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Abstract Background Multifollicular ovarian stimulation (MOS) is widely used in IVF and the compliance to treatment is deeply influenced by the tolerability of the medication(s) used and by the ease of self-administration. This prospective, controlled, randomised, parallel group open label, multicenter, phase III, equivalence study has been aimed to compare the clinical effectiveness (in terms of oocytes obtained) and tolerability of subcutaneous (s.c.) self-administered versus classical intramuscular (i.m.) injections of Merional, a new highly-purified hMG preparation. Methods A total of 168 normogonadotropic women undergoing IVF were enrolled. Among them, 160 achieved pituitary suppression with a GnRH-agonist long protocol and were randomised to MOS treatment with Merional s.c. or i.m. They started MOS with a standard hMG dose between 150–300 IU, depending upon patient's age, and underwent a standard IVF procedure. Results No statistically significant difference in the mean number of collected oocytes (primary endpoint) was observed between the two study subgroups (7.46, SD 4.24 vs. 7.86, SD 4.28 in the s.c. and i.m. subgroups, respectively). As concerns the secondary outcomes, both the pregnancy and the clinical pregnancy rates were comparable between subgroups. The incidence of adverse events was similar in the two groups (2.4% vs. 3.7%, respectively). Pain at injection site was reported only the i.m. group (13.9% of patients). Conclusion Merional may be used by s.c. injections in IVF with an effectiveness in terms of retrieved oocytes that is equivalent to the one obtained with i.m administration and with a better local tolerability. With the limitations due to the sample size af this study, s.c. and i.m. administration routes seem to have the same overall safety.

Abstract Background Hyperhomocysteinemia has been described as a risk factor for unexplained recurrent pregnancy loss. Increased levels of homocysteine may be due to inadequate dietary intake of folate and vitamin B12 and inherited defects within the methionine-homocysteine pathway such as MTHFR C677T gene polymorphism. However, the association between hyperhomocysteinemia and sterility problems have been underlined only for recurrent pregnancy loss while a relationship between hyperhomocysteinemia and female sterility is still matter of discussion. Aim This study sought to find out a possible relationship between sterility (primary sterility or secondary sterility due to recurrent pregnancy loss) and homocysteine metabolism. Patients and Methods We selected 20 patients with recurrent pregnancy loss, 20 patients with unexplained female sterility and 20 healthy women as control group. Several whole blood samples were collected by venipuncture. Firstly homocysteinemia and other related variables were tested (i.e. folate and vitamin B12 levels); thereafter DNA was extracted by a further whole blood sample collected in EDTA in order to screen MTHFR C677T gene polymorphism. Statistical analysis was performed by chi square test; differences were considered to be significant if p < 0.05. Results The median fasting total plasma homocysteine concentration was 19.2 ± 6.14 μM for patients with recurrent pregnancy loss, while was 21.05 ± 8.78 μM for patients with unexplained sterility, vs 7.85 ± 3.31 μM of control group (p < 0.05). Fifteen patients with unexplained female sterility showed MTHFR C677T homozigosity vs 17 with recurrent pregnancy loss and 3 in the control group (p < 0.05). On the other hand no significant differences were found in the levels of vitamin B 12 in the three groups, while reduced folate concentrations were found in women with unexplained female sterility and recurrent pregnancy loss (p < 0.05 vs control group. Discussion MTHFR C677T gene polymorphism is frequent in the studied populations. These data raise questions on the role of the homocysteine metabolism in sterility problems. Even though increased homocysteine (i.e. > 15 μM) and MTHFR C677T homozigosity have already been described as risk factors for recurrent pregnancy loss, few studies evaluated their role in women with unexplained sterility. Further studies on larger series are needed to better understand the role of homocysteine metabolism, including folate metabolism, in this clinical setting.

Abstract Background Carboplatin/paclitaxel is the chemotherapy of choice for advanced ovarian cancer, both in first line and in platinum-sensitive recurrence. Although a significant proportion of patients have some neurotoxicity during treatment, the long-term outcome of chemotherapy-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of patients in clinical remission after first-line carboplatin/paclitaxel for advanced ovarian cancer. Methods 120 patients have been included in this study (101 participating in a multicentre phase III trial evaluating the efficacy of consolidation treatment with topotecan, and 19 treated at the National Cancer Institute of Naples after the end of the trial). All patients received carboplatin (AUC 5) plus paclitaxel (175 mg/m2) every 3 weeks for 6 cycles, completing treatment between 1998 and 2003. Data were collected between May and September 2004. Residual sensory and motor neurotoxicity were coded according to the National Cancer Institute – Common Toxicity Criteria. Results 55 patients (46%) did not experience any grade of neurological toxicity during chemotherapy and of these none had signs of neuropathy during follow-up. The other 65 patients (54%) had chemotherapy-induced neurotoxicity during treatment and follow-up data are available for 60 of them. Fourteen out of 60 patients (23%) referred residual neuropathy at the most recent follow-up visit, after a median follow up of 18 months (range, 7–58 months): 12 patients had grade 1 and 2 patients grade 2 peripheral sensory neuropathy; 3 patients also had grade 1 motor neuropathy. The remaining 46/60 patients (77%) had no residual neuropathy at the moment of interview: recovery from neurotoxicity had occurred in the first 2 months after the end of chemotherapy in 22 (37%), between 2 and 6 months in 15 (25%), or after more than 6 months in 9 patients (15%). Considering all 120 treated patients, there was a 15% probability of persistent neurological toxicity 6 months after the end of chemotherapy. Conclusion A significant proportion of patients with advanced ovarian cancer treated with first-line carboplatin/paclitaxel suffer long-term residual neuropathy. This issue should be carefully taken into account before considering re-treatment with the same agents in sensitive recurrent disease.

Study Objective: To compare the tolerability and diagnostic accuracy of virtual ultrasonographic hysteroscopy (VUH) with that of conventional diagnostic outpatient hysteroscopy in the workup of patients who are infertile.Design: A single-center, retrospective cohort study.Setting: Department of Obstetrics and Gynecology, Gynecologic Oncology, and Minimally Invasive Pelvic Surgery Unit of Sacred Heart Hospital Don Calabria in Negrar, Italy.Patients: A total of 120 consecutive women who underwent hysterosalpingosonography and subsequent VUH and conventional hysteroscopy for infertility evaluation were included. The inclusion criterion was infertility for at least 1 year, with evaluation in the early or intermediate follicular phase of the menstrual cycle.Interventions: After the placement of an intracervical catheter, a Ringer Lactate solution was injected into the uterine cavity and fallopian tubes, and a 3D volume was obtained. The ultrasound volume acquired was successively elaborated offline, and a VUH was performed. Subsequently, a variable amount of air was introduced into the uterine cavity, and the patency of the salpinges was evaluated.Measurements and Main Results: The VUH findings were compared with those of conventional hysteroscopy performed in the subsequent month. For the detection of endometrial pathology in the overall pool, the sensitivity and specificity of VUH in comparison with conventional hysteroscopy were 100% (95% confidence interval [CI], 84.6%-100%) and 100% (95% CI, 96.3%-100%), respectively. For the detection of uterine cavity pathology and uterine malformations in the overall pool, the sensitivities of VUH were 80% (95% CI, 28.4%-99.5%) and 100% (95% CI, 75.3%-100%), respectively, with specificities of 100% (95% CI, 96.8%-100%) and 100% (95% CI, 96.6%-100%), respectively, when compared with conventional hysteroscopy. The positive predictive values for endometrial pathology, uterine cavity alterations, and uterine malformations were 100% (95% CI, 84.6%-100%), 100% (95% CI, 39.8%-100%), and 100% (95% CI, 75.3%-100%), respectively, with a receiver operating characteristic area of 100%, 90% (95% CI, 70%-100%), and 100%, respectively. There were no cases of severe vasovagal reactions or other complications. Most patients (67%, 81 of 120 women) described the examination as "less painful than expected," 25% (30 of 120 women) "just as expected," and only 7% (9 of 120 women) as "more painful than expected."Conclusion: VUH was well tolerated and showed a high accuracy (100%) in the study of the uterine cavity when compared with conventional hysteroscopy. [ABSTRACT FROM AUTHOR]

Abstract Background Antiphospholipid syndrome (APS) has been often associated to RPL since 1980 and some reports in the Literature rarely described antibodies to factor XII in patients with APS. Case history We report the case history of 34-year-old caucasian women with recurrent fetal loss and persistent prolonged activated partial thromboplastin time. Haemostatic tests revealed persistent light decrease of clotting factor XII with normal values of IgG and IgM anticardiolipin antibodies and transient positivity for lupus anticoagulant (LA). Few reports in the Literature described antibodies to factor XII in patient with antiphospholipid syndrome (APS) and transient LA. So, once other causes of RPL were excluded, the patient was diagnosed an unusual form of APS associated to antibodies to factor XII, reduced factor XII plasma levels, transient LA and prolonged activated partial thromboplastin time. Discussion We suggest to consider also antibodies directed to clotting factors (e.g. factor XII in our case) as second step of thrombophilia screening in RPL, in particular if a persistent prolonged aPTT is present without an apparent cause.

Abstract Background We investigated lifetime alcohol consumption and prostate cancer risk in a case-control study conducted in Buffalo, NY (1998–2001). Methods The study included 88 men, aged 45 to 85 years with incident, histologically-confirmed prostate cancer and 272 controls. We conducted extensive in-person interviews regarding lifetime alcohol consumption and other epidemiologic data. Results Prostate cancer risk was not associated with lifetime intake of total and beverage specific ethanol. In addition we found no association with number of drinks per day (average drinks per day over the lifetime) or drinks per drinking day (average drinks per day on drinking days only over the lifetime). However, we observed an inverse association with the total number of drinking years. Men in the lowest tertile of total drinking years had a two-fold prostate cancer risk than men in the highest tertile (OR 2.16, 95% CI 0.98–4.78, p for trend Conclusion Our results suggest that alcohol intake distribution across lifetime may play a more important role in prostate cancer etiology than total lifetime consumption.

Abstract Background D-dimer is considered a marker of hypercoagulable state and of endogenous fibrinolysis, so increased d-dimer is detectable in patients affected by thrombosis. Yet, several studies showed that also infertility, in particular secondary infertility due to recurrent fetal losses, has been often related to thrombotic events, in particular in women carrying thrombotic risk factors such as inherited thrombophilia (MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms and/or inhAfter this screening we selected 39erited protein C, protein S, AT III deficiency) or acquired thrombophilia (primary antiphospholipid syndrome, acquired protein C, protein S, AT III deficiency, drugs induced thrombophilia). However, because its high predictive negative value in case of suspected thrombosis, increased d-dimer has been often associated to subclinical thrombophilia. The aim of this study is to investigate the role of d-dimer as first marker of thrombophilia in women affected by unexplained infertility and subsequently to search the cause of increased d-dimer, such as inherited and/or acquired thrombophilia. Patients and Methods We selected 79 patients with unexplained primary or secondary infertility. We excluded 40 patients affected by hydrosalpinx, uterine fibroids, uterine malformations, endocrinological and immunological diseases, luteal insufficiency, cytogenetical alterations. All remaining 39 patients were tested for d-dimer and divided in two groups: the patients of group A (25 patients) showed increased plasma d-dimer, in group B were included 14 patients with normal plasma level of d-dimer. After this step all 39 patients were screened for MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms, protein C, protein S, AT III, anticardiolipin IgM and IgG, lupus anticoagulant. In the control group were included 15 age matched women without sterility problems referred to our outpatient's section of vascular medicine for suspected deep venous thrombosis. Statistical analysis was based on χ2 test, differences were considered to be significant if p < 0.05. Results D-dimer was increased in 25/39 and 20/25 showed inherited/acquired thrombophilia while patients with normal d-dimer showed inherited/acquired thrombophilia in 7/14 (p: < 0.05, s). Discussion D-dimer is a well known marker of hypercoagulable state, in particular its high predictive negative value in case of suspected thrombosis has been recognised by several reports. Yet, increased d-dimer has been identified also for subclinical thrombophilia besides for vascular thrombosis. Our data, in fact, for the first time suggest an interesting role of d-dimer to identify women affected by unexplained primary or secondary infertility and thrombophilia. So, probably there is a role for d-dimer in these subjects for its predictive positive value. Of course, further data on large based population are needed to confirm our results, because these findings may speed up a diagnostic screening in these patients also for a good cost/effectiveness of this test.

The clinico-pathological and molecular factors that drive the prognosis of invasive lobular breast carcinoma (ILC) are not entirely explored. In this regard, the development and validation of a prognostic model for ILC and the investigation of the distribution of molecular abnormalities (focusing on CDK4/6 alterations) according to prognosis were the aims of this study. Two clinico-pathological multi-center data-sets of early-stage ILC patients (Training/Validation Set, TS/VS) were gathered. A 3-class model was developed according to the multivariate analysis for disease-free-survival (DFS) and externally validated. Mutational, copy number variation and transcriptomic analyses by targeted next generation sequencing (NGS) were performed (and validated with quantitative PCR) in an explorative cohort of patients with poor and good prognosis. Data from overall 773 patients (TS/VS: 491/282) were gathered. The developed model significantly discriminated low/intermediate/high risk in the TS (10-years DFS: 76.3%/67.6%/39.8%, respectively, p<0.0001) and in the VS (p<0.0001). In the explorative cohort for molecular analysis (34 patients), CDK4 gain was present exclusively in the poor prognosis group (35.0%, p = 0.03 ; OR 7.98, 95%CI 1.51–42.1, p = 0.014). Moreover, CDK4 and 6 overexpression showed a trend toward an association with poor prognosis (OR 2.7, 95%CI 0.4–18.1, p = 0.3; OR 3.29, 95%CI 0.56–19.25, p = 0.18). A risk stratification model, able to accurately separate early-stage ILC patients' prognosis into different risk classes according to clinico-pathological variables, allowed to investigate potential biomarkers of prognosis with targeted NGS. CDK4 gain is suggested for future validation as a prognostic biomarker and a potential therapeutic opportunity in ILC patients. • The current multicenter analysis developed and validated a prognostic nomogram for early stage ILC. • A next-generation sequencing analysis was performed in prognostic 'outlier' patients. • CDK4 gain emerges as a potential negative prognostic factor in ILC patients.. [ABSTRACT FROM AUTHOR]

Study Objective: To evaluate safety and effectiveness of the combination of hysteroscopic endometrial focal resection with levonorgestrel-releasing intrauterine device (LNG-IUD) for International Federation of Gynecology and Obstetrics stage IA G1 early endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH) in young women to preserve their fertility.Design: Retrospective case series (Canadian Task Force classification II-3).Setting: University Federico II, Naples, Italy.Patients: The medical records of 69 consecutive patients treated from 2007 to 2017 with diagnosis of EEC (n = 14) or AEH (n = 55) meeting inclusion criteria were reviewed.Interventions: Patients with focal EEC were treated by hysteroscopic resection of the lesion according to Mazzon's technique; patients with AEH were treated by superficial endometrial resection, preserving the basal layer of the endometrium. An LNG-IUD was inserted in all patients after surgery. Patients were followed for 24 months with serial hysteroscopic biopsies.Measurements and Main Results: Rates of response, live birth, and recurrence were assessed. Of the 14 patients with EEC, 11 (78.6%) achieved a complete response, 2 (18.2%) of whom had subsequent relapse, 1 (7.1%) showed partial response, whereas 2 (14.3%) were nonresponders (1 stable disease and 1 progression). Of the 55 patients with AEH, 51 (92.7%) achieved a complete response, 2 (3.9%) of whom had subsequent relapse, 3 (5.5%) showed partial response, whereas only 1 (1.8%) was nonresponder with stable disease. Among 25 patients who had removed the LNG-IUD, 10 (40%) gave birth after natural conception in the last 12 months of follow-up.Conclusion: The combination of hysteroscopic resection with an LNG-IUD as fertility-sparing treatment of EEC and AEH showed similar response and live birth rates compared with those reported in literature for progestins alone, but with considerably lower relapse rate. We advocate the use of this combined approach as an alternative fertility-sparing option in patients with ECC and AEH. [ABSTRACT FROM AUTHOR]

Precision Medicine is becoming the new paradigm in healthcare as it enables better resources allocation, treatment optimization with a potential side-effects reduction and consequent impact on quality of life and survival. This revolution is being catalyzed by liquid biopsy technologies, which provide prognostic and predictive information for advanced cancer patients, without the analytical and procedural drawbacks of tissue-biopsy. In particular, circulating tumor DNA (ctDNA) is gaining momentum as a clinically feasible option capable to capture both spatial and temporal tumor heterogeneity. Several techniques are currently available for ctDNA extraction and analysis, each with its preferential case scenarios and preanalytical implications which must be taken into consideration to effectively support clinical decision-making and to better highlight its clinical utility. Aim of this review is to summarize both analytical developments and clinical evidences to offer a comprehensive update on the deployment of ctDNA in breast cancer's (BC) characterization and treatment. [ABSTRACT FROM AUTHOR]

Treatment for HER2-positive (+) metastatic breast cancer has improved in the last decade. We analyzed treatment changes over time and their impact on patients outcomes in a real-world dataset. Data from 637 HER2+ patients with metastatic breast cancer enrolled in the multicenter Italian GIM14/BIOMETA study were retrieved. Progression-free survival (PFS) over time was evaluated according to the type of anti-HER2 therapy, disease onset (de novo vs. relapsing), metastatic site, and year of treatment (2000–2013 vs. 2014–2020). Median follow-up was 64.4 months. Overall, for first-line therapies, mPFS was 16.5 vs 19.5 months for patients treated in 2000–2013 vs 2014–2020 (HR: 0.78, 95% CI:0.65–0.94, P = 0.008). mPFS improved over time in all patients except for those with brain metastasis. Interestingly mPFS was 17.4 vs13.4 months (HR, 1.49; 95% CI, 1.13–1.98, P = 0.005) in 2000–2013 and 24.4 vs 20.9 months (HR 1.04; 95% CI 0.78–1.40 p = 0.77) in 2014–2020 in pts without vs with liver metastases. For second line therapies, the overall median PFS was 9.6 months (95% CI, 8.31–10.97) and did not change over time. Median first-line PFS improved since 2014, mainly due to the introduction of pertuzumab. The outcome of patients with liver metastases appears to have improved in recent years. Patients with brain metastases had the worst PFS, which also did not improve over time. • Overall, from 2000 to 2020, mPFS of patients treated with 1st-line with anti-HER2 agents improved over time. • With the introduction of pertuzumab in 2014, mPFS significantly improved, especially in patients with liver metastases. • Brain metastasis were associated with a significantly worse PFS regardless the year of treatment. • For patients with brain metastases, novel, more active, therapeutic agents should be strongly advocated to improve outcome. [ABSTRACT FROM AUTHOR]

• HER2 overexpression historically linked to poor prognosis in breast cancer. • However, the availability of active anti-HER2 compounds/combinations is evolving. • In HER2CLIMB, the tucatinib-containing combination improved overall survival. • The trial included patients with active brain metastases, an unmet need. • The review highlights tucatinib's journey from preclinical to clinical use. Approximately 20% of breast cancers (BCs) overexpress human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein with tyrosine kinase activity, encoded by ERBB2 gene. Historically, HER2 overexpression has been linked with increased disease recurrence and a worse prognosis. However, the increasing availability of different anti-HER2 compounds and combinations is progressively improving HER2-positive BC outcome, thus requiring expertise to prioritize both overall survival (OS) prolongation and quality of life, without neglecting the accessibility to further treatment lines with a low attrition rate. In this context, tucatinib, an oral tyrosine kinase inhibitor, has recently been granted approval by regulatory agencies based on evidence from the HER2CLIMB, a clinical trial which randomized patients with metastatic BC to receive trastuzumab and capecitabine with either tucatinib or placebo. A distinctive feature of this study was the inclusion of patients with new or active brain metastases (BMs) at study entry, a population traditionally excluded from clinical trials. Thus, HER2CLIMB provides the first solid evidence of an OS benefit in patients with BC and BMs, addressing a long standing unmet medical need, especially given the high incidence of central nervous system metastatic spread in patients with HER2-positive disease. This review provides an overview of the molecular and clinical landscape of tucatinib for the treatment of advanced BC. It focuses on the technological journey that drove the development of this therapeutic innovation, from preclinical data to clinical practice. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) represents the 15-20% of all breast cancers (BC) and is characterized by a very aggressive behavior. Recent data suggest that TNBC is not a single disease, but it is rather an umbrella for different ontology-profiles such as basal like 1 and 2, mesenchymal, and the luminal androgen receptor (LAR). The LAR subtype is characterized by the expression of the Androgen Receptor (AR) and its downstream effects. Notwithstanding the role of the AR in several signaling pathways, its impact on a biological and clinical standpoint is still controversial. The LAR subtype has been associated with better prognosis, less chemotherapy responsiveness and lower pathologic complete response after neoadjuvant treatment. Clinical evidence suggests a role for anti-androgen therapies such as bicalutamide, enzalutamide and abiraterone, offering an interesting chemo-free alternative for chemo-unresponsive patients, and therefore potentially shifting current treatment strategies. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The application of an electronic database in clinical practice is used widespread in every field of medicine. The aim of the present study is to illustrate our experience to use a database software for documentation of two of our clinical activities, outpatient hysteroscopy and inpatient gynaecological surgery. PATIENTS AND METHODS: In 2004, we designed two databases, the first one to document surgical procedures in the operating theatre, the second to document outpatient hysteroscopy procedures using FileMaker v.8.5. The data entry interface contains free text fields for patient demographic data and the description of the surgical procedure, supplemented by drop-down lists for items such as clinical findings, procedures, instrumentation, technique, and complications. Copies were filed in the main hospital notes, sent to General Practitioners, and also given to our patients. RESULTS: Since August 2004, we have used our two databases to document 2766 gynaecological operations and 3777 outpatient hysteroscopies. All users particularly liked the dropdown lists as their use greatly reduced the time taken to enter each patient's data. The databases were regularly used to select patients for audit projects and research data collection for prospective studies. CONCLUSIONS: FileMaker is an user-friendly and easily configured software, extremely valuable in everyday clinical work. [ABSTRACT FROM AUTHOR]

Objectives Given their inclusion and exclusion criteria, randomized clinical trials (RCT) might not include a population that truly mirrors real life (RL). This raises concerns about the applicability of RCT results in clinical practice. We evaluated the efficacy of anti-HER2 treatment with pertuzumab combined with trastuzumab and a taxane as first-line treatment for HER2-positive metastatic breast cancer in a RL setting, and compared the safety results obtained in our population versus the experimental cohort of the CLEOPATRA RCT, which led to the approval of this therapy. Materials and methods Patients treated with trastuzumab, pertuzumab and a taxane were enrolled in this retrospective study. We compared the tumor features and the patients' characteristics of the RL cohort to those of the CLEOPATRA cohort. We also compared the median progression-free survival (PFS) in the RL population versus specific patients' subgroups. Results RL patients were more frequently HR-positive, less likely to have visceral metastases (P < .001 for both) and had more frequently received (neo)adjuvant hormone therapy or trastuzumab than CLEOPATRA patients (P = .004 and P < .001, respectively). The median number of anti-HER2 cycles was 8 vs 24 and the median number of cycles was 7 vs 8 for docetaxel in the RL versus CLEOPATRA population, respectively. Adverse reactions of all grades were less frequent in RL. Median PFS was 27.8 months in the RL population and the treatment was equally effective in all patients' subgroups. Conclusion This study provides compelling evidence that pertuzumab, trastuzumab and a taxane are effective and safe also in a clinical scenario. [ABSTRACT FROM AUTHOR]

To evaluate the hormonal profile in three breast cancer patients who underwent controlled ovarian stimulation in the presence of the aromatase inhibitor letrozole. PATIENTS AND METHODS: In IVF University referral center, a case series of three breast cancer patients who underwent controlled ovarian stimulation (COS) with recombinant FSH and letrozole were investigated. Ovulation was induced with hCG (case No. 1) or with GnRH agonist (case No. 2-3). The primary outcome of our study was the detection of progesterone levels in the luteal phase. RESULTS: Very high progesterone values (mean 186.6 ± 43.6 ng/mL) during the luteal phase were recorded in all three cases. CONCLUSIONS: High progesterone levels can be related to the use of letrozole independently of the most commonly used trigger regimen. Although progesterone has long been considered a protective factor against breast cancer, several studies have demonstrated that progesterone could expand a transformation-sensitive stem cell population in the mammary glands. The estrogen negative feedback effect on the hypothalamus-pituitary axis and the disruption of steroid biosynthesis and could represent an intriguing reason behind this phenomenon. Our results highlight the need to evaluate further the increase in progesterone levels in the luteal phase in women with breast cancer undergoing COS with letrozole. [ABSTRACT FROM AUTHOR]