Decreased growth differentiation factor 9, bone morphogenetic protein 15, and forkhead box O3a expressions in the ovary via ulipristal acetate

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SUMMARY

OBJECTIVE:

Folliculogenesis is a complex process involving various ovarian paracrine factors. During folliculogenesis, vitamin D3 and progesterone are significant for the proper development of follicles. This study aimed to investigate the effects of vitamin D3 and selective progesterone receptor modulator ulipristal acetate on ovarian paracrine factors.

METHODS:

In the study, 18 female Wistar-albino rats were randomly divided into three groups: control group (saline administration, n=6), vitamin D3 group (300 ng/day vitamin D3 oral administration, n=6), and UPA group (3 mg/kg/day ulipristal acetate oral administration, n=6). Ovarian tissue was analyzed by histochemistry and immunohistochemistry. For quantification of immunohistochemistry, the mean intensities of growth differentiation factor 9, bone morphogenetic protein 15, and forkhead box O3a expressions were measured by Image J and MATLAB. Blood samples were collected for the analysis of serum anti-Müllerian hormone levels by ELISA.

RESULTS:

Atretic follicles and hemorrhagic cystic structures were observed in the UPA group. After immunohistochemistry via folliculogenesis assessment markers, growth differentiation factor 9, bone morphogenetic protein 15, and cytoplasmic forkhead box O3a expressions decreased in the UPA group (p<0.05). Anti-Müllerian hormone level did not differ significantly between the experimental groups (p>0.05).

CONCLUSION:

Ulipristal acetate negatively affects folliculogenesis via ovarian paracrine factors. The recommended dietary vitamin D3 supplementation in healthy cases did not cause a significant change.

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A simple practice guide for dose conversion between animals and human

Anroop B. Nair, Shery Jacob (2016)

Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species. This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on human equivalent dose is also briefed.

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Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.

Sylvia Christakos, Puneet Dhawan, Annemieke Verstuyf … (2016)

1,25-Dihydroxvitamin D3 [1,25(OH)2D3] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH)2D3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH)2D3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

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Foxo3 is a PI3K-dependent molecular switch controlling the initiation of oocyte growth.

Liza John, Stacie T Gallardo, Devon L. Shirley … (2008)

In mammals, oocytes are packaged into compact structures-primordial follicles-which remain inert for prolonged intervals until individual follicles resume growth via a process known as primordial follicle activation. Here we show that the phosphoinositide 3-kinase (PI3K) signalling pathway controls primordial follicle activation through the forkhead transcription factor Foxo3. Within oocytes, Foxo3 is regulated by nucleocytoplasmic shuttling. Foxo3 is imported into the nucleus during primordial follicle assembly, and is exported upon activation. Oocyte-specific ablation of Pten resulted in PI3K-induced Akt activation, Foxo3 hyperphosphorylation, and Foxo3 nuclear export, thereby triggering primordial follicle activation, defining the steps by which the PI3K pathway and Foxo3 control this process. Inducible ablation of Pten and Foxo3 in adult oocytes using a new tool for genetic analysis of the germline, Vasa-Cre(ERT2), showed that this pathway functions throughout life. Thus, a principal physiologic role of the PI3K pathway is to control primordial follicle activation via Foxo3.

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Author and article information

Contributors

Damla Gül Fındık:

ORCID: http://orcid.org/0000-0001-8028-627X

Role: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: Writing – original draftRole: Writing – review & editing

Gülnur Take Kaplanoğlu:

ORCID: http://orcid.org/0000-0002-3661-3488

Role: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing

Gökçe Nur Arık:

ORCID: http://orcid.org/0000-0003-0129-8358

Role: Data curationRole: MethodologyRole: Project administration

Nagwa Bugumaa Abubaker Alemari:

ORCID: http://orcid.org/0000-0002-9304-9924

Role: Data curationRole: Project administration

Journal

Journal ID (nlm-ta): Rev Assoc Med Bras (1992)

Journal ID (iso-abbrev): Rev Assoc Med Bras (1992)

Journal ID (publisher-id): ramb

Title: Revista da Associação Médica Brasileira

Publisher: Associação Médica Brasileira

ISSN (Print): 0104-4230

ISSN (Electronic): 1806-9282

Publication date (Electronic, pub): 14 August 2023

Publication date (Electronic, collection): 2023

Volume: 69

Issue: 8

Electronic Location Identifier: e20230381

Affiliations

[1 ]Bilecik Şeyh Edebali University, Faculty of Medicine, Department of Histology and Embryology – Bilecik, Turkey.

[2 ]Gazi University, Faculty of Medicine, Department of Histology and Embryology – Ankara, Turkey.

Author notes

[* ]Corresponding author: damla.findik@ 123456bilecik.edu.tr

Conflicts of interest: the authors declare there is no conflicts of interest.

Author information

Damla Gül Fındık http://orcid.org/0000-0001-8028-627X

Gülnur Take Kaplanoğlu http://orcid.org/0000-0002-3661-3488

Gökçe Nur Arık http://orcid.org/0000-0003-0129-8358

Nagwa Bugumaa Abubaker Alemari http://orcid.org/0000-0002-9304-9924

Article

Other ID: 00615

DOI: 10.1590/1806-9282.20230381

PMC ID: 10427182

SO-VID: eceb1313-7bc4-40c6-af9b-3086e06ab10c

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 05 May 2023

Date accepted : 20 May 2023

Page count

Figures: 2, Tables: 1, Equations: 0, References: 25