Effect of breast cancer prognostic factors on ovarian reserve and response in fertility preservation.

RESEARCH QUESTION: Do breast cancer prognostic factors influence ovarian reserve and response to ovarian stimulation in the context of fertility preservation? DESIGN: Observational, bicentric retrospective study of 352 women with breast cancer who underwent ovarian stimulation using a random start gonadotrophin releasing hormone antagonist protocol and vitrified oocytes between November 2015 and August 2022. Serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) were measured. The number of oocytes recovered, maturation rate and follicular output rate (FORT) were analysed according to patients' characteristics and breast cancer prognostic factors. RESULTS: Median age was 34 years (31.1-37.1). Median AFC and serum AMH level were 17 (12-26) follicles and 2 (1.2-3.4) ng/ml, respectively. After ovarian stimulation, 10.5 (6.0-16.0) oocytes were recovered, with eight (4-13) being mature. Mean oocyte maturation rate was 79% (62-92). Antral follicle count (>12) significantly affected the risk of recovering fewer than eight mature oocytes (P < 0.0001, multivariate analysis). Follicular responsiveness to FSH, assessed by the follicular output rate (FORT index) and number of oocytes recovered, were 31% (21-50) and 10.5% (6.0-16.0), respectively. FORT index and ovarian stimulation outcomes were not influenced by breast cancer prognostic factors. CONCLUSION: Breast cancer prognostic factors do not influence ovarian reserve markers or response to ovarian stimulation in fertility preservation. Therefore, tumour grade, triple-negative status, HER2 overexpression and high Ki67 should not alter the fertility-preservation strategy when considering ovarian stimulation for oocyte vitrification.

Fertility outcomes several years after urgent fertility preservation for patients with breast cancer.

OBJECTIVE: To study the fertility outcomes of women who tried to conceive after breast cancer (BC) treatment and fertility preservation. DESIGN: Retrospective observational, bicentric cohort study. SETTING: University hospital. PATIENTS: Patients with BC. INTERVENTION: All patients who had undergone fertility preservation before BC treatment between January 2013 and July 2019 were included (n = 844). The endpoint date was March 1, 2022. Patients with missing data on pregnancy attempts after a cancer diagnosis (n = 195) were excluded from the pregnancy analysis. MAIN OUTCOME MEASURES: Cumulative incidences of pregnancy and live birth (LB) were calculated. For women who became pregnant, the time to conception was calculated between the first fertility preservation consultation and the estimated day of conception. For those who did not conceive, we considered the time between the first fertility preservation consultation and the endpoint date, or the date of patient death. A Cox regression model was used to study the predictive factors for pregnancy and LB. RESULTS: Among the 649 patients with available data on pregnancy attempts after BC diagnosis, 255 (39.3% [35.5-43.2]) tried to conceive (median follow-up of 6.5 years). Overall, 135 (52.9% [46.6-59.2]) of these patients achieved a pregnancy, mainly through unassisted conception (79.3% [72.8-84.8]), and 99 reported an LB (representing 38.8% of patients who attempted conception). In our cohort, 48 months after the first fertility preservation consultation, the cumulative incidence of pregnancy was 33.1% ([27.6-37.9]). After adjustment for age, parity, type of chemotherapy administration, and endocrine therapy, only multiparity at diagnosis and absence of chemotherapy were positive predictive factors of pregnancy after cancer. Of the 793 patients who had vitrified oocytes and embryos, 68 used them (27% [21.3-32.5] of the patients who tried to conceive), resulting in 8 LBs (11.8% [5.2-21.9]). Women who used their cryopreserved oocytes and embryos were older at the first consultation of fertility preservation (hazard ratio 1.71 [1.42-2.21]), and chose more often to vitrify embryos (hazard ratio 1.76 [1.28-2.23]). CONCLUSION: Although pregnancy rates after fertility preservation for patients with BC are low, most conceptions are achieved without medical assistance. Our findings provide useful information to advise women on the different techniques of fertility preservation, their efficacy, and safety, as well as the relatively high chances of unassisted conception.

[First-line management of infertile couple. Guidelines for clinical practice of the French College of Obstetricians and Gynecologists 2022]. / Prise en charge de première intention du couple infertile : mise à jour des RPC 2010 du CNGOF.

OBJECTIVE: To update the 2010 CNGOF clinical practice guidelines for the first-line management of infertile couples. MATERIALS AND METHODS: Five major themes (first-line assessment of the infertile woman, first-line assessment of the infertile man, prevention of exposure to environmental factors, initial management using ovulation induction regimens, first-line reproductive surgery) were identified, enabling 28 questions to be formulated using the Patients, Intervention, Comparison, Outcome (PICO) format. Each question was addressed by a working group that had carried out a systematic review of the literature since 2010, and followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) methodology to assess the quality of the scientific data on which the recommendations were based. These recommendations were then validated during a national review by 40 national experts. RESULTS: The fertility work-up is recommended to be prescribed according to the woman's age: after one year of infertility before the age of 35 and after 6months after the age of 35. A couple's initial infertility work-up includes a single 3D ultrasound scan with antral follicle count, assessment of tubal permeability by hysterography or HyFOSy, anti-Mullerian hormone assay prior to assisted reproduction, and vaginal swabbing for vaginosis. If the 3D ultrasound is normal, hysterosonography and diagnostic hysteroscopy are not recommended as first-line procedures. Chlamydia trachomatis serology does not have the necessary performance to predict tubal patency. Post-coital testing is no longer recommended. In men, spermogram, spermocytogram and spermoculture are recommended as first-line tests. If the spermogram is normal, it is not recommended to check the spermogram. If the spermogram is abnormal, an examination by an andrologist, an ultrasound scan of the testicles and hormonal test are recommended. Based on the data in the literature, we are unable to recommend a BMI threshold for women that would contraindicate medical management of infertility. A well-balanced Mediterranean-style diet, physical activity and the cessation of smoking and cannabis are recommended for infertile couples. For fertility concern, it is recommended to limit alcohol consumption to less than 5 glasses a week. If the infertility work-up reveals no abnormalities, ovulation induction is not recommended for normo-ovulatory women. If intrauterine insemination is indicated based on an abnormal infertility work-up, gonadotropin stimulation and ovulation monitoring are recommended to avoid multiple pregnancies. If the infertility work-up reveals no abnormality, laparoscopy is probably recommended before the age of 30 to increase natural pregnancy rates. In the case of hydrosalpinx, surgical management is recommended prior to ART, with either salpingotomy or salpingectomy depending on the tubal score. It is recommended to operate on polyps>10mm, myomas 0, 1, 2 and synechiae prior to ART. The data in the literature do not allow us to systematically recommend asymptomatic uterine septa and isthmoceles as first-line surgery. CONCLUSION: Based on strong agreement between experts, we have been able to formulate updated recommendations in 28 areas concerning the initial management of infertile couples.

Oocyte vitrification for fertility preservation following COS does not delay the initiation of neoadjuvant chemotherapy for breast cancer compared to IVM.

PURPOSE: The objective of the present study was to evaluate whether oocyte vitrification following controlled ovarian stimulation (COS) for fertility preservation (FP) delays the initiation of neoadjuvant chemotherapy (NAC) for breast cancer (BC) as compared to in vitro maturation (IVM). METHODS: We performed a retrospective cohort study including all BC patients eligible for oocyte vitrification following COS or in vitro maturation (IVM) before initiation of NAC between January 2016 and December 2020. The inclusion criteria were female patients aged between 18 and 40, with confirmed non metastatic BC, with indication of NAC, who have had oocyte retrieval for FP after COS, or IVM + / - cryopreservation of ovarian tissue (OTC). Various time points related to cancer diagnosis, FP, or chemotherapy were obtained from a medical record review. RESULTS: A total of 197 patients with confirmed BC who had oocyte retrieval following COS (n = 57) or IVM + / - OTC (n = 140) for FP prior to NAC were included. Overall, the average time from cancer diagnosis to chemotherapy start was similar between patients having undergone COS or IVM before oocyte vitrification (37.3 ± 13.8 vs. 36. 8 ± 13.5 days; p = 0.89). CONCLUSIONS: The indication of NAC for BC should not be considered as an impediment to urgent COS for oocyte vitrification for FP.

Response to Ovarian Stimulation for Urgent Fertility Preservation before Gonadotoxic Treatment in BRCA-Pathogenic-Variant-Positive Breast Cancer Patients.

BRCA 1/2 pathogenic variants increase the risk of developing early and aggressive breast cancers (BC). For these patients, fertility potential can be directly affected by oncologic treatments. In addition, evidence indicates that BRCA-mutated women had a significant reduction in their ovarian reserve. In order to improve their chances of conception after the completion of cancer treatments, fertility preservation should be proposed before the administration of gonadotoxic drugs, ideally by oocyte vitrification after controlled ovarian hyperstimulation (COH). The present investigation aims to assess the ovarian response to COH in BRCA 1/2-pathogenic-variant carriers diagnosed with BC. Patient characteristics and COH outcomes were compared between BRCA-positive (n = 54) and BRCA-negative (n = 254) patients. The number of oocytes recovered did not differ between the two groups. However, the oocyte maturation rate and the number of mature oocytes obtained (7 (4.5-11.5) vs. 9 (5-14) oocytes, p = 0.05) were significantly lower in the BRCA-mutated patients. Although individualized COH protocols should be discussed, BRCA-mutated patients would benefit from FP before BC occurs, in order to cope with the potential accelerated decline of their ovarian reserve, optimize the success rate of FP by repeating COH cycles, and to preserve the feasibility of PGT-M by collecting a large amount of eggs.

Disease-free survival does not differ according to fertility preservation technique for young women with breast cancer.

OBJECTIVE: To study whether fertility preservation strategies using ovarian stimulation or without using it impact long-term disease-free survival of patients with breast cancer. DESIGN: Retrospective bicentric cohort study. SETTING: Two university hospitals. PATIENT(S): In this study, 740 women with breast cancer, aged 18-43 years, who received primary fertility preservation between 2013 and 2019 after a diagnosis of localized breast cancer were included. INTERVENTION(S): Overall, 328 patients underwent at least 1 ovarian stimulation cycle (STIM group) and 412 had a technique without hormonal administration (no STIM group). MAIN OUTCOME MEASURE(S): Disease-free survival and overall survival up to May 2021 were compared between the 2 groups by log-rank test. Cox proportional-hazard regression model was used for multivariable analyses. RESULT(S): Out of the 740 women who underwent fertility preservation, follow-up data were available for 269 women in the STIM group (82%) and 330 (80%) in the no STIM group. Kaplan-Meier estimates of disease-free survival at 4 years were 87.9% (82.8%-92.2%) and 83.1% (78.4%-87.3%) in the STIM and no STIM groups, respectively. After adjustment on prognostic parameters, no significant difference in breast cancer recurrence rate was observed between the STIM and no STIM groups (hazard ratios, 0.83 [0.64-1.08]). Kaplan-Meier estimate of overall survival at 4 years was 97.6% (95.3%-99.2%) and 93.6% (90.9%-95.9%) in the STIM and no STIM groups, respectively. Overall survival was higher in the STIM group than no STIM group (log-rank test). After adjustment on prognostic parameters, the risk of death remained significantly lower in the STIM group (Hazard Ratio, 0.55 [0.35-0.85]). CONCLUSION(S): In our cohort, STIM for fertility preservation in breast cancer did not significantly impact disease-free survival but was associated with higher overall survival. The disease-free survival and overall survival of young patients with breast cancer were not impacted by fertility preservation techniques irrespective of the timing of chemotherapy (neoadjuvant or adjuvant) and the use of ovarian stimulation. Nevertheless, because death and recurrence were rare events, these results should be taken with caution.

Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine.

BACKGROUND: Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology. METHODS: 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. FINDINGS: A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromosomal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link. INTERPRETATION: We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogenesis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility. FUNDING: Université Paris Saclay, Agence Nationale de Biomédecine.

Is letrozole during ovarian stimulation useful in breast cancer patients undergoing fertility preservation to reduce early luteal progesterone levels following GnRH-agonist trigger?

BACKGROUND: In absence of contraindication, breast cancer patients of reproductive age can undergo fertility preservation with controlled ovarian stimulation for oocyte/embryo cryopreservation before the administration of potentially gonadotoxic treatments. High hormonal levels induced by ovarian stimulation might have an adverse impact on hormone-positive breast cancer. Whether letrozole supplementation during ovarian stimulation (COSTLES) reduces serum progesterone levels after GnRHa trigger remains unknown. We aimed to determine whether COSTLES might be useful for breast cancer patients undergoing fertility preservation to reduce early luteal progesterone levels following GnRH-agonist (GnRHa)trigger. METHODS: All women who underwent COS with GnRH antagonist protocol with GnRHa trigger were included. Serum progesterone level measured 12 h after GnRHa trigger was compared between patients undergoing COS with letrozole supplementation (COSTLES group) and patients undergoing COS without letrozole (Control group) for fertility preservation purposes. RESULTS: A total of 246 patients were included, of which 84 patients (34.1%) in the COSTLES group and 162 patients (65.6%) in the Control group. All patients in the COSTLES group were BC patients (n = 84, 100%), while the Control group included 77 BC patients (47.5%). Patients in the two groups were comparable. The mean number of oocytes recovered and vitrified at metaphase 2 stage did not significantly differ between the two groups. Serum progesterone levels on the day after GnRHa trigger were significantly lower in the COSTLES group (8.6 ± 0.7 vs. 10.5 ± 0.5 ng/mL, respectively, p < 0.03), as well as serum E2 levels (650.3 ± 57.7 vs. 2451.4.0 ± 144.0 pg/mL, respectively, p < 0.01). However, the GnRHa-induced LH surge was significantly higher in in the COSTLES group (71.9 ± 4.6 vs. 51.2 ± 2.6 UI/L, respectively, p < 0.01). CONCLUSIONS: Our results show that COSTLES for fertility preservation in breast cancer patients using GnRHa trigger reduces serum progesterone levels compared to ovarian stimulation without letrozole. These findings encourage the use of COSTLES in this context to decrease the potential deleterious effect of elevated hormonal levels on hormone-positive breast cancer.

Oocyte Vitrification for Fertility Preservation in Women with Benign Gynecologic Disease: French Clinical Practice Guidelines Developed by a Modified Delphi Consensus Process.

International guidelines are published to provide standardized information and fertility preservation (FP) care for adults and children. The purpose of the study was to conduct a modified Delphi process for generating FP guidelines for BGD. A steering committee identified 42 potential FP practices for BGD. Then 114 key stakeholders were asked to participate in a modified Delphi process via two online survey rounds and a final meeting. Consensus was reached for 28 items. Among them, stakeholders rated age-specific information concerning the risk of diminished ovarian reserve after surgery as important but rejected proposals setting various upper and lower age limits for FP. All women should be informed about the benefit/risk balance of oocyte vitrification-in particular about the likelihood of live birth according to age. FP should not be offered in rASRM stages I and II endometriosis without endometriomas. These guidelines could be useful for gynecologists to identify situations at risk of infertility and to better inform women with BGDs who might need personalized counseling for FP.

IVF impact on the risk of recurrence of endometrial adenocarcinoma after fertility-sparing management.

RESEARCH QUESTION: Do IVF treatments after conservative management of endometrial atypical hyperplasia or grade 1 endometrial adenocarcinoma (AH/EC) increase the risk of disease recurrence? DESIGN: This is a prospective cohort study from a national registry from January 2008 to July 2019. Sixty patients had an AH/EC and received progestin treatment using chlormadinone acetate for at least 3 months. After remission, 31 patients underwent IVF and 29 did not. The primary outcome was the recurrence rate at 24 months according to the use of IVF. The secondary outcome was the identification of risk factors for recurrence. RESULTS: The probability of 2-year recurrence was 37.7% (SD 10.41%) in the IVF group and 55.7% (SD 14.02%) in the no IVF group (P = 0.13). Obesity, nulliparity, polycystic ovary syndrome, age and tumoural characteristics were not associated with recurrence. Pregnancy was a protective factor for recurrence, with 2-year recurrence probabilities of 20.5% and 62.0% in the pregnancy and no pregnancy groups, respectively (P = 0.002, 95% CI 0.06-0.61). In contrast, the number of cycles, maximum serum oestradiol concentration during ovarian stimulation, ovarian stimulation protocol, total dose of gonadotrophin administered and thickness of the endometrium showed no significant differences in terms of the risk of recurrence in the IVF subgroup. CONCLUSION: IVF treatment after fertility-sparing management of AH/EC does not increase the risk of recurrence. Therefore, it is an acceptable strategy to decrease the time to pregnancy. Overall, the recurrence rate is high enough to justify close monitoring once remission occurs.

Women utilizing oocyte donation have a decreased live birth rate if they displayed a low progesterone level in a previous hormonal replacement mock cycle.

PURPOSE: Is serum progesterone(P) level on day 2 of vaginal P administration in a hormonally substituted mock cycle predictive of live birth in oocyte donation(OD)? METHODS: Retrospective analysis of 110 mock cycles from 2008 to 2016 of OD recipients having at least one subsequent embryo transfer (ET). Endometrial preparation consisted of sequential administration of vaginal estradiol, followed by transdermal estradiol and 600 mg/day vaginal micronized P. In mock cycles, serum P was measured 2 days after vaginal P introduction. OD was performed 1 to 3 years later, without P measurement. RESULTS: In mock cycles, mean serum P level on day 2 was 12.8 ± 4.5 ng/mL (range: 4-28 ng/mL). A total of 32% patients had P < 10 ng/mL. At the time of first OD, age of recipients and donors, number of retrieved and attributed oocytes, and number of transferred embryos were comparable between patients with P < 10 ng/mL in their mock cycles compared with P ≥ 10 ng/mL. Pregnancy and live birth rate after first ET were significantly lower for patients with P < 10ng/mL (9% vs. 35 %; P = 0.002 and 9% vs. 32%; P = 0.008, respectively). Considering both fresh and subsequent frozen-thawed ET, cumulative live birth rate per-patient and per-transfer were significantly lower in patients with P < 10 ng/mL in their mock cycle (14% vs. 35%; P = 0.02 and 11% vs. 27%; P = 0.03). CONCLUSION: A low P level in hormonally substituted cycles several years before ET performed with the same endometrial preparation is associated with a significantly lower chance of live birth. This suggests that altered vaginal P absorption is a permanent phenomenon. Monitoring serum P in hormonally substituted cycles appears mandatory to adjust luteal P substitution.

The proportion of cleaved anti-Müllerian hormone is higher in serum but not follicular fluid of obese women independently of polycystic ovary syndrome.

RESEARCH QUESTION: Does the relative distribution of anti-Müllerian hormone (AMH) isoforms differ between patients depending on their body mass index (BMI) and polycystic ovary syndrome (PCOS) status in serum and follicular fluid? DESIGN: Obese and normal weight patients (PCOS [n = 70]; non-PCOS [n = 37]) were selected for this case-control study in the serum. Between 2018 and 2019, obese (n = 19) and normal weight (n = 20) women with or without PCOS who were receiving IVF treatment were included in the follicular fluid study. The bio-banked serums and follicular fluid were tested for total AMH (proAMH and AMHN,C combined) and proAMH using an automatic analyzer. The AMH prohormone index (API = [proAMH]/[total AMH]x 100) was calculated as an inverse marker of conversion of proAMH to AMHN,C, with only the latter isoform that could bind to the AMH receptor complex. RESULTS: The API was not significantly different between controls and women with PCOS, whereas obese women had a lower API compared with their normal weight counterparts. Grouping PCOS and controls, a lower API was found in obese versus normal weight women, suggesting a greater conversion of proAMH to AMHN,C. The API in the serum was significantly correlated with metabolic parameters. In the follicular fluid, API is not different between obese and normal weight women independently of PCOS and is higher than in the concomitant serum. CONCLUSIONS: The proportion of inactive form of AMH in the serum is higher in normal weight versus obese women but not in the follicular fluid, independently of PCOS. The conversion of proAMH into the cleaved isoform is likely to occur in extra-ovarian tissues and to exacerbate in obese individuals.

A survey of French gynecologists' knowledge and attitudes toward conservative treatment for fertility preservation in young patients with endometrial cancer.

OBJECTIVE: To describe knowledge and attitudes toward fertility preservation (FP) in patients with endometrial atypical hyperplasia or adenocarcinoma (EC/AH) among French gynecologists MATERIALS AND METHODS: A national survey among French gynaecologists: one questionnaire with one common part and two specific parts for gynecological surgeon (GS) or for specialists in reproductive medicine (SRM) was sent from April 2017 to April 2018. Knowledge and attitudes toward FP in EC/AH were evaluated with a "knowledge score" and an "attitudes score" using a four- or five-point Likert scale. RESULTS: One hundred forty physicians completed the survey (87 GS, 53 SRM). The knowledge score was low (59.3% medium/low), but it was significantly higher for GS compared to SRM. The better-known treatments were oral progestins and hysteroscopic resection. Among the participants treating EC/AH, 52.6% found it "difficult" to manage patients and 61.8% regretted the lack of official recommendations. Most physicians seemed to be uncomfortable/unsupportive with FP in EC/AH (57.2% "attitude score' below 11/20). There was a positive correlation between knowledge and attitude scores. GS "usually/always" give advice to patients about FP before EC/AH treatment. After maximum 3-6 months, 56.6% of SRM chose In Vitro Fecundation (IVF) to reduce time-to-pregnancy, with GnRH antagonist protocols (28%) or mild-stimulation (15.1%) to avoid hyperoestrogenism. CONCLUSIONS: Despite reassuring results in the literature, French gynecologists are uncomfortable with FP using EC/AH conservative management, which may be because of a lack of confidence in their knowledge. Specific guidelines are needed to help physicians manage these young patients and their fertility.

Higher live birth rate with stimulated rather than artificial cycle for frozen-thawed embryo transfer.

OBJECTIVE: To study which endometrial preparation allows a better ongoing pregnancy rates (OPR) and live birth rate (LBR) after frozen-thawed embryo transfer (FET) between mild gonadotropin ovarian stimulation (OS) and artificial cycles (AC). STUDY DESIGN: Retrospective follow-up study including all FET performed in one fertility center from 2013 to 2016. In the OS group, gonadotropins were followed by r-hCG triggering. Vaginal micronized progesterone (200 mg/day) was given systematically. In the AC group, estradiol (E2) was started on Day 1. Vaginal micronized progesterone (600 mg/d) was added to E2 for 12 weeks. Data were analyzed using a multiple regression model. RESULTS: Among 1021 FETs, 35% underwent OS preparation, 65% had an AC. As expected, patients in the AC group suffered more from endometriosis (18.5% vs. 12.9%; p = .021) and polycystic ovarian syndrome (21.7% vs. 10.9%; p < .0001) than patients in the OS group. There was no difference between groups with respect to endometrial thickness, number of embryos transferred, development stage at FET, cryopreservation technique. Despite a similar clinical pregnancy rate (CPR) (24.4% vs. 20.8%; p = .189), the OPR was significantly higher in the OS than in the AC group (17.9% vs. 11%; p = .002), leading to an increased LBR (17.1% vs. 9.8%; p < .001). After adjusting for parameters usually linked to early pregnancy losses or potential bias (patient age at freezing, smoking status, PCOS, endometriosis, rank of transfer and previous miscarriages), the results remained significant. CONCLUSION: Despite a similar CPR, LBR was significantly higher with mild OS than with the AC preparation, even after adjusting for potential confounders. In light of these results, the first-line endometrial preparation could be OS instead of an AC. In an AC, a potential defect of the luteal phase may exist, treatment could be optimized to avoid pregnancy losses. A randomized controlled trial should be undertaken to assess the role of OS and ACs in FET.

Emerging Roles of Anti-Müllerian Hormone in Hypothalamic-Pituitary Function.

Since its initial discovery in the 1940s, research into the physiological actions of anti-Müllerian hormone (AMH), from its eponymous role in male developmental biology to its routine clinical use in female reproductive health, has undergone a paradigm shifting change. With several exciting studies recently reporting hitherto unforeseen AMH actions at all levels in the hypogonadal-pituitary-gonadal axis, the importance of this hormone for both hypothalamic and pituitary reproductive control is finding increasing support and significance. In this review, we will briefly summarize what is known about the traditional roles and biology of AMH and how this could be integrated with new findings of AMH actions at the level of the hypothalamic-pituitary axis. We also synthesize the important findings from these new studies and discuss their potential impact and significance to our understanding of one of the most common reproductive disorders currently affecting women, polycystic ovary syndrome.

Interactions between androgens, FSH, anti-Müllerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary.

BACKGROUND: Androgens, FSH, anti-Müllerian hormone (AMH) and estradiol (E2) are essential in human ovarian folliculogenesis. However, the interactions between these four players is not fully understood. OBJECTIVES AND RATIONALE: The purpose of this review is to highlight the chronological sequence of the appearance and function of androgens, FSH, AMH and E2 and to discuss controversies in the relationship between FSH and AMH. A better understanding of this interaction could supplement our current knowledge about the pathophysiology of the polycystic ovary syndrome (PCOS). SEARCH METHODS: A literature review was performed using the following search terms: androgens, FSH, FSH receptor, anti-Mullerian hormone, AMHRII, estradiol, follicle, ovary, PCOS, aromatase, granulosa cell, oocyte. The time period searched was 1980-2015 and the databases interrogated were PubMed and Web of Science. OUTCOMES: During the pre-antral ('gonadotropin-independent') follicle growth, FSH is already active and promotes follicle growth in synergy with theca cell-derived androgens. Conversely, AMH is inhibitory by counteracting FSH. We challenge the hypothesis that AMH is regulated by androgens and propose rather an indirect effect through an androgen-dependent amplification of FSH action on granulosa cells (GCs) from small growing follicles. This hypothesis implies that FSH stimulates AMH expression. During the antral ('gonadotropin-dependent') follicle growth, E2 production results from FSH-dependent activation of aromatase. Conversely, AMH is inhibitory but the decline of its expression, amplified by E2, allows full expression of aromatase, characteristic of the large antral follicles. We propose a theoretical scheme made up of two triangles that follow each other chronologically. In PCOS, pre-antral follicle growth is excessive (triangle 1) because of intrinsic androgen excess that renders GCs hypersensitive to FSH, with consequently excessive AMH expression. Antral follicle growth and differentiation are disturbed (triangle 2) because of the abnormally persisting inhibition of FSH effects by AMH that blocks aromatase. Beside anovulation, this scenario may also serve to explain the higher receptiveness to gonadotropin therapy and the increased risk of ovarian hyperstimulation syndrome (OHSS) in patients with PCOS. WIDER IMPLICATIONS: Within GCs, the balance between FSH and AMH effects is pivotal in the shift from androgen- to oestrogen-driven follicles. Our two triangles hypothesis, based on updated data from the literature, offers a pedagogic template for the understanding of folliculogenesis in the normal and polycystic ovary. It opens new avenues for the treatment of anovulation due to PCOS.

Is the suppressive effect of cyproterone acetate on serum anti-Müllerian-hormone levels in women with polycystic ovary syndrome stronger than under oral contraceptive pill?

OBJECTIVE: To compare the suppressive effect of anti-androgen therapy by cyproterone acetate (CPA) and by oral contraceptive pill (OCP) on anti-müllerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) in order to detect a putative direct anti-androgen effect on AMH excess. METHODS: This is a prospective longitudinal study including 58 women with PCOS between January 2010 and April 2014 at the Lille University Hospital. A total of 47 women with clinical hyperandrogenism were treated by CPA (50 mg/d was administered 20 days out of 28) and 11 women with PCOS but without clinical hyperandrogenism received OCP. RESULT(S): Serum AHM levels at baseline were similar in CPA and OCP groups (median [5-95th percentiles]: 60.4 pmol/l [25.1-200.2] versus 58 pmol/l [27.6-100], respectively, p = 0.39). After 3 months of treatment, serum AMH levels decreased significantly by 28% ± 20% and by 22% ± 27% in CPA and OCP groups, respectively. The decrease under both treatments was similar (p = 0.48). CONCLUSION(S): That any anti-androgen effect could be observed on AMH in our CPA group in addition to the gonadotropin-suppressing effect suggests that either androgens are not involved in AMH regulation or that they act by interfering with gonadotropin effects on granulosa cells.

[Usefulness and indications of AMH assay in women]. / Intérêts et indications du dosage de l'AMH chez la femme.

Anti-mullerian hormone (AMH) is expressed in women in the granulosa cells, in growing follicles. There is a high correlation between antral follicle count and AMH assay, which therefore makes it a good marker of ovarian reserve. Its indications are the fertility work-up, and the menstrual cycle disorders, to detect polycystic ovarian syndrome (PCOS) or premature ovarian failure on the opposite. During assisted reproductive techniques, AMH assay is very useful choosing the ovarian stimulation protocol and the dose of gonadotropins to begin with, in order to limit the risks of ovarian hyperstimulation syndrome or on the other hand, cancellation of cycles due to poor ovarian response. Finally, with the development of fertility preservation in the context of cancer, AMH assay is useful in evaluating the ovarian reserve after treatments that can be toxic for the ovaries, and the impact of the treatments on ovarian function, as well as organizing fertility preservation. AMH assays techniques are evolving, leading to a better homogeneisation of the results, and allowing the determination of thresholds used by everyone. Furthermore, we have to know that the AMH assay doesn't belong to the official definition of PCOS or premature ovarian failure for the moment, although it is useful in daily practice.

Long term complications of polycystic ovary syndrome (PCOS).

Polycystic ovary syndrome (PCOS) is a frequent endocrine disease affecting 10 to 15% of women. Menstrual disorders, hyperandrogenism and ultrasonographic aspect of ovaries are typical of the disease and are established diagnostic criteria. But PCOS has also long term complications frequently forgotten and underestimated. During pregnancy, gestational diabetes and gestational hypertensive disorders can occur. At an older age, metabolic disease such as glucose intolerance, type 2 diabetes or dyslipidaemia are frequently described. Women with PCOS have increased classical cardiovascular risks and increased subclinical cardio-vascular disease without proven increase of cardiovascular morbidity and mortality. Finally, endometrial cancer seems to be more frequent in women with PCOS. Therefore, PCOS have numerous long-term health risks and a life-long follow-up is necessary for these women "at-risk" to detect and prevent complications as soon as possible.

Toward a better follow-up of ovarian recovery in young women after chemotherapy with a hypersensitive antimüllerian hormone assay.

OBJECTIVE: To evaluate the utility of a hypersensitive assay for measuring low antimüllerian hormone (AMH) levels in young cancer patients during the ovarian recovery phase of their chemotherapy. DESIGN: Retrospective study. SETTING: Academic medical center. PATIENT(S): Fifty-eight samples drawn at least 3 months after the end of chemotherapy in 30 women having either breast cancer (n=13) or hematologic malignancies (n=17) were selected to constitute two equally size groups: amenorrhea (n=30 samples) or spontaneous cycle (n=28 samples). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum AMH levels were measured by a conventional AMH ELISA (EIA AMH/MIS) and a hypersensitive ELISA (PicoAMH, AnshLabs) on the same sample. RESULT(S): Using a conventional assay, serum AMH was detectable (≥3 pmol/L) in 6.7% and in 10.7% of the samples corresponding to amenorrheic or cycling patients, respectively (nonsignificant). By contrast, with PicoAMH, serum AMH was detectable (≥0.07 pmol/L) in 71.4% of the samples from cycling women vs. 16.7% of the samples from amenorrheic patients. Multivariate regression analysis showed that among putative contributors, only the menstrual status (r=0.307) and serum FSH level (r=-0.546) were independently correlated to a detectable serum AMH with the picoAMH assay exclusively. CONCLUSION(S): The picoAMH assay, allowing measurement of very low AMH concentrations in human serum, should refine postchemotherapy ovarian follow-up in young women.