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.

/pdf/ovarian-damage-from-chemotherapy-and-current-approaches-to-ytpqq99yv8.pdf

Ovarian damage from chemotherapy and current approaches to its protection.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on treatment and management considerations for AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for AYA Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

/pdf/adolescent-and-young-adult-oncology-version-2-2018-nccn-11rkit8j4a.pdf

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

Purpose We have reported previously that after 1-year follow up, gonadotropin-releasing hormone agonist (GnRHa) did not prevent chemotherapy-induced premature ovarian failure (POF) in patients with lymphoma, but may provide protection of the ovarian reserve. Here, we report the final analysis of the cohort after 5 years of follow up.

/pdf/no-evidence-for-the-benefit-of-gonadotropin-releasing-3pvl23lewq.pdf

No Evidence for the Benefit of Gonadotropin-Releasing Hormone Agonist in Preserving Ovarian Function and Fertility in Lymphoma Survivors Treated With Chemotherapy: Final Long-Term Report of a Prospective Randomized Trial

Study question Does surgical treatment of endometriomas impact on the ovarian reserve as evaluated with antral follicle count (AFC)? Summary answer This meta-analysis of published data shows that surgery for endometrioma does not significantly affect ovarian reserve as evaluated by AFC. What is known already Surgical excision of an ovarian endometrioma significantly affects ovarian reserve evaluated with anti-Mullerian hormone (AMH) levels. Data for other reliable markers of ovarian reserve, such as AFC, have not been pooled in meta-analyses. Study design, size, duration A systematic review with electronic searches of PubMed, MEDLINE and Embase up to April 2014 was conducted to identify articles evaluating AFC before and after surgery for ovarian endometriomas, or before or after surgery for the affected versus the contralateral ovary. Participants/materials, setting, methods Of the 24 studies evaluated in detail, 13 were included for data extraction and meta-analysis, including a total of 597 patients. The primary outcome at pooled analysis was AFC (mean and SD) for affected ovaries before and after surgery. Secondary outcomes were AFC for the affected ovary versus the contralateral ovary before surgery, and AFC for the operated versus the contralateral ovary after surgery. The data were pooled using the RevMan software by the Cochrane Collaboration. Heterogeneity between studies was based on the results of the χ(2) and I(2) statistics. A random-effect model was used for the meta-analysis because of high heterogeneity between studies. Main results and the role of chance AFC for the operated ovary did not change significantly after surgery (mean difference 0.10, 95% CI -1.45 to 1.65; P = 0.90). Lower AFC for the diseased ovary compared with the contralateral one was present before surgery, although the difference was not significant (mean difference -2.79, 95% CI -7.10 to 1.51; P = 0.20). After surgery, the operated ovary showed a significantly lower AFC compared with the contralateral ovary (mean difference -1.40, 95% CI -2.27 to -0.52; P = 0.002). Limitations, reasons for caution Heterogeneity among the selected studies was high; therefore, limiting the conclusions of the present systematic review. Wider implications of the findings Ovarian reserve evaluated with AFC is not reduced after surgical treatment of an endometrioma. A lower AFC is present for the affected ovary both before and after surgery. Recently, concerns have been raised as to the reliability of AMH as a marker of ovarian reserve. Based on the present findings, surgical treatment of an endometrioma may be considered safer for the ovarian reserve than previously thought. Study funding/competing interests No external funding was sought or obtained for this study. No conflicts of interest are declared.

The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis

Vitrification is a well-accepted procedure for cryopreservation of gametes and embryos. Less is known, however, about its performance in preserving ovarian tissue, for which slow freezing is the current convention. Increasing interest is being focused on vitrification, but there are as yet no standard protocols for its use with ovarian tissue. In part, this is because of the variety of cell types and complex nature of ovarian tissue. We performed a meta-analysis of 14 studies that compared vitrification with slow freezing for cryopreservation of ovarian tissue. In the pooled analysis, there was no significant difference between the two methods in terms of the proportion of intact primordial follicles, but vitrification was associated with significantly less DNA damage. Secondary endpoints included the number of stromal cells, significantly higher with vitrification, and primordial follicle density, which did not differ between the two methods. The present meta-analysis suggests that vitrification may be more effective than slow freezing, with less primordial follicular DNA strand breaks and better preservation of stromal cells. These advantages should lead to improved ovarian function after transplantation.

/pdf/vitrification-versus-slow-freezing-for-human-ovarian-tissue-2u0de8xtgc.pdf

Vitrification versus slow freezing for human ovarian tissue cryopreservation: a systematic review and meta-anlaysis

STUDY QUESTION Can granulosa cells produce progesterone (P) in response to FSH stimulation? SUMMARY ANSWER FSH actively promotes P synthesis and output from granulosa cells without luteinization by up-regulating the expression and increasing enzymatic activity of 3β-hydroxysteriod dehydrogenoase (3β-HSD), which converts pregnenolone to P. WHAT IS KNOWN ALREADY Serum P level may rise prematurely prior to ovulation trigger in stimulated IVF cycles and adversely affect implantation and clinical pregnancy rates by impairing endometrial receptivity. STUDY DESIGN, SIZE, DURATION A translational research study. PARTICIPANTS/MATERIALS, SETTING, METHODS Human ovarian cortical samples (n = 15) and non-luteinizing FSH-responsive human mitotic granulosa cell line (HGrC1) were stimulated with rec-FSH at 12.5, 25 and 50 mIU/ml concentrations for 24 and 48 h. FSH receptor expression was knocked-down and up-regulated in the granulosa cells using short hairpin RNA (shRNA) technology and activin-A administration, respectively. The expressions of the steroidogenic enzymes were analyzed at mRNA level by real-time quantitative RT-PCR, and protein level by western blot and immunoprecipitation assay. The enzymatic activity of 3β-HSD was measured using a spectrophotometric method. In vitro estradiol (E2) and P productions of the cells before and after FSH stimulation were measured by electro-chemiluminescence immunoassay method. MAIN RESULTS AND THE ROLE OF CHANCE Stimulation of the HGrC1 cells with FSH resulted in a dose-dependent increase in the mRNA and protein level of 3β-HSD. Overall, when all time points and FSH doses were analyzed collectively, FSH significantly up-regulated the mRNA expression of its own receptor (3.73 ± 0.06-fold, P   0.05) did not significantly change. Similar changes were observed in the protein expression analysis of these enzymes on western blotting after FSH stimulation. FSH significantly increased 3β-HSD, 17β-HSD and aromatase in a dose-dependent manner but did not affect 17α-OH. Protein expression of P was increased along with 3β-HSD after FSH stimulation, which was further evidenced by immunoprecipitation assay. Enzymatic activity of 3β-HSD was significantly enhanced by FSH administration in the HGrC1 cells in a dose-dependent manner. In line with these findings P output (1.05 ± 0.3 vs. 0.2 ± 0.1 ng/ml, respectively, P < 0.001) from the samples stimulated with FSH were significantly increased along with E2 (1918 ± 203 vs. 932 ± 102 pg/ml, respectively, P < 0.001) compared to unstimulated controls. FSH-induced increase in 3β-HSD expression was amplified and reversed in the HGrC1 cells when FSH receptor expression was up-regulated by activin-A and down-regulated with shRNA, respectively. LIMITATIONS AND REASONS FOR CAUTION As only the effect of FSH was studied we cannot extrapolate our findings to the potential effects of HMG and recombinant LH. WIDER IMPLICATIONS OF THE FINDINGS This data provides a molecular explanation for the largely unexplained phenomenon of P rise during the follicular phase of gonadotropin stimulated IVF cycles. Our findings may progress the research to uncover potential mechanisms for preventing premature P rise that appears to be associated with inferior outcomes in women undergoing IVF. STUDY FUNDING/COMPETING INTEREST(S) Funded by the School of Medicine and the Graduate School of Health Sciences of Koc University. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER None.

FSH Stimulation promotes progesterone synthesis and output from human granulosa cells without luteinization.

Endometrioma surgery by stripping the cyst capsule has been associated with a reduction in ovarian reserve. It is still not clear whether the inflicted damage is immediate, sustained over time or associated with the use of electrocautery, nor which marker is more accurately reflects the post-operative reduction in ovarian reserve. This observational study assessed the damage inflicted by endometrioma removal with anti-Mullerian hormone (AMH) concentration and antral follicle count (AFC) pre and post-operatively. Twenty-five women with unilateral endometrioma underwent laparoscopic stripping of the endometrioma cyst capsule. There was a significant decrease both in AMH concentration (24%) and in AFC (11%) 1 month following surgery ( P Endometrioma surgery by stripping the cyst capsule has been associated with a reduction in ovarian reserve. It is still not clear whether the inflicted damage is immediate, sustained over time or associated with the use of electrocautery, nor which marker more accurately reflects the post-operative reduction in ovarian reserve. In this observative study, we assessed the damage inflicted by endometrioma removal with anti-Mullerian hormone (AMH) and antral follicle count (AFC) pre- and post-operatively. Twenty-five women underwent laparoscopic stripping of the endometrioma cyst capsule. There was a 24% decrease in AMH concentration and an 11% decrease in AFC compared with the preoperative values 1month following surgery. The values did not change 6months after surgery over those recorded at 1month post-operatively (24 and 15% less than preoperative values. Primordial follicles embedded adjacent to the cyst capsule were found in 61.5% of the specimens. Endometrioma surgery by stripping of the cyst capsule is associated with a significant reduction in ovarian reserve. The reduction is immediate and sustained over time. AMH appears to be a better indicator for post-operative quantification of the ovarian reserve.

https://www.rbmojournal.com/article/S1472-6483(13)00241-1/pdf

Removal of unilateral endometriomas is associated with immediate and sustained reduction in ovarian reserve

https://www.fertstert.org/article/S0015-0282(11)00005-7/pdf

Vitrified human ovaries have fewer primordial follicles and produce less antimüllerian hormone than slow-frozen ovaries.

Study question Is there any in vitro evidence for or against ovarian protection by co-administration of a GnRH agonist with chemotherapy in human? Summary answer The co-administration of GnRH agonist leuprolide acetate with cytotoxic chemotherapy agents does not preserve ovarian reserve in vitro. What is known already Randomized controlled trials of the co-administration of gonadotrophin-releasing hormone (GnRH) agonists with adjuvant chemotherapy to preserve ovarian function have shown contradictory results. This fact, together with the lack of a proven molecular mechanism of action for ovarian protection with GnRH agonist (GnRHa) places this approach as a fertility preservation strategy under scrutiny. We therefore aimed in this study to provide in vitro evidence for or against the role of GnRHa in the prevention of chemotherapy-induced damage in human ovary. Study design, settings, size and duration This translational research study of ex vivo and in vitro models of human ovary and granulosa cells was conducted in a university hospital between 2013 and 2015. Participants/materials, setting, methods Ovarian cortical pieces (n = 15, age 14-37) and mitotic non-luteinized (COV434 and HGrC1) and non-mitotic luteinized human granulosa cells (HLGC) expressing GnRH receptor were used for the experiments. The samples were treated with cyclophosphamide, cisplatin, paclitaxel, 5-FU, or TAC combination regimen (docetaxel, adriamycin and cyclophosphamide) with and without GnRHa leuprolide acetate for 24 h. DNA damage, apoptosis, follicle reserve, hormone markers of ovarian function and reserve (estradiol (E2), progesterone (P) and anti-mullerian hormone (AMH)) and the expression of anti-apoptotic genes (bcl-2, bcl-xL, bcl-2L2, Mcl-1, BIRC-2 and XIAP) were compared among control, chemotherapy and chemotherapy + GnRHa groups. Main results and the role of chance The greatest magnitude of cytotoxicity was observed in the samples treated with cyclophosphamide, cisplatin and TAC regimen. Exposure to these drugs resulted in DNA damage, apoptosis and massive follicle loss along with a concurrent decline in the steroidogenic activity of the samples. GnRHa co-administered with chemotherapy agents stimulated its receptors and raised intracellular cAMP levels. But it neither activated anti-apoptotic pathways nor prevented follicle loss, DNA damage and apoptosis induced by these drugs. Limitations, reasons for caution Our findings do not conclusively rule out the possibility that GnRHa may offer protection, if any, through some other mechanisms in vivo. Wider implications of the findings GnRH agonist treatment with chemotherapy does not prevent or ameliorate ovarian damage and follicle loss in vitro. These data can be useful when consulting a young patient who may wish to receive GnRH treatment with chemotherapy to protect her ovaries from chemotherapy-induced damage.

/pdf/gnrh-agonist-leuprolide-acetate-does-not-confer-any-rspa5f9lmc.pdf

Ebru Alper

Papers

FSH Stimulation promotes progesterone synthesis and output from human granulosa cells without luteinization.

Removal of unilateral endometriomas is associated with immediate and sustained reduction in ovarian reserve

Vitrified human ovaries have fewer primordial follicles and produce less antimüllerian hormone than slow-frozen ovaries.

GnRH agonist leuprolide acetate does not confer any protection against ovarian damage induced by chemotherapy and radiation in vitro

The impact of laparoscopic ovarian cystectomy on ovarian reserve as assessed by antral follicle count and serum AMH levels