Obesity affects many aspects of health, including reproduction. Despite unrelenting warnings about the health consequences of obesity, its prevalence continues to rise. Beginning with the discovery of leptin in 1994, the endocrinology of energy homeostasis has been significantly advanced. More recently, brain imaging studies have been providing novel insights into homeostatic and hedonic aspects of human ingestive behavior.
A comprehensive MEDLINE search was conducted on the topic of neuroendocrine control of ingestive behavior with an emphasis on functional magnetic resonance imaging studies. Additional articles were collected by hand searching the bibliographies of all relevant articles retrieved.
This review describes recent advances in our understanding of endocrine signals that respond to acute and chronic energy states and regulate ingestive behavior so as to achieve a balance between energy intake and energy expenditure. Recently published brain imaging studies, describing the neural networks that process endocrine signals of energy state and hedonic cues associated with highly palatable foods, are highlighted. Brain responses to food cues are described in the context of appetite changes during the menstrual cycle both in normal physiology and under the conditions anorexia nervosa and bulimia nervosa.
The prevalence of obesity belies the plethora of endocrine signals in place to ensure energy homeostasis. However, satiety signals appear to be counteracted by hedonic signals derived from highly palatable foods typical of today's diet. A better understanding of the interaction between homeostatic and hedonic signals is needed to devise effective strategies for dealing with obesity. Menstrual cycle dependent changes in brain responses to food cues may provide insight into the normal physiological control of ingestive behavior as well as dysfunctional regulation associated with disordered eating.
Uterus transplantation (UTx) is developed in animal models as a future method to treat uterine factor infertility.
All published studies in the area of UTx research were identified. Aspects relating to surgery, cold-ischemia/reperfusion, rejection, immunosuppression, pregnancy, ethics and institutional requirements were examined.
Uterus retrieval surgery has been solved in animals, including primates. Studies on cold-ischemia/reperfusion indicate an ischemic tolerance of >24 h. The transplantation procedure, with vascular anastomosis, has not been fully developed in animal models, indicated by frequent thrombosis formation. Pregnancies have only been reported in syngenic/auto-UTx animal models. Several ethical issues in relation to UTx, and requirements for a team that would be suitable to undertake human UTx, exist.
Much research on UTx has been performed in appropriate animal models. Several aspects of the procedure have been optimized but some remain to be solved. It is predicted that the research will soon reach a stage that could merit introduction of human UTx as an experimental procedure.
It has been suggested that body mass index (BMI), especially obesity, is associated with subfertility in men. Semen parameters are central to male fertility and reproductive hormones also play a role in spermatogenesis. This review aimed to investigate the association of BMI with semen parameters and reproductive hormones in men of reproductive age.
MEDLINE, EMBASE, Biological Abstracts, PsycINFO and CINAHL databases and references from relevant articles were searched in January and February 2009. Outcomes included for semen parameters were sperm concentration, total sperm count, semen volume, motility and morphology. Reproductive hormones included were testosterone, free testosterone, estradiol, FSH, LH, inhibin B and sex hormone binding globulin (SHBG). A meta-analysis was conducted to investigate sperm concentration and total sperm count.
In total, 31 studies were included. Five studies were suitable for pooling and the meta-analysis found no evidence for a relationship between BMI and sperm concentration or total sperm count. Overall review of all studies similarly revealed little evidence for a relationship with semen parameters and increased BMI. There was strong evidence of a negative relationship for testosterone, SHBG and free testosterone with increased BMI.
This systematic review with meta-analysis has not found evidence of an association between increased BMI and semen parameters. The main limitation of this review is that data from most studies could not be aggregated for meta-analysis. Population-based studies with larger sample sizes and longitudinal studies are required.
The majority of Chlamydia trachomatis infections in women are asymptomatic, but may give rise to pelvic inflammatory disease (PID) and tubal infertility. Screening programmes aim at reducing morbidity in individuals by early detection and treatment, and at decreasing the overall prevalence of infection in the population. A number of modelling studies have tried to calculate the threshold prevalence of chlamydia lower genital tract infection above which screening becomes cost-effective. There is considerable debate over the exact complication rates after chlamydia infections, and more precise estimates of PID and tubal infertility are needed, for instance to be inserted in economic models.
With reference to key studies and systematic reviews, an overview is provided focusing on the epidemiology of chlamydia infection and the risk-estimates of its late complications.
In the literature, the generally assumed risk of developing PID after lower genital tract chlamydia infection varies considerably, and is up to 30%. For developing tubal infertility after PID the risks are 10–20%. This implies that the risk of test-positive women of developing tubal infertility would range between 0.1 and 6%. We included chlamydia IgG antibody testing in a model and estimated a risk of tubal infertility up to 4.6%.
The risk of developing late complications after chlamydia lower genital tract infection appears low. High quality RCTs dealing with the transition from cervicitis to infertility are needed to broaden the evidence. In screening programmes, chlamydia antibody testing, as an intermediate marker for potential adverse sequelae, might enable more precise estimates.
Preimplantation embryos are particularly susceptible to in vitro developmental blocks. These could be alleviated by lowering culture medium osmolarity. Because mammalian cells regulate their volumes by adjusting intracellular osmotic pressure, cell volume regulation could be critical to early embryos.
We reviewed the literature on cell volume regulation in preimplantation embryos and the effects of increased osmolarity on embryo development, focusing also on the relation with improvements in embryo culture media.
Embryos failed to develop from fertilized oocytes when osmolarity is increased. This could be alleviated by decreasing osmolarity or including certain compounds such as certain amino acids. Early preimplantation mouse embryos require intracellular accumulation of glycine to provide osmotic support and thus control cell volume. The glycine-specific transporter, GLYT1, mediates osmoregulated glycine accumulation in mouse embryos and likely in human embryos. GLYT1 is activated during meiotic maturation starting at ovulation. Prior to this, oocyte size is not independently controlled but instead is determined by strong adhesion between the oocyte plasma membrane and the inner surface of the zona pellucida.
Early preimplantation embryos are particularly sensitive to increased osmolarity, and require the importation of glycine to regulate their cell volumes using a mechanism unique to early embryos. Cell volume regulation first appears when ovulation is triggered, oocyte zona pellucida adhesion is released, and glycine transport is activated. The requirement for supporting these physiological functions in oocytes and embryos should be taken into account when developing and improving systems for in vitro oocyte maturation and embryo culture.
Hypergonadotropic hypoestrogenic infertility is the most burdensome complication for females suffering from classic galactosemia. In contrast, male gonadal function seems less affected. The underlying mechanism is not understood and several pathogenic mechanisms have been proposed. Timing of the lesion, prenatal or chronic post-natal, or a combination of both are not yet clear.
This review focuses on gonadal function in males and females, ovarian imaging and histology in this disease. It is based on the literature known to the authors and a Pubmed search using the keywords galactosemia, GALT deficiency, (premature) ovarian failure/insufficiency/dysfunction, testicular function, gonadotrophins, FSH, LH (published between January 1971 and April 2009).
Male gonads are less affected, boys spontaneously reach puberty, although onset can be delayed. Semen quality has not been extensively studied. Several affected males are known to have fathered a child. Female gonads are invariably affected, although to a varied extent (hypergonadotropic hypoestrogenic ovarian dysfunction). Intriguingly, FSH is often already increased in infancy. Imaging usually shows hypoplastic and streak-like ovaries. Histological findings in some cases reveal the presence of morphologically normal but decreased numbers of primordial follicles, with the absence of intermediate and Graafian follicles.
Gonads in males seem less affected than in females who exhibit hypergonadotropic hypoestrogenic subfertility. FSH can be elevated in infancy, and ovarian histology sometimes shows the presence of normal primordial follicles with absence of intermediate and Graafian follicles. These findings are similar to other genetic diseases primarily affecting the ovary.
Bilateral oophorectomy is commonly performed at the time of hysterectomy for benign disease. Indications for oophorectomy vary, but in most cases relatively little high-quality information is available to inform the surgeon or patient regarding the relative risks and benefits of ovarian conservation or removal. This review will address the common clinical situations when oophorectomy may be performed and will evaluate the evidence for risk and benefit in each of these circumstances. The aim of this review is to bring together the evidence regarding oophorectomy in pre- and post-menopausal women and to highlight the areas needing further study.
We searched the published literature for studies related to outcomes following surgical menopause, risk-reducing surgery for ovarian cancer, surgical treatment for endometriosis, bilateral oophorectomy for benign disease and treatment for premenstrual syndrome/premenstrual dysphoric disorder.
Rates of oophorectomy at the time of hysterectomy for benign disease appear to be increasing. There is good evidence to support bilateral salpingoophorectomy (BSO) as a risk-reducing surgery for women at high risk of ovarian cancer, but relatively little evidence to support oophorectomy or BSO in other circumstances. There is growing evidence from observational studies that surgical menopause may impact negatively on future cardiovascular, psychosexual, cognitive and mental health.
Clinicians and patients should fully consider the relative risks and benefits of oophorectomy on an individual basis prior to surgery.
In women, anti-Müllerian hormone (AMH) levels may represent the ovarian follicular pool and could be a useful marker of ovarian reserve. The clinical application of AMH measurement has been proposed in the prediction of quantitative and qualitative aspects in assisted reproductive technologies (ART). In men AMH is secreted in both the serum and seminal fluid. Its measurement may be useful in clinical evaluation of the infertile male.
The PubMed database was systematically searched for studies published until the end of January 2009, search criteria relevant to AMH, ovarian reserve, ovarian response to gonadotrophin stimulation, spermatogenesis and azoospermia were used.
AMH seems to be a better marker in predicting ovarian response to controlled ovarian stimulation than age of the patient, FSH, estradiol and inhibin B. A similar performance for AMH and antral follicular count has been reported. In clinical practice, AMH measurement may be useful in the prediction of poor response and cycle cancellation and also of hyper-response and ovarian hyperstimulation syndrome. In the male, the wide overlap of AMH values between controls and infertile men precludes this hormone from being a useful marker of spermatogenesis.
As AMH may permit the identification of both the extremes of ovarian stimulation, a possible role for its measurement may be in the individualization of treatment strategies in order to reduce the clinical risk of ART along with optimized treatment burden. It is fundamental to clarify the cost/benefit of its use in ovarian reserve testing. Regarding the role of AMH in the evaluation of infertile men, AMH as single marker of spermatogenesis does not seem to reach a satisfactory clinical utility.
microRNAs (miRNAs) are short, single-stranded RNAs that regulate gene expression at the post-transcriptional level. Recent research has shown that miRNAs and their target mRNAs are differentially expressed in endometriosis and other disorders of the female reproductive system. Since miRNAs control a broad spectrum of normal and pathological cellular functions, they may play pivotal roles in the pathogenesis of these disorders.
A systematic review was undertaken of the published literature on; (i) the expression and functions of miRNAs in mammalian female reproductive tissues with a focus on endometriosis and the malignancies and fertility disorders related to this disease; and (ii) the potential roles played by validated mRNA targets of endometriosis-associated miRNAs. The current understanding of the biology of miRNAs is overviewed and the potential diagnostic and therapeutic potential of miRNAs in endometriosis is highlighted.
The differential expression of miRNAs in endometriosis, and the putative molecular pathways constituted by their targets, suggests that miRNAs may play an important role in endometriotic lesion development. Models for miRNA regulatory functions in endometriosis are presented, including those associated with hypoxia, inflammation, tissue repair, TGFβ-regulated pathways, cell growth, cell proliferation, apoptosis, extracellular matrix remodelling and angiogenesis. In addition, specific miRNAs which may be associated with malignant progression and subfertility in endometriosis are discussed.
miRNAs appear to be potent regulators of gene expression in endometriosis and its associated reproductive disorders, raising the prospect of using miRNAs as biomarkers and therapeutic tools in endometriosis.
Functional male gametes are produced through complex processes that take place within the testis, epididymis and female reproductive tract. A breakdown at any of these phases can result in male infertility. The production of mutant mouse models often yields an unexpected male infertility phenotype. It is with this in mind that the current review has been written. The review aims to act as a guide to the ‘non-reproductive biologist’ to facilitate a systematic analysis of sterile or subfertile mice and to assist in extracting the maximum amount of information from each model.
This is a review of the original literature on defects in the processes that take a mouse spermatogonial stem cell through to a fully functional spermatozoon, which result in male infertility. Based on literature searches and personal experience, we have outlined a step-by-step strategy for the analysis of an infertile male mouse line.
A wide range of methods can be used to define the phenotype of an infertile male mouse. These methods range from histological methods such as electron microscopy and immunohistochemistry, to hormone analyses and methods to assess sperm maturation status and functional competence.
With the increased rate of genetically modified mouse production, the generation of mouse models with unexpected male infertility is increasing. This manuscript will help to ensure that the maximum amount of information is obtained from each mouse model and, by extension, will facilitate the knowledge of both normal fertility processes and the causes of human infertility.
Elucidation of the causes of premature ovarian failure (POF) is difficult due to the heterogeneity of the condition. Inhibin is a potential candidate gene for POF based on its dual actions on FSH secretion by the pituitary and gametogenesis in the gonads. A missense mutation in the inhibin subunit gene (INHA G769A) is associated with POF in several populations. However, there is phenotypic heterogeneity in INHA G769A mutation carriers.
Relevant studies were identified by searching PubMed and mutational frequencies combined for meta-analysis.
Meta-analysis of published studies revealed a risk difference of 0.04 (–0.030 to 0.11). The occurrence of asymptomatic carriers in populations suggests incomplete penetrance and/or a multi-genetic cause of POF. We propose that a decline in inhibin bioactivity caused by the mutation could increase FSH levels; and in a susceptible individual, the heightened sensitivity to gonadotrophins causes POF. Impaired paracrine effects of inhibin could impact folliculogenesis due to reduced antagonism of activin, bone morphogenetic protein 15 and growth differentiation factor 9. Functional studies of this mutation indicate normal production of dimeric inhibin A and B and impaired bioactivity of inhibin B.
The identification of an autosomal mutation in the inhibin subunit gene that is significantly linked to POF in certain ethnic populations highlights the role of inhibin in the regulation of ovarian biology and fertility. Although the reduction of inhibin B bioactivity by the INHA G769A mutation is clearly not the only cause, evidence suggests that this change may serve as a susceptibility factor, increasing the likelihood of POF.
Although hysteroscopy is frequently used in the management of subfertile women, a systematic review of the evidence on this subject is lacking.
We summarized and appraised the evidence for the benefit yielded by this procedure. Our systematic search was limited to randomized and controlled studies. The QUOROM and MOOSE guidelines were followed. Language restrictions were not applied.
We identified 30 relevant publications. Hysteroscopic removal of endometrial polyps with a mean diameter of 16 mm detected by ultrasound doubles the pregnancy rate when compared with diagnostic hysteroscopy and polyp biopsy in patients undergoing intrauterine insemination, starting 3 months after the surgical intervention [relative risk (RR) = 2.3; 95% confidence interval (CI): 1.6–3.2]. In patients with one fibroid structure smaller than 4 cm, there was a marginally significant benefit from myomectomy when compared with expectant management (RR = 1.9; 95% CI: 1.0–3.7). Hysteroscopic metroplasty for septate uterus resulted in fewer pregnancies in patients with subfertility when compared with those with recurrent pregnancy loss (RR = 0.7; 95% CI: 0.5–0.9). Randomized controlled studies on hysteroscopic treatment of intrauterine adhesions are lacking. Hysteroscopy in the cycle preceding a subsequent IVF attempt nearly doubles the pregnancy rate in patients with at least two failed IVF attempts compared with starting IVF immediately (RR = 1.7; 95% CI: 1.5–2.0).
Scarce evidence on the effectiveness of hysteroscopic surgery in subfertile women with polyps, fibroids, septate uterus or intrauterine adhesions indicates a potential benefit. More randomized controlled trials are needed before widespread use of hysteroscopic surgery in the general subfertile population can be justified.
Although sexual activity has, until very recently, been essential to reproduction, this did not preclude the non-reproductive importance of sexual relationships and non-conceptive copulations. Technological advances, however, now allow for both sex without reproduction and reproduction without sex. This review summarizes social and ethical commentaries on the new relationship between sex and reproduction.
For each main area discussed, a systematic search was made using (depending on the subject) PubMed, Medline, ScienceDirect, classic books, Google and/or religious websites. The search focused on publications between 1975 and 2009, although some materials from the first part of the 20th century were also utilized.
The classic picture of sex for reproduction and bonding between mating partners is increasingly being replaced by reproduction separate from sexual activity. Although not every advance in assisted reproduction produced, per se, a further separation from sexual intercourse, these two fundamental human activities are today increasingly carried out independently, as reproduction is possible, not only without sex, but even through the intervention of more than two partners. The possibility of reproduction with only one or even no gametes, although highly controversial and not yet feasible, is nonetheless being investigated.
Technological advances in the field of reproductive biology have enabled couples considered infertile to conceive and have healthy babies, causing a revolution in culture and customs. Today the independence of sex and reproduction is established and in the future human reproduction may move even further away from the sexual act, an option definitely unacceptable to some ethicists.
High-density lipoprotein (HDL) appears to be the dominant lipoprotein particle in human follicular fluid (FF). The reported anti-atherogenic properties of HDL have been attributed in part to reverse cholesterol transport. The discoveries of the scavenger receptor class B type I (SR-BI) and the ATP-binding cassette A1 lipid (ABCA1) transporter have generated studies aimed at unraveling the pathways of HDL biogenesis, remodeling and catabolism. The production of SR-BI and ABCA1 knockout mice as well as other lipoprotein metabolism-associated mutants has resulted in reduced or absent fertility, leading us to postulate the existence of a human hepatic-ovarian HDL-associated axis of fertility. Here, we review an evolving literature on the role of HDL metabolism on mammalian fertility and oocyte development.
An extensive online search was conducted of published articles relevant to the section topics discussed. All relevant English language articles contained in Pubmed/Medline, with no specific time frame for publication, were considered for this narrative review. Cardiovascular literature was highly cited due to the wealth of relevant knowledge on HDL metabolism, and the dearth thereof in the reproductive field.
Various vertebrate models demonstrate a role for HDL in embryo development and fertility. In our clinical studies, FF levels of HDL cholesterol and apolipoprotein AI levels were negatively associated with embryo fragmentation, but not with embryo cell cleavage rate. However, the HDL component, paraoxonase 1 arylesterase activity, was positively associated with embryo cell cleavage rate.
HDL contributes to intra-follicular cholesterol homeostasis which appears to be important for successful oocyte and embryo development.
For men with azoospermia, it is possible to father their own progeny by intracytoplasmic sperm injection (ICSI) with epididymal or testicular sperm. Some studies show that children born after assisted reproductive technology (ART) are at increased risk of birth defects, other studies suggest that there is no extra concern about ICSI children conceived with epididymal or testicular sperm.
Studies about the karyotypes of fetuses, congenital anomalies and the follow-up of the children born after ICSI with non-ejaculated sperm were identified by means of a systematic literature search.
Eight relevant studies were identified; two studies reported karyotype, five reported malformations and one reported follow-up of children after ICSI. In total, there were 55 out of 1973 (2.8%) abnormal karyotypes in the ICSI with ejaculated sperm group, 0 out of 31 in the ICSI with epididymal sperm group and 5 out of 191 (2.6%) in the ICSI with testicular sperm group. Major malformations were found in 543 out of 12 377 (4.4%) in the ICSI with ejaculated sperm group, 17 out of 533 (3.2%) in the ICSI with epididymal sperm group and 31 out of 670 (4.6%) in the ICSI with testicular sperm group.
Although there were no statistical differences, the study groups were small and heterogenic, with a number of potential biases. We therefore recommend a standardized methodology of follow-up studies after ART, with well-defined groups of ICSI with ejaculated sperm, ICSI with epididymal sperm and ICSI with testicular sperm, and a control group of naturally conceived children.
Due to various sociological factors, couples in developed countries are increasingly delaying childbearing. Besides ethical, economical and sociological issues, this trend presents us with several complex problems in reproduction. Although it is well-known that maternal age has a negative effect on fertility and increases the risk of adverse outcome during pregnancy and in offspring, the paternal influence on these outcomes is less well researched and not well-known.
We performed a systematic search of PubMed, and retrieved original articles and review articles to update our previous survey in this journal.
This review highlights the link between male age and genetic abnormalities in the germ line and summarizes the knowledge about the effects of paternal age on reproductive function and outcome. Increasing paternal age can be associated with decreasing androgen levels, decreased sexual activity, alterations of testicular morphology and a deterioration of semen quality (volume, motility, morphology). Increased paternal age has an influence on DNA integrity of sperm, increases telomere length in spermatozoa and is suggested to have epigenetic effects. These changes may, at least in part, be responsible for the association of paternal age over 40 years with reduced fertility, an increase in pregnancy-associated complications and adverse outcome in the offspring.
Although higher maternal age can be an indication for intensive prenatal diagnosis, including invasive diagnostics, consideration of the available evidence suggests that paternal age itself, however, provides no rationale for invasive procedures.
Micronutrient deficiencies have been associated with significantly high reproductive risks, ranging from infertility to fetal structural defects and long-term diseases. In this review we focus on the reproductive risks related to some micronutrients during the periconceptional period, a critical step in determining fetal development and health due to the potential onset of several disorders.
Embase Medline and PubMed databases, Google-indexed scientific literature and periodics from on-line University of Milan Bibliotecary Service were searched to identify relevant publications. In vivo human studies were mainly searched for, but when needed animal studies as well as in vitro and cell culture experiments were also considered.
Fertility, conception, implantation, fetal organogenesis and placentation are the critical stages potentially affected by nutrition during the periconceptional period. Reactive oxygen species (ROS) and total homocysteine (tHcy) plasma levels are factors involved in the respective mechanisms. The preconceptional period is particularly important since it affects both fertility and the early stages of gestation. Micronutrients' dietary intake and maternal status affect the different phases of the onset and development of pregnancy as well as of the conceptus.
Although human studies are scarce, and conclusive evidence is provided solely for periconceptional folate and prevention of neural tube defects (NTDs), the overall data indicate that micronutrients may affects fertility, embryogenesis and placentation, and the prophylactic use of some micronutrients may be useful in preventing several adverse pregnancy outcomes. Efforts to increase awareness of a healthy diet should be strengthened not only throughout pregnancy but also before. However, further researches in humans are necessary to optimise periconceptional micronutrient requirements.
Hirsutism is the presence of excess body or facial terminal (coarse) hair growth in females in a male-like pattern, affects 5–15% of women, and is an important sign of underlying androgen excess. Different methods are available for the assessment of hair growth in women.
We conducted a literature search and analyzed the published studies that reported methods for the assessment of hair growth. We review the basic physiology of hair growth, the development of methods for visually quantifying hair growth, the comparison of these methods with objective measurements of hair growth, how hirsutism may be defined using a visual scoring method, the influence of race and ethnicity on hirsutism, and the impact of hirsutism in diagnosing androgen excess and polycystic ovary syndrome.
Objective methods for the assessment of hair growth including photographic evaluations and microscopic measurements are available but these techniques have limitations for clinical use, including a significant degree of complexity and a high cost. Alternatively, methods for visually scoring or quantifying the amount of terminal body and facial hair growth have been in use since the early 1920s; these methods are semi-quantitative at best and subject to significant inter-observer variability. The most common visual method of scoring the extent of body and facial terminal hair growth in use today is based on a modification of the method originally described by Ferriman and Gallwey in 1961 (i.e. the mFG method).
Overall, the mFG scoring method is a useful visual instrument for assessing excess terminal hair growth, and the presence of hirsutism, in women.