Aging and erectile function.

The authors review and discuss numerous factors that influence erectile function and their interactions, based on the published literature. Of critical importance are vascular nitric oxide; nutrition; exercise; weight control and maintaining insulin sensitivity; early treatment of hypertension with attention to effects on erectile function; avoiding sources of oxidative stress such as obesity and smoking; reducing inflammation (e.g. from gingivitis); improving pelvic floor muscle strength; and inhibiting cyclic GMP break-down. The described interventions act on different aspects of erectile biochemistry and physiology. Therefore, combining multiple therapeutic approaches will yield maximum benefits for erectile and vascular and general health.

Erectile hydraulics: maximizing inflow while minimizing outflow.

INTRODUCTION: Penile rigidity depends on maximizing inflow while minimizing outflow. AIM: The aim of this review is to describe the principal factors and mechanisms involved. MAIN OUTCOME MEASURE: Erectile quality is the main outcome measure. METHODS: Data from the pertinent literature were examined to inform our conclusions. RESULTS: Nitric oxide (NO) is the principal factor increasing blood flow into the penis. Penile engorgement and the pelvic floor muscles maintain an adequate erection by impeding outflow of blood by exerting pressure on the penile veins from within and from outside of the penile tunica. Extrinsic pressure by the pelvic floor muscles further raises intracavernosal pressure above maximum inflow pressure to achieve full penile rigidity. Aging and poor lifestyle choices are associated with metabolic impediments to NO production. Aging is also associated with fewer smooth muscle cells and increased fibrosis within the corpora cavernosa, preventing adequate penile engorgement and pressure on the penile veins. Those same penile structural changes occur rapidly following the penile nerve injury that accompanies even "nerve-sparing" radical prostatectomy and are largely prevented in animal models by early chronic use of a phosphodiesterase type 5 (PDE5) inhibitor. Pelvic floor muscles may also decrease in tone and bulk with age, and pelvic floor muscle exercises have been shown to improve erectile function to a similar degree compared with a PDE5 inhibitor in men with erectile dysfunction (ED). CONCLUSIONS: Because NO is critical for vascular health and ED is strongly associated with cardiovascular disease, maximal attention should be focused on measures known to increase vascular NO production, including the use of PDE5 inhibitors. Attention should also be paid to early, regular use of PDE5 inhibition to reduce the incidence of ED following penile nerve injury and to assuring normal function of the pelvic floor muscles. These approaches to maximizing erectile function are complementary rather than competitive, as they operate on entirely different aspects of erectile hydraulics.

Forty years of IVF.

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field.

Introduction: Obesity and reproduction.

Women bear the predominant burden of our obesogenic environment, with a higher incidence of obesity than men, more impact on their fertility and success with treatment, and significant maternal and perinatal morbidity and mortality. In this series, the causes, consequences, and solutions regarding the obesity pandemic, the mechanisms of the effect of obesity on the female and male, the epigenetic consequences of male obesity, the marked effects on perinatal outcomes, and the effects of weight loss before conception and during pregnancy are explored. Lifestyle modifications, in particular a healthy diet and exercise during the 3-6 months before conception and during treatment, should result in better outcomes than requiring weight loss before fertility treatments. Such fundamental changes toward a healthier lifestyle will achieve steady and sustainable weight loss and long-term benefits for general health. The role of bariatric surgery before pregnancy requires careful consideration.

Obesity pandemic: causes, consequences, and solutions-but do we have the will?

Obesity has become pandemic owing to an obesogenic environment (inexpensive calorie dense food, technologies and structure of communities that reduce or replace physical activity, and inexpensive nonphysical entertainment) and excessive emphasis on low fat intake resulting in excessive intake of simple carbohydrates and sugar. Effects are greater for women owing to their smaller size and extra weight gain with each pregnancy, with 38% of American adult women being obese. Women are responsible for more than three-fourths of the more than 400 billion dollars of excess direct health care expenditures due to obesity. They are less likely to conceive naturally and with fertility treatments, more likely to miscarry, and have more prematurity and other complications with their pregnancies. We describe the many causes, including key roles that a dysbiotic intestinal microbiome plays in metabolic derangements accompanying obesity, increased calorie absorption, and increased appetite and fat storage. Genetic causes are contributory if these other factors are present but have limited effect in isolation. The numerous health consequences of obesity are discussed. The authors itemize ways that an individual and societies can mitigate the pandemic. However, individual will power, the will of society to enact change, and willingness of the public to accept outside intervention frustrate efforts to stabilize or reverse this crisis. The most promising strategies are education and efforts by individuals to make responsible choices several times every day to protect, most effectively by prevention, their most valuable asset.

Introduction: Examining the many potential reasons why euploid blastocysts do not always result in viable pregnancies: part 1.

The environment of the oocyte and embryo includes the metabolic effects of aging, lifestyle issues, psychological stress, nutritional supplements/replacements, cellular energy levels, endocrine and paracrine factors, the cumulus, exogenous gonadotropins and adjunctive medications, culture media, and the in vitro fertilization laboratory's conditions and manipulations. These complex factors, which will be examined in the following series of reviews, explain in part why not all euploid blastocysts result in viable pregnancies.

Introduction: Examining the many potential reasons why euploid blastocysts do not always result in viable pregnancies (and deliveries): part 2.

To result in a viable delivery: 1) a capable embryo must be accurately deposited and retained in an optimal location of the uterine cavity; 2) the endometrium must be receptive and synchronized to the developmental stage of the embryo; 3) the uterus must be physiologically and anatomically adequate; and 4) there should not be the presence of circulating factors capable of disrupting normal implantation and placentation, nor the absence of specific factors required for endometrial receptivity. The intricate interaction between the embryo and the uterus is discussed in this series of reviews.

Aging and the environment affect gamete and embryo potential: can we intervene?

Optimal maturation of the oocyte depends on its environment and determines embryo competence, because the embryonic genome is not active until the cleavage stage and new mitochondria are not produced until blastulation. Adverse environmental factors include aging, andropause, oxidative stress, obesity, smoking, alcohol, and psychologic stress, whereas androgen supplementation, a prudent diet, exercise, nutritional supplements, and psychologic interventions have beneficial effects. Mitochondrial function and energy production deteriorate with age, adversely affecting ovarian reserve, chromosome segregation, and embryo competence. In aging mice, the mitochondrial cofactor coenzyme Q10 reverses most of these changes. Early human experience has been encouraging, although only a small study using a shorter duration of intervention compared with the murine model has been carried out. Mitochondrial metabolic stress can result in an abnormal compensatory increase in mitochondrial DNA, which can be assessed in biopsied blastomeres of trophectoderm as a predictive biomarker of implantation failure. Psychologic stress may reduce oocyte competence by shifting blood flow away from the ovary as part of the classic "fight or flight" physiologic response, and methods to reduce stress or the body's reaction to stress improve pregnancy success. Enhancing oocyte competence is a key intervention that promises to reduce the number of euploid embryos failing to produce viable deliveries.

Introduction: nongenetic markers of oocyte and embryo competence.

The authors of this Views and Reviews have outlined the complexities of oocyte and embryo development and candidates for markers of embryo competence. Time-lapse monitoring of embryo development allows hierarchical selection of embryos for day 3 transfer. However, for normal-prognosis patients, extended embryo culture and comprehensive chromosome screening currently stand as the ultimate tools for the selection of embryos capable of a viable, normal delivery.

Introduction: Training in reproductive endocrinology and infertility: meeting worldwide needs.

Training in reproductive endocrinology (REI) and its male variant, andrology, has been profoundly influenced by the central role captured by assisted reproductive technologies (ART). The marked differences in financial, regulatory, and societal/ethical restrictions on ART in different countries of the world also prominently influence the clinical management of infertility. Training should strive for comprehensive teaching of all medically indicated procedures, even if only to optimize cross-border care. Better international standardization of infertility practices and training would benefit worldwide infertility care and should be promoted by international societies.

Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health.

Bidirectional somatic cell-oocyte signaling is essential to create a changing intrafollicular microenvironment that controls primordial follicle growth into a cohort of growing follicles, from which one antral follicle is selected to ovulate a healthy oocyte. Such intercellular communications allow the oocyte to determine its own fate by influencing the intrafollicular microenvironment, which in turn provides the necessary cellular functions for oocyte developmental competence, which is defined as the ability of the oocyte to complete meiosis and undergo fertilization, embryogenesis, and term development. These coordinated somatic cell-oocyte interactions attempt to balance cellular metabolism with energy requirements during folliculogenesis, including changing energy utilization during meiotic resumption. If these cellular mechanisms are perturbed by metabolic disease and/or maternal aging, molecular damage of the oocyte can alter macromolecules, induce mitochondrial mutations, and reduce adenosine triphosphate production, all of which can harm the oocyte. Recent technologies are now exploring transcriptional, translational, and post-translational events within the human follicle with the goal of identifying biomarkers that reliably predict oocyte quality in the clinical setting.

Training in reproductive endocrinology and infertility and assisted reproductive technologies: options and worldwide needs.

Standardized, high-quality training in reproductive endocrinology, infertility, and assisted reproductive technologies (REI-ART) faces challenges owing to the high-tech nature of ART and the important country-to-country differences in clinical practice and regulations overseeing training. Moreover, while the training capacity of the classical by-fellowship training platforms is shrinking, an increasing demand for REI-ART specialists is coming from emerging countries. To meet this expanding need for REI-ART specialists, we propose a novel by-network model linking a reference training center to satellite practical training sites. Simulation should be used more extensively to achieve competency before initiating live clinical experience, analogous to the highly effective training systems that have been used in aviation for decades. Large ART databases that exist because of obligations to report ART activity and results constitute unique yet so far untapped sources for developing by-scenario simulation training models. Online training materials incorporating these state-of-the-art information technology tools could be developed as a means of fulfilling training needs worldwide.

Introduction: Preimplantation genetic screening is alive and very well.

Aneuploidy screening of all chromosomes (preimplantation genetic screening) at each stage of embryo development, the techniques available, and the advantages and disadvantages of each technique are reviewed.

Aging gonads, glands, and gametes: immutable or partially reversible changes?

Decreased ovarian testosterone production, granulosa cell dysfunction, oocyte telomere shortening and mitochondrial defects, and sperm DNA fragmentation all contribute to reproductive aging. Maneuvers aimed at correcting these abnormalities, including reduction of oxidative stress, improved lifestyle and nutrition, and the role of supplements, are reviewed.

Introduction: Risk and safety management in infertility and assisted reproductive technology.

Drs. Meldrum and de Ziegler contrast medicine with the ultra-safe industry of aviation. Analogous to the "right patient, right side, and right organ" procedures already instituted widely throughout medicine, they emphasize the extreme importance and methods for identification and tracking of specimens and recipients for assisted reproductive technology (ART) procedures. One of the authors describes his experience with a formal "ISO" accreditation process that standardizes most aspects of risk and safety management. Because risk and safety management has yet to be commonly extended into physicians' offices and that is where ART procedures are usually recommended and carried out, detailed suggestions are offered regarding ways to reduce risk and maximize safety in that environment. Finally, a suggestion is made for establishment of a Clinical Safety Board for ART so adverse events are reported and investigated, promoting educative efforts and preventive strategies to enhance future patient safety.

Risk and safety management in infertility and assisted reproductive technology (ART): from the doctor's office to the ART procedure.

Risk and safety management (RSM) is receiving increasing attention in medicine, with the goals of reducing medical error and increasing quality of care. The principles and tools of RSM can and should be applied to assisted reproductive technology (ART), a field that has already made significant progress in reducing the undesirable and sometimes dangerous consequences of treatment. ART is a prime area of medicine to contribute and help to lead the application of RSM and patient safety because it has been ahead of many other fields of medicine in standardizing treatment, certifying and auditing practitioners, and reporting standardized outcomes, and because treatments are applied to otherwise healthy individuals where exposure to risk may be less acceptable.