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Infertility is a growing worldwide public health problem, and stress is a main factor exerting detrimental effects on female reproduction. However, knowledge regarding the neuroendocrine changes caused by chronic stress in females is limited. Therefore, this study assessed the effects of stress on hormones that control female reproduction during the proestrus and diestrus stages of the estrous cycle, as well as its effects on fertility. Adult females were assigned to either a control or a stress group. Stress consisted of exposure, for 15 min, to cold-water immersion daily for 30 days. Estrous cyclicity, female sexual behavior, as well as hypothalamic kisspeptin, gonadotropin releasing hormone (GnRH) content, serum luteinizing hormone (LH), estradiol (E2), progesterone (P4), corticosterone (CORT) and fertility were assessed after chronic stress. The results show that chronically stressed females exhibited disrupted estrous cyclicity, decreased receptivity, low pregnancy rates and lower numbers of fetuses. The content of Kisspeptin and GnRH in the Anteroventral Periventricular/medial Preoptic Area decreased during proestrus, while Kisspeptin increased in the Arcuate nucleus in proestrus and diestrus. Serum LH decreased only during proestrus, whereas E2 and P4 concentrations decreased during proestrus and diestrus, with a concomitant increase in CORT levels in both stages. As a whole, these results indicate that chronic stress decreases Kisspeptin content in AVPV nucleus and GnRH in POA in females, and might induce disruption of the LH surge, consequently disrupting estrous cyclicity and fertility, leading to lower rates of pregnancy and number of fetuses.

Glucocorticoids (GCs), stress-induced steroid hormones, are released by adrenal cortex and essential for stress adaptation. Recently, there has been renewed interest in the relationship between GCs and pregnancy following the discovery that glucocorticoid receptor is necessary for implantation. It has been widely recognized that stress is detrimental to pregnancy. However, effects of stress-induced GC exposure on uterine receptivity and decidualization are still poorly understood. This study aims to explore the effects of GCs exposure on uterine receptivity, decidualization, and their underlying mechanisms in mice. Single prolonged stress (SPS) and corticosterone (Cort) injection models were used to analyze effects of GC exposure on early pregnancy, respectively. SPS or Cort injection inhibits embryo implantation by interfering Lif signaling and stimulating the uterine deposition of collagen types I, III, and IV on day 4 of pregnancy. Uterine decidualization is also attenuated by SPS or Cort injection through suppressing Cox-2 expression. Cort-induced collagen disorder also suppresses decidualization through regulating mesenchymal-epithelial transition. Our data should shed lights for a better understanding for the effects of GCs on embryo implantation for clinical research.

Simple Summary A article proved that, in rats with PTU-induced hypothyroidism, the E2 level as well as the expression of the uterine-receptivity factors homeobox A10 and osteopontin was decreased. Additionally, we observed changes in the expression of PGE2, PGF2α, and PGI2 signaling pathway elements, and changes in the concentrations of those prostaglandins in uterine tissue. The results suggest that hypothyroidism may interfere with the prostaglandin signaling pathway, which may further result in a reduction in uterine receptivity. Abstract Thyroid hormones control the functions of almost all body systems. Reproductive dysfunctions, such as abnormal sexual development, infertility, or irregularities in the reproductive cycle, might be associated with thyroid disorders. Uterine receptivity is the period when the uterus is receptive to the implantation of an embryo. During the receptivity period (implantation window), a newly formed blastocyst is incorporated into the uterine epithelium. Prostaglandins are well-known primary mediators of pathological conditions such as inflammation and cancer but are also essential for the physiology of female reproduction. The aim of this study was to evaluate the possible relationship between hypothyroidism and changes in the prostaglandin signaling pathways in the uterus and in the process of uterine receptivity in a rat model. The results show that hypothyroidism impaired uterine receptivity by decreasing the level of E2 as well as decreasing the expression of the uterine-receptivity factors homeobox A10 and osteopontin. Moreover, hypothyroidism caused changes in the expression of elements of the prostaglandin E2, F2α, and I2 signaling pathways and changed the levels of those prostaglandins in the uterine tissue. The results suggest that the mechanisms by which hypothyroidism affects female reproductive abnormalities might involve the prostaglandin signaling pathway, resulting in a subsequent reduction in uterine receptivity.

International audience; This is a retrospective study to evaluate if the miRNome profile of endometrium samples collected during the implantation window predicts Assisted Reproduction Technology (ART) outcomes. We first investigated the endometrial miRNome profile according to the receptivity status in 20 patients with repeated implantation failures (RIF) (discovery cohort). After customized embryo transfer, the miRNome profiles of receptive patients with a positive or negative β-hCG, and with early miscarriage or live birth were analysed. Some differentially expressed miRNAs were selected for validation by RT-qPCR in endometrial samples from 103 RIF patients (validation cohort). Analysis of the different miRNome profiles identified endometrial receptivity, implantation failure, and early miscarriage-associated miRNA signatures that included 11, 261, and 76 miRNAs, respectively. However, only four miRNAs associated with the endometrial receptivity status (miR-455-3p and miR-4423-3p) and implantation failure (miR-152-3p and miR-155-5p) were significantly validated in endometrial samples. The miRNome profile of endometrial tissues during the implantation window can predict the pregnancy outcome. These data are crucial for opening new perspectives to predict implantation failure and consequently, to increase ART success.

Sexually naive female mice do not display high levels of sexual receptivity in their first sexual experience; they require around 4-5 sexual encounters to display the full receptive response, assessed by the lordosis reflex. In this study, we evaluated if repeated sexual stimulation with the same male is associated with changes in synaptic remodeling evaluated by synaptophysin (SYP) in brain structures involved in the control of sexual behavior such as the main and accessory olfactory bulbs (MOB and AOB, respectively), medial preoptic area (MPOA), ventromedial hypothalamus (VMH), and amygdala (AMG). Female mice were ovariectomized and hormonally primed to induce sexual receptivity. They were randomly distributed into three groups: a) sexually naive (SN), with no prior sexual stimulation; b) sexually inexperienced (SI), with one prior mating session; and c) sexually experienced (SE), with six mating sessions. The SI group showed a significant decrease in SYP in the glomerular, mitral and granular layers of the AOB in comparison to SN and SE females. SYP expression increased in the SE group in comparison to SN and SI females in the glomerular and mitral cell layers of the AOB. No significant differences between groups were found in the other brain regions (MOB, MPOA, VMH or AMG). These changes in SYP expression in the AOB suggest that plastic modifications in this brain region can be associated with receptivity increase in sexual experience in female mice.

Pubococcygeus muscle reflex activity has been reported to be driven by specialized neuronal circuitry, including the participation of spinal cord interneurons. Both the reflex and elements of the circuit are known to be sensitive to gonadal hormones, but studies using female rats have not considered the potential effects of estrous phase. Hence, in the present study we used mechanical stimulation of the clitoris to produce reflex activity, and recorded across the different phases of the estrous cycle, including the dark and light periods during each phase. Afterdischarge activity was observed only during the light and dark periods of proestrus, and during the light period of estrus coincident with the receptivity period in the rats reproductive behavior. Moreover, this reflex activity comprises at least five different motor unit groups with different firing patterns that are dependent on gonadal hormones variation.

Stress during gestation has harmful effects on pregnancy outcome and can lead to spontaneous abortion. Few studies, however, have addressed the impact of gestational stress, particularly auditory stress, on behavioural performance and pregnancy outcome in mice. This study aimed to examine the effect of two types of gestational stress on uterus receptivity and behavioural performance. Pregnant C57BL/6 mice were randomly assigned to either auditory or physical stress conditions or a control condition from gestational days 12–16. The auditory stress regimen used loud 3000 Hz tone, while the physical stressor consisted of restraint and exposure to an elevated platform. Three behavioural tests were performed in the dams after weaning. Uterine receptivity was investigated by counting the number of sites of implantation and fetal resorption. Also, the offspring survival rates during the early postnatal period were calculated. Auditory stress caused an increase in anxiety-like behaviour, reduced time spent exploring new object/environment, and reduced balance when compared to the physical stress and control groups. Auditory stress also caused higher rates of resorbed embryos and reduction of litter size. Our results suggest that the adverse effect of noise stress is stronger than physical stress for both uterus receptivity and behavioural performance of the dams.

It is still unclear whether Testosterone (T) increases sexual desire through a stimulation of the androgen receptor in relevant brain regions or through its conversion to estrogens. The aim of this study was to clarify the mechanisms of T facilitation of female sexual desire by assessing the effect of a non-aromatizable androgen (Dihydrotestosterone, DHT) in a validated animal model. Ovariectomized (OVX) Long-Evans rats were treated with oil (O) + O, 10 mcg Estradiol Benzoate (EB) + O, 10 mcg EB + 500 mcg Progesterone (P), O + 500 mcg DHT or 10 mcg EB + 500 mcg DHT (n = 12 per group). EB was administered 48 h, while P and DHT 4 h, prior to 4 sexual behavioral testing sessions in bisected unilevel pacing chambers. Appetitive behaviors (the frequencies of hops/darts and solicitations) were considered as the main outcome measure. Sexual receptivity indexes [lordosis magnitude, expressed as lordosis rating (LR), and lordosis quotient (LQ)], rejection responses, as well as mounts, intromissions and ejaculations received from the male were also coded. The probability of transition among sexual behaviors was evaluated by Transition Matrices; T-Pattern analysis was performed to detect hidden repeated temporal behavioral sequences. Preliminary analyses found no statistically significant differences between the O + O and EB + O groups, therefore we excluded the EB + O group from further analyses. Rats treated with EB + DHT displayed significantly more appetitive behaviors compared to negative controls (O + O and O + DHT), whereas no difference was observed between EB + DHT rats and positive controls (EB + P); noteworthy, a higher number of appetitive behaviors was observed in the O + DHT group compared to the O + O group. Furthermore, rats treated with EB + DHT showed significantly higher receptivity measures (LR and LQ) and received more mounts, intromissions and ejaculations compared to negative controls (O + O and O + DHT), to levels equivalent to EB + P. No differences were detected in female-male mounts or rejection responses among the 4 groups. Under a qualitative perspective, full solicitation was found exclusively in T-patterns of the EB + DHT group, which was also the only one to display T-patterns of higher order encompassing appetitive behaviors-only events. In conclusion, the administration of DHT in EB-primed OVX Long-Evans rats enhances sexual behavior measures. Specifically, DHT seems to stimulate sequences of appetitive behaviors separated from copulative/reproductive measures. Our data support an independent role of androgens in the facilitation of female sexual desire.

Introduction Depression is a psychiatric disorder with higher incidence in women. Among the most common and less investigated adverse effects of antidepressants are the female sexual dysfunctions. Up to one third of the patients fail to respond to antidepressants; therefore, more treatment alternatives are necessary. The combination of mirtazapine plus venlafaxine, known as “California Rocket Fuel” has shown to be an option for treatment-resistant depression. However, there are no reports of the effects of this combination in animal models and its action on female sexual behavior is unknown. Aim To analyze the effect of mirtazapine and venlafaxine alone or combined –given at doses with actions on the forced swim test- on female rat sexual behavior. Methods Mirtazapine (10, 20 or 40 mg/kg) and venlafaxine (15, 30 or 60 mg/kg) or their combinations (2.5/3.75, 5/7.5, 10/15 and 20/30 mg/kg mirtazapine and venlafaxine, respectively) were injected to sexually receptive female rats. We evaluated their effect on the forced swim test (FST). The doses that reduced immobility were tested on proceptivity and receptivity. Results Mirtazapine (40 mg/kg) and venlafaxine (60 mg/kg), administered alone, or combined (mirtazapine, 5, 10 and 20 mg/kg plus venlafaxine, 7.5, 15 and 30 mg/kg) reduced immobility, but affected motor activity. However, the reduced locomotion after the lowest combination (5/7.5 mg/kg) was smaller. Mirtazapine at 40 mg/kg reduced proceptivity and receptivity, while 60 mg/kg venlafaxine only decreased proceptivity. The combination of 5/7.5 mg/kg mirtazapine and venlafaxine did not affect female sexual behavior. Conclusions Mirtazapine and venlafaxine exerted an effect in the FST, which was also evident when sub-effective doses of both antidepressants were combined. This combination also lacked adverse effects on female sexual behavior. The results suggest that “California Rocket Fuel” could be an effective antidepressant therapy with no adverse sexual effects in women.

Aims: To clarify the role of fatty acid-binding protein 4 (FABP4) of endometrial epithelial cell in the establishment and maintenance of pregnancy and the involvement in the pathogenesis of pregnancy loss. Methods: The expression of FABP4 and uterine receptive factor (LIF, Integrin-β3 and Claudin 4) was determined by Western blotting or quantitative PCR. FABP4 siRNA was used to silence FABP4 while FABP4 inhibitor was used to inhibit the function of FABP4 in endometrial epithelial cell. ICR mice were raised to evaluate the effect of FABP4 silence or inhibition on embryo implantation in vivo after FABP4 siRNA mixture or inhibitor was injected into uterus, and an embryonic adhesion system using trophoblast spheroids mimicking embryos was set up to assess the effect of FABP4 silence or inhibition on embryonic adhesion onto endometrial cell in vitro. Results: The expression of FABP4 mRNA was significantly decreased in the deciduas of women with pregnancy loss compared with that of women with normal pregnancy. FABP4 siRNA significantly reduced the number of embryos implanted and FABP4 expression in ICR mice. FABP4 inhibition also significantly decreased the number of embryos implanted. Either silence or inhibition of FABP4 in endometrial epithelial cell abolished the expression of uterine receptive factors induced by the combination of estrogen and progesterone-induced, and reduced the number of trophoblast spheroids adhered onto endometrial cell. Conclusions: FABP4 regulates embryo implantation via altering uterine receptivity and decreased expression of FABP4 in endometrium may be linked with pregnancy loss, indicating FABP4 has biological role in the establishment and maintenance of pregnancy and subsequently is involved in pathogenesis of pregnancy loss.

Objectives We wanted to explore the effects of two different low doses (0.5μM and 0.05μM) of mifepristone, exposed during the receptive period, on the human embryo implantation process, using a well-established three-dimensional in vitro cell culture model, specifically developed to study this process. Methods An in vitro three-dimensional cell culture model was constructed using human endometrial cells isolated from the endometrium of proven fertile women, collected on cycle day LH+4. After 5 days of culture, supernumerary human embryos were added and cultured for another 5 days with mifepristone 0.5μM ( n =8) or 0.05μM ( n =10) or vehicle as control ( n =10). The cultures were checked for embryo attachment and terminated. We studied the expression of 16 reported endometrial receptivity markers in the endometrial constructs using real-time polymerase chain reaction. Results None of the embryos in 0.5μM of mifepristone attached to the endometrial constructs (p=.004), whereas 4 out of 10 in 0.05μM (p=.3698) and 7 out of 10 embryos in the control group attached to the cultures. We found that most of the studied receptivity markers were significantly altered with mifepristone exposure in a similar direction in both treatment groups. Only IL6 was significantly differentially expressed between the treatment groups (p=.017). Conclusion We report for the first time that exposure to a low concentration (0.5μM) of mifepristone during the receptive period successfully inhibits human embryo implantation process in vitro. Further, we observed a dose-dependent effect of mifepristone on endometrial receptivity at the functional level. Implication This study contributes new knowledge that low dose of mifepristone during the short period of receptive phase can inhibit endometrial receptivity, which further promotes mifepristone as a contraceptive agent. This could give women a treatment choice to avoid unwanted pregnancy with high efficacy and minimal side effects.

Although aromatase is expressed in both male and female brains, its functional significance in females remains poorly understood. In female quail, sexual receptivity is activated by estrogens. However it is not known whether sexual motivation is similarly estrogen-dependent and whether estrogens locally produced in the brain contribute to these behavioral responses. Four main experiments were designed to address these questions. In Experiment 1 chronic treatment of females with the anti-estrogen tamoxifen decreased their receptivity, confirming that this response is under the control of estrogens. In Experiment 2 chronic treatment with tamoxifen significantly decreased sexual motivation as treated females no longer approached a sexual partner. In Experiment 3 (a) ovariectomy (OVX) induced a significant decrease of time spent near the male and a significantly decreased receptivity compared to gonadally intact females, (b) treatment with testosterone (OVX + T) partially restored these responses and (c) this effect of T was prevented when estradiol synthesis was inhibited by the potent aromatase inhibitor Vorozole (OVX + T + VOR). Serum estradiol concentration was significantly higher in OVX + T than in OVX or OVX + T + VOR females. Together these data demonstrate that treatment of OVX females with T increases sexual motivation and that these effects are mediated at least in part by non-gonadal aromatization of the androgen. Finally, assays of aromatase activity on brain and peripheral tissues (Experiment 4) strongly suggest that brain aromatization contributes to behavioral effects observed here following T treatment but alternative sources of estrogens (e.g. liver) should also be considered.

Embryonic implantation requires synchrony between the endometrium and the embryo. When analyzed in isolation, competent embryos may be unsuccessful when placed on a nonreceptive endometrium or vice versa, contributing to the "black box" of implantation failure. It is when the two are assessed together that dyssynchrony becomes evident, due to premature progesterone stimulus on the endometrium, physiologic displacement of the window of implantation or late blastulation of the embryo, or all combined. From the embryonic component, detailed assessment of the timing of blastulation is essential. The molecular diagnosis of endometrial receptivity based on its transcriptomic signature could be superior to other techniques used in the past for defining the endometrial window of implantation.

In naturally cycling women, Roney and Simmons (2013) examined hormonal correlates of their desire for sexual contact. Estradiol was positively associated, and progesterone negatively associated, with self-reported desire. The current study extended these findings by examining, within a sample of 33 naturally cycling women involved in romantic relationships, hormonal correlates of sexual attraction to or interests in specific targets: women's own primary partner or men other than women's primary partner. Women's sexual interests and hormone (estradiol, progesterone, and testosterone) levels were assessed at two different time points. Whereas estradiol levels were associated with relatively greater extra-pair sexual interests than in-pair sexual interests, progesterone levels were associated with relatively greater in-pair sexual interests. Both hormones specifically predicted in-pair sexual desire, estradiol negatively and progesterone positively. These findings have implications for understanding the function of women's extended sexuality - their sexual proceptivity and receptivity outside the fertile phase, especially during the luteal phase.

Estradiol-induced plasticity involves changes in dendritic spine density and in the relative proportions of the different dendritic spine types that influence neurons and neural circuits. Such events affect brain structures that control the timing of neuroendocrine and behavioral processes, influencing both reproductive and cognitive functions during the estrous cycle. Accordingly, to investigate the dendritic spine-related plastic changes that may affect the neural processes involved in mating, estradiol-mediated dendritic spine plasticity was studied in type II cells situated in the ventrolateral portion of the ventromedial hypothalamic nucleus (VMN) of female, adult rats. The rats were assigned to four different groups (n=6) in function of their stage in the estrous cycle: proestrus, estrus, metaestrus, and diestrus. Dendritic spine density and the proportions of the different spine types on type II neurons were analyzed in the ventrolateral region of the VMN of these animals. Dendritic spine density on primary dendrites of VMN type II neurons was significantly lower in metaestrus than in diestrus, proestrus and estrus (with no differences between these latter stages). However, a significant variation in the proportional density of the different spine types was found, with a higher proportion of thin spines in diestrus, proestrus and estrus than in metaestrus. Likewise, a higher proportion of mushroom spines was seen in diestrus and proestrus than in metaestrus, and a higher proportion of stubby spines in estrus than in diestrus and metaestrus. Very few branched spines were found during proestrus and they were not detected during estrus or metaestrus. The different types of dendritic spines in non-projection neurons of the VMN could serve to maintain greater synaptic excitatory activity when receptivity and estradiol levels are maximal. However, they may also fulfill an additional functional role when receptivity and estradiol decline. To date specific roles of the different types of spines in neural hypothalamic activity during the estrous cycle remain unknown and they clearly deserve further study.

Female behavioral estrus is defined as the period between the first lordosis displayed during the estrus cycle to the lordosis that is not followed by another within 60 min. In a seminatural environment, an estrous female consistently displays lordosis in response to every male mount from the start of behavioral estrus until the end of it. This means that the female suddenly changes from a state of complete non-receptivity to full receptivity and then abruptly changes back to non-receptivity. It is unlikely that these abrupt changes are caused by sudden changes in serum concentration of ovarian steroids. Here, we present the results of a detailed study of sociosexual behaviors during the transition from non-receptivity to receptivity and vice versa. The frequency of male mounting was close to zero before and after estrus. It remained at a constant, high level throughout estrus. Female paracopulatory behavior and male pursuit of the female increased drastically from a very low level before estrus to a high level during estrus. They returned to low levels immediately after estrus. None of the many other behavior patterns registered changed during the transitions. It appears that the sudden increase in male pursuit and female paracopulatory behavior can explain the beginning of behavioral estrus, and their equally sudden disappearance causes it to end. The neurochemical mechanisms behind these almost instantaneous behavioral changes are unknown.

Recently, much work has been done to record the diurnal peak of does receptivity. It was found that the highest was in the morning and before allowing suckling. Such studies suggested that mating should be achieved in the morning or before suckling to avoid the negative effect of the circadian peak of prolactin on receptivity that occur around 15.00 to 19.00 h and after each suckling. Some cases of pseudo-pregnancy might be prevented by double mating; the second mating should be within at most five hours after the first, since mating later than this would have no effect. Total parturition time would be 10–14 minutes for a large litter and 5–7 minutes for an average litter, although parturition could be induced to allow prompt attention to does with poor maternal instinct and to those kindle for the first time kindling and to avoid situations such as: kindling at night or in cold weather and/or to avoid the variability in gestation periods (29 to 34 days). Mother-litter separation during night can influence species specific nursing behaviour and may lead to lower weaning weights of pups. Applying good management programs, as well as, change of place, gentle handling of the stressed dams, correcting nutritional deficiencies and inadequate drinking water and provision of adequate amount of straw, may well eliminate stress, correct behavioural disorders and certain types of maternal anomalies which appear to be not under the control of hormonal or genetic factors. Welfare for caged rabbits can be improved by feeding the animals in the afternoon rather than in the morning. Aggressive behaviour was greater in rabbits on nipple drinkers than in those on troughs. In conclusion, better understanding of rabbits natural behaviour under the different conditions, maintains optimal production compatible with welfare demands. Below, description of rabbits behaviour and its relation with modern commercial production conditions, were discussed.

Vascular endothelial growth factor (VEGF) and osteopontin (OPN) are suggested to facilitate angiogenesis and vascular remodeling in endometrial receptivity. Determination of the endometrial microvascular density (MVD) is the commonest method used to indirectly assess the levels of vasculogenesis and angiogenesis; however, the associations among VEGF, OPN and MVD remain unclear. Controlled ovarian hyperstimulation (COH) with the gonadotrophin-releasing hormone agonist-long protocol may impair endometrial receptivity, and Traditional Chinese Medicine (TCM) may exert therapeutic effects to relieve this impairment. The aim of the present study was to investigate the effects of COH on implantation biology and pregnancy outcome, and to explore the potential therapeutic role of the TCM Zi Dan Yin (ZDY). Female Sprague Dawley rats were divided into four groups: Control, COH, ZDY and COH + ZDY. On days 3, 4 and 5 of pregnancy (D3, D4 and D5, respectively), endometrial MVD was measured with cluster of differentiation 34 immunohistochemical detection, and VEGF and OPN protein and mRNA expression was detected through western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. On D10, the average number of implantation sites was observed. Subsequent to conceiving and bearing newborn rats, the number of live births from each group was recorded. COH was shown to have adverse effects on implantation and pregnancy outcome. The MVD was found to be significantly increased in the COH group compared with that in the control, ZDY and COH+ZDY groups. The results of the protein and RT-qPCR analysis of VEGF and OPN revealed the same trend. Conversely, ZDY reversed the changes in endometrial MVD, VEGF and OPN, and was indicated to improve uterine receptivity and pregnancy outcome. No significant difference was observed among the control, ZDY and COH + ZDY groups. In conclusion, since the results for MVD and VEGF and OPN expression were consistent, MVD could be used as an alternative approach to identify the period of receptivity in rats.

Successful embryonic implantation is the result of a receptive endometrium, a functional embryo at the blastocyst stage and a synchronized dialog between maternal and embryonic tissues. Successful implantation requires the endometrium to undergo steroid-dependent change during each menstrual cycle, exhibiting a short period of embryonic receptivity known as the window of implantation. The term "endometrial receptivity" was introduced to define the state of the endometrium during the window of implantation. It refers to the ability of the endometrium to undergo changes that will allow the blastocyst to attach, penetrate, and induce localized changes in the endometrial stroma. These changes are metabolically demanding, and glucose metabolism has been proven to be important for the preparation of the endometrium for embryo implantation. Obesity and polycystic ovary syndrome (PCOS) represent 2 common metabolic disorders that are associated with subfertility. The aim of this review is to summarize the effect of obesity and PCOS on endometrial receptivity at the time of implantation. Focus will be on metabolic alterations that regulate decidualization, including glucose metabolism, hyperinsulinemia, and hyperandrogenism.

The study was to evaluate whether fibrotic markers, endometrial receptivity markers and SDF-1/CXCR4 had been changed in the treatment of intrauterine adhesions (IUAs) by different dosages of estrogen.A total of 39 patients with IUAs were treated with EV 4 mg or 9 mg randomly post-surgery. TGF-β1/MMP-9, VEGF/αvβ3 and SDF-1/CXCR4 were detected in endometrial tissue before and after treatment by real-time PCR and Western blot.TGF-β1 and MMP-9 expression significantly decreased after treatment for 3 months than before (p .05), the falling range was larger with EV 4 mg than 9 mg in the mild-moderate degree IUAs (p .05); Integrin avβ3 expression significantly increased after treatment for 3 months than before (p .05), the variation range was larger with EV 4 mg than 9 mg (p .05); CXCR4 expression had no significant change after treatment 3 months compared to that before treatment (p .05). SDF-1 presented an upward tendency at early phase, and it came back to the level of pre-surgery. But there were no significant difference between treatment with 4 mg and 9 mg in the rate of menstrual restoration and pregnancy follow-up 3 months after the treatment.Endometrium fibrosis may be inhibited and endometrium receptivity may be improved by estrogen with moderate dosage therapy. Compared to the large one, it seems to be advantageous.

Sexually naïve estrous female mice seek out male urinary pheromones; however, they initially display little receptive (lordosis) behavior in response to male mounts. Vomeronasal - accessory olfactory bulb inputs to the medial amygdala (Me) regulate courtship in female rodents. We used a reversible inhibitory chemogenetic technique (Designer Receptors Exclusively Activated by Designer Drugs; DREADDs) to assess the contribution of Me signaling to females’ preference for male pheromones and improvement in receptivity normally seen with repeated testing. Sexually naïve females received bilateral Me injections of an adeno-associated virus carrying an inhibitory DREADD. Females were later ovariectomized, treated with ovarian hormones, and given behavioral tests following intraperitoneal injections of saline or clozapine-N-oxide (CNO; which hyperpolarizes infected Me neurons). CNO attenuated females’ preference to investigate male vs female urinary odors. Repeated CNO treatment also slowed the increase in lordosis otherwise seen in females given saline. However, when saline was given to females previously treated with CNO, their lordosis quotients were as high as other females repeatedly given saline. No disruptive behavioral effects of CNO were seen in estrous females lacking DREADD infections of the Me. Finally, CNO attenuated the ability of male pheromones to stimulate Fos expression in the Me of DREADD-infected mice but not in non-infected females. Our results affirm the importance of Me signaling in females’ chemosensory preferences and in the acute expression of lordosis. However, they provide no indication that Me signaling is required for the increase in receptivity normally seen after repeated hormone priming and testing with a male.

In recent decades, infertility is one of the health problems worldwide. One of the most crucial events in reproductive period is implantation window (IW). In the time after IW period, the embryo cannot connect to the endometrium; therefore the most critical issue for successful implantation is timely entrance of embryo to the uterine cavity during the IW. Implantation failure is responsible for many cases of infertility and is the most important limiting factor for achieving a successful outcome using the assisted reproductive techniques (ART). The aim of this study was to investigate the receptivity of the endometrium and factors affecting it with emphasizing on the role of angiogenesis. Interaction between the embryo and the endometrium is affected by molecular interactions among cytokines, growth factors, hormones, and cell adhesion molecules, causing endometrial receptivity. Also, angiogenesis is a process that has an important role in human implantation. Estrogen and progesterone hormones are two important regulation keys in angiogenesis and implantation process. It is expected that effective and stimulating drugs of angiogenesis can improve the characteristics of endometrial receptivity and prevent implantation failure in ART. It is hoped that with recent advances in the field of molecular medicine, improvement of angiogenesis in human endometrium and prevention of the implantation failure be achieved. Here, we summarized various factors could affect on endometrial receptivity and the role of them on angiogenesis. J. Cell. Biochem. 118: 4141-4151, 2017. © 2017 Wiley Periodicals, Inc.

To investigate whether clomiphene citrate (CC) affects uterine receptivity or not, we evaluated pregnancy rates (PR) during the hormone replacement cycle (HRC) according to the period between the last day of CC administration and the day of embryo transfer (ET).From March 2008 through March 2010, a total of 378 treatment cycles among 378 patients who received CC and had to avoid fresh ET due to a thin uterine endometrium were recruited. All patients underwent thawed ET using HRC. PRs were evaluated according to the period between the last CC treatment and the day of ET.PR for the groups in which the period between the last CC treatment and the day of ET increased to more than 91 days were significantly higher than that for group in which the period was less than 90 days (A lower PR was shown by the patients who underwent thawed ET in the HRC within 90 days after their last CC treatment, which shows that CC affects the receptivity of the uterine endometrium.

Male courtship signals often stimulate the production of sex steroids in both female and male receivers. Such effects benefit signallers by increasing receptivity in females, but impose costs on signallers by promoting sexual behaviour and aggression in male competitors. To resolve this androgen-based conflict, males should use strategies that suppress sex steroid production in rival males. In green treefrogs, Hyla cinerea, chorus sounds (i.e. advertisement calls from aggregates of males) are known to stimulate androgen production in receiver males. Here, I examined whether males of this species counter these effects by eliciting an endocrine stress response in male conspecifics during close-range vocal interactions. I show that corticosterone (CORT) levels were higher in males that lost vocal contests in natural choruses compared to contest winners and nonaggressive males. Testosterone levels were also lower in contest losers compared to nonaggressive males, but not contest winners; dihydrotesterone levels did not differ among the three groups. Aggressive and advertisement calls were then broadcast to males in an experiment that simulated close-range vocal communication. Aggressive calls rapidly (45 min) elicited an increase in CORT and a reduction in androgens in receivers. Advertisement calls did not elicit an increase in CORT, but CORT levels were sustained relative to controls exposed to silence and were accompanied by a reduction in androgens in small males. Endocrine responses to acoustic signals in this species thus vary depending upon context, call type and size of signal receivers. Signallers benefit from eliciting CORT production in competitors because elevated CORT suppresses vocalization.

SummaryMating induces pronounced changes in female reproductive behavior, typically including a dramatic reduction in sexual receptivity. In Drosophila, postmating behavioral changes are triggered by sex peptide (SP), a male seminal fluid peptide that acts via a receptor (SPR) expressed in sensory neurons (SPSNs) of the female reproductive tract. Here, we identify second-order neurons that mediate the behavioral changes induced by SP. These SAG neurons receive synaptic input from SPSNs in the abdominal ganglion and project to the dorsal protocerebrum. Silencing SAG neurons renders virgin females unreceptive, whereas activating them increases the receptivity of females that have already mated. Physiological experiments demonstrate that SP downregulates the excitability of the SPSNs, and hence their input onto SAG neurons. These data thus provide a physiological correlate of mating status in the female central nervous system and a key entry point into the brain circuits that control sexual receptivity.

Little is known about the occurrence of individual variation in sexual behavior and how maternal nutrition can affect this variation. We tested the hypothesis that male offspring of female meadow voles, Microtus pennsylvanicus, that were 30% food restricted (FR) during days 1-7 of lactation (FR 1-7), days 8-14 of lactation (FR 8-14), or late days 15-21 of lactation (FR 15-21) lactation show persistent, negative effects on their sexual behavior as adults relative to male offspring of females that were not food restricted. We measured three components of sexual behavior, attractivity, proceptivity and receptivity, beginning when the males were 98 days of age. Food restriction during middle lactation (FR 8-14) but not during early (FR 1-7) and late lactation (FR 15-21) was sufficient to induce adult male voles to produce anogenital marks that were not as attractive as those produced by control males. Food restriction during lactation did not affect the proceptive behavior of male voles but did affect their receptivity. Only 4 of 12 FR 8-14 male voles mated compared to 9 of 12 FR 1-7 males, 8 of 12 FR 15-21 males, and 8 of 11 control males. However, no differences existed in their copulatory behavior among the males that did mate. The body weight of FR 1-7 and FR 8-14 males was lower than that of FR 15-21 and control males when they were between 22 days of age (weaning) and 48 days of age (puberty) but was similar when the males were 98 days of age. Food intake was similar for the FR and control males between day 22 and day 98. It remains unclear, however, if this type of maternal effect represents strategic programming of offspring behavior in response to the environment experienced by mothers or is a product of developmental processes of food restriction prior to weaning (Forstmeier et al. 2004).

Female sexual behavior is sensitive to stress and diseases. Some studies have shown that status epilepticus (SE) can affect sexual proceptivity and receptivity in female rats and also increases reject responses towards males. However, epidemiologic studies indicate that SE is more frequent in young individuals. Herein, we assessed the effects of SE in infant females on their sexual behavior during adulthood. Thirteen-day-old (P13) rat pups received intraperitoneal injections of lithium chloride (3 mEq/kg). Twenty hours later, at P14, SE was induced by subcutaneous injection of pilocarpine hydrochloride (100 mg/kg s.c.). Control animals were given an equal volume of saline subcutaneously. The animals were weaned at P21 and, later in adulthood, were ovariectomized and hormone-primed with estradiol + progesterone, and their sexual behavior assessed during 4 separate trials of 30 min each with a stud male. Our results indicate that proceptive behaviors (solicitations and hops and darts) were impaired during the first trial, but no alterations were observed for receptivity and attractivity. By trial 3, all SE females displayed normal proceptivity. These results indicate that SE in infancy readily affects proceptivity in a reversible manner. We discuss the role of sexual experience in recovery.

Topoisomerase I (topo I) is an essential nuclear enzyme involved in virtually all aspects of gene expression, and is the target of the anti-cancer drugs- camptothecin (CPT) and its derivatives. Improvement of the survival rates of young women with cancer has led to the consideration of the effects of long-term chemotherapy on their fertility. The effect of anticancer drugs on ovarian function was previously investigated; however, no reports are available concerning their effect on the endometrium, whose integrity is an important factor in embryo implantation. Here we used a rat animal model to investigate the expression and activity of topo I in the various physiologic phases of the endometrium and the influence of CPT on its integrity and receptivity. The results show, for the first time, that the endometrial topo I level and activity are influenced by the physiologic phases of the endometrium (estrous cycle) and correlate with the estrogen blood concentration. Treatment with the anti-cancer drug CPT caused histological disruption of the endometrium and deleterious effect on its cyclicity. Moreover, CPT treatment significantly reduced the implantation rate of embryos, suggesting alteration in the receptivity of the endometrium. These results suggest that topo I is important for maintaining the normal physiologic cyclicity and functionality of the endometrium in rats. Anti-cancer agents that target topo I severely impair estrous cycle progression and endometrial integrity and receptivity, emphasizing the importance of addressing the effect of chemotherapy on the endometrial functionality.

It is unclear if the higher pregnancy rate in patients who experience ovarian hyperstimulation syndrome (OHSS) indicates that OHSS is favourable for embryo implantation, or if patients should be maintained in a hyperstimulation state in order to increase the success rate of embryo transplantation. We developed an animal model to determine the endometrial receptivity in rats with OHSS. Endometrial mRNA levels of ER, PR, HOXA10 and LIF were determined by semi-quantitative PCR and ER, PR, HOXA10, LIF and integrin α(v) β(3) protein levels were determined by Western blotting. Development of pinopodes in the hyperstimulation group was slightly delayed, while in the regular stimulation group, development was significantly inhibited. mRNA transcription in the regular stimulation group was lower, while transcription in the hyperstimulation group was not different from controls. Protein expressions were lowest in the regular stimulation. We conclude that OHSS is associated with favourable endometrial receptivity, similar to that seen in a normal cycle, and receptivity that is increased relative to that seen with a routine stimulation protocol.

The environment experienced by pups during lactation (nutrition and maternal behaviour) can contribute not only to sexual development, but also to individual differences in offspring sexual behaviour. We tested the hypothesis that female offspring of meadow vole dams (Microtus pennsylvanicus) that were 30% food restricted (FR) during days 1–7 of lactation (FR 1–7), days 8–14 of lactation (FR 8–14), or days 15–21 of lactation (FR 15–21) show negative effects on their food intake, growth, and the three components of sexual behaviour (attractivity, proceptivity and receptivity) as compared with female offspring of control dams. With the exception of age 29 days or age 34 days, the body weights of female offspring of FR 1–7 dams and FR 8–14 dams between days 21 and 48 were lower than the body weights of female offspring of FR 15–21 dams and those of control dams. Female offspring of FR 1–7 dams maintained a lower body weight than the other female offspring throughout the study. Female offspring of FR 8–14 and FR 15–21 dams produced odours that were less attractive to males than odours produced by those of FR 1–7 and control dams. Female offspring of FR dams and control dams did not differ in their measures of proceptivity and receptivity. However, the total amount of time allocated for copulation by males was shorter for those males that were paired with female offspring of FR 1–7 dams than it was for those that were paired with the female offspring of FR 8–14, FR15–21, and control dams. The results of this study, coupled with those found in a study conducted on the male offspring of FR dams, indicate that for female offspring days 1–7 and for male offspring days 8–14 of lactation are the time periods during which food restriction of dams had the greatest impact on deficits in sexual behaviour and body mass in meadow voles.

This study used radioimmunoassay (RIA) to explore the relationship between levels of hemolymph ecdysteroids and female reproductive behavior in Schizocosa wolf spiders. Specifically, we investigated the relationship between circulating ecdysteroid concentrations in females and 1) likelihood to copulate, or female receptivity (Experiment I— Schizocosa avida (Walckenaer 1837)), 2) time post copulation (Experiment 2— Schizocosa rovneri Uetz & Dondale 1979) and 3) exposure to conspecific male courtship (Experiment 3— Schizocosa uetzi Stratton 1997). In Experiment 1, we expected higher levels of circulating ecdysteroids in receptive versus unreceptive females, based upon prior research demonstrating an increase in receptivity following injections of 20-hydroexyedysone (e.g., Tegenaria atrica C.L. Koch 1843). In contrast, we found no relationship between female receptivity and ecdysteroid levels. Our second experiment compared ecdysteroid levels in mated versus virgin females at three time points following mating trials (24 h, 7 d and 14 d). We predicted low and constant ecdysteroid levels, independent of both mating status and time post mating trial—our results support this prediction. Our third experiment explored the relationship between exposure to conspecific courtship and ecdysteroid levels; again, we found no relationship. Thus, circulating ecdysteroid concentrations were not associated with any aspect of reproductive biology we explored. However, we found a negative trend between female age post maturation and circulating ecdysteroid concentration in the species for which we had the greatest age range, consistent with its role as a molting hormone.

Drosophila seminal fluid proteins elicit physiological and behavioral changes in the female after mating. For example, the seminal protein sex peptide (SP) causes females to lay more eggs, reduce receptivity to re-mating, consume more food and produce more concentrated excreta upon mating. It has been reported that SP indirectly increases food consumption as a result of its stimulation of egg production, but its role in producing more concentrated excreta in the mated female was reported to be independent of egg production. Additionally, it has been shown that SP's effect on food consumption persists for several days after mating, while it is unknown whether this is true for its effect on excretion. SP can have both transient and long-term effects on mated females; the latter occur because of the peptide's binding to, and slow release from, sperm in the female. Here we used timed measures of excretion by female flies that had mated to males mutant in SP or in its regulators, to test the duration of SP's effect on excretion. We found that SP's effect on excretion persists for at least ~1 week after mating, and that this persistence requires that SP bind to and be released from sperm. Although these binding/release requirements of SP are similar to those for increased egg production (and consequent increased food intake) following mating, we find that the long-term change in excretion phenotype is only partially dependent on the presence of eggs in the female. Our data indicate that a change in intestinal transit is part of the long-term post-mating response elicited by the gradual release of sperm-bound SP in the female after mating, even though it is not fully dependent on other long-term responses elicited by SP.

Progesterone (P4 ) and its product, 5α-pregnan-3α-ol-20-one (3α,5α-THP), act in the midbrain ventral tegmental area (VTA) to alter motivated behaviors, such as mating, and motor and anxiety behavior. Of interest is whether 3α,5α-THP formation requires the pregnane xenobiotic receptor (PXR), which is expressed in the midbrain of rats.The role of PXR in the midbrain for 3α,5α-THP formation, which precedes modulation of motivated behaviors, was investigated.Rats had estrous cycle phase determined and were assessed when they were in diestrus or proestrus. Diestrous and proestrous rats were infused with control or antisense oligodeoxyribonucleotides (AS-ODNs) targeted against PXR to the VTA.In pilot studies, PXR gene and protein expression in the midbrain were determined with quantitative reverse transcriptase polymerase chain reaction and Western blotting, respectively. Diestrous and proestrous rats infused with control or AS-ODNs to the VTA were tested for anxiety (open field and plus maze), social (social interaction), and sexual (paced mating) behavior. Expression of PXR in the midbrain was verified with Western blotting. Plasma estradiol, P4 , dihydroprogesterone (DHP), and 3α,5α-THP levels, and brain P4 , DHP, and 3α,5α-THP levels were measured. We predicted that proestrous rats infused with PXR AS-ODNs would have decreased anti-anxiety, social, and sexual behavior, lower midbrain expression of PXR, and lower midbrain levels of 3α,5α-THP compared with controls.Results supported the hypothesis that formation of 3α,5α-THP requires PXR and may be important for motivated behaviors. PXR AS-ODN, compared with control, infusions to the VTA reduced PXR expression and 3α,5α-THP levels in the midbrain and attenuated sexual receptivity of proestrous rats.Knockdown of PXR in the midbrain reduces 3α,5α-THP levels and sexual receptivity of proestrous rats. Thus, PXR in the midbrain may be required for the observed increase in 3α-5α-THP during proestrus, which has subsequent effects on motivated, reproductive behaviors.

The effects of male-derived extracts on female receptivity to remating were investigated in Trigonotylus caelestialium (Kirkaldy) (Heteroptera: Miridae). The aqueous extracts of male reproductive tracts were observed to reduce receptivity both at 3 h and at 1 d after injection into the abdomens of females. Next, ultrafiltration was used to divide the aqueous extracts of the male reproductive tracts into three molecular-weight (MW) fractions: 14 kDa. The filtrate containing the MW substances 14 kDa inhibited receptivity at 1 and 2 d after injection. Finally, the male reproductive tract organs were divided into the accessory glands, testes, and the remaining reproductive organs, including the seminal vesicles. Aqueous extracts of the accessory glands reduced the receptivity of females both at 3 h and 2 d after injection, whereas those of the testes decreased the receptivity of females at 3 h after injection. Together, the results indicate that more than one mechanism may be involved in the effects of male-derived substances on female receptivity in T. caelestialium. The findings suggest that low-MW male-derived substances in the accessory glands and testes cause short-term inhibition and that the high-MW substances in the accessory gland inhibit female mating at a later period.

To evaluate the effects of nutrition on the sexual behaviour of ewes, forty-eight mature (7.6 ± 1.9 yearsold) Merino d’Arles ewes with an average initial body condition score (BCS = 2.26 ± 0.23) and similar bodyweight (BW = 46.6 ± 3.8 kg) were fed three contrasting diets for three months. The diets provided vary-ing levels of energy expressed as proportion of Maintenance Energy Requirements (i.e. Low = 70%MER;Medium = 113%MER and High = 180%MER) with the ultimate objective of obtaining different BW andBCS. Blood samples were taken before and at the end of the three-month experimental period to mea-sure plasma metabolites (glucose, GLU; beta-Hydroxybutyrate, OHB; non-esterified fatty acids, NEFA)and hormones (insulin, INS and leptin, LEPT). The ewes’ sexual behaviour, e.g. attractiveness, receptivityand proceptivity, was estimated through normalized pen-tests before and at the end of the experimentafter hormonally-induced oestrus. As expected, the dietary treatments induced significant changes inBW (i.e. the final weights were 38.6 ± 2.5, 47.3 ± 3.6 and 55.0 ± 2.2 kg for Low, Medium and High groups,respectively) and BCS (1.33 ± 0.4, 1.90 ± 0.2 and 2.33 ± 0.2 for Low, Medium and High, respectively). Themetabolic and hormonal changes were in agreement with the known effects of feeding regimes.The sexual behaviours of ewes were only partially changed by feeding regimes. While the scores ofreceptivity (SR) of ewes to males (i.e. number of agonistic interactions with the courting ram) and scoresof proceptivity (SP) towards rams (i.e. time spent close to a pen with rams) remained unchanged (P > 0.05),there were significant (P < 0.001) changes (Low = 2.42; Medium = 3.63 and High = 4.47; P < 0.001) in theirscores of attractiveness (SA: i.e. a higher score is given to the preferred ewes by rams). This SA waswell correlated with the BW (r = +0.83; P < 0.0001) and BCS (r = +0.73; P < 0.0001) of ewes, it was alsonegatively correlated with metabolites (NEFA: r = −0.32; P < 0.05) and positively with anabolic hormones(INS: r = +0.42; P < 0.01). Combining these variables, the SA is clearly explained (R2= 0.79; P < 0.0001;n = 36) by a model including the static (long-term) effects of nutrition (BW and BCS) and the dynamiceffects of nutrition (NEFA and INS). This work demonstrates that the nutritional status of female sheep,during oestrus, produces efficient cues that clearly orient males in their mating choices.

Background Clinical ovulation induction induces blood estrogen (E2) in excess of physiological levels, which can hinder uterine receptivity. In contrast, progesterone produces the opposite clinical effect, suggesting that it might be capable of recovering the lost receptivity resulting from exposure to high estrogen levels. Integrins are the most widely used biological markers for monitoring uterine conditions. We studied progesterone-induced changes in integrin β expression patterns as biomarkers for changes in uterine receptivity in response to increased estrogen levels. Methods Endometrial biopsy samples from patients were screened for their estrogen (E2) and progesterone (P4) content and expressing levels of integrin β1 and β3. Uterine receptivity was evaluated using human endometrial adenocarcinoma cells in an embryo attachment model. The respective and concatenated effects of embryo attachment and changes in the integrin β1 and β3 expression patterns on the adenocarcinoma cell plasma membranes in response to 100 nM concentrations of E2 and P4 were evaluated. Results Increased blood E2 concentrations were associated with significantly decreased the levels of integrin β3 expression in uterine biopsy samples. In vitro experiments revealed that a 100 nM E2 concentration inhibited the distribution of integrin β3 on the plasma membranes of human endometrial adenocarcinoma cells used in the embryo attachment model, and resulted in decreased rates of embryo attachment. In contrast, P4 enhanced the expression of integrin β1 and promoted its distribution on the plasma membranes. Furthermore, P4 recovered the embryo attachment efficiency that was lost by exposure to 100 nM E2. Conclusions Blood E2 and P4 levels and integrin β3 and β1 expression levels in uterine biopsy samples should be considered as biomarkers for evaluating uterine receptivity and determining the optimal time for embryo transfer. Trial registration Trial number: ChiCTR-TRC-13003777; Name of registry: Chinese Clinical Trial Registry; Date of registration: 4 September 2013; Date of enrollment of the first study participant: 15 October 2013 Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-1052-0) contains supplementary material, which is available to authorized users.

Hypothesis Quercetin could induce changes to the fluid volume and receptivity development of the uterus during peri-implantation period. Methods Female rats were treated with quercetin (10, 25 and 50 mg/kg/day) subcutaneously beginning from day-1 pregnancy. Uterus was harvested at day-4 (following three days quercetin treatment) for morphological, ultra-structural, protein and mRNA expressional changes and plasma sex-steroid levels analyses. In another cohort of rats, implantation rate was determined at day-6 (following five days quercetin treatment). Results Administration of 50 mg/kg/day quercetin causes increased in uterine fluid volume and CFTR expression but decreased in γ-ENaC, AQP-5, AQP-9 claudin-4, occludin, E-cadherin, integrin αnβЗ, FGF, Ihh and Msx-1expression in the uterus. Pinopodes were poorly develop, tight junctions appear less complex and implantation rate decreased. Serum estradiol levels increased but serum progesterone levels decreased. Conclusions Interference in the fluid volume and receptivity development of the uterus during peri-implantation period by quercetin could adversely affect embryo implantation.

Endometrial receptivity defect can lead to a recurrent failures in ART. Data on endometrial receptivity assessment by the most studied biomarkers, such as pinopodes, leukemia-inhibitory factor, αVβ3 integrin, mucin MUC 1, are presented. Analysis of controlled ovarian stimulation protocols influence on endometrial receptivity is composed.

The endometrium is a complex tissue that lines the inside of the endometrial cavity. The gene expression of the different endometrial cell types is regulated by ovarian steroids and paracrine-secreted molecules from neighbouring cells. Due to this regulation, the endometrium goes through cyclic modifications which can be divided simply into the proliferative phase, the secretory phase and the menstrual phase. Successful embryo implantation depends on three factors: embryo quality, the endometrium's state of receptivity, and a synchronised dialogue between the maternal tissue and the blastocyst. There is a need to characterise the endometrium's state of receptivity in order to prevent reproductive failure. No single molecular or histological marker for this status has yet been found. Here, we review the global transcriptomic analyses performed in the last decade on a normal human endometrium. These studies provide us with a clue about what global gene expression can be expected for a non-pathological endometrium. These studies have shown endometrial phase-specific transcriptomic profiles and common temporal gene expression patterns. We summarise the biological processes and genes regulated in the different phases of natural cycles and present other works on different conditions as well as a receptivity diagnostic tool based on a specific gene set profile. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.

To what extent does the reward value of sexual stimulation in females depend on ovarian hormones? The effects of estradiol benzoate (EB) and progesterone (P) were examined on the acquisition and expression of sexual reward induced by paced copulation and clitoral stimulation (CLS) in ovariectomized (OVX) rats. In experiment 1 we examined the expression of a pacing‐induced conditioned place preference (CPP). Ovariectomized, hormone-primed rats were given experience with paced copulation associated with one side of a CPP apparatus. Changing hormonal status prior to the final CPP test did not alter pacing-induced CPP. However, subsequent partial extinction of CPP was observed only in rats primed with EB + P, a treatment previously shown to induce sexual desire and receptivity. In Experiment 2, significant CLS-induced CPP developed in ovariectomized rats regardless of hormone priming. Our results show that the expression of the sexual reward state induced by paced copulation, and CLS in particular, is independent of hormone priming. We propose that ovarian hormones sensitize sensory and motor pathways necessary for sexual behavior and stimulation to induce reward.

Background Proprotein convertase 5/6 (PC6) is critical for endometrial epithelial receptivity and stromal cell decidualization for embryo implantation in women. We hypothesized that inhibiting PC6 could block implantation for contraception. The aim of this study was to prove this concept using human cell models and rabbits. Study Design A potential PC6 inhibitor, C1239-PEG-Poly R, was biochemically confirmed to be a potent PC6 inhibitor. The potential contraceptive action of the inhibitor was then tested in decidualization of primary human endometrial stromal cells in a human trophoblast spheroid attachment model and in vivo in rabbits. Results The PC6 inhibitor C1239-PEG-Poly R inhibited in a dose-dependent manner both decidualization and spheroid attachment. Vaginal delivery of 200 μL of the inhibitor at a final concentration of 5 mM to rabbits over a 3-day period starting 6 days after mating resulted in a 60% decrease in implantation and, hence, pregnancy. Conclusions This study presents proof of concept that PC6 inhibition has the potential to block embryo implantation, providing nonhormonal contraception for women.

The hypothesis that levonorgestrel (LNG) used as an emergency contraceptive interferes with endometrial receptivity remains unproven. We compared the endometrial gene expression profile during the receptive period after administering a single dose of LNG 1.5 mg or placebo on day 1 of the luteal phase. An endometrial biopsy was done on day LH+7 or LH+8 and samples were taken from seven volunteers, each one contributing with one cycle treated with placebo and another with LNG. The expression of 20 383 genes was determined using cDNA microarrays. Real-time RT-PCR was used 1) to confirm the differences found in DNA microarray analysis and 2) to determine the effect of LNG on transcript levels ofC3,C4BPα,COX2,MAOA,S100A4, andSERPINB9, known to be upregulated during receptivity, and on cPLA2α,JAK1,JNK1,CTSL1, andGSTP1, known to respond to mifepristone. Additional endometrial biopsies were done during the pre-receptive (LH+3) and receptive (LH+7) period and samples were taken from eight untreated volunteers in order to determine the changes associated with acquisition of receptivity of 14 genes. Mean levels ofPAEP,TGM2,CLU,IGF2, andIL6STmRNAs increased after administering LNG while those ofHGD,SAT1,EVA1,LOC90133,ANXA1,SLC25A29,CYB5A,CRIP1, andSLC39A14decreased. Except for the level ofANXA1transcript, all changes remained within the range observed in untreated controls, and none of the transcripts responding to mifepristone changed in response to LNG. Post-ovulatory administration of LNG caused minimal changes in gene expression profiling during the receptive period. Neither the magnitude nor the nature or direction of the changes endorses the hypothesis that LNG interferes with endometrial receptivity.

Summary 1. The aim of the present study was to investigate the effect of the cannabinoid antagonist/inverse agonist SR 141716 (SR) on the receptive behaviour and sexual motivation of female rats. 2. Partner preference, receptivity and proceptivity were evaluated in ovariectomized female rats primed with oestrogen and progesterone and administered SR (1 or 2.5 mg/kg, i.p.) 20 min prior to testing. 3. In the partner preference test, a reduced interest in both stimulus animals (a sexually active male and an ovariectomized hormone-primed female) was detected in rats treated with SR at both doses, but no effect on preference score was observed. In the receptivity test, pronounced reductions in lordosis quotient, lordosis rating and in the percentage of receptive females were found in SR-treated rats compared with control rats. Proceptive behaviours were not significantly affected by either dose of SR. 4. In addition, we explored the behavioural effects induced by SR in female rats using the open field test. Only at the higher dose (i.e. 2.5 mg/kg) did SR markedly increased grooming and scratching behaviour. 5. The results demonstrate the ability of SR to reduce female sexual receptivity, but not sexual motivation. The reduction does not seem strictly related to the motor alterations induced by the cannabinoid antagonist.

Understanding of ectopic implantation within the Fallopian tube (FT) is limited. In the human uterus, the putative ‘window of implantation’ in the mid-luteal phase of the menstrual cycle is accompanied by increased endometrial epithelial expression of the integrins α1β1, α4β1 and αvβ3 and its ligand osteopontin. Similar cyclical changes in FT integrin expression have been proposed to contribute to ectopic implantation, but supporting data are limited. In the current study, we present quantitative data on human FT transcription and translation of the integrin subunits α1, α4, αV, β1 and β3 during the follicular and mid-luteal phases of the menstrual cycle, together with a supporting immuocytochemical analysis of their spatial distribution within the FT, and that of osteopontin. In contrast to previous studies, our data indicate that all five integrin receptivity markers are constitutively transcribed and translated in the FT, with no evidence for changes in their expression or distribution during the window of implantation in the mid-luteal phase of the cycle. Furthermore, we could find no evidence for cyclic redistribution of the integrin αvβ3 ligand osteopontin within the FT. Although we do not rule out the involvement of integrin endometrial receptivity markers in the establishment of ectopic pregnancy, our findings do not support their differential expression during a tubal implantation window.

The intensity and duration of sexual behavior in Bos indicus was assessed through the continuous observation of sexual receptivity. Two groups of cows were formed: only synchronized (n = 50) and other group further superovulated (n = 20). An intravaginal implant that released progesterone over 9 d was used. After removing the implant, 25 mg of PGF2α was administered. In the superovulated group, the administration of 280 mg (Follicle stimulant hormone) FSH-P1 per cow with a decreasing dosage over 4 d was utilized. In both groups, behavioral observations began at the moment of implant removal. Sexual behavior was analyzed using a Kruskal-Wallis test to compare the mean of hours in estrus, effective mountings and number of mounts/hour during estrus. A nonparametric survival analysis was performed using the time in two ways: i) when an event happened it was placed in a 24 h time frame and, ii) the time of observation in continuous form (96 h) assessing the difference between curves by the log rank test Chi-square. The only significant difference was the number of mounts/h during receptivity (p

The ovarian hormones estrogen and progesterone are required for the complete display of sexual behavior in female rats. Paced mating produces a reward state in intact cycling and ovariectomized (OVX), hormonally primed females as evaluated by the conditioned place preference (CPP) paradigm. Most of the studies that have evaluated CPP induced by paced mating in OVX females have used relatively high doses of estradiol benzoate (EB). In the present study we determined if different doses of EB, combined with progesterone (P), could induce CPP after paced mating. For this purpose OVX female rats were divided in five groups that received one of different doses of estradiol benzoate (5, 2.5, 1.25 or 0.625 μg estradiol + 0.5 mg of progesterone) before being allowed to pace the sexual interaction and conditioned in a CPP paradigm. We found that the lowest dose of EB used (0.625 μg) significantly reduced the lordosis quotient and the lordosis coefficient. Even though these females paced the sexual interaction, they didn't change its original preference, suggesting that sexual interaction did not induce a positive affective, reward state. Females allowed to pace the sexual interaction with higher doses of EB developed CPP after paced mating. These results indicate that a threshold of estradiol is required for paced mating to induce CPP.

Background A sizable proportion of essential tremor (ET) patients suffer from medically-refractory ET. Although deep brain stimulation (DBS) surgery is a safe and highly effective treatment, it may be under-utilized. We are unaware of studies that assess ET patients’ attitudes toward DBS surgery and the factors that motivate them toward or away from such surgery. Methods ET cases, enrolled in an ongoing clinical–pathological study, underwent an in-person evaluation. They were asked “What is the likelihood that you would allow yourself to have DBS surgery?”, thus rating their ‘surgical receptivity’ from 0 to 100. Results One-third (47/146, 32.2%) of ET cases reported that they would consider DBS surgery. In univariate analyses, younger age ( p = 0.017), self-reported embarrassment ( p = 0.001), more depressive symptoms ( p = 0.008), more dysthymia ( p = 0.029), higher total tremor score (marginal p = 0.13) and lower burden of medical comorbidity (marginal p = 0.16) were associated with greater surgical receptivity. In multivariate logistic regression models, only self-reported embarrassment ( p = 0.006) and, marginally, younger age ( p = 0.059) were independently associated with surgical receptivity. Conclusions We identified a number of factors that were associated with increased receptivity to DBS surgery. Interestingly, psychosocial variables (dysthymia, depressive symptoms, self-reported embarrassment) featured prominently among these factors; indeed, self-reported embarrassment was the most robust factor. Tremor severity, though associated in univariate analyses with increased surgical receptivity, was not as robust of a predictor as was self-reported embarrassment. Future studies, which are community-based as well as those which also assess the patient’s level of understanding about DBS will further add to the literature on this topic.

Rather than being a static, species specific trait, reproductive behavior in female amphibians is variable within an individual during the breeding season when females are capable of reproductive activity. Changes in receptivity coincide with changes in circulating estrogen. Estrogen is highest at the point when females are ready to choose a male and lay eggs. At this time female receptivity (her probability of responding to a male vocal signal) is highest and her selectivity among conspecific calls (measured by her probability of responding to a degraded or otherwise usually unattractive male signal) is lowest. These changes occur even though females retain the ability to discriminate different acoustic characteristics of various conspecific calls. After releasing her eggs, female amphibians quickly become less receptive and more choosy in terms of their responses to male sexual advertisement signals. Male vocal signals stimulate both behavior and estrogen changes in amphibian females making mating more probable. The changes in female reproductive behavior are the same as those generally accepted as indicative of a change in female sexual arousal leading to copulation. They are situationally triggered, gated by interactions with males, and decline with the consummation of sexual reproduction with a chosen male. The changes can be triggered by either internal physiological state or by the presence of stimuli presented by males, and the same stimuli change both behavior and physiological (endocrine) state in such a way as to make acceptance of a male more likely. Thus amphibian females demonstrate many of the same general characteristics of changing female sexual state that in mammals indicate sexual arousal.

The impact of gonadotropin-releasing hormone (GnRH) agonist long compared with GnRH antagonist protocols, under in vitro fertilization conditions on endometrial receptivity, is still debated. Therefore, we compared the effect of both GnRH antagonist and agonist long protocols on the endometrial receptivity by analyzing, to our knowledge for the first time, the global gene expression profile shift during the prereceptive and receptive stages of stimulated cycles under the two GnRH analogue protocols compared with natural cycles in the same patients. For the same normal-responder patients, endometrial biopsies were collected on the day of oocyte retrieval and on the day of embryo transfer after human chorionic gonadotropin administration of a stimulated cycle with either GnRH agonist long or GnRH antagonist protocols and compared with the prereceptive and receptive stages of a natural cycle. Samples were analyzed using DNA microarrays. Gene expression profiles and biological pathways involved during the prereceptive stage to the receptive endometrial transition of stimulated and natural cycles were analyzed and compared for each patient. Both protocols affect endometrial receptivity in comparison with their natural cycle in the same patients. Major differences in endometrial chemokines and growth factors under stimulated cycles in comparison with natural cycles were observed. Such an effect has been associated with gene expression alterations of endometrial receptivity. However, the endometrial receptivity under the GnRH antagonist protocol was more similar to the natural cycle receptivity than that under the GnRH agonist protocol.