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Treatment of female rhesus macaques with a somatostatin receptor antagonist that increases oocyte fertilization rates without affecting post-fertilization development outcomes

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

To determine the effects of PGL1001, a somatostatin receptor isoform-2 (SSTR-2) antagonist, on ovarian follicle development, oocyte fertilization, and subsequent embryo developmental potential in the rhesus macaque.

Methods

Cycling female rhesus macaques (N = 8) received vehicle through one menstrual (control) cycle, followed by daily injections of PGL1001, a SSTR-2 antagonist, for three menstrual (treatment) cycles. Main endpoints include overall animal health and ovarian hormones (e.g., estradiol [E2], progesterone [P4], and anti-Müllerian hormone [AMH]), ovarian circumference, numbers of oocytes and their maturation status following controlled ovarian stimulation (COS), as well as oocyte fertilization and subsequent blastocyst rates that were assessed in control and PGL1001 treatment cycles. Circulating PGL1001 levels were assessed at baseline as well as 6, 60, and 90 days during treatment.

Results

PGL1001 treatment did not impact overall animal health, menstrual cycle length, or circulating levels of ovarian hormones (E2, P4, and AMH) in comparison to vehicle treatment during natural cycles. PGL1001 treatment increased (p ˂ 0.05) ovarian circumference and the day 8 to day 1 ratio of AMH levels (p ˂ 0.05) during a COS protocol, as well as oocyte fertilization rates compared to the vehicle treatment interval. Blastocyst development rates were not significantly different between vehicle and PGL1001 treatment groups.

Conclusion

Prolonged treatment with PGL1001 appears to be safe and does not affect rhesus macaque general health, menstrual cycle length, or ovarian hormone production. Interestingly, PGL1001 treatment increased the fertilization rate of rhesus macaque oocytes collected following ovarian stimulation.

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Acknowledgements

We thank Dr. Cecily Bishop for assistance in ultrasound imaging and analysis and Ms. Cathy Ramsey and Dr. Carol Hanna in the ONPRC Assisted Reproductive Technologies (ART) Support Core for assistance in sperm collection, culture media preparation, and in vitro fertilization techniques, as well as Ms. Maralee Lawson and Mr. Nathan Halow for technical assistance. We are also grateful to the ONPRC Endocrine Technology Support and ART Cores (ETSC; NIH P51 OD011092) and the Division of Comparative Medicine, Surgical Services Unit and Clinical Medicine Unit.

Funding

This study was supported by NIH (P51 OD011092; JDH) and PregLem SA (JDH).

Author information

Author notes

  1. Jean-Pierre Gotteland

    Present address: ObsEva SA, Chemin des Aulx, 12 Plan-les-Ouates, 1228, Geneva, Switzerland

Authors and Affiliations

  1. Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA

    Alison Y. Ting, Melinda J. Murphy & Jon D. Hennebold

  2. PregLem SA, Geneva, Switzerland

    Pablo Arriagada & Jean-Pierre Gotteland

  3. Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR, USA

    Jon D. Hennebold

Authors
  1. Alison Y. Ting
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  2. Melinda J. Murphy
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  3. Pablo Arriagada
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  4. Jean-Pierre Gotteland
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  5. Jon D. Hennebold
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Corresponding author

Correspondence to Jon D. Hennebold.

Ethics declarations

The studies were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All animal protocols and procedures were approved by ONPRC’s Institutional Animal Care and Use Committee.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplemental Figure 1

The total number of oocytes (MII, MI, and GV), for each animal, collected during follicle aspiration following COS protocols performed prior to (Vehicle) and after 3 menstrual cycles of PGL1001 (PGL1001) treatment. The value of serum PGL1001 concentration (ng/ml) after PGL1001 treatment for each animal is included in the parenthesis. Similar patterns were observed when total oocytes were separated into MII, MI or GV oocytes (data not shown). (DOCX 45 kb) (DOCX 47 kb)

Supplemental Figure 2

Fertilization and blastocyst rates from oocytes collected prior to (Vehicle) and after 3 menstrual cycles of PGL1001 (PGL1001) treatment in each animal. Fertilization rate was calculated as the number of 2-cell stage embryos divided by the number of MII oocytes at 36 h post-IVF. Blastocyst rate was calculated as the number of blastocysts divided by the number of embryos that reached the 2-cell stage. The value of serum PGL1001 concentration (ng/ml) after PGL1001 treatment for each animal is included in the parenthesis. (DOCX 91 kb) (DOCX 93 kb)

Supplemental Table 1

(DOCX 12 kb)

Supplemental Table 2

(DOCX 19 kb)

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Ting, A.Y., Murphy, M.J., Arriagada, P. et al. Treatment of female rhesus macaques with a somatostatin receptor antagonist that increases oocyte fertilization rates without affecting post-fertilization development outcomes. J Assist Reprod Genet 36, 229–239 (2019). https://doi.org/10.1007/s10815-018-1369-0

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  • DOI: https://doi.org/10.1007/s10815-018-1369-0

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