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Molecular Regulation in Female Reproduction 2.0
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Molecular Regulation in Female Reproduction 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 12227

Special Issue Editor

Dr. Lalit Kumar Parameswaran Grace

E-Mail Website
Guest Editor
Karolinska Institutet, Stockholm, Sweden
Interests: assisted reproductive technology; fertility; gynaecology; female reproductive science
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

With the recent advances in molecular and cellular biology along with the incorporation of bioinformatics and systems biology, we are now able to gather deeper knowledge on the physiological mechanisms and pathophysiology of the female reproductive system—the ovary, uterus, cervix, and endometrium—at the cellular level (including MSC), and more in-depth at the level of protein, miRNA, and sRNA. This information is vital in maintaining and manipulating the normo-physiological conditions of the ovary and uterus in general, and more specifically in the development and maturation of oocytes, ovulation, hormonal regulation of ovaries, and endometrial functions that have direct impact on fertility/sub fertility management. This knowledge in fundamental science has facilitated exploring novel cellular and molecular therapies for subfertility and fertility regulation and new solutions in the management of pathophysiologic conditions such as PCOS, premature ovarian failure, ovulation disorders, fertilization failure, compromised embryo development, endometrial infertility, pregnancy-associated complications, adenomyosis, endometriosis, and gynecological malignancies.

This Special Issue on “Molecular Regulation in Female Reproduction” focuses on the collection of manuscripts and review articles on recent advances covering cellular and molecular sciences as well as translational medicine in the field of female reproduction.

Dr. Parameswaran Grace Luther Lalitkumar
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • female reproduction
  • fertility
  • pregnancy
  • genealogical disorders
  • cell therapy
  • ovary
  • endometrium
  • embryo development
  • molecular therapy

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Published Papers (5 papers)

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Research

14 pages, 3197 KiB  
Article
The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency
by Zixin Xu, Nozomi Takahashi, Miyuki Harada, Chisato Kunitomi, Akari Kusamoto, Hiroshi Koike, Tsurugi Tanaka, Nanoka Sakaguchi, Yoko Urata, Osamu Wada-Hiraike, Yasushi Hirota and Yutaka Osuga
Int. J. Mol. Sci. 2023, 24(24), 17193; https://doi.org/10.3390/ijms242417193 - 6 Dec 2023
Cited by 8 | Viewed by 1701
Abstract
Young female cancer patients can develop chemotherapy-induced primary ovarian insufficiency (POI). Cyclophosphamide (Cy) is one of the most widely used chemotherapies and has the highest risk of damaging the ovaries. Recent studies elucidated the pivotal roles of cellular senescence, which is characterized by [...] Read more.
Young female cancer patients can develop chemotherapy-induced primary ovarian insufficiency (POI). Cyclophosphamide (Cy) is one of the most widely used chemotherapies and has the highest risk of damaging the ovaries. Recent studies elucidated the pivotal roles of cellular senescence, which is characterized by permanent cell growth arrest, in the pathologies of various diseases. Moreover, several promising senolytics, including dasatinib and quercetin (DQ), which remove senescent cells, are being developed. In the present study, we investigated whether cellular senescence is involved in Cy-induced POI and whether DQ treatment rescues Cy-induced ovarian damage. Expression of the cellular senescence markers p16, p21, p53, and γH2AX was upregulated in granulosa cells of POI mice and in human granulosa cells treated with Cy, which was abrogated by DQ treatment. The administration of Cy decreased the numbers of primordial and primary follicles, with a concomitant increase in the ratio of growing to dormant follicles, which was partially rescued by DQ. Moreover, DQ treatment significantly improved the response to ovulation induction and fertility in POI mice by extending reproductive life. Thus, cellular senescence plays critical roles in Cy-induced POI, and targeting senescent cells with senolytics, such as DQ, might be a promising strategy to protect against Cy-induced ovarian damage. Full article
(This article belongs to the Special Issue Molecular Regulation in Female Reproduction 2.0)
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14 pages, 2525 KiB  
Article
Single-Cell RNA-Seq Identifies Pathways and Genes Contributing to the Hyperandrogenemia Associated with Polycystic Ovary Syndrome
by R. Alan Harris, Jan M. McAllister and Jerome F. Strauss III
Int. J. Mol. Sci. 2023, 24(13), 10611; https://doi.org/10.3390/ijms241310611 - 25 Jun 2023
Cited by 3 | Viewed by 3030
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenemia of ovarian thecal cell origin, resulting in anovulation/oligo-ovulation and infertility. Our previous studies established that ovarian theca cells isolated and propagated from ovaries of normal ovulatory women and women with PCOS [...] Read more.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenemia of ovarian thecal cell origin, resulting in anovulation/oligo-ovulation and infertility. Our previous studies established that ovarian theca cells isolated and propagated from ovaries of normal ovulatory women and women with PCOS have distinctive molecular and cellular signatures that underlie the increased androgen biosynthesis in PCOS. To evaluate differences between gene expression in single-cells from passaged cultures of theca cells from ovaries of normal ovulatory women and women with PCOS, we performed single-cell RNA sequencing (scRNA-seq). Results from these studies revealed differentially expressed pathways and genes involved in the acquisition of cholesterol, the precursor of steroid hormones, and steroidogenesis. Bulk RNA-seq and microarray studies confirmed the theca cell differential gene expression profiles. The expression profiles appear to be directed largely by increased levels or activity of the transcription factors SREBF1, which regulates genes involved in cholesterol acquisition (LDLR, LIPA, NPC1, CYP11A1, FDX1, and FDXR), and GATA6, which regulates expression of genes encoding steroidogenic enzymes (CYP17A1) in concert with other differentially expressed transcription factors (SP1, NR5A2). This study provides insights into the molecular mechanisms underlying the hyperandrogenemia associated with PCOS and highlights potential targets for molecular diagnosis and therapeutic intervention. Full article
(This article belongs to the Special Issue Molecular Regulation in Female Reproduction 2.0)
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11 pages, 277 KiB  
Article
Local Immune Biomarker Expression Depending on the Uterine Microbiota in Patients with Idiopathic Infertility
by Natalya I. Tapilskaya, Alevtina M. Savicheva, Kira V. Shalepo, Olga V. Budilovskaya, Aleksandr M. Gzgzyan, Olesya N. Bespalova, Tatiana A. Khusnutdinova, Anna A. Krysanova, Kseniia V. Obedkova and Galina Kh. Safarian
Int. J. Mol. Sci. 2023, 24(8), 7572; https://doi.org/10.3390/ijms24087572 - 20 Apr 2023
Viewed by 1879
Abstract
The endometrium has traditionally been considered sterile. Nowadays, active studies are performed on the female upper genital tract microbiota. Bacteria and/or viruses colonizing the endometrium are known to alter its functional properties, including receptivity and embryo implantation. Uterine cavity inflammation caused by microorganisms [...] Read more.
The endometrium has traditionally been considered sterile. Nowadays, active studies are performed on the female upper genital tract microbiota. Bacteria and/or viruses colonizing the endometrium are known to alter its functional properties, including receptivity and embryo implantation. Uterine cavity inflammation caused by microorganisms leads to disrupted cytokine expression, which, in turn, is mandatory for the successful implantation of the embryo. The present study assessed the vaginal and endometrial microbiota composition and its relation to the levels of cytokines produced by the endometrium in reproductive-aged women complaining of secondary infertility of unknown origin. The multiplex real-time PCR assay was applied for vaginal and endometrial microbiota analysis. The quantitative measurement of endometrial α-defensin (DEFa1), transforming growth factor (TGFβ1), and basic fibroblast growth factor (bFGF2) was carried out using the ELISA (Cloud-Clone Corporation (Katy, TX, USA; manufactured in Wuhan, China). A reliable decline in endometrial TGFβ1 and bFGF2 and an increase in DEFa1 were demonstrated in women with idiopathic infertility when compared to fertile patients. However, TGFβ1, bFGF2, and DEFa1 expression correlated reliably only with the presence of Peptostreptococcus spp. and HPV in the uterine cavity. The obtained results highlight the importance of local immune biomarker determination in the assessment of certain bacteria and viruses’ significance as causative agents of infertility. Full article
(This article belongs to the Special Issue Molecular Regulation in Female Reproduction 2.0)
10 pages, 2584 KiB  
Article
Lovastatin, an Up-Regulator of Low-Density Lipoprotein Receptor, Enhances Follicular Development in Mouse Ovaries
by Yu Jin Kim, Yong Il Cho, JuYi Jang, Yun Dong Koo, Sung Woon Park and Jae Ho Lee
Int. J. Mol. Sci. 2023, 24(8), 7263; https://doi.org/10.3390/ijms24087263 - 14 Apr 2023
Cited by 3 | Viewed by 1838
Abstract
Ovarian aging hampers in vitro fertilization in assisted reproductive medicine and has no cure. Lipoprotein metabolism is associated with ovarian aging. It remains unclear how to overcome poor follicular development with aging. Upregulation of the low-density lipoprotein receptor (LDLR) enhances oogenesis and follicular [...] Read more.
Ovarian aging hampers in vitro fertilization in assisted reproductive medicine and has no cure. Lipoprotein metabolism is associated with ovarian aging. It remains unclear how to overcome poor follicular development with aging. Upregulation of the low-density lipoprotein receptor (LDLR) enhances oogenesis and follicular development in mouse ovaries. This study investigated whether upregulation of LDLR expression using lovastatin enhances ovarian activity in mice. We performed superovulation using a hormone and used lovastatin to upregulate LDLR. We histologically analyzed the functional activity of lovastatin-treated ovaries and investigated gene and protein expression of follicular development markers, using RT-qPCR and Western blotting. Histological analysis showed that lovastatin significantly increased the numbers of antral follicles and ovulated oocytes per ovary. The in vitro maturation rate was 10% higher for lovastatin-treated ovaries than for control ovaries. Relative LDLR expression was 40% higher in lovastatin-treated ovaries than in control ovaries. Lovastatin significantly increased steroidogenesis in ovaries and promoted the expression of follicular development marker genes such as anti-Mullerian hormone, Oct3/4, Nanog, and Sox2. In conclusion, lovastatin enhanced ovarian activity throughout follicular development. Therefore, we suggest that upregulation of LDLR may help to improve follicular development in clinical settings. Modulation of lipoprotein metabolism can be used with assisted reproductive technologies to overcome ovarian aging. Full article
(This article belongs to the Special Issue Molecular Regulation in Female Reproduction 2.0)
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10 pages, 564 KiB  
Article
Effects of Estradiol/Micronized Progesterone vs. Conjugated Equine Estrogens/Medroxyprogesterone Acetate on Breast Cancer Gene Expression in Healthy Postmenopausal Women
by Parameswaran Grace Luther Lalitkumar, Eva Lundström, Birgitta Byström, Dorina Ujvari, Daniel Murkes, Edneia Tani and Gunnar Söderqvist
Int. J. Mol. Sci. 2023, 24(4), 4123; https://doi.org/10.3390/ijms24044123 - 18 Feb 2023
Cited by 2 | Viewed by 3114
Abstract
Recent studies suggest estradiol (E2)/natural progesterone (P) confers less breast cancer risk compared with conjugated equine estrogens (CEE)/synthetic progestogens. We investigate if differences in the regulation of breast cancer-related gene expression could provide some explanation. This study is a subset of [...] Read more.
Recent studies suggest estradiol (E2)/natural progesterone (P) confers less breast cancer risk compared with conjugated equine estrogens (CEE)/synthetic progestogens. We investigate if differences in the regulation of breast cancer-related gene expression could provide some explanation. This study is a subset of a monocentric, 2-way, open observer-blinded, phase 4 randomized controlled trial on healthy postmenopausal women with climacteric symptoms (ClinicalTrials.gov; EUCTR-2005/001016-51). Study medication was two 28-day cycles of sequential hormone treatment with oral 0.625 mg CEE and 5 mg of oral medroxyprogesterone acetate (MPA) or 1.5 mg E2 as percutaneous gel/day with the addition of 200 mg oral micronized P. MPA and P were added days 15–28/cycle. Material from two core-needle breast biopsies in 15 women in each group was subject to quantitative PCR (Q-PCR). The primary endpoint was a change in breast carcinoma development gene expression. In the first eight consecutive women, RNA was extracted at baseline and after two months of treatment and subjected to microarray for 28856 genes and Ingenuity Pathways Analysis (IPA) to identify risk factor genes. Microarray analysis showed 3272 genes regulated with a fold-change of >±1.4. IPA showed 225 genes belonging to mammary-tumor development function: 198 for CEE/MPA vs. 34 for E2/P. Sixteen genes involved in mammary tumor inclination were subject to Q-PCR, inclining the CEE/MPA group towards an increased risk for breast carcinoma compared to the E2/P group at a very high significance level (p = 3.1 × 10−8, z-score 1.94). The combination of E2/P affected breast cancer-related genes much less than CEE/MPA. Full article
(This article belongs to the Special Issue Molecular Regulation in Female Reproduction 2.0)
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