Folliculogenesis Is Not Fully Inhibited during GnRH Analogues Treatment in Mice Challenging Their Efficiency to Preserve the Ovarian Reserve during Chemotherapy in This Model

Abstract

As many chemotherapy regimens induce follicular depletion, fertility preservation became a major concern in young cancer patients. By maintaining follicles at the resting stage, gonadotropin-releasing hormone analogues (GnRHa) were proposed as an ovarian-protective option during chemotherapy. However, their efficacy and mechanisms of action remain to be elucidated. Mice were dosed with cyclophosphamide (Cy, 100–500mg/kg i.p) to quantify follicular depletion and evaluate apoptosis at different times. We observed a dose-dependent depletion of the follicular reserve within 24 hours after Cy injection with a mean follicular loss of 45% at the dose of 200mg/kg. Apoptosis occurs in the granulosa cells of growing follicles within 12 hours after Cy treatment, while no apoptosis was detected in resting follicles suggesting that chemotherapy acutely affects both resting and growing follicles through different mechanisms. We further tested the ability of both GnRH agonist and antagonist to inhibit oestrus cycles, follicular growth and FSH secretion in mice and to protect ovarian reserve against chemotherapy. Although GnRHa were efficient to disrupt oestrus cycles, they failed to inhibit follicular development, irrespective of the doses and injection sites (sc or im). Around 20% of healthy growing follicles were still observed during GnRHa treatment and serum FSH levels were not reduced either by antagonist or agonist. GnRHa had no effect on Cy-induced follicular damages. Thus, we showed that GnRHa were not as efficient at inhibiting the pituitary-gonadal axis in mice as in human. Furthermore, the acute depletion of primordial follicles observed after chemotherapy does not support the hypothesis that the ovary may be protected by gonadotropin suppression.

LH prevents cisplatin-induced apoptosis in oocytes and preserves female fertility in mouse

“…25, 26, 53, 54 Several groups reported that GnRH agonist-treated cancer patients resumed cyclic ovarian function, whereas patients in the chemotherapy alone group experienced amenorrhea. 55, 56 Ataya et al 21 showed that GnRH agonists administrated in parallel with cyclophosphamide significantly decreased the daily rate of follicular decline and the total number of primordial follicles lost during the chemotherapeutic insult.…”

“…However, the effectiveness and mechanisms of action of GnRHa, in protecting the ovarian reserve from chemotherapy-induced damage, is still debated. 24, 25, 26 …”

Assisted reproductive technology is effective for but does not affect the prognosis of young patients with breast cancer: Experience in a single institution

“…In this study, LHRH‐a was mainly administered for ovarian protection Table . Previous reports showed ovarian protection by LHRH‐a, although not in a mouse model and was not effective on pregnancy.…”

Follicle-stimulating Hormone Induced <i>In Vitro</i> Growth of Small Antral Follicles are not Affected by Gonadotropin-releasing Hormone Agonist or Antagonist Treatment in Mice

“…Our results suggest that in mice, FSH-driven in vitro growth of small antral follicles is not adversely affected by GnRHa or antagonist co-treatment in vitro. It has been shown by different groups that mouse ovaries express the GnRH receptor (1)(2)(3)(4). In rats, the comparison of GnRH receptor expression at different follicular stages demonstrated that these mRNA levels of the GnRH-R gene vary depending on follicles degree of maturation as well as the estrous cycle stage.…”

“…Previous studies showed that although systemic administration of GnRH agonist (GnRHa) was efficient to disrupt estrus cycles, it failed to inhibit follicular development, irrespective of the doses and injection sites (subcutaneous or intramuscular). Around 20% of healthy growing follicles were still observed during GnRHa treatment, and serum FSH levels were not reduced either by antagonist or agonist treatment, suggesting that GnRHa does not suppress follicular growth even beyond the gonadotropin-dependent stage in mice (4). Also, it might be challenging to interpret the intra-ovarian actions of GnRH analogs when they are administered systemically due to its effect on the hypothalamic-pituitary-ovarian axis.…”