Preservation Of Ovarian Function Research Articles

Recurrent Ovarian Torsion due to Paratubal Cysts in an Adolescent Female

BackgroundThough paratubal and paraovarian cysts are rare in adolescent females, the influence of post-menarchal hormonal stimulation on these tubal derivates can produce large and clinically significant adnexal pathology. Ovarian torsion secondary to paratubal cysts is rare due to the cyst’s location and ipsilateral recurrence is uncommon. CaseWe report a case of an 11-year-old female with a large right paratubal cyst causing ovarian torsion on two separate occasions within one year and our approach to surgical management. ConclusionExcision of a paratubal or paraovarian cyst that causes ovarian torsion is necessary to decrease the risk of cyst recurrence and ovarian torsion in the future. Timely diagnosis and treatment of ovarian torsion enables preservation of ovarian function and patient fertility.

Gonadotropin-Releasing Hormone Agonist for Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer

TO THE EDITOR: Munster et al are to be congratulated for their prospective, randomized study. However, the conclusion may be inaccurate and biased by the premature ending of the correctly planned study. The study was targeted for 124 patients with a planned 5-year follow-up but was “stopped for futility after 49 patients were enrolled,” p533 with only 47 patients evaluable. For protocols in which 88% to 90% of patients resume regular menstruation within two years after chemotherapy, there is apparently little need for any intervention toward preservation of ovarian function. For such low gonadotoxic protocols, the number of patients needed to enroll onto each arm is much higher than 21 or 26. Indeed, the prestudy calculation required inclusion of 124 patients. Only in protocols resulting in more than 30% premature ovarian failure could a gonadotropin-releasing hormone agonist-a cotreatment result in a significant beneficial effect on fertility preservation, as detected by the prospective, randomized, multicenter phase III Gruppo Italiano Mammella study of 281 patients or by the prospective, randomized trial by Badawy et al. Last, but not least, all the methods for preservation of fertility despite gonadotoxic chemotherapy and/or radiotherapy are relevant to patients younger than age 40 years, and premature ovarian failure is defined as amenorrhea and high follicle-stimulating hormone levels in women younger than age 40 years. The ovarian reserve after this age is so low that the efficiency of fertility preservation is negligible or undetected. Given that the authors included patients “younger than 45 years of age,” p534 their results may be affected by the diminished ovarian reserve in women older than age 40 years. Indeed, the inclusion criteria of a follicle-stimulating hormone level of “less than 40 mIU/mL” p534 may include patients with low ovarian reserve and impending ovarian failure. We believe, therefore, that the conclusion should be rephrased in a more careful way, awaiting the publication of more accurate studies that are free of similar possible biases.

Gonadotropin-Releasing Hormone Agonists for the Preservation of Ovarian Function During Chemotherapy

Gonadotropin-Releasing Hormone Agonists for the Preservation of Ovarian Function During Chemotherapy

Recognition and Handling of Discordant Negative Human Epidermal Growth Factor Receptor 2 Classification by Oncotype DX in Patients With Breast Cancer

REFERENCES 1. Blumenfeld Z: Gonadotropin-releasing hormone agonist for preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol 30:3310, 2012 2. Tomao F, Benedetti Panici P, Tomao S: Gonadotropin-releasing hormone agonists for the preservation of ovarian function during chemotherapy. J Clin Oncol 30:3310, 2012 3. Munster PN, Moore AP, Ismail-Khan R, et al: Randomized trial using gonadotropinreleasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol 30:533-538, 2012 4. Badawy A, Elnashar A, El-Ashry M, et al: Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: Prospective randomized study. Fertil Steril 91:694-697, 2009 5. Del Mastro L, Boni L, Michelotti A, et al: Effect of the gonadotropinreleasing hormone analogue triptorelin on the occurrence of chemotherapyinduced early menopause in premenopausal women with breast cancer: A randomized trial. JAMA 306:269-276, 2011 6. Gerber B, von Minckwitz G, Stehle H, et al: Effect of luteinizing hormone– releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: The GBG 37 ZORO study. J Clin Oncol 29:2334-2341, 2011 7. Leonard RC, Adamson D, Anderson R, et al: The OPTION trial of adjuvant ovarian protection by goserelin in adjuvant chemotherapy for early breast cancer. J Clin Oncol 28:89s, 2010 (abstr 590) 8. Sukumvanich P, Case LD, Van Zee K, et al: Incidence and time course of bleeding after long-term amenorrhea after breast cancer treatment: A prospective study. Cancer 116:3102-3111, 2010 9. Fornier MN, Modi S, Panageas KS, et al: Incidence of chemotherapyinduced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane. Cancer 104:1575-1579, 2005

Prevention of chemotherapy-induced damage to ovarian reserve by sphingosine-1-phosphate

1097 Background: Chemotherapy agents such as cyclophosphamide (Cy) and doxorubicin (D) are known to compromise ovarian function. We have previously shown that these agents alter ovarian function by causing apoptotic death of primordial follicles and thereby causing diminishment of ovarian reserve (Cancer Research 2007; Aging 2011). While assisted reproduction techniques exist to preserve fertility there has been no proven approach to pharmacologic preservation of ovarian function. Sphingosine-1-Phosphate (S1P) is a naturally occurring ceramide-induced death pathway inhibitor. Here we investigated whether S1P can prevent Cy or D-induced apoptotic follicle death in mouse ovaries. Methods: Eight wk old NOD mice (n=23) were treated with Cy (75 mg/kg), Cy+S1P (200 μM), D (10 mg/kg), D+S1P or vehicle only (Control). S1P was administered via continuous infusion using a mini-osmotic pump beginning 3 hours prior to single dose chemotherapy injection for 72 hours. Ovaries were removed 72h later and serially sectioned, and stained with anti-caspase 3 (AC-3) antibody for the detection of apoptosis in primordial follicles. The ratio of apoptotic to total follicles was expressed as percentage in each group. Results: Both Cy and D resulted in significant increase in apoptotic follicle death compared to controls (48.2±11.6 vs. 28.2±8.9, p=0.016 and 46.4±5.4 vs. 24.8±5.2, p=0.004, respectively). Percentages of apoptotic follicles were similar between Cy and D-treated groups (48.2±11.6 vs. 46.4±5.4, P=NS) indicating that these agents were equally gonadotoxic. S1P treatment resulted in a significant decrease in the percentage of apoptotic follicles both in the Cy (25.6±3.5, P<0.011) and the D group (32.2±10.8, P< 0.013) compared to controls. In the S1P-treated groups, the percentages of apoptotic follicles were similar to those in untreated controls indicating that S1P completely blocked Cy and D-induced apoptotic follicle death. Conclusions: S1P can block apoptotic follicle death induced by highly cytotoxics agents. In addition, we showed that S1P can block follicle death by chemotherapy agents that act through different molecular mechanisms. If targeted delivery systems can be developed, S1P may hold significant promise in preserving fertility by pharmacological means.

Association between the location of transposed ovary and ovarian function in patients with uterine cervical cancer treated with (postoperative or primary) pelvic radiotherapy

To evaluate the effectiveness of ovarian transposition procedures in preserving ovarian function in relation to the location of the transposed ovaries in patients who underwent surgery with or without pelvic radiotherapy. Retrospective. Uterine cancer center. A total of 53 patients with cervical cancer who underwent ovarian transposition between November 2002 and November 2010. Ovarian transposition to the paracolic gutters with or without radical hysterectomy and lymph node dissection. Preservation of ovarian function, which was assessed by patient's symptoms and serum FSH level. Lateral ovarian transposition was performed in 53 patients. Based on receiver operator characteristic curve analysis, optimum cutoff value of location more than 1.5 cm above the iliac crest was significantly associated with preservation of ovarian function after treatment (area under receiver operator characteristic curve: 0.757, 95% confidence interval [CI]: 0.572-0.943). In univariate analysis, higher location of transposed ovary more than 1.5 cm from the iliac crest was the only independent factor for intact ovarian function (odds ratio 9.91, 95% CI: 1.75-56.3). Multivariate analysis confirmed that the location of transposed ovary (odds ratio 11.72, 95% CI 1.64-83.39) was the most important factor for intact ovarian function. Location of transposed ovary higher than 1.5 cm above the iliac crest is recommended to avoid ovarian failure after lateral ovarian transposition after primary or adjuvant pelvic radiotherapy in cervical cancer.

Gonadotropin-Releasing Hormone Analog Cotreatment for Preservation of Ovarian Function

The phase II study of leuprolide for ovarian function preservation in hematopoietic stem cell transplantation patients by Cheng, Takagi, Milbourne et al. (The Oncologist 2012; 17:000–000) is reviewed.

Phase II Study of Gonadotropin-Releasing Hormone Analog for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients

Premature ovarian failure occurs in 40%-70% of patients who receive conventional chemotherapy alone. However, the incidence is higher, 70%-100%, in patients who undergo myeloablative chemotherapy with hematopoietic stem cell transplantation (HSCT). Gonadotropin-releasing hormone (GnRH) analogs, such as leuprolide, in a continuous-release formulation, may protect the ovaries from the gonadotoxic effects of chemotherapy. In non-HSCT settings, GnRH analogs have reduced the risk for premature ovarian failure to <10%. We conducted a phase II clinical trial based on the hypothesis that giving leuprolide before conditioning chemotherapy in HSCT patients reduces premature ovarian failure incidence. Eligible patients were women aged ≤40 years who were HSCT candidates, were premenopausal, and had both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels ≤20 IU/L. Two 22.5-mg leuprolide doses were delivered in 3-month depot i.m. injections, the first within 2 months before HSCT. Patients were monitored for menstruation return, and ovarian function tests (FSH, LH, and estradiol) were done every 2 months starting 90 days after the last leuprolide dose. Sixty eligible patients were enrolled, 59 underwent HSCT, and 44 were evaluable (median age, 25 years; median follow-up, 355 days). Only seven of 44 patients (16%) regained ovarian function. Of the 33 who received myeloablative regimens, six (18%) regained ovarian function. However, among the 11 who received nonmyeloablative regimens, only one (9%) regained ovarian function (p = .66). Leuprolide did not preserve ovarian function in patients who underwent HSCT using either myeloablative or nonmyeloablative regimens. Other measures that protect ovarian function need to be investigated.

Ovarian Suppression for Prevention of Premature Menopause and Infertility: Empty Promise or Effective Therapy?

Fertility and premature menopause are major concerns for young patients who are undergoing treatment for cancer. Young women with breast cancer face particular challenges when considering future fertility compared with other young cancer survivors. The greatest concern is whether preservation of ovarian function and a subsequent pregnancy in a breast cancer survivor could increase the risk of recurrence, particularly in patients with hormone receptor– positive disease. Although there have been a number of observational studies that have suggested no detriment from having a pregnancy after breast cancer, concerns remain for many women and their providers. Even if a woman does not go on to become pregnant, continued menstrual cycling, an imperfect surrogate measure for ovarian function and fertility, has been associated with decreased survival in women with hormone-sensitive disease. Whether suppressing ovarian function in women who remain premenopausal after chemotherapy reduces risk in the era of tamoxifen is the subject of ongoing study, notably the Suppression of Ovarian Function with Triptorelin (SOFT) trial; it has closed to accrual and we await its results. Importantly, for women who are interested in a future biologic child, breast cancer chemotherapy can diminish a woman’s fertility even if she does not experience immediate menopause. In addition, standard hormonal therapy with tamoxifen for women with hormone-sensitive disease entails 5 years of treatment during which a pregnancy is contraindicated and a woman’s ovaries are aging, with an associated decline in fertility. Finally, it can be difficult to determine whether a survivor of breast cancer is fertile. A woman who is menstruating may be infertile, and women who are amenorrheic, especially women who are receiving tamoxifen, which can affect menstrual cycling, may remain fertile. Nevertheless, for young breast cancer survivors who are interested future fertility, as well as those who are concerned about the potential effects of premature menopause on quality of life, sexual functioning, and bone and cardiovascular health, there has been great interest in trying to maintain ovarian functioning after breast cancer chemotherapy. Reported rates of chemotherapy-related amenorrhea and premature menopause range from 10% to 90% depending on age and treatment regimen studied, definition of amenorrhea or menopause, and length and method of follow-up. Several uncontrolled studies have suggested decreased incidence of amenorrhea with the use of gonadotrophin-releasing hormone (GnRH) agonists throughout chemotherapy, compared with historical controls. The use of these agents is appealing, given that they are readily available and are generally less cumbersome than available alternative strategies including in vitro fertilization and embryo cryopreservation before treatment. However, available data from both human and animal studies have been mixed, and reproductive biologists have questioned the biologic plausibility of the preservation of fertility by GnRH agonists, arguing that randomized controlled trials are needed to evaluate efficacy. In the article that accompanies this editorial, Munster et al present one such trial. In their study, premenopausal women age 44 years and younger were randomly assigned to receive triptorelin or no triptorelin during adjuvant or neoadjuvant modern breast cancer chemotherapy. In contrast to previous studies, women were stratified by age, estrogen receptor status, hormonal therapy use, and chemotherapy regimen. The main outcome measures were resumption of menses and levels of follicle-stimulating hormone (FSH), inhibin A, and inhibin B. The study was stopped early for futility after 49 patients (of a planned 124) had been enrolled. Menses resumed in 90% of the women in the control group and 88% of women in the triptorelin group (P .36). There was also no difference in the time to return of menses between the two groups (median of 5.8 months in the triptorelin group and median of 5.0 months in the control group; P .58). Two patients were reported to have had spontaneous pregnancies in follow-up, both of whom were in the control group, although follow-up was relatively short for this outcome. The measurement of markers of ovarian reserve, including FSH, inhibin A, and inhibin B, measured at baseline and serially in follow-up, seemed to show diminished fertility in both groups over time, consistent with the menopausal status of these patients. This study provides important information for our evolving understanding of the potential role of ovarian suppression in women with breast cancer. The investigators used rigorous definitions of continued or resumption of menses, and there was a median follow-up of 18 months. Importantly, they accounted for age mix and chemotherapy regimen as well as the use of tamoxifen in their analysis. Tamoxifen does not seem to have a detrimental JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 30 NUMBER 5 FEBRUARY 1

Randomized Trial Using Gonadotropin-Releasing Hormone Agonist Triptorelin for the Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer

Chemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer. Premenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels. Targeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status. When stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.

P5-23-04: Gonadotrophin-Releasing Hormone Analogues for Ovarian Function Preservation in Women with Premenopausal Breast Cancer Undergoing Adjuvant Chemotherapy: A Systematic Review and Meta-Analysis.

Abstract Background: Breast cancer, the most common female malignancy, is also the most frequent tumor in women of reproductive age. Young women with breast cancer usually present adverse prognostic features and higher rates of recurrence when compared with their older counterparts. Adjuvant chemotherapy is usually recommended for this group of patients and premature ovarian failure (POF) is a potential complication. Material and Methods: We conducted a systematic search in MEDLINE, EMBASE, Cochrane Systematic Reviews databases and ***ClinicalTrials.gov from their inception until June 2011. The search was conducted to include published peer-reviewed studies on the issue of fertility preservation in women with breast cancer undergoing adjuvant chemotherapy. The search terms were tailored individually for each database to include the following Medical Subject Headings (MeSH) and text words: gonadotropin releasing hormone, breast neoplasms, drug therapy, premature ovarian failure and fertility. No language restriction was applied. We also searched for additional studies by reviewing the reference lists of retrieved articles, and studies presented in abstract form were also located in this manner. The main outcomes were return of spontaneous menstruation, ovulation and pregnancy rate. Results: We found 8 RCTs that met the inclusion criteria. Data were extracted from 3 RCTs. Data were only available for resumption of ovulation. There were no data available for markers of ovarian function, rate of ovulation and pregnancy. The rate of women with spontaneous menstruation demonstrated a statistically significant difference in favor of the use of GnRH-a (OR 3.11;95% CI, 2.04-472). Discussion: Use of GnRH concomitant to adjuvant chemotherapy in premenopausal breast cancer women aiming to reduce rates of POF has been subject of controversy during the last decade. Evidence from recently presented RCTs suggests there is a benefit of GnRH for ovarian function protection in this setting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-23-04.

Preservation of Ovarian Function and Minimizing Premature Ovarian Failure during Chemotherapy Using Gonadotropin-Releasing Hormone Analogs

Evaluation of: Del Mastro L, Boni L, Michelotti A et al. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA 306(3), 269-276 (2011). This study is a randomized, open-label, Phase III trial, conducted in 16 Italian centers that enrolled 281 patients between 2003 and 2008. The recruited patients were prospectively and randomly allocated to either chemotherapy alone or combined with monthly triptorelin gonadotropin-releasing hormone analog, started before chemotherapy and repeated every month throughout chemotherapy. The clinical and tumor characteristics of the patients in the control or treatment groups were similar. A total of 12 months after ending chemotherapy, the premature ovarian failure rate was 25.9% in the chemotherapy-alone group versus 8.9% in the chemotherapy and gonadotropin-releasing hormone analog group, an absolute difference of -17% (95% CI: -26 to -7.9%; p < 0.001). The odds ratio for treatment-induced premature ovarian failure was 0.28 (95% CI: 0.14-0.59; p < 0.001). The authors concluded that use of gonadotropin-releasing hormone analog chemotherapy in premenopausal breast cancer patients can significantly reduce the occurrence of chemotherapy-induced early menopause.

Effect of Luteinizing Hormone–Releasing Hormone Agonist on Ovarian Function After Modern Adjuvant Breast Cancer Chemotherapy: The GBG 37 ZORO Study

Observational studies suggested that luteinizing hormone-releasing hormone agonists (LHRHa) might prevent premature ovarian failure resulting from adjuvant chemotherapy in premenopausal patients. We aimed to test the efficacy of ovarian function preservation with the LHRHa goserelin in patients with breast cancer. In a prospective, randomized, open-label, controlled multicenter study, 60 patients younger than age 46 years with hormone-insensitive breast cancer were allocated to receive anthracycline/cyclophosphamide (with or without taxane) -based neoadjuvant chemotherapy with or without goserelin. The first goserelin injection was administered at least 2 weeks before the first chemotherapy cycle, continuing at 3.6 mg subcutaneously every 4 weeks until the end of the last cycle. The primary objective was the reappearance of normal ovarian function, defined as two consecutive menstrual periods within 21 to 35 days at 6 months after end of chemotherapy. Fifty-three patients (88.3%) experienced temporary amenorrhea (93.3% with v 83.3% without goserelin). No significant difference was observed regarding the reappearance of menstruation at 6 months after chemotherapy (70.0% with v 56.7% without goserelin; difference of 13.3%; 95% CI, -10.85 to 37.45; P = .284). All but one evaluable patient reported regular menses at 2 years after chemotherapy. Time to restoration of menstruation was 6.8 months (95% CI, 5.2 to 8.4) with goserelin and 6.1 months (95% CI, 5.3 to 6.8) without goserelin (P = .304). Chemotherapy resulted in a decreased ovarian reserve measured by inhibin B and anti-Müllerian hormone during follow-up, supporting the other findings. Premenopausal patients with breast cancer receiving goserelin simultaneously with modern neoadjuvant chemotherapy did not experience statistically significantly less amenorrhea 6 months after end of chemotherapy compared with those receiving chemotherapy alone.

Medical approaches to preservation of fertility in female cancer patients

Introduction: The loss or impairment of ovarian function is an irreversible side effect that can occur in young cancer patients undergoing anticancer treatments. Its incidence varies according to the type of chemotherapy and the patient's age.Areas covered: The review includes studies or data available in literature from 1987 to 2010, examining current strategies to protect ovarian function and/or fertility in patients undergoing chemotherapy, which include oocyte, embryo or ovarian tissue cryopreservation, and temporary ovarian suppression during chemotherapy obtained by the administration of gonadotropin-releasing hormone analogues (GnRHa). The reader will gain an understanding of the incidence of premature ovarian function loss associated with chemotherapy; the advantages and disadvantages of the different strategies in protecting ovarian function; and the magnitude of the effect of GnRHa strategy in preserving ovarian function during chemotherapy.Expert opinion: The administration of GnRHa before and during chemotherapy is associated with an absolute reduction in the incidence of early menopause of nearly 20%. Such a strategy may be offered to young cancer patients who are candidates for chemotherapy. The capability of such an approach in inducing long-term preservation of ovarian function including fertility is still unknown.

Single-port access laparoscopic ovarian transposition and cryopreservation of ovarian tissue before chemo-radiotherapy in a young woman with rectal cancer

To introduce the first case of single-port access (SPA) laparoscopic ovarian transposition (LOT) and cryopreservation of ovarian tissue before chemo-radiotherapy in a young woman with rectal cancer. We report our experience of SPA-LOT and cryopreservation of ovarian tissue with only minimal skin incision. Patient successfully underwent SPA-LOT and cryopreservation of ovarian tissue before chemo-radiotherapy in a reasonable time without operative complication in order to relocate their ovaries outside the radiation field. A concomitant ovarian wedge resection was performed for ovarian cryopreservation. After surgery and chemo-radiotherapy, she continued to have regular menstrual cycles. For a preservation of ovarian function, SPA-LOT and cryopreservation of ovarian tissue before chemo-radiotherapy is feasible with only minimalskin incision.

Abstract P2-14-04: Co-Administration of GnRH-Agonists with Adjuvant Chemotherapy in Young Breast Cancer Patients: The Effect on Ovarian Function and on Clinical Outcome

Abstract Background: Loss of fertility is a major concern for young breast cancer (BC) patients who require adjuvant chemotherapy. The risk of ovarian failure depends on patient's age and chemotherapy regimen. Use of GnRH agonists (GnRHa) has been proposed as a mean for ovarian function preservation but has been investigated mainly in small single arm studies. Objectives: To evaluate ovarian function preservation and disease free survival (DFS) in young breast cancer patients following GnRHa and adjuvant chemotherapy co-administration. Methods: In this multicenter retrospective study, we reviewed medical records of 560 breast cancer patients diagnosed before the age of 40, from 1990 through 2006. All patients were treated in one of 5 Israeli cancer centers with standard adjuvant or neoadjuvant chemotherapy regimens with curative intent. GnRHa were prescribed at the discretion of the treating physician. Ovarian function preservation was determined by resumption of menses, premenopausal hormonal profile or pregnancy during follow up. Multivariate analysis was applied in order to determine whether coadministration of GnRHa with chemotherapy affects DFS. Results: Data was available for 71 patients who received GnRHa during chemotherapy (group A), 60 of those were evaluable for fertility and 68 were evaluated for DFS. The group not receiving GnRHa included 460 patients (group B). Of those 207 were evaluable for fertility and 370 for DFS. Data concerning patients’ characteristics and outcome in each group are presented in the table 1. In a Cox regression model including age, stage, ER/PR status and GnRHa administration, the latter variable predicted a better DFS rate (RR 0.31; 95% CI 0.16-0.70; p=0.003), excluding the subgroup with ER/PR positive tumors (p=0.128). This probably reflects selection bias of prognostic factors not included in the analysis and not a real anti neoplastic hormonal effect. Conclusions: Patients who received GnRHa were younger and had less advanced disease. Fertility was preserved independent of GnRHa administration and regardless of cumulative doses of cyclophosphamide or taxans. This observation suggests that GnRHa are unnecessary for fertility preservation in patients younger than 40yrs. No detrimental effect of GnRHa during chemotherapy was observed on disease outcome. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-04.

Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function during gonadotoxic chemotherapy: a systematic review and meta-analysis

To determine whether gonadotropin-releasing hormone (GnRH) analog cotreatment with chemotherapy provides better reproductive outcomes for women at risk of premature ovarian failure (POF) as a side-effect of gonadotoxic chemotherapy. Systematic review and meta-analysis. University-affiliated research centers. None. Electronic and manual searches (e.g., MEDLINE, EMBASE, CENTRAL) up to January 2010 were performed to identify randomized controlled trials (RCTs) comparing GnRH cotreatment with chemotherapy alone in premenopausal women. Incidence of POF after treatment, incidence of women with resumption of ovulation, POF after an initial normal cycle, normal cycles but abnormal markers of ovarian reserve, spontaneous occurrence of pregnancy after treatment, and time to reestablishment of menstruation; data also extracted to allow for an intention-to-treat analysis. Twenty-eight RCTs were identified, but only six met the inclusion criteria. Data were only available for the incidence of women with new onset of POF, resumption of ovulation, and occurrence of pregnancy. The incidence of POF or resumption of ovulation both demonstrated a statistically significant difference in favor of the GnRH cotreatment. The occurrence of spontaneous pregnancy showed no statistically significant difference between GnRH cotreatment and the control groups. Evidence from RCTs suggests a potential benefit of GnRH cotreatment with chemotherapy in premenopausal women, with higher rates of spontaneous resumption of menses and ovulation but not improvement in pregnancy rates. Data relating to study quality and possible bias for the majority of the outcomes in this review were not available, denoting possible selective reporting of trial data.

Fertility preservation and infertility treatment in breast cancer patients

About 12% of breast cancer cases occur before the age of 35 years. Thus, young patients may consider preservation of ovarian function during cytotoxic therapy and/or childbearing after treatment. Besides the exposure to cytotoxic agents over several months, a significant number of patients will need sequential antihormonal therapy for years. Thus, even young patients at diagnosis may have to postpone pregnancy for years. At that time, the probability of pregnancy may per se be considerably reduced. Young patients per se carry a worse prognosis compared to their postmenopausal counterparts. Ovaries may harbor viable tumor cells. Premenopausal patients have a higher prevalence of BRCA gene mutation than older patients. Thus, even if the ovaries are preserved, the risk of developing cancer in the ovary may be high. Normal menstrual cyclicity after chemotherapy/antihormonal therapy does not preclude premature ovarian failure. After antineoplastic therapy, it is recommended to wait at least for two months before the evaluation of the ovarian function. The most reliable parameter to assess the ovarian reserve is the anti-muellerian factor (AMH; Muellerian Inhibiting Factor, MIF). Four randomized studies have investigated the protective effect of the GnRH analogue goserelin on ovarian function. Due to the inconsistent results observed, the concurrent administration of GnRH analogues with cytostatic chemotherapy now has to be considered experimental and cannot be recommended. Emergency in vitro fertilization may be performed between breast cancer diagnosis and the start of chemotherapy in selected cases. Extracorporal in vitro fertilization may be performed and the resultant embryo cryopreserved to preserve fertility.

Preservation of Ovarian Function During Chemotherapy

Preservation of Ovarian Function During Chemotherapy

Inguinal uterus, fallopian tube, and ovary associated with adult Mayer-Rokitansky-Küster-Hauser syndrome

To report a case of Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) with a utero-ovarian inguinal hernia, and to present a review of the pertinent literature. Case report and literature review. Hospital clinic. A 31-year-old married woman. Ultrasound, magnetic resonance imaging, intravenous pyelography, hormone analysis, peripheral karyotyping, ovarian biopsy, repositioning of the uterus, fallopian tube, and ovary, herniorrhaphy, and Williams vulvovaginoplasty. Accuracy of diagnosis, preservation of ovarian function, hernia repair and creation of neovagina. Our patient represented an adult case of MRKH syndrome associated with renal abnormality and utero-ovarian inguinal hernia. Our English-language literature search for similar well-documented cases revealed only two. Our management consisted of thorough counseling, and successful one-step ovarian biopsy, repositioning of the uterus, fallopian tube, and ovary, herniorrhaphy, and Williams vulvovaginoplasty. This is the third case of adult 46,XX MRKH with utero-ovarian inguinal hernia in the English literature. Genital repositioning is mandatory to avoid torsion and preserve ovarian function. The choice of the type of hernia repair and vaginoplasty or any other procedure should be individualized to the patient's medical status.