The hypothalamic control of prolactin secretion is different from other anterior pituitary hormones, in that it is predominantly inhibitory, by means of dopamine from the tuberoinfundibular dopamine neurons. In addition, prolactin does not have an endocrine target tissue, and therefore lacks the classical feedback pathway to regulate its secretion. Instead, it is regulated by short loop feedback, whereby prolactin itself acts in the brain to stimulate production of dopamine and thereby inhibit its own secretion. Finally, despite its relatively simple name, prolactin has a broad range of functions in the body, in addition to its defining role in promoting lactation. As such, the hypothalamo-prolactin axis has many characteristics that are quite distinct from other hypothalamo-pituitary systems. This review will provide a brief overview of our current understanding of the neuroendocrine control of prolactin secretion, in particular focusing on the plasticity evident in this system, which keeps prolactin secretion at low levels most of the time, but enables extended periods of hyperprolactinemia when necessary for lactation. Key prolactin functions beyond milk production will be discussed, particularly focusing on the role of prolactin in inducing adaptive responses in multiple different systems to facilitate lactation, and the consequences if prolactin action is impaired. A feature of this pleiotropic activity is that functions that may be adaptive in the lactating state might be maladaptive if prolactin levels are elevated inappropriately. Overall, my goal is to give a flavour of both the history and current state of the field of prolactin neuroendocrinology, and identify some exciting new areas of research development.

ABSTRACT

It has been suggested that the tight junctions formed between Sertoli cells during the peripubertal period constitute a barrier to circulating FSH in the adult testis, limiting its access to the lumen of the seminiferous tubules. There are also reports of FSH receptor-binding inhibitors. These obervations prompted us to study the extent of FSH receptor availability in vivo in the adult rat. Experimental rats were given an intracardiac injection of rat FSH (rFSH), and the occupied receptor was measured by radioimmunoassay of acid-released rFSH from the testis. In the saline-injected control animals, there were 247 fmol occupied FSH receptors/g testis, and as much as 1788 fmol of the unoccupied high-affinity receptors/g testis, as measured by in-vitro binding studies. After intracardiac injection of increasing amounts of rFSH (up to 606 pmol), receptor occupancy increased to a maximum plateau of only 448 fmol/g testis. In contrast, when rFSH was given by intratesticular injection in order to achieve pharmacological doses in the testis, the maximum binding was 662 fmol/g testis. Scatchard analysis of the in-vivo data revealed, however, that the maximum concentration of the high-affinity receptor was 452 fmol/g testis, a value concordant with the highest in-vivo binding observed in animals given intracardiac rFSH (448 fmol/g). A single injection of the hormone did not induce down-regulation of FSH receptors, regardless of the dose, whereas multiple injections of menotrophin were effective, at least to some extent. Despite the receptor loss, the immediate receptor availability was maintained, suggesting the presence of a receptor pool.

In conclusion, in-vivo binding of FSH to its high-affinity receptor is limited in adult rat testis, and the available receptor concentration appears to be regulated so as to maintain a constant level.

Journal of Endocrinology (1990) 125, 293–299

Glucocorticoid hormones constitute an integral component of the response to stress, and many of the manifestations of glucocorticoid excess (Cushing's syndrome) are predictable on the basis of their acute effects to raise blood pressure, induce insulin resistance, increase protein catabolism and elevate plasma glucose. However, it appears to be a paradox that the acute lipolytic effect of glucocorticoids is not manifest in long-term weight loss in humans. The effects of glucocorticoids on glucose metabolism are well characterised, involving impaired peripheral glucose uptake and hepatic insulin resistance, and there is mounting evidence that subtle abnormalities in glucocorticoid concentrations in the plasma and/or in tissue sensitivity to glucocorticoids are important in metabolic syndrome. The effects of glucocorticoids on fatty acid metabolism are less well understood than their influence on glucose metabolism. In this article, we review the literature describing the effects of glucocorticoids on fatty acid metabolism, with particular reference to in vivo human studies. We consider the implications for contrasting acute versus chronic effects of glucocorticoids on fat accumulation, effects in different adipose depots and the potential role of glucocorticoid signalling in the pathogenesis and therapy of metabolic syndrome.

Connective tissue growth factor (CCN2) is a 349-residue mosaic protein that contains four structural modules (modules 1–4), which are presumptive domains for interactions with regulatory binding proteins and receptors. Module 3, corresponding to residues 199–243, is a thrombospondin structural homology repeat (TSR) and is flanked by regions that are highly susceptible to proteolytic cleavage. To test whether CCN2 module 3 (CCN2₃) has intrinsic biological properties, it was produced recombinantly in Escherichia coli (E. coli) and examined for its effects on the function of hepatic stellate cells (HSC), the principal fibrogenic cell type in the liver. CCN2₃ stimulated dose-dependent HSC adhesion and activity of p42/p44 mitogen activated protein kinase, the latter of which was antagonized by blocking the activity of focal adhesion kinase. HSC adhesion to immobilized CCN2₃ was attributed to binding interactions with cell surface integrin α6β1. As assessed by RT-PCR or Western blotting, CCN2₃ stimulated production of fibronectin and pro-collagen type IV(α5), both of which are downstream components of HSC-mediated fibrogenesis and which are constituents of high density matrix in fibrotic lesions. These data show that while the full length CCN2 protein is strongly associated with fibrosis and stellate cell function, key integrinbinding properties, signaling, and fibrogenic pathways are exhibited by module 3 alone. These data indicate that module 3 of CCN2 is intrinsically active and suggest that liberation of module 3 following CCN2 proteolysis may contribute to HSC-mediated fibrogenesis, as well as other CCN2-dependent processes.

Acute exercise transiently suppresses the orexigenic gut hormone acylated ghrelin, but the extent to which exercise intensity and duration determine this response is not fully understood. The effects of manipulating exercise intensity and duration on acylated ghrelin concentrations and hunger were examined in two experiments. In experiment one, nine healthy males completed three, 4-h conditions (control, moderate-intensity running (MOD) and vigorous-intensity running (VIG)), with an energy expenditure of ~2.5 MJ induced in both MOD (55-min running at 52% peak oxygen uptake (V.O_2peak)) and VIG (36-min running at 75% V.O_2peak). In experiment two, nine healthy males completed three, 9-h conditions (control, 45-min running (EX45) and 90-min running (EX90)). Exercise was performed at 70% V.O_2peak. In both experiments, participants consumed standardised meals, and acylated ghrelin concentrations and hunger were quantified at predetermined intervals. In experiment one, delta acylated ghrelin concentrations were lower than control in MOD (ES = 0.44, P = 0.01) and VIG (ES = 0.98, P < 0.001); VIG was lower than MOD (ES = 0.54, P = 0.003). Hunger ratings were similar across the conditions (P = 0.35). In experiment two, delta acylated ghrelin concentrations were lower than control in EX45 (ES = 0.77, P < 0.001) and EX90 (ES = 0.68, P < 0.001); EX45 and EX90 were similar (ES = 0.09, P = 0.55). Hunger ratings were lower than control in EX45 (ES = 0.20, P = 0.01) and EX90 (ES = 0.27, P = 0.001); EX45 and EX90 were similar (ES = 0.07, P = 0.34). Hunger and delta acylated ghrelin concentrations remained suppressed at 1.5 h in EX90 but not EX45. In conclusion, exercise intensity, and to a lesser extent duration, are determinants of the acylated ghrelin response to acute exercise.

Low birth weight in humans is predictive of hypertension in adult life. Although the mechanisms underlying this link remain unknown, fetal overexposure to glucocorticoids has been implicated. We previously showed that prenatal dexamethasone (DEX) exposure in the rat lowers birth weight and programmes adult hypertension. The current study aimed to further investigate the nature of this hypertension and to elucidate its origins. Unlike previous studies, we assessed offspring blood pressure (BP) with radiotelemetry, which is unaffected by stress artefacts of measurement. We show that prenatal DEX during the last week of pregnancy results in offspring of low birth weight (14% reduction) that have lower basal BP in adulthood (∼4–8 mmHg lower); with the commonly expected hypertensive phenotype only being noted when these offspring are subjected to even mild disturbance or a more severe stressor (up to 30 mmHg higher than controls). Moreover, DEX-treated offspring sustain their stress-induced hypertension for longer. Promotion of systemic catecholamine release (amphetamine) induced a significantly greater rise of BP in the DEX animals (77% increase) over that observed in the vehicle controls. Additionally, we demonstrate that the isolated mesenteric vasculature of DEX-treated offspring display greater sensitivity to noradrenaline and other vasoconstrictors. We therefore conclude that altered sympathetic responses mediate the stress-induced hypertension associated with prenatal DEX programming.

Glucose-dependent insulinotropic polypeptide (GIP) is a 42 amino acid hormone secreted from intestinal K-cells, which exhibits a number of actions including stimulation of insulin release. A truncated form, GIP(1–30), has recently been demonstrated in intestine and islet α-cells. To evaluate the potential physiological significance of this naturally occurring form of GIP, the present study has examined and compared the bioactivity of enzymatically stabilised forms, [d-Ala²]GIP(1–30) and [d-Ala²]GIP(1–42), in high-fat fed mice. Twice-daily injection of GIP peptides for 42 days had no significant effect on food intake or body weight. However, non-fasting glucose levels were significantly lowered, and insulin levels were elevated in both treatment groups compared to saline controls. The glycaemic response to i.p. glucose was correspondingly improved (P<0.05) in [d-Ala²]GIP(1–30)- and [d-Ala²]GIP(1–42)-treated mice. Furthermore, glucose-stimulated plasma insulin levels were significantly elevated in both treatment groups compared to control mice. Insulin sensitivity was not significantly different between any of the groups. Similarly, plasma lipid profile, O₂ consumption, CO₂ production, respiratory exchange ratio, and energy expenditure were not altered by 42 days twice-daily treatment with [d-Ala²]GIP(1–30) or [d-Ala²]GIP(1–42). In contrast, ambulatory activity was significantly (P<0.05) elevated during the light phase in both GIP treatment groups compared to saline controls. The results reveal that sustained GIP receptor activation exerts a spectrum of beneficial metabolic effects in high-fat fed mice. However, no differences were discernable between the biological actions of the enzyme-resistant analogues of the naturally occurring forms, GIP(1–30) and GIP(1–42).

SUMMARY

Treatment for 5 days of female rats with perphenazine (5 mg/kg/day) induced full lobulo—alveolar differentiation. Long-standing adrenalectomy (12 days) decreased this mammotrophic effect of perphenazine. The mechanism of this reaction was studied in male rats in order to avoid fluctuations of the prolactin content in the anterior pituitary. Adult male rats were adrenalectomized and injected s.c. after 12 days with perphenazine (10 mg/kg). Two hours later the rats were killed and pituitary and serum prolactin levels assayed by double antibody radioimmunoassay. In intact rats, perphenazine treatment enhanced serum prolactin up to 104 ± 4 (s.e.m.) ng/ml (± 350%). Adrenalectomy alone increased serum prolactin from 30± 5 to 47 ± 6 ng/ml (+56%), and augmented the perphenazine-induced release of prolactin from the pituitary into the blood from 104 ± 4 to 147 ± 10 ng/ml (+ 42%).

In chronically adrenalectomized adult female rats extremely high amounts of prolactin (+ 1617%) were detected in the serum at the end of 5 days' treatment with perphenazine (5 mg/kg/day).

These results indicate that removal of the adrenals in male and female rats does not interfere with the ability of the pituitary to secrete prolactin. Moreover, they also show that in adrenalectomized rats the impaired mammotrophic effect of perphenazine is not due to prolactin deficiency (since high serum levels of this hormone were present) but to the absence of corticosteroids at the target organ.

Apelin is a peptide hormone with cardiovascular and glucose homeostasis properties, and obstructive sleep apnea (OSA) is complicated by cardiovascular and metabolic comorbidities. Plasma apelin has not been previously assessed in OSA. We investigated the response of plasma apelin to a 2-h 75 g oral glucose tolerance test (OGTT) and the effect of 3 months compliant continuous positive airway pressure (CPAP) therapy in 15 obese males with newly diagnosed OSA. Plasma apelin and serum cortisol were recorded 10 minutely, while serum insulin and glucose were measured 30 minutely. Ten subjects had plasma apelin measured at intervals across a 24-h period to investigate for circadian variation in apelin levels, and this was repeated following 3 months compliant CPAP therapy. Fasting (0.342±0.038 vs 0.288±0.024 ng/ml, P=0.04), 30 min (0.399±0.035 vs 0.312±0.036 ng/ml, P=0.007) and 120 min (0.402±0.030 vs 0.259±0.024 ng/ml, P<0.001) apelin levels were reduced following CPAP. The area under curve for apelin OGTT response was lower post-CPAP (44.1±3.3 vs 35.8±2.3 ng/ml per min, P<0.001). Mean OGTT apelin levels showed a significant treatment effect (P=0.006) and a time effect (P<0.001), and the effect of time was different pre- versus post-CPAP (P=0.005). No significant variability in apelin levels existed across the 24-h period at diagnosis. Lower levels were evident overnight following treatment (P=0.004). Improvements in insulin and glucose parameters and reduced cortisol levels were found post-CPAP. In summary, untreated OSA was associated with elevated plasma apelin levels, altered apelin secretory dynamics in response to oral glucose and lack of an apparent circadian variability, which was restored following CPAP.

Survivin (BIRC5) is a cell survival gene that is overexpressed in endometrial cancer and has been implicated to have a physiological role in normal endometrial function. To determine whether survivin gene expression is regulated by reproductive steroid hormones in the human endometrium, RNA was prepared from normal cycling women in the proliferative and secretory phases of the menstrual cycle. RNA was also isolated from 21 endometrial biopsies from premenopausal women at baseline and following 3 months of treatment with depot medroxyprogesterone acetate. Finally, RNA was isolated from endometrial biopsies from ten healthy postmenopausal women participating in a clinical trial of estrogen replacement therapy at baseline and following 6 months of treatment with conjugated equine estrogen. Quantitative RT-PCR analysis was used to determine survivin, insulin-like growth factor binding protein 1 (IGFBP1), Ki67, and IGF1 gene expression levels. Survivin gene expression was highest in the proliferative phase of the menstrual cycle and showed a statistically significant 4-fold increase in expression following chronic treatment with estrogens; this was strongly correlated with increased Ki67, a marker of proliferation. Survivin gene expression decreased 4.6-fold following chronic progestin treatment in the human endometrium. These data suggest that survivin transcript is regulated by estrogens and progestins in the disease-free human endometrium. The data also suggest that survivin transcript may be used as a biomarker of estrogen and progestin treatment efficacy, but validation studies must be conducted to support this conclusion.