Efficacy of dehydroepiandrosterone to overcome the effect of ovarian ageing (DITTO): a proof of principle randomised controlled trial protocol

Introduction: Dehydroepiandrosterone (DHEA) has been proposed to improve pregnancy rates in women with diminished ovarian reserve undergoing in vitro fertilisation (IVF) treatment. However, evidence regarding its efficacy is supported by a limited number of randomised controlled trials (RCTs). This doubleblinded RCT aims to measure the effect of DHEA supplementation prior to and during controlled ovarian hyperstimulation on ovarian response prior to IVF treatment in women predicted to have poor ovarian reserve. Methods and analysis: Sixty women with ovarian antral follicle count ≤10 and serum anti-Mullerian hormone ≤5 pmol/L undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment at the Nurture fertility clinic, Nottingham will be recruited. They will be randomised to either receive DHEA capsule 75 mg/day or placebo for at least 12 weeks before egg collection. All participants will undergo standard long down regulation protocol using human menopausal gonadotropin 300 IU/day. Serum samples and follicular fluids at the time of egg collection will be collected for hormonal immunoassays. For ICSI participants, cumulus cells stripped from oocyte will be collected for cumulus gene expression analyses regarding oocyte competence. Microdrops of oocyte culture media before the time of ICSI will be assessed for glucose, pyruvate and lactate utilisation. Embryo transfer will be performed on day 2, 3 or 5 based on the number and quality of the embryos available. Pregnancy will be defined as urine pregnancy test positive (biochemical pregnancy) and 6–8 weeks ultrasound scan with fetal heart beat (clinical pregnancy) and live birth. It is planned to perform the molecular and nutritional fingerprint analyses in batches after finishing the clinical phase of the study. Ethics and dissemination: The approval of the study was granted by the NHS Research Ethics Committee (Ref number NRES 12/EM/0002), the Medicines and Healthcare products Regulatory Agency (MHRA), and the Nottingham University Hospitals Trust Research and Development department. All participants shall provide written informed consent before being randomised into allocated treatment groups

Efficacy of dehydroepiandrosterone (DHEA) to overcome the effect of ovarian ageing (DITTO): a proof of principle double blinded randomized placebo controlled trial

Objective: To evaluate the effect of DHEA supplementation on In-Vitro Fertilisation (IVF) outcome as assessed by ovarian response, oocyte developmental competence and live birth rates in women predicted to have poor ovarian reserve (OR). The feasibility of conducting a large trial is also assessed by evaluating the recruitment rates and compliance of the recruited participants with DHEA/placebo intake and follow-up rates. Study design: A single centre, double blinded, placebo controlled, randomized trial was performed over two years with 60 women undergoing in-vitro fertilisation (IVF). Subjects were randomized, based on a computer-generated pseudo-random code to receive either DHEA or placebo with both capsules having similar colour, size and appearance. 60 women with poor OR based on antral follicle count or anti-Mullerian hormone thresholds undergoing IVF were recruited. They were randomised to receive DHEA 75 mg/day or placebo for at-least 12 weeks before starting ovarian stimulation. They had long protocol using hMG 300 IU/day. Data analysed by “intention to treat”. Ovarian response, live birth rates and molecular markers of oocyte quality were compared between the study and control groups. Results: The recruitment rate was 39% (60/154). A total of 52 participants (27 versus 25 in the study and placebo groups) were included in the final analysis after excluding eight. While the mean (standard deviation) DHEA levels were similar at recruitment (9.4 (5) versus 7.5 (2.4) ng/ml; P = 0.1), the DHEA levels at pre-stimulation were higher in the study group than in the controls (16.3 (5.8) versus 11.1 (4.5) ng/ml; P < 0.01). The number (median, range) of oocytes retrieved (4, 0–18 versus 4, 0–15 respectively; P = 0.54) and live birth rates (7/27, 26% versus 8/25, 32% respectively; RR (95% CI): 0.74 (0.22-2.48) and mRNA expression of developmental biomarkers in granulosa and cumulus cells were similar between the groups. Conclusion: Pre-treatment DHEA supplementation, albeit statistical power in this study is low, did not improve the response to controlled ovarian hyperstimulation or oocyte quality or live birth rates during IVF treatment with long protocol in women predicted to have poor OR

A nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges

<p>Abstract</p> <p>Background</p> <p>Advances in childhood cancer treatment over the past decades have significantly improved survival, resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affect reproductive function. This paper describes the design and encountered methodological challenges of a nationwide study in the Netherlands investigating the effects of treatment on reproductive function, ovarian reserve, premature menopause and pregnancy outcomes in female childhood cancer survivors (CCS), the DCOG LATER-VEVO study.</p> <p>Methods</p> <p>The study is a retrospective cohort study consisting of two parts: a questionnaire assessing medical, menstrual, and obstetric history, and a clinical assessment evaluating ovarian and uterine function by hormonal analyses and transvaginal ultrasound measurements. The eligible study population consists of adult female 5-year survivors of childhood cancer treated in the Netherlands, whereas the control group consists of age-matched sisters of the participating CCS. To date, study invitations have been sent to 1611 CCS and 429 sister controls, of which 1215 (75%) and 333 (78%) have responded so far. Of these responders, the majority consented to participate in both parts of the study (53% vs. 65% for CCS and sister controls respectively). Several challenges were encountered involving the study population: dealing with bias due to the differences in characteristics of several types of (non-) participants and finding an adequately sized and well-matched control group. Moreover, the challenges related to the data collection process included: differences in response rates between web-based and paper-based questionnaires, validity of self-reported outcomes, interpretation of clinical measurements of women using hormonal contraceptives, and inter- and intra-observer variation of the ultrasound measurements.</p> <p>Discussion</p> <p>The DCOG LATER-VEVO study will provide valuable information about the reproductive potential of paediatric cancer patients as well as long-term survivors of childhood cancer. Other investigators planning to conduct large cohort studies on late effects may encounter similar challenges as those encountered during this study. The solutions to these challenges described in this paper may be useful to these investigators.</p> <p>Trial registration</p> <p>NTR2922; <url>http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922</url></p

Effects of dehydroepiandrosterone on in vivo ovine follicular development

STUDY QUESTION: What are the effects of exposure of ovarian tissue to dehydroepiandrosterone (DHEA) supplementation in vivo? SUMMARY ANSWER:DHEA exposure stimulates initiation of primordial follicles and development of gonadotrophin-responsive preantral/early antral follicles possibly mediated through promoting granulosa cell proliferation and enhancing anti-Mullerian hormone (AMH) expression. WHAT IS KNOWN ALREADY? Ovarian ageing is a cause of subfertility and is associated with poor outcomes of IVF treatment and premature menopause. A few clinical studies have shown that DHEA can improve ovarian response and increase the chances of pregnancy after IVF treatment in women with a diminished ovarian reserve (DOR) suggesting DHEA may help to overcome the effect of ovarian ageing. However, there are no data about how DHEA acts on ovarian folliculogenesis. STUDY DESIGN, SIZE AND DURATION: A cortical autograft experimental model was conducted in six female sheep aged at least 24 months. The period of DHEA treatment in the animals lasted for 10 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: All the animals were subjected to unilateral oophorectomy. Half of the ovary was fixed for histological analysis as a time-zero control. The remaining tissue was used to isolate patches of ovarian cortex which were autografted back onto the ovarian pedicle. The grafting procedure eradicated all growing follicles and synchronized early follicular development. After a 10-week treatment period with DHEA implants, the ewes were sacrificed and the graft and remaining ovary were harvested. Histological and immunohistochemistry (IHC) findings, accompanied with serum hormonal profiles were compared to determine the effect on the follicle population. MAIN RESULTS AND THE ROLE OF CHANCE: Higher proportions of the follicle population in the remaining ovary were observed to be in the antral stage after DHEA treatment. The observation coincided with an increase in the rate of primordial follicle initiation and preantral follicle development in cortical grafts and the remaining ovarian tissue, respectively. The IHC results indicated that DHEA increased the expression of both the proliferation marker (KI-67) in granulosa cells and the follicular AMH expression at the preantral and early antral follicle stages. LIMITATIONS, REASONS FOR CAUTION: The experimental design compared follicle populations before and after DHEA treatment within individual animals to allow changes over time to be detected against a background of high inter-animal variation. However, since no controls without DHEA were included, we cannot say what would have happened over time in its absence, and it is possible that other factors may have resulted in the changes in follicle development observed during the experiment. WIDER IMPLICATIONS OF THE FINDING: Our data supports the idea that DHEA might be a useful therapy to delay the effects of ovarian ageing. Therefore, it may have a role as an adjunct during IVF to improve ovarian response in women with DOR and as a treatment for premature ovarian insufficiency

Pv Single Phase Grid Connected Converter Using Fuzzy Pid Controller

This paper proposes the Single phase multy stage&nbsp; grid interfaced Photo Voltaic System. The primary stage is DC-DC Booster stage which is governed &nbsp;by a MPPT system. Output voltage of Booster stage is controlled by Incremental conductance&nbsp; algorithm .Depending upon the solar Irradiation and temperature the output voltage of&nbsp; PV panel is varied. By MPPT the maximum power is drawn from the PV system and fed to Inverter stage. This stage controls the power flow to the grid. The proposed control will reduce the voltage ripple in DC link voltage. The conversion efficiency of Inverter will decrease due to ripples in DC link voltage ,because it it will cause an excessive stress on the IGBTs or MOSFETs. This also results harmonics in the grid current. This paper describes &nbsp;an efficient and reliable&nbsp; control technique , Fuzzy Proportional Integral Differential (FPID) for stabilizing the DC- link voltage. PV Array output is varied with variations in solar irradiation, temperature and shadow that means Photo Voltaic &nbsp;system is&nbsp; nonlinear. The change of plant parameters will not affect the proposed control technique. In&nbsp; this proposed scheme, power flow and THD levels&nbsp; are analyzed at different DC-link voltage. This study describes that this&nbsp; control technique have a capability to maintain a same grid current THD at transient and steady state conditions. Comparing to conventional PID control the % THD is small. Minimum settling time and Fast DC-link voltage stabilization are also shown in this paper by this control technique. Finally the proposed system offers an excellent dynamic performance for reducing the DC-link voltage ripples and stabilization that is verified in MATLAB simulink too

Electrocoagulation versus suture after laparoscopic stripping of ovarian endometriomas assessed by antral follicle count: preliminary results of randomized clinical trial

PURPOSE: The assessment of ovarian reserve by antral follicle count (AFC) following electrocoagulation versus suture after laparoscopic stripping of ovarian endometriomas. ----- METHODS: Forty-five patients between 18 and 35 years, with unilateral endometriomas were randomly analyzed. Laparoscopic cystectomy was performed by the stripping method. Ovarian hemostasis was obtained either by suturing (group A, n = 23) or by bipolar electrocoagulation (group B, n = 22). AFC was performed by ultrasound on the third day of the three postoperative menstrual cycles. The sum of AFC was compared between sutured (A1) and electrocoagulated (B1) ovaries, as well as between intact ovaries of both groups (A0: intact ovaries in sutured group, B0: intact ovaries in electrocoagulated group). ----- RESULTS: The median of AFC was significantly lower in operated ovaries than in intact ovaries in both groups of patients, regardless of suturing [A1 median: 12 (range 9-19) vs. A0 median: 21.0 (range 15-27), p < 0.05] or electrocoagulation [B1: 5.0 (2-10) vs. B0: 18.5 (8-29), p < 0.05]. The median AFC was significantly higher in sutured ovaries than in electrocoagulated ovaries [A1: 12 (9-19) vs. B1: 5.0 (2-10), p < 0.05]. ----- CONCLUSION: Our preliminary data show that operation on ovarian endometriomas could reduce ovarian reserve. The AFC value suggests that the ovarian reserve was less reduced in sutured ovaries than in those electrocoagulated. Suturing as a method of hemostasis could be a better choice after stripping ovarian endometriomas