Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles

To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the quiescence of primordial follicles. In mutant mice lacking the Tsc1 gene in oocytes, the entire pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in the oocyte, ending up with follicular depletion in early adulthood and causing premature ovarian failure (POF). We further show that maintenance of the quiescence of primordial follicles requires synergistic, collaborative functioning of both Tsc and PTEN (phosphatase and tensin homolog deleted on chromosome 10) and that these two molecules suppress follicular activation through distinct ways. Our results suggest that Tsc/mTORC1 signaling and PTEN/PI3K (phosphatidylinositol 3 kinase) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. Deregulation of these signaling pathways in oocytes results in pathological conditions of the ovary, including POF and infertility

Improvement in cognitive and psychosocial functioning and self image among adolescent inpatient suicide attempters

BACKGROUND: Psychiatric treatment of suicidal youths is often difficult and non-compliance in treatment is a significant problem. This prospective study compared characteristics and changes in cognitive functioning, self image and psychosocial functioning among 13 to 18 year-old adolescent psychiatric inpatients with suicide attempts (n = 16) and with no suicidality (n = 39) METHODS: The two-group pre-post test prospective study design included assessments by a psychiatrist, a psychologist and medical staff members as well as self-rated measures. DSM-III-R diagnoses were assigned using the SCID and thereafter transformed to DSM-IV diagnoses. Staff members assessed psychosocial functioning using the Global Assessment Scale (GAS). Cognitive performance was assessed using the Wechsler Adult Intelligence Scale, while the Offer Self-Image Questionnaire (OSIQ) was used to assess the subjects' self-image. ANCOVA with repeated measures was used to test changes from entry to discharge among the suicide attempters and non suicidal patients. Logistic regression modeling was used to assess variables associated with an improvement of 10 points or more in the GAS score. RESULTS: Among suicide attempter patients, psychosocial functioning, cognitive performance and both the psychological self and body-image improved during treatment and their treatment compliance and outcome were as good as that of the non-suicidal patients. Suicidal ideation and hopelessness declined, and psychosocial functioning improved. Changes in verbal cognitive performance were more pronounced among the suicide attempters. Having an improved body-image associated with a higher probability of improvement in psychosocial functioning while higher GAS score at entry was associated with lower probability of functional improvement in both patient groups. CONCLUSION: These findings illustrate that a multimodal treatment program seems to improve psychosocial functioning and self-image among severely disordered suicidal adolescent inpatients. There were no changes in familial relationships, possibly indicating a need for more intensive family interventions when treating suicidal youths. Multimodal inpatient treatment including an individual therapeutic relationship seems recommendable for severely impaired psychiatric inpatients tailored to the suicidal adolescent's needs

Bone Marrow Transplantation Restores Follicular Maturation and Steroid Hormones Production in a Mouse Model for Primary Ovarian Failure

Recent studies suggest that bone marrow stem cells (BMSCs) are promising grafts to treat a variety of diseases, including reproductive dysfunction. Primary ovarian failure is characterized by amenorrhea and infertility in a normal karyotype female, with an elevated serum level of follicle-stimulating hormone (FSH) and a decrease level of estrogen caused by a mutation in FSH receptor (FSHR) gene. Currently, there is no effective treatment for this condition. The phenotype of FSHR (−/−) mouse, FORKO (follitropin receptor knockout), is a suitable model to study ovarian failure in humans. Female FORKO mice have elevated FSH, decreased estrogen levels, are sterile because of the absence of folliculogenesis, and display thin uteri and small nonfunctional ovaries. In this study, we determined the effects of BMSC transplantation on reproductive physiology in this animal model. Twenty four hours post BMSC transplantation, treated animals showed detectable estroidogeneic changes in daily vaginal smear. Significant increase in total body weight and reproductive organs was observed in treated animals. Hemotoxylin and eosin (H&E) evaluation of the ovaries demonstrated significant increase in both the maturation and the total number of the follicles in treated animals. The FSH dropped to 40–50% and estrogen increased 4–5.5 times in the serum of treated animals compared to controls. The FSHR mRNA was detected in the ovaries of treated animals. Our results show that intravenously injected BMSCs were able to reach the ovaries of FORKO mice, differentiate and express FHSR gene, make FSHR responsive to FSH, resume estrogen hormone production, and restore folliculogenesis

Biological versus chronological ovarian age:implications for assisted reproductive technology

<p>Abstract</p> <p>Background</p> <p>Women have been able to delay childbearing since effective contraception became available in the 1960s. However, fertility decreases with increasing maternal age. A slow but steady decrease in fertility is observed in women aged between 30 and 35 years, which is followed by an accelerated decline among women aged over 35 years. A combination of delayed childbearing and reduced fecundity with increasing age has resulted in an increased number and proportion of women of greater than or equal to 35 years of age seeking assisted reproductive technology (ART) treatment.</p> <p>Methods</p> <p>Literature searches supplemented with the authors' knowledge.</p> <p>Results</p> <p>Despite major advances in medical technology, there is currently no ART treatment strategy that can fully compensate for the natural decline in fertility with increasing female age. Although chronological age is the most important predictor of ovarian response to follicle-stimulating hormone, the rate of reproductive ageing and ovarian sensitivity to gonadotrophins varies considerably among individuals. Both environmental and genetic factors contribute to depletion of the ovarian oocyte pool and reduction in oocyte quality. Thus, biological and chronological ovarian age are not always equivalent. Furthermore, biological age is more important than chronological age in predicting the outcome of ART. As older patients present increasingly for ART treatment, it will become more important to critically assess prognosis, counsel appropriately and optimize treatment strategies. Several genetic markers and biomarkers (such as anti-Müllerian hormone and the antral follicle count) are emerging that can identify women with accelerated biological ovarian ageing. Potential strategies for improving ovarian response include the use of luteinizing hormone (LH) and growth hormone (GH). When endogenous LH levels are heavily suppressed by gonadotrophin-releasing hormone analogues, LH supplementation may help to optimize treatment outcomes for women with biologically older ovaries. Exogenous GH may improve oocyte development and counteract the age-related decline of oocyte quality. The effects of GH may be mediated by insulin-like growth factor-I, which works synergistically with follicle-stimulating hormone on granulosa and theca cells.</p> <p>Conclusion</p> <p>Patients with biologically older ovaries may benefit from a tailored approach based on individual patient characteristics. Among the most promising adjuvant therapies for improving ART outcomes in women of advanced reproductive age are the administration of exogenous LH or GH.</p

New insight into rheology and flow properties of complex fluids with Doppler optical coherence tomography

Flow properties of complex fluids such as colloidal suspensions, polymer solutions, fiber suspensions and blood have a vital function in many technological applications and biological systems. Yet, the basic knowledge on their properties is inadequate for many practical purposes. One important reason for this has been the lack of effective experimental methods that would allow detailed study of the flow behavior of especially opaque multi-phase fluids. Optical Coherence Tomography (OCT) is an emerging technique capable of simultaneous measurement of the internal structure and motion of most opaque materials, with resolution in the micrometer scale and measurement frequency up to 100 kHz. This mini-review will examine the recent results on the use of Doppler-OCT in the context of flows and rheological properties of complex fluids outside biomedical field