The liver has been shown to bind glycoproteins through its hepatocyte asialoglycoprotein receptor by recognizing terminal Gal residues after removal of sialic acid from their SiaAc-Gal-GlcNAc-Man complex carbohydrate chains. In contrast to FSH and CG, LH from different species bear very low amounts of sialic acid and bear sulfated-GalNAc-GlcNac-Man instead. Specific receptors for this type of chain has been described in liver  and they have been proposed to be responsible for the very fast elimination of pituitary native LH compared to the sialylated recombinant LH produced in CHO cells.
Native pituitary LH from various species disappear rapidly from the circulation and their t1/2 during this first phase of elimination have been found to be approximately 15 min for hLH in the human [17, 18] and as low as low as 1.2 min for bovine LH in the rat . In agreement with these previous data, we found that the initial phase of elimination of porcine LH from the circulation in the pig and rat is extremely fast. In pig, a half-life (t1/2) of less than 5 minutes was observed for pLH despite we injected the hormone in arteria to avoid hepatic first-pass effect. Since pLH is the homologous hormone, it is likely that this low t1/2 value is meaningful. We expected that the elimination of injected pLH would be slower when hepatic portal circulation was totally derived to vena cava and jugular vein since receptors for sulfated-GalNAc-GlcNac-Man are present in the liver . To our surprise, we found that the initial phase of pLH elimination was not significantly changed by liver shunt and its t1/2 value remained at 5 minutes.
In rat, the t1/2 of pituitary pLH determined by ELISA after bolus injection (6 min) is quite similar to that found in pig (5 min) and in rat as in pig, eCG did not exhibit any fast elimination phase. The similarity of t1/2 of pLH in pig and rat prompted us to determine more precisely the route of fast elimination of pLH in the rat which is more amenable to scintigraphic imaging than the pig.
Only about one molecule out of 1000 is radioiodinated in 123I-pLH solution and thus radioactive molecules are most likely mono-iodinated on their tyrosine residue in position 21 of their α-subunit . The substitution of the Tyr α-21 residue of pLH by two cold iodine atoms leads to a moderate decrease in the in-vivo bioactivity of pLH in rats . The substitution by only one iodine atom is expected to have an even lower effect on pLH bioactivity indicating that its mono-iodination does not modify its rate of elimination and consequently does not change its route of elimination.
We determined the t1/2 of 123I-pLH by following its emission in blood at heart level making the assumption that there is no binding of LH in heart. The found t1/2 of 2.6 min is consistent with the values of 1.2 min for 125I-bLH  and 6.2 min for unlabeled pLH (this work) in the rat and confirms the very fast elimination of LH molecules from the circulation. The slightly lower t1/2 values obtained with radioiodinated LHs could arise from preferential iodination of basic isoforms which are known to exhibit shorter half-life than acidic isoforms. Alternatively, it could be that acidic isoforms are detected slightly more efficiently than basic ones in ELISA. In any case, 123I-pLH like native LH is rapidly eliminated from blood and scintigraphic imaging of its early distribution has permitted to localize its initial route of elimination.
After injection of 123I-pLH, emission was located in the stomach, intestine and thyroid only after 30 minutes p.i. This indicates that free iodine due to deiodination of the hormone, had no contribution during the initial 30-min period.
The most prominent observation in this study was that 123I-pLH was trapped very rapidly and very efficiently at the level of kidneys not the liver. Free 123I binding to stomach, gut and thyroid after radiolabeled hormone injections arose only after 30 min, much later than after Na123I injection. Since these sites are known sites for iodide binding , it is clear that the initial very fast binding at the kidneys is not due to 123I from radiolabeled pLH, but to the capture of 123I-pLH itself.
The rapid renal trapping of 123I-pLH observed in the present study is at variance with the hypothesis that LH is rapidly cleared from circulation by the sulfated-GalNAc-GlcNac-Man receptors of hepatic reticuloendothelial cells . By contrast, our data are in agreement with previous results  that showed an increase of the half-life of [3H-methyl]ovine LH in nephrectomized rats relative to intact rats. These authors also showed that LH accumulates in the renal cortex after glomerular filtration and is reabsorbed by tubular epithelia, with subsequent lysosomal catabolism. Half-life of LH had also been shown to increase in castrated nephrectomized rats and sheep [5, 6]. Altogether, our results and these data strongly support the view that kidneys play a major role in the fast clearance of LH. Interestingly, there was no significant transfer to urine in the bladder, at least over the first hour after injection. This puzzling observation suggests that LH is not simply filtrated by the glomerulus but must be linked to some binding sites. Bioactive forms of human LH and FSH are found in large quantities in the urine of post-menopausal women indicating that these gonadotropins are filtrated in the kidneys and pass to urine without extensive degradation. In this physiological situation, kidneys are faced to long-lasting presence of a large concentration of hormone and not to a single bolus of it. We thus suggest that the binding sites for LH in the kidney become saturated in post-menopausal women in the permanent presence of large concentrations of LH. In the near future, we will test this hypothesis in the rat model using the scintigraphic approach described here.
No LH/CG receptors have been reported in the kidney, at least in the human species . Binding of 125I-oLH to ovine kidney membrane fractions has been evidenced in vitro but, interestingly, it was not diminished in the presence of a large excess of cold LH (Combarnous Y, unpublished). Thus, this binding cannot be attributed to saturable high-affinity receptors, but rather to low-affinity high-capacity binding sites. Renotropic activity of oLH [24, 25] and pLH  has been reported and it has been proposed that a carbohydrate moiety of these gonadotropins containing a sulfate group is implicated in this activity . For the time being, the presence of binding site for sulfated carbohydrates has not been demonstrated in the kidney.
In the case of 123I-eCG, the activities measured in the liver and in the lungs were very similar. This indicates that the hormone can be detected in blood in highly vascularized organs without accumulation in a specific organ, explaining its well-known long half-life. We didn't find noticeable radioactivity in the genital tract for both hormones. The number of LH/CG receptors is known to be only 20 000 per Leydig cell  which might be unsufficient for efficient scintigraphic detection.
At the molecular level, it is now of interest to find out what are the structural features of the LH molecule, not present in eCG, that are responsible for its very fast trapping by kidneys. Since the carbohydrate moieties of glycoprotein hormones are known to play a prominent role in their pharmacokinetic properties, it will be of particular interest to perform a comparative scintigraphic study of eCG and eLH elimination. Indeed these two hormones are encoded by the same α and β genes and consequently their α and β polypeptide chains are identical. However, they are expressed in the pituitary or placenta respectively and bear very different carbohydrate chains. It has already been shown by Smith et al  that eLH has a much lower half-life than eCG and possess sulphated carbohydrate chains in contrast to eCG. These authors also found radioactive eLH mainly in the liver at the end of the 30 min-experiment but they did not study the kinetics of binding to the different organs at shorter times. It would be very interesting to see by scintigraphic imaging whether 123I-eLH like 123I-pLH is rapidly trapped by kidneys before it is by liver. Sulfated carbohydrate chains of pLH also bind to the Macrophage Mannose Receptor (MMR)  found not only in macrophages and dendritic cells but also in hepatic endothelial cells and kidney mesangial cells. It is thus of interest not only to determine the balance between the hepatic and renal routes for the elimination of the different gonadotropins from plasma at different times after injection but also to determine the respective roles of the membrane lectins (Gal asialoglycoprotein receptor of Ashwell, sulfated-GalNAc of Baenziger or MMR) involved in this process.