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

Horicks F, Van Den Steen G, Houben S, Englert Y, Demeestere I - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Research Laboratory on Human Reproduction, Université Libre de Bruxelles (ULB), Brussels, Belgium.

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, 100-500 mg/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.

No MeSH data available.


Related in: MedlinePlus

Fertility impact of chemotherapy.Mice were treated with Cy (200 or 500mg/kg) or saline and mated for 36 weeks. The number of litter per month, of pups per litter and the number of days between two consecutive litters (DBL) were calculated. Results are expressed as mean ± SD; N = 2 mice per condition.
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pone.0137164.g002: Fertility impact of chemotherapy.Mice were treated with Cy (200 or 500mg/kg) or saline and mated for 36 weeks. The number of litter per month, of pups per litter and the number of days between two consecutive litters (DBL) were calculated. Results are expressed as mean ± SD; N = 2 mice per condition.

Mentions: The toxic effect of Cy on fertility was assessed by mating female mice treated with 200mg/kg or 500mg/kg of Cy for 36 weeks. The experiment was aborted at 19 weeks for the highest dose because of healthy issues (Fig 2). The experiment was not repeated due to ethical consideration. A dose of Cy of 200 mg/kg was chosen for the next experiment. This dose reduced the ovarian reserve of around 50% without significantly affecting fertility.


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

Horicks F, Van Den Steen G, Houben S, Englert Y, Demeestere I - PLoS ONE (2015)

Fertility impact of chemotherapy.Mice were treated with Cy (200 or 500mg/kg) or saline and mated for 36 weeks. The number of litter per month, of pups per litter and the number of days between two consecutive litters (DBL) were calculated. Results are expressed as mean ± SD; N = 2 mice per condition.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556658&req=5

pone.0137164.g002: Fertility impact of chemotherapy.Mice were treated with Cy (200 or 500mg/kg) or saline and mated for 36 weeks. The number of litter per month, of pups per litter and the number of days between two consecutive litters (DBL) were calculated. Results are expressed as mean ± SD; N = 2 mice per condition.
Mentions: The toxic effect of Cy on fertility was assessed by mating female mice treated with 200mg/kg or 500mg/kg of Cy for 36 weeks. The experiment was aborted at 19 weeks for the highest dose because of healthy issues (Fig 2). The experiment was not repeated due to ethical consideration. A dose of Cy of 200 mg/kg was chosen for the next experiment. This dose reduced the ovarian reserve of around 50% without significantly affecting fertility.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Research Laboratory on Human Reproduction, Université Libre de Bruxelles (ULB), Brussels, Belgium.

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, 100-500 mg/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.

No MeSH data available.


Related in: MedlinePlus