Regulation of functional and regressing stages of corpus luteum development in mice. Role of reactive oxygen species

2008 ◽  
Vol 20 (7) ◽  
pp. 760 ◽  
Author(s):  
Valeria A. Sander ◽  
Lidia Piehl ◽  
Graciela B. Facorro ◽  
Emilio Rubín de Celis ◽  
Alicia B. Motta

The endocrine and immune systems modulate ovarian function. The aim of the present work was to compare the status of various modulating factors in two well-defined stages of corpus luteum (CL) development (the functional stage and the regressing stage) by means of a gonadotropin-synchronised mouse model. At the regressing stage of CL development, we found that ovarian tissue showed increased prostaglandin (PG) F2α and diminished PGE levels concomitantly with enhanced protein abundance of ovarian cyclooxygenase 2, the inducible isoform of the limiting enzyme of PG synthesis. We also found both enhanced lipid peroxidation and enhanced total superoxide dismutase activity, as well as inhibited catalase activity and inhibited total hydroxyl radical scavenger capacity, when compared with ovaries at the functional stage. In addition, at the regressing stage we observed an increased percentage of CD8+ (cytotoxic/suppressor) T-cells and a decreased percentage of CD4+ (helper) T-cells from ovarian-draining lymph nodes. Also, the serum interleukin (IL)-2, IL-4 and IL-10 were diminished as compared with the functional stage. We conclude that a pro-oxidant status together with a pro-inflammatory response is responsible for the loss of luteal function.

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
A Volodarsky-Perel ◽  
M Zajicek ◽  
D Shai ◽  
H Raanani ◽  
N Gruber ◽  
...  

Abstract Study question What is the predictive value of ovarian reserve evaluation in patients with non-iatrogenic primary ovarian insufficiency (NIPOI) for follicle detection in ovarian tissue harvested for cryopreservation? Summary answer Ovarian tissue cryopreservation (OTCP) should be considered if patients present at least one of the following parameters: detectable AMH, FSH≤20mIU/ml, detection of ≥ 1 antral follicle. What is known already In pre-pubertal girls suffering from NIPOI, which majorly has a genetic etiology, fertility preservation using OTCP is commonly practiced. When OTCP was performed in an unselected group of children and adolescents with NIPOI, only 26% of them had follicles in ovarian tissue while 74% did not benefit from the surgery. The role of preoperative evaluation of anti-müllerian hormone (AMH) serum level, follicular stimulating hormone (FSH) serum level, and trans-abdominal ultrasound for the antral follicle count to predict the detection of primordial follicles in the harvested ovarian tissue is unclear. Study design, size, duration We conducted a retrospective analysis of all patients ≤ 18 years old who were referred for fertility preservation counseling due to NIPOI at a single tertiary hospital between 2010 and 2020. If initial evaluation suggested a diminished ovarian reserve and at least one positive parameter indicating a follicular activity (AMH > 0.16ng/ml, FSH ≤ 20mIU/ml, detection of ≥ 1 antral follicle by transabdominal sonography), OTCP was offered. Patients with 46XY gonadal dysgenesis were excluded. Participants/materials, setting, methods OTCP was performed laparoscopically in all cases. A fresh sample of cortical tissue was fixed in buffered formaldehyde for histological analysis. The rest of the ovarian tissue was cut into small cuboidal slices 1–2 mm in thickness and cryopreserved. After the serial sections, the histological slides were evaluated for the presence of follicles by a certified pathologist. Follicles were counted and categorized as primordial, primary, and secondary. Main results and the role of chance During the study period, 39 patients with suspected NIPOI were referred to the fertility preservation center. Thirty-seven patients included in the study were diagnosed with Turner’s syndrome (n = 28), Galactosemia (n = 3), Blepharophimosis-Ptosis-Epicanthus Inversus syndrome (n = 1), and idiopathic NIPOI (n = 6). Of 28 patients with Turner’s syndrome, 6 had 45X monosomy, 15 had mosaicism and 7 had structural anomalies in X-chromosome. One patient with gonadal dysgenesis and one with the presence of Y-chromosome in 20% of somatic cells were excluded from the study. OTCP was conducted in 14 patients with at least one positive parameter suggesting ovarian function. No complications of the surgical procedure or the anesthesia were observed. Primordial follicles were found in all patients with two or three positive parameters (100%) and in three of six cases with one positive parameter (50%). In total, of the 14 patients who underwent OTCP with at least one positive parameter, 11 (79%) had primordial follicles at biopsy (mean 23.9, range 2–47). This study demonstrates a positive predictive value of 79% for the detection of primordial follicles in patients who had at least one positive parameter of ovarian reserve evaluation. If two or three parameters were positive, the positive predictive value increased to 100%. Limitations, reasons for caution This study did not examine the negative predictive value of our protocol as OTCP was not recommended in the absence of positive parameters. The future fertility potential of cryopreserved tissue in the population with NIPOI is unclear and should be discovered in further studies. Wider implications of the findings: We suggest the evaluation of ovarian reserve by antral follicles count, AMH, and FSH serum levels prior to OTCP in patients with NIPOI. By recommendation of OTCP only if ≥ 1 parameter suggesting the ovarian function is positive, unnecessary procedures can be avoided. Trial registration number Not applicable


2019 ◽  
Vol 31 (1) ◽  
pp. 82 ◽  
Author(s):  
José-Alfonso Abecia ◽  
Fernando Forcada ◽  
María-Isabel Vázquez ◽  
Teresa Muiño-Blanco ◽  
José A. Cebrián-Pérez ◽  
...  

Melatonin is a natural hormone synthesised in the pineal gland, the activity of which is regulated by day–night perception and dictates seasonal rhythms in reproduction in ovine species. Exogenous melatonin, administered via subcutaneous implants, is used to prolong the breeding season of ewes and can increase the proportion of pregnant ewes (fertility rate) and litter size. The increased proportion of ewes that become pregnant and the number of lambs born per lambing among melatonin-treated sheep may be caused by increased embryo survival, through enhanced luteal function, reduced antiluteolytic mechanisms, or improved embryo quality. This review focuses on the effects of melatonin on embryo viability and summarises the processes by which this hormone affects the ovary, follicle, oocyte, corpus luteum and embryo. Moreover, the effects of melatonin on the mechanisms of invivo maternal recognition of pregnancy in sheep and the protective action that it appears to have on the invitro procedures that are used to obtain healthy embryos are reviewed.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17019-e17019
Author(s):  
Valeria Bandovkina ◽  
Elena Mikhaylovna Frantsiyants ◽  
Nailya Guskova ◽  
Tatiana Moiseenko ◽  
Marina Vovkochina ◽  
...  

e17019 Background: The purpose of the study was to analyze hormonal disorders in tissues of histologically unchanged ovaries of patients with cervical cancer infected with HPV/Chlamydia trachomatis. Methods: We studied levels of estrone (E1), estradiol (E2), free estriol (E3), free (fT) and total (T) testosterone, progesterone (P4), steroid-binding globulin (SBG) and prolactin (PRL) by the ELISA in intact ovaries of 25 patients aged 53.4±3.2 years with cervical cancer T1b-2aN0M0. HPV presence was determined by Е7 protein expression, Chlamydia trachomatis (Ch. tr.) – by IgG and IgА to Ch. tr. and antigen/DNA by ELISA and Real-time PCR. Tissues of intact ovaries obtained during hysterectomy from 22 non-infected women of similar age with endometrial cancer T1N0M0 were used as the control. Results: The data demonstrated a sharp decrease in E2 level by 9.3 times and increase in E1 by 2.3 times in intact ovaries of cervical cancer patients infected with HPV and Ch. tr., compared with the values in controls. Changes were noted in the balance between some estrogen fractions: E1 percentage increased by 5 times, E3 – by 2.4 times and E2 percentage decreased by 4 times. Androgenic status in intact ovaries in cervical cancer was characterized with increased levels of T (by 5.1 times) and fT (by 1.6 times). We noted an increase in SBG concentration by more than 3 times in response to the release of androgens registered in ovarian tissue, as well as significant (by 4.4 times) increase in PRL and decrease in P4 by 1.5 times compared with non-infected tissues. Estrogens to P4 ratio in co-infected patients reduced by 1.6 times, while the PRL to P4 ratio increased by 6.4 times, mainly due to disorders in hormone-producing ovarian function. Conclusions: The development of malignant process in the cervix in a combined HPV and Chlamydia trachomatis infection is accompanied by disorders of the endocrine status in tissues of intact ovaries and shows the undeniable role of consequences of HPV/Chlamydia trachomatis coinfection in this process.


1989 ◽  
Vol 121 (3) ◽  
pp. 417-425 ◽  
Author(s):  
M. L. Swahn ◽  
M. Bygdeman ◽  
S. A. Matlin ◽  
Z. Y. Wu

Abstract. The aim of the present study was to investigate the effects of tamoxifen on pituitary and luteal function and on the bleeding pattern when administered continuously in the secretory phase. The study included 16 women with regular menstrual cycles followed during one control, one treatment and one follow-up cycle. Each volunteer received 20 mg tamoxifen twice daily from cycle day 18 to menstruation in the treatment cycle. The luteal phase was slightly, but significantly prolonged during treatment, and FSH, progesterone, 17-hydroxyprogesterone, 20α-dihydro progesterone, estrone, estrone sulphate and estradiol significantly elevated in comparison with corresponding data during the control cycle. The results indicate that estrogen may be of some importance for the regulation of the life span of the corpus luteum in the human. The significantly elevated levels of pregnanediol glucuronide and estrone glucuronide during the follow-up cycle are most likely a result of either a direct effect of remaining circulating tamoxifen levels on the ovary, or mediated through the increased release of FSH. If estrogens are of importance for the process of implantation, which has recently been suggested in subhuman primates, also in the human remains unclear. Studies on the effect of anti-estrogens on the endometrium during the secretory phase of the cycle are ongoing.


1990 ◽  
Vol 125 (2) ◽  
pp. 279-285 ◽  
Author(s):  
K. Taya ◽  
S. Sasamoto

ABSTRACT The role of the adrenal gland in the regulation of gonadotrophin and prolactin secretion in the lactating rat was investigated. Changes in secretion of LH, FSH, prolactin, ACTH, β-lipotrophin (β-LPH), inhibin, corticosterone and progesterone after adrenalectomy were examined during the second half of lactation. Follicular maturation was determined by the ability of the follicles to ovulate in response to 10IU human chorionic gonadotrophin (hCG). Adrenalectomy on day 10 of lactation prevented an increase in plasma concentrations of LH and FSH in response to ovariectomy performed at the same time as adrenalectomy, and markedly stimulated secretion of ACTH, β-LPH and prolactin. Adrenalectomy reduced the number of follicles capable of ovulating in response to hCG. Concentrations of inhibin and progesterone in the plasma significantly decreased after adrenalectomy, indicating that development of ovulatory follicles and luteal function had been suppressed. Abolishing the increase in plasma concentrations of LH and inducing a decrease in FSH in the plasma by adrenalectomy therefore prevented maturation of a new set of follicles usually seen during the second half of lactation in rats. The decrease in plasma concentrations of LH also inhibited the ability of the corpus luteum to secrete progesterone, although high concentrations of plasma prolactin were maintained in adrenalectomized lactating rats. These results indicate that the pituitary-adrenal system is capable of influencing the maintenance of a normal secretion of gonadotrophin and prolactin as well as the maintenance of ovarian function during lactation in the rat. Journal of Endocrinology (1990) 125, 279—285


Reproduction ◽  
2017 ◽  
Vol 153 (6) ◽  
pp. R187-R204 ◽  
Author(s):  
Dallas A Vanorny ◽  
Kelly E Mayo

The Notch pathway is a contact-dependent, or juxtacrine, signaling system that is conserved in metazoan organisms and is important in many developmental processes. Recent investigations have demonstrated that the Notch pathway is active in both the embryonic and postnatal ovary and plays important roles in events including follicle assembly and growth, meiotic maturation, ovarian vasculogenesis and steroid hormone production. In mice, disruption of the Notch pathway results in ovarian pathologies affecting meiotic spindle assembly, follicle histogenesis, granulosa cell proliferation and survival, corpora luteal function and ovarian neovascularization. These aberrations result in abnormal folliculogenesis and reduced fertility. The knowledge of the cellular interactions facilitated by the Notch pathway is an important area for continuing research, and future studies are expected to enhance our understanding of ovarian function and provide critical insights for improving reproductive health. This review focuses on the expression of Notch pathway components in the ovary, and on the multiple functions of Notch signaling in follicle assembly, maturation and development. We focus on the mouse, where genetic investigations are possible, and relate this information to the human ovary.


2018 ◽  
Vol 30 (1) ◽  
pp. 192
Author(s):  
R. Carrasco ◽  
C. E. Leonardi ◽  
J. Singh ◽  
G. P. Adams

Neurotrophins are molecules involved in the development and survival of neurons and its cellular projections. Results of recent studies have implicated the local role of the high affinity neurotropin receptor, trkA, in bovine ovarian follicle selection and early luteogenesis (Carrasco et al. 2016 Reprod. Biol. Endocrinol. 14, 47), but innervation and neuropeptide control remains an unexplored aspect of ovarian function. P75 is the low-affinity receptor for all neurotrophins and is expressed in ovarian tissue. The objective of this study was to explore the distribution of P75 neurons and fibres within the ovary and to examine the relationship of these components with follicular development. The ovaries of cows (n = 5) were collected at the time of slaughter, 36 h after induced luteolysis (i.e. proestrus). The ovaries were fixed in 4% paraformaldehyde for 48 h, and samples from the ovarian hilus, medulla, and cortex (3 blocks per ovary) were cryo-sectioned (20–50 µm). Tissue sections were incubated for 48 h with a rabbit antibody against rat P75 or a mouse monoclonal antibody against neurofilament. Immunodetection was visualised by an amplification procedure with horseradish peroxidase using nickel DAB as a chromogen. Sections were counterstained with nuclear fast red for follicle identification. Immunoreactive cell bodies were counted in 10 to 20 fields (40×) per section, and data were expressed based on ovarian areas (cortex, medulla, or hilus) as an average count per 40× field per animal. Data among ovarian regions were compared by ANOVA; differences were considered significant when P < 0.05. Antral follicles ≤5 mm displayed strong immunoreactivity in the theca layer, without reaction in the granulosa cells. In contrast, preovulatory follicles were devoid of P75 immuno-reactivity in the theca layer. Oval P75 immunoreactive neuron-like cells were present in all ovarian areas studied. The neuronal nature of the P75 immunoreactive cells was confirmed by the presence of a similar pattern when adjacent sections were stained for neurofilaments, a protein characteristic of neurons. In the stroma of the ovarian cortex and medulla, neurons were present individually (scattered) rather than grouped; however, a dense network of neurons and fibres was detected immediately beneath the ovarian surface epithelium. No differences between the cortex, medulla, and hilus were found in the mean number of immunoreactive cells (10.6 ± 2.8, 14.4 ± 3.6 and 13.9 ± 2.0 cells/40× field, respectively). Immunoreactive neuron-like cells and fibres were in close proximity to blood vessels in the ovarian medulla. Corpora lutea were devoid of P75 immunoreactivity. In conclusion, results document the existence of a neuronal network in the bovine ovary, displaying an association with follicles at different stages of development. The abundance of neuronal components (i.e. neuron cell bodies and axons) in the ovarian stromal and surface epithelium implies a role of innervation (either extrinsic or intrinsic) in the control of ovarian follicular development and function. Research was supported by the Natural Sciences and Engineering Research Council of Canada.


1999 ◽  
pp. 93-107 ◽  
Author(s):  
M A Nash ◽  
G Ferrandina ◽  
M Gordinier ◽  
A Loercher ◽  
R S Freedman

Normal ovarian tissue is rich in cytokines. Cytokines and chemokines are important in the physiology of ovarian function and of ovulation. Cytokines and chemokines may recruit cytokine-producing lymphocytes to the site of a developing follicle, and cytokines appear to play an important role in pre and post follicle development. Most of the same cytokines that are found in normal ovarian tissue are also found in association with malignancy in contrast to their functions in normal tissues. It is reasonable to assume that the functions of cytokines associated with malignancy may serve to promote the unregulated growth if tumor cells and metastasis. It is also likely that cytokines produced by tumors will modulate immune responses that favor tumor progression. In the following review, we have highlighted those functions of cytokines that have been identified as having the most significant impact on tumor growth and development. By examining activities of these cytokines in normal and in malignant ovarian tissues, it is hoped that future possible avenues for investigation may be opened up and that the results of these investigations will lead to strategies that can modulate the production or the activity of the cytokines leading to the growth of tumors or their metastases. Such strategies now fall under the general discipline of bioimmunotherapy. This is an expanding discipline as more is learned about growth regulation in cancer, and with the availability and rapid development of new molecules for therapeutic approaches.


Reproduction ◽  
2006 ◽  
Vol 131 (3) ◽  
pp. 591-602 ◽  
Author(s):  
Valeria Sander ◽  
Carolina Griselda Luchetti ◽  
María Emilia Solano ◽  
Evelin Elia ◽  
Guillermo Di Girolamo ◽  
...  

The present study investigated the role of the N, N{′ }-dimethylbiguanide metformin (50 mg/100 g body weight in 0.05 ml water, given orally with a canulla) in the prevention of endocrine and immune disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The treatment with DHEA (6 mg/100 g body weight in 0.1 ml oil) for 20 consecutive days, recreates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA did not modify either body mass index (BMI) or blood glucose levels, but did increase fasting insulin levels when compared with controls. Markers of ovarian function – serum estradiol (E), progesterone (P) and ovarian prostaglandin E (PGE) – were evaluated. The treatment with DHEA increased serum E and P levels while ovarian PGE diminished. When metformin was administered together with DHEA, serum insulin, E and P levels, and ovarian PGE values did not differ when compared with controls. Using flow cytometry assays we found that the treatment with DHEA diminished the percentage of the CD4 + T lymphocyte population and increased the percentage of the CD8 + T lymphocyte population from both ovarian tissue and retroperitoneal lymph nodes. However, when metformin was administered together with DHEA, the percentages of CD4 + and CD8 + T lymphocyte populations from both ovarian tissue and retroperitoneal lymph nodes were similar to those observed in controls. Finally, when DHEA was administered alone it increased the serum tumor necrosis factor-alpha (TNF-α ) levels when compared with controls; however, when metformin was administered together with DHEA, serum TNF-α levels were similar to controls. These results indicate that metformin is able, directly or indirectly, to avoid the endocrine and immune alterations produced when mice are hyperandrogenized with DHEA.


2013 ◽  
Vol 305 (7) ◽  
pp. E845-E852 ◽  
Author(s):  
Anne Bachelot ◽  
Nadège Carré ◽  
Olivier Mialon ◽  
Melody Matelot ◽  
Nathalie Servel ◽  
...  

Transgenic female mice overexpressing the hCGβ subunit (hCGβ+) and producing elevated levels of luteinizing hormone (LH)/hCG bioactivity present as young adults with enhanced ovarian steroidogenesis, precocious puberty, and infertility. They subsequently develop pituitary prolactinomas, high circulating prolactin (PRL) levels, and marked mammary gland lobuloalveolar development followed by adenocarcinomas. None of these phenotypes appear in gonadectomized mice, indicating that the hCG-induced aberrations of ovarian function are responsible for the extragonadal phenotypes. PRL receptor-deficient (PRLR−/−) female mice are sterile, despite ovulating, due to a failure of embryo implantation, as a consequence of decreased ovarian LH receptor (Lhcgr) expression and inadequate corpus luteum formation and progesterone production. To study further the presumed permissive role of PRL in the maintenance of gonadal responsiveness to LH/hCG stimulation, we crossed the hCGβ+ and PRLR−/− mice. The double-mutant hCGβ+/PRLR−/− females remained sterile with an ovarian phenotype similar to PRLR−/− mice, indicating that LH action, Lhcgr expression, and consequent luteinization are not possible without simultaneous PRL signaling. The high frequency of pituitary prolactinomas in PRLR−/− mice was not affected by transgenic hCGβ expression. In contrast, none of the hCGβ+/PRLR−/− females showed either mammary gland lobuloalveolar development or tumors, and the increased mammary gland Wnt-5b expression, possibly responsible for the tumorigenesis in hCGβ+ mice, was absent in double-mutant mice. Hence, high LH/hCG stimulation is unable to compensate for missing PRL signaling in the maintenance of luteal function. PRL thus appears to be a major permissive regulator of LH action in the ovary and of its secondary extragonadal effects.


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