Carbohydrate-targeted optimization of therapeutic gonadotropins - Carbohydrate Chemistry: Chemical and Biological Approaches - page 473

Regarding terminal glycosylation, FSH glycoforms with terminal
GalNAc-sulfate residues display shorter half-lives than those without. 103
Various studies showed that the less acidic isoforms have a faster
clearance from the circulation. 104-107 Moreover, minor hFSH isoforms
were identified which possess no glycosylation on their b-subunit, are
associated with less acidic isoforms and rapid clearance. 108 Conversely
acidic glycoforms of pituitary FSH consistently exhibit lower in vitro
activity than less acidic forms 104,109,110 but acidic glycoforms display
higher in vivo activity. 104,105,107 All together, these results clearly indicate
that the circulatory half-life and activity of FSH molecule is governed by
the presence of acidic sialylated glycoforms. In this respect, clinical trials
with two different preparations of recombinant FSH (Puregon s and
Gonal-F s ) have demonstrated higher ecacy at achieving pregnancy
than urinary FSH. 70,111-115
Even if recombinant hormones satisfactorily stimulate ovarian
response, there is a general expectation that availability of individualized
glycoforms would allow a more physiological approach to assisted
reproduction by mimicking the natural follicle maturation process. At
present, it is believed that optimal treatment may start with long acting
FSH to recruit a large crop of follicles, to continue with short-lived less
acidic isoforms to achieve optimal maturation and growth of the follicles.
It can be further argued that using a more physiological set of FSH
glycoforms will result in a smaller number but more ''naturally'' matured
oocytes of high quality capable of developing into better quality embryos
and leading to a higher ''take-home baby'' rate.
5.2 LH
Enzymatic removal of N-glycans did not decrease in vitro activity of LH. 116
LH molecules with GalNAc-sulfate ended glycans are more rapidly
cleared from the circulation 96,103 than sialylated glycoforms which cul-
minate at the mid cycle ovulatory peak. 103 Interestingly, a common
genetic variant form of LH contains an extraglycosylation site on b-Asn13
and displays a 40% increase in half- life based on a higher content in
sialic acid. 117 Clinical implications of LH glycoforms have been reported
to include a higher frequency of reproductive disorders in women in-
cluding unexplained infertility, ovulatory disorders, and premature
ovarian failure. 118,119 Pulsatile exposure to LH is essential for the control
of ovulation and luteinization of follicular cells and it has been suggested
that the longer half-life of LH will decrease of the amplitude of hormone
pulses and disturb ovarian functions. 117 Sialic acid in the b-Asn30 linked
glycan appears to be responsible for the superactivity in in vitro
bioactivity test. 120
5.3 hCG
Both hCG and LH binds a common receptor, the LH/hCG receptor.
The major difference between LH and hCG is that LH is a basic protein
(pI 8.0) with a circulating half-life of 25-30 minutes 121 while hCG is an
acidic protein (pI 3.5) with a circulating half-life of approximately
15 hours. 122 Numerous investigations have shown that truncation as well