Non-conception Cycles Research Articles

IVF/ICSI outcome and serum LH concentration on day 1 of ovarian stimulation with recombinant FSH under pituitary suppression

Down-regulation with GnRH agonist has been suggested to result in a profound suppression of LH bioactivity, reduced estradiol synthesis, and thus impaired IVF and pregnancy outcome. The aims of this study were: (i) to assess the usefulness of serum LH measurement on stimulation day 1 as a predictor of ovarian response, conception and pregnancy outcome in patients treated with long-term down-regulation with GnRH agonist and recombinant FSH, and (ii) to define the best threshold LH value, if any, to discriminate between women with different outcomes of IVF. Records of 2625 cycles in 1652 infertile women undergoing IVF (n = 1856) and/or ICSI (n = 769) treatment were reviewed. The range of LH concentrations on stimulation day 1 overlapped among non-conception cycles, conception cycles, ongoing pregnancies and early pregnancy losses. Receiver operating characteristic (ROC) analysis showed that serum LH concentrations on stimulation day 1 were unable to discriminate between conception and non-conception cycles (AUC(ROC) = 0.51; 95% CI: 0.49-0.54) or ongoing pregnancies versus early pregnancy loss groups (AUC(ROC) = 0.52; 95% CI: 0.47-0.57). Stratification for various low serum levels of LH did not reveal significant differences with respect to conception or pregnancy outcome among different LH levels on stimulation day 1. Serum LH concentration on stimulation day 1 cannot predict ovarian response, conception and pregnancy outcome in women receiving long-term down-regulation during assisted reproduction treatment.

A transformation approach for incorporating monotone or unimodal constraints

Samples of curves are collected in many applications, including studies of reproductive hormone levels in the menstrual cycle. Many approaches have been proposed for correlated functional data of this type, including smoothing spline methods and other flexible parametric modeling strategies. In many cases, the underlying biological processes involved restrict the curve to follow a particular shape. For example, progesterone levels in healthy women increase during the menstrual cycle to a peak achieved at random location with decreases thereafter. Reproductive epidemiologists are interested in studying the distribution of the peak and the trajectory for women in different groups. Motivated by this application, we propose a simple approach for restricting each woman's mean trajectory to follow an umbrella shape. An unconstrained hierarchical Bayesian model is used to characterize the data, and draws from the posterior distribution obtained using a Gibbs sampler are then mapped to the constrained space. Inferences are based on the resulting quasi-posterior distribution for the peak and individual woman trajectories. The methods are applied to a study comparing progesterone trajectories for conception and nonconception cycles.

ETS and Conception: Smoking Out a Mechanism of Action

Vol. 113, No. 4 News | Science SelectionsOpen AccessETS and Conception: Smoking Out a Mechanism of Action Laura Alderson Laura Alderson Search for more papers by this author Published:1 April 2005https://doi.org/10.1289/ehp.113-a254aView Article in:中文版AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Numerous studies have shown that women who smoke have a harder time getting pregnant and a greater risk of spontaneous abortion and having low-birth-weight babies. Smoking also has long been associated with menstrual disturbances and possibly other antiestrogen effects. But findings on reproductive outcomes have been less straightforward when it comes to the harmful effects of women’s exposure to environmental tobacco smoke (ETS). Now a team of U.S. and Chinese researchers report a link between ETS exposure and significantly lower urinary levels of estrone conjugates (E1C; the main metabolite of estrogen)[EHP113:412–417]. The findings suggest that ETS exposure, like active smoking, may affect reproduction in part through antiestrogen effects.The study was part of a large, prospective reproductive health study conducted from 1997 to 2000 among women working full-time at the Anqing Textile Mill in southeast China’s Anhui Province. In an earlier study of the same cohort, the investigators reported a dose–response relationship between ETS exposure and risk of early pregnancy loss.This study included 371 newly married women aged 20–34 who had stopped contraception and intended to conceive. None had borne children. All were nonsmoking, all had the same occupation, and all were of the same socioeconomic background. ETS exposure in this homogeneous group was very high because of the high prevalence of smoking among Chinese men. In China, it is estimated that 63% of men are smokers (compared to only 3.8% of women).For up to a year, or until pregnancy, the women kept daily diaries recording exposure to ETS at both home and work. They also collected first-morning urine specimens each day. The researchers calculated the percentage of days in each menstrual cycle that included ETS exposure, then analyzed the independent association between ETS exposure and profiles of pregnanediol-3-glucuronide (PdG) and E1C in the women’s menstrual cycles. PdG and E1C are urinary metabolites of hormones that regulate reproductive function.Because individual women’s hormone levels vary significantly during their menstrual cycles, it was critical to accurately determine the day of ovulation in order to compare hormone levels among the study subjects. The researchers used the estimated day of ovulation to align the individual menstrual cycles for comparison.Of the 673 cycles included in the study, 344 (51%) were non-conceptive and 329 (49%) resulted in conception. Only 76 cycles did not include ETS exposure; of these, 42% resulted in conception. During nonconception cycles, ETS-exposed women had a consistently lower daily urinary E1C level compared to nonexposed women. During conception cycles, the association was not significant; the investigators write that their study may not have had the power to detect a relatively small effect of ETS exposure in these cycles. They also reported no significant difference in PdG levels between women who were exposed to ETS and those who weren’t, regardless of conception status.These findings suggest that ETS exposure, like active smoking, may affect estrogen levels. Estrogen affects the timing of ovulation during the menstrual cycle, thus potentially affecting the ability to become pregnant. In shedding new light on the biological mechanisms by which ETS exposure may affect reproduction, the study adds to the body of knowledge on the harmful impact of smoking upon smokers and nonsmokers alike.Conception smokescreen. A study of Chinese women trying to conceive adds to the body of evidence that ETS exposure—not just active smoking—may hamper reproduction.FiguresReferencesRelatedDetails Vol. 113, No. 4 April 2005Metrics About Article Metrics Publication History Originally published1 April 2005Published in print1 April 2005 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Compartmental distinctions in uterine Muc-1 expression during early pregnancy in cynomolgous macaque (Macaca fascicularis) and baboon (Papio anubis)

Loss of the transmembrane mucin, Muc-1, is a molecular correlate of the acquisition of uterine receptivity to embryo adhesion in most species examined. In macaques, two distinct adhesion events occur at opposite sides of the uterus. Attachment to the secondary site is delayed relative to the primary site. The aim was to determine if Muc-1 is removed at secondary sites prior to trophoblast attachment. We examined Muc-1 expression in the uteri of cynomolgus macaque and baboon during early implantation by immunocytochemistry. Luminal epithelia were devoid of Muc-1 at all stages examined at both primary and secondary adhesion sites. Loss of Muc-1 in luminal epithelia was found to be maternally determined, accompanied membrane transformation in both macaque and baboon, and at secondary implantation sites, preceded trophoblast attachment. In contrast, glandular epithelia in pregnant macaques exhibited a temporal and compartmentalized gradient of Muc-1 loss confined to the implantation sites. Glandular epithelia in the pregnant baboon uterus were uniformly negative for Muc-1. Restriction of the Muc-1 loss in glandular epithelia to conceptual cycles may reflect the fundamental distinctions among epithelia of the various uterine compartments and the differential modulation of Muc-1 that occurs within these compartments in conceptual and non-conceptual cycles.

High magnitude of light retardation by the zona pellucida is associated with conception cycles

Failures in expression of zona proteins correlate to subfertility in animals. Low expression of the zona proteins by the growing human oocyte may indicate reduced developmental potential. Therefore, we non-invasively analysed the thickness and the structure of the zona pellucida (ZP) of human oocytes with respect to embryo fate after ICSI. Retardance magnitude and thickness of the inner, middle and outer layers of the ZP were quantitatively analysed by a Polscope in 166 oocytes selected for transfer after ICSI (63 patients; 32.8 +/- 4.4 years) on the basis of pronuclear score at day 1. Blastomere number was determined at day 2. Data were compared between conception cycles (CC; 65 oocytes/23 patients) and non-conception cycles (NCC; 101 oocytes/40 patients) and with respect to maternal age. The thickness was slightly elevated (P < 0.001), and the mean magnitude of light retardance was nearly 30% higher (P < 0.001) in the inner layer of the zona pellucida of oocytes contributing to CC compared to NCC. Embryos in the CC group tended to develop faster. The magnitude of light retardance by the zona pellucida inner layer appears to present a unique non-invasive marker for oocyte developmental potential.

Effect of Environmental Tobacco Smoke on Levels of Urinary Hormone Markers

Our recent study showed a dose–response relationship between environmental tobacco smoke (ETS) and the risk of early pregnancy loss. Smoking is known to affect female reproductive hormones. We explored whether ETS affects reproductive hormone profiles as characterized by urinary pregnanediol-3-glucuronide (PdG) and estrone conjugate (E1C) levels. We prospectively studied 371 healthy newly married nonsmoking women in China who intended to conceive and had stopped contraception. Daily records of vaginal bleeding, active and passive cigarette smoking, and daily first-morning urine specimens were collected for up to 1 year or until a clinical pregnancy was achieved. We determined the day of ovulation for each menstrual cycle. The effects of ETS exposure on daily urinary PdG and E1C levels in a ±10 day window around the day of ovulation were analyzed for conception and nonconception cycles, respectively. Our analysis included 344 nonconception cycles and 329 conception cycles. In nonconception cycles, cycles with ETS exposure had significantly lower urinary E1C levels (β= –0.43, SE = 0.08, p < 0.001 in log scale) compared with the cycles without ETS exposure. There was no significant difference in urinary PdG levels in cycles having ETS exposure (β= –0.07, SE = 0.15, p = 0.637 in log scale) compared with no ETS exposure. Among conception cycles, there were no significant differences in E1C and PdG levels between ETS exposure and nonexposure. In conclusion, ETS exposure was associated with significantly lower urinary E1C levels among nonconception cycles, suggesting that the adverse reproductive effect of ETS may act partly through its antiestrogen effects.

Follicular phase serum levels of luteinizing hormone do not influence delivery rates in in vitro fertilization cycles down-regulated with a gonadotropin-releasing hormone agonist and stimulated with recombinant follicle-stimulating hormone

To assess the value of serum LH measurements in early and late follicular phase as predictors of ovarian response and IVF outcome in patients treated with recombinant FSH with GnRH agonist (GnRH-a) pituitary down-regulation. Retrospective cohort analysis. Institutional. Women undergoing 157 consecutive IVF cycles suppressed with leuprolide acetate (LA) started in the midluteal phase and stimulated with recombinant FSH. Only women <40 years of age and with a basal cycle day 3 serum FSH </=9 IU/L were included. Serum LH levels were measured on cycle days 3 (D3) and 10 (D10). Delivery rates. Other secondary outcome measures included fertilization rate, clinical pregnancy rate, and parameters of ovarian response (peak E(2), number of metaphase II oocytes, and number of ampules of recombinant FSH). No significant differences were found with respect to ovarian response, fertilization rate, and outcome of pregnancy, when three threshold values of D3 and D10 serum LH (1, 1.5, and 2 mIU/mL) were analyzed. In addition, no significant differences were found between conception (n = 87) and no conception (n = 71) groups with respect to D3 or D10 LH. Receiver operator characteristic (ROC) analysis showed that neither the serum LH concentration on D3 nor on D10 was able to discriminate between conception and nonconception cycles (area under the curve [AUC](ROC)= 0.54, AUC(ROC)= 0.56), or between delivered pregnancies and first trimester pregnancy loss (AUC(ROC)= 0.53, AUC(ROC) = 0.61). The suppressed levels of early and late follicular serum LH in women <40 years of age with normal ovarian function desensitized with a GnRH-a and treated with recombinant FSH are not predictive of ovarian response, pregnancy, or delivery. These data do not support the use of exogenous LH supplementation in this clinical scenario.

The midluteal decline in serum estradiol levels is drastic but not deleterious for implantation after in vitro fertilization and embryo transfer in patients with normal or high responses

To determine the impact of the peak E(2) level and its midluteal decline on IVF-ET outcome in a group of normal- and high-responding patients. Retrospective analysis of IVF-ET data. Tertiary-care, university-affiliated teaching hospital. A total of 100 patients aged </=38 years and receiving up to three embryos per transfer who underwent a similar standard controlled ovarian hyperstimulation for IVF-ET. Morning blood was collected on days 0 (hCG day), +9, and +14. Treatment cycle hormonal characteristics and percent midluteal E(2) decline in conception and nonconception cycles. Among all cycles, a mean decline of 95.0% in serum E(2) was observed at the midluteal phase. No significant differences were found in various parameters comparing conception with nonconception cycles. Occurrence of conception did not correlate with the absolute E(2) level or with percent E(2) decline in good and high responders. Early spontaneous abortion occurred more frequently in high responders with >98% E(2) decline; however, the difference did not reach statistical significance. Multifactorial analysis refutes the negative role of supraphysiologic levels of E(2) on the day of hCG administration or its dramatic decline at the midluteal phase on the success rate after embryo transfer. A possibly increased rate of early spontaneous abortion in the high-response group warrants further verification.

Fecal cortisol levels in free-ranging female chacma baboons: relationship to dominance, reproductive state and environmental factors

Savannah baboons are one of the few mammalian species that do not exhibit seasonal reproduction patterns and are therefore ideally suited to study the effect of female reproductive states (cycling, pregnant, lactating) on cortisol levels independent of seasonal factors. Fecal samples from 10 free-ranging female chacma baboons ( Papio hamadryas ursinus), collected during a period of 17 months, were analyzed using a steroid-extraction method. Reproductive state had a significant effect on fecal cortisol, with lowest levels found in estrous females. Fertility was not related to fecal cortisol levels; we found no significant differences between samples collected on conceptive and nonconceptive cycles. Environmental factors explained most of the variance of fecal cortisol levels. Cortisol measures were strongly correlated with seasonal differences such as daylight duration, temperature and the amount of time that baboons spent resting. We measured higher cortisol levels during winter months and suggest that this could be related to shorter resting periods and to the cold minimum ambient temperatures at this study site. Finally, we found no relationship between social rank nor the rate of agonistic interactions with basal fecal cortisol levels.

Assessment of female reproductive status by male longtailed macaques, Macaca fascicularis, under natural conditions

Recent theories on primate sexual selection have paid increasing attention to the importance of reproductive strategies of females living in multimale groups. However, the extent to which females are able effectively to conceal or advertise the time of ovulation as part of these strategies remains unclear. Few studies have investigated the ability of males to discern female reproductive status under natural conditions, and none has taken into account differences in male rank, and thus ability to gain access to females or cues. We tested male assessment of a female's fertile phase under natural conditions in longtailed macaques. We used timing of mate guarding by dominant males and the response of subordinate males towards the repeated playback of a female copulation call to measure male interest in females throughout the ovarian cycle. Relating the degree of male interest to female reproductive status, as determined noninvasively by faecal hormone analysis, we found that interest in females shown by both dominant and subordinate males was strongest during and around the fertile phase. Our results also indicate that males were better able to recognize the fertile period in conception than in nonconception cycles. Furthermore, our finding of a strong positive relation between male interest and female oestrogen levels in all cycles indicates that at least some of the cues used by males to assess female reproductive status are oestrogen related.

Assessment of changes in utero-ovarian arterial impedance during the peri-implantation period by Doppler sonography in women undergoing assisted reproduction.

To investigate changes in utero-ovarian blood flow during the peri-implantation period and their significance in successful embryo implantation. A prospective longitudinal study was conducted in 317 women undergoing in-vitro fertilization-embryo transfer (IVF-ET) treatment. All of them had at least one good-quality embryo for transfer on the second or third day after oocyte retrieval. Measurement of endometrial thickness and color flow imaging with pulsed waveform analysis of uterine and ovarian arteries were performed before ET and 5-6 days after ET. There were no significant differences in the age of patients, duration of infertility or number of embryos transferred between women who became pregnant (n = 91) and those who did not (n = 226). There was no difference in mean endometrial thickness between the two groups before ET, while a thicker endometrium was found in women who had conceived compared with those who had not 5-6 days after ET (P = 0.02). Mean uterine arterial resistance index (RI) and pulsatility index (PI) values were significantly lower in the pregnant than in the non-pregnant group before ET (P = 0.04 and P = 0.003, respectively), but no significant differences were found between the two groups 5-6 days after ET. In contrast, the mean ovarian arterial RI and PI values were similar between the two groups before ET, yet the pregnant group showed significantly lower RI and PI values compared with the non-pregnant group 5-6 days after ET (P = 0.002 and P = 0.01, respectively). A significantly higher peak systolic velocity (PSV) of intraovarian vessels was also noted in the pregnant group 5-6 days after ET. Different utero-ovarian blood flow changes during the peri-implantation period occur in conception and non-conception cycles in women following IVF. Doppler assessment of uterine arterial resistance can help to determine a time interval within the menstrual cycle that is of optimal endometrial status for embryo implantation in assisted conception programs. Delay in achieving adequate uterine perfusion during the temporal window of embryo implantation may have an impact on endometrial receptivity.

Enhanced oestradiol secretion briefly after embryo transfer in conception cycles from IVF

The hypothesis was tested that conception cycles (CC) resulting from IVF can be distinguished from non-conception cycles (NC) by differences in corpora lutea function that are detectable at the earliest stage of embryo implantation. Luteal oestradiol secretion was analysed retrospectively in 409 ovarian stimulation cycles of 296 patients from the day of embryo transfer until 14 days after embryo transfer (ET+14) in IVF/intracytoplasmic sperm injection (ICSI) cycles. Human chorionic gonadotrophin (HCG) was administered in 330 of 409 cycles in addition to vaginal progesterone in all cycles. Differences in serum oestradiol concentrations between CC and NC increased from day ET+1 onward and became statistically significant on days ET+4 through ET+14, with higher oestradiol concentrations in CC compared with NC. Even though exogenous HCG administration prevented the fall in luteal oestradiol concentrations after ET+4 both in CC and NC, increasing differences in oestradiol concentrations between CC and NC after embryo transfer were observed in both groups of HCG-supplemented and non-supplemented cycles. It is concluded that luteal oestradiol secretion is affected at the earliest stage of embryo implantation. The putative early signal to the corpus luteum associated with embryo attachment and early implantation appears to be superimposed onto the effect of exogenous luteal HCG administration and is clearly distinguishable as early as 4 days after embryo transfer in conception cycles.

Placental protein 14 concentrations in circulation related to hormonal parameters and reproductive outcome in women undergoing IVF/ICSI

Serum concentrations of placental protein 14 (PP14), steroids and gonadotrophins were related to the outcome of IVF/intracytoplasmic sperm injection in 195 normogonadotrophic women subjected to the long protocol gonadotrophin-releasing hormone agonist (GnRHa; buserelin) pituitary down-regulation protocol and gonadotrophin stimulation (HMG or rFSH). Pituitary down-regulation was initiated on cycle day 21 and the patients were randomized to either intranasal or s.c. administration of buserelin. After 14 days of down-regulation, the patients were randomized on stimulation day 1 (S1) to ovarian stimulation with 225 IU per day of either human menopausal gonadotrophin (HMG) or recombinant FSH (rFSH) for a fixed period of 7 days. The daily gonadotrophin dose was adjusted on the following day according to ovarian response. Patient's blood was sampled for PP14 and hormone analysis on cycle days 21, S1, S8 and on the day of oocyte retrieval. Mean concentrations of PP14 on day 21 of the cycle were significantly lower in conception than in non-conception cycles, whereas progesterone and oestradiol were similar in conception and non-conception cycles. PP14 concentrations on the first day of stimulation and at oocyte retrieval were significantly higher in conception than in non-conception cycles, whereas concentrations after 8 days of stimulation were similar. Neither mode of GnRHa administration nor type of gonadotrophin significantly influenced PP14 concentrations throughout ovarian stimulation. Circulating PP14 is thus an important physiological signal of the fertility status of the individual in the cycle antecedent to and during ovarian stimulation. Measuring mid-luteal serum PP14 may offer a clinical test helping to decide if infertility treatment should be initiated in the subsequent cycle.

Results of in vitrofertilization cycles in women aged 43–45 years

Our objective was to evaluate the results of in vitro fertilization (IVF) cycles in the elderly (43–45 years old) female population. All consecutive women aged 43–45 years admitted to our IVF unit from January 1996 to December 2001 were enrolled in the study. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryos transferred and pregnancy rate were assessed. Seven hundred and eight consecutive IVF cycles in 276 patients were evaluated. Two hundred and seven cycles were cancelled (cancellation rate 29.2%). Forty-seven patients achieved a clinical pregnancy (pregnancy rate 6.6% per cycle and 9.4% embryo transfer) with a 30% live birth rate. In patients who underwent embryo transfer, there were no differences between conception and non-conception cycles in patient's age, number of gonadotropin ampules used, length of ovarian stimulation, number of oocytes retrieved, fertilization rate or cleavage rate. However, the conception cycles were associated with a significantly lower peak estradiol level (p<0.04) and higher number of total (p<0.03) and good-quality (p<0.005) embryos transferred, in addition to a lower ratio of estradiol level/number of follicles > 14 mm on day of human chorionic gonadotropin administration and of estradiol level/number of oocytes retrieved. We conclude that, although older female age is a major contributor to IVF failure, successful IVF cycles can be expected in patients aged 43–45 years in the presence of low ratios of peak estradiol to either number of follicles > 14 mm on day of human chorionic gonadotropin administration or number of oocytes retrieved that reach the stage of embryo transfer with at least two good-quality embryos.

Concentrations of gonadotrophins and steroids in pre-ovulatory follicular fluid and serum in relation to stimulation protocol and outcome of assisted reproduction treatment

In this prospective, randomized study, concentrations of gonadotrophins and steroids in pre-ovulatory follicular fluid (FF) and serum were related to type of stimulation protocol as well as to the outcome of assisted reproduction in 280 women subjected to the long protocol gonadotrophin-releasing hormone (GnRH) agonist pituitary down-regulation and ovarian stimulation with either human menopausal gonadotrophin (HMG) or recombinant FSH. In the women treated with HMG, concentrations of LH, FSH, oestradiol and androstenedione in FF were significantly higher, and those of human chorionic gonadotrophin (HCG) and progesterone significantly lower, than in the women treated with recombinant FSH (rFSH). More women became pregnant and delivered in the HMG than in the rFSH group. These differences, however, were not statistically significant. Concentrations of FSH in serum and of FSH and LH in FF were significantly higher in conception than in non-conception cycles, whereas all other hormone concentrations in FF and serum were similar. The present study demonstrates that the pre-ovulatory follicular fluid hormone profile is significantly influenced by the gonadotrophin preparation used for ovarian stimulation, and suggests that ovarian stimulation with HMG results in an intra-follicular hormone profile more similar to that characterizing conception cycles than stimulation with rFSH. However, as the present data represent means of FF hormone profiles, they do not allow the conclusion of a direct correlation between the intra-follicular concentration of a certain hormone and the ability of the corresponding embryo to implant and establish an ongoing pregnancy.

Serum progesterone concentrations on the day of HCG administration cannot predict pregnancy in assisted reproduction cycles

The effect of subtle rises of progesterone in the late follicular phase of cycles of ovarian stimulation with gonadotrophin-releasing hormone (GnRH) agonists on pregnancy outcome is controversial. This study used receiver-operating characteristic (ROC) analysis to gain further insight into the predictive value of serum progesterone concentrations on the day of human chorionic gonadotrophin (HCG) injection in normally responding patients receiving the long protocol of GnRH agonist (group L; n = 218) and in low responders receiving the short (‘flare-up’) protocol (group S; n = 159). ROC analysis showed that serum progesterone concentration on the HCG day was not indicative of conception and non-conception cycles in the whole population studied, in group L or in group S. To further assess the potential impact of ‘high’ concentrations of circulating progesterone on the day of HCG administration on pregnancy rates and outcome, the threshold value (<0.9 ng/ml) to discriminate between women with ‘high’ (group H; n = 197) and ‘normal’ (group N; n = 180) progesterone was applied. No significant differences were found with respect to pregnancy and miscarriage rates between these two groups. Serum progesterone concentrations on the day of HCG administration therefore cannot predict pregnancy in assisted reproduction cycles using GnRH agonists and gonadotrophins.

Luteal phase defects following agonist-triggered ovulation: a patient-dependent response

The luteal phase (LP) of patients receiving triptorelin 0.1 mg to trigger ovulation was studied. Patients not pregnant in the first cycle with 0.1 mg were randomized into different groups for a second cycle: 0.1 mg again for patients who experienced a normal LP (group 1); patients affected with LP disorders were randomized into the following groups: 0.1 mg again (group 2); increasing dosage of triptorelin 0.5 mg once (group 3) or 0.1 mg three times (group 4); luteal support either with oral micronized progesterone (group 5) or human chorionic gonadotrophin (HCG) 1500 IU (group 6). Ovulation occurred in all cycles, but an inadequate LP was observed in 34.4% of the non-conceptional cycles. Patients demonstrating a normal LP as well as those affected with luteal disorders in their first cycle showed the same luteal pattern in their consecutive cycles triggered in the same way. In defective LP patients, increasing or repeating triptorelin doses did not restore the luteal phase or the pregnancy rate, both returning closer to normal after luteal support. Defective LP observed after agonist-triggered ovulation do not occur at random; therefore this patient-dependant response may be related to the personal characteristics of each patient's pre-ovulatory physiological surge profile.

LH serum levels during ovarian stimulation as predictors of ovarian response and assisted reproduction outcome in down-regulated women stimulated with recombinant FSH.

There has been much debate about the effect of 'residual' LH levels in normogonadotrophic women undergoing assisted reproduction with GnRH agonist down-regulation and recombinant FSH ovarian stimulation. The aim of this prospective study, where receiver-operating characteristic (ROC) analysis was used, was to assess further the usefulness of serum LH levels as predictors of ovarian response, assisted reproduction treatment outcome, and the outcome of pregnancy when measured throughout the ovarian stimulation period in a large cohort of such assisted reproduction treatment women. A total of 246 consecutive women undergoing their first cycle of IVF or ICSI treatment were included in this study. Blood samples for hormone analyses were obtained on day S0 (the day when pituitary suppression was evidenced) and every other day from stimulation day 5 (S5) until the day of hCG injection. LH serum levels throughout ovarian stimulation treatment were similar for cancelled (n =32) versus non-cancelled (n = 214) cycles, non-conception (n = 132) versus conception (n = 82) cycles, and ongoing pregnancy (n = 66) versus early pregnancy loss (n = 16) groups. There was no correlation between LH serum levels in non-cancelled cycles and parameters of ovarian response and assisted reproduction treatment outcome. ROC analysis showed that serum LH concentration during ovarian stimulation was unable to discriminate between cancelled and non-cancelled cycles, conception versus non-conception cycles, or early pregnancy loss versus ongoing pregnancy groups. Serum LH measurements during ovarian stimulation with recombinant FSH under pituitary suppression in normogonadotrophic women undergoing assisted reproduction treatment cannot predict ovarian response, IVF/ICSI outcome, implantation, and the outcome of pregnancy. Thus, there is little underlying physiological support for the addition of LH in stimulation protocols if daily doses of an appropriate GnRH agonist (leuprolide or triptorelin having lower potency than buserelin) and a step-down regimen of recombinant FSH administration are used.

Mifepristone for luteal phase contraception

The concept of luteal phase contraception and the use of mifepristone in clinical trials, which allows for testing of its validity, as well as clinical pharmacological research designed to understand its mode of action, are reviewed. Early luteal phase administration has a variety of morphological, physiological and biochemical effects on the endometrium that are likely to interfere with embryonic–endometrial interactions. In fact, specifically designed pilot clinical trials as well as data derived from emergency contraception studies indicate that early luteal phase administration of mifepristone is highly effective in preventing pregnancy, with minimal disturbance of hormonal parameters or menstrual cyclicity. Mid and late luteal phase administration of mifepristone at doses above 25 mg are highly effective in inducing endometrial bleeding in nonconceptional cycles. However, administration of mifepristone within the period between implantation and expected menses fails to induce bleeding in a significant proportion of cases, and furthermore the bleeding induced does not insure the termination of pregnancy. While the data suggest there is potential for a once-a-month contraceptive pill, it is likely that no molecule endowed with partial agonistic properties, like mifepristone, will completely and reliably suppress the essential functions of progesterone in order to achieve contraceptive efficacy comparable to that of modern contraceptive methods.

Ovarian modulators of type 1 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity and intra-follicular cortisol:cortisone ratios correlate with the clinical outcome of IVF.

Follicular fluid (FF) contains compounds that can modulate NADP(+)-dependent oxidation of cortisol by type 1 11beta-hydroxysteroid dehydrogenase (11betaHSD). The objective of this study was to investigate the relationships between levels of the ovarian modulators of type 1 11betaHSD, intra-follicular cortisol:cortisone ratios and the clinical outcome of IVF cycles. A single random sample of FF was aspirated from each of 132 patients undergoing gonadotrophin-stimulated IVF. Components of FF, resolved using C18 column chromatography, were evaluated for effects on NADP(+)-dependent cortisol oxidation in rat kidney homogenates. Intra- follicular steroid concentrations were measured by radioimmunoassays. Clinical pregnancies were confirmed by ultrasonography at 6 weeks post-embryo transfer. Levels of the hydrophilic ovarian 11betaHSD stimuli were significantly lower (P<0.0001) and levels of the hydrophobic ovarian 11betaHSD inhibitors were significantly higher (P<0.002) in conception versus non-conception cycles. Intra-follicular cortisol:cortisone ratios increased with the degree of inhibition of 11betaHSD by the hydrophobic FF fractions. FF obtained from conception cycles had significantly higher cortisol:cortisone ratios than samples from non-conception cycles (12.9+/-0.3 versus 8.5+/-0.2, respectively; P<0.0001). Conception by IVF is associated with elevated intra-follicular cortisol:cortisone ratios, which reflect low levels of ovarian stimuli and/or high levels of ovarian inhibitors of type 1 11betaHSD.