Journal of Assisted Reproduction and Genetics

, Volume 36, Issue 2, pp 229–239 | Cite as

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

  • Alison Y. Ting
  • Melinda J. Murphy
  • Pablo Arriagada
  • Jean-Pierre Gotteland
  • Jon D. HenneboldEmail author
Reproductive Physiology and Disease



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.


Somatostatin 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.

Supplementary material

10815_2018_1369_MOESM1_ESM.docx (48 kb)
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)
10815_2018_1369_MOESM2_ESM.docx (93 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)
10815_2018_1369_MOESM3_ESM.docx (13 kb)
Supplemental Table 1 (DOCX 12 kb)
10815_2018_1369_MOESM4_ESM.docx (19 kb)
Supplemental Table 2 (DOCX 19 kb)


  1. 1.
    Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 1996;17(2):121–55.PubMedGoogle Scholar
  2. 2.
    Macklon NS, Fauser BC. Aspects of ovarian follicle development throughout life. Horm Res. 1999;52(4):161–70.PubMedGoogle Scholar
  3. 3.
    Fortune JE, Cushman RA, Wahl CM, Kito S. The primordial to primary follicle transition. Mol Cell Endocrinol. 2000;163(1–2):53–60.PubMedGoogle Scholar
  4. 4.
    Fauser BC, Van Heusden AM. Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocr Rev. 1997;18(1):71–106.PubMedGoogle Scholar
  5. 5.
    Murray PG, Higham CE, Clayton PE. 60 years of neuroendocrinology: the hypothalamo-GH axis: the past 60 years. J Endocrinol. 2015;226(2):T123–40.PubMedGoogle Scholar
  6. 6.
    Hejna M, Schmidinger M, Raderer M. The clinical role of somatostatin analogues as antineoplastic agents: much ado about nothing? Ann Oncol. 2002;13(5):653–68.PubMedGoogle Scholar
  7. 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
  8. 8.
    Rai U, Thrimawithana TR, Valery C, Young SA. Therapeutic uses of somatostatin and its analogues: current view and potential applications. Pharmacol Ther. 2015;152:98–110.PubMedGoogle Scholar
  9. 9.
    Gevers TJ, Drenth JP. Somatostatin analogues for treatment of polycystic liver disease. Curr Opin Gastroenterol. 2011;27(3):294–300.PubMedGoogle Scholar
  10. 10.
    Gambineri A, Patton L, De Iasio R, Cantelli B, Cognini GE, Filicori M, et al. Efficacy of octreotide-LAR in dieting women with abdominal obesity and polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90(7):3854–62.PubMedGoogle Scholar
  11. 11.
    Gahete MD, Cordoba-Chacon J, Duran-Prado M, Malagon MM, Martinez-Fuentes AJ, Gracia-Navarro F, et al. Somatostatin and its receptors from fish to mammals. Ann N Y Acad Sci. 2010;1200:43–52.PubMedGoogle Scholar
  12. 12.
    Unger N, Ueberberg B, Schulz S, Saeger W, Mann K, Petersenn S. Differential expression of somatostatin receptor subtype 1-5 proteins in numerous human normal tissues. Exp Clin Endocrinol Diabetes. 2012;120(8):482–9.PubMedGoogle Scholar
  13. 13.
    Riaz H, Dong P, Shahzad M, Yang L. Constitutive and follicle-stimulating hormone-induced action of somatostatin receptor-2 on regulation of apoptosis and steroidogenesis in bovine granulosa cells. J Steroid Biochem Mol Biol. 2014;141:150–9.PubMedGoogle Scholar
  14. 14.
    Gougeon A, Delangle A, Arouche N, Stridsberg M, Gotteland JP, Loumaye E. Kit ligand and the somatostatin receptor antagonist, BIM-23627, stimulate in vitro resting follicle growth in the neonatal mouse ovary. Endocrinology. 2010;151(3):1299–309.PubMedGoogle Scholar
  15. 15.
    Nakamura E, Otsuka F, Inagaki K, Tsukamoto N, Ogura-Ochi K, Miyoshi T, et al. Involvement of bone morphogenetic protein activity in somatostatin actions on ovarian steroidogenesis. J Steroid Biochem Mol Biol. 2013;134:67–74.PubMedGoogle Scholar
  16. 16.
    Nestorovic NM, Manojlovic-Stojanoski MN, Trifunovic SL, Ristic NM, Filipovic BR, Sosic-Jurjevic BT, et al. Long-term effects of somatostatin 14 on the pituitary-ovarian axis in rats. Gen Physiol Biophys. 2014;33(2):157–68.PubMedGoogle Scholar
  17. 17.
    Andreani CL, Lazzarin N, Pierro E, Lanzone A, Mancuso S. Somatostatin action on rat ovarian steroidogenesis. Hum Reprod. 1995;10(8):1968–73.PubMedGoogle Scholar
  18. 18.
    Moaeen-ud-Din M, Malik N, Yang LG. Somatostatin can alter fertility genes expression, oocytes maturation, and embryo development in cattle. Anim Biotechnol. 2009;20(3):144–50.PubMedGoogle Scholar
  19. 19.
    Nestorovic N, Lovren M, Sekulic M, Filipovic B, Milosevic V. Effects of multiple somatostatin treatment on rat gonadotrophic cells and ovaries. Histochem J. 2001;33(11–12):695–702.PubMedGoogle Scholar
  20. 20.
    Phillips KA, Bales KL, Capitanio JP, Conley A, Czoty PW, ‘t Hart BA, et al. Why primate models matter. Am J Primatol. 2014;76(9):801–27.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Wolf DP, Vandevoort CA, Meyer-Haas GR, Zelinski-Wooten MB, Hess DL, Baughman WL, et al. In vitro fertilization and embryo transfer in the rhesus monkey. Biol Reprod. 1989;41(2):335–46.PubMedGoogle Scholar
  22. 22.
    Macklon NS, Stouffer RL, Giudice LC, Fauser BC. The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocr Rev. 2006;27(2):170–207.PubMedGoogle Scholar
  23. 23.
    Wolf DP, Thomson JA, Zelinski-Wooten MB, Stouffer RL. In vitro fertilization-embryo transfer in nonhuman primates: the technique and its applications. Mol Reprod Dev. 1990;27(3):261–80.PubMedGoogle Scholar
  24. 24.
    Hanna CB, Yao S, Ramsey CM, Hennebold JD, Zelinski MB, Jensen JT. Phosphodiesterase 3 (PDE3) inhibition with cilostazol does not block in vivo oocyte maturation in rhesus macaques (Macaca mulatta). Contraception. 2015;91(5):418–22.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Bishop CV, Sparman ML, Stanley JE, Bahar A, Zelinski MB, Stouffer RL. Evaluation of antral follicle growth in the macaque ovary during the menstrual cycle and controlled ovarian stimulation by high-resolution ultrasonography. Am J Primatol. 2009;71(5):384–92.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Young KA, Hennebold JD, Stouffer RL. Dynamic expression of mRNAs and proteins for matrix metalloproteinases and their tissue inhibitors in the primate corpus luteum during the menstrual cycle. Mol Hum Reprod. 2002;8(9):833–40.PubMedGoogle Scholar
  27. 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
  28. 28.
    Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA, et al. Anti-Mullerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod. 2004;10(2):77–83.PubMedGoogle Scholar
  29. 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
  30. 30.
    Mimuro T, Smith H, Iwashita M, Illingworth PJ. The somatostatin analogue, octreotide, modifies both steroidogenesis and IGFBP-1 secretion in human luteinizing granulosa cells. Hum Reprod. 1998;13(1):150–3.PubMedGoogle Scholar
  31. 31.
    McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev. 2000;21(2):200–14.PubMedGoogle Scholar
  32. 32.
    Liu L, Kong N, Xia G, Zhang M. Molecular control of oocyte meiotic arrest and resumption. Reprod Fertil Dev. 2013;25(3):463–71.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Alison Y. Ting
    • 1
  • Melinda J. Murphy
    • 1
  • Pablo Arriagada
    • 2
  • Jean-Pierre Gotteland
    • 2
    • 3
  • Jon D. Hennebold
    • 1
    • 4
    Email author
  1. 1.Division of Reproductive & Developmental Sciences, Oregon National Primate Research CenterOregon Health & Science UniversityBeavertonUSA
  2. 2.PregLem SAGenevaSwitzerland
  3. 3.ObsEva SAGenevaSwitzerland
  4. 4.Department of Obstetrics & GynecologyOregon Health & Science UniversityPortlandUSA

Personalised recommendations