The effect of leuprolide acetate on steroidogenesis by granulosa and theca cells in vitro

Enhancement of follicular response to controlled ovarian hyperstimulation for human in vitro fertilization (IVF) has been suggested following pretreatment with leuprolide acetate (LA). However, additional human menopausal gonadotropin (hMG) is required to achieve follicle maturity in the presence of LA. We studied the effect of LA on steroidogenesis of granulosa and theca cells in vitro. Human granulosa cells obtained from IVF follicular fluid aspirations were cultured for 14 days in the presence and absence of human chorionic gonadotropin (hCG). hCG significantly enhanced progesterone (P) and estradiol (E₂) production by the cells, however, the addition of LA in concentrations of 10, 100, and 1000 ng/ml had no effect. Porcine granulosa cells were cultured for 48 hr in the presence and absence of follicle stimulating hormone (FSH) with the addition of LA at the same doses. LA did not affect the FSH-induced increase in P production. Porcine theca cells were cultured for 48 hr in the presence and absence of hCG. The addition of LA did not affect androstenedione (A) production by these cells. We conclude that in this dynamic model in vitro, LA does not inhibit or stimulate P or E₂ production by granulosa or A production by theca cells.     

Estradiol level on day 9 as a predictor of risk for ovarian hyperresponse during controlled ovarian hyperstimulation

Purpose : To investigate the estradiol (E₂) level in the mid-follicular phase during controlled ovarian hyperstimulation (COH) and evaluate it as a predictor of a high risk for ovarian hyperresponse. Methods : From January 1996 to October 2001, the records of a total of 146 patients undergoing 164 COH cycles were retrospectively reviewed. All patients received the long protocol of GnRH agonists from the previous mid-luteal phase and then hMG or FSH from day 3 of the menstrual cycle. The E₂ level was evaluated on day 9. Ovarian hyperresponse was defined as 1) an E₂ level on the day of hCG injection was >4000 pg/mL, or 2) the necessity for coasting during COH to decrease the risk of ovarian hyperstimulation syndrome (OHSS). Results : Of the 52 cycles in which day 9 E₂ level was >800 pg/mL, 29 (55.8%) fulfilled the criteria for ovarian hyperresponse. None of patients whose day 9 E₂ level was <300 pg/mL met the criteria for hyperresponse. The pregnancy rate in the groups with day 9 E₂ level <300 pg/mL was 42.9%; for an E₂ level = 300–800 pg/mL, 49.2%; and for an E₂ level >800 pg/mL, 32.7%. The corresponding implantation rates were 18.8, 28.0, and 17.0%. The E₂ level on day 9 did not correlate with clinical pregnancy rates or implantation rates. Conclusions : A high E₂ level in the mid-follicular phase was predictive of patients with a high ovarian response. An E₂ level on day 9 of menstrual cycle of >800 pg/mL suggests an increased risk for ovarian hyperresponse, and appropriate management should be instituted to decrease the risk of OHSS.     

Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation

OBJECTIVE: To assess the efficacy, safety, and local tolerance of ganirelix acetate for the inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation (COH). DESIGN: Phase III, multicenter, open-label randomized trial. SETTING: In vitro fertilization (IVF) centers in North America. PATIENT(S): Healthy female partners (n = 313) in subfertile couples for whom COH and IVF or intracytoplasmic sperm injection were indicated. INTERVENTION(S): Patients were randomized to receive one COH cycle with ganirelix or the reference treatment, a long protocol of leuprolide acetate in conjunction with follitropin-beta for injection. OUTCOME MEASURE(S): Number of oocytes retrieved, pregnancy rates, endocrine variables, and safety variables. RESULT(S): The mean number of oocytes retrieved per attempt was 11.6 in the ganirelix group and 14.1 in the leuprolide group. Fertilization rates were 62.4% and 61.9% in the ganirelix and leuprolide groups, respectively, and implantation rates were 21.1% and 26.1%. Clinical and ongoing pregnancy rates per attempt were 35.4% and 30.8% in the ganirelix group and 38.4% and 36.4% in the leuprolide acetate group. Fewer moderate and severe injection site reactions were reported with ganirelix (11.9% and 0.6%) than with leuprolide (24.4% and 1.1%). CONCLUSION(S): Ganirelix is effective, safe, and well tolerated. Compared with leuprolide acetate, ganirelix therapy has a shorter duration and fewer injections but produces a similar pregnancy rate.     

Subclinical Pregnancy Losses Among Women Undergoing In-Vitro Fertilization With ICSI

Background: The purpose of this study is to asses the frequency of subclinical pregnancy loss (SPL) among women undergoing controlled ovarian hyperstimulation (COH) and in-vitro fertilization with ICSI. Methods: The study was retrospectively conducted in a private IVF center. SPL was defined by a temporary rise in serum βhCG, along with the absence of signs of intra- and extra-uterine pregnancy by transvaginal ultrasonography. Overall 5273 COH and ICSI cycles with embryo transfer (ET) were segregated according to serum E₂ levels percentiles (-24th, 25th, 74th, and 75th), women age and the type of spermatozoa for assisted fertilization (ejaculated and surgically retrieved). Those groups were assessed for SPL rates. Results: Among the 3125 (59.25) conception cycles, 305 (9.7%) were diagnosed as SPL. There was no difference in SPL rate among E₂ percentile groups. Women older than 35 years of age had significantly higher rate of SPL compared to younger women. There was also no difference in SPL rate among pregnancies in whom surgically retrieved spermatozoa used or ejaculated spermatozoa used for assisted fertilization. Conclusion: Our results demonstrated that SPL rate was not influenced by the levels of E₂ during COH or the origin of spermatozoa used for assisted fertilization. However, maternal age was found to be detrimental for SPL.     

Why more is less and less is more when it comes to ovarian stimulation

PurposeThe purpose of the present study is to describe the possible mechanisms which may explain the apparent paradox of “less is more.” Mild ovarian stimulation for in vitro fertilization (IVF) minimizes ovarian hyperstimulation syndrome (OHSS) and multiple gestations without compromising the pregnancy rate (PR).MethodsThe pertinent English literature (PubMed) addressing mild stimulation for IVF/assisted reproductive technology (ART) and publications addressing “mild” or “soft” controlled ovarian stimulation (COS) vs conventional COS for IVF, OHSS, natural cycle IVF, and IVF outcome in association with COS was searched.ResultsFour possible mechanisms can be put forward to explain the apparent paradox of “less is more.” (1) In the natural or mild stimulation cycles, the healthiest follicles are selected by the principle of “quality for quantity”; (2) high estradiol (E₂) in the late follicular phase significantly correlated with higher rates of small for gestational age (SGA) and low-birth-weight (LBW) neonates; (3) anti-Mullerian hormone (AMH), LH, testosterone, and E₂ are significantly higher in natural cycle (NC)-IVF than in stimulated IVF follicles, suggesting an alteration of the follicular metabolism in stimulated cycles; and (4) supraphysiological E₂ may increase the growth hormone-binding protein (GH-BP) bio-neutralizing GH and diminishing the resultant insulin-like growth factor (IGF) levels, necessary for optimal synergism with follicle-stimulating hormone (FSH).ConclusionsIt is suggested to aim at the retrieval of around eight to ten eggs. Mild stimulation should be the common practice for IVF. In cases where more than ten ova are retrieved or high E₂ levels are reached, either intentionally or unintentionally, “freeze-all policy” should be considered and embryo transfer (ET) done in a subsequent natural cycle.     

The influence of estradiol/follicle and estradiol/oocyte ratios on the outcome of controlled ovarian stimulation for in vitro fertilization

Objective. The aim of the study was to evaluate the influence of the ratios of estradiol (E₂) to either the number of follicles >14 mm on the day of human chorionic gonadotropin administration (E₂/follicle) or the number of oocytes retrieved (E₂/oocytes) during controlled ovarian hyperstimulation (COH) with gonadotropin-releasing hormone (GnRH)-agonist (agonist group) and GnRH-antagonist (antagonist group), on the outcome of in vitro fertilization (IVF) cycles.

Patients and methods. All consecutive women aged <35 years admitted to our IVF unit during a 6-year period with normal to high response to COH were retrospectively studied. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryos transferred and pregnancy rate were assessed.

Results. Six hundred and ninety consecutive IVF cycles were evaluated, 301 in the agonist group and 389 in the antagonist group. The ratios of E₂/follicle and E₂/oocyte were significantly higher in the agonist group (p < 0.001 for both). Moreover, while pregnancy rates within E₂/oocyte ratio of 100–200 pg/ml were comparable between the agonist and antagonist groups, when E₂/oocyte ratios were <100 pg/ml or >200 pg/ml, pregnancy rates were significantly higher in the agonist group. Furthermore, no difference in pregnancy rates was observed within the agonist group between different E₂/oocytes ratios, while within the antagonist group, higher pregnancy rates were observed when comparing those with E₂/oocyte ratio of 100–200 pg/ml with those with E₂/oocyte ratio <100 pg/ml or >200 pg/ml.

Conclusion. While E₂/oocyte ratio cannot predict the success of GnRH-agonist protocol, patients undergoing GnRH-antagonist protocol should reach E₂/oocyte ratio within the 100–200 pg/ml range in order to achieve the best IVF outcome.     

The dynamic changes of anti-Mullerian hormone and inhibin B during controlled ovarian hyperstimulation in decreased ovarian reserve women and the effect on clinical outcome

Abstract

Objective: To investigate the dynamics of anti-Mullerian hormone (AMH) and inhibin B (INHB) levels during controlled ovarian hyperstimulation (COH) in women with decreased ovarian reserve (DOR), and assess the effect of these dynamic changes on the prediction of clinical outcome in in-vitro fertilization (IVF).

Methods: A total of 124 women undergoing IVF cycles were divided into normal ovarian reserve (NOR) and DOR groups. AMH and INHB levels were measured in serum on menstrual cycle day 2 or 3 (D2/3), day 5 of stimulation (D5), hCG day (D-hCG) and follicular fluid (FF) on oocyte retrieval day.

Results: Serum AMH levels were gradually decreased while INHB levels were gradually increased from D2/3 to D-hCG during the COH in both groups. Serum AMH, INHB levels on D2/3 and FF AMH, INHB levels were highly positively correlated with AFC and oocytes retrieval. Multivariate logistic regression analysis revealed that clinical pregnancy did not directly correlate with serum and FF AMH and INHB levels.

Conclusion: Serum AMH and INHB levels were not directly related to clinical pregnancy, dynamic serum AMH and IHNB levels were positively correlated with COH outcomes.     

GnRH agonist versus GnRH antagonist in ovarian stimulation: the role of elevated peak serum progesterone levels

Abstract

Aim: We sought to evaluate the influence of subtle serum progesterone elevation on in vitro fertilization (IVF) cycle outcome and to assess the impact of the type of gonadotropin-releasing hormone (GnRH)-analogue used during controlled ovarian hyperstimulation (COH) on the probability of clinical pregnancy.

Patients and methods: We reviewed the files of all consecutive patients undergoing COH with either GnRH-agonist or antagonist in our IVF unit during a 10-year period and who had their peak serum progesterone levels determined on the day of human chorionic gonadotropin (hCG) administration.

Results: Of the 2244 IVF cycles evaluated, 2103 had peak progesterone level of <1.5?ng/mL (normal-P group) and 141 of >1.5?ng/mL (high-P group) (6.28% of all the study population). Clinical pregnancy rate was significantly higher in the normal-P group (25.4% versus 16.6%; p?<?0.006). Moreover, among the high-P group patients, the use of the long GnRH-agonist suppressive protocol (GnRH-ag) was more prevalent in patients who conceived as compared to those who did not (60.9% versus 39%, respectively; p?<?0.05), with a tendency toward an increase pregnancy rate in those using GnRH-ag compared with GnRH-antagonist protocol (GnRH-antag; p?<?0.059) COH protocols.

Conclusion: While subtle progesterone elevation in patients undergoing COH using GnRH-antag COH protocols, should dictate embryo cryopreservation and cancelation of the fresh transfer, in those undergoing the GnRH-ag COH protocol, a fresh embryo transfer should be recommended.     

Arterial stiffness during controlled ovarian hyperstimulation and early pregnancy in women exposed to assisted reproduction

ABSTRACT

Introduction: Female sex hormones have vasorelaxing effects in non-pregnant and pregnant women. We aimed to investigate the effect of controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF), and early pregnancy, on arterial stiffness as assessed by digital pulse wave analysis (DPA), hypothesizing reduced arterial stiffness as an effect of increased estrogen levels.

Material and methods: A total of 68 women undergoing IVF were examined with DPA before conception and during IVF treatment with COH and embryo transfer (ET), and in gestational week seven in 19 women who became pregnant. Heart rate (HR), mean arterial pressure (MAP) and the DPA variables cardiac ejection elasticity index (EEI), b/a, dicrotic index (DI), d/a and aging index (AI) were measured.

Results: HR was significantly increased at all measuring points (p ≤ 0.003) but MAP only at ET (p 0.007). DPA variables representing large arteries (EEI, b/a) and peripheral arteries (DI, but not d/a), and the global variable AI, indicated increased arterial stiffness at ET compared with baseline (p ≤ 0.035). No DPA variable was significantly changed at pregnancy measurements compared to baseline.

Conclusion: During COH for IVF treatment, DPA showed no changes in arterial stiffness during the follicular phase or in early pregnancy, but increased arterial stiffness in central and peripheral arteries in the early luteal phase. The result suggests a hormonal hemodynamic activation counteracting the effects of estrogen.     

The Lupron screening test: tailoring the use of leuprolide acetate in ovarian stimulation for in vitro fertilization

STUDY OBJECTIVE: To evaluate the prognostic and therapeutic value of a Lupron (leuprolide acetate; Tap Pharmaceuticals, North Chicago, IL) screening test before ovarian stimulation for in vitro fertilization (IVF). DESIGN: Prospective. SETTING: Outpatient IVF program. PATIENTS: Eighty patients exhibited four early estradiol (E2) patterns. Patients with pattern A and B remained on a flare-up ovarian stimulation protocol. Patients with pattern C were randomized to three ovarian stimulation protocols. Patients with pattern D were treated with the flare-up protocol using a high pure follicle-stimulating hormone (FSH) dose. RESULTS: Patterns, A, B, C, and D occurred in 44%, 16%, 25%, and 15% of the patients, respectively. The E2 pattern recurred in 77% of subsequent IVF cycles. Pattern A and B patients achieved a 41% (23/56) and 22% (5/23) ongoing pregnancy rate (PR) per stimulated cycle. An early luteal phase Lupron protocol had the best ongoing PR per stimulated cycle (10/27, 37%) in patients with a pattern C response. Pattern D patients had a 20% (5/25) ongoing PR per stimulated cycle. CONCLUSION: The Lupron screening test allows prospective selection of stimulation protocols in ovulatory patients undergoing IVF. Early E2 patterns A and B should be treated with the flare-up protocol. Pattern C patients benefit from the luteal phase Lupron protocol and pattern D patients benefit from a high pure FSH flare-up protocol.     

Comparison of a single half-dose, long-acting form of gonadotropin-releasing hormone analog (GnRH-a) and a short-acting form of GnRH-a for pituitary suppression in a controlled ovarian hyperstimulation program

OBJECTIVE: To compare the effect of a single low-dose leuprolide acetate depot (LA depot) and leuprolide acetate (LA) on pituitary down-regulation in women undergoing controlled ovarian hyperstimulation (COH). DESIGN: Retrospective study.Setting: An IVF unit of an academic medical center. PATIENT(s): Women who underwent COH and IVF-ET. INTERVENTION(s): Pituitary down-regulation with half-dose LA depot (1.88 mg sc, group 1) or LA (0.5 mg/d sc, group 2) was started on menstrual days 21-23. MAIN OUTCOME MEASURE(s): The concentrations of estradiol (E(2)), FSH, LH, gonadotropin dosages, the numbers of oocytes retrieved, oocytes fertilized and embryos transferred, and pregnancy rates of the two groups were compared. RESULT(s): A total of 289 patients in group 1 and 158 in group 2 were included. There were no statistically significant differences between the two groups in baseline concentrations of E(2) and FSH, concentrations of E(2), FSH, and LH during hCG administration, gonadotropin dosage, the number of oocytes retrieved, the number of oocytes fertilized and embryos transferred, and pregnancy rates. CONCLUSION(s): Single half-dose LA depot offers a useful alternative for pituitary suppression in ovarian stimulation for IVF.     

Clinical significance of transvaginal color Doppler ultrasonography of the ovarian artery as a predictor of ovarian response in controlled ovarian hyperstimulation for in vitro fertilization and embryo transfer

Purpose : Our purpose was to verify whether the blood flow impedance of the ovarian stromal artery in transvaginal color Doppler ultrasonography can predict the in vitro fertilization and embryo transfer (IVF–ET) outcomes. Methods : Transvaginal color Doppler ultrasonographic examinations were performed in 99 patients undergoing controlled ovarian hyperstimulation (COH) for IVF–ET. The pulsatility index (PI) was evaluated in the bilateral ovarian stromal arteries on the starting day of COH (PI₁) and the day of hCG administration (PI₂). The patients were classified into three groups by the mean PI₁, PI₂, and PI (PI₁ – PI₂), respectively, and the IVF–ET outcomes were analyzed and compared. Results : There were no significant differences in the duration of COH, the total dosage of gonadotropins used for COH, the serum E₂ concentration on day of hCG administration, the number of follicles on the day of hCG administration, the number of oocytes retrieved or fertilized in vitro, and the number of embryos transferred between their respective PI₁, PI₂, and PI values. However, the pregnancy rate was significantly lower in the higher PI₁ and PI₂ groups than in the lower groups (p < 0.05, p < 0.05). Significant positive correlations were also found between PI₁ and PI₂ and the total dosage of gonadotropins for COH (Y = 0.483 X + 27.1, r = 0.052, p < 0.05; Y = 0.877 X + 26.6, r = 0.075, p < 0.05). Conclusions : Our results showed that the lower PI in the ovarian stromal artery during COH is associated with the higher the pregnancy rate and the smaller amount of gonadotropins used for effective COH. This study suggests that the color Doppler ultrasonographic index (PI) of the ovarian stromal artery during COH may be useful for predicting the success of IVF–ET in infertile patients.     

Sequential clomiphene/corifollitrophin alpha as a technique for mild controlled ovarian hyperstimulation in IVF: a proof of concept study

Purpose

Mild controlled ovarian hyperstimulation (COH), combined with oocyte retrieval (OR) under local anaesthesia (LA), may provide low-impact IVF. Since a single injection of corifollitrophin alfa (CFA) provides 7 days of COH, we hypothesised that clomiphene-citrate (CC) followed by CFA may provide adequate COH response from one single FSH injection. Therefore, the aim was to assess IVF outcomes after a novel clomiphene citrate/CFA (CC/CFA) protocol, compared to women undergoing standard rFSH COH protocols (good prognosis comparative cohort:GPCC) in a 1:2 matched design.

Materials and methods

In this pilot study of 25 patients (ANZCTR id:ACTRN12612000740897, MINIVA:Minimal_Stimulation_in_IVF), we examined the effectiveness of oral clomiphene (100 mg-days 2–6) followed by CFA in a GnRH antagonist protocol producing a single injection COH stimulation regime. All OR were conducted under LA pre-ovarian block. Cycle outcomes were compared to a matched good prognosis comparative cohort (GPCC) undergoing standard rFSH COH.

Results

Mild stimulation was achieved with less oocytes being collected compared to the GPCC (6.4?±?0.7 vs. 10.7?±?0.9, p?<?0.001), resulting in a reduced number of good quality embryos available for transfer/cryopreservation (3.7?±?0.6 vs. 5.7?±?0.5, p?=?0.01). While embryo quality was similar between the two groups, endometrial thickness was significantly lower in the group receiving CC/CFA. Pregnancy rates were significantly lower in the CC/CFA cohort compared to GPCC (31.8 vs. 57.1%, p?=?0.04) and 44% of CC/CFA participants required supplemental rFSH in order to achieve the hCG trigger criteria.

Conclusion

Sequential clomiphene CFA protocol does not appear to be an optimal regime for low impact IVF treatment as it does not provide adequate COH from a single CFA injection and results in lower fresh embryo transfer pregnancy rates and fewer embryos for cryopreservation.

     

Serum CA-125 and inhibin B levels in the prediction of ovarian response to gonadotropin stimulation in in vitro fertilization cycles

There is much controversy about the relationship between serum CA-125 levels during in vitro fertilization (IVF) cycles and ovarian function. To evaluate the prognostic value of serum CA-125 and inhibin B measurements in predicting ovarian response to gonadotropin stimulation, we compared the CA-125 and inhibin B levels of poor and normal responders on the first day of ovarian stimulation, on the day of ovulation induction (OI) and at oocyte pick-up. Sixteen patients with poor ovarian response (???3 oocytes, serum estradiol (E₂) ??900?pg/ml at OI) in IVF/intracytoplasmic sperm injection cycles were matched with normal responders (???6 oocytes, E₂ ??1800?pg/ml) by age, spontaneous cycle day-3 follicle-stimulating hormone level and cause of infertility. Inhibin B concentrations were significantly lower at all three time points in poor responders, but CA-125 levels were not. No statistically significant correlation was found between CA-125 levels and any of the clinical or laboratory parameters examined. Thus, CA-125 measurements during stimulation are not useful in predicting or identifying poor ovarian response to gonadotropin stimulation in IVF cycles. The lack of difference in CA-125 concentrations between poor and normal responders and lack of correlation with E₂ or inhibin B levels suggest that ovarian steroidogenesis and other granulosa cell functions do not influence the production of CA-125. Inhibin B, however, seems to predict ovarian response as early as at the start of stimulation.     

Luteal phase support with estrogen in addition to progesterone increases pregnancy rates in in vitro fertilization cycles with poor response to gonadotropins

In this study, our objective was to determine the effect of adding estradiol hemihydrate (E₂) to progestin (P) for luteal phase support on pregnancy outcome in in vitro fertilization (IVF) cycles with poor response to gonadotropins. Ninety-five women with poor ovarian response who underwent controlled ovarian hyperstimulation (COH) with gonadotropin releasing hormone (GnRH) agonist or GnRH antagonist plus gonadotropin protocol for IVF were prospectively randomized into three groups of luteal phase support after oocyte retrieval. Group 1 (n?=?33) received only intravaginal progesterone gel (Crinone 8% gel). Group 2 (n?=?27) and Group 3 (n?=?35) received intravaginal progesterone plus oral 2 and 6?mg estradiol hemihydrate, respectively. Main outcome measures were overall and clinical pregnancy rates (PRs) per patient. Serum LH, E₂ and P levels at 7th and 14th days of luteal phase were also measured. Overall and clinical PRs were significantly higher in 2?mg E₂?+?P than P-only group (44% versus 18% and 37% versus 12.1%, respectively). There were no statistically significant differences between 6?mg E₂?+?P versus P-only and 2?mg E₂?+?P versus 6?mg E₂?+?P groups regarding PRs. Addition of 2?mg/day E₂ in addition to P for luteal support significantly increase overall and clinical PRs in cycles with poor response to gonadotropins after IVF.     

Leuprolide acetate elevates prolactin during ovarian stimulation with gonadotropins

Objective The purpose of this study was to determine whether gonadotropin-releasing hormone agonist further increases the prolactin rise accompanying ovarian stimulation.Design Serum prolactin concentrations were compared between cycles with and cycles without the use of leuprolide acetate (LA) matched for estradiol levels. Relationships of prolactin levels to cycle outcomes were examined.Setting The study took place at a private fertility center.Patients Patients were women receiving stimulation for oocyte retrieval using human menopausal gonadotropins.Interventions No interventions were used.Main Outcome Measures Serum prolactin level, fertilization rate, embryo quality, and pregnancy were the main outcome measures.Results Higher serum prolactin was associated with both higher estradiol levels and use of LA but did not have any effects on fertilization rate, embryo quality, or occurrence of pregnancy.Conclusion LA stimulates prolactin release during ovarian stimulation but without apparent consequence.     

The initial flare-up induced by gonadotropin releasing hormone agonist May serve as a predictor of ovarian response in the current IVF-ET treatment cycle in normogonadotropic women aged 40–48 years

Objective: Our purpose was to assess the potential role of the baseline hormone profile in combination with the initial pattern of response to gonadotropin releasing hormone (GnRH) analogue in predicting ovarian function and hence reproductive outcome in normogonadotropic patients aged 40 years or older undergoing IVF treatment. Patients and Methods: A retrospective analysis of 394 controlled ovarian hyperstimulation (COH) cycles that reached the stage of oocyte retrieval was conducted. The study included 163 normogonadotropic (serum FSH 15 IU/L) patients aged between 40 and 48 years who had regular menstrual cycles. Superovulation was achieved using menotropins in combination with GnRH analog (short protocol, beginning on menstrual day 2). The ovarian response was monitored on the third cycle day, the day following the first GnRH analogue administration. Results: Cycle distribution by patient age was 175 (44.4%), 122 (30.9%), and 97 (24.7%), while the patient distribution was 85 (52.2%), 48 (29.5%), and 30 (18.3%) for age groups 40–41, 42–43, and 44–48 years, respectively. The mean total dose of menotropins needed for optimal COH was 1787 IU (range, 600–6000 IU). This dose increased with age, while the yield of oocytes and embryos declined (P<0.05; ANOVA). A positive correlation was demonstrated between the E₂ level on day 3 (GnRH analogue flare effect) and the outcome of the treatment cycle (number of oocytes and embryos). Using multiple stepwise regression analysis, it was demonstrated that the initial (day 3) serum E₂ levels, combined with baseline FSH levels, patient's age and body mass index enabled early prediction of the ovarian response in the current IVF-ET treatment cycle (oocytes=8.2–0.18×Age+0.17×BMI–0.12×FSH+0.0042×E₂). Conclusions: Multiple-parameter analysis demonstrated that the use of the initial E₂ response to GnRH analogue stimulation combined with basic clinical data may assist in the prediction of ovarian function and hence the reproductive outcome in normogonadotropic IVF patients aged 40 years or older. This may serve as a clinical tool for improving patient selection and treatment outcome in IVF-ET.Presented at the IXth World Congress on In Vitro Fertilization and Alternate Assisted Reproduction, April 3–7, 1995, Vienna, Austria.     

Dose of GnRH agonist (nafarelin acetate) affects intrafollicular PAPP-A expression in controlled ovarian hyperstimulation cycle

OBJECTIVE: To determine the effect of dose of GnRH agonist on the follicular environment in controlled ovarian hyperstimulation (COH) cycles. STUDY DESIGN: Twenty-eight IVF patients with normal ovarian function were divided into three groups: group I received GnRHa (nafarelin acetate/Synarel) intranasally at 200 microg daily, group II received 400 microg daily until hCG injection, and group III was given 400 microg daily before the initiation of ovarian stimulation, then 200 microg daily before the day of hCG injection. Serum estradiol, progesterone, and leptin levels were measured on the day of hCG injection. After aspiration, expression of pregnancy-associated alpha-plasma protein (PAPP)-A in the follicular fluid of dominant follicles (>20 mm) was determined by Western blot analysis. RESULTS: No significant difference was noted in serum estradiol, progesterone, and leptin levels. But intrafollicular PAPP-A expression was significantly higher in group II compared to other groups (P<0.05). CONCLUSION: The dose of GnRHa may have an impact on the intrafollicular environment of dominant follicles in COH cycles.     

减少GnRHa剂量对长方案促排卵卵巢反应性的影响

目的:探讨减少GnRHa剂量对长方案促排卵的卵巢反应性影响。方法:对37例采用长方案进行促排卵且第一周期未妊娠或流产的患者进行自身对照研究,第一个周期GnRHa用量为0.05mg/d,第二个周期GnRHa用量为0.03mg/d。结果:Gn使用天数、Gn用量、受精率第一、第二促排卵周期间无显著性差异(P>0.05)。获卵数、可移植胚胎数第二周期组较第一周期组显著增加(P<0.05)。结论:本研究认为在长方案促排卵过程中减少GnRHa的剂量可以增加获卵数,改善卵巢反应性,增加IVF妊娠率。     

A short length of gonadotropin hyperstimulation is sufficient to achieve an optimal IVF outcome in advance-aged women

ObjectiveTo analyze the duration of gonadotropin hyperstimulation's impacts on oocyte quality and clinical outcomes in aged in vitro fertilization (IVF) patients.Materials and methodsThis retrospective study was carried out using IVF records of the Chang Gung Memorial Hospital IVF center from January 2017 to December 2019. A total of 308 IVF cycles with patients aged 40–44 years were included. Clinical characteristics of patients who received a short controlled ovarian hyperstimulation (COH) (i.e., 6–7 days; s-COH group) or a long COH treatment (i.e., 9–10 days; l-COH group) were compared. In addition, analysis was conducted using data within two age subgroups: 40–42 years and 42–44 years subgroups.ResultsThe s-COH group received significantly lower total doses of gonadotropin and had smaller leading follicles at the time of ovulation trigger when compared to the l-COH group. The s-COH group also produced a significantly lower number of oocytes, mature metaphase II (MII) oocytes, and 2 PN zygotes compared to the l-COH group. However, there was no significant difference in the number of transferable and good-quality embryos between the two treatment groups. Likewise, the pregnancy rate and live birth rate were comparable in the s-COH and l-COH groups. Similar results were obtained when the analysis was limited to select age subgroups (i.e., 40–42 and 42–44 years subgroups).ConclusionWhile a long COH generates more oocytes per cycle, a 6–7 days COH treatment, which is at the lower end of the recommended window of stimulation, could achieve a pregnancy outcome comparable to that applied 9–10 days of COH in aged patients.