Sex ratio and birth weights of infants born as a result of blastocyst transfers compared with early cleavage stage embryo transfers.

OBJECTIVE: To analyze the birth weights and sex ratio of infants born as a result of blastocyst transfer and compare them with data resulting from the transfer of early-cleavage stage embryos. DESIGN: Retrospective analysis. SETTING: Monash IVF (private in vitro fertilization clinic). PATIENTS(S): One hundred twenty-five infertile patients who became pregnant after IVF procedures involving blastocyst transfer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sex ratio and birth weights of infants born after blastocyst transfer. RESULT(S): The sex ratio of 129.6 for infants born after blastocyst transfer was not significantly different from the sex ratio calculated from data compiled by NPSU for births resulting from early cleavage stage embryo transfers at Monash IVF (100.6) and all other assisted conception units in Australia and New Zealand (97.9). No differences were observed in the combined mean birth weight of male and female infants born as a result of blastocyst transfers and early-cleavage stage embryo transfers. CONCLUSION(S): There is no evidence of abnormal fetal growth or a shift in the sex ratio for infants born as a result of blastocyst transfer when compared with the case of births resulting from early cleavage stage embryo transfers within our unit or all other assisted conception units in Australia and New Zealand.

What is the probability of conception for couples entering an IVF program?

The outcome of 4225 couples undergoing 8207 in vitro fertilisation (IVF) cycles over a six year period has been analysed using life table analysis. Pregnancy was expressed as a 'clinical pregnancy - fetus visible on ultrasound' per stimulated cycle oocyte collection, with pregnancies obtained from frozen embryos being referred to the cycle where they were collected. We found that only 1 in 200 patients proceeded beyond six cycles and the cumulative per cent pregnant was 20.7% after the first cycle, with nearly half pregnant within three and over two-thirds being pregnant within six cycles. We find this is a useful way to present the chance of pregnancy to prospective couples.

Maternal serum inhibin A concentrations in early pregnancy after IVF and embryo transfer reflect the corpus luteum contribution and pregnancy outcome.

To compare maternal serum inhibin A concentrations in early pregnancy with pregnancy outcomes and treatment protocols, serum samples were collected from 237 women undergoing in-vitro fertilization (IVF) and embryo transfer cycles. Samples were collected on day 16 after oocyte retrieval for beta human chorionic gonadotrophin (HCG) pregnancy testing and inhibin A measurement. The samples were divided into non-pregnant (n = 128) and pregnant (n = 109) groups, the pregnancies were followed and outcomes determined. Inhibin A concentrations were significantly lower in non-pregnant women than in women with ongoing pregnancies (P: < 0.001) and those resulting in spontaneous abortions (P: < 0.001). In ongoing pregnancies, inhibin A concentrations were significantly lower in the absence of functioning ovaries (donor oocyte/embryo) (P: < 0.01) and in natural cycles (frozen-thawed embryo transfer) (P: < 0.01) compared with concentrations after ovarian stimulation. Further, since inhibin A concentrations were not significantly different between singleton and multiple pregnancies in the ovarian stimulation protocol, the size of the early trophoblast does not appear to influence the secretion of inhibin A. These data strongly support the concept that the corpus luteum is a major source of circulating inhibin A in early pregnancy. Additionally, low concentrations of serum inhibin A may be useful in predicting betaHCG-positive preclinical 'biochemical' pregnancies.

Relationship between serum inhibin A and B and ovarian follicle development after a daily fixed dose administration of recombinant follicle-stimulating hormone.

The aim of this study was to investigate the relationship of serum inhibin A and inhibin B to ovarian follicular development in women undergoing pituitary down-regulation and ovarian stimulation with a fixed daily dose of recombinant human FSH in an in vitro fertilization program. Thirty-eight patients were treated randomly with either 100 or 200 IU/day recombinant human FSH (Puregon) for a period of 9-14 days. Serum FSH, inhibin A, inhibin B, 17beta-estradiol, and follicular size and number were determined before FSH treatment and every second day from days 4-6 throughout FSH treatment. Serum FSH increased in a dose-related manner to reach a maximum by days 4-6 and remained unchanged over the duration of treatment. Serum inhibin A and 17beta-estradiol also increased with increasing FSH dose and continued to rise throughout the FSH treatment period. By contrast, serum inhibin B was increased by days 4-6 at both doses of FSH to reach a maximum by days 7-8, remaining unchanged thereafter. Serum inhibin B and, to a lesser extent, inhibin A correlated significantly with the number of oocytes retrieved even when assessed early (days 4-6) in the treatment period (inhibin B vs. number of oocytes: r = 0.89; P < 0.001; inhibin A vs. number of oocytes: r = 0.61; P < 0.05). Serum inhibin A, inhibin B, and 17beta-estradiol were weakly correlated with the number of follicles less than 11 mm when assessed on a daily basis; stronger correlations were observed with the greater than 11-mm follicles during the late stages of treatment. It is concluded that serum inhibin B levels determined during the early stages (e.g. days 4-6) of fixed dose FSH treatment provide an early indicator of the number of recruited follicles that are destined to form mature oocytes. In this context, serum inhibin B may be of predictive value in monitoring ovarian hyperstimulation treatment for in vitro fertilization.

Different influence of incongruent follicular development on in vitro fertilization-embryo transfer and gamete intrafallopian transfer pregnancy rates.

OBJECTIVE: To compare the influence of incongruent (asymmetric) follicular development on treatment outcome in IVF-ET and GIFT cycles. DESIGN: A retrospective comparative study. SETTING: Tertiary referral center for infertility. PATIENT(S): Five hundred forty-three consecutive assisted reproduction cycles (428 IVF-ET and 115 GIFT) in 422 infertile patients. INTERVENTION(S): Controlled ovarian hyperstimulation (COH) and IVF-ET or GIFT. MAIN OUTCOME MEASURE(S): The incongruity ratio as a parameter of the asymmetry in follicular development and pregnancy rate (PR). RESULT(S): For GIFT cycles, the PRs were 37.8% and 15.7% in cycles with congruent and incongruent follicular development, respectively. However, for IVF-ET cycles, the PR was not affected by incongruent follicular development: 28.2% and 29.0%, respectively. An inverse relationship was observed between the degree of incongruity and the estimated probability of pregnancy in GIFT cycles but not in IVF-ET cycles. Neither the side of the dominant ovary nor the degree of incongruity were consistent in consecutive cycles. CONCLUSION(S): Incongruent follicular development during COH has a significantly negative influence on the outcome of GIFT cycles but not on the outcome of IVF-ET cycles. The reason for this difference is not clear. We recommend considering IVF-ET instead of GIFT if incongruent follicular development occurs.

Effect of intramural, subserosal, and submucosal uterine fibroids on the outcome of assisted reproductive technology treatment.

OBJECTIVE: To investigate the effect of subserosal, intramural, and submucosal fibroids on the outcome of assisted reproductive technology (ART) treatment. DESIGN: A retrospective comparative study. SETTING: A tertiary referral center for infertility. PATIENT(S): Treatment outcome of 106 ART cycles in 88 patients with uterine fibroids (33 subserosal, 46 intramural without cavity distortion, and 9 submucosal) was compared with that of 318 ART cycles in age-matched patients without fibroids. INTERVENTION(S): Controlled ovarian hyperstimulation and ART. MAIN OUTCOME MEASURE(S): Findings on transvaginal uterine ultrasonography performed before the initiation of treatment and pregnancy and implantation rates. RESULT(S): The pregnancy rates per transfer were 34.1%, 16.4%, 10%, and 30.1% in the patients with subserosal fibroids, intramural fibroids, submucosal fibroids and no fibroids, respectively. The implantation rates were 15.1%, 6.4%, 4.3%, and 15.7%, respectively. Both rates were significantly lower in patients with intramural fibroids than in those with subserosal fibroids or no fibroids. CONCLUSION(S): Pregnancy and implantation rates were significantly lower in the groups of patients with intramural and submucosal fibroids, even when there was no deformation of the uterine cavity. Pregnancy and implantation rates were not influenced by the presence of subserosal fibroids. Surgical or medical treatment should be considered in infertile patients who have intramural and/or submucosal fibroids before resorting to ART treatment.

Recruitment of follicles by recombinant human follicle-stimulating hormone commencing in the luteal phase of the ovarian cycle.

OBJECTIVE: To investigate, in patients who previously had a suboptimal ovarian stimulation cycle, the benefit of starting ovarian stimulation before the onset of menses. DESIGN: Prospective, randomized, controlled study. SETTING: A tertiary referral center for infertility treatment. PATIENT(S): Forty patients undergoing IVF or GIFT from whom only 3-6 oocytes were retrieved in their last cycle. INTERVENTION(S): Recombinant human FSH was administered before the onset of the menstrual period (experimental group) or in the early follicular phase after the onset of menses (control group). MAIN OUTCOME MEASURE(S): The number of oocytes retrieved. RESULT(S): Patients in the experimental group were ready for oocyte retrieval on menstrual cycle day 11 instead of cycle day 14. The number of oocytes retrieved was not significantly different between the two groups. CONCLUSION(S): Poor responders do not benefit from commencing recombinant human FSH therapy in the luteal phase.

Double-blind placebo controlled study: human biosynthetic growth hormone for assisted reproductive technology.

OBJECTIVE: To study whether the effect of cotreatment with human biosynthetic GH improves the outcome of poor IVF responders. DESIGN: A double-blind placebo-controlled study using a GnRH agonist (GnRH-a) and gonadotropin in a "boost" flare-up protocol for ovarian stimulation together with either placebo, 4, or 12 IU of human GH followed by oocyte retrieval and IVF-ET. PATIENTS: Twenty-two patients with previously demonstrated poor responses in at least two assisted reproductive technology cycles were recruited. INTERVENTIONS: Pretreatment and post-treatment blood samples and daily morning blood samples during ovarian stimulation were collected after an overnight fast. Human GH or placebo and GnRH-a were administered SC; gonadotropin was administered IM. Oocytes were collected by ultrasound-guided transvaginal aspiration of follicles. Embryos were cultured in vitro and transferred transcervically. MAIN OUTCOME MEASURES: Serum E2, FSH, GH, insulin-like growth factor-I (IGF-1), IGF binding protein 1 (IGFBP-1), and IGFBP-3 concentrations. Number of FSH ampules, follicles, oocytes, embryos, and pregnancies. RESULTS: No improvement in cycle outcome was demonstrated with daily adjuvant human GH administration with either 4 or 12 IU. Serum IGF-I levels were highest in the 12 IU human GH group and lowest in the placebo group. Serum IGFBP-3 levels increased 2 days after IGF-I levels in the 12 IU human GH group only. Serum IGFBP-1 levels were unchanged in all groups. CONCLUSION: Poor IVF responders do not benefit from cotreatment with human GH during their ovarian stimulation.

Ultrasonographic appearance of polycystic ovaries is associated with exaggerated ovarian androgen and oestradiol responses to gonadotrophin-releasing hormone agonist in women undergoing assisted reproduction treatment.

While no single biochemical test is diagnostic of polycystic ovary syndrome (PCOS), most patients show a characteristic ovarian ultrasonographic appearance. It has been proposed that a dysfunction of cytochrome P-450c17 alpha in PCOS leads to an increased 17-hydroxyprogesterone (17-OHP) response to a gonadotrophin-releasing hormone (GnRH) agonist-induced gonadotrophin rise. We postulated that this abnormality of steroid metabolism might influence the ovarian response during assisted reproduction treatment. We investigated 106 patients undergoing a short 'boost' stimulation regimen for assisted reproduction treatment, including in-vitro fertilization and gamete intra-Fallopian transfers. The ovarian ultrasound pattern was correlated with serum testosterone, 17-OHP, androstenedione and oestradiol responses, and with the clinical outcome. Polycystic ovaries, defined ultrasonographically as the presence of > or = 10 follicles between 2 and 10 mm diameter in either ovary, were found in 48% of the whole study population. Dexamethasone was given to suppress adrenal androgen secretion. Functional ovarian hyperandrogenism (FOH) was defined as serum testosterone > 0.5 nmol/l after dexamethasone. There was a significantly (P < 0.001) higher prevalence of FOH in patients with polycystic ovaries (23%) compared with normal ovaries (7%). Patients with polycystic ovaries had approximately double the 17-OHP, androstenedione and oestradiol responses to a GnRH agonist as patients with non-polycystic ovaries. Exaggerated 17-OHP and oestradiol responses to GnRH agonist were found in 89% of patients with clinically diagnosed PCOS. The number of oocytes retrieved was positively correlated (r = 0.51, P < 0.001) with the oestradiol responses in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective study of inhibin in granulosa cell tumors of the ovary.

Elevated preoperative serum inhibin concentrations have been reported in patients with granulosa cell tumor of the ovary. The aim of this study was to determine if elevations in serum inhibin predated clinical recurrence in patients with a diagnosis of granulosa cell tumor. Twenty-seven consecutive patients with granulosa cell tumor were followed prospectively to assess the relationship between serum inhibin concentrations and disease status. The serum inhibin concentrations in normal postmenopausal women were < 77-130 U/liter. In patients with granulosa cell tumor at initial surgery, mean inhibin concentrations preoperatively were 2831 U/liter in 4 postmenopausal subjects (range 2130-3323 U/liter) and 3680 U/liter in each of 2 premenopausal women. In 5 postmenopausal subjects with a histological diagnosis of granulosa cell tumor who underwent secondary surgery because of a recurrent palpable mass, mean inhibin concentrations were 4216 U/liter (range 2672-7360). In 3 patients with known or suspected residual disease despite a secondary debulking operation the serum inhibin concentrations were 475, 1000, and 2541 U/liter. In 13 subjects who were clinically disease free with a previous diagnosis of granulosa cell tumor, serum inhibin concentrations remained within the normal range for reproductive status. We conclude: (1) Preoperative serum inhibin concentrations are typically elevated sevenfold above the normal premenopausal follicular phase levels in women with granulosa cell tumor; (2) after surgery, serum inhibin levels may become elevated up to 2 years before further surgery is undertaken; and (3) serum inhibin concentrations appear to be a valuable tumor marker for the diagnosis of primary or recurrent granulosa cell tumor.

Is the luteo-placental shift a myth? Analysis of low progesterone levels in successful art pregnancies.

Progesterone (P4) is considered vital to the maintenance of human pregnancy, but the minimal concentration of P4 necessary to sustain human pregnancy remains unclear. The aim of this study was to examine endocrine profiles for serum P4, 17 beta-estradiol (E2), and human (h) beta-CG in early pregnancy from a group of assisted reproductive technologies (ART) patients. These subjects delivered normally but had P4 concentrations below the fifth percentile of the normal singleton pregnancy range from 2 weeks after ART. Normal ranges of these hormones were determined from 118 consecutive ART pregnancies which resulted in singleton births. Values below the fifth percentile (P4 < 35.9 nmol/L at 4 weeks gestation) were considered abnormal. Eight patients who subsequently delivered normally, with serum P4 values below this criterion at 4 weeks gestation, were found. They had serum P4 values at 4 weeks gestation ranging from 1.9-29.9 nmol/L, and their mean P4 values at 5 weeks (30.2 +/- 9.2 nmol/L; mean +/- SE) and 6 weeks gestation (48.0 +/- 10.2 nmol/L) remained below the fifth percentile. No statistically significant increase in serum P4 concentrations occurred between 7 and 11 weeks gestation in these women. Their mean E2 value in serum at 4 weeks gestation (382 +/- 73 pmol/L) was also below the fifth percentile but their mean beta-hCG concentration was within the normal range. We conclude that successful human pregnancy is possible with serum P4 values within the anovulatory range in early gestation and that, in individual patients, serum P4 concentration of 2 nmol/L can be sufficient to maintain human pregnancy.

Serum immunoactive inhibin levels in early pregnancy after in vitro fertilization and embryo transfer.

OBJECTIVE: To determine the maternal serum concentrations of inhibin, E2, P, and hCG in early pregnancies arising from IVF and ET or GIFT and to assess the value of these hormone measurements in determining outcome of pregnancy. DESIGN: Serum immunoactive inhibin, E2, P, and hCG levels were measured in the first trimester of pregnancies after IVF-ET and GIFT procedures. SETTING: In vitro fertilization and ET or GIFT was undertaken at Monash IVF, Melbourne, Victoria, Australia. PATIENTS: At least two blood samples were collected from 117 women between 4 and 11 weeks of gestation. MAIN OUTCOME MEASURES: The hormone concentrations in the IVF-ET and GIFT pregnancies were compared with those in pregnancies and related to outcome of pregnancy. RESULTS: Serum inhibin levels in singleton pregnancies were significantly higher than in comparable normal pregnancies. In contrast to normal conceptions in which inhibin concentrations rose to peak at 11 weeks, the levels found in IVF-ET and GIFT singleton pregnancies were high at 5 weeks' gestation and declined subsequently. In twin pregnancies, the inhibin levels were significantly greater than those in singleton pregnancies. In biochemical pregnancies diagnosed by increasing hCG concentrations in the absence of an embryonic sac, inhibin levels were significantly lower than those found in singleton pregnancy, as were E2, P, and hCG levels. In anembryonic pregnancies, diagnosed by the confirmation of an intrauterine gestation sac with no evidence of a fetal complex, inhibin concentrations were highest at week 4 and declined, being significantly lower at all stages of gestation. In ectopic pregnancy, serum inhibin levels were lower at all stages of gestation, whereas E2 concentrations were not lower until 6 weeks and P levels until week 5. Serum hCG levels were significantly lower at all stages of gestation. In women with spontaneous abortions, inhibin levels were lower than singleton pregnancies at 7 weeks. CONCLUSIONS: Serum inhibin concentrations are elevated in pregnancies arising from ovarian hyperstimulation in the first trimester when compared with those in normal pregnancy, probably as a result of the presence of multiple corpora lutea resulting from ovarian hyperstimulation. Serum inhibin, E2, P, and hCG are useful markers of abnormal pregnancy outcome.

A controlled study of gonadotropin-releasing hormone agonist (buserelin acetate) for folliculogenesis in routine in vitro fertilization patients.

STUDY OBJECTIVE: To determine if gonadotropin-releasing hormone agonist (GnRH-a) and gonadotropin therapy could improve folliculogenesis and pregnancy rates (PRs) in women with a previously satisfactory response to clomiphene citrate and human menopausal gonadotropin (hMG). DESIGN: Randomized prospective study. SETTING: Assisted reproduction clinic. PATIENTS: One hundred fifty-seven women were randomized to receive either hMG alone or the GnRH-a buserelin acetate 600 microgram/d or buserelin acetate 1,200 microgram/d plus hMG. RESULTS: Compared with hMG alone, pretreatment with buserelin acetate significantly increased the PR per cycle started by preventing a premature luteinizing hormone rise and thereby reducing the number of abandoned cycles. There was, however, no difference between the number of follicles aspirated, oocytes obtained, or fertilization rates between groups. Furthermore, agonist therapy significantly increased both the dose of hMG required and the duration of stimulation. CONCLUSION: The routine use of GnRH-a in in vitro fertilization programs must be questioned.

Do raised serum luteinizing hormone levels during stimulation for in-vitro fertilization predict outcome?

Previous reports associating raised LH concentrations with reduced fertilization and pregnancy rates in women undergoing in-vitro fertilization (IVF) have assumed a Gaussian distribution of LH values with IVF treatment. We have determined the serum LH range during ovarian stimulation for IVF with a single regimen of clomiphene citrate/hMG from 102 consecutive IVF conception cycles. The results show a non-Gaussian distribution of LH values. Application of this LH range to a consecutive series of 596 women undergoing IVF treated with this single regimen showed no difference in pregnancy rates, fertilization rates, median number of oocytes fertilized or retrieved when analysed with respect to serum LH concentrations above the 75th or 95th centile for greater than or equal to 3 days of an IVF treatment cycle. We conclude that follicular-phase LH concentrations do not predict IVF fertilization rates or clinical outcome and are not clinically useful in individual patient management.

A controlled study of luteinizing hormone-releasing hormone agonist (buserelin) for the induction of folliculogenesis before in vitro fertilization.

Treatment with clomiphene citrate and human menopausal gonadotropin (HMG) is often used to induce folliculogenesis before in vitro fertilization, but not all women have an adequate response. It has been hypothesized that abnormally high levels of luteinizing hormone (LH) may contribute to the reduced folliculogenesis. We therefore performed a controlled, open trial in which treatment with buserelin, an agonist of luteinizing hormone-releasing hormone citrate and HMG in 44 consecutive women in whom no oocytes or only one had been produced by standard treatment with clomiphene and HMG. Twenty-nine women received buserelin with HMG, and 15 received clomiphene citrate with HMG. The median number of oocytes per patient recovered from those who received buserelin with HMG was 4 (range, 0 to 19), as compared with 0 (range, 0 to 5) in those who received clomiphene citrate with HMG. The fertilization rates of oocytes recovered from both groups of patients were similar (75.8 percent and 76.5 percent, respectively). Fifty-four percent of patients given buserelin with HMG underwent triple-embryo transfer, as compared with 13 percent of those given clomiphene citrate with HMG. Pregnancy (n = 3) occurred only among the patients receiving buserelin with HMG. In the buserelin-HMG group, significantly fewer oocytes were recovered from patients with occult ovarian failure (infertility and elevated follicular-phase levels of follicle-stimulating hormone, with regular menses) (median, 1; range, 0 to 4) than from those with other causes of infertility (median, 8; range, 0 to 19). Our data suggest that, except in women with occult ovarian failure, buserelin and HMG improve embryologic and clinical outcomes in patients with previously unsatisfactory stimulation of the ovaries for in vitro fertilization.

Predicting pregnancy outcome after in vitro fertilization and embryo transfer using estradiol, progesterone, and human chorionic gonadotropin beta-subunit.

Two hundred twenty consecutive in vitro fertilization (IVF) conception cycles were studied prospectively in order to examine the predictive value of serum human chorionic gonadotropin beta-subunit (beta-hCG), estradiol (E2), and progesterone (P) in predicting pregnancy outcome between 2 and 4 weeks after oocyte collection. To examine the predictive value of each hormone in predicting clinical pregnancy outcome, each patient's result at each week was assigned a scoring system based on the 25th percentile value of the concentration of beta-hCG, E2, and P in ongoing singleton IVF pregnancies for each week of the study. All but one ectopic pregnancies had scores of 0 or 1 points between 2 and 4 weeks after oocyte collection. The scores in successful pregnancies were significantly higher than in unsuccessful pregnancies 2 weeks after oocyte collection. Ninety percent of women scoring 3 points 2 weeks after oocyte collection had ongoing IVF pregnancies. The authors conclude that determination of serum beta-hCG, E2, and P concentrations between 2 and 4 weeks after oocyte collection provides clinically useful information not only in the prediction of ectopic IVF pregnancy, but also, conversely, in the identification of IVF pregnancies that are destined to be ongoing.

Serum inhibin levels in polycystic ovary syndrome: basal levels and response to luteinizing hormone-releasing hormone agonist and exogenous gonadotropin administration.

Serum inhibin levels were measured by RIA twice weekly for 4 weeks in 5 women with the polycystic ovary syndrome (PCOS). These were compared to those in 10 women with normal menstrual cycles. Serum inhibin levels were similar in the 5 PCOS women (mean, 199; range, 126-266 U/L) and were not significantly different from those in the normal women during the early follicular phase (227; 100-485 U/L) or midfollicular phase (243; 143-412 U/L) of their cycles. Inhibin levels were higher (P less than 0.001) in the late follicular phase (408; 227-732 U/L), at midcycle (623; 367-1058 U/L), and during the midluteal phase (1245; 898-1727 U/L) in the normal women compared to those in the PCOS group. Serum inhibin levels were also measured in PCOS (n = 8) and infertile (n = 14) women after the rise and subsequent diminished gonadotropin secretion that occurred during LHRH agonist administration. In both groups, serum LH and FSH increased after initiation of LHRH agonist administration; this increase was accompanied by parallel rises in serum estradiol and inhibin before suppression (PCOS women: r = 0.71; P less than 0.001; n = 108; infertile women: r = 0.42; P less than 0.05; n = 163). All hormone levels, including inhibin, decreased during continued LHRH administration. Five PCOS women underwent ovulation induction using combined LHRH agonist and human menopausal gonadotropin administration. Serum estradiol and inhibin rose in parallel in response to exogenous gonadotropins (r = 0.92; P less than 0.001; n = 77). In conclusion, we found no evidence of a primary defect in ovarian inhibin physiology in women with PCOS in terms of either basal or gonadotropin-stimulated (exogenous or endogenous) secretion.