Cristin C. Slater

Monozygotic twins and triplets in association with blastocyst transfer.

AbstractPurpose: To compare the incidence of monozygotic twins following blastocyst versus day-3 embryo transfer (ET). Methods: A retrospective analysis of the outcome of assisted reproductive technology (ART) cycles utilizing blastocyst ET during 1999–2000 was compared to a similar group of patients undergoing day-3 ET during 1997–1998. Results: Blastocyst ET was used in 75 cycles with 2.0 ± 2 embryos transferred. The comparison group consisted of 90 cycles with day-3 ET and 3.0 ± 2 embryos transferred. Conclusions: High pregnancy rates are maintained with blastocyst ET even though fewer embryos are transferred. The rate of monozygotic twins is higher with blastocyst ET than with day-3 ET. This increase may partially negate the benefit of reduced high-order multiple gestations attributed to blastocyst ET.

Endocrine and clinical effects of micronized estradiol administered vaginally or orally

OBJECTIVE To determine the impact of the vaginal route of micronized estradiol (E(2)) administration upon hepatic globulin and lipid production and upon the outcome of oocyte donation cycles in which the recipients received E(2) via this route. DESIGN Series report. SETTING University-based assisted reproduction techniques (ART) program. PATIENT(S) Recipients of donor oocytes. INTERVENTION(S) Administration of micronized E(2) via the oral or vaginal route, oocyte donation, and embryo transfer. MAIN OUTCOME MEASURE(S) Measurements of the serum levels of free E(2), sex hormone-binding globulin (SHBG), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), as well as endometrial thickness and pregnancy outcome. RESULT(S) Serum SHBG and lipoprotein levels were unaltered by the vaginal as compared with the oral route of E(2) administration. Serum free E(2) levels were significantly higher after vaginal administration. Ten patients who had previously failed to achieve adequate endometrial thickness with an oral regimen were found to have adequate endometrial thickness after vaginal E(2) administration and seven of them achieved an ongoing pregnancy after embryo transfer. CONCLUSION(S) Vaginal administration of micronized E(2) results in significantly higher free serum E(2) levels when compared to levels achieved after oral E(2) administration. Hepatic globulin and lipoprotein production is similar despite 10-fold higher serum E(2) levels after the vaginal administration. The greater efficiency of E(2) delivery to the endometrium after vaginal administration makes this route a good option for patients who fail to achieve adequate endometrial thickness with oral E(2) administration.

Markedly elevated levels of estrone sulfate after long-term oral, but not transdermal, administration of estradiol in postmenopausal women.

ObjectiveTo compare serum estrone sulfate (E1S) levels in postmenopausal women during long-term treatment with commonly prescribed doses of oral and transdermal estradiol (E2). DesignA retrospective study performed in a University setting in the United States involving 33 healthy postmenopausal women. Two groups of postmenopausal women were studied: group 1 (n = 10) received 1 mg oral micronized E2 daily for 16 months; blood was drawn at 0, 7, and 15 months. Group 2 (n = 23) was randomized into three subgroups. Two of the subgroups (n = 8;n = 7) received E2 delivered at a rate of 0.05 mg/day and 0.1 mg/day, respectively, by transdermal patch, changed twice weekly; the third subgroup received a placebo (without E2) patch for 9 continuous months. Blood samples were drawn at 0, 6, and 9 months. Serum E1S and E2 were quantified by specific radioimmunoassays. Statistical analysis was performed by analysis of variance. ResultsAfter oral E2 treatment, E1S levels increased significantly (p < 0.01) from baseline, reaching an average level of 38.8 ng/mL at 15 months. After transdermal E2 treatment, E1S levels increased significantly, yet to a much lesser extent, reaching levels of 1.8 ng/mL and 3.2 ng/mL after 9 months of treatment with the 0.05 mg/day and 0.1 mg/day patches, respectively. ConclusionsMarkedly elevated levels of E1S were found after long-term oral estrogen treatment. In comparison to the increase in E1S levels after long-term oral estrogen treatment, there was only a small increase in E1S levels after transdermal E2 therapy. This difference may be attributed to the higher dosage of oral E2 that is required because of the low bioavailability compared with the transdermal dosages.

Pharmacokinetics of testosterone after percutaneous gel or buccal administration

OBJECTIVE To determine the pharmacokinetics of testosterone following its administration using transdermal gel or buccal lozenges. DESIGN Pilot study. SETTING University-based hospital. PATIENT(S) Ten bilaterally oophorectomized women. INTERVENTION(S) Daily micronized testosterone gel (1 mg) and testosterone propionate lozenge (1 mg). MAIN OUTCOME MEASURE(S) Total testosterone, androstenedione, dihydrotestosterone, 3alpha-androstanediol glucuronide, and sex hormone-binding globulin were measured in serum by specific radioimmunoassays; free testosterone levels were also calculated. RESULT(S) Before treatment, serum testosterone levels in the groups using the lozenge and gel were 16 +/- 4.0 and 20 +/- 6.0 ng/dL, respectively. Mean maximum testosterone levels obtained with the lozenge occurred 1 hour after administration on days 1 (692 +/- 236 ng/dL) and 14 (836 +/- 309 ng/dL) of treatment and fell precipitously thereafter. In contrast, testosterone levels obtained with the gel showed a prolonged rise reaching maximal levels of 97 +/- 78 and 100 +/- 60 ng/dL after 18 hours. The serum level patterns of free testosterone, dihydrotestosterone, and 3alpha-androstanediol glucuronide were similar to the corresponding total testosterone levels. CONCLUSION(S) Administration of testosterone lozenge by buccal absorption produced a rapid and brief elevation of testosterone levels, with levels reaching upper limits of the male range. In contrast, transdermal testosterone gel absorption resulted in a prolonged elevation of testosterone levels, which were in the hyperandrogenic female range but resembled steady state pharmacokinetics.

Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization

OBJECTIVE To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF. DESIGN Phase 3 randomized, double-blind, noninferiority trial. SETTING Multicenter trial. PATIENT(S) A total of 1,390 women aged 35-42 years. INTERVENTION(S) A single injection of 150 μg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach ≥17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3. MAIN OUTCOME MEASURE(S) Vital pregnancy rate (PR), number of oocytes, and live birth rate. RESULT(S) Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (-7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (-0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) -2.3% (-6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups. CONCLUSION(S) Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated. CLINICAL TRIAL REGISTRATION NUMBER NCT01144416.

Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term oral dehydroepiandrosterone treatment in postmenopausal women

Objective: Some postmenopausal women use over-the-counter dehydroepiandrosterone because of its purported beneficial effects. Although without major inherent androgenic activity, it is metabolized to potent androgens and estrogens. We investigated the pharmacokinetics of dehydroepiandrosterone and its relevant metabolites after prolonged treatment of postmenopausal women with 25 mg/d of dehydroepiandrosterone. Methods: Twenty healthy postmenopausal women were randomized to either 25 mg/d of dehydroepiandrosterone or placebo for 6 months. Frequent blood samples were obtained over 24 hours on day 1 and after 3 and 6 months. Results: Mean baseline androgen levels at day 1 and month 3 in the treated group (seven evaluable women) were the following: dehydroepiandrosterone, 1.82 and 3.56 ng/mL; dehydroepiandrosterone sulfate, 0.96 and 3.37 &mgr;g/mL; 5-androstene-3&bgr;,17&bgr;-diol, 0.32 and 0.66 ng/mL; androstenedione, 0.50 and 0.86 ng/mL; testosterone, 17.9 and 28.7 ng/dL; dihydrotestosterone, 6.91 and 17.4 ng/dL; and 3&agr;-androstanediol glucuronide, 2.66 and 10.7 ng/mL, respectively; these increases were significant. Small changes (−6% to 16%) were observed from month 3 to month 6. Nonsignificant increases were observed in baseline estrone and estradiol levels and in Cmax and AUC0-24h values for the androgens and estrogens from day 1 to months 3 and 6 of treatment. Sex hormone-binding globulin levels were unchanged, but free testosterone increased significantly from day 1 to month 3. Baseline hormone levels did not increase in the placebo group (six evaluable women). Changes in baseline values over time differed significantly between the groups for all hormones except estrone and estradiol. Conclusions: In postmenopausal women treated orally with a commonly available dose of dehydroepiandrosterone, the daily exposure (AUC) of dehydroepiandrosterone and its principal androgenic metabolites was found to be similar during 6 months of treatment despite increased serum baseline concentrations of these androgens.

Treatment-Associated Serum FSH Levels in Very Poor Responders to Ovarian Stimulation

AbstractPurpose: To compare treatment-associated follicle-stimulating hormone (FSH) response in patients undergoing controlled ovarian hyperstimulation with either microdose flare (MDF) leuprolide acetate or clomiphene citrate and human menopausal gonadotropin (CC/hMG). Methods: Thirteen patients who were deemed poor responders underwent stimulation with one of two poor responder stimulation protocols (MDF group: n = 8; CC/hMG group: n = 5). Serum FSH, estrone (E1), estrone sulfate (E1S), and estradiol (E2) levels were measured at baseline, day 5 of medication, and on day of hCG administration. Ovarian and uterine responses were evaluated by ultrasound. Results: Treatment-associated FSH levels were consistently higher in the group that took CC/hMG. However, serum E1, E1S, and E2 values were similar in both groups as were the number of oocytes retrieved and the endometrial echo complex. There were no differences between the two groups with regards to the quality of the oocytes obtained, fertilization rate, or the quality of the embryos. Conclusion: Clomiphene citrate, when administered in conjunction with exogenous hMG, is a more potent stimulator of FSH production than MDF leuprolide acetate among poor responders to ovarian stimulation. However, the number of oocytes is not increased.

Clinical Assisted Reproduction: Altered Balance Between the 5α-Reductase and Aromatase Pathways of Androgen Metabolism During Controlled Ovarian Hyperstimulation with Human Menopausal Gonadotropins

AbstractPurpose: To evaluate androgen production and metabolism during controlled ovarian hyperstimulation. Methods: Five women, aged 33–42, were studied. All participants were undergoing controlled ovarian hyperstimulation with gonadotropin-releasing hormone agonist and human menopausal gonadotropins. Serum estradiol, estrone, androstenedione, testosterone, 3α-androstanediol glucuronide, and sex hormone-binding globulin levels were measured at 6 time points during the cycle. Results: The levels of all steroids increased significantly from baseline during controlled ovarian hyperstimulation. Mean total testosterone levels increased from 0.29 ± 0.05 ng/mL to 0.58 ± 0.07 ng/mL after gonadotropin stimulation. Sex hormone-binding gonadotropin levels increased from 50 ± 16 nM to 73 ± 12 nM after gonadotropin stimulation. Estrone/androstenedione and estradiol/testosterone ratios, reflecting the aromatase pathway, increased whereas 3α-androstanediol glucuronide/androstenedione and 3α-androstanediol glucuronide/testosterone ratios, reflecting 5α-reductase activity, decreased. Conclusions: Controlled ovarian hyperstimulation with human menopausal gonadotropins results in increased serum testosterone and androstenedione levels. Whereas there is an enhancement in androgen metabolism by aromatase, 5α-reductase activity with regard to androgen metabolism is diminished.

The prognostic significance of day 3 embryo cleavage stage on subsequent blastocyst development in a sequential culture system.

AbstractPurpose: To determine prognostic significance of blastomere number on Day 3 of culture upon subsequent blastocyst (BL) development. Methods: A retrospective analysis was conducted in 37 IVF subjects undergoing standard protocols and BL transfer after sequential embryo culture in P1 and BL media. Results: Of Day 3 embryos containing 7 or more blastomeres, 68.9% (186/270) developed into BL compared to embryos containing 4–6 blastomeres, 38.1% (56/147), P < 0.0001. The majority of BL, 68.9% (168/244), were observed on Day 5. Extended Day 6 culture represented 31.1% (76/244) of all BLs. Conclusions: The observation of 7 or more blastomeres on Day 3 yielded a significantly greater likelihood of BL development. Embryos containing 4–6 blastomeres are still relatively likely to progress to a BL. Extended culture to Day 6 still yields a significant proportion of BL. Cell cleavage stage on Day 3 appears to be a useful prognostic indicator of subsequent BL development.