A prospective cohort study with serum anti-mullerian hormone levels change in patients undergoing uterine preservation after gestational trophoblastic neoplasia treatment with a methotrexate regimen.

Objectives: To monitor changes in serum anti-Mullerian hormone (AMH) levels of the patients with gestational trophoblastic neoplasia (GTN) who have undergone uterine preservation during treatment with a Methotrexate (MTX) regimen and associations with AMH variations. Methods: This observational prospective cohort study included 35 patients with low-risk GTN with uterine preservation during single-agent MTX chemotherapy at Hanoi Obstetrics and Gynecology Hospital from August 2021 to August 2022. Serum AMH levels were measured before initiation of chemotherapy and after the 1st, 2nd, and 3rd chemotherapy cycles. AMH evolution and its associations with some factors were analyzed. Results: The median basal AMH level before chemotherapy was 2.87 ng/mL (0.96 - 7.9 ng/mL) and negatively correlated with age. The serum AMH levels decreased significantly after each chemotherapy cycle (2.87 vs. 1.16, 0.91, 0.41 ng/mL). The median magnitude of the AMH levels decline after 1st, 2nd, and 3rd chemotherapy cycles were 51.2%, 69.4%, and 84.6% (p<0.001), respectively. AMH variation was associated with the basal AMH level, but not with age, ßhCG at diagnosis and menstrual status. Conclusion: Our study has shown that the serum AMH levels declined rapidly and steadily in all patients during chemotherapy for GTN. Although AMH cannot be used to monitor fertility potential lonely, these new studies improve our knowledge of ovarian toxicity and ovarian reserve during chemotherapy and strongly support the use of fertility preservation strategies.

Comparison of the multiples of the median of serum anti-müllerian hormone and pregnancy outcomes in patients with gestational trophoblastic disease: A case-control study.

INTRODUCTION: Chemotherapy is crucial in treating gestational trophoblastic neoplasia (GTN), but its impact on gonadotoxicity is unclear. MATERIALS AND METHODS: This case-control study included 57 GTN patients and 19 age-matched patients with molar pregnancies (MP) in 2012-2018. Multiples of the median (MoM) of the serum AMH levels were compared between the two groups, and between patients using single-agent and combination chemotherapy, at baseline, 6, 12, and 24 months after treatment. Their pregnancy outcomes were also compared. RESULTS: There was no significant difference in the MoM of serum AMH between GTN and MP groups at all time points. Single-agent chemotherapy did not adversely affect the MoM. However, those receiving combination chemotherapy had lower MoM than those receiving single-agent chemotherapy at all time points. The trend of decline from the baseline was marginally significant in patients with combination chemotherapy, but the drop was only significant at 12 months (Z = -2.69, p = 0.007) but not at 24 months (Z = -1.90; p = 0.058). Multivariable analysis revealed that combination chemotherapy did not affect the MoM. There was no significant difference in the 4-year pregnancy rate and the livebirth rate between the single-agent and combination groups who attempting pregnancy, but it took 1 year longer to achieve the first pregnancy in the combination group compared to the single-agent group (2.88 vs. 1.88 years). CONCLUSION: This study showed combination chemotherapy led to a decreasing trend of MoM of serum AMH especially at 12 months after treatment, but the drop became static at 24 months. Although pregnancy is achievable, thorough counseling is still needed in this group especially those wish to achieve pregnancy 1-2 years after treatment or with other risk factors.

Identifying risk factors for polycystic ovary syndrome in women with epilepsy: A comprehensive analysis of 248 patients.

To assess the risk factors for polycystic ovary syndrome (PCOS) in women with epilepsy (WWE) and develop a practical approach for PCOS screening based on clinical characteristic, blood indicator, and anti-seizure medication (ASM) profiles. This cross-sectional study was conducted with 248 WWE who were consecutively enrolled from the Epilepsy Center of West China Hospital between April 2021 and March 2022. The epilepsy characteristics, blood indicators, and use of ASMs were compared between WWE with and without PCOS. Multivariate logistic regression was used to identify the factors independently associated with PCOS. The differential analysis showed that younger age at onset of epilepsy (<13 years), a history of birth hypoxia, obesity (BMI ≥25 kg/m2 ), use of levetiracetam (LEV) (≥1 year), higher levels of cholesterol, luteinizing hormone (LH) and anti-Müllerian hormone (AMH), and lower levels of sex hormone-binding globulin were associated with PCOS (p < .05). Multivariate logistic regression identified that obesity (BMI ≥25 kg/m2 ), use of LEV (≥1 year), and higher levels of AMH and LH were independently associated with PCOS in WWE (p < .05). Obesity (BMI ≥25 kg/m2 ), LEV use (≥1 year), and elevated AMH and LH levels suggest an increased in the probability of occurrence of PCOS in WWE. The combination of these profiles provides a practical approach for screening PCOS in WWE.

[Puberty induction in boys with congenital isolated hypogonadotropic hypogonadism].

BACKGROUND: Gonadotropin therapy in boys with congenital isolated hypogonadotropic hypogonadism helps to increase testes volume and induce spermatogenesis in comparison with testosterone therapy. However, difficulties with dose titration, partial therapy success, absence of generally accepted regimen protocols don't allow to use this therapy in order to induce puberty in adolescents with Kallmann syndrome or normosmic hypogonadotropic hypogonadism. AIM: To assess the effectiveness of combination hormonal replacement therapy via human chorionic gonadotropin and recombinant follicle stimulation hormone in adolescents with congenital isolated normosmic hypogonadotropic hypogonadism and with Kallmann syndromeMATERIALS AND METHODS: This is an open single-center prospective non-controlled study. Boys with hypogonadotropic hypogonadism were receiving hormonal replacement therapy for 12 months. Initial dose of human chorionic gonadotropin was 500 IU per week. Initial dose of recombinant follicle stimulation hormone was 37.5 IU per week. Doses were doubled in 6 months. Antropometric data, Tanner stage, testes volumes, inhibin B and anti-Mullerian hormone (AMH) levels were evaluated in all the patients before the treatment, after 6 and 12 months of the therapy. RESULTS: 8 boys with hypogonadotropic hypogonadism were included into the study. Median age before therapy initiation was 15.7 years [15.33; 16.41]. In 12 months after the therapy initiation puberty development, testosterone increase from 0.44 [0.34;0.62] to 4.39 [0.88;10.51] nmol/l (p=0.012), AMH decrease from 35.70 [18.00;59.00] to 14.41 [11.60;16.65] ng/ml were noted in all the patients (p=0.017). Testes volumes increase and inhibin B level increase were not statistically significant. CONCLUSION: Gonadotropin therapy is effective in order to puberty initiation in adolescents with congenital hypogonadotropic hypogonadism. In helps to achieve not only androgenization, but also to Sertoli cells maturation.

Systemic isotretinoin for acne treatment: Ovarian reserve is safe with the low dose.

Isotretinoin is among the most frequently used medications in the dermatologic daily practice. With a Black box warning, teratogenicity is a major concern. Female fertility may be an issue to be investigated when it comes to its use in females. The aim of this work was to assess the effect of low dose isotretinoin on the ovarian reserve in female patients with moderate to severe acne. Sixty-sex female acne patients candidate for isotretinoin therapy and 66 controls were enrolled in this prospective controlled cohort study. Low dose isotretinoin (0.25-0.4 mg/kg/day) was given to the patients group for 6 months. Serum anti-Mullarian hormone (AMH), ovarian volume (OV) and Antral follicle count (AFC) were evaluated at baseline and 6 months after the last dose in the patients' group, and 1 year after the baseline assessment for the control subjects. There was no significant difference in serum AMH between patients after isotretinoin treatment and control subjects (p = 0.898). AMH failed to show any significant change in pre- and post- treatment levels in patients' group (p = 0.747). Both OV and AFC showed no significant changes in patient group when comparing pre- post- treatment levels on both sides (p > 0.05) and in control group between baseline and 1-year-interval levels on both sides (p > 0.05). Low-dose isotretinoin in treatment of moderate to severe acne seems to be safer on ovarian reserve as indicated by non-significant change in AMH levels as a sensitive parameter of female fertility.

Assessment of the Ovarian Reserve by Serum Anti-Müllerian Hormone in Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: The ovarian reserve has been reported to be diminished in patients with rheumatoid arthritis. However, these results are still controversial. Anti-Müllerian hormone (AMH) is considered a reliable biomarker for the ovarian reserve. We thus performed a meta-analysis to evaluate the AMH levels and the effect of DMARDs on the ovarian reserve in rheumatoid arthritis patients. METHODS: PubMed, EMBASE, the Cochrane Library, and 2 Chinese databases (CNKI and Wanfang database), up to September 2021, were searched for relevant studies. The Newcastle-Ottawa scale (NOS) was used to assess the quality of the included studies. Pooled standard mean difference (SMD) with 95% confidence intervals (CIs) were determined with the random-effects model. The heterogeneity was described by I2 statistic and p value from the Cochrane Q test. RESULTS: Eight eligible studies (679 patients and 1,460 controls) were included in the meta-analysis. Compared with healthy control, the AMH levels in RA patients were significantly lower with the pooled SMD of -0.40 (95% CI: -0.66 to -0.14). However, in comparison of AMH with and without DMARD treatment, there was no significant difference with the pooled SMD of -0.1 (95% CI: -0.39 to 0.19). CONCLUSION: The results indicated that there was an increased risk of ovarian failure in RA patients and which is not related to DMARD treatment.

Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process.

Polycystic ovary syndrome (PCOS) is the most common reproductive and metabolic disorder affecting women of reproductive age. PCOS has a strong heritable component, but its pathogenesis has been unclear. Here, we performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control and third-generation PCOS-like mice. We found that DNA hypomethylation regulates key genes associated with PCOS and that several of the differentially methylated genes are also altered in blood samples from women with PCOS compared with healthy controls. Based on this insight, we treated the PCOS mouse model with the methyl group donor S-adenosylmethionine and found that it corrected their transcriptomic, neuroendocrine, and metabolic defects. These findings show that the transmission of PCOS traits to future generations occurs via an altered landscape of DNA methylation and propose methylome markers as a possible diagnostic landmark for the condition, while also identifying potential candidates for epigenetic-based therapy.

Anti-Müllerian hormone and Inhibin B after stem cell transplant in childhood: a comparison of myeloablative, reduced intensity and treosulfan-based chemotherapy regimens.

Serum concentrations of Anti-Müllerian hormone (AMH) and Inhibin B were used to assess potential fertility in survivors of childhood haematopoietic stem cell transplantation (HSCT) after three chemotherapy-conditioning regimens of differing intensity. Of 428 patients transplanted between 1990-2012 for leukaemia and immunodeficiency 121 surviving >1 year after a single HSCT were recruited. Group A had a treosulfan-based regimen (low-toxicity); Group B had fludarabine/melphalan (Flu-Mel) (reduced-intensity) and Group C had busulphan/cyclophosphamide (Bu-Cy) (myelo-ablative). Mean age at HSCT and follow-up and length of follow-up were 3.6, 11.8 and 9.9 years. Mean AMH standard deviation scores (SDS) were significantly higher in Group A (-1.047) and Group B (-1.255) than Group C (-1.543), suggesting less ovarian reserve impairment after treosulfan and Flu-Mel than after Bu-Cy. Mean serum AMH concentration was significantly better with treosulfan (>1.0 µg/l) than with Flu-Mel or Bu-Cy. In males, mean Inhibin B SDS was significantly higher in Group A (-0.506) than in Group B (-2.53) and Group C (-1.23) with the Flu-Mel group suffering greatest impairment. In conclusion, a treosulfan-based regimen confers a more favourable outlook for gonadal reserve than Flu-Mel or Bu-Cy in both sexes. Higher values of Inhibin B after Bu-Cy than after Flu-Mel may reflect recovery over time.

AMH-based ovarian stimulation versus conventional ovarian stimulation for IVF/ICSI: a systematic review and meta-analysis.

BACKGROUND: Anti-Müllerian hormone (AMH) used to establish patient profiles and predict ovarian response to stimulation, its role in assisted reproductive technology techniques is crucial. PURPOSE: To evaluate the evidence from published RCTs about the efficacy and safety of AMH-based ovarian stimulation versus conventional ovarian stimulation. METHOD: Search strategy: electronic databases were searched using the following MeSH terms (Anti-Müllerian hormone OR AMH) AND (IVF OR ICSI) and (tailored OR based). SELECTION CRITERIA: only RCTs were included. Four studies were included in the quantitative synthesis. DATA COLLECTION AND ANALYSIS: the extracted data were entered into RevMan software, the relative risk (RR) and 95% confidence interval (CI) were used for data analysis. RESULTS: Primary outcomes: ongoing pregnancy: test for overall effect was in favor of AMH-based group, but there was no statistically significant difference [RR = 0.95, 95% CI (0.84-1.08), P = 0.44]. Severe ovarian hyperstimulation syndrome (OHSS) test or overall effect was in favor of AMH-based group, but there was still no statistically significant difference [RR = 0.68, 95% CI (0.43-1.06), P = 0.09]. Secondary outcomes were dose of rFSH, the number of oocytes retrieved, fertilized oocytes, embryos (day 3), blastocysts (day 5), and duration of stimulation. Only the dose of rFSH and duration of stimulation were in the favor of AMH-based group, with statistically significant difference. The other four secondary outcomes were in the favor of the conventional group but with no statistically significant difference. CONCLUSION: AMH-based stimulation has the same results of pregnancy rate and risk of OHSS and can reduce the dose of rFSH and duration of stimulation.

Effects of malignancies on fertility preservation outcomes and relevant cryobiological advances.

A decrease in cancer deaths has resulted in the possibility of child bearing for many young adult cancer survivors. Most antitumor treatment modalities are detrimental to female fertility, and methods for fertility preservation before gonadotoxic treatment, including cryopreservation of oocytes, embryos and ovarian tissue, have therefore been developed. This review focuses on the ovarian function of cancer patients, the safety and efficacy of fertility preservation methods, and the pregnancy outcomes of these patients. Breast cancer and hematological tumors constitute the majority of cancers in reproductive-aged female oncology patients. Ovarian function may not be impacted by breast cancer cells, while in patients with hematological malignancies, decreases in anti-Müllerian hormone and antral follicle counts have been demonstrated. In most cases, patients can undergo ovarian stimulation without delaying treatment, and a new stimulation protocol known as dual stimulation, which may be more efficient, has now been developed. Birth outcomes are also acceptable in cancer patients.

The role of anti-Müllerian hormone (AMH) in ovarian disease and infertility.

PURPOSE: In this review, the current knowledge on anti-Müllerian hormone (AMH) is presented, concerning its value in disease and IVF treatment as well as in terms of its prospective clinical use. METHODS: AMH is becoming the most appropriate biomarker for the ovarian reserve measured predominantly for assisted reproductive treatment (ART) patients in comparison to the currently used antral follicle count (AFC). However, this is not the only way AMH measurements can be used in the clinics. Because of this, we reviewed the current literature for the use of AMH in current or prospective clinical practice. RESULTS: We found that AMH has a high predictive value in assessing the ovarian reserve, which can lead to a better efficiency of in vitro fertilization (IVF) procedures. It has a high potential to be developed as a staple diagnostic marker of ovarian disease, especially for ovarian cancers and even as a possible treatment tool for certain cancers. It could potentially be used to prevent oocyte loss due to chemo- or radiotherapy. CONCLUSION: AMH is an important hormone especially in women reproductive organs and is currently seen as the best biomarker for a multitude of uses in reproductive medicine. Currently, the biggest issue lies in the lack of international standardization of AMH. However, it is encouraging to see that there is interest in AMH in the form of research on its action and use in reproductive medicine.

Müllerian inhibiting substance/anti-Müllerian hormone as a fertility preservation agent.

PURPOSE OF REVIEW: The nascent field of oncofertility is quickly gaining traction as novel experimental treatments are being developed, driving a renewed interest in Müllerian inhibiting substance (MIS) as an ovarian fertoprotectant. RECENT FINDINGS: MIS is unique in its mechanisms of ovarian protection by virtue of acting directly on granulosa cells of primordial follicles and for being a benign reproductive hormone, with few side effects. We will explore in this review how it may be utilized to protect the ovary from chemotherapy, or to enhance ovarian tissue cryopreservation therapy. We will also examine potential mechanisms of action of MIS across multiple cell types, as well as current limitations in our understanding of the pharmacology of recombinant MIS. SUMMARY: The usefulness of MIS as a fertoprotectant may be dependent on the mechanisms of gonadotoxicity of each chemotherapeutic. Further investigation is needed to determine how to best deliver and combine MIS treatment to existing fertility management strategies.

The use of anti-Müllerian hormone for controlled ovarian stimulation in assisted reproductive technology, fertility assessment and -counseling.

Ovarian reserve can be determined by serum anti-Müllerian hormone (AMH) level and/or antral follicle count before controlled ovarian stimulation. The aim of controlled ovarian stimulation is to achieve an appropriate number of mature follicles and avoid complications such as ovarian hyperstimulation syndrome. Measurement of the ovarian reserve is useful for clinicians as it predicts the ovarian response to controlled ovarian stimulation. Further, it assists in giving the patient realistic expectations regarding the treatment. By determining the ovarian reserve, the most appropriate stimulation protocol and gonadotropin dose can be chosen specifically for each woman enabling so-called "individualized treatment" in line with the personalized treatment concept. Many benefits come with using AMH as a biomarker for ovarian reserve; the hormone is considered fairly cycle independent apart from a small decrease in the late follicular phase and there is no inter-observer variance. However, the use of AMH also has limitations; since the implementation of AMH in fertility treatment several AMH assays have been developed. This has made direct comparisons of AMH serum levels complicated. Currently, no international standardized assays exist. AMH is a valid predictor of the ovarian response to controlled ovarian stimulation and to some extent the chance of pregnancy in relation to assisted reproductive technology, but AMH is less optimal in prediction of spontaneous pregnancy and live birth after assisted reproductive technology. Accordingly, AMH can be used to optimize gonadotropin stimulation in fertility treatment, but is not recommended as a screening tool in the general population.

Potential therapeutic applications of human anti-Müllerian hormone (AMH) analogues in reproductive medicine.

Members of the transforming growth factor-beta (TGF-beta) superfamily are key regulators of various physiological processes. Anti-Müllerian hormone (AMH) which is also commonly known as Müllerian-inhibiting substance (MIS) is a member of the TGF-beta superfamily and an important regulator of reproductive organ differentiation and ovarian follicular development. While AMH has been used for diagnostic purposes as a biomarker for over 15 years, new potential therapeutic applications of recombinant human AMH analogues are now emerging as pharmacologic agents in reproductive medicine. Therapeutic uses of AMH in gonadal tissue may provide a unique opportunity to address a broad range of reproductive themes, like contraception, ovulation induction, onset of menopause, and fertility preservation, as well as specific disease conditions, such as polycystic ovarian syndrome (PCOS) and cancers of the reproductive tract. This review explores the most promising therapeutic applications for a novel class of drugs known as AMH analogues with agonist and antagonist functions.

Short-term exposure of human ovarian follicles to cyclophosphamide metabolites seems to promote follicular activation in vitro.

How chemotherapy affects dormant ovarian primordial follicles is unclear. The 'burnout' theory, studied only in mice, suggests cyclophosphamide enhances primordial follicle activation. Using 4-hydroperoxycyclophosphamide (4hc) and phosphoramide mustard (PM), this study assessed how the active cyclophosphamide metabolites 4-hydroxycyclophosphamide (4-OHC) and PM, affect human primordial follicles. Frozen-thawed human ovarian samples were sliced and cultured with basic culture medium (cultured controls) or with 4hc/PM (3 µmol/l/10 µmol/l) (treated samples) for 24-48 h. Follicular counts and classification, Ki67 and anti-Müllerian hormone (AMH) immunohistochemistry and an apoptosis assay were used for evaluation, and 17ß-oestradiol and AMH were measured in spent media samples. Generally, there was primordial follicle decrease and elevated developing follicle rates in treated samples compared with cultured (P = 0.04 to P < 0.0005) and uncultured controls (P < 0.05 to P < 0.0001). No traces of apoptosis were found. There were almost twicethe levels of AMH and 17ß-oestradiol in treated compared with untreated samples (AMH with 4hc 3 µmol/l; P = 0.04). All follicles stained positively for AMHincluded treated samples. Ki67 positive staining was noted in all samples. Cyclophosphamide metabolites seem to enhance human primordial follicle activation to developing follicles, in vitro. Study findings support the 'burnout' theory as the mechanism of chemotherapy-induced ovarian toxicity.

Anti-Müllerian Hormone in Female Adolescent Cancer Patients Before, During, and After Completion of Therapy: A Pilot Feasibility Study.

STUDY OBJECTIVE: Alkylating agents are implicated in premature ovarian insufficiency. To optimize counseling regarding future ovarian function in survivors of adolescent cancer, we describe anti-Müllerian hormone (AMH) levels in female adolescents at diagnosis, during, and shortly after completion of chemotherapy. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: This was a prospective single-institution study. Participants were a mixed population of newly diagnosed postmenarchal female adolescents with malignancy. AMH was performed at diagnosis (T1), 6 months from diagnosis (T2), at end of therapy or 12 months [T3, whichever came first], 1 year after the end of therapy or 24 months from diagnosis [T4, whichever came first], and 18 months from the time of diagnosis (T5). All patients had baseline pelvic ultrasound examinations. Presence of menses and hot flashes were recorded at each time point. RESULTS: Sixteen participants with a median age at diagnosis of 14.3 years (range 12-17 years) were followed for 18.2 months (range, 14-24 months). Oncology diagnoses included leukemia, lymphoma, and sarcoma. Ten patients (62.5%) received alkylating agents with a median cumulative dose of 3041 mg/m2 (range, 2639-6478 mg/m2) of cyclophosphamide. Almost half (n = 7; 44%) experienced amenorrhea during treatment with resumption of menses in 6 of 7 patients (85%). Fifteen of 16 (94%) participants showed a decline in mean AMH levels by 6 months (T2) from diagnosis (15.8 IU/mL at T1 vs 6.5 IU/mL at T2; P = .003) and 12 of 15 (80%) showed at least some recovery of AMH (mean AMH at T4 = 13.2 IU/mL compared with 6.5 IU/mL at T2; P = .02). There was no difference in the mean decline nor recovery of AMH in those who did, vs did not receive cyclophosphamide. CONCLUSION: To our knowledge, this is the largest series to date in adolescents showing that AMH is uniformly suppressed during cancer therapy and short-term recovery occurs in just more than half of the patients by 18-24 months. The contribution of short-term AMH measurements in predicting long-term ovarian function remains to be defined. Long-term follow-up with serial AMH levels is required to help predict those at risk for premature ovarian insufficiency.

Is anti-Müllerian hormone associated with IVF outcomes in young patients with diminished ovarian reserve?

AIM: To investigate whether anti-Müllerian hormone (AMH) is associated with IVF cycle outcomes in young patients with diminished ovarian reserve. MATERIALS & METHODS: Retrospective study of patients <35 years of age undergoing fresh IVF who had at least two 8-cell, day-3 embryos transferred with grades 1, 1.5 or 2. Patients were subgrouped, a priori, based on serum AMH levels: <1 or >1 ng/ml and <0.5 or >0.5 ng/ml. RESULTS: In total, 1005 patients were included. Patients in the >1 ng/ml group required lesser gonadotropins compared with the <1 ng/ml and the <0.5 ng/ml group. More oocytes were retrieved from the same group compared with the latter two (p < 0.001). Despite these differences, the overall rates of clinical pregnancy, spontaneous abortion and live birth were comparable between the two groups. CONCLUSION: In patients with diminished ovarian reserve who have good quality embryos, AMH is not associated with clinical pregnancy, spontaneous miscarriage or live birth rates.

AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer.

To improve ovarian cancer patient survival, effective treatments addressing chemoresistant recurrences are particularly needed. Mullerian inhibiting substance (MIS) has been shown to inhibit the growth of a stem-like population of ovarian cancer cells. We have recently engineered peptide modifications to human MIS [albumin leader Q425R MIS (LRMIS)] that increase production and potency in vitro and in vivo. To test this novel therapeutic peptide, serous malignant ascites from highly resistant recurrent ovarian cancer patients were isolated and amplified to create low-passage primary cell lines. Purified recombinant LRMIS protein successfully inhibited the growth of cancer spheroids in vitro in a panel of primary cell lines in four of six patients tested. Adeno-associated virus (AAV) -delivered gene therapy has undergone a clinical resurgence with a good safety profile and sustained gene expression. Therefore, AAV9 was used as a single i.p. injection to deliver LRMIS to test its efficacy in inhibiting growth of palpable tumors in patient-derived ovarian cancer xenografts from ascites (PDXa). AAV9-LRMIS monotherapy resulted in elevated and sustained blood concentrations of MIS, which significantly inhibited the growth of three of five lethal chemoresistant serous adenocarcinoma PDXa models without signs of measurable or overt toxicity. Finally, we tested the frequency of MIS type II receptor expression in a tissue microarray of serous ovarian tumors by immunohistochemistry and found that 88% of patients bear tumors that express the receptor. Taken together, these preclinical data suggest that AAV9-LRMIS provides a potentially well-tolerated and effective treatment strategy poised for testing in patients with chemoresistant serous ovarian cancer.

Prediction of different ovarian responses using anti-Müllerian hormone following a long agonist treatment protocol for IVF.

OBJECTIVE: The purpose of this study was to predict the poor and excessive ovarian response using anti-Müllerian hormone (AMH) levels following a long agonist protocol in IVF candidates. RESEARCH DESIGN AND METHODS: Through a prospective cohort study, the type of relationship and appropriate scale for AMH were determined using the fractional polynomial regression. To determine the effect of AMH on the outcomes of ovarian stimulation and different ovarian responses, the multi-nominal and negative binomial regression models were fitted using backward stepwise method. The ovarian response of study subject who entered a standard long-term treatment cycle with GnRH agonist was evaluated using prediction model, separately and in combined models with (ROC) curves. RESULTS: The use of standard long-term treatments with GnRH agonist led to positive pregnancy test results in 30% of treated patients. With each unit increase in the log of AMH, the odds ratio of having poor response compared to normal response decreases by 64% (OR 0.36, 95% CI 0.19-0.68). Also the results of negative binomial regression model indicated that for one unit increase in the log of AMH blood levels, the odds of releasing an oocyte increased 24% (OR 1.24, 95% CI 1.14-1.35). The optimal cut-off points of AMH for predicting excessive and poor ovarian responses were 3.4 and 1.2 ng/ml, respectively, with area under curves of 0.69 (0.60-0.77) and 0.76 (0.66-0.86), respectively. CONCLUSION: By considering the age of the patient undergoing infertility treatment as a variable affecting ovulation, use of AMH levels showed to be a good test to discriminate between different ovarian responses.

Fertility preservation and reproductive health in the pediatric, adolescent, and young adult female cancer patient.

PURPOSE OF REVIEW: As treatments for malignancies become increasingly successful, emphasis on quality of life in survivorship becomes important. Of equal importance is the role of gonadotoxic agents in the management of chronic medical conditions, such as nonmalignant blood disorders and rheumatologic and genetic conditions. Gonadotoxic agents have long-term effects to include ovarian insufficiency, pubertal arrest and subsequent infertility. RECENT FINDINGS: In 2004, ovarian tissue cryopreservation emerged as an investigational but viable option for prepubertal patients and those unable to undergo ovarian stimulation. In 2012, oocyte preservation became standard therapy for patients without a partner or who elected not to use donor sperm or freeze embryos. Ovarian reserve testing with antimullerian hormone to assess fertility after gonadotoxic therapy is a rapidly growing area of interest with potentially significant benefits in personalizing the approach to fertility preservation. SUMMARY: A systematic approach to fertility preservation prior to treatment in all patients receiving gonadotoxic agents optimizes care. Fertility preservation strategies can restore hormonal function and preserve reproductive potential. Future research in personalizing approach to care is critical to meeting the needs of this patient population.