Oral follicle-stimulating hormone agonist tested in healthy young women of reproductive age failed to demonstrate effect on follicular development but affected thyroid function

Gerrits, Mireille; Kramer, Hester; Galta, Rachid El; Beerendonk, Geertje van; Hanssen, Rob; Abd‐Elaziz, Khalid; Klipping, Christine; Duijkers, Ingrid; Stoch, S. Aubrey

doi:10.1016/j.fertnstert.2015.12.017

Cited by 11 publications

(10 citation statements)

References 11 publications

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“…In addition, binding kinetic profiles of these small molecules may also shed light on the distinct endosomal signaling and trafficking properties of these ligands, although factors such as ligand potency and residency time can also poorly correlate with sustained endosomal signaling profiles of GPCRs where the environment of the lumen could facilitate rebinding of the ligand ( Sposini and Hanyaloglu, 2017 ). At least for LHR, the trafficking of rodent and human receptors is very different ( Nakamura et al, 2000 ; Hirakawa et al, 2003 ) and so far a clinical study of an FSHR LMW agonist failed to induce follicular development in healthy volunteers, although only low doses were assessed ( Gerrits et al, 2016 ). Given that the majority of the FSHR-induced acute cAMP signaling is endosomal, it is likely these early events would have key physiological functions.…”

Section: Discussionmentioning

confidence: 99%

“…Among glycoprotein receptors, most of the LMW allosteric compounds developed so far target FSHR; these include positive allosteric modulators ( Sriraman et al, 2014 ; Yu et al, 2014 ), negative allosteric modulators ( Dias et al, 2011 ; Dias et al, 2014 ) and allosteric agonists and antagonists ( Yanofsky et al, 2006 ; van Koppen et al, 2013 ). While pre-clinical studies in animal models for these LMW agonists showed promise, the only molecule that entered clinical development failed to demonstrate follicular development in healthy patients ( Gerrits et al, 2016 ). Given the recent advances in our understanding of GPCR signaling, including the requirement of these receptors to signal from distinct intracellular compartments, how such compounds engage mechanisms such as trafficking and endosomal signaling remains to be determined yet could offer a novel developmental avenue for the future application of such compounds.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Programming of Endosomal Signaling Activated by Small Molecule Ligands of the Follicle Stimulating Hormone Receptor

et al. 2020

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Follicle-stimulating hormone receptor (FSHR) is a G protein-coupled receptor (GPCR) with pivotal roles in reproduction. One key mechanism dictating the signal activity of GPCRs is membrane trafficking. After binding its hormone FSH, FSHR undergoes internalization to very early endosomes (VEEs) for its acute signaling and sorting to a rapid recycling pathway. The VEE is a heterogeneous compartment containing the Adaptor Protein Phosphotyrosine Interacting with Pleckstrin homology Domain and Leucine Zipper 1 (APPL1) with distinct functions in regulating endosomal Gαs/cAMP signaling and rapid recycling. Low molecular weight (LMW) allosteric FSHR ligands were developed for use in assisted reproductive technology yet could also provide novel pharmacological tools to study FSHR. Given the critical nature of receptor internalization and endosomal signaling for FSHR activity, we assessed whether these compounds exhibit differential abilities to alter receptor endosomal trafficking and signaling within the VEE. Two chemically distinct LMW agonists (benzamide, termed B3 and thiazolidinone, termed T1) were employed. T1 was able to induce a greater level of cAMP than FSH and B3. As cAMP signaling drives gonadotrophin hormone receptor recycling, rapid exocytic events were evaluated at single event resolution. Strikingly, T1 was able to induce a 3-fold increase in recycling events compared to FSH and two-fold more compared to B3. As T1-induced internalization was only marginally greater, the dramatic increase in recycling and cAMP signaling may be due to additional mechanisms. All compounds exhibited a similar requirement for receptor internalization to increase cAMP and proportion of FSHR endosomes with active Gαs, suggesting regulation of cAMP signaling induced by T1 may be altered. APPL1 plays a central role for GPCRs targeted to the VEE, and indeed, loss of APPL1 inhibited FSH-induced recycling and increased endosomal cAMP signaling. While T1-induced FSHR recycling was APPL1-dependent, its elevated cAMP signaling was only partially increased following APPL1 knockdown. Unexpectedly, B3 altered the dependence of FSHR to APPL1 in an opposing manner, whereby its endosomal signaling was negatively regulated by APPL1, while B3-induced FSHR recycling was APPL1-independent. Overall, FSHR allosteric compounds have the potential to re-program FSHR activity via altering engagement with VEE machinery and also suggests that these two distinct functions of APPL1 can potentially be selected pharmacologically.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacological Programming of Endosomal Signaling Activated by Small Molecule Ligands of the Follicle Stimulating Hormone Receptor

et al. 2020

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“…As a result of this, attempts to produce an oral drug for ovarian stimulation have focussed on FSH agonists. One oral FSH agonist has been evaluated in healthy females but no effect on follicular development was observed, which was eventually attributed to the low doses used (141). Non-conclusive data is available for this option nowadays.…”

Section: Oral Gonadotropinsmentioning

confidence: 99%

The Development of Gonadotropins for Clinical Use in the Treatment of Infertility

et al. 2019

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The first commercially available gonadotropin product was a human chorionic gonadotropin (hCG) extract, followed by animal pituitary gonadotropin extracts. These extracts were effective, leading to the introduction of the two-step protocol, which involved ovarian stimulation using animal gonadotropins followed by ovulation triggering using hCG. However, ovarian response to animal gonadotropins was maintained for only a short period of time due to immune recognition. This prompted the development of human pituitary gonadotropins; however, supply problems, the risk for Creutzfeld–Jakob disease, and the advent of recombinant technology eventually led to the withdrawal of human pituitary gonadotropin from the market. Urinary human menopausal gonadotropin (hMG) preparations were also produced, with subsequent improvements in purification techniques enabling development of products with standardized proportions of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) activity. In 1962 the first reported pregnancy following ovulation stimulation with hMG and ovulation induction with hCG was described, and this product was later established as part of the standard protocol for ART. Improvements in immunopurification techniques enabled the removal of LH from hMG preparations; however, unidentified urinary protein contaminants remained a problem. Subsequently, monoclonal FSH antibodies were used to produce a highly purified FSH preparation containing <0.1 IU of LH activity and <5% unidentified urinary proteins, enabling the formulation of smaller injection volumes that could be administered subcutaneously rather than intramuscularly. Ongoing issues with gonadotropins derived from urine donations, including batch-to-batch variability and a finite donor supply, were overcome by the development of recombinant gonadotropin products. The first recombinant human FSH molecules received marketing approvals in 1995 (follitropin alfa) and 1996 (follitropin beta). These had superior purity and a more homogenous glycosylation pattern compared with urinary or pituitary FSH. Subsequently recombinant versions of LH and hCG have been developed, and biosimilar versions of follitropin alfa have received marketing authorization. More recent developments include a recombinant FSH produced using a human cell line, and a long-acting FSH preparation. These state of the art products are administered subcutaneously via pen injection devices.

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“…This is in contrast to LHR LMW molecules which have been demonstrated to be efficacious in stimulating ovulation in women. One example is MK-8389 (developed by MSD) which had promising activity in a rat model but when tested in an ascending dose study on pituitary-suppressed females, showed an effect on thyroid function, despite no effect on follicular development, or estradiol production (64). Thus, further research endeavors are required to produce efficacious orally-active FSH LMW agonists as substitutes for multiple injections of conventional polypeptide FSH.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Small Molecule Follicle-Stimulating Hormone Receptor Agonists and Antagonists

2019

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The follicle-stimulating hormone receptor (FSHR) has been targeted therapeutically for decades, due to its pivotal role in reproduction. To date, only purified and recombinant/biosimilar FSH have been used to target FSHR in assisted reproduction, with the exception of corifollitropin alfa; a modified gonadotropin in which the FSH beta subunit is joined to the C-terminal peptide of the human choriogonadotropin beta subunit, to extend serum half-life. Assisted reproduction protocols usually entail the trauma of multiple injections of FSH to initiate and promote folliculogenesis, which has prompted the development of a number of orally-available low molecular weight (LMW) chemical scaffolds targeting the FSHR. Furthermore, the recently documented roles of the FSHR in diverse extragonadal tissues, including cancer, fat metabolism, and bone density regulation, has highlighted the potential utility of LMW modulators of FSHR activity. Despite these chemical scaffolds encompassing a spectrum of in vitro and in vivo activities and pharmacological profiles, none have yet reached the clinic. In this review we discuss the major chemical classes of LMW molecules targeting the FSHR, and document their activity profiles and current status of development, in addition to discussing potential clinical applications.

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Oral follicle-stimulating hormone agonist tested in healthy young women of reproductive age failed to demonstrate effect on follicular development but affected thyroid function

Abstract: EudraCT Number 2010-022396-57.

Cited by 11 publications

References 11 publications

Pharmacological Programming of Endosomal Signaling Activated by Small Molecule Ligands of the Follicle Stimulating Hormone Receptor

Pharmacological Programming of Endosomal Signaling Activated by Small Molecule Ligands of the Follicle Stimulating Hormone Receptor

The Development of Gonadotropins for Clinical Use in the Treatment of Infertility

Small Molecule Follicle-Stimulating Hormone Receptor Agonists and Antagonists

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