Frequency, morbidity and equity - the case for increased research on male fertility.

Currently, most men with infertility cannot be given an aetiology, which reflects a lack of knowledge around gamete production and how it is affected by genetics and the environment. A failure to recognize the burden of male infertility and its potential as a biomarker for systemic illness exists. The absence of such knowledge results in patients generally being treated as a uniform group, for whom the strategy is to bypass the causality using medically assisted reproduction (MAR) techniques. In doing so, opportunities to prevent co-morbidity are missed and the burden of MAR is shifted to the woman. To advance understanding of men's reproductive health, longitudinal and multi-national centres for data and sample collection are essential. Such programmes must enable an integrated view of the consequences of genetics, epigenetics and environmental factors on fertility and offspring health. Definition and possible amelioration of the consequences of MAR for conceived children are needed. Inherent in this statement is the necessity to promote fertility restoration and/or use the least invasive MAR strategy available. To achieve this aim, protocols must be rigorously tested and the move towards personalized medicine encouraged. Equally, education of the public, governments and clinicians on the frequency and consequences of infertility is needed. Health options, including male contraceptives, must be expanded, and the opportunities encompassed in such investment understood. The pressing questions related to male reproductive health, spanning the spectrum of andrology are identified in the Expert Recommendation.

Fertility assessment and treatment in adolescent and young adult cancer survivors.

In the survivorship setting, adolescent and young adult (AYA) cancer survivors frequently demonstrate little knowledge of infertility risk, are unclear regarding their fertility status, and may under- or overestimate their treatment-related risk for infertility. In female AYA survivors, ovarian function usually parallels fertility, and can be assessed with serum hormone levels and ultrasonography. Posttreatment fertility preservation may be appropriate for survivors at risk for primary ovarian insufficiency. In male AYA survivors, fertility and gonadal function are not always equally affected, and can be assessed with a semen analysis and serum hormones, respectively. As reproductive health issues are commonly cited as an important concern by survivors of AYA cancer, multidisciplinary care teams including oncology, endocrinology, psychology, and reproductive medicine are advocated, with the aim of optimal provision of fertility advice and care for AYA cancer survivors.

Understanding the barriers to, and facilitators of, ovarian toxicity assessment in breast cancer clinical trials.

BACKGROUND: Detailed toxicity data are routinely collected in breast cancer (BC) clinical trials. However, ovarian toxicity is infrequently assessed, despite the adverse impacts on fertility and long-term health from treatment-induced ovarian insufficiency. OBJECTIVES: To determine the barriers to and facilitators of ovarian toxicity assessment in BC trials of anti-cancer drugs. METHODS: Semi-structured interviews were conducted with purposively selected stakeholders from multiple countries involved in BC clinical trials (clinicians, consumers, pharmaceutical company representatives, members of drug-regulatory agencies). Participants were asked to describe the perceived benefits and barriers to evaluating ovarian toxicity. Interviews were transcribed verbatim, coded in NVivo software and analysed using inductive thematic analysis. RESULTS: Saturation of the main themes was reached and the final sample size included 25 participants from 14 countries (9 clinicians, 7 consumers, 5 members of regulatory agencies, 4 pharmaceutical company representatives); half were female. The main reported barrier to ovarian toxicity assessment was that the issue was rarely considered. Reasons included that these data are less important than survival data and are not required for regulatory approval. Overall, most participants believed evaluating the impact of BC treatments on ovarian function is valuable. Suggested strategies to increase ovarian toxicity assessment were to include it in clinical trial design guidelines and stakeholder advocacy. CONCLUSION: Lack of consideration about measuring ovarian toxicity in BC clinical trials that include premenopausal women suggest that guidelines and stronger advocacy from stakeholders, including regulators, would facilitate its more frequent inclusion in future trials, allowing women to make better informed treatment decisions.

Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism.

Male hypogonadism (MH) is a common endocrine disorder. However, uncertainties and variations in its diagnosis and management exist. There are several current guidelines on testosterone replacement therapy that have been driven predominantly by single disciplines. The Society for Endocrinology commissioned this new guideline to provide all care providers with a multidisciplinary approach to treating patients with MH. This guideline has been compiled using expertise from endocrine (medical and nursing), primary care, clinical biochemistry, urology and reproductive medicine practices. These guidelines also provide a patient perspective to help clinicians best manage MH.

Assessment of Ovarian Function in Phase III (Neo)Adjuvant Breast Cancer Clinical Trials: A Systematic Evaluation.

BACKGROUND: Loss of ovarian function is a recognized adverse effect of chemotherapy for breast cancer and of great importance to patients. Little is known about the ovarian toxicity of newer cancer treatments. This study examined whether breast cancer clinical trials include assessment of the impact of trial interventions on ovarian function. METHODS: Eligible trials were phase III (neo)adjuvant trials of pharmacologic treatments for breast cancer, recruiting between June 2008 and October 2019, which included premenopausal women. MEDLINE, EMBASE, Clinicaltrials.gov, and EudraCT were searched. Data were extracted from trial publications, protocols, databases, and a survey sent to all trial chairs. Tests of statistical significance were 2-sided. RESULTS: Of 2354 records identified, 141 trials were eligible. Investigational treatments included chemotherapy (36.9%), HER2 targeted (24.8%), endocrine (12.8%), immunotherapy (7.8%), cyclin-dependent kinase 4/6 inhibitors (5.0%), and poly-ADP-ribose polymerase inhibitors (2.8%). Ovarian function was a prespecified endpoint in 13 (9.2%) trials. Forty-five (31.9%) trials collected ovarian function data, but only 33 (23.4%) collected posttrial-intervention data. Common postintervention data collected included menstruation (15.6%), pregnancy (13.5%), estradiol (9.9%), and follicle-stimulating hormone levels (8.5%). Only 4 (2.8%) trials collected postintervention anti-müllerian hormone levels, and 3 (2.1%) trials collected antral follicle count. Of 22 trials investigating immunotherapy, cyclin-dependent kinase 4/6 inhibitors, or poly-ADP-ribose polymerase inhibitors, none specified ovarian function as an endpoint, but 4 (18.2%) collected postintervention ovarian function data. CONCLUSIONS: The impact of pharmacologic interventions on ovarian function is infrequently assessed in phase III breast cancer (neo)adjuvant trials that include premenopausal women. Trialists should consider inclusion of ovarian function endpoints when designing clinical trials, given its importance for informed decision making.

Fertility preservation and preimplantation genetic assessment for women with breast cancer.

Breast cancer is the most common cancer diagnosed among reproductive aged women, and its treatment can compromise future fertility. Options for fertility preservation include oocyte or embryo cryopreservation after ovarian stimulation (OS), which are the most established choices and are applicable for adult women with cancer. Ovarian tissue freezing may also be appropriate, as it offers potentially the least delay. The recognisation of the role of BRCA1 and BRCA2 mutations in some women has led to the involvement of preimplantation genetic diagnosis (PGD), recently renamed preimplantation genetic testing for monogenic disorder (PGT-M), whereby embryos are created by IVF and cell(s) are removed and genetically analyzed for specific disease-related mutations. PGT-M offers a valid option for women wishing to avoid transmission of the predisposition for hereditary breast cancer to their offspring. The aim of this paper is to provide an overview of the factors that influence fertility preservation in newly diagnosed breast cancer patients, and to illustrate the option of PGT-M to enable conception of an unaffected child.

Cardiovascular magnetic resonance in emergency patients with multivessel disease or unobstructed coronary arteries: a cost-effectiveness analysis in the UK.

OBJECTIVE: To identify the key drivers of cost-effectiveness for cardiovascular magnetic resonance (CMR) when patients activate the primary percutaneous coronary intervention (PPCI) pathway. DESIGN: Economic decision models for two patient subgroups populated from secondary sources, each with a 1 year time horizon from the perspective of the National Health Service (NHS) and personal social services in the UK. SETTING: Usual care (with or without CMR) in the NHS. PARTICIPANTS: Patients who activated the PPCI pathway, and for Model 1: underwent an emergency coronary angiogram and PPCI, and were found to have multivessel coronary artery disease. For Model 2: underwent an emergency coronary angiogram and were found to have unobstructed coronary arteries. INTERVENTIONS: Model 1 (multivessel disease) compared two different ischaemia testing methods, CMR or fractional flow reserve (FFR), versus stress echocardiography. Model 2 (unobstructed arteries) compared CMR with standard echocardiography versus standard echocardiography alone. MAIN OUTCOME MEASURES: Key drivers of cost-effectiveness for CMR, incremental costs and quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios. RESULTS: In both models, the incremental costs and QALYs between CMR (or FFR, Model 1) versus no CMR (stress echocardiography, Model 1 and standard echocardiography, Model 2) were small (CMR: -£64 (95% CI -£232 to £187)/FFR: £360 (95% CI -£116 to £844) and CMR/FFR: 0.0012 QALYs (95% CI -0.0076 to 0.0093)) and (£98 (95% CI -£199 to £488) and 0.0005 QALYs (95% CI -0.0050 to 0.0077)), respectively. The diagnostic accuracy of the tests was the key driver of cost-effectiveness for both patient groups. CONCLUSIONS: If CMR were introduced for all subgroups of patients who activate the PPCI pathway, it is likely that diagnostic accuracy would be a key determinant of its cost-effectiveness. Further research is needed to definitively answer whether revascularisation guided by CMR or FFR leads to different clinical outcomes in acute coronary syndrome patients with multivessel disease.

Confirmation of ovulation from urinary progesterone analysis: assessment of two automated assay platforms.

Urinary concentrations of the major progesterone (P4) metabolite pregnanediol-3-glucuronide (PDG) are used to confirm ovulation. We aimed to determine whether automated immunoassay of urinary P4 was as efficacious as PDG to confirm ovulation. Daily urine samples from 20 cycles in 14 healthy women in whom ovulation was dated by ultrasound, and serial weekly samples from 21 women in whom ovulation was unknown were analysed. Daily samples were assayed by two automated P4 immunoassays (Roche Cobas and Abbott Architect) and PDG ELISA. Serial samples were assayed for P4 by Architect and PDG by ELISA. In women with detailed monitoring of ovulation, median (95% CI) luteal phase increase was greatest for PDG, 427% (261-661), 278% (187-354) for P4 Architect and least for P4 Cobas, 146% (130-191), p < 0.0001. Cobas P4 also showed marked inaccuracy in serial dilution. Similar ROC AUCs were observed for individual threshold values and two-sample percent rise analyses for P4 Architect and PDG (both >0.92). In serial samples classified as (an)ovulatory by PDG, P4 Architect gave ROC AUC 0.95 (95% CI 0.89 to 1.01), with sensitivity and specificity for confirmation of ovulation of 0.90 and 0.91 at a cutoff of 1.67 µmol/mol. Automated P4 may potentially be as efficacious as PDG ELISA but research from a range of clinical settings is required.

Formal consensus to identify clinically important changes in management resulting from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway.

OBJECTIVE: To define important changes in management arising from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway. DESIGN: Formal consensus study using literature review and cardiologist expert opinion to formulate consensus statements and setting up a consensus panel to review the statements (by completing a web-based survey, attending a face-to-face meeting to discuss survey results and modify the survey to reflect group discussion and completing the modified survey to determine which statements were in consensus). PARTICIPANTS: Formulation of consensus statements: four cardiologists (two CMR and two interventional) and six non-clinical researchers. Formal consensus: seven cardiologists (two CMR and three interventional, one echocardiography and one heart failure). Forty-nine additional cardiologists completed the modified survey. RESULTS: Thirty-seven draft statements describing changes in management following CMR were generated; these were condensed into 12 statements and reviewed through the formal consensus process. Three of 12 statements were classified in consensus in the first survey; these related to the role of CMR in identifying the cause of out-of-hospital cardiac arrest, providing a definitive diagnosis in patients found to have unobstructed arteries on angiography and identifying patients with left ventricular thrombus. Two additional statements were in consensus in the modified survey, relating to the ability of CMR to identify patients who have a poor prognosis after PPCI and assess ischaemia and viability in patients with multivessel disease. CONCLUSION: There was consensus that CMR leads to clinically important changes in management in five subgroups of patients who activate the PPCI pathway.

Severe symptomatic aortic stenosis: medical therapy and transcatheter aortic valve implantation (TAVI)-a real-world retrospective cohort analysis of outcomes and cost-effectiveness using national data.

OBJECTIVES: Determine the real-world difference between 2 groups of patients with severe aortic stenosis and similar baseline comorbidities: surgical turn down (STD) patients, who were managed medically prior to the availability of transcatheter aortic valve implantation (TAVI) following formal surgical outpatient assessment, and patients managed with a TAVI implant. DESIGN: Retrospective cohort study from real-world data. SETTING: Electronic patient letters were searched for patients with a diagnosis of severe aortic stenosis and a formal outpatient STD prior to the availability of TAVI (1999-2009). The second group comprised the first 90 cases of TAVI in South Wales (2009 onwards). 2 years prior to and 5 years following TAVI/STD were assessed. Patient data were pseudoanonymised, using the Secure Anonymized Information Linkage (SAIL) databank, and extracted from Office National Statistics (ONS), Patient-Episode Database for Wales (PEDW) and general practitioner databases. POPULATION: 90 patients who had undergone TAVI in South Wales, and 65 STD patients who were medically managed. MAIN OUTCOME MEASURES: Survival, hospital admission frequency and length of stay, primary care visits, and cost-effectiveness. RESULTS: TAVI patients were significantly older (81.8 vs 79.2), more likely to be male (59.1% vs 49.3%), baseline comorbidities were balanced. Mortality in TAVI versus STD was 28% vs 70% at 1000 days follow-up. There were significantly more hospital admissions per year in the TAVI group prior to TAVI/STD (1.5 (IQR 1.0-2.4) vs 1.0 IQR (0.5-1.5)). Post TAVI/STD, the TAVI group had significantly lower hospital admissions (0.3 (IQR 0.0-1.0) vs 1.2 (IQR 0.7-3.0)) and lengths of stay (0.4 (IQR 0.0-13.8) vs 11.0 (IQR 2.5-28.5), p<0.05). The incremental cost-effectiveness ratio (ICER) for TAVI was £10 533 per quality-adjusted life year (QALY). CONCLUSIONS: TAVI patients were more likely to survive and avoid hospital admissions compared with the medically managed STD group. The ICER for TAVI was £10 533 per QALY, making it a cost-effective procedure.

Prospective study into the value of the automated Elecsys antimüllerian hormone assay for the assessment of the ovarian growing follicle pool.

OBJECTIVE: To evaluate a new fully automated assay measuring antimüllerian hormone (AMH; Roche Elecsys) against antral follicle count in women of reproductive age. DESIGN: Prospective cohort study. SETTING: Hospital infertility clinics and academic centers. PATIENT(S): Four hundred fifty-one women aged 18 to 44 years, with regular menstrual cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): AMH and antral follicle count (AFC) determined at a single visit on day 2-4 of the menstrual cycle. RESULT(S): There was a statistically significant variance in AFC but not in AMH between centers. Both AFC and AMH varied by age (overall Spearman rho -0.50 for AFC and -0.47 for AMH), but there was also significant between-center variation in the relationship between AFC and age but not for AMH. There was a strong positive correlation between AMH and AFC (overall spearman rho 0.68), which varied from 0.49 to 0.87 between centers. An agreement table using AFC cutoffs of 7 and 15 showed classification agreement in 63.2%, 56.9% and 74.5% of women for low, medium, and high groups, respectively. CONCLUSION(S): The novel fully automated Elecsys AMH assay shows good correlations with age and AFC in women of reproductive age, providing a reproducible measure of the growing follicle pool.

The regulation and assessment of follicular growth.

Folliculogenesis is the process by which waves of small primordial follicles possessing immature oocytes are recruited to undergo development into large antral follicles, with one then being selected for ovulation of a fully competent oocyte. Folliculogenesis can be divided into three stages: follicle recruitment, selection and ovulation, and has two phases: the initial gonadotrophin-independent phase and the later gonadotrophin-dependent phase. It involves an elaborate array of biochemical signalling factors, both stimulatory and inhibitory, and the regulation of follicle growth relies on these being tightly controlled. Their increasing understanding allows reproductive biologists to attempt manipulation of folliculogenesis, which can be useful in clinical areas such as assisted reproduction and contraception. The rising average age of childbearing in many developed countries is bringing an additional focus on the importance of assessing a woman's non-growing follicular pool; i.e. her ovarian reserve. This review examines the important regulatory players in the different stages of folliculogenesis and describes some of the currently available measures of ovarian reserve.

Antimüllerian hormone, the assessment of the ovarian reserve, and the reproductive outcome of the young patient with cancer.

The accurate assessment of the ovarian reserve has long been a key goal in reproductive medicine. The recognition that serum antimüllerian hormone provides an indirect measure of the ovarian reserve has led to its rapid adoption in assisted conception, and wide exploration of its potential across the reproductive lifespan from the neonate to the menopause. In this short review we discuss its relationship with the ovarian reserve in its varied meanings, and in various contexts. These include in childhood and adolescence, and in the assessment of the impact of cancer therapy on the female reproductive tract. These therapies can adversely impact all aspects of female reproduction, including hypothalamic, pituitary, and ovarian hormonal activity, and the ability of the uterus to support a successful pregnancy.

Determinants of the rate and extent of spermatogenic suppression during hormonal male contraception: an integrated analysis.

CONTEXT: Male hormonal contraceptive methods require effective suppression of sperm output. OBJECTIVE: The objective of the study was to define the covariables that influence the rate and extent of suppression of spermatogenesis to a level shown in previous World Health Organization-sponsored studies to be sufficient for contraceptive purposes (< or =1 million/ml). DESIGN: This was an integrated analysis of all published male hormonal contraceptive studies of at least 3 months' treatment duration. SETTING: Deidentified individual subject data were provided by investigators of 30 studies published between 1990 and 2006. PARTICIPANTS: A total of 1756 healthy men (by physical, blood, and semen exam) aged 18-51 yr of predominantly Caucasian (two thirds) or Asian (one third) descent were studied. This represents about 85% of all the published data. INTERVENTION(S): Men were treated with different preparations of testosterone, with or without various progestins. MAIN OUTCOME MEASURE: Semen analysis was the main measure. RESULTS: Progestin coadministration increased both the rate and extent of suppression. Caucasian men suppressed sperm output faster initially but ultimately to a less complete extent than did non-Caucasians. Younger age and lower initial blood testosterone or sperm concentration were also associated with faster suppression, but the independent effect sizes for age and baseline testicular function were relatively small. CONCLUSION: Male hormonal contraceptives can be practically applied to a wide range of men but require coadministration of an androgen with a second agent (i.e. progestin) for earlier and more complete suppression of sperm output. Whereas considerable progress has been made toward defining clinically effective combinations, further optimization of androgen-progestin treatment regimens is still required.