Objective: To study different antim€ ullerian hormone (AMH) isoforms in women with polycystic ovary syndrome (PCOS) and healthy regularly cycling women and to investigate whether levels of AMH isoforms combined with baseline characteristics can predict PCOS. Design: Cross-sectional study. Setting: Fertility clinic. Patient(s): Eighty-eight women with PCOS and 24 age-and body mass index (BMI)-matched normal control subject women recruited from April 2010 to February 2013. AMH isoforms were analyzed in biobanked serum samples collected at Holbaek Fertility Clinic, Denmark. All study participants went through a baseline examination including gynecologic history, objective examination, transvaginal ultrasound, and blood sampling. Each woman was characterized by measurement of total T, free T, SHBG, A, DHEAS, FSH, LH, E 2 , PRL, TSH, serum insulin, plasma glucose, and C-peptide. Interventions(s): None. Main Outcome Measure(s): Serum levels of three different AMH isoforms. Result(s): Levels of AMH measured with each of three AMH ELISAs were significantly higher in women with PCOS compared with control women. The ratio between AMH isoforms showed significant associations with metabolic parameters (BMI, SHBG, C-peptide, cholesterols, triglycerides, and the modified homeostasis-model assessment). Prediction of PCOS showed a high precision with areas under the receiver operating characteristic curve of 97% when AMH measurements were combined with androgens and BMI. Conclusion(s): Three ELISAs detecting different parts of the AMH molecule all detected significantly higher levels in women with PCOS compared with control women. The relative distribution of AMH isoforms did not differ between women with PCOS and control women. AMH isoforms alone and in combination with baseline characteristics predicted PCOS with close to 100% area under the receiver operating characteristic curve. (Fertil Steril Ò 2019;112:149-55. Ó2019 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.

STUDY QUESTION Does letrozole co-treatment during ovarian stimulation with gonadotrophins for IVF reduce the proportion of women with premature progesterone levels above 1.5 ng/ml at the time of triggering final oocyte maturation? SUMMARY ANSWER The proportion of women with premature progesterone above 1.5 ng/ml was not significantly affected by letrozole co-treatment. WHAT IS KNOWN ALREADY IVF creates multiple follicles with supraphysiological levels of sex steroids interrupting the endocrine milieu and affects the window of implantation. Letrozole is an effective aromatase inhibitor, normalizing serum oestradiol, thereby ameliorating some of the detrimental effects of IVF treatment. STUDY DESIGN, SIZE, DURATION A randomized, double-blinded placebo-controlled trial investigated letrozole intervention during stimulation for IVF with FSH. The trial was conducted at four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS A cohort of 129 women with expected normal ovarian reserve (anti-Müllerian hormone 8–32 nmol/l) completed an IVF cycle with fresh embryo transfer and received co-treatment with either 5 mg/day letrozole (n = 67) or placebo (n = 62), along with the FSH. Progesterone, oestradiol, FSH, LH and androgens were analysed in repeated serum samples collected from the start of the stimulation to the mid-luteal phase. In addition, the effect of letrozole on reproductive outcomes, total FSH consumption and adverse events were assessed. MAIN RESULTS AND THE ROLE OF CHANCE The proportion of women with premature progesterone >1.5 ng/ml was similar (6% vs 0% (OR 0.0, 95% CI [0.0; 1.6], P = 0.12) in the letrozole versus placebo groups, respectively), whereas the proportion of women with mid-luteal progesterone >30 ng/ml was significantly increased in the letrozole group: (59% vs 31% (OR 3.3, 95% CI [1.4; 7.1], P = 0.005)). Letrozole versus placebo decreased oestradiol levels on the ovulation trigger day by 68% (95% CI [60%; 75%], P < 0.0001). Other hormonal profiles, measured as AUC, showed the following results. The increase in LH in the letrozole group versus placebo group was 38% (95% CI [21%; 58%], P < 0.0001) and 34% (95% CI [11%; 61%], P = 0.006) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, testosterone increased by 79% (95% CI [55%; 105%], P < 0.0001) and 49% (95% CI [30%; 72%], P < 0.0001) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, the increase in androstenedione was by 85% (95% CI [59%; 114%], P < 0.0001) and 69% (95% CI [48%; 94%], P < 0.0001) in the follicular and luteal phases, respectively. The ongoing pregnancy rate was similar between the letrozole and placebo groups (31% vs 39% (risk-difference of 8%, 95% CI [−25%; 11%], P = 0.55)). No serious adverse reactions were recorded in either group. The total duration of exogenous FSH stimulation was 1 day shorter in the intervention group, significantly reducing total FSH consumption (mean difference −100 IU, 95% CI [−192; −21], P = 0.03). LIMITATIONS, REASONS FOR CAUTION Late follicular progesterone samples were collected on the day before and day of ovulation triggering for patient logistic considerations, and the recently emerged knowledge about diurnal variation of progesterone was not taken into account. The study was powered to detect hormonal variations but not differences in pregnancy outcomes. WIDER IMPLICATIONS OF THE FINDINGS Although the use of letrozole has no effect on the primary outcome, the number of women with a premature increase in progesterone on the day of ovulation triggering, the increased progesterone in the mid-luteal phase due to letrozole may contribute to optimizing the luteal phase endocrinology. The effect of letrozole on increasing androgens and reducing FSH consumption may be used in poor responders. However, the effect of letrozole on implantation and ongoing pregnancy rates should be evaluated in a meta-analysis or larger randomized controlled trial (RCT). STUDY FUNDING/COMPETING INTEREST(S) Funding was received from EU Interreg for ReproUnion and Ferring Pharmaceuticals, and Roche Diagnostics contributed with assays. N.S.M. and A.P. have received grants from Ferring, Merck Serono, Anecova and Gedeon Richter, and/or personal fees from IBSA, Vivoplex, ArtPred and SPD, outside the submitted work. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBERS NCT02939898 and NCT02946684 TRIAL REGISTRATION DATE 15 August 2016. DATE OF FIRST PATIENT’S ENROLMENT 22 August 2016.

OBJECTIVE: To evaluate whether diminished ovarian reserve (DOR) and its etiology impact the AMH/AFC ratio?MATERIALS AND METHODS: From November 2018 to December 2021, we conducted a monocentric, retrospective study including a total of 484 infertile patients <37 years with DOR. All patients underwent measurement of AMH levels and AFC. DOR was diagnosed according to the Bologna criteria (AMH<1.1 ng/mL and AFC<7). AMH/AFC ratio was compared to values obtained in 154 tubal or male infertility patients matched for age and BMI, with AMH and AFC in the normal ranges. This ratio was studied according to the etiology of DOR: genetic (n¼26), post-chemotherapy (n¼102), idiopathic (n¼215) or ovarian diseases (ovarian cyst or history of ovarian surgery, n¼141).RESULTS: Overall, median age of women with DOR was 30 (18-37) years. As expected, age and BMI were comparable in women with DOR and those having normal ovarian reserve tests. In addition, the AMH/AFC ratio failed to show any difference between these 2 groups (0.143 AE 0.22 vs. 0.166 AE 0.11, NS, respectively). Among women with DOR, the etiology was significantly associated with different AMH/AFC ratio. Indeed, patient with DOR of surgical origin (ovarian diseases group) displayed higher mean values (0.283 AE 0.32 ng/mL/ Foll) when compared with those included in genetic (0.079 AE 0.15 ng/mL/ Foll, p<0.01), idiopathic (0.103 AE 0.16 ng/ mL/ Foll, p<0.03) or post-chemotherapy (0.084 AE 0.20 ng/mL/ Foll, p<0.01) groups. Moreover, genetic and post-chemotherapy DOR was also associated with lower AMH/AFC ratio in comparison with idiopathic DOR.CONCLUSIONS: AMH/AFC ratio varies according to the etiology of DOR in young women, suggesting different impact on the follicular health, and further oocyte quality.IMPACT STATEMENT: AMH/AFC ratio may represent an innovative tool aiming to indirectly assess follicular health and possibly oocyte quality in young women with DOR. The etiology of DOR differently impacts the follicular function as reflected by AMH/AFC ratio. Further data on live birth rates following natural or medically assisted pregnancies is needed.