Changes in Dopaminergic Control of Circulating Melanocyte-Stimulating Hormone-Related Peptides at Puberty

Abstract

Desacetyl a-melanocyte-stimulating hormone (MSH) (ACTH 1-13) is the main form of immunoreactive a-MSH circulating in human plasma. This study evaluates the possibility that a dopaminergic inhibitory mechanism could be operative during human development. Thus, a-MSH and ACTH 1-13 plasma levels were measured after dopaminergic blockade (domperidone (0.3 m a g body weight, maximum 10 mg, p.0.) in 13 prepubertal (aged 4.5-12.3 y) and 12 pubertal (aged 10.2-16.9 y) children. Both peptides were measured by RIA after plasma extraction on Sep-pak C-18 cartridges and reverse phase HPLC. The chromatographic profile of a-MSH immunoreactivity falls into two main peaks, corresponding to the retention time of a-MSH and ACTH 1-13. Moreover, in prepubertal children domperidone induced a significant increase of a-MSH from 1.7 (median) to 5.0 pmol/L, whereas no changes in a-MSH plasma levels were found in pubertal subjects (from 5.0 to 4.1 pmol/L). Similarly, ACTH 1-13 plasma levels significantly increased from 3.0 to 19.8 pmol/L in prepubertal children remaining stable in pubertal ones (from 7.8 to 4.6 pmol/L). Moreover, a significant negative correlation was found between basal DHEA-S levels and the plasma a-MSH increase after domperidone. These data demonstrate that: 1 ) ACTH 1-13 is the main form of immunoreactive a-MSH in prepubertal life and 2) the dopaminergic inhibition of both ACTH 1-13 and a-MSH plasma levels is apparent only in prepubertal subjects. (Pediatr Res 38: 91-94, 1995) Abbreviations a-MSH, a-melanocyte-stimulating hormone ACTH 1-13, desacetyl a-melanocyte-stimulating hormone POMC, proopiomelanocortin DHEA-S, dehydroepiandrosterone sulfate a-MSH is a peptide deriving from a two steps cleavage of POMC for the formation of which the activity of a-Nacetyltransferase is required (1). In lower mammals, these enzymatic events are absent from the anterior pituitary, whereas they are typical of the neurointermediate lobe, which is well developed in these species (2). In humans, the neurointermediate lobe is virtually absent in adults (3), whereas it has been detected in the fetal pituitary (4) and in a subgroup of patients with Cushing's disease (5).In contrast to the studies of late 1970s, detectable levels of a-MSH plasma have been found in healthy adult volunteers (6, 7), and they have been found higher than normal in patients affected by Cushing disease (8). The results of the abovementioned studies were obtained coupling the classical a-MSH RIA to purification procedures, such as extraction and HPLC, and revealed that the des-acetylated form of a-MSH (i.e. ACTH 1-13 amide) is the main form of plasma immunoreactive a-MSH. This finding also suggests a possible functional activity of neurointermediate lobe in some physiopathologic conditions.We previously demonstrated that, in contrast to ACTH levels, plasma P-endorphin concentrations increased progressively throughout prepuberty, reaching adult levels at the beginning of pubertal development (9). These data were in keeping with the suggested role of POMC-related...

60 YEARS OF POMC: Purification and biological characterisation of melanotrophins and corticotrophins

“…The use of a dopaminergic antagonist provided indirect evidence for active zona intermedia-like cells in prepubertal children, as it resulted in a significant increase in plasma α-MSHlike concentrations but not in post-pubertal controls. The elution position on HPLC suggested that the immunoreactive material was mainly desacetyl α-MSH (Facchinetti et al 1995). Desacetyl α-MSH does stimulate adrenal steroidogenesis, albeit at high concentrations, but its secretion would be accompanied by significant concentrations of other potential biologically active intermedia-like processed POMC peptides, e.g.…”

Agouti Antagonism of Melanocortin-4 Receptor: Greater Effect with Desacetyl-α-Melanocyte-Stimulating Hormone (MSH) than withα -MSH

“…I N CONTRAST TO the majority of ␣-MSH produced by pituitary melanotrophs, desacetyl-␣-MSH is the predominant form of ACTH 1-13 NH 2 produced in the brain (1,2), the fetus (3,4), human blood (5), and amniotic fluid (6). Desacetyl-␣-MSH may also be more abundant than ␣-MSH in the pituitary of the A vy yellow mouse (7).…”

Peripherally administered desacetyl α-MSH and α-MSH both influence postnatal rat growth and associated rat hypothalamic protein expression

“…NH 2 -terminal acetylation of desacetyl ␣-MSH to form ␣-MSH occurs in secretory vesicles just prior to exocytosis (42,66), but not all desacetyl ␣-MSH is acetylated, since desacetyl ␣-MSH is present in the circulation and brain of rodents and humans. The major form of plasma immunoreactive MSH is ␣-MSH in rodents and desacetyl ␣-MSH in humans (22,40), and the relative abundance of these two MSH peptides is developmentally regulated (11,23). Desacetyl ␣-MSH predominates in rodent and human brains and fetuses (23,54).…”