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Epidemiologic studies have shown an increased rate of adverse perinatal outcomes, including small for gestational age (SGA) births, in fresh in vitro fertilization (IVF) cycles compared with frozen embryo transfer cycles. This increase is not seen in the donor oocyte population, suggesting that it is the peri-implantation environment created after superovulation that is responsible for these changes. During a fresh IVF cycle, multiple corpora lutea secrete high levels of hormones and other factors that can affect the endometrium and the implanting embryo. In this review, we discuss both animal and human data demonstrating that superovulation has significant effects on the endometrium and embryo. Additionally, potential mechanisms for the adverse effects of gonadotropin stimulation on implantation and placental development are proposed. We think that these data, along with the growing body of epidemiologic evidence, support the proposal that frozen embryo transfer should be considered preferentially, particularly in high responders, as a means to potentially decrease at least some of the adverse perinatal outcomes associated with IVF., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To examine whether visfatin administration during superovulation improves ovarian response, developmental competence of oocytes, and fertility in aged female mice., Design: Controlled experimental study., Setting: University hospital., Animal(s): Two groups of differently aged C57BL female mice (6-11 and 26-31 weeks)., Intervention(s): Female mice were coinjected intraperitoneally with 5 IU pregnant mare's serum gonadotropin (PMSG) and visfatin of various doses (0-500 ng/mL), followed by 5 IU human chorionic gonadotropin (hCG) injection 48 hours later. Then the mice were immediately mated with an individual male. After 18 hours zygotes were cultured, and expression of ovarian visfatin and vascular endothelial growth factor (VEGF) was examined. Potential pregnancies of visfatin-administered aged female mice were monitored for delivery of offspring., Main Outcome Measure(s): Number of zygotes retrieved, embryo developmental competency, fertility potential, ovarian visfatin and VEGF expression., Result(s): Ovarian visfatin expression was significantly decreased in the aged mice group compared with the young. Visfatin administration significantly increased embryo developmental rate and ovarian visfatin and VEGF expressions in the aged mice. Visfatin-administered aged mice delivered significantly higher numbers of offspring than controls., Conclusion(s): This study suggests that visfatin administration during superovulation plays an important role in regulating oocyte quality and can improve oocyte quality and fertility of aged female mice., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Because of its size of 32 kDa and physicochemical properties, urinary FSH cannot permeate intact skin. We report the first pregnancy after laser microporation and transdermal delivery of FSH for ovarian superovulation as a substitute for SC or IM injections., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Our objective is to report observed changes in thyroid-stimulating hormone (TSH) in two patients undergoing super-ovulation for IVF., Design: Case report., Setting: Private assisted reproduction practices., Patient(s): Two hypothyroid women taking thyroxine replacement therapy undergoing super-ovulation for IVF., Intervention(s): Laboratory records for TSH taken during ovulation induction cycles were retrieved retrospectively for six cycles and measured prospectively for one cycle each in both women., Main Outcome Measure(s): To document changes in thyroid status during super-ovulation., Result(s): Despite being euthyroid at the start of the super-ovulation cycle, both patients demonstrated a rise in TSH to hypothyroid levels during ovulation induction, even in the absence of ongoing pregnancy., Conclusion(s): High circulating E(2) during super-ovulation for IVF induces increased thyroxine-binding globulin binding of thyroxine. In women taking thyroxine replacement therapy, hypothyroidism develops during a super-ovulation cycle. Whether such acute biochemical hypothyroidism is a hindrance to ovum quality, fertilization, conception, or ongoing pregnancy and whether thyroxine dose adjustment during a super-ovulation cycle would improve IVF outcomes requires further study. These case studies identify a potential management gap in assisted reproduction for women taking thyroxine therapy., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the ASRM Publication Committee Several reports of randomized clinical trials were recently the subject of an investigation conducted by the publications committee of the ASRM. The committee reviewed concerns related to the validity of data reported in those reports. The committee noted significant duplication of data reported in this manuscript with data reported in another journal (PMID: 17582406; https://doi.org/10.1016/j.fertnstert.2007.02.062) pertaining to a different study group that could not be explained. As we cannot vouch for the validity of the data, we have issued a retraction of this paper.

Objective: To determine which protocols work better between cetrorelix and long protocols in older patients in a randomized controlled study., Design: A controlled randomized study in a single private IVF center., Setting: Infertile women referred to a private IVF center., Patient(s): Five hundred sixty-four women 40 years or older undergoing IVF., Intervention(s): At their first IVF cycle, the women were randomized into two study groups using a computer-generated number sequence: 281 cases were treated with the cetrorelix protocol, and 283 patients were treated with a long protocol for controlled ovarian hyperstimulation., Main Outcome Measure(s): Days of stimulation, E(2) on the day of hCG administration, amount of FSH administered, number of oocytes yielded, number of embryos obtained, pregnancy rate, and implantation rate., Result(s): Patients treated with the long protocol showed a significantly higher number of oocytes retrieved and a higher pregnancy rate for both the cycle and transfer with respect to the cetrorelix protocol patients. The other parameter evaluated did not show any statistically significant differences., Conclusion(s): Our study showed that the long protocol performed better in older women than the cetrorelix protocol and that the GnRH antagonist may be detrimental in older women.

Objective: To investigate whether sodium nitroprusside (SNP) treatment during the superovulation process improves ovarian response and oocyte developmental competence in aged female mice., Design: Controlled experimental study., Setting: Large urban medical center., Animal(s): C57BL inbred female mice of three age groups: 6 to 9, 14 to 16, and 25 to 27 weeks., Intervention(s): Female mice were co-injected intraperitoneally with SNP (1 muM or 10 muM) and pregnant mare's serum gonadotropin (PMSG), followed by human chorionic gonadotropin injection 48 hours later and then mated with individual males. After 18 hours, zygotes were flushed and the ovaries were isolated. The control group was injected with PMSG., Main Outcome Measure(s): The number of zygotes flushed, embryo development to blastocyst stage, and vascular endothelial growth factor (VEGF) expression in ovary., Result(s): Treatment with SNP statistically significantly increased the number of flushed zygotes and blastocyst formation rate in mice aged 25 to 27 weeks, not but in mice aged less than 16 weeks compared with the control group. The SNP treatment in aged mice increased VEGF expression of the ovary in a dose-dependent manner., Conclusion(s): These results demonstrate that SNP treatment during the superovulation process improves ovarian response and oocyte developmental competence in aged female. The positive effect of SNP may be associated with increased VEGF expression.

Objective: To evaluate the individual functionality of gonadotropin-stimulated preovulatory follicles, for understanding embryo failure in assisted reproductive technique cycles, in a sheep model., Design: Observational, model study., Setting: Public research unit., Animal(s): Fifteen adult Manchega ewes., Intervention(s): Synchronization of the estrous cycle with intravaginal progestagens and ovarian stimulation with FSH; evaluation of reproductive activity, plasma sampling, ovarian ultrasonography, and ovariectomies., Main Outcome Measure(s): Determination of estrus behavior, plasma and intrafollicular concentrations of E(2) and inhibin A, number and size of ovarian follicles, and developmental competence of oocytes., Result(s): These results support the usefulness of serial measurements of plasma inhibin A for assessment of follicular growth during the FSH treatment, rather than of E(2) assays commonly used. Functionality of FSH-stimulated preovulatory follicles is clearly disturbed, as confirmed by a negative correlation between follicular size and intrafollicular concentrations of inhibin A and E(2) in preovulatory follicles after individual dissection; moreover, the ability of their oocytes to resume meiosis was diminished., Conclusion(s): Functionality of follicles in controlled ovarian stimulation (COS), and developmental competence of their oocytes, is disturbed by the high doses of gonadotropin supplied and finally determined by follicular sizes at starting FSH treatment.

Objective: To determine whether the short or long protocol for controlled ovarian hyperstimulation works better in older patients undergoing IVF., Design: Controlled, randomized study., Setting: A single private IVF center., Patient(s): Two hundred twenty infertile women aged > or = 40 years undergoing IVF., Intervention(s): At their first IVF cycle, the women were randomized into two study groups according to a computer-generated number sequence: 110 patients were treated with a long protocol, and the other 110 were treated with a short protocol for controlled ovarian hyperstimulation., Main Outcome Measure(s): Days of stimulation, E2 level at the day of hCG administration, amount of FSH administered, number of oocytes collected, number of embryos obtained, pregnancy rate, implantation rate., Result(s): Patients treated with a long protocol showed a significantly higher number of oocytes retrieved, a higher number of embryos obtained, and a higher pregnancy rate, both for cycle and transfer, compared with the short-protocol patients. The other parameters evaluated did not show any statistically significant differences., Conclusion(s): Our study showed that the long protocol performed better than the short protocol in older women. Our findings demonstrated that flare-up in older women might be detrimental.

Objective: To investigate the effects of letrozole in patients undergoing superovulation with gonadotropins and IUI., Design: Retrospective analysis., Setting: Academic teaching hospital., Patient(s): Women younger than 40 years of age with patent fallopian tubes and infertility of more than 1 year in duration who were undergoing IUI and gonadotropin therapy., Intervention(s): Gonadotropins alone administered from day 3 or a combination of letrozole, 5 mg/d on day 3 to 7, and gonadotropins starting on day 5 of the menstrual cycle. Ultrasonography was performed before initiation of treatment, on day 9 of menstrual cycle, and as required thereafter until the dominant follicle reached 18 mm in diameter. Ovulation was triggered with 10,000 IU of hCG, and IUI was performed 24 and 48 hours later., Main Outcome Measure(s): Gonadotropin requirements, endometrial thickness, number of follicles, and pregnancy rate., Result(s): All 205 IUI treatment cycles conducted from March 2001 to March 2002 were included. Gonadotropins alone were used in 145 cycles and combination therapy was used in 60 cycles. Patients cotreated with letrozole required fewer gonadotropin administrations (median difference, 300 IU [95% confidence interval (CI), 225-375 IU]), developed more follicles larger than 14 mm (median difference, 1 follicle [95% CI, 1-2 follicles), and had a thinner endometrium (median difference, 1 mm [95% CI, 0.4-1.6 mm]). The pregnancy rate did not differ between patients using gonadotropin alone and those using gonadotropin plus letrozole (20.9% vs. 21.6%)., Conclusion(s): The addition of letrozole to gonadotropins decreases gonadotropin requirements, increases the number of pre-ovulatory follicles and decreases endometrial thickness, without a negative effect on pregnancy rates.

Objective: To investigate the clinical efficacy of mild inhibition of ovarian steroidogenesis by very low-dose ketoconazole during induction of ovulation in patients with polycystic ovary syndrome (PCOS)., Design: Prospective, randomized, cross-controlled study in consecutive cycles., Setting: Large tertiary care center., Patient(s): Eighteen patients with PCOS undergoing hMG superovulation with or without ketoconazole., Intervention(s): A fixed hMG dosage was initiated on cycle days 5-9 in both of the study cycles. Further hMG adjustment was done according to serum E2 levels and follicular measurements. Ketoconazole was administered in one of the cycles by two protocols., Main Outcome Measure(s): Serum E2 and P levels, lead follicles, pregnancy rate, and development of ovarian hyperstimulation syndrome., Result(s): Although higher daily hMG doses were needed in cycles with ketoconazole compared with cycles without the drug, the peak E2 levels were substantially lower in the ketoconazole cycles. Although the number of lead follicles did not differ between treatments, the addition of ketoconazole significantly reduced the number of hyperstimulated cycles. Consequently, the cancellation rate dropped dramatically, thus yielding a higher pregnancy rate per patient in the ketoconazole protocols., Conclusion(s): Use of a very low dose of ketoconazole during ovulation induction effectively attenuates ovarian steroidogenesis in patients with PCOS. This effect may serve as an adjunct to better control the ovarian response in women who are prone to hyperstimulated cycles.

Objective: To determine the efficacy of superovulation with buserelin acetate, human menopausal gonadotropins (hMG), and human chorionic gonadotropin (hCG) in the treatment of infertility associated with minimal or mild endometriosis., Design: Prospective, randomized, controlled study., Subjects: Forty-nine infertile women with a laparoscopic diagnosis of endometriosis stage I (n = 29) or II (n = 20) according to the revised American Fertility Society classification, randomly assigned to three superovulation cycles (n = 24) or 6 months' expectant management (n = 25)., Main Outcome Measures: Cycle fecundity rates and cumulative pregnancy rates (CPR) in the two groups., Results: Nine pregnancies were obtained in the superovulation-treated patients and six in the nontreated ones. The cycle fecundity rates and CPR were 0.15% and 37.4% after three superovulation cycles and 0.045% and 24% after 6 months of expectant management (P less than 0.05 and P = not significant, respectively). The women who did not achieve a pregnancy after three cycles of superovulation were followed for a total of 50 months during which no therapy was given. One pregnancy started in this period (cycle fecundity rate = 0.020). One spontaneous abortion occurred in each group. Three treated patients had multiple pregnancies, and four had ovarian hyperstimulation syndrome., Conclusion: Superovulation seems to be associated with a better cycle fecundity rate but not a better CPR than expectant management in infertile women with endometriosis stages I and II. The efficacy and side effects of this therapeutic approach should be evaluated in larger series.

Ovarian stimulation after pituitary suppression with gonadotropin-releasing hormone agonists (GnRH-a) has been effective in women who have exhibited a poor response to conventional superovulation strategies. Their effectiveness in unselected women undergoing their first cycle of in vitro fertilization or gamete intrafallopian transfer, however, remains to be established. To address this question, we randomized 114 women to one of two treatment protocols. Protocol 1 consisted of 100 mg of clomiphene citrate on days 5 to 9, followed by 150 IU human menopausal gonadotropin (hMG) beginning on day 9. Protocol 2 consisted of daily GnRH-a beginning in the midluteal phase. Stimulation with 150 IU hMG commenced after pituitary down regulation and ovarian suppression were achieved. Human menopausal gonadotropin was continued in both protocols until adequate follicular development and serum estradiol concentrations were obtained. Protocol 2 patients reached egg retrieval significantly more often (87%) than Protocol 1 patients (61%), but the mean number of mature eggs retrieved and the pregnancy rate per retrieval were not significantly different between the two groups.

Pituitary suppression with leuprolide acetate (LA) was used before and during ovarian stimulation with human menopausal gonadotropins in 45 consecutive women having their first cycle of in vitro fertilization embryo transfer (IVF-ET). As anticipated, a low rate of cycle cancellation (6.7%) was necessary for poor responses. Follicles were allowed to develop to a larger diameter than with our prior protocol without LA. On the day of human chorionic gonadotropin (hCG), 11.5 + 0.7 follicles of at least 1.0 cm were visualized; 11.7 + 0.9 oocytes were retrieved; 67.5% fertilized and 6.7 + 0.6 normal embryos were available for transfer. Of the 3.4 + 0.1 embryos transferred per patient, 24.6% implanted. The rates of clinical pregnancy per retrieval and per stimulation were 54% and 47%, respectively, of which 23.8% aborted. Routine use of LA resulted in a highly efficient level of ongoing pregnancy per initiated cycle, and therefore may produce a superior first cycle for IVF-ET.

A total of 54 human fetal cord sera, 42 lots of Ham's F-10 medium, and 36 lots of plastics were tested during a 10-month period with a mouse in vivo fertilization system. Two-cell embryos were collected from the oviducts of superovulated and mated (C57BL/6 X CBA)F1 mice. After collection, 2-cell embryos were distributed among test media and a modified Krebs-Ringer control medium. The test material passed quality control standards if a minimum of 80% of the original 2-cell embryos reached the blastocyst stage. Of the 54 cord sera examined, 8 (15%) were below our standards; 6 (14%) of the Ham's F-10 media and 4 (11%) of the plastics failed to pass minimum requirements. In all cases, the failed materials promoted slower-growing mouse embryos and increased the number of degenerates. It is our opinion that the mouse in vivo fertilization system has a valuable place in any in vitro fertilization program.

Sequential treatment with clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin was successfully applied to 149 women in the framework of an in vitro fertilization and embryo transfer program and led to the birth of normal children. An average of 3.5 follicles was promoted at each cycle. Oocyte maturity was evaluated at recovery either histologically or with respect to cumulus-oocyte complexes (COC) and correlated to oocyte fertilizability. Three types of COC are described according to cell dissociation and mucification. The most expanded cumulus mass (type I) was highly fertilizable, compared with granular and poorly dissociated cumulus complexes (types II and III, respectively). No improvement in the type II and III oocyte fertilizability was obtained when type I follicular fluid was added to the incubation medium. Moreover, incubation of type III oocytes in medium containing type III follicular fluid seemed to decrease their fertilizability.

This report is an analysis of 16 cycles in 15 patients stimulated with human menopausal gonadotropin and clomiphene citrate for the purpose of follicular recruitment in an in vitro fertilization program, all of which resulted in endogenous luteinizing hormone (LH) surges. A study of the pattern of estradiol (E2) response to stimulation revealed two groups of cycles, designated "leap" pattern (9 cycles) and "plateau" pattern (7 cycles), the rate of rise of E2 increasing or decreasing, respectively, as the time of the LH surge was approached. There were no significant differences between these groups of cycles in the peak E2 level attained or the number of follicles greater than or equal to 12 mm on the day of peak E2. In the plateau, but not in the leap pattern cycles, a significant correlation (r = 0.958) was found between the number of follicles greater than or equal to 12 mm and the peak E2. We tentatively conclude that "plateau" pattern cycles reflect relatively synchronous follicular recruitment; the greater the number of follicles recruited, the higher the E2 level attained, increased amounts of inhibin-like substances being available to restrain the LH surge; "leap" pattern cycles reflect asynchronous follicular recruitment.

Aged (12- to 14-month-old) estrous and diestrous C57BL mice exhibited lower histochemically demonstrable ovarian delta5-3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity in thecal, luteal, and interstitial cells, and lower (P less than 0.01) ovarian 3beta-HSD concentration and total content than did young (3-month-old) estrous animals. Administration of pregnant mare serum (PMS, 10 IU subcutaneously), followed in 40 hours by human chorionic gonadotropin (HCG, 5 IU subcutaneously) or HCG (2 IU daily for 4 days) alone, restored luteal and interstitial 3beta-HSD in aged mice. Follicular, lutea, and interstitial 3beta-HSD activity was increased in aged mice by a single PMS injection (10 IU). The total ovarian dehydrogenase concentration was increased 100% in aged animals by PMS and/or HCG administration. Restoration of histochemically demonstrable ovarian 3beta-HSD and total enzyme content in aged mice by PMS and/or HCG indicates ovarian sensitivity to gonadotropin and subnormal tropic hormone stimulation of the ovary in situ.

Twenty patients entered a randomized, crossover study of purified follicle-stimulating hormone (pure-FSH) or human menopausal gonadotropin (hMG) superovulation, 2 ampules per day after pituitary desensitization with the luteinizing hormone-releasing hormone (LH-RH) analogue Buserelin (D-Ser tBu6 LH-RH 1-9 ethylamide) nasal spray. There were no cycles cancelled. Six patients conceived (five on pure-FSH, one on hMG). There were 24.2 +/- 2.5 (mean +/- standard error of the mean [SEM]) ampules of pure-FSH and 24.3 +/- 3.6 ampules of hMG stimulation required. There were similar numbers of preoperation follicles: 6.9 +/- 1.0 on hMG and 6.6 +/- 1.1 on pure-FSH, of oocytes collected; 8.5 +/- 1.4 on hMG and 5.8 +/- 1.4 on pure-FSH, and of pre-embryos achieved; 5.1 +/- 0.9 on hMG and 3.4 +/- 1.0 on pure-FSH; on either treatment. The fertilization rate on hMG was 60% and on pure-FSH was 55%. Pre-embryo transfer rates were 3.2 +/- 0.3 in the hMG group and 2.7 +/- 0.4 in the pure-FSH group. There were no differences in serum FSH, LH, estradiol, or progesterone levels between the hMG and pure-FSH groups. Mean +/- SEM luteal phase length was 10.6 +/- 0.4 days in the nonpregnant cycles.

A study was undertaken as a controlled comparison of two different superovulation induction protocols currently in use in major Australian in vitro fertilization (IVF) clinics. Thirty patients each from the Monash University and the Royal Women's Hospital (RWH) IVF programs were stimulated for ovulation induction by the other program. Once timing for oocyte retrieval was scheduled, all care reverted to the program from which the patient first came. Results given as pregnancies per patient commencing stimulation were: RWH patients on Monash protocol, 27%; RWH control patients, 15%; Monash patients on RWH protocol, 7%; Monash control patients, 13%. In the year preceding the trial pregnancy rates were 16.9% at Monash and 10.6% at RWH. Stimulation protocols were also compared with respect to each of administration, cost, and patient stress. The results of this cross-over trial demonstrated major differences between the two ovulation induction protocols studied, although it was not possible to conclude that differences in pregnancy rate were due to stimulation alone.