Treatment of female rhesus macaques with a somatostatin receptor antagonist that increases oocyte fertilization rates without affecting post-fertilization development outcomes
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.
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.
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.
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.
KeywordsSomatostatin receptor antagonist Nonhuman primate Follicle development Oocyte Embryo
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.
This study was supported by NIH (P51 OD011092; JDH) and PregLem SA (JDH).
Compliance with ethical standards
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.
- 7.Narayanan S, Kunz PL. Role of somatostatin analogues in the treatment of neuroendocrine tumors. J Natl Compr Cancer Netw. 2015;13(1):109–17.Google Scholar
- 27.Xu J, Bernuci MP, Lawson MS, Yeoman RR, Fisher TE, Zelinski-Wooten MB, et al. Survival, growth, and maturation of secondary follicles from prepubertal, young and older adult, rhesus monkeys during encapsulated three-dimensional (3D) culture: effects of gonadotropins and insulin. Reproduction. 2010.Google Scholar
- 29.Thomas FH, Telfer EE, Fraser HM. Expression of anti-Mullerian hormone protein during early follicular development in the primate ovary in vivo is influenced by suppression of gonadotropin secretion and inhibition of vascular endothelial growth factor. Endocrinology. 2007;148(5):2273–81.PubMedGoogle Scholar