Ovarian Physiology Research Articles

Hypoxia-Inducible Factor inhibition affects luteal function with no effect on fertility in mice.

Hypoxia-inducible factors (HIFs) are transcription factors responsible for sensing low oxygen levels and, in response, inducing the transcription of numerous genes. One of the main processes stimulated by HIFs is the formation of new vessels to increase oxygen supply to the tissue. Formation of the corpus luteum strongly depends on the vasculature and an active angiogenesis occurs during luteinization. In this study, we aimed to analyze the role of HIF in corpora lutea early formation and function, and in female fertility. To this aim, we superovulated mice by eCG and hCG, and administered the HIF inhibitor acriflavine (ACF) to the mice 3 h before hCG. We found a decrease in ovarian HIF1A and VEGFA, and in the vascular area in the animals treated with ACF. Moreover, we observed an increase in aberrant structures in the ovaries and in luteal cell apoptosis. Serum progesterone levels were decreased together with ovarian STAR expression. However, the animals treated with ACF during the early formation of the corpus luteum were completely fertile and no alterations were observed when the treated females were mated with fertile males. These results collectively suggest that HIF regulates gonadotropin-induced corpus luteum formation acting on luteal blood vessel formation, luteal cell survival, and progesterone synthesis. However, adequate HIF activity may not be essential to achieve and maintain pregnancy. These findings are significant to better understand the complex mechanisms of corpus luteum formation and identify potential abnormalities to allow better knowledge of ovarian physiology and pathologies in which this factor could be involved.

Immune system regulation of physiological and pathological aspects of the ovarian follicle pool throughout the female reproductive lifespan.

The immune system plays a major role in ovarian physiology by regulating the ovarian follicle pool through complex signaling of different growth factors, cytokines, and chemokines. These may promote follicle activation and further growth but could also trigger follicle atresia and clearance of aging or damaged cells within the ovarian cortex. Moreover, extraglandular steroidogenesis potentially occurring in different immune cells like macrophages and natural killer cells might be another way of modulating follicle growth. Ovarian macrophages have recently been found to contain two different populations, namely resident macrophages and monocyte-derived cells, with potentially different roles. The immune system also plays a role in the development of pathological conditions, including premature ovarian insufficiency (POI). Indeed, autoimmune activation against various ovarian antigen targets results in lymphocytic oophoritis mainly targeting early growing follicles, but later leading to complete follicle pool depletion. Immune-mediated ovarian damage may also be caused by viral infection or be the consequence of iatrogenic damage. Certain novel cancer immunotherapies like checkpoint inhibitors have recently been shown to induce ovarian reserve damage in a murine model. Studies are needed to corroborate these findings and further investigate the potential of newly developed immunotherapies to treat POI. Technological advances such as single-cell analyses of less represented cell populations like immune cells inside the ovary are now contributing to valuable new information, which will hopefully lead to the development of new therapeutic strategies for women with fertility issues.

The Functions and Application Prospects of Hepatocyte Growth Factor in Reproduction.

Hepatocyte growth factor (HGF) is expressed in multiple systems and mediates a variety of biological activities, such as mitosis, motility, and morphogenesis. A growing number of studies have revealed the expression patterns and functions of HGF in ovarian and testicular physiology from the prenatal to the adult stage. HGF regulates folliculogenesis and steroidogenesis by modulating the functions of theca cells and granulosa cells in the ovary. It also mediates somatic cell proliferation and steroidogenesis, thereby affecting spermatogenesis in males. In addition to its physiological effects on the reproductive system, HGF has shown advantages in preclinical studies over recent years for the treatment of male and female infertility, particularly in women with premature ovarian insufficiency. This review aims to summarize the pleiotropic functions of HGF in the reproductive system and to provide prospects for its clinical application.

Role of IL-6 in Physiology and Pathology of the Ovary

Objective: We aimed to explore the roles of interleukin (IL)-6 in ovarian physiology and pathology. Mechanism: IL-6 is a common and important cytokine in numerous physiological and pathological processes. Findings in Brief: In the ovary, IL-6 is secreted by granulosa cells, and involved in many crucial physiological functions, including normal ovulation and menstrual cycle, hormone secretion, egg cell maturation, and even in the fertilization process of egg cells. The abnormal secretion of IL-6 is associated with premature ovarian failure, polycystic ovary syndrome and ovarian cancer. Conclusions: This review will summarize existing clues and explore the key roles of IL-6 in ovarian physiology and pathology, which will provide new targets for the treatment of common ovarian diseases.

MiR-29b inhibits COC expansion and oocyte in vitro maturation via induction of ROS by targeting CYCS

Cumulus-oocyte complex (COC) expansion and oocyte maturation are crucial processes for embryo development and fertility across species. Although miR-29b has been detected in porcine ovarian granulosa cells, its specific role in regulating oocyte maturation remains largely unknown. In this study, using the pig as a model, we report that over-expression of miR-29b lead to a decrease of COC expansion area and inhibits oocyte maturation (P<0.05). This suppression correlated with a decrease expression of COC-expansion-associated genes, including SHAS2, ADAMTS1, ADAMTS2, ADAMTS17 and PTX 3 in both mural granulosa cells (mGCs) and cumulus granulosa cells (cGCs). Further investigation revealed that miR-29b over-expression induces reactive oxygen species (ROS) accumulation in both mGCs and cGCs, conversely, knock-down of miR-29b reverses all these effects. Treatment with the antioxidant β-mercaptoethanol alleviates ROS accumulation, rescues COC expansion and restores oocyte polar body formation impaired by miR-29b mimics. Computational analysis predicted CYCS, the gene encoding cytochrome C, as a potential target of miR-29b. Subsequent examination demonstrated that miR-29b downregulates CYCS at both mRNA and protein levels. Dual-luciferase reporter assays further confirmed that miR-29b interacts with the 3’-untranslated region (3’UTR) of CYCS. Over-expression of CYCS decreases ROS accumulation and promotes COC expansion (P<0.05). These results indicate that miR-29b regulates COC expansion and oocyte maturation in vitro by inducing ROS, likely through targeting of CYCS. This study sheds light on the role of miR-29b in oocyte maturation and provides insight into the regulatory function of miRNAs in ovarian physiology.

Intraovarian Platelet-Rich Plasma Administration for Anovulatory Infertility: Preliminary Findings of a Prospective Cohort Study.

Background/Objectives: Infertility constitutes a significant challenge for couples around the world. Ovarian dysfunction, a major cause of infertility, can manifest with anovulatory cycles, elevated follicle-stimulating hormone levels, and diminished ovarian reserve markers such as anti-Müllerian hormone (AMH) levels or the Antral Follicle Count (AFC). Blood-derived therapies including platelet-rich plasma (PRP) have been used in fertility treatments in women with low ovarian reserve or premature ovarian insufficiency. This prospective clinical cohort study aims to assess the effects of intraovarian PRP therapy on ovarian function in women diagnosed with anovulatory cycles. Methods: The preliminary findings of this prospective cohort study are based on the first 32 patients enrolled. In this study, patients over 40 years old with anovulatory infertility were included. Venous blood samples were collected from each participant for the preparation of autologous platelet-rich plasma (PRP). Each participant received two courses of intraovarian PRP injections using a transvaginal ultrasound-guided approach. Serum levels of reproductive hormones before and after PRP intervention were measured. Results: This study's results demonstrate a significant improvement in ovarian physiology following transvaginal ultrasound-guided PRP infusion. A 75% increase in Antral Follicle Count (AFC) was observed, which was statistically significant. Furthermore, statistically significant reductions in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin levels were observed. Serum Vitamin D 1-25 levels were substantially increased after the injection. Conclusions: These findings highlight the beneficial impact of intraovarian PRP injection in optimizing ovarian function and other metabolic parameters. However, the published literature on this subject is limited and further clinical studies should be conducted to confirm the role of intraovarian PRP in fertility treatments.

Elucidating metformin action on the ovary and fertility in healthy mice.

The hypoglycemic drug metformin has shown reproductive effects in women, although its mechanism of action is not fully understood. In this study, we demonstrate the direct effects of metformin on the ovary of healthy mice, with no alterations in fertility. Metformin is a hypoglycemic drug widely used in type-2 diabetes (T2D) patients. In recent years, this drug has been suggested as a treatment for gestational diabetes and recommended to women with ovarian hyperstimulation syndrome (PCOS) to increase the chances of pregnancy or avoid early miscarriages. However, the exact effects of metformin on the female reproductive tract in general, and on the ovary in particular, are still not completely understood. In this study, we analyzed the effect of metformin on fertility and ovarian physiology in healthy female mice. We found that this drug altered the estrous cycle, early follicular development, serum estradiol and progesterone levels, and ovarian steroidogenic enzyme expression. Moreover, ovarian angiogenesis was lower in metformin-treated animals compared with untreated ones, whereas natural or gonadotropin-induced fertilization rates remained unchanged. However, offspring of metformin-treated animals displayed decreased body weight at birth. In this work, we unraveled the main effects of metformin on the ovary, isolated from other conditions such as hyperglycemia and hyperandrogenism, which is essential for a better understanding of metformin's mechanisms of action on reproduction and fertility.

The evolution of ovarian somatic cells characterized by transcriptome and chromatin accessibility across rodents, monkeys, and humans

Abstract The ovary plays a crucial role in the reproductive system of female mammals by producing mature oocytes through folliculogenesis. Non-human model organisms are extensively utilized in research on human ovarian biology, thus necessitating the investigation of conservation and divergence in molecular mechanisms across species. In this study, we employed integrative single-cell analysis of transcriptome and chromatin accessibility to identify the evolutionary conservation and divergence patterns of ovaries among humans, monkeys, mice, rats, and rabbits. Our analyses revealed that theca cells exhibited the most significant changes during evolution based on scRNA-seq and scATAC-seq datasets. Furthermore, we discovered common cis-regulatory architectures in theca cells across species by conducting joint analyses of scRNA-seq and scATAC-seq datasets. These findings have potential applications in non-human biomedical and genetic research to validate molecular mechanisms found in human organisms. Additionally, our investigation into non-coding genomic regions identified intergenic highly transcribed regions (igHTRs) that may contribute to the evolution of species-specific phenotypic traits. Overall, our study provides valuable insights into understanding the molecular characteristics of adult ovaries while offering new perspectives for studying human ovarian physiology and diseases.

Lower Serum ATG7 Levels Linked to Insulin Resistance in Women with Polycystic Ovary Syndrome.

BACKGROUND Previous studies have suggested that autophagy, a cellular process regulated by ATG7, plays a critical role in ovarian physiology and pathology. In this study, our objective was to examine ATG7 levels in women with and without polycystic ovary syndrome (PCOS) and to explore potential associations between serum ATG7 levels and PCOS. MATERIAL AND METHODS The study included 188 women diagnosed with PCOS, matched with an equal number of healthy women for comparison. Serum levels of ATG7 were determined using the ELISA technique, and the difference was assessed using an independent samples t test. The association between ATG7 serum levels and the risk of developing PCOS was evaluated by using a multivariable logistic regression model. Additionally, the potential of ATG7 to predict PCOS was investigated through logistic regression and receiver operating characteristic (ROC) analysis. RESULTS Our study found that women with PCOS had significantly lower serum ATG7 levels than their healthy counterparts. Lower ATG7 levels were associated with a higher risk of developing PCOS after adjusting for various confounding variables. The combination of ATG7 with HOMA-IR performed well in predicting PCOS, with an AUC of 92.3%, a sensitivity of 88.3%, and a specificity of 85.3%. CONCLUSIONS Our study found that serum ATG7 levels were significantly lower in women with PCOS and were associated with an increased risk of developing PCOS. This suggests that ATG7 could potentially serve as a biomarker for diagnosing and managing PCOS.

Potential exacerbation of polycystic ovary syndrome by saccharin sodium Via taste receptors in a letrozole rat model

The most common cause of anovulatory infertility is polycystic ovarian syndrome (PCOS), which is closely associated with obesity and metabolic syndrome. Artificial sweetener, notably saccharin sodium (SS), has been utilized in management of obesity in PCOS. However, accumulating evidence points towards SS deleterious effects on ovarian physiology, potentially through activation of ovarian sweet and bitter taste receptors, culminating in a phenotype reminiscent of PCOS. This research embarked on exploration of SS influence on ovarian functions within a PCOS paradigm. Rats were categorized into six groups: Control, Letrozole-model, two SS groups at 2 dose levels, and two groups receiving 2 doses of SS with Letrozole. The study underscored SS capability to potentiate PCOS-related anomalies. Elevated cystic profile with outer thin granulosa cells, were discernible. This owed to increased apoptotic markers as cleaved CASP-3, mirrored by high BAX and low BCL-2, with enhanced p38-MAPK/ERK1/2 pathway. This manifestation was accompanied by activation of taste receptors and disruption of steroidogenic factors; StAR, CYP11A1, and 17β-HSD. Thus, SS showed an escalation in testosterone, progesterone, estrogen, and LH/FSH ratio, insinuating a perturbation in endocrine regulation. It is found that there is an impact of taste receptor downstream signaling on ovarian steroidogenesis and apoptosis instigating pathophysiological milieu of PCOS.

MicroRNAs are involved in ovarian physiology of greater amberjack (Seriola dumerili) under captivity

Gonad maturation is critical for the reproductive success of any organism, and in fish, captivity can significantly affect their reproductive performance, leading to maturation incompetence and spawning failure. The greater amberjack (Seriola dumerili), a fish species recently introduced to aquaculture fails to undergo oocyte maturation, ovulation, and spawning when reared in aquaculture facilities. Since confinement has been shown to influence gonad maturation and completion of the reproductive cycle, investigations into epigenetic mechanisms may shed light on the reasoning behind the reproductive dysfunctions of fish under captivity. Among the known important epigenetic regulators are small non-coding RNAs (sncRNAs), and in particular microRNAs (miRNAs). In this study, immature, maturing (late vitellogenesis), and spent ovaries of captive greater amberjack were collected, and the differential expression of miRNAs in the three different ovarian development stages was examined. Expression patterns of conserved and novel miRNAs were identified, and potential targets of highly differentially expressed miRNAs were detected. Additionally, read length distribution showed two prominent peaks in the three different ovarian maturation stages, corresponding to miRNAs and putative piwi-interacting RNAs (piRNAs), another type of ncRNAs with a germ-cell specific role. Furthermore, miRNA expression patterns and their putative target mRNAs are discussed, in relevance with the different ovarian maturation stages of captive greater amberjack. Overall, this study provides insights into the role of miRNAs in the reproductive dysfunctions observed in fish under captivity and highlights the importance of epigenetic mechanisms in understanding and managing the reproductive performance of economically important fish species.

Serum androgen dynamics in young women aged 18-40 treated with chemotherapy for breast cancer: an observational, multicentric, prospective study in France

Although the deleterious impact of chemotherapy regimen used to treat women of reproductive age with breast cancer on ovarian reserve has been extensively studied, hardly anything has been reported on the effect of these protocols on theca cell function and ovarian androgen secretion. The aim of this prospective multicentric cohort study was to describe serum levels of total testosterone and androstenedione during chemotherapy and 24-month follow-up in 250 patients <40 years treated for breast cancer. Mean basal levels of androstenedione and total testosterone at diagnosis were 1.68 ng/mL and 0.20 ng/mL respectively. No correlation with age was found. Serum levels of androstenedione and total testosterone rapidly decreased after chemotherapy completion, before slowly increasing and almost returning to basal levels in all patients during 2-year follow-up. In conclusion our study demonstrates a chemotherapy-induced alteration of ovarian thecal function, resulting in a significant decrease in serum androgen levels. This alteration of theca cell function adds to the well-known alteration of granulosa cell function, resulting in a global, but partly transient, ovarian failure in young women treated for breast cancer. These data bring new insight into ovarian physiology and emphasize the need for pre and post-treatment ovarian follow-up. Trial registration: ClinicalTrial.gov identifier NCT01114464

P-671 Modelling human follicle growth and development during ovarian stimulation: a physiological computational approach

Abstract Study question Can key elements of ovarian physiology be accurately modelled, thereby providing a tool to generate novel insights and guide development of new therapeutics? Summary answer A physiological computational model was developed to describe follicle growth and follicle size distributions observed in agonist and antagonist ovarian stimulation (OS) protocols. What is known already The outcome of OS remains unpredictable despite identification of several prognostic factors. The average first cycle pregnancy rate is 30-40% across fertility centres, highlighting the need for improved stimulation protocols. This is an active area of clinical research; however, clinical trials are costly, time-consuming, and frequently have outcomes that are unexpected or difficult to interpret. We integrated available physiological knowledge of human follicle growth and development and clinical trial data into a computational model to enable in silico simulations with the aim to optimise clinical trial design. Study design, size, duration Computational model building was performed using a mechanistic approach aimed at capturing well-understood physiology that is relevant in OS protocols. Model inputs included patient characteristics (such as anti-Müllerian hormone (AMH) level), OS regimen and pituitary downregulation with gonadotrophin releasing hormone (GnRH) agonist or antagonist. Key outputs of the model included follicle number and mean size, duration of stimulation and serum hormone concentrations (oestradiol, testosterone, inhibin B and androstenedione). Participants/materials, setting, methods Published physiological data on regulation of follicle development and hormone production informed model design. Following implementation of the model in the Python platform, data from two OS clinical trials were used to calibrate (partially censored) and test the model. The two trials provided data on the effects of the recombinant follicle stimulating hormone preparation follitropin delta over a range of fixed doses and compared the effects of follitropin delta in agonist and antagonist OS protocols. Main results and the role of chance The computational model describes the interplay between pituitary gonadotrophins ovarian steroid hormones and follicle growth and development. Processes spanning the cellular level (such as steroidogenesis and receptor dynamics in theca and granulosa cells), the ovaries (follicle number and size) and the organism (pharmacokinetics and hypothalamic-pituitary-ovarian axis) are included as a system of coupled differential equations. Approximately 70 compartments, 500+ parameters and 1700+ reactions constitute the model framework. Follicles are recruited in the model at variable times, starting from 7 days prior to the start of stimulation. Follicles are initialised with individual sensitivity to gonadotrophins and growth rates. The fate of each follicle (dominance or atresia) is governed by these properties, which determine whether the balance shifts towards proliferation or atresia under the influence of gonadotrophins. Model-simulated numbers of follicles, their average size and mean serum hormone concentrations match closely with observed values in the two clinical trials. For each of these variables, their dependence on time, the dose of follitropin delta, AMH level and downregulation protocol were described with good precision. The inter-patient variability in the simulated number of follicles and in serum hormone levels matched closely with the observed variability based on comparison of the interquartile range. Limitations, reasons for caution The computational model currently describes follicle development during treatment with follitropin delta. We envision extending the model to encompass other treatment outcomes and additional preparations of exogenous gonadotrophins. While the model incorporates our current understanding of mechanisms important for follicle development, ongoing research in the field will likely drive improvements. Wider implications of the findings The computational model is hypothesis-generating and can improve the design of future clinical trials through in silico trial simulation. For instance, the effects of changing subject inclusion/exclusion criteria or of novel dosing regimens can be investigated. Trial registration number NCT01426386, NCT03809429

Increased Vasoactive Intestinal Peptide (VIP) in polycystic ovary syndrome patients undergoing IVF.

Polycystic ovary syndrome (PCOS) is a common multifactorial and polygenic disorder of the endocrine system, affecting up to 20% of women in reproductive age with a still unknown etiology. Follicular fluid (FF) represents an environment for the normal development of follicles rich in metabolites, hormones and neurotransmitters, but in some instances of PCOS the composition can be different. Vasoactive intestinal peptide (VIP) is an endogenous autonomic neuropeptide involved in follicular atresia, granulosa cell physiology and steroidogenesis. ELISA assays were performed to measure VIP and estradiol levels in human follicular fluids, while AMH, FSH, LH, estradiol and progesterone in the plasma were quantified by chemiluminescence. UHPLC/QTOF was used to perform the untargeted metabolomic analysis. Our ELISA and metabolomic results show: i) an increased concentration of VIP in follicular fluid of PCOS patients (n=9) of about 30% with respect to control group (n=10) (132 ± 28 pg/ml versus 103 ± 26 pg/ml, p=0,03) in women undergoing in vitro fertilization (IVF), ii) a linear positive correlation (p=0.05, r=0.45) between VIP concentration and serum Anti-Müllerian Hormone (AMH) concentration and iii) a linear negative correlation between VIP and noradrenaline metabolism. No correlation between VIP and estradiol (E2) concentration in follicular fluid was found. A negative correlation was found between VIP and noradrenaline metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPGAL) in follicular fluids. VIP concentration in follicular fluids was increased in PCOS patients and a correlation was found with noradrenaline metabolism indicating a possible dysregulation of the sympathetic reflex in the ovarian follicles. The functional role of VIP as noradrenergic modulator in ovarian physiology and PCOS pathophysiology was discussed.

Neonicotinoids differentially modulate nicotinic acetylcholine receptors in immature and antral follicles in the mouse ovary†.

Neonicotinoids are the most widely used insecticides in the world. They are synthetic nicotine derivatives that act as nicotinic acetylcholine receptor agonists. Although parent neonicotinoids have low affinity for the mammalian nicotinic acetylcholine receptor, they can be activated in the environment and the body to positively charged metabolites with high affinity for the mammalian nicotinic acetylcholine receptor. Imidacloprid, the most popular neonicotinoid, and its bioactive metabolite desnitro-imidacloprid differentially interfere with ovarian antral follicle physiology in vitro, but their effects on ovarian nicotinic acetylcholine receptor subunit expression are unknown. Furthermore, ovarian nicotinic acetylcholine receptor subtypes have yet to be characterized in the ovary. Thus, this work tested the hypothesis that ovarian follicles express nicotinic acetylcholine receptors and their expression is differentially modulated by imidacloprid and desnitro-imidacloprid in vitro. We used polymerase chain reaction, RNA in situ hybridization, and immunohistochemistry to identify and localize nicotinic acetylcholine receptor subunits (α2, 4, 5, 6, 7 and β1, 2, 4) expressed in neonatal ovaries (NO) and antral follicles. Chrnb1 was expressed equally in NO and antral follicles. Chrna2 and Chrnb2 expression was higher in antral follicles compared to NO and Chrna4, Chrna5, Chrna6, Chrna7, and Chrnb4 expression was higher in NO compared to antral follicles. The α subunits were detected throughout the ovary, especially in oocytes and granulosa cells. Imidacloprid and desnitro-imidacloprid dysregulated the expression of multiple nicotinic acetylcholine receptor subunits in NO, but only dysregulated one subunit in antral follicles. These data indicate that mammalian ovaries contain nicotinic acetylcholine receptors, and their susceptibility to imidacloprid and desnitro-imidacloprid exposure varies with the stage of follicle maturity.

Shear wave elastography to assess stiffness of the human ovary and other reproductive tissues across the reproductive lifespan in health and disease†.

The ovary is one of the first organs to show overt signs of aging in the human body, and ovarian aging is associated with a loss of gamete quality and quantity. The age-dependent decline in ovarian function contributes to infertility and an altered endocrine milieu, which has ramifications for overall health. The aging ovarian microenvironment becomes fibro-inflammatory and stiff with age, and this has implications for ovarian physiology and pathology, including follicle growth, gamete quality, ovulation dynamics, and ovarian cancer. Thus, developing a non-invasive tool to measure and monitor the stiffness of the human ovary would represent a major advance for female reproductive health and longevity. Shear wave elastography is a quantitative ultrasound imaging method for evaluation of soft tissue stiffness. Shear wave elastography has been used clinically in assessment of liver fibrosis and characterization of tendinopathies and various neoplasms in thyroid, breast, prostate, and lymph nodes as a non-invasive diagnostic and prognostic tool. In this study, we review the underlying principles of shear wave elastography and its current clinical uses outside the reproductive tract as well as its successful application of shear wave elastography to reproductive tissues, including the uterus and cervix. We also describe an emerging use of this technology in evaluation of human ovarian stiffness via transvaginal ultrasound. Establishing ovarian stiffness as a clinical biomarker of ovarian aging may have implications for predicting the ovarian reserve and outcomes of Assisted Reproductive Technologies as well as for the assessment of the efficacy of emerging therapeutics to extend reproductive longevity. This parameter may also have broad relevance in other conditions where ovarian stiffness and fibrosis may be implicated, such as polycystic ovarian syndrome, late off target effects of chemotherapy and radiation, premature ovarian insufficiency, conditions of differences of sexual development, and ovarian cancer. Summary sentence: Shear Wave Elastography is a non-invasive technique to study human tissue stiffness, and here we review its clinical applications and implications for reproductive health and disease.

Local effect of allopregnanolone in rat ovarian steroidogenesis, follicular and corpora lutea development

Allopregnanolone (ALLO) is a known neurosteroid and a progesterone metabolite synthesized in the ovary, CNS, PNS, adrenals and placenta. Its role in the neuroendocrine control of ovarian physiology has been studied, but its in situ ovarian effects are still largely unknown. The aims of this work were to characterize the effects of intrabursal ALLO administration on different ovarian parameters, and the probable mechanism of action. ALLO administration increased serum progesterone concentration and ovarian 3β-HSD2 while decreasing 20α-HSD mRNA expression. ALLO increased the number of atretic follicles and the number of positive TUNEL granulosa and theca cells, while decreasing positive PCNA immunostaining. On the other hand, there was an increase in corpora lutea diameter and PCNA immunostaining, whereas the count of TUNEL-positive luteal cells decreased. Ovarian angiogenesis and the immunohistochemical expression of GABAA receptor increased after ALLO treatment. To evaluate if the ovarian GABAA receptor was involved in these effects, we conducted a functional experiment with a specific antagonist, bicuculline. The administration of bicuculline restored the number of atretic follicles and the diameter of corpora lutea to normal values. These results show the actions of ALLO on the ovarian physiology of the female rat during the follicular phase, some of them through the GABAA receptor. Intrabursal ALLO administration alters several processes of the ovarian morpho-physiology of the female rat, related to fertility and oocyte quality.

Serum erythropoietin level is increased during stimulation for IVF but not in OHSS

BackgroundErythropoietin (Epo) is a potent vascular growth factor that induces angiogenesis and antiapoptotic signalling. We investigated whether the development of numerous follicles and corpora lutea during in vitro fertilization (IVF) cycle affects circulating Epo levels and further, if Epo could be used as a novel marker for ovarian hyperstimulation syndrome (OHSS).Methods24 women were included in the uncomplicated IVF group and 35 women in the OHSS group. Repeated blood samples from both groups were analysed for Epo, progesterone, blood haemoglobin, and creatinine. Follicular fluid from the IVF group was analysed for Epo and progesterone. Repeated measure analysis was performed for the variables and circulating Epo levels were compared between the IVF group and early OHSS. Furthermore, related growth factors, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1) were analysed from subgroup of women to test for correlation with Epo.ResultsDuring IVF, circulating Epo increased from natural mid-luteal phase to stimulated mid-luteal phase (median 9.5; 95% CI 7.2–13.4 IU/L and 12.5; 10.3–13.4 IU/L; p = 0.003). In cycles resulting in pregnancy, Epo level decreased 14 days after oocyte pick-up (OPU) and remained low thereafter. In cycles not resulting in pregnancy, Epo level increased again 35 days after OPU. Follicle fluid Epo concentration was 1.5 times higher than the serum concentration (median 15.4; 95% CI 10.4–19.2 IU/L vs. 10.2; 8.8–12.7; p = 0.006). There was no difference in circulating Epo concentration between early OHSS and uncomplicated IVF. Circulating Epo did not correlate with VEGF or HIF-1.ConclusionsCirculating Epo levels fluctuate during IVF cycle. We hypothesise this may suggest Epo’s involvement in ovarian physiology and angiogenesis. However, Epo was not a clinical marker for OHSS.

Insight into vitamin D3 action within the ovary-Basic and clinical aspects.

Vitamin D3 is a fat-soluble secosteroid predominantly synthesized in the skin or delivered with a diet. Nevertheless, recently it is considered more as a hormone than a vitamin due to its pleiotropic function within the organism ensured by widely distributed vitamin D receptors and metabolic enzymes. Besides the main role in calcium and phosphorus homeostasis, vitamin D3 was shown to regulate many cellular and metabolic processes in normal and cancerous tissues within the immune system, the cardiovascular system, the respiratory system and the endocrine system. The ovary is an important extraskeletal tissue of vitamin D3 action and local metabolism, indicating its role in the regulation of ovarian functions upon physiological and pathological conditions. This chapter reviews firstly the updated information about vitamin D3 metabolism and triggered intracellular pathways. Furthermore, the basic information about ovarian physiology and several aspects of vitamin D3 effects within the ovary are presented. Finally, the special attention is paid into possible mechanism of vitamin D3 action within ovarian pathologies such as premature ovarian failure, polycystic ovary syndrome, and ovarian cancer, considering its clinical application as alternative therapy.

The differential sensitivity of the hypothalamic-hypophysial-ovarian axis to 5-hydroxytryptophan alters the secretion of estradiol.

Serotonin [5-hydroxytryptamine (5-HT)] modulates ovarian function. The precursor of 5-HT, 5-hydroxytryptophan (5-HTP), has been used to treat depression. However, the effects of 5-HTP on ovarian and reproductive physiology remain unknown. In this research, we analysed the impact of 5-HTP on the monoaminergic system and its interactions with the reproductive axis and ovarian estradiol secretion when administered by distinct routes. Female rats 30 days of age were injected with 5-HTP i.p. (100mg/kg), into the ovarian bursa (1.5µg/40µL) or into the median raphe nucleus (20µg/2.5µL) and were killed 60 or 120min after injection. As controls, we used rats of the same age injected with vehicle (0.9% NaCl). Monoamine, gonadotrophin and steroid ovarian hormone concentrations were measured. The injection of 5-HTP either i.p. or directly into the ovarian bursa increased the concentrations of 5-HT and the metabolite 5-hydroxyindole-3-acetic acid in the ovary. For both routes of administration, the serum concentration of estradiol increased. After i.p. injection of 5-HTP, the concentrations of luteinizing hormone were decreased and follicle-stimulating hormone increased after 120min. Micro-injection of 5-HTP into the median raphe nucleus increased the concentrations of 5-HT in the anterior hypothalamus and dopamine in the medial hypothalamus after 120min. Our results suggest that the administration of 5-HTP either i.p. or directly into the ovarian bursa enhances ovarian estradiol secretion.