NMN does not protect the ovarian reserve from cancer treatments

Primordial follicle oocytes are extremely vulnerable to DNA damage caused by exogenous agents, such as those commonly used to treat cancer. Consequently, female cancer patients often have diminished ovarian reserve, which if severe enough, can cause premature ovarian failure and early menopause. Advances in cancer therapies have resulted in significantly improved cancer survival rates; therefore, it is becoming increasingly important to devise strategies to protect the ovarian reserve from cancer treatments, to avoid loss of fertility and endocrine dysfunction. In this study, we aimed to determine whether supplementation with nicotinamide mononucleotide (NMN) could preserve the ovarian reserve following exposure to DNA-damaging cancer treatments. Adult female mice (n = 5–6/group) received saline or NMN (500 mg/kg/day) for 8 days. Mice were left untreated or exposed to γ-irradiation (0.1 Gy) or cyclophosphamide (150 mg/kg) on day 7 and ovaries and serum collected for analysis on day 12. We report that γ-irradiation treatment significantly reduced the number of primordial follicles, but supplementation with NMN did not prevent the observed follicle loss. Similarly, cyclophosphamide treatment significantly reduced primordial follicle numbers, but these losses were not prevented by NMN supplementation. In conclusion, depletion of the ovarian reserve following γ-irradiation or cyclophosphamide was not protected by NMN supplementation under the conditions employed in this study.

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Gastrointestinal side effects of cancer treatments

Therapeutic Advances in Chronic Disease ◽

10.1177/2040622320970354 ◽

2020 ◽

Vol 11 ◽

pp. 204062232097035

Author(s):

Mary O’Reilly ◽

Gregory Mellotte ◽

Barbara Ryan ◽

Anthony O’Connor

Keyword(s):

Quality Of Life ◽

Radiation Therapy ◽

Side Effects ◽

Cancer Survival ◽

Survival Rates ◽

Cancer Therapies ◽

Cancer Treatments ◽

Gastrointestinal Side Effects

Cancer survival rates have significantly improved over the last number of years due to advancements in cancer therapies. Unfortunately this has come at a cost. Therapeutic side effects are feared complications of therapy that may result in decreased quality of life and early cessation of the therapy, which can have knock-on effects on outcomes. This article outlines the main gastrointestinal side effects seen with radiation therapy, chemotherapy and immunotherapy, and discusses appropriate investigation and management.

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Single-Oocyte Gene Expression Suggests That Curcumin Can Protect the Ovarian Reserve by Regulating the PTEN-AKT-FOXO3a Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22126570 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6570

Author(s):

Yue Lv ◽

Rui-Can Cao ◽

Hong-Bin Liu ◽

Xian-Wei Su ◽

Gang Lu ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Reserve ◽

Primordial Follicle ◽

Term Treatment ◽

New Drugs ◽

Gene Profiling ◽

Primordial Follicles ◽

Long Term Treatment ◽

Follicle Activation

A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single oocytes were isolated from primordial and primary follicles, and were used for gene profiling with TaqMan array cards. Bioinformatics analysis was performed on the gene expression data, and Ingenuity Pathway Analysis was used to analyze and predict drugs that affect follicle activation. An ovarian in vitro culture system was used to verify the function of the drug candidates, and we found that curcumin maintains the ovarian reserve. Long-term treatment with 100 mg/kg curcumin improved the ovarian reserve indicators of AMH, FSH, and estradiol in aging mice. Mechanistic studies show that curcumin can affect the translocation of FOXO3, thereby inhibiting the PTEN-AKT-FOXO3a pathway and protecting primordial follicles from overactivation. These results suggest that curcumin is a potential drug for the treatment of POI patients and for fertility preservation.

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Asciminib Mitigates DNA Damage Stress Signaling Induced by Cyclophosphamide in the Ovary

International Journal of Molecular Sciences ◽

10.3390/ijms22031395 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1395

Author(s):

Luca Mattiello ◽

Giulia Pucci ◽

Francesco Marchetti ◽

Marc Diederich ◽

Stefania Gonfloni

Keyword(s):

Ovarian Reserve ◽

Kinase Inhibitor ◽

Concomitant Administration ◽

Cancer Therapies ◽

Cancer Treatments ◽

Abl Tyrosine Kinase ◽

Negative Impacts ◽

Abl Tyrosine Kinase Inhibitor

Cancer treatments can often adversely affect the quality of life of young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of dormant follicles while promoting follicle activation and growth. Herein, we demonstrate the in vivo protective effect of the allosteric Bcr-Abl tyrosine kinase inhibitor Asciminib on signaling pathways activated by cyclophosphamide in mouse ovaries. We also provide evidence that Asciminib does not interfere with the cytotoxic effect of cyclophosphamide in Michigan Cancer Foundation (MCF)7 breast cancer cells. Our data indicate that concomitant administration of Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without affecting the anticancer potential of cyclophosphamide. Taken together, these observations are relevant for the development of effective ferto-protective adjuvants to preserve the ovarian reserve from the damaging effects of cancer therapies.

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Assessment of follicular development in cryopreserved primate ovarian tissue by xenografting: prepubertal tissues are less sensitive to the choice of cryoprotectant

Reproduction ◽

10.1530/rep-10-0454 ◽

2011 ◽

Vol 141 (4) ◽

pp. 481-490 ◽

Cited By ~ 7

Author(s):

V von Schönfeldt ◽

R Chandolia ◽

L Kiesel ◽

E Nieschlag ◽

S Schlatt ◽

...

Keyword(s):

Cancer Survival ◽

Ovarian Tissue ◽

Survival Rates ◽

Follicular Development ◽

Nuclear Antigen ◽

Primate Model ◽

Primordial Follicles ◽

Cellular Compartments ◽

Proliferating Cell ◽

Human Primate

Improvements in cancer survival rates have renewed interest in the cryopreservation of ovarian tissue for fertility preservation. We used the marmoset as a non-human primate model to assess the effect of different cryoprotectives on follicular viability of prepubertal compared to adult ovarian tissue following xenografting. Cryopreservation was performed with dimethylsulfoxide (DMSO), 1,2-propanediol (PrOH), or ethylene glycol (EG) using a slow freezing protocol. Subsequently, nude mice received eight grafts per animal from the DMSO and the PrOH groups for a 4-week grafting period. Fresh, cryopreserved–thawed, and xenografted tissues were serially sectioned and evaluated for the number and morphology of follicles. In adult tissue, the percentage of morphologically normal primordial follicles significantly decreased from 41.2±4.5% (fresh) to 13.6±1.8 (DMSO), 9.5±1.7 (PrOH), or 6.8±1.0 (EG) following cryopreservation. After xenografting, the percentage of morphologically normal primordial (26.2±2.5%) and primary follicles (28.1±5.4%) in the DMSO group was significantly higher than that in the PrOH group (12.2±3 and 5.4±2.1% respectively). Proliferating cell nuclear antigen (PCNA) staining suggests the resumption of proliferative activity in all cellular compartments. In prepubertal tissues, primordial but not primary follicles display a similar sensitivity to cryopreservation, and no significant differences between DMSO and PrOH following xenografting were observed. In conclusion, DMSO shows a superior protective effect on follicular morphology compared with PrOH and EG in cryopreserved tissues. Xenografting has confirmed better efficacy of DMSO versus PrOH in adult but not in prepubertal tissues, probably owing to a greater capacity of younger animals to compensate for cryoinjury.

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Maternal low protein diet programmes low ovarian reserve in offspring

Reproduction ◽

10.1530/rep-18-0247 ◽

2018 ◽

Cited By ~ 7

Author(s):

Amy L Winship ◽

Sarah E Gazzard ◽

Luise A Cullen McEwen ◽

John F Bertram ◽

Karla J Hutt

Keyword(s):

Ovarian Reserve ◽

Histological Analysis ◽

Maternal Diet ◽

Primordial Follicle ◽

In Utero ◽

Primordial Follicles ◽

Maternal Undernutrition ◽

Low Protein ◽

Pregnancy And Lactation ◽

In Utero Development

The ovarian reserve of primordial follicle oocytes is formed during in utero development and represents the entire supply of oocytes available to sustain female fertility. Maternal undernutrition during pregnancy and lactation diminishes offspring ovarian reserve in rats. In mice, maternal oocyte maturation is also susceptible to undernutrition, causing impaired offspring cardiovascular function. We aimed to determine whether programming of the ovarian reserve is impacted in offspring when maternal undernutrition extends from preconception oocyte development through to weaning. C57BL6/J female mice were fed normal protein (20%) or low protein (8%) diet during preconception, pregnancy and lactation periods. Maternal ovaries were harvested at weaning and offspring ovaries collected at postnatal day (PN)21 and 24 weeks of age. Total follicle estimates were obtained by histologically sampling one ovary per animal (n=5/group). There was no impact of diet on maternal follicle numbers. However, in offspring, maternal protein restriction significantly depleted primordial follicles by 37% at PN21 and 51% at 24 weeks (p<0.05). There were no effects of diet on other follicle classes. Histological analysis showed no differences in the proportion of proliferative follicles (pH3-positive), but increased atresia (cleaved caspase-3-positive, or TUNEL-positive) was detected in ovaries of protein-restricted offspring at both ages (p<0.05). Our data show that maternal diet during the preconception period, in utero development and early life has significant impacts on follicle endowment and markers of follicle health later in life. This highlights the need for further investigation into the importance of maternal preconception diet for offspring reproductive development and health.

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In Vivo Mechanisms of Chemotherapy-Induced Acute Follicle Loss in the Human Ovary: An Individual-Oocyte Transcriptomic Analysis from Human Ovarian Xenografts

10.1101/2020.06.23.167783 ◽

2020 ◽

Author(s):

S. Titus ◽

K.J. Szymanska ◽

B. Musul ◽

V. Turan ◽

E. Taylan ◽

...

Keyword(s):

Dna Damage ◽

Single Cell ◽

Rna Sequencing ◽

Ovarian Reserve ◽

Xenograft Model ◽

Primordial Follicle ◽

Human Ovary ◽

Primordial Follicles ◽

Growth Initiation

AbstractGonadotoxic chemotherapeutics, such as cyclophosphamide, cause early menopause and infertility in women. Earlier histological studies showed ovarian reserve depletion via severe DNA damage and apoptosis, but others suggested activation of PI3K/PTEN/Akt pathway and follicle ‘burn-out’ as a cause. Using a human ovarian xenograft model, we performed single-cell RNA-sequencing on laser-captured individual primordial follicle oocytes 12h after a single cyclophosphamide injection to determine the mechanisms of acute follicle loss after gonadotoxic chemotherapy. RNA-sequencing showed 190 differentially expressed genes between the cyclophosphamide- and vehicle-exposed oocytes. Ingenuity Pathway Analysis predicted a significant decrease in the expression of anti-apoptotic pro-Akt PECAM1 (p=2.13E-09), IKBKE (p=0.0001), and ANGPT1 (p=0.003), and reduced activation of PI3K/PTEN/Akt after cyclophosphamide. The qRT-PCR and immunostaining confirmed that in primordial follicle oocytes, cyclophosphamide did not change the expressions of Akt (p=0.9), rpS6 (p=0.3), Foxo3a (p=0.12) and anti-apoptotic Bcl2 (p=0.17), nor affect their phosphorylation status. There was significantly increased DNA damage by γH2AX (p=0.0002) and apoptosis by active-caspase-3 (p=0.0001) staining in the primordial follicles and no change in the growing follicles 12h after chemotherapy. These data suggest that the mechanism of acute follicle loss by cyclophosphamide is via apoptosis, rather than growth activation of primordial follicle oocytes in the human ovary.One Sentence SummarySingle-cell transcriptomic interrogation of primordial follicles in human ovarian xenografts reveals that chemotherapy causes acute ovarian reserve depletion by inducing a pro-apoptotic state rather than activating pathways that result in follicle growth initiation.

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Translational Physiology of Anti-Müllerian Hormone: Clinical Applications in Female Fertility Preservation and Cancer Treatment

Frontiers in Endocrinology ◽

10.3389/fendo.2021.689532 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rachael Jean Rodgers ◽

Jason Anthony Abbott ◽

Kirsty A. Walters ◽

William Leigh Ledger

Keyword(s):

Ovarian Reserve ◽

Ovarian Tissue ◽

Ovarian Follicle ◽

Primordial Follicle ◽

Chemotherapeutic Agents ◽

Clinical Applications ◽

Ovarian Cancer Cells ◽

Primordial Follicles ◽

Degree Of Protection ◽

Biological Actions

BackgroundWhilst the ability of AMH to induce the regression of the Müllerian ducts in the male fetus is well appreciated, AMH has additional biological actions in relation to steroid biosynthesis and ovarian follicle dynamics. An understanding of the physiology of AMH illuminates the potential therapeutic utility of AMH to protect the ovarian reserve during chemotherapy and in the treatment of female malignancies. The translation of the biological actions of AMH into clinical applications is an emerging focus of research, with promising preliminary results.Objective and RationaleStudies indicate AMH restrains primordial follicle development, thus administration of AMH during chemotherapy may protect the ovarian reserve by preventing the mass activation of primordial follicles. As AMH induces regression of tissues expressing the AMH receptor (AMHRII), administration of AMH may inhibit growth of malignancies expressing AMHR II. This review evaluates the biological actions of AMH in females and appraises human clinical applications.Search MethodsA comprehensive search of the Medline and EMBASE databases seeking articles related to the physiological functions and therapeutic applications of AMH was conducted in July 2021. The search was limited to studies published in English.OutcomesAMH regulates primordial follicle recruitment and moderates sex steroid production through the inhibition of transcription of enzymes in the steroid biosynthetic pathway, primarily aromatase and 17α-hydroxylase/17,20-lyase. Preliminary data indicates that administration of AMH to mice during chemotherapy conveys a degree of protection to the ovarian reserve. Administration of AMH at the time of ovarian tissue grafting has the potential to restrain uncontrolled primordial follicle growth during revascularization. Numerous studies demonstrate AMH induced regression of AMHR II expressing malignancies. As this action occurs via a different mechanism to traditional chemotherapeutic agents, AMH has the capacity to inhibit proliferation of chemo-resistant ovarian cancer cells and cancer stem cells.Wider ImplicationsTo date, AMH has not been administered to humans. Data identified in this review suggests administration of AMH would be safe and well tolerated. Administration of AMH during chemotherapy may provide a synchronistic benefit to women with an AMHR II expressing malignancy, protecting the ovarian reserve whilst the cancer is treated by dual mechanisms.

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Impact of nicotinamide mononucleotide on transplanted mouse ovarian tissue

Reproduction ◽

10.1530/rep-20-0539 ◽

2020 ◽

Author(s):

Michael J Bertoldo ◽

Valentina Rodriguez Paris ◽

Debra A Gook ◽

Melissa C Edwards ◽

Katherine Wu ◽

...

Keyword(s):

Ovarian Tissue ◽

Ovarian Follicle ◽

Primordial Follicle ◽

Young Female ◽

Female Adolescent ◽

Ovarian Tissue Cryopreservation ◽

Post Transplantation ◽

Primordial Follicles ◽

Nicotinamide Mononucleotide ◽

The Impact

Ovarian tissue cryopreservation and future transplantation is the only strategy to preserve the fertility of young female adolescent and pre-pubertal patients. The primary challenge to ovarian graft longevity is the substantial loss of primordial follicles during the period of ischemia post-transplantation. Nicotinamide mononucleotide (NMN), a precursor of the essential metabolite nicotinamide adenine dinucleotide (NAD+), is known to reduce ischemic damage. Therefore, the objective of the current study was to assess the impact of short- and long-term NMN administration on follicle number and health following ovarian tissue transplantation. Hemi-ovaries from C57Bl6 mice (n=8-12/group) were transplanted under the kidney capsule of bilaterally ovariectomised severe combined immunodeficient (SCID) mice. Recipient mice were administered either normal drinking water or water supplemented with NMN (2g/L) for either 14 or 56 days. At the end of each treatment period ovarian transplants were collected. There was no effect of NMN on the resumption of oestrous or length of oestrous cycles. Transplantation significantly reduced the total number of follicles with the greatest impact observed at the primordial follicle stage. We report that NMN did not prevent this loss. While NMN did not significantly impact the proportion of apoptotic follicles, NMN normalised PCNA expression at the primordial and intermediate stages but not at later stages. In conclusion, NMN administration did not prevent ovarian follicle loss under the conditions of this study.

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Hyperactivation of dormant primordial follicles in ovarian endometrioma patients

Reproduction ◽

10.1530/rep-20-0265 ◽

2020 ◽

Vol 160 (6) ◽

pp. R145-R153

Author(s):

Sachiko Matsuzaki ◽

Michael W Pankhurst

Keyword(s):

Surgical Treatment ◽

Ovarian Reserve ◽

Severe Pain ◽

Primordial Follicle ◽

Primordial Follicles ◽

Relative Contribution ◽

Ovarian Endometrioma ◽

Main Factor ◽

Surgical Injury

Serum anti-Müllerian hormone (AMH) levels decrease after surgical treatment of ovarian endometrioma. This is the main reason that surgery for ovarian endometrioma endometriosis is not recommended before in vitro fertilization, unless the patient has severe pain or suspected malignant cysts. Furthermore, it has been suggested that ovarian endometrioma itself damages ovarian reserve. This raises two important challenges: (1) determining how to prevent surgical damage to the ovarian reserve in women with ovarian endometrioma and severe pain requiring surgical treatment and (2) deciding the best treatment for women with ovarian endometrioma without pain, who do not wish to conceive immediately. The mechanisms underlying the decline in ovarian reserve are potentially induced by both ovarian endometrioma and surgical injury but the relative contribution of each process has not been determined. Data obtained from various animal models and human studies suggest that hyperactivation of dormant primordial follicles caused by the local microenvironment of ovarian endometrioma (mechanical and/or chemical cues) is the main factor responsible for the decreased primordial follicle numbers in women with ovarian endometrioma. However, surgical injury also induces hyperactivation of dormant primordial follicles, which may further reduce ovarian reserve after removal of the endometriosis. Although further studies are required to elucidate the mechanisms underlying diminished ovarian reserve in women with ovarian endometrioma, the available data strongly suggests the need to prevent/minimize hyperactivation of dormant primordial follicles, regardless of whether surgery is performed, for better clinical management of ovarian endometrioma.

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Advances in immunotherapy for colorectal cancer: a review

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284820917527 ◽

2020 ◽

Vol 13 ◽

pp. 175628482091752 ◽

Cited By ~ 4

Author(s):

Gol Golshani ◽

Yue Zhang

Keyword(s):

Colorectal Cancer ◽

Literature Review ◽

Cancer Survival ◽

Advanced Colorectal Cancer ◽

Advanced Disease ◽

Survival Rates ◽

Cancer Treatments ◽

Gastrointestinal Malignancies ◽

Current Role

Immunotherapy is a new and exciting modality of cancer treatments. Its role in gastrointestinal malignancies has been promising, especially in advanced disease. Although various therapies are available for treatment of advanced colorectal cancer, survival rates for these patients remain very poor. The application of immunotherapy in colorectal cancer has shown remarkable results for a subset of patients with mismatch-repair-deficient mutations or microsatellite instability in their tumors. This literature review evaluates the current role of immunotherapy in advanced colorectal cancer, potential challenges clinicians face with immunotherapy-based regimens, and the possible future approach of combined modality immunotherapy.

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