NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer.

Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, exploring their dynamic reactions within the context of cancer. Concentration-dependent signaling reveals distinctive processes in cancer, with three levels of NO influencing oncogenic properties. In this context, NO plays a crucial role in cancer cell proliferation, metastasis, chemotherapy resistance, and immune suppression. Increased NOS2 expression correlates with poor survival across different tumors, including breast cancer. Additionally, NOS2 can crosstalk with the proinflammatory enzyme cyclooxygenase-2 (COX-2) to promote cancer progression. NOS2 and COX-2 co-expression establishes a positive feed-forward loop, driving immunosuppression and metastasis in estrogen receptor-negative (ER-) breast cancer. Spatial evaluation of NOS2 and COX-2 reveals orthogonal expression, suggesting the unique roles of these niches in the tumor microenvironment (TME). NOS2 and COX2 niche formation requires IFN-γ and cytokine-releasing cells. These niches contribute to poor clinical outcomes, emphasizing their role in cancer progression. Strategies to target these markers include direct inhibition, involving pan-inhibitors and selective inhibitors, as well as indirect approaches targeting their induction or downstream effectors. Compounds from cruciferous vegetables are potential candidates for NOS2 and COX-2 inhibition offering therapeutic applications. Thus, understanding the chemical biology of NO and RNS, their spatial distribution, and their implications in cancer progression provides valuable insights for developing targeted therapies and preventive strategies.

[When to Stop Contraception - Reasons and Consequences of Delaying Parenthood]. / Verhüten bis es (fast) zu spät ist ­ Gründe und Konsequenzen eines Aufschubs der Elternschaft.

When to Stop Contraception - Reasons and Consequences of Delaying Parenthood Abstract. Women are delaying motherhood for many reasons. However, knowledge on age-related decline of fertility is limited. Many patients and even physicians are not aware that female fertility starts to diminish significantly after the age of thirty-two years, and success rates of in vitro treatment are overestimated in the general population. Apart from maternal age there is no predictor for future fecundity. Physicians should actively discuss reasons for delaying motherhood and options for improving fecundity. During the reproductive life span, women need reliable counselling on contraception and fertility.

Spatial analysis of NOS2 and COX2 interaction with T-effector cells reveals immunosuppressive landscapes associated with poor outcome in ER- breast cancer patients.

Multiple immunosuppressive mechanisms exist in the tumor microenvironment that drive poor outcomes and decrease treatment efficacy. The co-expression of NOS2 and COX2 is a strong predictor of poor prognosis in ER- breast cancer and other malignancies. Together, they generate pro-oncogenic signals that drive metastasis, drug resistance, cancer stemness, and immune suppression. Using an ER- breast cancer patient cohort, we found that the spatial expression patterns of NOS2 and COX2 with CD3+CD8+PD1- T effector (Teff) cells formed a tumor immune landscape that correlated with poor outcome. NOS2 was primarily associated with the tumor-immune interface, whereas COX2 was associated with immune desert regions of the tumor lacking Teff cells. A higher ratio of NOS2 or COX2 to Teff was highly correlated with poor outcomes. Spatial analysis revealed that regional clustering of NOS2 and COX2 was associated with stromal-restricted Teff, while only COX2 was predominant in immune deserts. Examination of other immunosuppressive elements, such as PDL1/PD1, Treg, B7H4, and IDO1, revealed that PDL1/PD1, Treg, and IDO1 were primarily associated with restricted Teff, whereas B7H4 and COX2 were found in tumor immune deserts. Regardless of the survival outcome, other leukocytes, such as CD4 T cells and macrophages, were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to a massive cell infiltration, thus validating the hypothesis that COX2 is an essential component of the Teff exclusion process and, thus, tumor evasion. Our study indicates that NOS2/COX2 expression plays a central role in tumor immunosuppression. Our findings indicate that new strategies combining clinically available NOS2/COX2 inhibitors with various forms of immune therapy may open a new avenue for the treatment of aggressive ER-breast cancers.

[Contraception and Sexual Health]. / Kontrazeption und Sexualität.

Contraception and Sexual Health Abstract. Reliable contraceptive methods allow a free development of sexuality without fear of unwanted pregnancies. They have contributed significantly to a more self-determined sexuality of both women and men at reproductive age. Hormonal contraceptives, which are available in different compositions and application forms, are highly effective, but are nevertheless used less and less for fear of physical and psychological side effects. Current study data regarding sexual health is heterogenous but reflects the clinical experience that hormonal contraceptives usually have no significant effect. However, some women report improved sexual experience, while others suffer from sexual dysfunction. Hormonal contraceptives act primarily on the hypothalamic-pituitary-ovarian axis to prevent folliculogenesis and ovulation. However, they have an effect on all tissues with sex steroid receptors, including peripheral tissues such as genitals, skin. But they also have an effect on neurobiological mechanisms (mainly in the hypothalamic region) essential for human sexual response. They can impact self and partnership perception, libido, and arousal. The observed influences can be explained via various mechanisms such as: lack of fear of unwanted pregnancies and accordingly more liberated sexuality, decrease in gynecological complaints, such as endometriosis-associated dyspareunia or dysmenorrhea, possible improvement of the individual body image (subjective perception of the physical self) and correspondingly improved self-confidence (e.g., by decreasing acne and hirsutism). Individualized contraceptive counselling, taking into account somatic and emotional aspects, is essential and can contribute to the promotion of sexual health and well-being. This review article summarizes the influence of hormonal contraceptive methods on sexual health and well-being and gives recommendations how to deal with contraception-induced sexual dysfunction.

Randomized controlled trial on the effect of an online decision aid for young female cancer patients regarding fertility preservation.

STUDY QUESTION: Does the use of an online decision aid (DA) about fertility preservation (FP), in addition to standard counselling by a specialist in reproductive medicine, reduce decisional conflict compared to standard counselling alone? SUMMARY ANSWER: Female cancer patients who could make use of the online DA had a significantly lower short-term decisional conflict score. WHAT IS KNOWN ALREADY: Nowadays, female cancer patients have several options for preserving fertility, but having to decide whether to opt for FP within a short time frame after cancer diagnosis and before the start of treatment is challenging. According to previous studies focussing mainly on breast cancer patients, decisional conflict among these women is high, and they have expressed the need for additional support. STUDY DESIGN, SIZE, DURATION: The study was a randomized controlled trial including female cancer patients who were referred by their treating oncologist to a specialist in reproductive medicine for fertility counselling. Participants were randomly assigned to the control group (counselling only) or to the intervention group (counselling and additional use of the online DA immediately after counselling). Recruitment was ongoing from July 2016 to December 2017 at eight fertility centres in Switzerland and Germany. PARTICIPANTS/MATERIALS, SETTING, METHODS: The online DA was developed by an interdisciplinary team of specialists in reproductive medicine, gynaecologists, oncologists and psychologists. Of 79 recruited participants, 59 completed the first assessment and could therefore be enrolled in the study. They were asked to complete an online questionnaire at three time points: at T1, after counselling (control group, n = 27) or after counselling and the additional use of the DA (intervention group, n = 24); at T2, 1 month later (N = 41: control group, n = 23; intervention group, n = 18); and at T3, 12 months later (N = 37: control group, n = 20; intervention group, n = 17). The survey comprised questions about fertility-related knowledge, attitude towards FP, willingness to undergo FP and socio-demographic data, as well as the decisional conflict and decisional regret scales. MAIN RESULTS AND THE ROLE OF CHANCE: All participants showed low decisional conflict scores. Women who used the online DA in addition to counselling (intervention group) showed a significantly lower total score on the Decisional Conflict Scale (DCS) compared to the control group at T1 (P = 0.008; M = 12.15, SD = 4.38; 95% CI, 3.35-20.95) and at T2 (P = 0.043; M = 9.35, SD = 4.48; 95% CI, 0.31-18.38). At T3, the mean total score of the DCS was still lower in the intervention group compared to the control group; however, this group difference was no longer significant (P = 0.199, M = 6.86, SD = 5.24; 95% CI, -3.78 to 17.51). The majority of participants had already made a decision regarding FP (yes or no) at T1 (72.5%): 91.7% in the intervention group compared to 55.6% in the control group (P = 0.014). Those who had decided already at T1 showed significantly lower decisional conflict (P = 0.007; M = 13.69, SD = 4.89; 95% CI, 3.86-23.52). The average number of DA sessions per user was 2.23, and 80.8% of the participants completed the DA's value clarification exercises. Participants in the intervention group were satisfied with the DA and would recommend it to other patients. LIMITATIONS, REASONS FOR CAUTION: The recruitment of participants was challenging because of the emotionally difficult situation patients were in. This led to the limited sample size for final analysis. Education levels were high in two-thirds of the participants. It is difficult to say whether the DA would be equally effective in women with a lower educational background. WIDER IMPLICATIONS OF THE FINDINGS: There is evidence that the DA served as a helpful complement to the decision-making process for young female cancer patients qualifying for FP. This is, to our knowledge, the first randomized controlled trial evaluating a DA targeted at patients with several cancer types and in a language other than English (i.e. German). This study contributes to extending the range of the still limited number of DAs in the context of FP. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a research grant of the Swiss Cancer Research. The authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, trial no. NCT02404883. TRIAL REGISTRATION DATE: 19 March 2015. DATE OF FIRST PATIENT'S ENROLMENT: 4 July 2016.

Addressing decisional conflict about fertility preservation: helping young female cancer survivors' family planning decisions.

BACKGROUND: Health professionals are challenged by a growing number of young long-term cancer survivors with their specific needs with regard to family planning. This study aimed at assessing decisional conflict (DC) in young female cancer patients regarding fertility preservation, identifying demographic, fertility and fertility preservation related factors, which may affect DC, and assessing the helpfulness of various decision-supports. METHODS: A retrospective, cross-sectional, web-based survey via an online questionnaire available in three languages with specific items concerning cancer, fertility, fertility preservation and the validated Decisional Conflict Scale targeted at current or former female cancer patients aged 18-45 years, with cancer types or treatment potentially affecting reproductive function. RESULTS: The 155 participating women showed considerable DC, especially with regard to missing information and support. DC was significantly lower in patients when the risk of infertility was discussed with a health professional, when they had undergone any procedure to preserve fertility, and when they had a university education. A longer time interval since cancer diagnosis was associated with higher DC. The most helpful decision-support tools were specialised websites and leaflets. CONCLUSIONS: Young female cancer patients' DC with regard to fertility preservation is very high. Information and support seem to be deficient. More information through standardised information tools might be an effective strategy to lower their DC at the time when treatment decisions need to be taken, and to improve their reproductive health after they have overcome cancer in the future.

Fertility Preservation in Young Female Cancer Patients: Development and Pilot Testing of an Online Decision Aid.

PURPOSE: Impairment of fertility is a common sequela of successful cancer treatment. Therefore, fertility preservation (FP) should be discussed with all young cancer patients. Decisions about FP are challenging. Patients wish more specific support and the first results concerning the helpfulness of decision aids (DA) were promising. Aside from describing the process of development and the content of an online DA in German, the objective of this study was to pilot test users' satisfaction with the DA and its effect on knowledge about FP and decisional conflict (DC). METHODS: In this prospective consecutive study, a control group (n = 20, fertility counseling) was followed by and compared with an intervention group (n = 20, counseling and additional use of the DA, developed by an interdisciplinary team) of recently diagnosed female cancer patients between 18 and 40 years. RESULTS: Nearly all participants who applied the DA considered it helpful for decision-making and recommendable. Knowledge about FP was high with regard to FP techniques women went for. DC was moderate according to the mean score (M = 27.92, standard deviation = 13.27) and only in 20%, the score was above the threshold for high DC. There was no difference between the control and intervention group for knowledge and DC. CONCLUSION: The DA seems to serve as additional and well-accepted support tool in decision-making for patients and professionals. Referral to a reproductive specialist is crucial to warrant comprehensive information. These results need to be confirmed with the current ongoing randomized controlled study.

Endometrial thickness influences neonatal birth weight in pregnancies with obstetric complications achieved after fresh IVF-ICSI cycles.

PURPOSE: Pregnancy-associated complications, duration of gestation and parity are well-known predictors of neonatal birth weight. Assisted reproductive technology (ART) affects neonatal birth weight as well. Endometrial thickness as measured on the day of HCG triggering may therefore impact on the neonatal birth weight. METHODS: The data of 764 singleton deliveries achieved after fresh transfer between November 1997 and 2014 were collected retrospectively with the intention to analyze the relationship of maternal and neonatal characteristics with endometrial thickness and the possible predictive value of endometrial thickness on neonatal birth weight. RESULTS: Higher maternal age (p < 0.001), diminished ovarian reserve (p < 0.001), endometriosis (p = 0.008) and hypogonadotropic hypogonadism (p < 0.001) predicted thin endometrium. Neonatal birth weight (p = 0.004), longer duration of pregnancy (p = 0.008), parity (p = 0.026) and higher maternal BMI (p = 0.003) were correlated significantly with the degree of endometrial proliferation. Endometrial thickness strongly predicted neonatal birth weight (p = 0.004). After adjusting regression analysis for maternal age and BMI, parity, neonatal gender and pregnancy duration, endometrial thickness remained predictive for neonatal birth weight in pregnancies with obstetric complications (p = 0.017). In uneventful pregnancies duration and parity are determinants of neonatal birth weight. CONCLUSIONS: Our findings suggest that endometrial thickness is an additional ART-related factor influencing neonatal birth weight. This finding should be confirmed in large cohort studies.

Unintended pregnancy during the first year after breast cancer diagnosis.

OBJECTIVES: Young women experience high levels of anxiety and distress during cancer diagnosis and therapy, and it can be devastating to become pregnant in this vulnerable state. Pregnancy during cancer treatment is strongly discouraged, as radiotherapy and chemotherapy administered during the first trimester of pregnancy result in increased congenital malformations. METHODS: In this study, we analysed an unselected, consecutive cohort of young breast cancer (BC) patients with regard to unintended pregnancy during the first year after BC diagnosis. We analysed all patients who were ≤40 years of age at initial BC diagnosis (n = 100, mean age at diagnosis: 35.9 years), according to data from the Basel Breast Cancer Database. The frequency of unintended pregnancy was assessed, and particular attention was given to patients' obstetric and reproductive history. RESULTS: Forty-two percent of the cohort (mean age 36.5 years) were identified as not at risk of unintended pregnancy during the first year after BC diagnosis. However, 58% of the cohort (mean age 35.6 years) were using an ineffective contraceptive method and thus were at risk of unintended pregnancy. The rate of unintended pregnancy was 3.5% in this group (two patients). Oncologists should be aware that the use of reliable contraception should be discussed before starting, and also during, adjuvant therapy. CONCLUSIONS: Oncologists should consider actively referring young BC patients to a gynaecologist to ensure proper contraceptive counselling.

Contraception counseling for young breast cancer patients: A practical needs assessment and a survey among medical oncologists.

BACKGROUND/METHODS: We analyzed an unselected, consecutive cohort of young breast cancer (BC) patients (≤40 years, n = 100) with regard to the contraceptive methods used at the time of diagnosis. Based on this data, we assessed the individual need for contraceptive counseling before cancer therapy. Secondly, in a study-specific self-report questionnaire, we surveyed 101 medical oncologists with the aim of evaluating attitudes towards contraception and how young patients are being counseled in the practical clinical setting. RESULTS: In 62% of our cohort of young BC patients, we identified situations in which contraceptive counseling was necessary at the time of BC diagnosis. The patients did not use contraception or used an ineffective method (TIER III/IV, 42%), or were using hormonal methods (12%) or IUDs (8%). Almost all respondents of the survey (99%) stated that contraception is an important aspect in the surveillance of young BC patients and the vast majority (90%) discussed this item before starting therapy. Only 20% of the respondents reported that they a) inform the patients that reliable contraception is necessary before starting therapy, b) ask whether contraceptive methods are used during ongoing therapy, and c) regularly refer their patients to specialist counseling by a gynecologist. CONCLUSIONS: A large proportion of young women require contraceptive counseling after newly diagnosed BC. Oncologists should be aware that the use of reliable contraceptive methods should not only be discussed before starting therapy, but also during ongoing therapy. Oncologists should consider actively referring their young patients to gynecologists to ensure proper contraceptive counseling.

Family ties: young breast cancer patients and their children.

BACKGROUND: This study assessed the interaction of "family ties" in a cohort of young breast cancer patients. METHODS: Based on the Basel Breast Cancer Database, we analysed an unselected, consecutive cohort of patients who were ≤40 years at breast cancer diagnosis (n = 100). RESULTS: Sixty patients had children at the time of diagnosis (mean number of children: 1.03). Only four patients had desired children after BC therapy. The average age of the children at breast cancer diagnosis of their mother was 7.7 years. The mean age of the children whose mothers died of breast cancer at the time of their mother's death was 13.1 years; these children (n = 37) lived an average of 84.7 months with the illness of their mother. Parity status was not a significant factor for compliance/persistence to adjuvant chemotherapy (p = 1.00). Patients who had children were more likely to be compliant/persistent to endocrine therapy (p = 0.021). Out of these patients, 41.2% rejected or discontinued endocrine therapy with the explicit intention to get pregnant. CONCLUSIONS: Desire for children was an important factor in refusing endocrine therapy. This clearly highlights the enormous pressure that many young women face in this situation. About a third of the children whose mothers were diagnosed with breast cancer experienced the palliative situation and the death of their mother. Since many of these children are confronted with a cancerous disease of their mothers during half of their childhood, special attention should be paid to age-appropriate support of a child in all phases of the mother's disease.

Twenty years' experience with the Swiss data registry for assisted reproductive medicine: outcomes, key trends and recommendations for improved practice.

QUESTIONS UNDER STUDY: The impact of assisted reproductive technology (ART) on Swiss demography was quantified. From 1993 to 2012 the number of deliveries, including multiples, generated by ART was compared with overall delivery numbers. Swiss experts in ART collaborated in a consensus to increase successful outcomes, to reduce the incidence of complications of ART and to validate recommendations through statistical review of available data. METHODS: Data generated between 1993 and 2012 and published by the Federal Office of Statistics (BfS) were compared with the Swiss database on ART (FIVNAT-CH) as organised by the Swiss Society of Reproductive Medicine (SGRM). From these analyses a panel of Swiss experts in ART extracted recommendations to improve current practice, to prevent complications related to ART and to recommend changes in current Swiss legislation dealing with ART. RESULTS: Since 1993 the age of women giving birth rose together with the number of women asking for ART. This demographic trend was reflected in a rise in the number of deliveries generated by ART (in 2012: 2.2%) and the proportion of multiple births (in 2012: 17.6%). The outcome of ART was most negatively influenced by the age of the treated patient. The number of retrieved oocytes decisively impacted the likelihood of delivery, the risk of multiple births and the incidence of ovarian hyperstimulation syndrome. CONCLUSIONS: Optimal ovarian stimulation should be designed for the retrieval of 10 to 15 oocytes per treatment. Swiss legislation should enable and stimulate a policy of elective single embryo transfer to avoid multiple births.

Dual ovarian stimulation is a new viable option for enhancing the oocyte yield when the time for assisted reproductive technnology is limited.

Ovarian stimulation improves assisted reproductive technology outcome by increasing the number of oocytes available for insemination and in-vitro handling. A recent Duplex protocol features a dual stimulation, with the second stimulation started immediately after the first oocyte retrieval. Remarkably, the Duplex protocol is unexpectadly well tolerated by women and provides twice as many oocytes and embryos as a regular antagonist protocol in less than 30 days.

Preserving fertility in patients undergoing treatment for breast cancer: current perspectives.

Invasive breast cancer (BC) is the most frequent cancer of young women. Considering the trend toward postponing childbearing until the later reproductive years, the number of childless women at diagnosis of BC will continue to increase. The American Society of Clinical Oncology and the American Society for Reproductive Medicine have recommended that the impact of cancer treatments on fertility should be addressed with all cancer patients of reproductive age and that options for fertility preservation, such as cryopreservation of embryos and oocytes, ovarian tissue, in vitro maturation of immature oocytes, and ovarian suppression with gonadotropin-releasing hormone analogs, should be discussed routinely. To optimally counsel patients on how to best weigh the risks and benefits of fertility preservation, both the health care provider and the patient must know about the options, their risks, and their likelihood of success. The aim of this review is to summarize current knowledge on fertility preservation options for young BC patients, surrogates of ovarian function, psychosocial aspects of infertility after cancer treatment, women's attitudes towards childbearing after cancer treatment, and health care providers' attitudes towards fertility preservation.

Does prior hysteroscopy affect pregnancy outcome in primigravid infertile women?

OBJECTIVE: An increasing proportion of infertile women are subjected to hysteroscopy. The effect of hysteroscopy on the pregnancy rate in assisted reproduction has been demonstrated to be favorable, but cervical dilation in the course of hysteroscopy may have an adverse effect on pregnancy outcome. We sought to investigate the effect of hysteroscopy on the risk of early miscarriage, preterm delivery, low birthweight, and other complications of pregnancy. STUDY DESIGN: This was a longitudinal retrospective cohort study at a university hospital. Data of 654 first-time singleton pregnancies between January 1997 and March 2011 in women with primary infertility were retrieved from a prospective data collection. Four cohorts were constructed based on exposure to hysteroscopy and pregnancy outcome (early miscarriage vs live birth). The primary endpoint was the duration of pregnancy at 37 weeks. Pregnancy outcomes of 167 infertile patients exposed to cervical dilation and hysteroscopy were compared with those of 327 infertile women unexposed to hysteroscopy. RESULTS: The incidence of miscarriage, preterm birth, placenta previa, and premature rupture of membranes after maternal exposure to hysteroscopy was similar to that in women not exposed. CONCLUSION: Prior hysteroscopy in infertile women does not affect subsequent pregnancy outcome.

Urinary phytoestrogens and depression in perimenopausal US women: NHANES 2005-2008.

BACKGROUND: Fluctuating hormonal levels observed during the menopausal transition may increase vulnerability to depression in susceptible women. Thus, it is of interest to examine the effect of natural estrogens such as phytoestrogens on the risk of depression in perimenopausal women. METHODS: Our analysis included 193 perimenopausal women of the National Health and Nutrition Survey (NHANES) 2005-2008 aged 45-55 years. Urinary concentrations of phytoestrogens (isoflavones and lignans) were measured by HPLC-APPI-MS/MS. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9). Logistic regression models examined the association of phytoestrogens concentrations (creatinine-standardized and log-transformed) with depression (yes/no). RESULTS: Unadjusted odds ratios (OR) of the associations between urinary phytoestrogen concentrations and perimenopausal depression were below 1; however, only lignans were significantly inversely associated with depression. The latter findings were not attenuated in multivariate analysis including age, race, body mass index, poverty income ratio, smoking, alcohol consumption, cancer, diabetes, and cardiovascular disease (lignans: OR=0.66; 95% confidence intervals (CI) 0.50-0.87, enterodiol: OR=0.63; 95% CI 0.51-0.78, enterolactone: OR=0.75; 95% CI 0.60-0.93). LIMITATIONS: Our cross-sectional study design does not allow for causal inferences. Because information to precisely assess perimenopausal symptoms was missing, we defined perimenopause based on women's age. CONCLUSIONS: Lower lignans but not isoflavones concentrations were statistically significantly associated with an increased risk of depression in perimenopausal women. Because of medical risks associated with the use of hormone therapy, further investigation on the effect of lignans on the risk of depression in perimenopausal women is warranted.

Similar prevalence of expanded CGG repeat lengths in the fragile X mental retardation I gene among infertile women and among women with proven fertility: a prospective study.

PURPOSE: We sought to determine the usefulness of fragile X mental retardation 1 (FMR1) carrier testing among young infertile women with or without signs of ovarian insufficiency as compared with fertile women. METHODS: Three cohorts of women were recruited to determine the cytosine-guanine-guanine (CGG) repeats trinucleotide repeat length in the 5'-untranslated region of the FMR1 gene in lymphocyte DNA. A total of 199 fertile women, who were reported to have conceived within 3 months, were recruited together with 372 infertile women with ongoing menstrual cycles and 48 infertile women with primary ovarian insufficiency. The various ranges of FMR1 CGG repeat lengths among infertile women were compared with those of fertile controls. In infertile women with ongoing menstrual cycles, the serum concentrations of follicle-stimulating hormone, anti-Muellerian hormone, and inhibin B were measured during the early follicular phase. RESULTS: None of the three categories of FMR1 CGG repeat length expansions (premutation, intermediate range, and high normal range) were more prevalent among infertile women than among fertile women. The CGG repeat length was not correlated with any of the ovarian reserve parameters. CONCLUSION: In comparison with a generalized preconception screening strategy, infertility as a criterion, even together with reduced ovarian reserve, is not suitable for identifying a higher proportion of women with expanded FMR1 CGG repeat length.

Young women with breast cancer: how many are actually candidates for fertility preservation?

PURPOSE: There are no data regarding the actual need for fertility preservation (FP) in breast cancer (BC) patients. Our study provides a practical needs assessment for reproductive medicine by analyzing an unselected cohort of young BC patients. This assessment considers oncological factors as well as the patient's obstetrical and gynecological history and reproductive outcome after BC diagnosis. We aimed to identify how many patients are actually potential candidates for FP and how many patients might consequently use their cryopreserved gametes to achieve pregnancy. METHODS: Based on a prospective BC database, we analyzed all patients who were ≤40 years at initial diagnosis (time period of diagnosis: 1990-2007; n=100; 7.7% of the entire BC cohort; median age: 35.9 years). RESULTS: Using an algorithm of exclusion criteria considering disease-specific, therapy-specific and family history characteristics, 36 patients who received chemotherapy were identified as potential "classical" candidates for FP. After 5 years, 22 women were identified as potential candidates for using their cryopreserved gametes to achieve pregnancy; the majority of these patients were childless (n=16, 72.7%) and in their late reproductive years (n=12, 54.5%). CONCLUSIONS: Our study demonstrates that in a cohort of young BC patients only a minority of women are candidates for FP. Young BC patients who wish to have children in the future usually carry risk factors both from oncological and reproductive medicine perspective. Due to this high-risk profile, the rarity of BC in young age and the limited number of patients who might actually have opted for FP, these women must be offered timely and multidisciplinary counseling in highly specialized centers.

The CC-allele of the PvuII polymorphic variant in intron 1 of the α-estrogen receptor gene is significantly more prevalent among infertile women at risk of premature ovarian aging.

OBJECTIVE: To study the distribution of a set of polymorphic alleles of genes encoding key regulators of the menstrual cycle in cohorts of women with different levels of fertility. DESIGN: Prospective cohort study. SETTING: University hospital. PATIENT(S): Two hundred fertile women, who reported to have conceived within 3 months, 348 women with ongoing menstrual cycles suffering of infertility, and 48 infertile women diagnosed with infertility and premature ovarian failure (POF). INTERVENTION(S): Eleven polymorphisms of genes with known associations with surrogate parameters of female ovarian function were analyzed. MAIN OUTCOME MEASURE(S): The prevalence of polymorphic alleles in the three distinct cohorts after adjustment for age. RESULT(S): The distributions of the allelic variants were compared with the fertility status of the recruited women. Using age-adjusted logistic regression analysis and the Bonferroni correction for multiple corrections, the CC-allele of the PvuII polymorphic variant in intron 1 of the ESR1 gene was twice as prevalent among women suffering from infertility. None of the other polymorphisms were distributed differently among the three cohorts. CONCLUSION(S): The ESR1-PvuII polymorphism emerges as a potential candidate for the early prediction of infertility due to premature ovarian aging.

Menopausal state in breast cancer: how reliable is the data?

UNLABELLED: Despite the high importance of the menopausal state for the management of breast cancer, above all, when planning antihormonal adjuvant therapy, the menopausal state cannot be defined at the time of diagnosis ina significant proportion of women. The scope of uncertainties regarding the recording of the menopausal state in a cohort of patients with breast cancer is evaluated. INTRODUCTION: Menopause is a cornerstone both in breast cancer (BC) pathophysiology and in clinical management. The scope of uncertainties regarding the recording of the menopausal state in a cohort of patients with BC is evaluated in this study. PATIENTS AND METHODS: The data of a Swiss prospective relational BC database that covered a 20-year period (1990-2009; n=1457) was analyzed. For the definition of menopause, the guidelines of the National Comprehensive Cancer Network were used. RESULTS: The menopausal state was unclear in 150 patients (10.2%). Of these, 122 (81.3%) had undergone a hysterectomy before menopause; in 28 women (18.7%), an endocrine therapy obscured the patient's actual endocrine status. When taking only the subgroup of women in which menopause usually occurs (45-55 years) into consideration, the menopausal state was unclear in 91 cases of 337 women (27.0%). From the entire cohort, the date of last menstruation remained obscure in 450 patients (30.9%). CONCLUSION: Despite the high importance of the menopausal state for the management of BC, above all, when planning antihormonal adjuvant therapy, the menopausal state was unable to be defined at the time of BC diagnosis in a significant proportion of women. The dilemma that menopause cannot be assessed in some BC cases is increasingly being recognized. Close cooperation between oncologists and endocrinologists is desirable to establish an optimal, individually tailored therapy for women with an unclear menopausal state due to hormonal therapies, hysterectomy, or chemotherapy.