CHAPTER 6. GENERAL DISCUSSION AND CONCLUSION
6.4. General Conclusion
The studies in this dissertation provided new evidences that investigational kisspeptin and NKB analog, or their receptor agonist are considered to have a remarkable effect in regulation of LH secretion, and their action is strongly associated with the ovarian steroid milieu. Kisspeptin analog has a stimulatory effect on gonadotropin secretion of cycling goats, whereas NKB receptor agonist may have either stimulatory or suppressive effect.
Characteristic of kisspeptin analog stimulation tends to be different at specific stages of an estrous cycle. The stimulatory effect at the early luteal phase is similar to that at follicular phase. During this stage, acute treatment of the analog will stimulate an initial sustain increase of pulsatile LH secretion, followed by a maturation of dominant follicles which produce high circulating estrogen necessary for inducing LH surge. Although the initial effect on pulsatile LH secretion were similar, the stimulatory effect appears to be reduced by the increase of progesterone level produced by corpora lutea, as the luteal phase progressed.
In accordance to the result of the studies in this dissertation, the characteristic of NKB receptor agonist (NK3R) stimulation is most-likely depend on the dose and duration of its administration. Low-dose of continuous intravaginal infusion stimulated
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LH pulse during the infusion period, while acute injection stimulate LH pulse for short period, i.e. 1 h, tends to stimulate small-amplitude and high-frequency of LH secretion.
In addition, high-dose acute intravenous injection tends to stimulate rapid and short-period of LH release, which are less influenced by the ovarian milieu.
The suppressive effect of NKB receptor agonist is notably related to its interaction with kisspeptin analog. Simultaneous injection of kisspeptin analog and the NKB receptor agonist can briefly elevate the LH secretion without giving distinctive influences on the ovarian steroid, as well as its dynamics. It is suggested that the NKB analog or its receptor may abrogate the stimulatory action of kisspeptin.
On the other hand, NKB receptor agonist and kisspeptin analog may have synergic effect on gonadotropin release. During the high-circulating estradiol and low-circulating progesterone milieu, concomitant injection of kisspeptin analog with NKB receptor agonist stimulated an immediate and sustains release of LH, followed by a robust increase of LH secretion, as well as early ovulation. This revealed the possibility of another pathway of kisspeptin and NKB regulatory role that may exist in the hypothalamic-pituitary-gonadal axis. It is postulated that the kisspeptin analog may bind to other receptor than the most preferable one, GPR54, although this study is still lack of evidences to prove the hypothesis.
In conclusion, according to the result in Chapter 3, 4, and 5, the stimulatory effect of kisspeptin/NKB analog or its receptor agonist on gonadotropin secretion is strongly influenced by the ovarian milieu, i.e. the circulating estradiol and progesterone level. It is suggested that the progesterone tend to reduce the response of LH secretion to kisspeptin/NKB analog, which in turn causes less or no response of ovarian steroid hormone production, as well as follicle maturation. Meanwhile, in the low-circulating
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progesterone milieu, kisspeptin/NKB analog or its receptor agonist may act synchronically with estradiol to induce more robust LH secretion. In accordance to the four studies, treatment with kisspeptin/NKB analog or their receptor agonist is suggested to be a potential drug in ovarian quiescence animals, such as postpartum anestrus, as these peptides analog stimulate increase of pulsatile LH in the low-circulating progesterone milieu. The immediate increase of frequency, followed by amplitude of LH will modulate the ovarian steroid as well as its dynamic, which is contributed to the recovery of estrous cycle.
Further studies are necessary to determine and confirm (1) the effective dosage of NK3R agonist, B21-750, for stimulating more sustainable LH secretion needed for spontaneous LH surge and probably optimization of follicle maturation; (2) the specific mechanism involved along the hypothalamic-pituitary-gonadal axis in regards of the dual action after concomitant injection of kisspeptin analog and NK3R agonist.
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ACKNOWLEDGEMENTS
I would like to express my deepest gratitude and respect to my main academic supervisor, Prof. Tomomi Tanaka, D.V.M., Ph.D. from Laboratory of Veterinary Reproduction, Tokyo University of Agriculture and Technology, for the patience, valuable guidance, advices and encouragement during my degree study. My deep gratitude also belongs to Assistant Prof. Natsumi Endo, D.V.M., Ph.D., for the valuable guidance and supports during my stay in the Laboratory.
I dedicate a great acknowledge to the Directors, Staff, and Students Awardee from Indonesia Endowment Fund for Education, for the financial and moral supports during my doctoral study.
I would like to express my appreciation to Prof. Gen Watanabe of Tokyo University of Agriculture and Technology for the valuable guidance throughout my doctoral work and constructive comments for my dissertation. My appreciation also belongs to Prof. Toru Takahashi of Iwate University for the valuable insight throughout my doctoral study. I appreciate Prof. Motozumi Matsui of Obihiro University of Agriculture and Veterinary Medicine and Prof. Tetsuma Murase of Gifu University for the valuable insights and constructive suggestions for my dissertation work.
I wish a great acknowledge to Dr. Hisanori Matsui of Takeda Pharmaceutical Co.
Ltd. Japan for provision of TAK-683; Prof. Shinya Oishi for provision of Senktide and B21-750; Dr. Y. Mori of University of Tokyo and Dr. A.F. Parlow of Harbor-UCLA Medical Center for provision of assay reagents.
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I dedicate a special thankfulness to Prof. Hideo Kamomae for the encouragement. In the memory of Prof. Kei-Ichiro Maeda, I indebted priceless helps and support during the early-year of my doctoral study.
I owe my gratitude to the past and present students (2014–2018) in the Laboratory of Veterinary Reproduction for the supports, technical assistance, and precious time spent together. Especially to my tutor, Chie Matsuda, for her supports, and to the present student, Youko Uematsu, for the assistance and great time spent together. I greatly indebted former visiting researcher, Dr. Mohammed Assran El Behiry, for the knowledge shared and technical support throughout my early study.
Finally and specially, I would like to dedicate my deepest gratitude for my family and friends. I thank my father, Dr. Purwoko, M.Si, my mother, Eva Mutia Noviani Setiarini, and my brother, Bagus Satrio Budiharjo, for their continuous supports.
I owe thankfulness to my best friends, Marissa Malahayati and Faizal Hardi for the greatest understanding and heartful supports.
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