The impact of disturbances in natural conception cycles.

PURPOSE: Many physicians and other healthcare professionals are often asked questions on interfering factors for conception by couples with a desire for children. Such possible disturbances include, for example, the very common minor diseases, stress and also sexual intercourse during the suspected implantation period. Non-scientifically based statements about disturbances in conception cycles, as found in many layman publications and on the internet, can strongly unsettle couples with a desire for children and force them into corset of rules of conduct. Therefore, a systematic scientific evaluation of the impact of disturbances on conception is urgently needed. METHODS: A search for possible disturbances in natural conception cycles together with up to three of the respective pre-cycles in a large cycle database from users of the symptothermal method of natural family planning in Germany was performed. Disturbances were qualified by scientific panel decision and analysed statistically with their effects on the chances of spontaneous conception. Mixed logistical regression models and survival time analyses were used. RESULTS: A total of 237 women with a total of 747 cycles could be included in the analysis. In 61% of all 237 conception cycles, disturbances occurred. The statistical analysis shows that disturbances in natural conception cycles unexpectedly increase the likelihood of pregnancy by an overall factor of 1.32 (95% CI 1.04-1.70). Sexual intercourse in the window of implantation does not decrease the chances of conception. Relaxation states at the time of ovulation and/or during the implantation period have no representable effect and do not increase the chance of pregnancy. CONCLUSIONS: Couples trying to conceive should at least be informed that disturbances in conception cycles, such as minor diseases, stress or sexual intercourse during the implantation period do not interfere with conception. Relaxation has no effect in favour of success. This takes away the guilty feeling of couples, fearing that they possibly did something wrong in cycles without the desired pregnancy.

Luteinising hormone profiles in conception and non-conception natural cycles.

OBJECTIVE: The aim of this study was to assess whether luteinising hormone (LH) surge characteristics influenced the likelihood of conceiving naturally. METHODS: This was a single-cycle, home-based, observational, case-controlled study. Volunteers collected daily urine samples for one menstrual cycle. LH was measured and the basal levels, surge day, peak day, peak concentration and magnitude of LH surges were examined. Predictive models using sociodemographic data, LH surge characteristics, and sociodemographic data combined with LH profile properties, were evaluated. RESULTS: The surge profile did not differ between cycles with early or late ovulation and was not affected by age or body mass index (BMI). The mean LH surge day was day 16 for both groups. Mean LH surge and concentrations did not differ between groups (surge concentration 54.8 IU/l vs. 58.2 IU/l and peak concentration 82.0 IU/l vs. 81.6 IU/l for pregnant vs. non-pregnant volunteers, respectively). Non-pregnant volunteers were more likely, however, to have a raised or a reduced basal LH on day 6 or have an atypical LH profile. Sociodemographic characteristics were significant predictors of pregnancy, and sociodemographic variable-based models had the greatest predictive ability for conception, providing up to 65% predictive accuracy. CONCLUSIONS: Sociodemographic variables can be used to predict the likelihood of a woman conceiving naturally. Provided an LH surge is present, its profile does not relate to the likelihood of spontaneous pregnancy. The conception rate was significantly lower, however, in women with elevated or reduced basal levels of LH, suggesting that follicular maturation needs an optimal basal level of LH in natural conception cycles.

Relationship between anti-Müllerian hormone and antral follicle count across the menstrual cycle using the Beckman Coulter Access assay in comparison with Gen II manual assay.

BACKGROUND: The study aim was to validate Beckman Coulter's fully automated Access Immunoassay System (BC Access assay) for anti-Müllerian hormone (AMH) and compare it with Beckman Coulter's Modified Manual Generation II assay (BC Mod Gen II), with regard to cycle AMH fluctuations and antral follicle counts. METHODS: During one complete menstrual cycle, transvaginal ultrasound was performed on regularly menstruating women (n=39; 18-40years) every 2 days until the dominant ovarian follicle reached 16mm, then daily until observed ovulation; blood samples were collected throughout the cycle. Number and size of antral follicles was determined and AMH levels measured using both assays. RESULTS: AMH levels measured by the BC Access assay vary over ovulatory menstrual cycles, with a statistically significant pre-ovulatory decrease from -5 to +2 days around objective ovulation. Mean luteal AMH levels were significantly lower (-7.99%) than mean follicular levels but increased again towards the end of the luteal phase. Antral follicle count can be estimated from AMH (ng/mL, BC Access assay) concentrations on any follicular phase day. BC Access assay-obtained AMH values are considerably lower compared with the BC Mod Gen II assay (-19% on average); conversion equation: AMH BC Access (ng/mL)=0.85 [AMH BC Mod Gen II (ng/mL)]0.95. CONCLUSIONS: AMH levels vary throughout the cycle, independently of assay utilised. A formula can be used to convert BC Access assay-obtained AMH levels to BC Mod Gen II values. The number of antral follicles can be consistently estimated from pre-ovulatory AMH levels using either assay.

Determinants of cumulative ART live-birth rates in a single-center study: age, fertilization modality, and first-cycle outcome.

PURPOSE: To analyze cumulative and single-cycle success rates of IVF and intracytoplasmic sperm injection (ICSI) separately in relation to female age, fertilization modality, and first-cycle outcome. METHODS: The study involved 2997 patients and couples, respectively, who underwent 5339 fresh and 3006 cryo cycles using pronuclear-stage oocytes. Fertilization was achieved by the conventional IVF or ICSI. Because of legal restrictions in Germany, no embryo selection was performed. All cycles were documented prospectively. Kaplan-Meier survival rates were calculated for all treatment cycles and transferred embryos. RESULTS: Essentially, the success of assisted reproductive technology (ART) depends on a woman's age and on skilful counselling. Cumulative pregnancy and live-birth rates are the best indicators of successful ART. Probably for the first time, we determined these cumulative rates separately for IVF and ICSI, and found them to be almost identical. Live-birth rates reached 70-95 %, except for women aged over 40 years, whose chances of life birth are limited to about 25 %. Live-birth rate per retrieval was 25.61 % for IVF and 26.3 % for ICSI. Time to pregnancy was shorter for women who underwent a successful treatment in their first cycle. CONCLUSIONS: The primary intention for the choice of fertilization modality between IVF and ICSI is the prevention of a relative or total fertilization failure. Such treatment failure is best prevented through ICSI, which results in slightly higher clinical pregnancy rates per started cycle. After embryo transfer, there are no differences in the success rates of IVF and ICSI. The supposed cumulative live-birth rates are useful as a basis for counselling subfertile couples to help reduce the high discontinuation rate, which is still the main reason for inefficacy in ART. Following an unsuccessful first treatment cycle, the prognosis remains positive, but until success is achieved, more treatment cycles are necessary.

Development of the first urinary reproductive hormone ranges referenced to independently determined ovulation day.

BACKGROUND: Urinary hormone level analysis provides valuable fertility status information; however, previous studies have not referenced levels to the ovulation day, or have used outdated methods. This study aimed to produce reproductive hormone ranges referenced to ovulation day determined by ultrasound. METHODS: Women aged 18-40 years (no reported infertility) collected daily urine samples for one complete menstrual cycle. Urinary luteinising hormone (LH), estrone-3-glucuronide (E3G, an estradiol metabolite), follicle stimulating hormone (FSH) and pregnanediol-3-glucuronide (P3G, a progesterone metabolite) were measured using previously validated assays. Volunteers underwent trans-vaginal ultrasound every 2 days until the dominant ovarian follicle size reached 16 mm, when daily scans were performed until ovulation was observed. Data were analysed to create hormone ranges referenced to the day of objective ovulation as determined by ultrasound. RESULTS: In 40 volunteers, mean age 28.9 years, urinary LH surge always preceded ovulation with a mean of 0.81 days; thus LH is an excellent assay-independent predictor of ovulation. The timing of peak LH was assay-dependent and could be post-ovulatory; therefore should no longer be used to predict/determine ovulation. Urinary P3G rose from baseline after ovulation in all volunteers, peaking a median of 7.5 days following ovulation. Median urinary peak E3G and FSH levels occurred 0.5 days prior to ovulation. A persistent rise in urinary E3G was observed from approximately 3 days pre- until 5 days post-ovulation. CONCLUSIONS: This study provides reproductive hormone ranges referenced to the actual day of ovulation as determined by ultrasound, to facilitate examination of menstrual cycle endocrinology.

Comparison between the different methods developed for determining the onset of the LH surge in urine during the human menstrual cycle.

PURPOSE: To determine whether an optimal method exists for the detection of the luteinising hormone (LH) surge onset in research datasets of urinary hormonal profiles of menstrual cycles. METHODS: The scientific literature was searched to compare published methodologies for detection of the LH surge onset in urine. Their performance was tested using complete hormonal profiles from 254 ovulatory cycles from 227 women attempting pregnancy (normal regular menstrual cycles; no known infertility). RESULTS: Three major methodologies to determine the onset of the LH surge in urine were identified. The key difference between these methods is how the cycle days that contribute to LH baseline assessment are determined: using fixed days (method #1), based on peak LH day (method #2), based on a provisional estimate of the LH surge (method #3). Method #1 requires no prior cycle information, whereas methods #2 and #3 need to consider complete cycle data. The most reliable method for calculation of baseline LH was using 2 days before the estimated surge day, plus the previous 4/5 days. CONCLUSIONS: Different methods for identification of the urinary LH surge can provide very different determinations of LH surge day, thus care must be taken when comparing between studies that apply different methodologies. The optimal method for determining the onset of the LH surge in urine requires retrospective estimation of day of LH surge to identify the most appropriate part of the cycle to consider as the baseline. This method can be adopted for application in population studies.

Impact of sperm cell source on the results of intracytoplasmic sperm injection.

PURPOSE: There is an ongoing debate whether the source of sperm cells, the etiology or the extent of male factor infertility has influence on the outcome of ICSI cycles. METHODS: The results of intracytoplasmic sperm injection (ICSI) according to the source of spermatozoa in patients with severe male factor infertility were compared in a retrospective study: 249 couples underwent a total of 337 fresh ICSI cycles with the use of fresh motile testicular or fresh motile ejaculated spermatozoa. RESULTS: For all variables, there were no statistically significant differences in the ICSI results between both groups. Fertilization rates were 46.8% for testicular and 47.6% for ejaculated spermatozoa. Live birth rates per embryo transfer were 20.4% using testicular spermatozoa and 22.8% using ejaculated spermatozoa. CONCLUSIONS: Neither the source of spermatozoa nor the etiology of severe male infertility has relevant impact on the results of ICSI cycles as long as fresh motile, morphologically normal spermatozoa are used. Therefore, in case of cryptozoospermia, we recommend to preferentially use ejaculated spermatozoa to prevent those men from an unnecessary testicular biopsy avoiding risks and costs implied.

Monitoring the menstrual cycle: Comparison of urinary and serum reproductive hormones referenced to true ovulation.

OBJECTIVE: The aim of the study was to examine relationships and interindividual variations in urinary and serum reproductive hormone levels relative to ultrasound-observed ovulation in menstrual cycles of apparently normally menstruating women. METHODS: This was a prospective study of normally menstruating women (no known subfertility), aged 18-40 years (n = 40), who collected daily urine samples and attended the study centre for blood samples and transvaginal ultrasound during one complete menstrual cycle. Serum luteinising hormone (LH), progesterone, estradiol, urinary LH, pregnanediol-3- glucuronide (P3G) and estrone-3-glucuronide were measured. Ultrasound was conducted by two physicians and interpreted by central expert review. RESULTS: Menstrual cycle length varied from 22 to 37 days (median 27 days). Ovulation by ultrasound ranged from day 8 to day 26 (median day 15). Serum and urinary hormone profiles showed excellent agreement. Estrogen and LH hormone peaks in urine and serum showed a range of signal characteristics across the study group before and after ovulation. The rise in estrogen and LH always occurred before ovulation; the progesterone rise from baseline always occurred after ovulation. CONCLUSIONS: Urinary and serum reproductive hormones showed excellent agreement and may be used interchangeably. The beginning of the surge in serum and urinary LH was an excellent predictor of ovulation. The rise in progesterone and P3G above baseline was a consistent marker of luteinisation confirming ovulation. Both LH and progesterone surges delivered clear, sharp signals in all volunteers, allowing reliable detection and confirmation of ovulation.

Impact of female and male obesity on IVF/ICSI: results of 700,000 ART-cycles in Germany.

To our knowledge, this is the first analysis in which male and female weights have been combined. The registry dataset covering a 12-year period was analysed for all treatment cycles where an embryo transfer was reported. In all, 706,360 cycles were analysed. Treatments include IVF, ICSI, IVF/ICSI and CPE. The highest success rate in IVF cycles was found in couples, with an obese male partner. In the group of obese women, the pregnancy rate decreased to 27.2%. Similar to IVF treatment, the highest success rate in ICSI cycles was found in couples, where either the male or the female partner was obese. The highest success rate in cycles with a cryopreserved embryo transfer was observed in couples where both partner were obese. The lowest success rate was seen where the female partner was obese. Our data analysis suggests that the combination of an obese male and a normal-weight female is positively related to better implantation rates in IVF as well as ICSI-cycles. This combination is more likely to be found in couples with a higher social status. Therefore, the increased pregnancy rate in this group might as well be related to other lifestyle factors associated with higher social status.

Antimüllerian hormone levels and numbers and sizes of antral follicles in regularly menstruating women of reproductive age referenced to true ovulation day.

OBJECTIVE: To assess menstrual cycle antimüllerian hormone (AMH) levels in reproductive age women and which/how many follicles substantially produce AMH. DESIGN: Prospective study of menstruating women using mixed-effects models to analyze AMH variability and correlation of follicle counts/size classes to AMH levels. SETTING: Clinic. PATIENT(S): Regular menstruating women with ovulatory cycles (n = 40, aged 18-37 years) and no known subfertility. INTERVENTION(S): Women collected daily urine samples and visited the study center for blood samples/transvaginal ultrasound during one complete menstrual cycle (visits were every 2 days; daily from follicle size >16 mm until postovulation). MAIN OUTCOME MEASURE(S): AMH levels throughout the menstrual cycle, correlated with antral follicles as observed by ultrasound and identification of follicles producing AMH. RESULTS: Of all antral follicles visible by high-resolution ultrasound, AMH is produced substantially only by follicles up to 7 mm in diameter. For women with basal AMH >1 ng/mL, mean AMH concentrations vary across ovulatory menstrual cycles, showing a statistically significant decrease from -5 to 2 days after objective ovulation; significantly lower mean luteal AMH levels (-7.59% to mean follicular AMH) are detected. The number of antral follicles can be estimated from AMH (ng/mL) levels using the modified Beckman Coulter Generation II AMH assay for any day of the follicular phase. CONCLUSION(S): AMH concentrations vary across ovulatory menstrual cycles, showing a significant periovulatory decrease. The number of small antral follicles can be estimated from preovulatory AMH levels with relevance for patient management. CLINICAL TRIAL REGISTRATION NUMBER: NCT01802060.

Age-related normograms of serum antimüllerian hormone levels in a population of infertile women: a multicenter study.

OBJECTIVE: To produce age-related normograms for serum antimüllerian hormone (AMH) level in infertile women without polycystic ovaries (non-PCO). DESIGN: Retrospective cohort analysis. SETTING: Fifteen academic reproductive centers. PATIENT(S): A total of 3,871 infertile women. INTERVENTION(S): Blood sampling for AMH level. MAIN OUTCOME MEASURE(S): Serum AMH levels and correlation between age and different percentiles of AMH. RESULT(S): Age-related normograms for the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles of AMH were produced. We found that the curves of AMH by age for the 3rd to 50th percentiles fit the model and appearance of linear relation, whereas the curves of >75th percentiles fit cubic relation. There were significant differences in AMH and FSH levels and in antral follicle count (AFC) among women aged 24-33 years, 34-38 years, and ≥39 years. Multivariate stepwise linear regression analysis of FSH, age, AFC, and the type of AMH kit as predictors of AMH level shows that all variables are independently associated with AMH level, in the following order: AFC, FSH, type of AMH kit, and age. CONCLUSION(S): Age-related normograms in non-PCO infertile women for the 3rd to 97th percentiles were produced. These normograms could provide a reference guide for the clinician to consult women with infertility. However, future validation with longitudinal data is still needed.

Persistent ascites after ovarian hyperstimulation syndrome and administration of mifepristone (RU 486) for the termination of pregnancy.

UNLABELLED: We describe two cases with persistent ascites after ovarian hyperstimulation syndrome (OHSS). Mifepristone (RU 486), an anti-progestin was administered to terminate pregnancy in both cases. DISCUSSION: To our knowledge, this is the first such report and we discuss the implications.

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.

Mucus observations in the fertile window: a better predictor of conception than timing of intercourse.

BACKGROUND: Intercourse results in a pregnancy essentially only if it occurs during the 6-day fertile interval ending on the day of ovulation. The strong association between timing of intercourse within this interval and the probability of conception typically is attributed to limited sperm and egg life times. METHODS: A total of 782 women recruited from natural family planning centres in Europe contributed prospective data on 7288 menstrual cycles. Daily records of intercourse, basal body temperature and vaginal discharge of cervical mucus were collected. Probabilities of conception were estimated according to the timing of intercourse relative to ovulation and a 1-4 score of mucus quality. RESULTS: There was a strong increasing trend in the day-specific probabilities of pregnancy with increases in the mucus score. Adjusting for the mucus score, the day-specific probabilities had limited variability across the fertile interval. CONCLUSIONS: Changes in mucus quality across the fertile interval predict the observed pattern in the day-specific probabilities of conception. To maximize the likelihood of conception, intercourse should occur on days with optimal mucus quality, as observed in vaginal discharge, regardless of the exact timing relative to ovulation.