Genomic instability in individuals with sex determination defects and germ cell cancer.

The ability to transmit genetic information through generations depends on the preservation of genome integrity. Genetic abnormalities affect cell differentiation, causing tissue specification defects and cancer. We addressed genomic instability in individuals with Differences of Sex Development (DSD), characterized by gonadal dysgenesis, infertility, high susceptibility for different types of cancer, especially Germ Cell Tumors (GCT), and in men with testicular GCTs. Whole proteome analysis of leukocytes, supported by specific gene expression assessment, and dysgenic gonads characterization, uncovered DNA damage phenotypes with altered innate immune response and autophagy. Further examination of DNA damage response revealed a reliance on deltaTP53, which was compromised by mutations in the transactivation domain in DSD-individuals with GCT. Accordingly, drug-induced rescue of DNA damage was achieved by autophagy inhibition but not by stabilization of TP53 in DSD-individuals' blood in vitro. This study elucidates possibilities for prophylactic treatments of DSD-individuals, as well as new diagnostic approaches of GCT.

Sex chromosome DSD individuals with mosaic 45,X0 and aberrant Y chromosomes in 46,XY cells: distinct gender phenotypes and germ cell tumour risks§.

"Differences of Sexual Development (DSD)," individuals with rearranged Y chromosome breaks in their 46,XY cells are reported with male and female gender phenotypes and differences in germ cell tumour (GCT) risk. This raised the question of whether male or female gender and GCT risk depends on the site of the break and/or rearrangement of the individual´s Y chromosome. In this paper, we report molecular mapping of the breakpoint on the aberrant Y chromosome of 22 DSD individuals with a 45,X/46,XY karyotype reared with a different gender. Their Y chromosome breaks are found at different sites on the long and short Y arms. Our data indicate that gender rearing is, neither dependent on the site of Y breakage, nor on the amount of 45,X0 cells in the individuals' leukocytes. Most prominent are secondary rearrangements of the Y chromosome breaks forming di-centric Y-structures ("dic-Y"). Duplications of the short Y arm and the proximal part of the long Y arm are the results. A putative GCT risk has been analysed with immunohistochemical experiments on some dysgenetic gonadal tissue sections. With specific antibodies for OCT3/4 expression, we marked the pluripotent germ cell fraction being potential tumour precursor cells. With specific antibodies for DDX3Y, TSPY, and UTY we analyzed their putative Gonadoblastoma Y (GBY) tumour susceptibility function in the same specimen. We conclude GBY expression is only diagnostic for GCT development in the aberrant germ cells of these DSD individuals when strong OCT3/4 expression has marked their pluripotency.

Plausibility of Menstrual Cycle Apps Claiming to Support Conception.

The interval of peak fertility during the menstrual cycle is of limited duration, and the day of ovulation varies, even in women with fairly regular cycles. Therefore, menstrual cycle apps identifying the "fertile window" for women trying to conceive must be quite precise. A deviation of a few days may lead the couple to focus on less- or non-fertile days for sexual intercourse and thus may be worse than random intercourse. The aim of the present investigation was to develop a scoring system for rating available apps for determining the fertile window and secondarily pilot test 12 apps currently available in both German and English (consisting of 6 calendar-based apps: Clue Menstruations- und Zykluskalender, Flo Menstruationskalender, Maya-Mein Periodentracker, Menstruationskalender Pro, Period Tracker Deluxe, and WomanLog-Pro-Kalender; 2 calculothermal apps: Ovy and Natural Cycles; and 4 symptothermal apps: myNFP, Lady Cycle, Lily, and OvuView). The calendar-based apps were investigated by entering several series of cycles with varying lengths, whereas the symptom-based apps were examined by entering data of cycles with known temperature rise, cervical mucus pattern, and clinical ovulation. The main criteria for evaluating the cycle apps were as follows: (1) What methods/parameters were used to determine the fertile window? (2) What study results exist concerning that underlying method/parameters? (3) What study results exist concerning the app itself? (4) Was there a qualified counseling service? The calendar-based apps predicted the fertile days based on data of previous cycles. They obtained zero points in our scoring system, as they did not comply with any of the evaluated criteria. Calculothermal apps had similar deficits for predicting the most fertile days and produced suboptimal results (Ovy 3/30 points and Natural Cycles 2/30 points). The symptothermal apps determined the fertile days based on parameters of the current cycle: Lady Cycle scored 20/30 points, myNFP 20/30 points, Lily 19/30 points, and OvuView 11/30 points. We concluded that the available cycle apps vary according to their underlying scientific quality and clear rating criteria have been suggested. Three of the tested apps were judged to be eligible for further study. The scientific evaluation of cycle apps depends on good prospective studies undertaken by independent investigators who are free of commercial bias.

A new method to detect significant basal body temperature changes during a woman's menstrual cycle.

OBJECTIVE: To compare the results of a computer programme based on the Trigg's tracking system (TTS) identification of the basal body temperature (BBT) shift day from daily records of BBT values (TTS transition day), with the BBT shift day identified from the same records using the Sensiplan(®) symptothermal method of natural family planning. METHODS: A computer programme was written to display the daily BBT readings for 364 menstrual cycles from 51 women aged 24 to 35 years, obtained from the German Natural Family Planning (NFP) database. The TTS transition day so identified from each record was then compared with the BBT shift day estimated from the same record by the Sensiplan(®) method. RESULTS: Total agreement between the methods was obtained for 81% (294/364) of the cycles and 18% (67) cycles differed by ± 1 day. For the 364 pairs of values distributed among 51 women the medians of the differences between the TTS transition day and Sensiplan(®) initial day of the BBT rise (shift day) were not significantly different (χ(2) = 65.28, df = 50, p = 0.07205). CONCLUSION: The advantages of the tracking signal algorithm are that in many cases it was possible to identify the BBT shift day on that very day - rather than only some days later - and to estimate the probability that a transition had occurred from the different values of the tracking signal.

Determination of the fertile window: reproductive competence of women--European cycle databases.

OBJECTIVES: The objective of the present paper is to review the main results of recent European cycle databases on ovulation detection and determination of the fertile window performed by the women themselves. METHODS: The ongoing German Long-term Cycle Database currently comprises 32788 prospectively collected cycle charts of 1551 women, the I European Cycle Database (10 countries) 1328 women/19048 cycles, the II European Cycle Database (six countries) 782 women/6724 cycles, and the World Health Organization Database (one European country) 234 women/2808 cycles. The women record cycle parameters (cervical mucus changes, temperature rise, etc.), family planning intention and sexual behavior. RESULTS: With the symptothermal method of natural family planning it has become possible to determine the fertile window in order to avoid pregnancy with a method effectiveness of 0.3%. According to a small sub-study, the ovulation time observed by the women themselves correlates closely with ovulation detected by ultrasound and measurement of luteinizing hormone (correlation within 1 day in 89% of the 62 cycles). Fertility awareness methods can be integrated into the management of sub-fertility. They seem to shorten the time to pregnancy. CONCLUSIONS: Self-observation of the fertile window puts women into a position to develop a high level of reproductive competence that could be used much more in different areas than is currently the case.

Opinion: natural family planning and the management of infertility.

Reproductive behaviour in modern western society has changed dramatically in the last two decades. Parenthood is now well planned. If planned pregnancies do not occur as expected, early infertility care is often demanded with the risk of over-treatment. Live birth rates in untreated subfertile couples reach nearly 55% in 36 months. During this period, self-monitoring with natural family planning (NFP) methods may be all that is necessary, especially in couples with unexplained infertility.