This project explores the implication of the telomere pathway in ovarian premature and regular aging. Telomere length and maintenance underlie several biological processes such cancer, aging, human diseases and the biology of stem cells. The reactivation of telomerase should lead to a rejuvenation of the ovarian tissue and the improvement of fertility. The correlation of telomeric factors in blood and granulosa cells will be studied with the aim of finding telomeric biomarkers of ovarian aging.
This is a pilot study, randomized, controled, blind, parallelo arm clinical trial with inactive substance and medicine. A pilot study will be developed with a total of 45 individuals from 30 to 45 years old, who represent the most frequent population of women seeking for ART. A control group composed of women with normal ovarian reserve (30 to 45 years old) is needed to compare telomeric and fertility parameters with the group of women with compromised ovarian reserve. Women in the control group irrespective of their age, will have a greater number of follicles compared to women belonging to the group with compromised ovarian reserve. A group of women with diminished ovarian reserve that will take an inactive substance has been incluided to avoid biases and to set the fertility base line for women with compromised ovarian reserve. The use of an inactive substance or placebo will help obtain better quality results. For instance, if Danazol happened to improve the fertility outcome, then, there could be a possibility that the IVF improvement might be due to other components of the pill. Using placebo, this possibility would be eliminated, since the placebo will contain all components of the pill, except Danazol. The development of a pilot study will help us understand the statisticl behavior or the telomeric factors as well as to determine the appropriate number of individuals that shoyuld be recruited in a clinical trial to have results with statistical significance. In addition, a pilot study will help us learn errors or undesired events that may happen during the clinical trial. For instance, if patients cannot follow the indications of their doctors and why, or what proportion of patients will drop the study and the reasons for it. Furthermore, it will also help us understand if there exist a tendency, an indication or even a clear beneficial effect for patients without harming them. The number of participants selected for the study is considered adequate for each group, since each group will be measured in an independent manner.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
19
This group will be randomized 1:1 for either inactive substance or Danazol, according to a computer-generated randomization list prepared. Women will be treated with Danazol/Placebo oral way for 3 months.
Women with normal ovarian reserve will not be treated in anyway, thus, randomization will not be necessary.
Ivirma Madrid
Madrid, Spain
Telomere length in granulosa cells
Measured in arbitrary units of fluorescence (a.u.) from 0 to 255 gray intensity (8bit) or Kb (continuous variable). Below 3 kb are considered critically short telomeres in humans.
Time frame: The evaluation of the main assessment criterion will be done both after eighth visit (36 hours post induction) for women with low ovarian reserve and fifth visit for woman with normal ovarian reserve
Accumulation of short telomeres
Measured in arbitrary units of fluorescence (a.u.) from 0 to 255 gray intensity (8bit) or Kb (continuous variable). Below 3 kb are considered critically short telomeres in humans.
Time frame: Through study completion, an average of 1 year
Telomerase activity
Product of PCR amplification, run in acrylamide gels and quantified as band intensity (continuous variable)
Time frame: Through study completion, an average of 1 year
DNA damage measurement
If damage is positive, then different foci should be apparent in the nucleus of the cell. The number of foci present in the nuclei of at least 100 cells will be counted. If there is DNA damage at telomeres, then yH2AX or 53BPI foci will colocalize with telomeres (labelled with anti TRF1 antibody). Spots will be counted (continuous variable).
Time frame: Through study completion, an average of 1 year
Other telomeric factors.
The mRNA expression levels of the telomerase gene and the shelterins, which are involved in telomere lengthening and protection, will be measured by qPCR. (continuous variable).
Time frame: Through study completion, an average of 1 year
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