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DXR induced atrophy of the myometrium. ( A–D ) Macroscopic appearance of uteri from two different females at two months after treatment with either saline (A,B) or DXR (C,D). Notice the difference in the thickness of the uterine horns. ( E–H ) Uterine sections stained with H&E. Notice the decrease in the thickness and sarcopenia of the outer myometrial layers of DXR-treated females (G,H) compared to control females (E,F). doi:10.1371/journal.pone.0017877.g002
Source publication
[This corrects the article on p. e17877 in vol. 6.].
Contexts in source publication
Context 1
... various tissues (e.g. heart, brain, eyes, liver) [33,34,35,36,37]. Specifically, DXR decreases muscle mass and tone in some tissues [38,39]. Therefore, we hypothesized that the delivery complications observed in DXR-treated females must have been the result of DXR actions on the uterus. We observed apparent macroscopic differences between control (Fig. 2A&B) and treated ( Fig. 2C&D) females; uteri from treated females were smaller. Histological analysis of those uteri revealed that the thickness of the myometrial layers of DXR-treated females was highly decreased (5.760.25 mm, N = 30, Fig. 2G&H) compared to untreated females (1061.3 mm, N = 30, Fig. 2E&F). In addition, in treated females, ...
Context 2
... brain, eyes, liver) [33,34,35,36,37]. Specifically, DXR decreases muscle mass and tone in some tissues [38,39]. Therefore, we hypothesized that the delivery complications observed in DXR-treated females must have been the result of DXR actions on the uterus. We observed apparent macroscopic differences between control (Fig. 2A&B) and treated ( Fig. 2C&D) females; uteri from treated females were smaller. Histological analysis of those uteri revealed that the thickness of the myometrial layers of DXR-treated females was highly decreased (5.760.25 mm, N = 30, Fig. 2G&H) compared to untreated females (1061.3 mm, N = 30, Fig. 2E&F). In addition, in treated females, sarcopenia (decreased ...
Context 3
... the result of DXR actions on the uterus. We observed apparent macroscopic differences between control (Fig. 2A&B) and treated ( Fig. 2C&D) females; uteri from treated females were smaller. Histological analysis of those uteri revealed that the thickness of the myometrial layers of DXR-treated females was highly decreased (5.760.25 mm, N = 30, Fig. 2G&H) compared to untreated females (1061.3 mm, N = 30, Fig. 2E&F). In addition, in treated females, sarcopenia (decreased muscle fibers) of the outer myometrial layers was apparent (Fig. 2H), these side effects were observed in approximately 70% of treated ...
Context 4
... macroscopic differences between control (Fig. 2A&B) and treated ( Fig. 2C&D) females; uteri from treated females were smaller. Histological analysis of those uteri revealed that the thickness of the myometrial layers of DXR-treated females was highly decreased (5.760.25 mm, N = 30, Fig. 2G&H) compared to untreated females (1061.3 mm, N = 30, Fig. 2E&F). In addition, in treated females, sarcopenia (decreased muscle fibers) of the outer myometrial layers was apparent (Fig. 2H), these side effects were observed in approximately 70% of treated ...
Context 5
... Histological analysis of those uteri revealed that the thickness of the myometrial layers of DXR-treated females was highly decreased (5.760.25 mm, N = 30, Fig. 2G&H) compared to untreated females (1061.3 mm, N = 30, Fig. 2E&F). In addition, in treated females, sarcopenia (decreased muscle fibers) of the outer myometrial layers was apparent (Fig. 2H), these side effects were observed in approximately 70% of treated ...
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Citations
... When fertilization occurs in oocytes merging from follicles that were recently exposed to chemotherapy, it can result in fertilization failure, high spontaneous abortion rate, and high congenital malformation rate in the embryo-a murine study demonstrated a significant increase in fetal resorptions and more than 10 times the incidence of fetal malformations in conceptions attributable to follicles exposed to Cy during growth [97]. Another study found fetal malformations, chromosomal defects, and also fetal death up to six generations after chemotherapy treatment [98]. ...
Dormant primordial follicles (PMF), which constitute the ovarian reserve, are recruited continuously into the cohort of growing follicles in the ovary throughout female reproductive life. Gonadotoxic chemotherapy was shown to diminish the ovarian reserve pool, to destroy growing follicle population, and to cause premature ovarian insufficiency (POI). Three primary mechanisms have been proposed to account for this chemotherapy-induced PMF depletion: either indirectly via over-recruitment of PMF, by stromal damage, or through direct toxicity effects on PMF. Preventative pharmacological agents intervening in these ovotoxic mechanisms may be ideal candidates for fertility preservation (FP). This manuscript reviews the mechanisms that disrupt follicle dormancy causing depletion of the ovarian reserve. It describes the most widely studied experimental inhibitors that have been deployed in attempts to counteract these affects and prevent follicle depletion.
... If unable to take place before initiation of gonadotoxic therapy, OC should be pursued later during a prolonged treatment-free period owing to concerns over the diminished response to ovarian stimulation and teratogenic effects [84]. Animal studies have shown increased miscarriage, aneuploidy, and fetal malformation rates in pregnancies resulting from oocytes being exposed to chemotherapy, with decreasing risk as the time between exposure and ovulation increases [85,86]. Reassuringly, large population-based human studies have not shown increased chromosomal abnormalities in the children of patients who were previously treated with radiation or chemotherapy [87,88]. ...
Oocyte cryopreservation (OC) is the process in which ovarian follicles are stimulated, the follicular fluid is retrieved, and mature oocytes are isolated and vitrified. Since the first successful pregnancy utilizing previously cryopreserved oocytes in 1986, OC has become increasingly utilized as an option for future biologic children in patients facing gonadotoxic therapies, such as for the treatment of cancer. Planned OC, also termed elective OC, is growing in popularity as a means to circumvent age-related fertility decline. In this narrative review, we describe both medically indicated and planned OC, focusing on the physiology of ovarian follicular loss, OC technique and risks, timing of when OC should be performed, associated financial considerations, and outcomes.
... However, two studies suggest that effects persist in generations removed from the direct J o u r n a l P r e -p r o o f exposure. One study used a single intraperitoneal injection of the common chemotherapeutic agent doxorubicin to investigate the long-term effects in a female-treated mouse model 32,33 . The study determined that the effects were in fact transgenerational and were the most prominent in the fourth and sixth generations 33 . ...
... One study used a single intraperitoneal injection of the common chemotherapeutic agent doxorubicin to investigate the long-term effects in a female-treated mouse model 32,33 . The study determined that the effects were in fact transgenerational and were the most prominent in the fourth and sixth generations 33 . Specifically, there were heightened rates of neonatal death, physical malformations, and chromosomal abnormalities in mice from the treated lineage 33 . ...
... The study determined that the effects were in fact transgenerational and were the most prominent in the fourth and sixth generations 33 . Specifically, there were heightened rates of neonatal death, physical malformations, and chromosomal abnormalities in mice from the treated lineage 33 . ...
The current study was designed to use a rodent model to determine if exposure to the chemotherapy drug ifosfamide during puberty can induce altered phenotypes and disease in the grand-offspring of exposed individuals through epigenetic transgenerational inheritance. Pathologies such as delayed pubertal onset, kidney disease and multiple pathologies were observed to be significantly more frequent in the F1 generation offspring of ifosfamide lineage females. The F2 generation grand-offspring ifosfamide lineage males had transgenerational pathology phenotypes of early pubertal onset and reduced testis pathology. Reduced levels of anxiety were observed in both males and females in the transgenerational F2 generation grand-offspring. Differential DNA methylated regions (DMRs) in chemotherapy lineage sperm in the F1 and F2 generations were identified. Therefore, chemotherapy exposure impacts pathology susceptibility in subsequent generations. Observations highlight the importance that prior to chemotherapy, individuals need to consider cryopreservation of germ cells as a precautionary measure if they have children.
Impaired fertility is the major side effect of chemotherapy for female cancer patients, accumulated evidence indicates this is associated with damage on oocyte quality, but the underlying mechanisms remain unclear. Previously we reported that doxorubicin (DXR) exposure, one of the most widely used chemotherapy drugs, disrupted mouse oocyte meiotic maturation in vitro. In the current study, we identified that SIRT1 expression was remarkably reduced in DXR exposure oocytes. Next, we found that increasing SIRT1 expression by resveratrol partially alleviated the effects of DXR exposure on oocyte maturation, which was counteracted by SIRT1 inhibition. Furthermore, we revealed that increasing SIRT1 expression mitigated DXR induced oocyte damage through reducing ROS levels, increasing antioxidant enzyme MnSOD expression, and preventing spindle and chromosome disorganization, lowering the incidence of aneuploidy. Importantly, by performing in vitro fertilization and embryo transfer assays, we demonstrated that increasing SIRT1 expression significantly improved the fertilization ability, developmental competence of oocytes and early embryos. In summary, our data uncover that SIRT1 reduction represents one mechanism that mediates the effects of DXR exposure on oocyte quality.
Objective
To report ovarian tissue autotransplantation (AT) results and describe the relationship between technical and clinical factors and outcomes.
Design
Multicenter retrospective cohort study.
Setting
Tertiary medical centers.
Patient(s)
Infertile patients who had stored ovarian tissue before sterilizing treatment and returned for AT with the aim of conceiving.
Interventions(s)
Ovarian tissue cryopreservation (OTC) and AT, endocrine monitoring, in vitro fertilization.
Main Outcome Measure(s)
Endocrine performance, pregnancy and live-birth rates.
Result(s)
From 2004 to 2018, 70 patients underwent 87 ATs. Sixty patients undergoing 70 ATs met the inclusion criteria. After AT, menses returned in 94% of patients and median FSH dropped from 68 to 19 IU/mL. Fifty pregnancies and 44 deliveries were attained, with 50% of women achieving at least one pregnancy and 41.6% at least one delivery. Twelve patients underwent AT more than once and had their endocrine activity restored in case menses recurred after the first transplantation. Repeated transplantations yielded five live births in three patients, two of whom had already given birth after the first transplantation. Preharvesting chemotherapy was not associated with inferior outcomes. Of seven patients whose pelvis was exposed to radiation before AT, four conceived and delivered. Neither tissue dimensions nor surgical approach affected fertility outcomes.
Conclusion(s)
OTC is highly effective at restoring fertility in sterilized patients, and prior exposure to chemotherapy should not be considered a contraindication. Repeated AT should be contemplated in case of graft malfunction, especially if previous transplantation was successful. In selected cases, conception and delivery may be feasible after pelvic exposure to radiation
Background:
Anti-cancer therapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy. While oocyte, embryo and ovarian cortex cryopreservation can help some women with cancer-induced infertility achieve pregnancy, the development of effective methods to protect ovarian function during chemotherapy would be a significant advantage.
Objective and rationale:
This paper critically discusses the different damaging effects of the most common chemotherapeutic compounds on the ovary, in particular, the ovarian follicles and the molecular pathways that lead to that damage. The mechanisms through which fertility-protective agents might prevent chemotherapy drug-induced follicle loss are then reviewed.
Search methods:
Articles published in English were searched on PubMed up to March 2019 using the following terms: ovary, fertility preservation, chemotherapy, follicle death, adjuvant therapy, cyclophosphamide, cisplatin, doxorubicin. Inclusion and exclusion criteria were applied to the analysis of the protective agents.
Outcomes:
Recent studies reveal how chemotherapeutic drugs can affect the different cellular components of the ovary, causing rapid depletion of the ovarian follicular reserve. The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. They also cause an increase in damage to blood vessels and the stromal compartment and increment inflammation. In the past 20 years, many compounds have been investigated as potential protective agents to counteract these adverse effects. The interactions of recently described fertility-protective agents with these damage pathways are discussed.
Wider implications:
Understanding the mechanisms underlying the action of chemotherapy compounds on the various components of the ovary is essential for the development of efficient and targeted pharmacological therapies that could protect and prolong female fertility. While there are increasing preclinical investigations of potential fertility preserving adjuvants, there remains a lack of approaches that are being developed and tested clinically.
Increasing numbers of female patients survive cancer, but succumb to primary ovarian insufficiency after chemotherapy. We tested the hypothesis that Bortezomib (Bort) protects ovaries from doxorubicin (DXR) chemotherapy by treating female mice with Bort 1 hour prior to DXR. By preventing DXR accumulation in the ovary, Bort attenuated DXR-induced DNA damage in all ovarian cell types, subsequent γH2AFX phosphorylation, and resulting apoptosis in preantral follicles. Bort pretreatment extended the number of litters per mouse, improved litter size and increased pup weight following DXR treatment, thus increasing the duration of post-chemotherapy fertility and improving pup health. As a promising prophylactic ovoprotective agent, Bort does not interfere with cancer treatment, and is currently used as a chemotherapy adjuvant. Bort-based chemoprotection may preserve ovarian function in a non-invasive manner that avoids surgical ovarian preservation, thus diminishing the health complications of premature menopause following cancer treatment.
The mechanism of chemotherapy-induced acceleration of ovarian aging is not fully understood. We used doxorubicin, a widely used cancer chemotherapeutic, in a variety of in vivo xenograft, and in vitro models to investigate the impact of chemotherapy-induced aging on the human ovary. Doxorubicin caused massive double-strand-DNA-breaks in primordial follicles, oocytes, and granulosa cells in a dose dependent fashion as revealed by accumulating γH2AX foci. This damage was associated with apoptotic oocyte death and resulted in the activation of ATM. It appeared that the repair response enabled a minor proportion of oocytes (34.7%) and granulosa cells (12.1%) to survive while the majority succumbed to apoptotic death. Paradoxically, inhibition of ATM by KU-55933 resulted in improved survival, probably via prevention of downstream activation of TAp63α. Furthermore, doxorubicin caused vascular and stromal damage in the human ovary, which might impair ovarian function both pre- and post-menopausally. Chemotherapy-induced premature ovarian aging appears to result from a complex process involving both the germ- and non-germ cell components of the ovary. These effects may have clinical implications in aging both for premenopausal and postmenopausal cancer survivors.
