scholarly journals Discovery and Preclinical Development of Orally Active Small Molecules that Exhibit Highly Selective Follicle Stimulating Hormone Receptor Agonism

2021 ◽  
Vol 11 ◽  
Author(s):  
Selva Nataraja ◽  
Henry Yu ◽  
Joie Guner ◽  
Stephen Palmer
Keyword(s):  
Ovarian Stimulation ◽  
Hormone Receptor ◽  
Ovulation Induction ◽  
Low Dose ◽  
Intrauterine Insemination ◽  
Follicle Stimulating Hormone ◽  
Controlled Ovarian Stimulation ◽  
Orally Active ◽  
Stimulating Hormone

An orally active follicle stimulating hormone receptor allosteric agonist would provide a preferred treatment for over 16 million infertile women of reproductive age in low complexity methods (ovulation induction-intrauterine insemination) or in high complexity methods (controlled ovarian stimulation-in vitro fertilization). We present two oral follicle stimulating hormone receptor allosteric agonist compounds that have the desired pharmacology, drug metabolism, pharmacokinetics, and safety profile for clinical use. These molecules provide a single agent suitable for ovulation induction-intrauterine insemination or controlled ovarian stimulation-in vitro fertilization that is more convenient for patients and achieves similar preclinical efficacy as rec-hFSH. TOP5668, TOP5300 were evaluated in vitro in Chinese hamster ovary cells transfected with individual glycoprotein receptors measuring cAMP (FSHR, LH/CGR, thyroid stimulating hormone receptor). TOP5668 was found to have solely follicle stimulating hormone receptor allosteric agonist activity while TOP5300 was found to have mixed follicle stimulating hormone receptor allosteric agonist and LHR-AA activity. Both compounds stimulated concentration-dependent increases in estradiol production from cultured rat granulosa cells in the presence or absence of low dose rec-hFSH, while only TOP5300 stimulated testosterone production from rat primary Leydig cells. In pooled human granulosa cells obtained from patients undergoing controlled ovarian stimulation-in vitro fertilization, TOP5300 stimulated 7-fold greater maximal estradiol response than rec-hFSH and TOP5668 was 10-fold more potent than TOP5300. Both TOP5300 and TOP5668 stimulated follicular development in immature rat to the same efficacy as recombinant follicle stimulating hormone. In mice treated with TOP5300, in the presence of low dose of follicle stimulating hormone, there were no differences in oocyte number, fertilization rate, and hatched blastocyst rate in mice with TOP5300 and low dose follicle stimulating hormone vs. reference proteins pregnant mare serum gonadotropin or high dose rec-hFSH. ADME/PK and safety profiles were favorable. In addition, there was no appreciable activity on thyroid hormones by TOP5300 in 14-days toxicological study in rat or dog. The selected lead compound, TOP5300 stimulated a more robust increase in estradiol production from granulosa-lutein cells from women with polycystic ovarian syndrome patient compared to rec-hFSH. Conclusions: Two novel oral FSHR allosteric agonist, TOP5668 and TOP5300, were found to mimic the biological activity of rec hFSH in preclinical studies. Both compounds led to folliculogenesis and superovulation in rat and mice. Specifically, TOP5300 led to a similar number of ovulated oocytes that fertilized and developed into hatched blastocysts in mice when compared to rec-hFSH. The safety profile demonstrated lack of toxicity.

scholarly journals The ratio of exogenous Luteinizing hormone to Follicle stimulating hormone administered for controlled ovarian stimulation is associated with oocytes’ number and competence

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Dragos Albu ◽  
Alice Albu
Keyword(s):  
Luteinizing Hormone ◽  
Ovarian Stimulation ◽  
Follicle Stimulating Hormone ◽  
Fertilization Rate ◽  
Controlled Ovarian Stimulation ◽  
Human Menopausal Gonadotropin ◽  
Male Factor ◽  
Entire Study ◽  
Stimulating Hormone

Abstract We performed a retrospective study aiming to study the relationship between the ratio of the exogenous luteinizing hormone to follicle stimulating hormone (LH/FSH) administrated for controlled ovarian stimulation (COS) and the number and competence of the oocytes retrieved for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Eight hundred sixty-eight consecutive infertile patients (mean age 34.54 ± 4.01 years, mean anti-Müllerian hormone (AMH) 2.94 ± 2.07 ng/ml) treated with long agonist protocol and a mixed gonadotropin protocol (human menopausal gonadotropin in association with recombinant FSH (recFSH)) who performed IVF/ICSI between January 2013 and February 2016, were included. Patients with severe male factor were excluded. LH/FSH was calculated based on total doses of the two gonadotropins. We found, after adjustment for confounders, a positive relationship between LH/FSH and the retrieved oocytes’ (β = 0.229, P<0.0001) and zygotes’ number (β = 0.144, P<0.0001) in the entire study group and in subgroups according to age (<35 and ≥35 years) and ovarian reserve (AMH < 1.1 and ≥ 1.1 ng/ml). The fertilization rate was positively associated with LH/FSH in patients with LH/FSH in the lowest three quartiles (below 0.77) (β = 0.096, P=0.034). However, patients in the fourth quartile of LH/FSH had a lower fertilization rate as compared with patients in quartiles 1–3 which, after adjustment for covariates, was only marginally negatively related with LH/FSH (β = −0.108, P=0.05). In conclusion, our results suggest that the adequate LH/FSH administrated during COS can improve the oocytes’ and zygotes’ number in IVF/ICSI cycles, but also the fertilization rate when a certain proportion of LH/FSH is not exceeded.

scholarly journals The N680S variant in the follicle-stimulating hormone receptor gene identifies hyperresponders to controlled ovarian stimulation

2019 ◽  
Vol 29 (5) ◽  
pp. 114-120 ◽  
Author(s):  
Hannah A. Nenonen ◽  
Ida A. Lindgren ◽  
Alexandra S. Prahl ◽  
Dorota Trzybulska ◽  
Isabella Kharraziha ◽  
...  
Keyword(s):  
Ovarian Stimulation ◽  
Hormone Receptor ◽  
Receptor Gene ◽  
Follicle Stimulating Hormone ◽  
Controlled Ovarian Stimulation ◽  
Hormone Receptor Gene ◽  
Stimulating Hormone

P–588 Follicle-stimulating hormone receptor genotype and its influence on the results of double ovarian stimulation in IVF cycles

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
M Horta. Foronda ◽  
B Lledó ◽  
J A Ortiz ◽  
A Fuentes ◽  
A Cascales ◽  
...  
Keyword(s):  
Ovarian Stimulation ◽  
Hormone Receptor ◽  
Luteal Phase ◽  
Follicle Stimulating Hormone ◽  
Follicular Phase ◽  
Fsh Receptor ◽  
Vitro Fertilization ◽  
Urinary Fsh ◽  
Stimulating Hormone

Abstract Study question Does the follicle-stimulating hormone receptor (FSHR) genotype influence the results of the ovarian stimulation treatment in the luteal phase? Summary answer All patients undergoing in-vitro fertilization benefit from luteal phase ovarian stimulation, regardless of their follicle-stimulating hormone receptor genotype. What is known already Previous studies suggest that FSH receptor polymorphism in position 680 influences the response to ovarian stimulation in the luteal phase. It was observed that patients with SS genotype seems to require a higher dose to obtain an optimal ovarian response. Later, it was reported that, in patients with SS genotype, a better performance seems to be obtained by administering highly purified urinary FSH while, in SN patients, better results were obtained with recombinant FSH. In patients with NN genotype, no differences were found. Our aim was to test whether this concept is applicable to ovarian stimulation in the luteal phase. Study design, size, duration One hundred and thirty-four patients were included in a retrospective study between July 2017 and September 2020. In these patients, a double stimulation protocol was carried out and the FSH receptor was genotyped either as part of the pre-treatment fertility tests or for the current study. Patients with a double stimulation treatment who could not be genotyped were excluded from the analysis. Participants/materials, setting, methods To genotype the 680 position of the FSH receptor, a real-time PCR for allelic discrimination was carried out using StepOnePlus™ Real-Time PCR System (Applied Biosystems™. Ref: 4376600). Non-parametic tests were used to study the differences between the groups. They were performed with the software R Statistical Software, version 4.0.3. Main results and the role of chance The results of ovarian stimulation in the luteal phase were better compared to the conventional follicular phase. Statistically significant differences (p < 0.001) were found in the number of retrieved oocytes (5.06 versus 3.51), retrieved MII (4.13 versus 2.91), fertilized oocytes (3.22 versus 1.81) and blastocysts formed (1.79 versus 0.62). Furthermore, these differences remained regardless of the genotype for the 680 position of the FSH receptor in all groups (p < 0.05). In addition, better results were obtained in the luteal phase in patients who have been stimulated with the type of gonadotropin that already had better performance in the follicular phase for its genotype, that is, highly purified urinary FSH in SS patients and recombinant FSH in SN patients, compared to other types of gonadotropin (p < 0.05). We also observed that stimulation in the luteal phase lasts longer and consume more gonadotropins than in the follicular phase. This is especially notable in the case of patients with SS genotype, who required slightly higher consumption of gonadotropins compared to the other genotypes in the luteal phase, as had previously been observed in the follicular phase for this genotype. Limitations, reasons for caution The retrospective study design and the sample size could be a limitation. Furthermore, we cannot determine whether the improvement in luteal phase performance is related to differences in the physiological environment between phases of the cycle or is caused by a possible activation of the ovary from the previous stimulation. Wider implications of the findings: All patients undergoing in-vitro fertilization seems to benefit from luteal phase ovarian stimulation, regardless of their genotype for FSHR. In addition, the pharmacogenetic recommendation when choosing the type of FSH for ovarian stimulation should be the same both in the follicular phase and in the luteal phase. Trial registration number Not applicable

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