Abstract
Premature ovarian insufficiency (POI) is a heterogeneous disorder and lacks effective interventions in clinical applications. This research aimed to elucidate the potential effects of recombinant human PEGylated growth hormone (rhGH) on follicular development and mitochondrial function in oocytes as well as ovarian parameters in POI rats induced by the chemotherapeutic agent. The impacts of rhGH on ovarian function before superovulation on follicles, estrous cycle, and sex hormones were evaluated. Oocytes were retrieved to determine oocyte quality and oxidative stress parameters. Single-cell sequencing was applied to investigate the latent regulatory network. This study provides new evidence that a high dosage of rhGH increased the number of retrieved oocytes even though it did not completely restore the disturbed estrous cycle and sex hormones. rhGH attenuated the apoptosis of granulosa cells and oxidative stress response caused by reactive oxygen species (ROS) and mitochondrial superoxide. Additionally, rhGH modulated the energy metabolism of oocytes concerning the mitochondrial membrane potential and ATP content but not mtDNA copy numbers. Based on single-cell transcriptomic analysis, we found that rhGH directly or indirectly promoted the balance of oxidative stress and cellular oxidant detoxification. Four hub genes, Pxmp4, Ehbp1, Mt-cyb, and Enpp6, were identified to be closely related to the repair process in oocytes as potential targets for POI treatment.
Highlights
Premature ovarian insufficiency (POI) is characterized by the loss of ovarian function before 40 years of age with primary or secondary amenorrhea, increased follicle-stimulating hormone (FSH) and reduced estradiol (E2), and it affects about 1% of women worldwide (Liu et al, 2014; Ghahremani-Nasab et al, 2020)
The principal objectives of this study were to investigate the therapeutic effects of the long-acting recombinant human PEGylated growth hormone (rhGH) modified by drug PEGylation or polyethylene glycol recombinant human growth hormone, the structure of which is conjugated with polyethylene glycol moiety (Hou et al, 2016; Saenger and Mejia-Corletto, 2016) on ovarian function, especially oocyte quality, in POI rats induced by chemotherapeutic agent, and to explore the possible mechanisms associated with the improved outcomes
Rats were maintained for one week to aid acclimatization in specific pathogen-free conditions and were divided into five groups: (I) Wt; (II) Mo (rats intraperitoneally injected with 50 mg/kg cyclophosphamide (CTX) for the first time, followed by a 14-day consecutive injection of 8 mg/kg CTX to establish a POI animal model); (III) Tl (POI model rats injected with low dosage, 0.4 mg/kg rhGH); (IV) Tm (POI model rats injected with medium dosage, 0.8 mg/kg rhGH); and (V) Th (POI model rats injected with high dosage, 1.6 mg/kg rhGH)
Summary
Premature ovarian insufficiency (POI) is characterized by the loss of ovarian function before 40 years of age with primary or secondary amenorrhea, increased follicle-stimulating hormone (FSH) and reduced estradiol (E2), and it affects about 1% of women worldwide (Liu et al, 2014; Ghahremani-Nasab et al, 2020). Patients benefit from GH supplementation during controlled ovarian hyperstimulation or in vitro maturation, and recombinant human PEGylated growth hormone (rhGH) improves the likelihood of pregnancy by affecting the oocyte and subsequent embryo quality (Yovich and Stanger, 2010; Weall et al, 2015). The third study in 2018 made similar conclusions besides a reduced use of gonadotropin during controlled ovarian stimulation cycles (Li et al, 2017). All these studies support the potential of GH for fertility improvement. Most studies focused on individuals with poor ovarian response or aging, and no unified drug regimen on the timing and dosage of rhGH is available in clinical application for these patients. There is still insufficient evidence to ascertain the therapeutic effect of GH in POI, as the underlying mechanisms on oocytes remain not so clear
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