Editors' ChoiceReproduction

Re-productive brain stimulation

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Science Translational Medicine  09 Dec 2020:
Vol. 12, Issue 573, eabf7737
DOI: 10.1126/scitranslmed.abf7737

Abstract

Kisspeptin agonists restore gonadotropin secretion.

Proteins called kisspeptins activate gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus, initiate puberty, and regulate reproductive function. After stimulation with kisspeptin peptides, GnRH neurons activate release of follicular stimulating hormone (FSH) and luteinizing hormone (LH), which in turn affect ovarian follicle maturation and release. Female reproductive disorders result from dysregulation of GnRH, FSH, and LH secretion. Treatment with endogenous kisspeptin peptides, namely kisspeptin 54 (KP54), has been successful in treatment of female reproductive disorders but have been limited by its short half-life and tachyphylaxis. The kisspeptin receptor agonist MVT-602 given subcutaneously has been shown to have a longer half-life than KP54; however, it has never been tested in women.

Abbara et al. investigated the effect of MVT-602 administration on the reproductive axis of healthy women and women with polycystic ovary syndrome (PCOS) or hypothalamic amenorrhea (HA) through several experiments. Initially, the authors showed that the maximal dose of MVT-602 was 0.03 nmol/kg. The peak response of FSH and LH to 0.01 nmol/kg and 0.03 nmol/kg dose of MVT-602 and KP54 was similar in amplitude, but LH and FSH peak occurred later with MVT-602.Estradiol was elevated for 48 hours after a single dose of MVT-602. In vitro, MVT-602 and KP54 activated the kisspeptin receptor similarly, but MVT-602 increased the firing of GnRH neurons for a longer period than KP54. After an injection of MVT-602, women with PCOS had a LH, FSH, and estradiol response similar to healthy women. However, women with HA had an earlier LH peak and a higher FSH and estradiol peak compared with healthy women or women with PCOS. Further, estradiol supplementation in addition to MVT-602 in healthy women showed a synergistic action on both LH and FSH response compared with MVT-602 alone.

Together, these experiments show that the kisspeptin agonist MVT-602 is a promising treatment for women with reproductive disorders. Further studies need to be performed to assess whether kisspeptin receptor agonists restore ovulatory cycles and increase live births, as well as ideal dosing regimens.

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