Naturally Occurring Antihormones: Secretion of FSH Antagonists by Women Treated with a GnRH Analog

Dahl, Kristine D.; Bicsak, Thomas A.; Hsueh, Aaron J. W.

doi:10.1126/science.3122320

Cited by 116 publications

(32 citation statements)

References 26 publications

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“…the ratio of tetraantennary versus biantennary oligosaccharides, is also positively correlated with the in vivo activity of recombinant human erythropoietin (Takeuchi et al 1989). The formation of follicle-stimulating hormone (FSH) antagonistic "glycoforms" that are devoid of bioactivity but capable of binding to receptors (Dahl et al 1988) clearly demonstrates the regulation by glycosylation of the bioactivity of glycoproteins that interact with cell-bound receptors. Glycosylation of hormone receptors may also regulate the binding of their ligands, as was shown for the insulin receptor (Podskalny et al 1986).…”

Section: Discussionmentioning

confidence: 95%

Petunia hybrida S-proteins: ribonuclease activity and the role of their glycan side chains in self-incompatibility

Broothaerts

Vanvinckenroye

Decock

et al. 1991

Sexual Plant Reprod

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Summary. Self-incompatibility in flowering plants is controlled by the S-gene, encoding stylar S (allele-specific) glycoproteins. In addition to three previously characterized Petunia hybrida S-proteins, we identified by N-terminal sequence analysis another stylar S-protein, cosegregating with the Sb-allele. Purified S-proteins reveal biological activity, as is demonstrated for two of them by the allele-specific inhibition of pollen tube growth in vitro. Moreover, the four isolated S-proteins are ribonucleases (S-RNases). Specific activities vary from 30 ($1) to 1000 (82) units per min per mg protein. We attempted to investigate the functionality of the carbohydrate portion of the S-RNases. Deglycosylation studies with the enzyme peptide-N-glycosidase F (PNGase F) reveals differences in the number of N-linked glycan chains present on the four S-RNases. Variability in the extent of glycosylation accounts for most of the molecular weight differences observed among these proteins. By amino acid sequencing, the positions of two of the three N-glycosylation sites on the S2-RNase could be located near the N-terminus. Enzymic removal of the glycan side chains has no effect on the RNase activity of native S-RNases. This suggests another role of the glycan moiety in the self-incompatibility mechanism.

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Section: Discussionmentioning

confidence: 95%

Petunia hybrida S-proteins: ribonuclease activity and the role of their glycan side chains in self-incompatibility

Broothaerts

Vanvinckenroye

Decock

et al. 1991

Sexual Plant Reprod

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“…Although this isoform was identified in those fractions that flew from the column unrestricted and thus its exact pH value could not be determined, previous studies performed on a similar less acidic isoform also exhibiting FSH antagonist properties but recovered from the serum of GnRH antagonist- treated hypogonadal women, have revealed that this particular FSH charge isoform may in fact be composed by at least 3 components with more basic elution pH values (9.6–9.4) [9]. Furthermore, recent lectin-binding studies have indicated that this FSH isoform bears more high mannose- and hybrid-type oligosaccharides thus indicating that, unlike other FSH antagonist isoforms [30, 33], it is not a completely deglycosylated isoform but rather an underglycosylated variant [34].…”

Section: Discussionmentioning

confidence: 99%

“…The means of this abnormal production of basic FSH isoforms in terms of FSH-induced in vivo functions and whether it is the cause or consequence of this patient’s infertility is a matter of speculation at this time. Further support for the possibility that this naturally occurring FSH antagonist may be produced and secreted by the pituitary gland during certain conditions comes from the finding that hypogonadal women treated with GnRH antagonist may exhibit circulating immunoreactive FSH isoforms that are devoid of bioactivity but are otherwise capable of blocking FSH action in ovarian granulosa cells [9]. …”

Section: Discussionmentioning

confidence: 99%

“…In the rat assay, the in vitro biopotency of this isoform was intermediate between those of the less and more acidic analogs whereas in the human assay it exhibited the highest in vitro biopotency [8]. The present study was conducted to further characterize the biological properties of this particular isoform which has been detected in abnormally high concentrations in some hypogonadal women [9, 10] and whose relative abundance in the circulation changes throughout the normal menstrual cycle [3, 11]. Since this isoform coelutes with extremely high quantities of luteinizing hormone (LH) in the CF procedure employed to fractionate the different FSH isoforms (fig.…”

Section: Introductionmentioning

confidence: 99%

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A Naturally Occurring Basically Charged Human Follicle-Stimulating Hormone (FSH) Variant Inhibits FSH-Induced Androgen Aromatization and Tissue-Type Plasminogen Activator Enzyme Activity in vitro

et al. 1998

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It is well known that deglycosylation of gonadotropins by enzymatic or chemical procedures or by deletion of sites for N-linked glycosylation produces antagonistic analogs which are able to interact strongly with the receptor and to inhibit binding of the wild-type hormone. In the present study, we analyzed the antagonistic properties of a naturally occurring basic follicle-stimulating hormone (FSH) charge isoform obtained after high-resolution chromatofocusing of human anterior pituitary glycoprotein extracts. Coincubation of increasing amounts of this isoform with a highly purified human pituitary FSH preparation or with recombinant human FSH at doses equivalent to their corresponding ED₅₀ for estradiol and tissue-type plasminogen activator (tPA) production, inhibited FSH-induced estrogen production and tPA enzyme activity by cultured rat granulosa cells in a dose-dependent manner. These inhibitory effects were apparently exerted at steps following 3′,5′-cyclic adenosine monophosphate (cAMP) formation and did not involve activation of the protein kinase C pathway since: (a) at low doses, this basic FSH isoform moderately increased FSH-induced cAMP production by cultured rat granulosa cells; (b) coincubation of the antagonist isoform with dibutyryl cAMP completely inhibited the effects of this cAMP analog on estrogen and tPA production; (c) the isoform was able to stimulate production of cAMP in a human fetal cell line expressing the recombinant human FSH receptor, and (d) the inhibitory effects of the isoform were not affected by staurosporine, a protein kinase C inhibitor. The effects of this isoform upon dibutyryl cAMP-induced estrogen and tPA production were blocked by the addition of a highly specific antibody directed against human FSH, further demonstrating that the antagonistic effects observed were due to FSH-like molecules. In contrast to the inhibitory effects exhibited by this basic FSH isoform, a more acidic FSH charge variant consistently acted as an agonist of pituitary and recombinant FSH on both estrogen production and induction of tPA enzyme activity. These results indicate that the anterior pituitary gland normally produces FSH isoforms which act as either agonists or antagonists of FSH at the target cell level.

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“…It is not known whether the FSH molecule secreted in the GnRH antagonist treated and/or steroid treated rats, in the present investigation, was bioactive. In women it has been reported that GnRH an tagonist treatment suppressed serum FSH bioactivity more than immunoactivity [7].…”

Section: Discussionmentioning

confidence: 99%

Testosterone and Dihydrotestosterone, but Not Estradiol, Selectively Maintain Pituitary and Serum Follicle-Stimulating Hormone in Gonadotropin-Releasing Hormone Antagonist Treated Male Rats

Arslan

Weinbauer²,

Khan³

et al. 1989

Neuroendocrinology

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Recently it has been found that testosterone can maintain and restimulate serum and pituitary follicle-stimulating hormone (FSH) in the gonadotropin-releasing hormone (GnRH) antagonist treated adult male rat. The present investigation was undertaken to determine (1) which metabolite of testosterone, dihydrotestosterone (DHT), or estradiol accounts for the effects of testosterone in GnRH antagonist suppressed rats and (2) whether these effects of testosterone are influenced by other testicular factors. Eight groups of 6–8 adult male Sprague-Dawley rats were subjected to the following treatments: vehicle, GnRH antagonist (75 µg/day s.c), testosterone-filled Silastic implants (3 × 5 cm, s.c), DHT-filled Silastic implants (3 × 5 cm, s.c), estradiol ben-zoate (15 µg/day s.c), and combined administration of GnRH antagonist with either steroid. In addition, the GnRH antagonist/ testosterone treatment regimen was applied to rats orchidectomized 72 h prior to initiation of treatments. After 3 weeks of treatment, serum was analyzed for concentrations of luteinizing-hormone (LH), FSH, testosterone, DHT, and estradiol. Pituitary extracts were analyzed for LH and FSH content. Except for the vehicle-treated groups, serum and pituitary LH concentrations were markedly suppressed by all treatments. In intact rats treated with GnRH antagonist alone and/or estradiol, the pituitary FSH level was reduced by more than 70% relative to controls, while both testosterone and DHT maintained pituitary FSH. Similarly, testosterone and DHT, but not estradiol, delayed the decline of serum FSH induced with GnRH antagonist alone. In orchidectomized animals, testosterone was also capable of preventing a reduction of pituitary FSH despite concomitant GnRH antagonist administration. It is concluded that testosterone and DHT selectively maintain FSH in the GnRH antagonist treated male rat. This paradoxical stimulation of FSH occurs in the absence of other testicular factors.

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Naturally Occurring Antihormones: Secretion of FSH Antagonists by Women Treated with a GnRH Analog

Cited by 116 publications

References 26 publications

Petunia hybrida S-proteins: ribonuclease activity and the role of their glycan side chains in self-incompatibility

Petunia hybrida S-proteins: ribonuclease activity and the role of their glycan side chains in self-incompatibility

A Naturally Occurring Basically Charged Human Follicle-Stimulating Hormone (FSH) Variant Inhibits FSH-Induced Androgen Aromatization and Tissue-Type Plasminogen Activator Enzyme Activity in vitro

Testosterone and Dihydrotestosterone, but Not Estradiol, Selectively Maintain Pituitary and Serum Follicle-Stimulating Hormone in Gonadotropin-Releasing Hormone Antagonist Treated Male Rats

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