FSH isoforms: bio and immuno‐activities in post‐menopausal and normal menstruating women

Creus, Silvina; Pellizzari, Eliana Herminia; Cigorraga, Selva Beatriz; Campo, Stella

doi:10.1046/j.1365-2265.1996.646467.x

Cited by 31 publications

(25 citation statements)

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“…Less acidic isoforms, which presumably possess relatively low amounts of sialic acid residues and greater amounts of high mannose-and hybrid-type oligosaccharides (Creus et al 1996), exhibited a greater capability to induce expression of cytochrome P450 arom mRNA and tPA mRNA and protein than the variants bearing more complex, highly sialylated oligosaccharides. The mechanism(s) subserving these differences in potency among the isoforms is uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…The main difference among the various isoforms is caused by charge, which in FSH is mainly determined by its content in terminal sialic acid residues (Chappel et al 1983, Baenzinger & Green 1988, Ulloa-Aguirre et al 1995, although differences in nonterminal carbohydrates also play an important role in determining the heterogenous nature of the several members of the glycoprotein hormone family (Ulloa-Aguirre et al 1988b, Papandreou et al 1993, Creus et al 1996. We and others have found that the receptor binding activity of the intrapituitary FSH isoforms varies depending on the charge of the isoform (Stanton et al 1992, Ulloa-Aguirre et al 1992, Yding Andersen et al 1999.…”

Section: Discussionmentioning

confidence: 99%

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Differential effects of the charge variants of human follicle-stimulating hormone

Timossi¹,

Barrios-De-Tomasi²,

González-Suárez³

et al. 2000

Journal of Endocrinology

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FSH is synthesized and secreted by the anterior pituitary gland in multiple molecular forms; the release of these isoforms depends on the endocrine status of the donor at the time of sample collection. In the present study, we analysed the possibility that the FSH charge isoforms may exert differential effects at the target cell. Seven FSH isoform mixes were isolated from pooled anterior pituitary glycoprotein extracts by high resolution chromatofocusing, followed by affinity chromatography, which removed nearly 90% of the LH that co-eluted with the FSH isoforms during chromatofocusing. The isoforms (isoform I, pH >7·10; II, pH range 6·60-6·20; III, pH 5·47-5·10; IV, pH 5·03-4·60; V, pH 4·76-4·12; VI, pH 4·05-3·82 and VII, pH <3·80) were then tested for their capacity to stimulate cAMP release, androgen aromatization and tissue-type plasminogen activator (tPA) enzyme activity and cytochrome P450 aromatase, tPA and inhibin -subunit mRNA production by rat granulosa cells in culture. cAMP and oestradiol production were determined by RIA, tPA enzyme activity by SDS-PAGE and zymography and all mRNAs by northern blot hybridization analysis and semiquantitative RT-PCR. All isoforms, with the exception of isoform I, stimulated synthesis and release of cAMP, oestrogen and tPA enzyme activity in a dosedependent manner; the potency of the less acidic isoforms (pH 6·60-4·60) was greater than that exhibited by the more acidic/sialylated analogs (pH 4·76 to <3·80; potencies II>III>IV>V>VII>VI). A similar trend was observed in terms of cytochrome P450 aromatase and tPA mRNA production. In contrast, when FSH-stimulated production of -inhibin mRNA was analysed, isoforms V-VII were significantly more potent (two-to threefold) than the less acidic/sialylated counterparts (II-IV). In contrast to isoforms II-VII (which behaved as FSH agonists), isoform I (elution pH >7·10) completely blocked P450 aromatase and tPA mRNA expression, without altering that of a constitutively expressed gene (glyceraldehyde-3-phosphate dehydrogenase). These results show for the first time that the naturally occurring human FSH isoforms may exhibit differential or even unique effects at the target cell level.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential effects of the charge variants of human follicle-stimulating hormone

Timossi¹,

Barrios-De-Tomasi²,

González-Suárez³

et al. 2000

Journal of Endocrinology

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“…In previous studies, we found that it was the relative proportion of these two types of glycosylation variants that were more affected by changes in ovarian cyclicity and ageing in normal women. FSH glycoforms, bearing triantennary and bisecting oligosaccharides, circulate in the follicular phase of the normal menstrual cycle, when a fully functional gonad is present; however, they are absent in postmenopausal women (Creus et al 1996, Velasquez et al 2006. During the perimenopause, there is a relative decrease in circulating FSH glycoforms bearing triantennary and bisecting oligosaccharides, concomitantly with the appearance of a small proportion of glycosylation variants bearing high mannose and hybrid-type oligosaccharides (Loreti et al 2009).…”

Section: Distribution Profile Of Native Rhfsh Glycoforms After Concanmentioning

confidence: 99%

“…The presence of N-acetylglucosamine residues, frequently present in glycoproteins bearing biantennary and truncated carbohydrate chains, considerably weakens binding to the lectin, weakly bound fraction: WB (Goldstein et al 1965). The technique described by Narasimhan et al (1979), modified by Cheng et al (1984) and Creus et al (1996), was employed. Briefly, equilibrium buffer (50 mm Tris-HCl; pH 7.4, 0.5 M NaCl, 1 mM MgCl 2 , 1 mM CaCl 2 , and 1 mM MnCl 2 ) was used to elute unbound rhFSH glycoforms (rhFSH-UB); equilibrium buffer containing 10 mM methyl-a-D-glucopyranoside (glucoside) was used to elute the weakly bound rhFSH glycoforms (rhFSH-WB) and equilibrium buffer containing 0.1 M methyl-a-D-mannopyranoside (mannoside) was used to elute the firmly bound rhFSH glycoforms (rhFSH-FB).…”

Section: Cona Chromatographymentioning

confidence: 99%

Effect of sialylation and complexity of FSH oligosaccharides on inhibin production by granulosa cells

Loreti¹,

Ambao²,

Andreone³

et al. 2013

Reproduction

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Granulosa cell (GC) inhibin A and B production is regulated by FSH and gonadal factors. This gonadotrophin is released as a mixture of glycoforms, which induce different biological responses in vivo and in vitro. Our aim was to determine the effect of recombinant human FSH (rhFSH) glycosylation variants on inhibin A and B production by rat GCs. Preparative isoelectro focusing was used to isolate more acidic/sialylated (pH !4.00) and less acidic/sialylated (pH O5.00) rhFSH charge analogues. Concanavalin A was used to isolate unbound and firmly bound rhFSH glycoforms on the basis of their oligosaccharide complexity. GCs, obtained from oestrogen-primed immature rats, were cultured with either native rhFSH or its glycosylation variants. Inhibin A and B were determined using specific ELISAs. Results were expressed as meanGS.E.M. Under basal conditions, inhibin A was the predominant dimer produced (inhibin A: 673G55; inhibin B: 80G4 pg/ml). More acidic/sialylated charge analogues stimulated inhibin B production when compared to inhibin A at all doses studied; by contrast, less acidic/sialylated charge analogues stimulated inhibin A production and elicited no effect on inhibin B. Glycoforms bearing complex oligosaccharides showed a potent stimulatory effect on inhibin B when compared to inhibin A production (i.e. dose 1 ng/ml: 4.9G0.5 vs 0.9G0.1-fold stimulation, P!0.001). Glycoforms bearing hybrid-type oligosaccharides favoured inhibin A production (i.e. dose 4 ng/ml 2.9G0.1 vs 1.6G0.1-fold stimulation, P!0.05). These results show that the sialylation degree as well as the complexity of oligosaccharides present in the rhFSH molecule may be considered additional factors that differentially regulate dimeric inhibin production by rat GCs.

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“…FSH is encoded by a single gene, but the pituitary is capable of making more than 17 different isoforms of FSH through post-translational modifications (14). Alteration of the carbohydrate sulfonation and sialylation patterns can lower the pH of the protein and increase the half-life of the isoform.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of native and hyperglycosylated follicle-stimulating hormone analogs for promoting fertility in female mice

Trousdale

Pollak

et al. 2009

Fertility and Sterility

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Objective-To compare the efficacy of recombinant human follicle stimulating hormone (rhFSH), to rhFSH with 4 additional O-linked carbohydrates (rhFSH-CTP), rhFSH with 4 additional N-linked carbohydrates (rhFSH-N4) and the current gold-standard for rodent ovarian stimulation, pregnant mare serum gonadotropin (PMSG), on fertility parameters in mice. Design-Animal Study Setting-Academic Research CenterSubjects-Adult C57Bl/6J female mice Interventions-Ovarian stimulation with 5IUof rhFSH, rhFSH-CTP, rhFSH-N4 or PMSG. 46 hours later 5IU of hCG was injected to promote ovulation then females were mated overnight. Main Outcome Measures-Eggs retrieved following ovulation, in vitro embryo development, delivery rate, litter sizeResults-Hyperglycosylated FSH analogues, rhFSH-CTP and rhFSH-N4, enhanced egg ovulation and embryo maturation significantly better than rhFSH. RhFSH-N4 produced more eggs (28.5±1.9 per mouse) and embryos (17.8±1.6) compared to rhFSH-CTP (18.3±1.2 and 9.0±1.0, respectively). Treatment with rhFSH, rhFSH-N4 and PMSG produced statistically equivalent delivery rates and

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FSH isoforms: bio and immuno‐activities in post‐menopausal and normal menstruating women

Cited by 31 publications

References 0 publications

Differential effects of the charge variants of human follicle-stimulating hormone

Differential effects of the charge variants of human follicle-stimulating hormone

Effect of sialylation and complexity of FSH oligosaccharides on inhibin production by granulosa cells

Efficacy of native and hyperglycosylated follicle-stimulating hormone analogs for promoting fertility in female mice

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