaired prolactin response persists in such women clopramide crosses the blood ± brain barrier and the despite their subsequent attainment of nearly normal release of prolactin, following its intravenous injec- weight.17 Furthermore, some obese children have been tion, probably results from its action on both hypo- reported to show no prolactin response to hypogly- thalamic and pituitary dopaminergic receptors.22 caemia.18 Jung and colleagues19 found no signi®cant , in contrast, does not cross the blood ± rise of plasma noradrenaline to hypoglycaemia in brain barrier and its prolactin releasing action is obese subjects with an impaired prolactin response, predominantly at the pituitary level.23 Additional although the response remained unim- support for an abnormality of central neural pathways paired. This suggests that the hypothalamic alteration, in some obese subjects is the ®nding that `non- which may occur in those with a propensity for responders' have a prolactin release after metoclopra- obesity, not only involves the control of pituitary mide which is signi®cantly less than obese `respon- but also affects the control of the sympathetic nervous ders', but a comparable prolactin response to domperidone (Figure 2).24 The composition of the diet may also alter the prolactin response to hypo- glycaemia.24 An isocaloric high carbohydrate diet impairs the prolactin response in obese subjects who previously had a normal response (ie `responders'), while an identical diet has no effect in normal weight subjects. It has been suggested that a central de®ciency of serotonin or an alteration in may be the explanation for altered prolactin secretion in obesity. Treatment of obesity with fen¯uramine, a centrally acting serotoninergic , restores to normal impaired prolactin responses to intravenous TRH and an arginine infusion.25,26 Furthermore, naloxone does not alter the fen¯uramine-enhanced prolactin response to TRH, suggesting that the pro- lactin alterations are not the result of an interaction between central opioidergic and serotoninergic path- ways.27 Evidence for a possible alteration in dopami- nergic control of prolactin in obesity comes indirectly from a study of weight loss in association with the normalisation of plasma prolactin in patients with prolactin secreting pituitary adenomas.28 A clear rela- tionship was seen between high prolactin levels and increased body mass: neither increased body weight nor recent weight gain could be attributed to tumoural mass effect on the central hypothalamic area. More- over, there was a strong relationship between the occurrence of post-treatment weight loss and prolactin normalization. There is evidence to suggest that hyperinsulinaemia may be an explanation for the impaired prolactin responses seen in obesity. Signi®cant associations are observed between increased insulin secretion and Figure 1 Blood glucose, prolactin and growth hormone resistance and the prolactin release to insulin-hypo- responses to insulin-induced hypoglycaemia in obese and con- glycaemia (Figure 3).29 In addition, an inverse corre- trol (c) women. Obese non-responders are de®ned as those with lation is observed between increasing upper body an absent prolactin response to symptomatic hypoglycaemia. Such women additionally have an attenuated growth hormone obesity (as measured by an increasing waist-to-hip response. ratio) and the prolactin response to hypoglycaemia.

International Journal of Obesity Prolactin and obesity PG Kopelman S107

Figure 2 Plasma prolactin responses (total integrated response: area under the prolactin curve from time zero to 120 min) following intravenous bolus injections, on separate occasions, of and domperidone. Obese non-responders are women with an absent prolactin response to insulin-hypoglycaemia.

Table 2 Summary of the relationship observed in obese men (n ˆ 8) and obese women (n ˆ 44) between fasting plasma prolactin and leptin

Prolactin r value Prolactin P value

Men BMI 0.15 P ˆ 0.7 Leptin 0.89 P ˆ 0.006 Women BMI 0.38 P ˆ 0.03 Leptin 0.2 P ˆ 0.19

genetic basis to altered prolactin secretion has not been excluded, although there have been no reports of associations between polymorphisms of the prolactin gene and obesity. A recent report has, however, Figure 3 Inverse relationship (P < 0.01) between log prolactin suggested a possible association between variants of area under curve to insulin-hypoglycaemia and log steady-state the ob (obesity) gene, body mass index and inter- plasma glucose (SSPG) attained during a simultaneous intrave- actions with the dopamine D2 receptor gene, while nous infusion of insulin, dextrose and . SSPG is a measure of insulin sensitivity. variants of the D2 receptor gene have been linked to obesity and impulsive-addictive-compulsive beha- viour.30,31 It is intriguing that a relationship has These ®ndings suggest that subtle alterations in recently been found between fasting plasma leptin hypothalamic function account for altered prolactin and prolactin concentrations in obese men, which secretion found in some obese subjects, but the situa- suggests a possible role for prolactin in regulating tion is compounded by the metabolic alterations fat deposition and possibly reproductive function. associated with regional fat distribution. This relationship was not seen in women, presumably because of the in¯uence of circulating oestrogens (Table 2). In conclusion, altered prolactin secretion in obesity Prolactin in obesity Ð a hormone appears to be a marker of hypothalamic ± pituitary worth revisiting dysfunction that may be explained by alterations in central dopaminergic and serotoninergic tone. Such There are clearly many unanswered questions about changes in prolactin release are associated with the role of prolactin in obesity. There are no published peripheral hyperinsulinaemia and, in men, with fast- reports on levels of different prolactin isoforms in ing leptin concentrations. The latter relationship raises obesity nor whether glycosylated hormone levels intriguing questions about a role for prolactin in fat differ between obese and lean. The possibility of a deposition and fertility in obesity.

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International Journal of Obesity