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Effect of oral administration of low-dose follicle stimulating hormone on hyperandrogenized mice as a model of polycystic ovary syndrome.

Tessaro I, Modina SC, Franciosi F, Sivelli G, Terzaghi L, Lodde V, Luciano AM - J Ovarian Res (2015)

Bottom Line: The presumptive bioactive peptide was added during in vitro maturation of bovine COCs and the effects on cumulus expansion and on maturation rate were evaluated.Orally administered rhFSH restored estradiol level and reduced the percentage of cystic follicles.Despite these results indicating a reduction of the severity of PCOS in the mouse model, the presumptive bioactive peptide did not mimic the effect of rhFSH and failed to induce bovine cumulus expansion and oocyte maturation in vitro.

View Article: PubMed Central - PubMed

Affiliation: Reproductive and Developmental Biology Laboratory, Department of Health, Animal Science and Food Safety, Università degli Studi di Milano, Via Celoria 10, Milan, 20133, Italy. irene.tessaro@unimi.it.

ABSTRACT

Background: Polycystic Ovary Syndrome (PCOS) is a widespread reproductive disorder characterized by a disruption of follicular growth and anovulatory infertility. In women with PCOS, follicular growth and ovulation can be induced by subcutaneous injections of low doses of follicle stimulating hormone (FSH). The aim of this study was to determine the effect of oral administration of recombinant human FSH (rhFSH) on follicle development in a PCOS murine model. Moreover, since it is unlikely that intact rhFSH is present into the circulation after oral administration, the biological activity of a peptide fragment, derived from the predicted enzymatic cleavage sites with the FSH molecule, was investigated in vitro on cumulus-enclosed oocytes (COCs).

Methods: Female peripubertal mice were injected with dehydroepiandrosterone (DHEA) diluted in sesame oil for 20 consecutive days and orally treated with a saline solution of rhFSH. A control group received only sesame oil and saline solution. At the end of treatments, blood was analyzed for hormone concentrations and ovaries were processed for morphological analysis. The presumptive bioactive peptide was added during in vitro maturation of bovine COCs and the effects on cumulus expansion and on maturation rate were evaluated.

Results: DHEA treatment increased serum levels of testosterone, estradiol and progesterone as well as the percentage of cystic follicles. Orally administered rhFSH restored estradiol level and reduced the percentage of cystic follicles. Despite these results indicating a reduction of the severity of PCOS in the mouse model, the presumptive bioactive peptide did not mimic the effect of rhFSH and failed to induce bovine cumulus expansion and oocyte maturation in vitro.

Conclusions: Although further studies are needed, the present data supports the concept that orally administrated FSH could attenuate some of the characteristic of PCOS in the mouse model.

No MeSH data available.


Related in: MedlinePlus

Effect of different hormonal treatments on the percentage of follicles presenting atretic/cystic signs. Upper panel Representative images of typical morphological changes in antral follicle walls of ovaries isolated from controls (a) compared to DHEA-treated mice (b, c, d, e, f), stained with hematoxylin and eosin. In the control (a) theca externa, theca interna, basal membrane and granulosa cells layers appear normal. b, c and d represent progressive changes associated with follicular atresia (ie. pyknosis, disruption of the basement membrane (asterisks) and of granulosa layers (white arrows) and invasion of blood cells). Cystic features are described by thin and elongated epithelioid cells in the inner surface of the wall (e, black arrows) and macrophages in the cystic fluid (f, red arrows). Bar = 50 μm. Lower panel The effect of different hormonal treatment was evaluated on the population of antral follicles >300 μm of diameter. Data were analyzed by one-way ANOVA, followed by Fisher’s LSD multiple comparison test; different letters indicate significant differences between groups (P <0.05)
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Fig6: Effect of different hormonal treatments on the percentage of follicles presenting atretic/cystic signs. Upper panel Representative images of typical morphological changes in antral follicle walls of ovaries isolated from controls (a) compared to DHEA-treated mice (b, c, d, e, f), stained with hematoxylin and eosin. In the control (a) theca externa, theca interna, basal membrane and granulosa cells layers appear normal. b, c and d represent progressive changes associated with follicular atresia (ie. pyknosis, disruption of the basement membrane (asterisks) and of granulosa layers (white arrows) and invasion of blood cells). Cystic features are described by thin and elongated epithelioid cells in the inner surface of the wall (e, black arrows) and macrophages in the cystic fluid (f, red arrows). Bar = 50 μm. Lower panel The effect of different hormonal treatment was evaluated on the population of antral follicles >300 μm of diameter. Data were analyzed by one-way ANOVA, followed by Fisher’s LSD multiple comparison test; different letters indicate significant differences between groups (P <0.05)

Mentions: Finally, morphological signs of progressive follicle atresia and cystic formations were observed (Fig. 6, upper panel). These include granulosa cell pyknosis (Fig. 6b), disruption of the basement membrane (indicated by asterisks in Fig. 6b, c, d) and granulosa cells layers (pointed out by white arrows in Figs. 6b and c) as well as invasion of blood cells, the presence of elongated epithelioid cells in the inner surface of the follicle wall (indicated by black arrows in Fig. 6e), macrophages in the cystic fluid (showed by red arrows in Fig. 6f), and reduction of granulosa cells layers. DHEA significantly increased the occurrence of morphological cystic features in antral follicles with a diameter >300 μm per ovary (Fig. 6, lower panel); the oral administration of rhFSH in DHEA-treated mice was able to significantly decrease the percentage of atretic/cystic signs in large follicles, even if it is still higher than CTRL (P <0.05). Moreover in the 150–300 μm follicle population, rhFSH administration importantly reduced the percentage of atretic/cystic follicles on total follicular population compared to DHEA treatment alone (Fig. 7).Fig. 6


Effect of oral administration of low-dose follicle stimulating hormone on hyperandrogenized mice as a model of polycystic ovary syndrome.

Tessaro I, Modina SC, Franciosi F, Sivelli G, Terzaghi L, Lodde V, Luciano AM - J Ovarian Res (2015)

Effect of different hormonal treatments on the percentage of follicles presenting atretic/cystic signs. Upper panel Representative images of typical morphological changes in antral follicle walls of ovaries isolated from controls (a) compared to DHEA-treated mice (b, c, d, e, f), stained with hematoxylin and eosin. In the control (a) theca externa, theca interna, basal membrane and granulosa cells layers appear normal. b, c and d represent progressive changes associated with follicular atresia (ie. pyknosis, disruption of the basement membrane (asterisks) and of granulosa layers (white arrows) and invasion of blood cells). Cystic features are described by thin and elongated epithelioid cells in the inner surface of the wall (e, black arrows) and macrophages in the cystic fluid (f, red arrows). Bar = 50 μm. Lower panel The effect of different hormonal treatment was evaluated on the population of antral follicles >300 μm of diameter. Data were analyzed by one-way ANOVA, followed by Fisher’s LSD multiple comparison test; different letters indicate significant differences between groups (P <0.05)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4594749&req=5

Fig6: Effect of different hormonal treatments on the percentage of follicles presenting atretic/cystic signs. Upper panel Representative images of typical morphological changes in antral follicle walls of ovaries isolated from controls (a) compared to DHEA-treated mice (b, c, d, e, f), stained with hematoxylin and eosin. In the control (a) theca externa, theca interna, basal membrane and granulosa cells layers appear normal. b, c and d represent progressive changes associated with follicular atresia (ie. pyknosis, disruption of the basement membrane (asterisks) and of granulosa layers (white arrows) and invasion of blood cells). Cystic features are described by thin and elongated epithelioid cells in the inner surface of the wall (e, black arrows) and macrophages in the cystic fluid (f, red arrows). Bar = 50 μm. Lower panel The effect of different hormonal treatment was evaluated on the population of antral follicles >300 μm of diameter. Data were analyzed by one-way ANOVA, followed by Fisher’s LSD multiple comparison test; different letters indicate significant differences between groups (P <0.05)
Mentions: Finally, morphological signs of progressive follicle atresia and cystic formations were observed (Fig. 6, upper panel). These include granulosa cell pyknosis (Fig. 6b), disruption of the basement membrane (indicated by asterisks in Fig. 6b, c, d) and granulosa cells layers (pointed out by white arrows in Figs. 6b and c) as well as invasion of blood cells, the presence of elongated epithelioid cells in the inner surface of the follicle wall (indicated by black arrows in Fig. 6e), macrophages in the cystic fluid (showed by red arrows in Fig. 6f), and reduction of granulosa cells layers. DHEA significantly increased the occurrence of morphological cystic features in antral follicles with a diameter >300 μm per ovary (Fig. 6, lower panel); the oral administration of rhFSH in DHEA-treated mice was able to significantly decrease the percentage of atretic/cystic signs in large follicles, even if it is still higher than CTRL (P <0.05). Moreover in the 150–300 μm follicle population, rhFSH administration importantly reduced the percentage of atretic/cystic follicles on total follicular population compared to DHEA treatment alone (Fig. 7).Fig. 6

Bottom Line: The presumptive bioactive peptide was added during in vitro maturation of bovine COCs and the effects on cumulus expansion and on maturation rate were evaluated.Orally administered rhFSH restored estradiol level and reduced the percentage of cystic follicles.Despite these results indicating a reduction of the severity of PCOS in the mouse model, the presumptive bioactive peptide did not mimic the effect of rhFSH and failed to induce bovine cumulus expansion and oocyte maturation in vitro.

View Article: PubMed Central - PubMed

Affiliation: Reproductive and Developmental Biology Laboratory, Department of Health, Animal Science and Food Safety, Università degli Studi di Milano, Via Celoria 10, Milan, 20133, Italy. irene.tessaro@unimi.it.

ABSTRACT

Background: Polycystic Ovary Syndrome (PCOS) is a widespread reproductive disorder characterized by a disruption of follicular growth and anovulatory infertility. In women with PCOS, follicular growth and ovulation can be induced by subcutaneous injections of low doses of follicle stimulating hormone (FSH). The aim of this study was to determine the effect of oral administration of recombinant human FSH (rhFSH) on follicle development in a PCOS murine model. Moreover, since it is unlikely that intact rhFSH is present into the circulation after oral administration, the biological activity of a peptide fragment, derived from the predicted enzymatic cleavage sites with the FSH molecule, was investigated in vitro on cumulus-enclosed oocytes (COCs).

Methods: Female peripubertal mice were injected with dehydroepiandrosterone (DHEA) diluted in sesame oil for 20 consecutive days and orally treated with a saline solution of rhFSH. A control group received only sesame oil and saline solution. At the end of treatments, blood was analyzed for hormone concentrations and ovaries were processed for morphological analysis. The presumptive bioactive peptide was added during in vitro maturation of bovine COCs and the effects on cumulus expansion and on maturation rate were evaluated.

Results: DHEA treatment increased serum levels of testosterone, estradiol and progesterone as well as the percentage of cystic follicles. Orally administered rhFSH restored estradiol level and reduced the percentage of cystic follicles. Despite these results indicating a reduction of the severity of PCOS in the mouse model, the presumptive bioactive peptide did not mimic the effect of rhFSH and failed to induce bovine cumulus expansion and oocyte maturation in vitro.

Conclusions: Although further studies are needed, the present data supports the concept that orally administrated FSH could attenuate some of the characteristic of PCOS in the mouse model.

No MeSH data available.


Related in: MedlinePlus