Assessment of the in vitro and in vivo biological activities of the human follicle-stimulating isohormones

Barrios-De-Tomasi, Jorgelina; Timossi, Carlos; Merchant, Hugo; Quintanar, Andres; Avalos, Javier; Andersen, Claus Yding; Ulloa‐Aguirre, Alfredo

doi:10.1016/s0303-7207(01)00657-8

Cited by 75 publications

(56 citation statements)

References 33 publications

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“…In vivo glycosylation has been shown to alter the stability, intracellular transport, secretion, distribution, and overall activity of a variety of proteins (Hilgenfeldt, 1988;Mann et al, 1996;Gimenez-Roqueplo et al, 1998;Barrios-De-Tomasi et al, 2002). We, along with others, have hypothesized that glycosylation of smaller peptides may have desirable effects on the pharmacokinetic and/or pharmacodynamic properties of the parent peptide (Albert et al, 1993;Polt et al, 1994;Negri et al, 1998;Susaki et al, 1999;Suzuki et al, 1999a,b;Bilsky et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…The glycoprotein follicle-stimulating hormone (FSH), for example, has multiple glycosylation sites and exists as a family of isoforms that differ with respect to their oligosaccharide structure (Ulloa-Aguirre et al, 1995;Stanton et al, 1996). The isoforms can differ substantially with respect to their in vitro and in vivo potency and efficacy (Barrios-De-Tomasi et al, 2002). These observations have led to the modification of human FSH and other glycoproteins in an effort to improve pharmacokinetic properties while maintaining optimal activity.…”

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confidence: 99%

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Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Elmagbari¹,

Egleton²,

Palian³

et al. 2004

J Pharmacol Exp Ther

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Development of opioid peptides as therapeutic agents has historically been limited due to pharmacokinetic issues including stability and blood-brain barrier (BBB) permeability. Glycosylation of opioid peptides can increase peptide serum stability and BBB penetration. To further define the requirements for optimizing in vivo antinociceptive potency following intravenous administration, we synthesized a series of enkephalin-based glycopeptides using solid phase 9-fluorenylmethyloxy carbamate methods. The compounds differed in the sixth and subsequent amino acid residues (Ser or Thr) and in the attached carbohydrate moiety. In vitro binding and functional smooth muscle bioassays indicated that the addition of mono-or disaccharides did not significantly affect the opioid receptor affinity or agonist activity of the glycopeptides compared with their unglycosylated parent peptides. All of the glycopeptides tested produced potent antinociceptive effects in male ICR mice following intracerebroventricular injection in the 55°C tail-flick test. The calculated A 50 values for the Ser/Thr and monosaccharide combinations were all very similar with values ranging from 0.02 to 0.09 nmol. Selected compounds were administered to mice intravenously and tested for antinociception to indirectly assess serum stability and BBB penetration. All compounds tested produced full antinociceptive effects with calculated A 50 values ranging from 2.2 to 46.4 mol/kg with the disaccharides having potencies that equaled or exceeded that of morphine on a micromoles per kilogram basis. Substitution of a trisaccharide or bis-and tris-monosaccharides resulted in a decrease in antinociceptive potency. These results provide additional support for the utility of glycosylation to increase central nervous system bioavailability of small peptides and compliment our ongoing stability and blood-brain barrier penetration studies.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Elmagbari¹,

Egleton²,

Palian³

et al. 2004

J Pharmacol Exp Ther

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“…The more basic isoforms are recombinant molecules that demonstrate higher receptor binding affinity and higher biopotency in vivo than the more acidic isoforms. [5][6][7] This difference in charge enables separation of isoforms using techniques such as isoelectric focusing. The isoelectric point (pI) is the pH at which the protein has no net charge; it is high for basic proteins and low for acidic proteins.…”

Section: Fsh Heterogeneitymentioning

confidence: 99%

“…6 Experiments employing a human embryonic kidney-derived cell line transfected with human FSH receptor cDNA suggest that in homologous cell systems, FSH bioactivity may also be influenced by factors other than receptorbinding affinity, such as media half life; more acidic isoforms show a longer half-life than more basic isoforms.…”

Section: 11mentioning

confidence: 99%

What is the Clinical Relevance of Follicle-Stimulating Hormone Isoforms in Fertility Treatment?

Andersen

Ezcurra²

2011

Reproductive Biology Insights

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Follicle-stimulating hormone, both naturally synthesized and as commercial preparations, exists as different isoforms. Variation in the process of glycosylation, particularly in the number of terminal sialic-acid residues, gives rise to isoforms of varying acidic profiles with differences in half-life and bioactivity. Based on the known follicle-stimulating hormone isoform variation across the reproductive cycle, it is possible that the follicle-stimulating hormone isoform profile used in controlled ovarian stimulation may impact follicular recruitment and clinical treatment outcomes. In light of the uncertainty regarding the clinical relevance of folliclestimulating hormone isoforms in fertility treatment, published studies exploring this topic are reviewed.

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“…Elevation of estradiol levels is essential for the induction of the preovulatory LH surge in proestrous. Induction of cytochrome P450 aromatase (CYP19) mRNA, the key enzyme that catalyzes the final rate-limiting step in the biosynthesis of estradiol from androgen, is characteristic of a mature follicle (7,8). Moreover, the regulation of CYP19 gene expression is related to follicular development in rat GC (9,10).…”

Section: Introductionmentioning

confidence: 99%

Effect of Thyroid Hormone on CYP19 Expression in Ovarian Granulosa Cells From Gonadotropin-Treated Immature Rats

et al. 2004

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Abstract. The present study was designed to determine the mechanisms by which serum estradiol levels are enhanced during gonadotropin-induced ovarian development in hypothyroid immature rats. Thyroidectomized (Tx)-immature rats receiving thyroidectomy on day 22 were treated with 8 IU equine chorionic gonadotropin (eCG) at 26 days of age to induce follicular development in ovaries. Ovaries or ovarian granulosa cells were collected on the first proestrus (day 28). Enhanced expression of aromatase (CYP19) mRNA induced by eCG treatment was inhibited by injection of thyroxine (T 4 : 5 m g´6 times) in Tx rats. Ovarian granulosa cells harvested from Tx rats were cultured for 24 h in chemically defined serum-free medium containing gonadotropin in the presence of 3,5,3'-triidothyronine (T 3 ). Addition of low doses of T 3 (10 -8 , 10 -7 M) to the medium significantly decreased 17b-estradiol (E 2 ) levels, whereas high doses of T 3 (10 -6 , 10 -5 M) did not inhibit the levels. Similar effects of T 3 on CYP19 mRNA expression were observed. These results indicate that augmentation of E 2 production in hypothyroid animals may be mediated, in part, via the stimulation of CYP19 mRNA expression in granulosa cells, which is suppressed by thyroid hormone.

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Assessment of the in vitro and in vivo biological activities of the human follicle-stimulating isohormones

Cited by 75 publications

References 33 publications

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

What is the Clinical Relevance of Follicle-Stimulating Hormone Isoforms in Fertility Treatment?

Effect of Thyroid Hormone on CYP19 Expression in Ovarian Granulosa Cells From Gonadotropin-Treated Immature Rats

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