Letter to the editor |
Total and active ghrelin levels in women with polycystic ovary syndrome
Department of Obstetrics and Gynaecology, San Martino Hospital and University of Genoa, Largo R.Benzi 1, 16132 Genoa, Italy
1 To whom correspondence should be addressed. E-mail: simone.ferrero{at}fastwebnet.it
Sir,
We read with interest the recent manuscript by Panidis et al. (2005)
determining the correlation of ghrelin with the metabolic and hormonal features of women with polycystic ovary syndrome (PCOS). Although the investigators should be congratulated for their observations on a large group of PCOS patients, we would like to bring to your attention some issues concerning the measurement and structural characteristics of ghrelin.
Although the authors correctly described ghrelin activities, they did not clarify that ghrelin requires post-translational n-octanoylation of the Ser 3-hydroxyl group for its activity (Kojima et al., 1999; Hosoda et al., 2000a). This acylation enables the binding to type 1a growth hormone (GH) secretagogue receptor that is essential for the biological functions of the hormone (Kojima et al., 1999). Non-octanoylated ghrelin does not activate type 1a GH secretagogue receptor (Bednarek et al., 2000; Hosoda et al., 2000b), and it is presumed to be inactive (Kojima et al., 1999).
Importantly, Panidis et al. used a polyclonal antibody (Phoenix Pharmaceuticals Inc., Belmond, CA, USA) to measure plasma ghrelin levels; this antibody does not distinguish octanoylated and non-octanoylated ghrelin, and, as a consequence, the total ghrelin level was measured.
Although the same enzyme-linked immunosorbent assay was previously used in other studies evaluating ghrelin levels in women with PCOS (Pagotto et al., 2002; Orio et al., 2003; Wasko et al., 2004), it should be noted that a monoclonal antibody specific for the active form of ghrelin (with the octanoyl group on serine 3) is now commercially available (Linco Research, St Charles, MO, USA).
Plasma inactive ghrelin (without the n-octanoyl modification) accounts for >90% of total circulating ghrelin and the ratio of inactive to active ghrelin can be modified under some physiological or pathological conditions (Ariyasu et al., 2002). Some precautions are required when the active form of ghrelin is measured, because it is very unstable and labile in plasma. Blood samples should be collected with EDTA–aprotinin and centrifuged as quickly as possible after blood is withdrawn; in addition, the plasma should be acidified to stabilize the n-octanoyl modification of the serine residue and prevent a rapid desacylation of ghrelin (Hosoda et al., 2004).
Measuring the levels of both total ghrelin and active ghrelin may improve our understanding of the role of this molecule in women with PCOS.
References
Ariyasu H, Takaya K, Hosoda H, Iwakura H, Ebihara K, Mori K, Ogawa Y, Hosoda K, Akamizu T, Kojima M et al (2002) Delayed short-term secretory regulation of ghrelin in obese animals: evidenced by a specific RIA for the active form of ghrelin. Endocrinology 143,3341–3350.
Bednarek MA, Feighner SD, Pong SS, McKee KK, Hreniuk DL, Silva MV, Warren VA, Howard AD, Van Der Ploeg LH and Heck JV (2000) Structure–function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 43,4370–4376.[CrossRef][Web of Science][Medline]
Hosoda H, Kojima M, Matsuo H and Kangawa K (2000a) Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 275,21995–22000.
Hosoda H, Kojima M, Matsuo H and Kangawa K (2000b) Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 279,909–913.[CrossRef][Web of Science][Medline]
Hosoda H, Doi K, Nagaya N, Okumura H, Nakagawa E, Enomoto M, Ono F and Kangawa K (2004) Optimum collection and storage conditions for ghrelin measurements: octanoyl modification of ghrelin is rapidly hydrolyzed to desacyl ghrelin in blood samples. Clin Chem 50,1077–1080.
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H and Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402,656–660.[CrossRef][Medline]
Orio F Jr, Lucidi P, Palomba S, Tauchmanova L, Cascella T, Russo T, Zullo F, Colao A, Lombardi G and De Feo P (2003) Circulating ghrelin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab 88,942–945.[Abstract]
Pagotto U, Gambineri A, Vicennati V, Heiman ML, Tschop M and Pasquali R (2002) Plasma ghrelin, obesity, and the polycystic ovary syndrome: correlation with insulin resistance and androgen levels. J Clin Endocrinol Metab 87,5625–5629.
Panidis D, Farmakiotis D, Koliakos G, Rousso D, Kourtis A, Katsikis I, Asteriadis C, Karayannis V and Diamanti-Kandarakis E (2005) Comparative study of plasma ghrelin levels in women with polycystic ovary syndrome, in hyperandrogenic women and in normal controls. Hum Reprod, 20,2127–2132.
Wasko R, Komarowska H, Warenik-Szymankiewicz A and Sowinski J (2004) Elevated ghrelin plasma levels in patients with polycystic ovary syndrome. Horm Metab Res 36,170–173.[CrossRef][Web of Science][Medline]
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