Effect of Timing by Endometrial Receptivity Testing vs Standard Timing of Frozen Embryo Transfer on Live Birth in Patients Undergoing In Vitro Fertilization: A Randomized Clinical Trial.

Importance: Endometrial receptivity testing is purported to improve live birth following frozen embryo transfer by identifying the optimal embryo transfer time for an individual patient; however, data are conflicting. Objective: To compare live birth from single euploid frozen embryo transfer according to endometrial receptivity testing vs standardized timing. Design, Setting, and Participants: Double-blind, randomized clinical trial at 30 sites within a multicenter private fertility practice in the Eastern US. Enrollment was from May 2018 to September 2020; follow-up concluded in August 2021. Participants underwent in vitro fertilization, preimplantation genetic testing for aneuploidy, endometrial receptivity testing, and frozen embryo transfer. Those with euploid blastocyst(s) and an informative receptivity result were randomized. Exclusion criteria included recurrent pregnancy loss, recurrent implantation failure, surgically aspirated sperm, donor egg(s), and unmitigated anatomic uterine cavity defects. Interventions: The intervention group (n = 381) underwent receptivity-timed frozen embryo transfer, with adjusted duration of progesterone exposure prior to transfer, if indicated by receptivity testing. The control group (n = 386) underwent transfer at standard timing, regardless of receptivity test results. Main Outcomes and Measures: The primary outcome was live birth. There were 3 secondary outcomes, including biochemical pregnancy and clinical pregnancy. Results: Among 767 participants who were randomized (mean age, 35 years), 755 (98%) completed the trial. All randomized participants were analyzed. The primary outcome of live birth occurred in 58.5% of transfers (223 of 381) in the intervention group vs 61.9% of transfers (239 of 386) in the control group (difference, -3.4% [95% CI, -10.3% to 3.5%]; rate ratio [RR], 0.95 [95% CI, 0.79 to 1.13]; P = .38). There were no significant differences in the intervention vs the control group for the prespecified secondary outcomes, including biochemical pregnancy rate (77.2% vs 79.5%, respectively; difference, -2.3% [95% CI, -8.2% to 3.5%]; RR, 0.97 [95% CI, 0.83 to 1.14]; P = .48) and clinical pregnancy rate (68.8% vs 72.8%, respectively; difference, -4.0% [95% CI, -10.4% to 2.4%]; RR, 0.94 [95% CI, 0.80 to 1.12]; P = .25). There were no reported adverse events. Conclusions and Relevance: Among patients for whom in vitro fertilization yielded a euploid blastocyst, the use of receptivity testing to guide the timing of frozen embryo transfer, compared with standard timing for transfer, did not significantly improve the rate of live birth. The findings do not support routine use of receptivity testing to guide the timing of embryo transfer during in vitro fertilization. Trial Registration: ClinicalTrials.gov Identifier: NCT03558399.

Preconception hemoglobin A1c concentration in healthy women is not associated with fecundability or pregnancy loss.

Objective: To examine the relationship of preconception hemoglobin A1c, a marker of cumulative exposure to glucose over the preceding 2-3 months, with time to pregnancy, pregnancy loss, and live birth among fecund women without diagnosed diabetes or other medical diseases. Design: A secondary analysis of a prospective cohort of women participating in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial. Setting: Four US academic medical centers. Patients: A total of 1,194 healthy women aged 18-40 years with a history of one or two pregnancy losses attempting spontaneous conception were observed for up to six cycles while attempting pregnancy and throughout pregnancy if they conceived. Interventions: Not applicable. Main Outcome Measures: Time to pregnancy, human chorionic gonadotropin pregnancy, clinical pregnancy, pregnancy loss, and live birth. Results: Although increasing preconception A1c level was associated with reduced fecundability (fecundability odds ratio [FOR] per unit increase in A1c 0.74; 95% confidence interval [CI] 0.57, 0.96) in unadjusted models and models adjusted for age, race, smoking and treatment arm (FOR 0.79; 95% CI 0.60, 1.04), results were attenuated after further adjustment for body mass index (FOR 0.91; 95% CI 0.68, 1.21). Preconception A1c levels among women without diagnosed diabetes were not associated with live birth or pregnancy loss. Conclusionss: Among healthy women without diagnosed diabetes, we observed no association of A1c with live birth or pregnancy loss. The association between A1c and fecundability was influenced by body mass index, a strong risk factor for both diabetes and infertility. These data support current recommendations that preconception A1c screening should be reserved for patients with risk factors for diabetes. Clinical Trial Registration Number: ClinicalTrials.gov: NCT00467363.

Follicle flushing does not improve live birth and increases procedure time: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To determine whether follicle flushing during oocyte retrieval improves live birth or secondary outcomes in assisted reproductive technology (ART). DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women undergoing ART using autologous gametes. INTERVENTION(S): A systematic search of PubMed, EMBASE, Cochrane Database, and Web of Science for randomized controlled trials comparing follicle flushing to direct aspiration during oocyte retrieval published in English between 1989 to 2020. MAIN OUTCOME MEASURE(S): Live birth as primary outcome, and clinical and ongoing pregnancy, total and mature metaphase II (MII) oocytes retrieved, and operating time as secondary outcomes. RESULT(S): Eleven studies were included totaling 1,178 cases. No difference in live birth was demonstrated between follicle flushing and direct aspiration. Clinical pregnancy and ongoing pregnancy were not improved with flushing. Total oocyte and MII yield were lower with flushing compared with direct aspiration. Procedure time was increased with flushing by 2 minutes in poor responders and 9 minutes in normal responders. Other sensitivity analyses did not demonstrate any changes, except the difference in MII yield was no longer statistically significant. CONCLUSION(S): Follicle flushing during oocyte retrieval increases procedure time and does not improve live birth or secondary ART outcomes. Randomized data do not support the use of follicle flushing as an intervention in ART.

Circulating Vascular Endothelial Growth Factor and Soluble fms-Like Tyrosine Kinase-1 as Biomarkers for Endometrial Remodeling Across the Menstrual Cycle.

OBJECTIVE: To characterize variation in circulating vascular endothelial growth factor (VEGF) and its receptor, soluble fms-like tyrosine kinase-1 (sFLT-1), across the menstrual cycle in normal ovulating women in relation to reproductive hormones to identify the utility of VEGF and sFLT-1 as peripheral biomarkers of endometrial remodeling. METHODS: Ninety-six healthy, regularly menstruating ovulatory women, aged 18-44 years, enrolled in the BioCycle Study, a prospective cohort study at a U.S. academic research center. Vascular endothelial growth factor and sFLT-1 were measured in concurrently collected plasma, serum, and urine up to eight times across a single cycle. Reproductive hormones were measured in serum. Mean concentrations of VEGF and sFLT-1 were compared across phases of the cycle, and correlations between specimen types were calculated. Harmonic models estimated associations between VEGF and sFLT-1 and characteristics of hormonal patterns. RESULTS: No variation in VEGF or sFLT-1 levels were detected over the menstrual cycle. Median (25th percentile, 75th percentile) concentrations of VEGF during the menstrual cycle were 31.2 pg/mL (24.1, 56.9) in plasma, 194.1 pg/mL (125.4, 350.2) in serum, and 101.7 pg/mL (64.2, 165.8) in urine. Plasma and serum measures were consistently correlated, whereas urinary measures were not. Vascular endothelial growth factor was not consistently associated with reproductive hormone concentrations, although sFLT-1 was associated with higher mean and amplitude of estradiol. CONCLUSION: Circulating VEGF and sFLT-1 did not vary across the menstrual cycle and therefore are unlikely to be useful peripheral biomarkers of endometrial changes across the menstrual cycle. For studies measuring circulating VEGF for other reasons, plasma may be the preferred medium and timing to menstrual cycle phase need not be considered for reproductive-age women.

Polycystic Ovarian Syndrome Genetics and Epigenetics.

Polycystic ovarian syndrome and its associated endocrine abnormalities comprise one of the most common metabolic spectrum disorders within the human race. Because of the variance in phenotypic expression among individuals and within family lineages, attention has been turned to genetic and epigenetic changes in which the root cause of the disorder may lie. Further understanding of DNA/histone methylation and microRNA patterns may help to improve the accuracy of diagnosis and lead to future treatment options.

Donor oocyte recipients do not benefit from preimplantation genetic testing for aneuploidy to improve pregnancy outcomes.

STUDY QUESTION: Do donor oocyte recipients benefit from preimplantation genetic testing for aneuploidy (PGT-A)? SUMMARY ANSWER: PGT-A did not improve the likelihood of live birth for recipients of vitrified donor oocytes, but it did avoid embryo transfer in cycles with no euploid embryos. WHAT IS KNOWN ALREADY: Relative to slow freeze, oocyte vitrification has led to increased live birth from cryopreserved oocytes and has led to widespread use of this technology in donor egg IVF programs. However, oocyte cryopreservation has the potential to disrupt the meiotic spindle leading to abnormal segregation of chromosome during meiosis II and ultimately increased aneuploidy in resultant embryos. Therefore, PGT-A might have benefits in vitrified donor egg cycles. In contrast, embryos derived from young donor oocytes are expected to be predominantly euploid, and trophectoderm biopsy may have a negative effect relative to transfer without biopsy. STUDY DESIGN, SIZE, DURATION: This is a paired cohort study analyzing donor oocyte-recipient cycles with or without PGT-A performed from 2012 to 2018 at 47 US IVF centers. PARTICIPANTS/MATERIALS, SETTING, METHODS: Vitrified donor oocyte cycles were analyzed for live birth as the main outcome measure. Outcomes from donors whose oocytes were used by at least two separate recipient couples, one couple using PGT-A (study group) and one using embryos without PGT-A (control group), were compared. Generalized estimating equation models controlled for confounders and nested for individual donors contributing to both PGT-A and non-PGT-A cohorts, enabling a single donor to serve as her own control. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 1291 initiated recipient cycles from 223 donors were analyzed, including 262 cycles with and 1029 without PGT-A. The median aneuploidy rate per recipient was 25%. Forty-three percent of PGT-A cycles had only euploid embryos, whereas only 12.7% of cycles had no euploid embryos. On average 1.09 embryos were transferred in the PGT-A group compared to 1.38 in the group without PGT-A (P < 0.01). Live birth occurred in 53.8% of cycles with PGT-A versus 55.8% without PGT-A (P = 0.44). Similar findings persisted in cumulative live birth from per recipient cycle. LIMITATIONS, REASONS FOR CAUTION: Pooled clinical data from 47 IVF clinics introduced PGT-A heterogeneity as genetic testing were performed using different embryology laboratories, PGT-A companies and testing platforms. WIDER IMPLICATIONS OF THE FINDINGS: PGT-A testing in donor oocyte-recipient cycles does not improve the chance for live birth nor decrease the risk for miscarriage in the first transfer cycle but does increase cost and time for the patient. Further studies are required to test if our findings can be applied to the young infertility patient population using autologous oocytes. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Recalled maternal lifestyle behaviors associated with anti-müllerian hormone of adult female offspring.

Anti-müllerian hormone (AMH) is an established marker of ovarian reserve that decreases with age. Though the pool of ovarian follicles is established during fetal development, impacts of in utero exposures on AMH are uncertain. Thus, we sought to evaluate associations of in utero exposures with AMH of adult daughters with a prospective cohort study of adult daughters at university medical centers. Women noted their mother's reported use of diethylstilbestrol (DES), vitamins, tobacco, alcohol, and caffeine during pregnancy, and their mother's occupation during pregnancy. All participants were reproductive age women (18-40 years) enrolled in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial. Serum AMH concentrations were measured at baseline prior to conception and categorized using clinical guidelines. Multinomial regression models estimated associations between each exposure and high (>3.5 ng/mL) and low (<1.0 ng/mL) versus normal AMH (1.0-3.5 ng/mL), adjusting for participant's age, mother's age, mother's history of fertility treatment, and mother's use of vitamins. In 1202 women with available data, maternal caffeine use was associated with an increased risk of low AMH, compared to normal (relative risk [RR] 1.90, 95 % confidence interval [CI] 1.09, 3.30). Vitamins were associated with an increased risk of high AMH compared to normal (RR 1.93, 95 % CI 1.24, 3.00). Other exposures were not associated with AMH concentrations in offspring. Maternal caffeine and vitamin use during pregnancy may be associated with ovarian reserve in adult offspring, highlighting the potential importance of pregnancy lifestyle on the reproductive health of daughters.

Ovarian vein sampling, and serum and urine testosterone monitoring in ovarian Leydig cell tumors: A report of two cases.

BACKGROUND: Ovarian Leydig cell tumors are rare, testosterone-producing tumors that pose diagnostic challenges. CASES: A 36-year-old woman presented with 10 years of amenorrhea, facial hair growth and clitoromegaly. A 59-year-old woman presented after 2 years of voice deepening and terminal hair growth. Testosterone concentrations were elevated for both patients; however, imaging failed to identify ovarian or adrenal pathology. For the first patient, selective ovarian venous sampling was performed with results suggesting right ovarian testosterone production. Right ovarian Leydig cell tumors were found in both patients after salpingo-oophorectomy. Testosterone levels immediately declined following tumor removal. CONCLUSION: Additional diagnostic modalities, such as ovarian venous sampling, should be considered when the etiology of hyperandrogenism cannot be identified through lab work or imaging. In addition, sequential post-operative testosterone levels in serum or urine can help confirm adequate removal of the ovarian tumor.

Defining polycystic ovary syndrome phenotype in Vietnamese women.

AIM: This study aimed to evaluate the unique phenotype of the Vietnamese polycystic ovarian syndrome (PCOS) population. METHODS: In this multicenter cross-sectional descriptive study, a total of 901 reproductive-age women were recruited at three medical centers in Vietnam from June 2016 to May 2018. Group I included 479 patients with PCOS (Rotterdam 2003 consensus) and Group II included 422 non-PCOS women, consisted of women with regular menstrual cycle, collected at the same time of PCOS recruitment, without ovarian disease or ovarian failure. Main outcome measures were anthropomorphic, serum hormone, ultrasound and physical characteristics of PCOS. RESULTS: The Vietnamese PCOS population was lean, but with a higher weight and body mass index compared to controls. About 34.4% of PCOS subjects had hirsutism, primarily confined to the leg, arm and pubis. The PCOS population had higher serum luteinizing hormone (LH), LH : follicle stimulating hormone ratio, anti-Mullerian hormone and testosterone. The PCOS population had double the ovarian volume compared to controls. PCOS subjects had no increase in metabolic disease history and had on average optimal serum markers for low metabolic disease risk. Group D (O + polycystic ovary morphology [PCOM]) was the most prevalent phenotype noted in our Vietnamese PCOS cohort (67.6%). Modified Ferriman-Gallwey, levels of LH, testosterone and anti-Mullerian hormone were highest in Group A (O + H + PCOM) and lowest in Group D (O + PCOM). CONCLUSION: The Vietnamese PCOS population is characterized by a lean body type, nonfacial hirsutism, anovulatory, enlarged ovaries and typical PCOS serum hormone markers, low risk factors for metabolic syndrome. Nonclassical phenotypes for PCOS were more frequent than the classic phenotype.

Evaluation of the cost-effectiveness of ovulation suppression with progestins compared with GnRH analogs in assisted reproduction cycles.

RESEARCH QUESTION: Is ovulation suppression with progestins, requiring a freeze-all approach and subsequent frozen embryo transfer resulting from progestenic endometrial changes, cost-effective compared with gonadotropin releasing hormone analogues (GnRH) during assisted reproduction cycles. DESIGN: Cost-effectiveness analysis derived from a PubMed literature search of average US costs of GnRH agonist and antagonist IVF cycles. RESULTS: In all fresh IVF cycle models, progestin cycles were more expensive owing to the additional costs of increased gonadotropin use, embryo freezing and subsequent frozen embryo transfer (FET). The average cost per live birth with progestins ($32,466-$56,194) was higher than fresh IVF cycles with short (flare) GnRH agonist ($4,447-$12,797 higher) and GnRH antagonist ($1,542-$9,893 higher). When analyzing an initial embryo transfer plus additional FET in patients not initially pregnant, progestin cycles were still more expensive per live birth compared with conventional protocols. When planned freeze only cycles were analyzed, progestins became more cost-effective per live birth compared with antagonist cycles ($2,079 lower) but remained more expensive than short agonist cycles ($823 more expensive). CONCLUSIONS: Ovulation inhibition in IVF using progestins requires a freeze-only approach of embryos, and thus progestin use was not cost-effective compared with fresh embryo transfer cycles. Progestins, however, may be cost-effective compared with GnRH antagonist in planned freeze only cycles such as in preimplantation genetic testing or fertility preservation.

Defining thresholds for abnormal premature progesterone levels during ovarian stimulation for assisted reproduction technologies.

OBJECTIVE: To evaluate methodologies to establish abnormal progesterone (P) levels on the day of trigger for recommending freeze only cycles. DESIGN: Threshold analysis and cost analysis. SETTING: Private ART practice. PATIENT(S): Fresh autologous ART. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): Live birth. RESULT(S): Fourteen established statistical methodologies for generating clinical thresholds were evaluated. These methods were applied to 7,608 fresh ART transfer cycles to generate various P thresholds which ranged widely from 0.4 to 3.0 ng/mL. Lower thresholds ranged from 0.4 to 1 ng/mL and classified the majority of cycles as abnormal as well as required very large number needed to treat (NNT) to increase one live birth. Frozen embryo transfer was cost-effective when P was ≥1.5 ng/mL, with 12% of the population having an abnormal test result and an NNT of 13. Statistical and cost-effective thresholds clustered between 1.5 and 2.0 ng/mL. CONCLUSION(S): Statistically significant thresholds for P were demonstrated as low as 0.4 ng/mL but resulted in a very large NNT to increase one live birth. A clinical benefit to a freeze-only approach was demonstrated above P thresholds ranging from 1.5 to 2.0 ng/dL. At these thresholds, elevated P has a demonstrable and clinically significant negative effect and captures a smaller percentage of the patient population at higher risk for fresh transfer failure, thus making freeze-only a cost-effective option.

Adverse effect of prematurely elevated progesterone in in vitro fertilization cycles: a literature review.

Premature progesterone (P) elevation was commonly seen in IVF prior to the utilization of GnRH analogues for suppression of endogenous gonadotropin release. The cause and effect of premature P elevation has finally been better elucidated in the past decade. Although still occurring in 5-38% of all IVF cycles, the adverse effects of premature P elevation on pregnancy outcomes are now well known.

Midluteal Progesterone: A Marker of Treatment Outcomes in Couples With Unexplained Infertility.

Context: Adequate luteal phase progesterone exposure is necessary to induce endometrial changes required for a successful pregnancy outcome. The relationship between low midluteal progesterone concentration and the outcome of live birth in ovarian stimulation with intrauterine insemination (OS-IUI) treatments is not defined. Objective: To determine the level of midluteal progesterone portending a low chance of live birth after OS-IUI in couples with unexplained infertility. Design and Setting: Secondary analyses of data from a prospective, randomized, multicenter clinical trial that determined pregnancy outcomes following OS-IUI with clomiphene citrate, letrozole, or gonadotropins for couples with unexplained infertility. Participants: Couples (n = 900) underwent 2376 OS-IUI cycles during the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial. Main Outcome Measures: Live birth as it relates to midluteal progesterone level and thresholds below which no live births occur by treatment group. Results: Thresholds for non-live birth cycles were similar for clomiphene (14.4 ng/mL) and letrozole (13.1 ng/mL) yet were lower for gonadotropin (4.3 ng/mL) treatments. A midluteal progesterone level >10th percentile specific for each treatment group independently was associated with greater odds for a live birth in all OS-IUI cycles (adjusted OR: 2.17; 95% CI: 1.05, 4.48). Conclusions: During OS-IUI, a low midluteal progesterone level was associated with a low probability of live birth. Thresholds differed by medication, with the lowest threshold for gonadotropin. Several pathophysiologic mechanisms may account for low progesterone levels. Refinement of the predictive range associated with particular ovarian stimulation medications during treatment of unexplained infertility may improve accuracy.

Oocyte cryopreservation for women with GATA2 deficiency.

PURPOSE: To describe controlled ovarian stimulation (COS) in a population of women with GATA2 deficiency, a genetic bone marrow failure syndrome, prior to allogeneic hematopoietic stem cell transplant METHODS: This is a retrospective case series of nine women with GATA2 deficiency who underwent oocyte preservation at a research institution. Main outcomes measured include baseline fertility characteristics ((antimullerian hormone (AMH) and day 3 follicle-stimulating hormone (FSH) and estradiol (E2)) and total doses of FSH and human menopausal gonadotropins (HMG), E2 on day of trigger, and total number of metaphase II oocytes retrieved. RESULTS: The mean age was 24 years [16-32], mean AMH was 5.2 ng/mL [0.7-10], and day 3 mean FSH was 5.1 U/L [0.7-8.1], and E2 was 31.5 pg/mL [< 5-45]. The mean dose of FSH was 1774 IU [675-4035], and HMG was 1412 IU [375-2925] with a mean E2 of 2267 pg/mL [60.7-4030] on day of trigger. The mean total of metaphase II oocytes was 7.7 [0-15]. One patient was diagnosed with a deep vein thrombosis (DVT) with pulmonary embolism (PE) during COS. CONCLUSION: This study is the first to analyze the outcomes of COS in women with GATA2 deficiency. The response to ovarian stimulation suggests that oocyte cryopreservation should be considered prior to gonadotoxic therapy. However, due to the risk of potentially life-threatening complications, it is prudent that patients are properly counseled of the risks and are evaluated by a multi-disciplinary medical team prior to COS.

Does premature elevated progesterone on the day of trigger increase spontaneous abortion rates in fresh and subsequent frozen embryo transfers?

Recent evidence has shown elevated progesterone (P) advances the endometrium in fresh ART cycles, creating asynchrony with the embryo and thus implantation failure and decreased live birth rates. If the window of implantation is closing as the embryo attempts to implant, there may be difficulty with trophoblastic invasion, leading to failure of early pregnancies. Our objective was to evaluate if P on the day of trigger was associated with spontaneous abortion (SAB) rates in fresh ART transfers. This was a retrospective cohort study involving fresh autologous and FET cycles from 2011 to 2013. The main outcome was spontaneous abortion rates. About 4123 fresh and FET transfer cycles were included which resulted in 1547 fresh and 491 FET pregnancies. The overall SAB rate was 20% among fresh cycles and 19% in FET cycles. P on the day of trigger, as a continuous variable or when > 2 ng/mL, was not associated with SAB in fresh cycles. Similar results were found after adjusting for age, embryo quality, and embryo stage. Despite elevated P likely advancing the window of implantation, once implantation occurs, pregnancies were no longer negatively impacted by progesterone.

Progesterone luteal support after ovulation induction and intrauterine insemination: an updated systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of progesterone (P) for luteal phase support after ovulation induction (OI) and intrauterine insemination (IUI). DESIGN: An updated systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Patients undergoing OI-IUI for infertility. INTERVENTION(S): Exogenous P luteal support after OI-IUI. MAIN OUTCOME MEASURE(S): Live birth. RESULT(S): Eleven trials were identified that met inclusion criteria and constituted 2,842 patients undergoing 4,065 cycles, more than doubling the sample size from the previous meta-analysis. In patients receiving gonadotropins for OI, clinical pregnancy (relative risk [RR] 1.56, 95% confidence interval [CI] 1.21-2.02) and live birth (RR 1.77, 95% CI 1.30-2.42) were more likely in P supplemented patients. These findings persisted in analysis of live birth per IUI cycle (RR 1.59, 95% CI 1.24-2.04). There were no data on live birth in clomiphene citrate or clomiphene plus gonadotropin cycles. There was no benefit on clinical pregnancy with P support for patients who underwent OI with clomiphene (RR 0.85, 95% CI 0.52-1.41) or clomiphene plus gonadotropins (RR 1.26, 95% CI 0.90-1.76). CONCLUSION(S): Progesterone luteal phase support is beneficial to patients undergoing ovulation induction with gonadotropins in IUI cycles. The number needed to treat is 11 patients to have one additional live birth. Progesterone support did not benefit patients undergoing ovulation induction with clomiphene citrate or clomiphene plus gonadotropins.