Recent advances in our understanding of the causes of infertility and of assisted reproductive technology (ART) have led to the development of complex diagnostic tools, prognostic models and treatment options. The Third Evian Annual Reproduction (EVAR) Workshop Meeting was held on 26–27 April 2008 to evaluate evidence supporting current approaches to the diagnosis and management of infertility and to identify areas for future research efforts.
Specialist reproductive medicine clinicians and scientists delivered presentations based on published literature and ongoing research on patient work-up, ovarian stimulation and embryo quality assessment during ART. This report is based on the expert presentations and subsequent group discussions and was supplemented with publications from literature searches and the authors' knowledge.
It was agreed that single embryo transfer (SET) should be used with increasing frequency in cycles of ART. Continued improvements in cryopreservation techniques, which improve pregnancy rates using supernumerary frozen embryos, are expected to augment the global uptake of SET. Adaptation and personalization of fertility therapy may help to optimize efficacy and safety outcomes for individual patients. Prognostic modelling and personalized management strategies based on individual patient characteristics may prove to represent real progress towards improved treatment. However, at present, there is limited good-quality evidence to support the use of these individualized approaches.
Greater quality control and standardization of clinical and laboratory evaluations are required to optimize ART practices and improve individual patient outcomes. Well-designed, good-quality studies are required to drive improvements to the diagnosis and management of ART processes.
The aim was to evaluate the impact of early pregnancy events and complications as predictors of adverse obstetric outcome.
We conducted a literature review on the impact of first trimester complications in previous and index pregnancies using Medline and Cochrane databases covering the period 1980–2008.
Clinically relevant associations of adverse outcome in the subsequent pregnancy with an odds ratio (OR) > 2.0 after complications in a previous pregnancy are the risk of perinatal death after a single previous miscarriage, the risk of very preterm delivery (VPTD) after two or more miscarriages, the risk of placenta praevia, premature preterm rupture of membranes, VPTD and low birthweight (LBW) after recurrent miscarriage and the risk of VPTD after two or more termination of pregnancy. Clinically relevant associations of adverse obstetric outcome in the ongoing pregnancy with an OR > 2.0 after complications in the index pregnancy are the risk of LBW and very low birthweight (VLBW) after a threatened miscarriage, the risk of pregnancy-induced hypertension, pre-eclampsia, placental abruption, preterm delivery (PTD), small for gestational age and low 5-min Apgar score after detection of an intrauterine haematoma, the risk of VPTD and intrauterine growth restriction after a crown-rump length discrepancy, the risk of VPTD, LBW and VLBW after a vanishing twin phenomenon and the risk of PTD, LBW and low 5-min Apgar score in a pregnancy complicated by severe hyperemesis gravidarum.
Data from our literature review indicate, by finding significant associations, that specific early pregnancy events and complications are predictors for subsequent adverse obstetric and perinatal outcome. Though, some of these associations are based on limited or small uncontrolled studies. Larger population-based controlled studies are needed to confirm these findings. Nevertheless, identification of these risks will improve obstetric care.
Hormonal effects of soy and isoflavones have been investigated in numerous trials with equivocal findings. We aimed to systematically assess the effects of soy and isoflavones on circulating estrogen and other hormones in pre- and post-menopausal women.
The Cochrane Library, MEDLINE and EMBASE (plus reviews and experts) were searched to December 2007. Inclusion of randomized or residential crossover trials of soy or isoflavones for 4 or more weeks on estrogens, SHBG, FSH, LH, progesterone and thyroid hormones in women was assessed independently in duplicate. Six percent of papers assessed were included. Data concerning participants, interventions, outcomes, potential effect modifiers and trial quality characteristics were extracted independently in duplicate.
Forty-seven studies (11 of pre-, 35 of post- and 1 of perimenopausal women) were included. In premenopausal women, meta-analysis suggested that soy or isoflavone consumption did not affect primary outcomes estradiol, estrone or SHBG concentrations, but significantly reduced secondary outcomes FSH and LH [by ~20% using standardized mean difference (SMD), P = 0.01 and 0.05, respectively]. Menstrual cycle length was increased by 1.05 days (95% CI 0.13, 1.97, 10 studies). In post-menopausal women, there were no statistically significant effects on estradiol, estrone, SHBG, FSH or LH, although there was a small statistically non-significant increase in total estradiol with soy or isoflavones (~14%, SMD, P = 0.07, 21 studies).
Isoflavone-rich soy products decrease FSH and LH in premenopausal women and may increase estradiol in post-menopausal women. The clinical implications of these modest hormonal changes remain to be determined.
Although surgery is currently the treatment of choice for managing endometriosis, recurrence poses a formidable challenge. To delay or to eliminate the recurrence is presently an unmet medical need in the management of endometriosis. To this end, proposals to investigate patterns of recurrence, to develop biomarkers for recurrence and to carry out biomarker-based intervention have been made.
Publications pertaining to the recurrence of endometriosis and its related yet unaddressed issues were identified through MEDLINE. The reported recurrence rates, risk factors for recurrence, the effects of post-operative medication and causes of recurrence were reviewed and synthesized. In addition, several poorly explored issues such as time hazard function and mechanisms of recurrence were reviewed. Approaches to the development of biomarkers for recurrence and future intervention are discussed.
The reported recurrence rate was high, estimated as 21.5% at 2 years and 40–50% at 5 years. Few risk factors for recurrence have been consistently identified, and the evidence on the efficacy of the post-operative use of medication was scanty. The investigation on the patterns of recurrence may provide us with new insight into the possible mechanisms of recurrence and its control. The attempt to identify biomarkers for recurrence has started only very recently.
Much research is needed to better understand the patterns of recurrence and risk factors, and to develop biomarkers. One top priority is to develop biomarkers for recurrence, which may provide much needed clues to the possible mechanisms underlying recurrence and would allow the identification of patients with high recurrence risk, and permit for targeted intervention.
Insulin-like factor 3 (INSL3) is a neohormone that has evolved to address specific mammalian traits, in particular, the first phase of testicular descent towards the scrotum during mid-gestation.
A thorough literature search was made in PubMed using the terms INSL3, as well as the older synonyms RLF and Ley-IL.
INSL3 is a major secretory product of the testicular Leydig cells in the fetus and in adult men, and in rodent models, reduction in fetal INSL3 expression is an early marker of the testicular dysgenesis syndrome. In women, it is produced in lower amounts by ovarian theca and luteal cells, and circulating levels are increased in women with polycystic ovarian syndrome. During pregnancy, there is evidence for an interaction regulating the feto-placental unit. The presence of INSL3 in amniocentesis samples taken at 12–14 weeks gestation is absolutely specific for male gender, and levels are predictive of subsequent pre-eclampsia and/or birthweight. INSL3 is also involved in adult traits, such as spermatogenesis and bone metabolism. In adult men, INSL3 is constitutively expressed and secreted into the bloodstream at a constant level, reflecting the number and/or functional capacity of the Leydig cells. In complete contrast, testosterone is highly variable within individuals, is acutely responsive to fluctuations in the hypothalamic–pituitary–gonadal axis and appears to have marginal diagnostic value. INSL3 declines consistently with age in adult men.
INSL3 promises to become an important new diagnostic tool to characterize those men with late-onset hypogonadism and to add clinical diagnostic value at amniocentesis.
Polycystic ovary syndrome (PCOS) is a common condition in women of reproductive age with well established metabolic abnormalities. There are numerous diagnostic criteria generating several reproductive diagnostic phenotypes [National Institute of Health (NIH) hyperandrogenic anovulatory PCOS and non-NIH PCOS including hyperandrogenic ovulatory or non-hyperandrogenic anovulatory PCOS]. There is ongoing debate regarding the optimal diagnostic criteria for PCOS and on the metabolic implications of newer non-NIH PCOS phenotypes.
We reviewed the literature on the presence of risk factors for type 2 diabetes (DM2) and cardiovascular disease (CVD) across the reproductive diagnostic phenotypes of PCOS with the aims of comparing the metabolic features of the NIH and non-NIH groups and identifying potential high metabolic risk phenotypes of PCOS.
NIH PCOS patients present with greater obesity, abdominal obesity, insulin resistance (IR) and risk factors for DM2 and CVD compared with non-NIH ovulatory and non-hyperandrogenic PCOS patients. Where differences in metabolic features exist between the phenotypes, they are generally related to the degree of total and abdominal obesity. There is emerging evidence suggesting ovulatory and non-hyperandrogenic PCOS have greater metabolic abnormalities than controls primarily linked to abdominal adiposity. There is currently no evidence that non-hyperandrogenic PCOS is associated with a less adverse metabolic profile than ovulatory PCOS.
Current metabolic evidence appears to justify the inclusion of both non-NIH PCOS groups (ovulatory and non-hyperandrogenic) as PCOS subgroups. NIH PCOS is associated with a more adverse metabolic profile including greater total and abdominal obesity, IR and risk factors for CVD and DM2 than non-NIH phenotypes.
Intrauterine insemination (IUI) with or without ovarian stimulation is a common treatment for infertility. Despite its popularity, the effectiveness of IUI treatment is not consistent, and the role of IUI and in vitro fertilization (IVF) treatment in practice protocols has not been clarified.
Medline searches were done by individual topics (utilization, procedures, effectiveness of partner but not donor IUI and related endocrine issues). Effectiveness of IUI was evaluated in relevant randomized controlled trials, using meta-analysis and meta-regression where necessary.
Stimulated IUI is ineffective in male infertility and the effect on other diagnoses is small. With clomiphene citrate and IUI, the most common IUI protocol, pregnancy rates average 7% per cycle. FSH ovarian stimulation and IUI treatment is only modestly better than observation only with pregnancy rate 12% per cycle but multiple birth rates averaging 13%. Mildly stimulated (1–2 follicles) cycles might reduce the cost and multiple birth rates but may require more cycles of treatment. Prevention of premature luteinizing hormone surges and luteal phase support do not appear to be major requirements in IUI cycles.
IUI treatment requires ovarian stimulation to achieve modest results, but the high multiple pregnancy rates mean that it is no more than a poor substitute for IVF treatment. More trials are needed on IUI treatment with mild stimulation and on the order of IUI and other treatments.
Psychological interventions for infertile patients seek to improve mental health and increase pregnancy rates. The aim of the present meta-analysis was to examine if psychological interventions improve mental health and pregnancy rate among infertile patients. Thus, controlled studies were pooled investigating psychological interventions following the introduction of assisted reproductive treatments (ART).
The databases of Medline, PsycINFO, PSYNDEX, Web of Science and the Cochrane Library were searched to identify relevant articles published between 1978 and 2007 (384 articles). Included were prospective intervention studies on infertile patients (women and men) receiving psychological interventions independent of actual medical treatment. The outcome measures were mental health and pregnancy rate. A total of 21 controlled studies were ultimately included in a meta-analysis comparing the efficacy of psychological interventions. Effect sizes (ES) were calculated for psychological measures and risk ratios (RR) for pregnancy rate.
The findings from controlled studies indicated no significant effect for psychological interventions regarding mental health (depression: ES 0.02, 99% CI: –0.19, 0.24; anxiety: ES 0.16, 99% CI: –0.10, 0.42; mental distress: ES 0.08, 99% CI: –0.10, 0.51). Nevertheless, there was evidence for the positive impact of psychological interventions on pregnancy rates (RR 1.42, 99% CI: 1.02, 1.96). Concerning pregnancy rates, significant effects for psychological interventions were only found for couples not receiving ART.
Despite the absence of clinical effects on mental health measures, psychological interventions were found to improve some patients’ chances of becoming pregnant. Psychological interventions represent an attractive treatment option, in particular, for infertile patients who are not receiving medical treatment.
Conflicting results regarding adiponectin levels in women with polycystic ovary syndrome (PCOS) have been reported. To evaluate adiponectin levels in PCOS, a systematic review of all studies comparing adiponectin levels in women with PCOS with healthy controls and a meta-analysis of those involving women with similar body mass index (BMI) were performed. The influence of possible effect modifiers, such as insulin resistance (IR) and testosterone, was investigated. The influence of obesity was investigated through a ‘nested’ meta-analysis after within-study BMI stratification and appropriate pooling.
Literature search was conducted through MEDLINE, EMBASE, Cochrane CENTRAL (through June 2008), references from relevant studies and personal contact with the authors. Thirty-one studies, reporting data on 3469 subjects, were reviewed and 16 included in the main meta-analysis.
Women with PCOS demonstrated significantly lower adiponectin values [weighted mean difference (95% confidence interval) –1.71 (–2.82 to –0.6), P < 10–4], yet with significant between-study heterogeneity. Lower adiponectin levels are associated with the IR observed in women with PCOS, compared with controls. IR, but not total testosterone, was found significant among biological parameters explored in the meta-regression model. Hypoadiponectinaemia was present in both lean and obese women with PCOS when compared with non-PCOS counterparts. Data on high molecular weight (HMW) adiponectin are limited (three studies).
After controlling for BMI-related effects, adiponectin levels seem to be lower in women with PCOS compared with non-PCOS controls. Low levels of adiponectin in PCOS are probably related to IR but not to testosterone. Total adiponectin should not be used as a biomarker of PCOS severity. Further investigation is needed for HMW adiponectin levels in PCOS.
Recombinant DNA technologies have been used to develop longer-acting therapeutic proteins. One approach is to introduce sequences containing additional glycosylation sites. Using this technique, a new chimeric gene has been developed containing the coding sequences of the FSH β-subunit and the C-terminal peptide of the hCG β-subunit, which bears four O-linked oligosaccharide binding sites. Co-expression of the -subunit and the chimeric FSH β-subunit produces a new recombinant molecule, named corifollitropin alfa, with a prolonged elimination half-life and enhanced in vivo bioactivity compared with wild-type FSH.
Medline searches by subject and additional searching by hand.
Initial studies in pituitary suppressed female volunteers confirmed the extended half-life of the compound. Phase II studies have shown that corifollitropin alfa is able to induce and sustain multi-follicular growth for an entire week in women undergoing ovarian stimulation using GnRH antagonist co-treatment for IVF. Corifollitropin alfa regimens have been developed with dosages of 100 and 150 µg, for patients with body weight ≤60 and >60 kg, respectively.
Corifollitropin alfa is the first long-acting hybrid molecule with sustained follicle-stimulating activity developed for the induction of multi-follicular growth along with GnRH antagonist co-treatment for IVF. This new treatment option may be simpler and more convenient for patients compared with conventional long protocols of daily FSH injections in combination with GnRH agonist co-treatment. The safety and efficacy of such regimens is currently being evaluated in large comparative phase III clinical trials. The development of corifollitropin alfa is the first step towards a new generation of recombinant gonadotrophins.
Breast cancer is the most common cancer in women in developed countries, and 12% of breast cancer occurs in women 20–34 years. Survival from breast cancer has significantly improved, and the potential late effects of treatment and the impact on quality of life have become increasingly important. Young women constitute a minority of breast cancer patients, but commonly have distinct concerns and issues compared with older women, including queries regarding fertility, contraception and pregnancy. Further, they are more likely than older women to have questions regarding potential side effects of therapy and risk of relapse or a new primary. In addition, many will have symptoms associated with treatment and they present a management challenge. Reproductive medicine specialists and gynaecologists commonly see these women either shortly after initial diagnosis or following adjuvant therapy and should be aware of current management of breast cancer, the options for women at increased genetic risk, the prognosis of patients with early stage breast cancer and how adjuvant systemic treatments may impact reproductive function.
No systematic literature search was done. The review focuses on the current management of breast cancer in young women and the impact of treatment on reproductive function and subsequent management. With reference to key studies and meta-analyses, we highlight controversies and current unanswered questions regarding patient management.
Chemotherapy for breast cancer is likely to negatively impact on reproductive function. A number of interventions are available which may increase the likelihood of future successful pregnancy, but the relative safety of these interventions is not well established. For those who do conceive following breast cancer, there is no good evidence that pregnancy is detrimental to survival. We review current treatment; effects on reproductive function; preservation of fertility; contraception; pregnancy; breastfeeding and management of menopausal symptoms following breast cancer.
This paper provides an update on the management of breast cancer in young women and is targeted at reproductive medicine specialists and gynaecologists.
Estrogens regulate growth hormone (GH) secretion and modulate the tissue responsiveness to GH. After the menopause, and during ageing, a decline in GH secretion (somatopause) is physiologically observed. This article (i) provides a brief overview of the different regulators of GH secretion, (ii) reviews the mechanisms involved in age-related changes in GH concentrations, with particular emphasis on the interrelationships between menopause and GH, and (iii) discusses the interventions aimed at the restoration of GH and insulin-like growth factor (IGF-1) circulating levels.
A systematic literature search was conducted in the PubMed database using the search terms ‘Growth Hormone’, ‘Somatopause’ and ‘Menopause’. The search included full English articles covering the period 1972–2008. We selected 234 relevant citations. We also included three chapters from books.
Estrogen deficiency may contribute, through its action on GH, to the complex physical and metabolic alterations of menopause. Several attempts have been made to restore the GH and IGF-1 levels within the young adult range.
There is no definite evidence that elderly subjects really benefit from treatment with GH or GH secretagogues. Strategies aimed at enhancing spontaneous GH secretion such as sleep and exercise are safer and certainly less expensive than GH supplementation regimen.
The aim of this paper is to review the available information on ovarian radiation sensitivity and the genetic hazard of ionizing radiation in female mammals including humans.
The literature present in the author's laboratories (international papers from the 1970s) was complemented by a Medline literature search using the keywords ‘ionizing radiation genetic effects’, ‘oocyte radiosensitivity’ and ‘oocyte DNA repair’ (1990–2008). Further articles were acquired from citations in the research papers and reports.
Animal data show that oocyte radiosensitivity varies widely according to the follicle/oocyte stage and the species. Oocytes near ovulation show the highest susceptibility to radiation induction of mutational events. Congenital anomalies have been observed after exposure to high doses (1–5 Gy), but extrapolation of these data to humans requires caution. In humans, the dose required to induce permanent ovarian failure would vary from 20.3 Gy at birth to 14.3 Gy at 30 years. Most epidemiological studies found little evidence of genetic diseases at the doses at which medical, occupational or accidental exposure occurred.
The fact that genetic effects were observed in irradiated animals suggests that these could also occur in humans. The probability of such events remains low compared with the ‘spontaneous’ risks of genetic effects.
Advances in stem cell research have opened new perspectives for regenerative and reproductive medicine. Stem cells (SC) can differentiate under appropriate in vitro and in vivo conditions into different cell types. Several groups have reported their ability to differentiate SCs into germline cells, and some of them have been successful in obtaining male and female gamete-like cells by using different methodologies.
This review summarizes the current knowledge in this field and emphasizes significant embryological, genetic and epigenetic aspects of germ cells and gametes in vitro differentiation in humans and other species, highlighting major obstacles that need to be overcome for successful gametogenesis in culture: studies reporting development of germ cell-like cells from murine and human embryonic (ESC) and somatic SCs are critically reviewed.
Published studies indicate that germ cells can be consistently differentiated from mouse and human ESC. However, further differentiation of germ cells through gametogenesis still has important genetic and epigenetic obstacles to be efficient.
Differentiation of germ cells from SCs has the potential of becoming a future source of gametes for research use, although further investigation is needed to understand and develop the appropriate niches and culture conditions. Additionally, if genetic and epigenetic methodological limitations could be solved, therapeutic opportunities could be also considered.
Despite interest in cryopreservation of individual or small number of human spermatozoa, to date, little data is available as regards its effectiveness. We systematically reviewed the outcome after cryopreservation of individual or small numbers of human spermatozoa in patients with severe male factor of infertility.
We searched the MEDLINE, EMBASE, Cochrane Systematic Reviews, CENTRAL, Web of Science, Scopus databases for relevant studies up to June of 2008. The search used terms referring to cryopreservation of small amount of sperm. Included studies were limited to human studies with no language restrictions.
We identified 30 reports including 9 carriers used for cryopreservation of small quantities/numbers of human spermatozoa (7 non-biological and 2 biological carriers). A wide variety of cryopreservation vehicles were reported. The recovery rate of spermatozoa cryopreserved in a known small number varied widely from 59 to 100%. Fertilization rates were in the range of 18–67%. Frozen–thawed spermatozoa, using this method, were subsequently used for intracytoplasmic sperm injection in only five studies, with few pregnancies reported so far. To date, there remains no consensus as to the ideal carrier for cryopreservation of small number of spermatozoa for clinical purposes.
Cryopreservation of individual or small numbers of human spermatozoa may replace the need for repeated surgical sperm retrieval. A controlled multicenter trial with sufficient follow-up would provide valid evidence of the potential benefit of this approach.
More than 15 million women, many of reproductive age, were infected with human immunodeficiency virus (HIV) at the end of 2007. As the HIV epidemic evolves, heterosexual intercourse is increasingly risky: the risk of infection in exposed young women is 4- to 7-fold higher than in young men and nearly half a million newborns annually have HIV. This review aims to show the effect of contraceptive choices on risk of HIV and on the course of disease in women with HIV.
Relevant citations were selected by agreement between the authors after a search of MEDLINE using the terms HIV/AIDS and contraception.
Risk of transmission of HIV varies from 1 in 200 to 1 in 10 000 coital incidents, depending in part on the integrity of the vaginal epithelium. Consistent use of male condoms has been proven to reduce horizontal transmission of HIV by 80% among HIV-serodiscordant couples. Hormonal contraception may increase the risk of HIV acquisition in high-risk women such as commercial sex workers, but not in women at low risk of HIV. While hormonal contraception did not affect progression of disease in two cohort studies involving 370 women, in a randomized trial among women not receiving antiretroviral medication, clinical disease accelerated in the oral contraception group (13.2/100 woman-years) compared with the copper intrauterine devices group (8.6/100 woman-years; hazard ratio, 1.5; 95% confidence interval, 1.04–2.1). Hormonal contraception does not interfere with antiviral drug effectiveness.
All the available reversible contraceptive methods can generally be used by women at risk of HIV infection and by HIV-infected women. Further studies are needed to investigate the safety and efficiency of hormonal contraception in women living with HIV/AIDS.
Surgery is often considered the best treatment option in women with symptomatic endometriosis. However, extent and duration of the therapeutic benefit are still poorly defined.
The best available evidence on surgery for endometriosis-associated pain has been reviewed to estimate the effect size of interventions in the most frequently encountered clinical conditions.
Methodological drawbacks limit considerably the validity of observational, non-comparative studies on the effect of laparoscopy for stage I–IV disease. As indicated by the results of three RCTs, the absolute benefit increase of destruction of lesions compared with diagnostic only operation in terms of proportion of women reporting pain relief was between 30% and 40% after short follow-up periods. The effect size tended to decrease with time and the re-operation rate, based on long-term follow-up studies, was as high as 50%. In most case series on excisional surgery for rectovaginal endometriosis, substantial short-term pain relief was experienced by ~70–80% of the subjects who continued the study. However, at 1 year follow-up, ~50% of the women needed analgesics or hormonal treatments. Major complications were observed in 3–10% of the patients. Medium-term recurrence of lesions was observed in ~20% of the cases, and around 25% of the women underwent repetitive surgery.
Pain recurrence and re-operation rates after conservative surgery for symptomatic endometriosis are high and probably underestimated. Clinicians and patients should be aware that the expected benefit is operator-dependent.
After many cycles of weight loss and weight gain, more and more morbidly obese patients undergo bariatric surgery, like gastric banding or gastric bypass, as the ultimate treatment for their obesity-problem. Since women of reproductive age are candidates for bariatric surgery, concerns arise regarding the potential impact on future pregnancy.
English-language articles were identified in a PUBMED search from 1982 to January 2008 using the keywords for pregnancy and bariatric surgery or gastric bypass or gastric banding.
The few reported case–control and cohort studies clearly show improved fertility and a reduced risk in obstetrical complications, including gestational diabetes, macrosomia and hypertensive disorders of pregnancy, in women after operatively induced weight loss when compared with morbidly obesity women. The incidence of intrauterine growth restriction (IUGR) appears to be increased, however. No conclusions can be drawn concerning the risk for preterm labour and miscarriage, although these risks are probably increased compared with controls matched for body mass index. Operative complications are not uncommon with bariatric surgery and several cases have pointed to the increased risk for intestinal hernias and nutritional deficiencies in subsequent pregnancy. Deficiencies in iron, vitamin A, vitamin B12, vitamin K, folate and calcium can result in both maternal complications, such as severe anaemia, and fetal complications, such as congenital abnormalities, IUGR and failure to thrive.
Close supervision before, during and after pregnancy following bariatric surgery and nutrient supplementation adapted to the patient’s individual requirements can help to prevent nutrition-related complications and improve maternal and fetal health, in this high-risk obstetric population.
Kisspeptins, and their cognate receptor gpr-54, were first found to regulate the hypothalamic–pituitary–gonadal (HPG) axis in 2003, when two groups demonstrated that mutations in gpr-54 cause idiopathic hypogonadotropic hypogonadism characterized by delayed or absent puberty. This review aims to highlight discoveries in the KiSS-1/gpr-54 system, focusing on their regulation of the HPG axis in male and female reproductive systems of both mammalian and non-mammalian vertebrates.
A search of PUBMED and the authors' files was done without limitations by language or species for citations relevant to kisspeptin, reproduction and signal transduction.
Kisspeptins and gpr-54 are critical for puberty and the regulation of reproduction. Kisspeptins have been implicated in mediating many of the important signals relayed to the gonadotrophin-releasing hormone (GnRH) neuron such as positive and negative feedback, metabolic input and photoperiod. The ability of kisspeptin neurons to co-ordinate different signals impinging on the HPG axis makes it one of the most important regulators of GnRH and the reproductive axis.
Kisspeptins are pivotal regulators of the HPG axis and reproduction, with the ability to integrate signals from both internal and external sources. Knowledge about the signalling mechanisms involved in kisspeptin stimulation of GnRH would help improve the understanding of the importance of this critical pathway in reproduction.
The epididymis performs an important role in the maturation of spermatozoa including their acquisition of progressive motility and fertilizing ability. However, the molecular mechanisms that govern these maturational events are still poorly defined. This review focuses on recent progress in our understanding of epididymal function including its development, role of the luminal microenvironment in sperm maturation, regulation and novel mechanisms the epididymis utilizes to carry out some of its functions.
A systematic search of Pubmed was carried out using the search term ‘epididymis’. Articles that were published in the English language until the end of August 2008 and that focused on the specific topics described above were included. Additional papers cited in the primary reference were also included.
While the majority of these findings were the result of studies in animal models, recent studies in the human epididymis are also presented including gene profiling studies to examine regionalized expression in normal epididymides as well as in those from vasectomized patients.
Significant progress has been made in our understanding of epididymal function providing new insights that ultimately could improve human health. The data also indicate that the human epididymis plays an important role in sperm maturation but has unique properties compared with animal models.
A better understanding of endometrial receptivity is crucial to the creation and optimization of tests to assess the window of implantation in a clinical setting. Testing endometrial receptivity via scanning electron microscopy of endometrial samples reveals that pinopodes are a very good marker of endometrial receptivity in the rat. There is still disagreement in the literature as to their usefulness as a receptivity marker in both mice and humans.
Publications related to the discovery, study and usefulness of pinopodes as a marker of endometrial preparation for implantation in both rodents and humans were identified through MEDLINE and other bibliographic databases.
There is substantial evidence that pinopodes are good markers of endometrial receptivity in the rat. Pinopodes are not useful in the mouse or human as consistent markers of endometrial receptivity for implantation. In the human, pinopodes have a prolonged (>5 days) presence in the luteal phase and fail to delineate the brief (24–48 h) window of receptivity.
While there are many publications arising from one group supporting the use of pinopodes as a reliable marker of human endometrial receptivity, few independent groups have been able to confirm these results. The clinical usefulness of pinopodes to delineate a period of endometrial receptivity seems unlikely following recent findings that pinopodes are present throughout the luteal phase of the menstrual cycle.
Proprotein convertase subtilisin/kexin type 4 (PCSK4), also known as proprotein convertase 4, belongs to a family of endoproteinases involved in the proteolytic conversion of secretory precursor proteins to their active forms. Its amino acid sequence is highly conserved in mammals, an indication of its biological importance.
We have searched PubMed and molecular biology databases for information relating to the structure, expression and biological functions of PCSK4.
PCSK4 is predominantly expressed in male germ cells and located on the plasma membrane overlying the acrosome of sperm. It is also present in ovary and placenta. Inactivation of its gene in mouse does not alter spermatogenesis, but renders sperm incapable of fertilizing oocytes. This incapacity results in part from sperm susceptibility to a premature acrosome reaction and their reduced ability to bind to the zona pellucida. In female mice, a lack of PCSK4 causes subfertility associated with impaired folliculogenesis. In addition, this enzyme has been shown to stimulate the invasiveness of human placental trophoblasts in culture, suggesting that it may facilitate placentation in vivo.
PCSK4 appears to be a crucial enzyme for reproduction. Alterations of PCSK4 expression or activity could be the underlying cause of some unexplained cases of human infertility. Conversely, inactivation of this protease represents a potential strategy for non-hormonal contraception.
Monoamines play important roles in decidualization, implantation, immune modulation and inflammation. Furthermore, monoamines are potent vasoactive mediators that regulate blood flow and capillary permeability. Regulation of the uterine blood flow is important both during menstruation and pregnancy. Adequate monoamine concentrations are essential for a proper implantation and physiological development of pregnancy. Unlike most transmitter substances, monoamines are recycled by monoamine transporters rather than enzymatically inactivated. Their intracellular fate is influenced by their lower affinity for inactivating enzymes than for vesicular transporters located in intracellular vesicles. Thus, cells are capable not only of recapturizing and degrading monoamines, but also of storing and releasing them in a controlled fashion.
The general objective of the present review is to summarize the role of the monoamine transporters in the female human reproduction. Since the transporter proteins critically regulate extracellular monoamine concentrations, knowledge of their distribution and cyclic variation is of great importance for a deeper understanding of the contribution of monoaminergic mechanisms in the reproductive process. MEDLINE was searched for relevant publications from 1950 to 2007.
Two families of monoamine transporters, neuronal and extraneuronal monoamine transporters, are present in the human endometrium and deciduas.
New knowledge about monoamine metabolism in the endometrium during menstruation and pregnancy will increase understanding of infertility problems and may offer new pharmacological approaches to optimize assisted reproduction.