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Short-term pharmacological suppression of the hyperprolactinemia of infertile hCG-overproducing female mice persistently restores their fertility.

ABSTRACT: Female infertility is often associated with deregulation of hormonal networks, and hyperprolactinemia is one of the most common endocrine disorders of the hypothalamic-pituitary axis affecting the reproductive functions. We have shown previously that transgenic female mice overexpressing human chorionic gonadotropin ?-subunit (hCG?+ mice), and producing elevated levels of bioactive LH/hCG, exhibit increased production of testosterone and progesterone, are overweight and infertile, and develop hyperprolactinemia associated with pituitary lactotrope adenomas in adult age. In the present study, we analyzed the influence of the hyperprolactinemia of hCG?+ females on their reproductive phenotype by treating them with the dopamine agonists, bromocriptine and cabergoline. Long-term bromocriptine treatment of adult mice was effective in the control of obesity, pituitary growth, and disturbances in the hormone profile, demonstrating that hyperprolactinemia was the main cause of the hCG?+ female phenotype. Interestingly, short-term treatment (1 wk) with cabergoline applied on 5-wk-old mice corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, prevented pituitary overgrowth, normalized gonadal function, and recovered fertility of adult hCG?+ females after hormone-induced and natural ovulation. The same cabergoline treatment in the short term applied on 3-month-old hCG?+ females failed to recover their reproductive function. Hence, we demonstrated that the short-term cabergoline treatment applied at a critical early stage of the phenotype progression effectively prevented the hyperprolactinemia-associated reproductive dysfunction of hCG-overproducing females.

SUBMITTER: Ratner LD

PROVIDER: S-EPMC3544356 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Short-term pharmacological suppression of the hyperprolactinemia of infertile hCG-overproducing female mice persistently restores their fertility.

Ratner Laura D LD Gonzalez Betina B Ahtiainen Petteri P Di Giorgio Noelia P NP Poutanen Matti M Calandra Ricardo S RS Huhtaniemi Ilpo T IT Rulli Susana B SB

Endocrinology 20121101 12

Female infertility is often associated with deregulation of hormonal networks, and hyperprolactinemia is one of the most common endocrine disorders of the hypothalamic-pituitary axis affecting the reproductive functions. We have shown previously that transgenic female mice overexpressing human chorionic gonadotropin β-subunit (hCGβ+ mice), and producing elevated levels of bioactive LH/hCG, exhibit increased production of testosterone and progesterone, are overweight and infertile, and develop hy ...[more]

PMID: 23117930

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Project description:BackgroundGene drives based on CRISPR-Cas9 technology are increasingly being considered as tools for reducing the capacity of mosquito populations to transmit malaria, and one of the most promising options is driving endonuclease genes that reduce the fertility of female mosquitoes. In particular, there is much interest in constructs that target the conserved mosquito doublesex (dsx) gene such that the emergence of functional drive-resistant alleles is unlikely. Proof of principle that these constructs can lead to substantial population suppression has been obtained in population cages, and they are being evaluated for use in sub-Saharan Africa. Here, we use simulation modelling to understand the factors affecting the spread of this type of gene drive over a one million-square kilometre area of West Africa containing substantial environmental and social heterogeneity.ResultsWe found that a driving endonuclease gene targeting female fertility could lead to substantial reductions in malaria vector populations on a regional scale. The exact level of suppression is influenced by additional fitness costs of the transgene such as the somatic expression of Cas9, and its deposition in sperm or eggs leading to damage to the zygote. In the absence of these costs, or of emergent drive-resistant alleles that restore female fertility, population suppression across the study area is predicted to stabilise at ~ 95% 4 years after releases commence. Small additional fitness costs do not greatly affect levels of suppression, though if the fertility of females whose offspring transmit the construct drops by more than ~ 40%, then population suppression is much less efficient. We show the suppression potential of a drive allele with high fitness costs can be enhanced by engineering it also to express male bias in the progeny of transgenic males. Irrespective of the strength of the drive allele, the spatial model predicts somewhat less suppression than equivalent non-spatial models, in particular in highly seasonal regions where dry season stochasticity reduces drive efficiency. We explored the robustness of these results to uncertainties in mosquito ecology, in particular their method of surviving the dry season and their dispersal rates.ConclusionsThe modelling presented here indicates that considerable suppression of vector populations can be achieved within a few years of using a female sterility gene drive, though the impact is likely to be heterogeneous in space and time.

Dataset Information

Short-term pharmacological suppression of the hyperprolactinemia of infertile hCG-overproducing female mice persistently restores their fertility.

Publications

Short-term pharmacological suppression of the hyperprolactinemia of infertile hCG-overproducing female mice persistently restores their fertility.

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