Mild Ovarian Stimulation Research Articles

Anti-Müllerian hormone and antral follicle count for prediction of ovarian stimulation response in polycystic ovary syndrome

Objective: To evaluate the ability of a combination of multiple ovarian reserve markers to predict ovarian stimulation response in polycystic ovary syndrome (PCOS).Methods: On cycle Day 3 of 75 infertile patients with PCOS, serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and anti-Müllerian hormone (AMH) were measured, and antral follicle count (AFC) and ovarian volume (OV) were evaluated by transvaginal sonography (TVS). All patients underwent the same mild ovarian stimulation protocol using clomiphene citrate and highly purified FSH. Ovulation was monitored by TVS and confirmed by midluteal serum progesterone level.Results: AMH, AFC, and “ovulation index” [OI, serum AMH (ng/ml) × bilateral AFC] were significantly lower in the ovulatory group (n = 57, 76%) compared with the anovulatory group, whereas LH, FSH, LH/FSH ratio, and OV were not significantly different. Using receiver-operating characteristic curve analysis, the OI at a cutoff value of “85” had a sensitivity of 73.7% and a specificity of 72.2% in the prediction of ovulation, with an area under the curve of 0.733. Patients with OI < 85 had significantly higher ovulation rate (p < 0.001).Conclusion: The OI, combining both AMH and AFC, is a potentially useful predictor of the outcome of ovarian stimulation in PCOS.

Using a mild stimulation protocol combined with clomiphene citrate and recombinant follicle-stimulating hormone to determine the optimal number of oocytes needed to achieve pregnancy and reduce the concerns of patients.

The purpose of this study was to investigate how many oocytes are needed to achieve an adequate pregnancy rate per 1 oocyte retrieval cycle in mild ovarian stimulation. This protocol consisted of clomiphene citrate and recombinant-follicle-stimulating hormone injection without a gonadotropin-releasing hormone-antagonist. From January 2009 through December 2010, there were 1,227 women who underwent assisted reproductive technologies treatment with mild stimulation at the Sugiyama Clinic. The overall pregnancy rate per single oocyte retrieval cycle was evaluated using both fresh and cryopreserved-and-thawed embryos according to the retrieved oocyte number. According to the retrieved oocyte number, a total of 1,227 cycles were divided into 4 groups: group A (the oocyte number <4; 433 cycles), group B (the oocyte number = 4, 5; 317 cycles), group C (the oocyte number = 6, 7; 206 cycles), and group D (the oocyte number ≥8; 271 cycles). The overall pregnancy rates for groups A, B, C, and D were 22.2, 42.9, 52.4, and 56.0 %, respectively, the rates for groups C and D were significantly higher than that for group A (p < 0.01). The optimal number of retrieved oocytes proved to be between 6 and 7 for the patients who received our milder stimulation protocol and experienced no reduction in their overall pregnancy rate.

Mild ovarian stimulation for in vitro fertilization: one perspective from the USA

To provide a perspective regarding mild ovarian stimulation, taking into account particular issues relevant in the United States Literature review and editorial commentary Mild ovarian stimulation for IVF has some proven and some theoretical advantages over conventional stimulation, such as lower risk of ovarian hyperstimulation syndrome and lower cost per fresh IVF cycle. However, cumulative live birth rate, including transfers from fresh and frozen embryos, is likely to be lower with mild stimulation. The cost-effectiveness of mild stimulation IVF in the United States has not been established. Mild ovarian stimulation is an appropriate option to consider for certain patient groups or based on patient preference. However, significant potential disadvantages limit its widespread acceptability for patients in the United States at this time.

Impact of Estradiol Monitoring on the Prediction of Intrauterine Insemination Outcome

ABSTRACT Purpose To evaluate the predictive value of estradiol levels on the day of human chorionic gonadotropin (hCG) administration on intrauterine insemination success rate. Materials and methods The present study included 200 intrauterine insemination (IUI) cycles performed between June 2011 and October 2012. All IUI cycles were preceded by ovarian stimulation with gonadotropins starting on cycle day 3. A single IUI was performed 24 to 36 hours after hCG administration. Binary logistic regression analysis was performed to define the covariates of IUI success. The main outcome measure, the clinical pregnancy rate per cycle, was assessed according to the estradiol level. Results With LR ± 2 and AUC=0.73, ROC analysis revealed out the estradiol level as 465 pg/ml to predict the pregnancy with 60% sensitivity and 66% specificity. Binary logistic regression analysis identified the presence of estradiol levels higher than 465 pg/ml (p &lt; 0.01, 95% CI = 0.147 – 0.687) and stimulation duration (p &lt; 0.01, 95% CI = 0.201 – 0.705) as the covariates approached statistical significance for IUI success. Conclusion Estradiol level &gt;465 pg/ml on the day of hCG administration might point out advanced outcome on mild ovarian stimulation combined with insemination. How to cite this article Atilgan R, Ekinci M, Sapmaz E, Ozkan ZS. Impact of Estradiol Monitoring on the Prediction of Intrauterine Insemination Outcome. Int J Infertility Fetal Med 2013;4(3):88-92.

Introduction of the method of intravaginal culture (IVC), through the device InVOCell routine laboratory RHA in Brazil

The conventional in vitro fertilization and the intracytoplasmic sperm microinjection are currently the established techniques for the treatment of infertility. In the last decade, however, the process of in vitro fertilization has suffered several changes in ovulation induction and oocyte retrieval (Ranoux 1990, ; ).The INVO procedure has been used to treat patients with different causes of infertility in many countries. This is a procedure which was developed over 20 years ago and is simpler and less costly to the infertility treatment when compared to conventional techniques. Interesting finding of this intravaginal culture technique are the physiological benefits and the reduction of the number of handling steps, reducing the risk of contamination. This study aimed to evaluate the possibility of including the method INVO through the use of the deviceINVOCell™ in routine laboratory treatments of couple infertility. That, in turn, tends to provide the simplification of laboratory work and thereby reduce the costs of infertility treatment. 40 women were included in this study, who were treated at the Service of Human Reproduction School Hospital Álvaro Alvim, in the period from August 2011 to January 2012. On all of them it was used the protocol of modified mild ovarian stimulation. The number of pre-embryos transferred into the uterine cavity followed the CFM Resolution nº. 1.957/10. There was no significant difference in the results presented by the device INVOCell™. Therefore showing that it can be included in routine laboratory assisted human reproduction.

MILD ovarian stimulation with GnRH-antagonist vs. long protocol with low dose FSH for non-PCO high responders undergoing IVF: a prospective, randomized study including thawing cycles

To compare the effectiveness of two stimulation protocols in non-polycystic ovary (PCO) high responders undergoing in vitro fertilization (IVF). Prospective randomized trial. A Reproductive Medicine and IVF Unit of a University Hospital and a private IVF Clinic. Four hundred-and-twelve normoovulatory women with good ovarian responsiveness were randomized to receive either the "mild" (FSH 150IU/day from day 4 of a spontaneous cycle followed by GnRH-antagonist from day 8; n = 205) or the "long" (FSH 150IU/day; n = 207) stimulation protocol. The outcome of these two regimens was compared including "fresh" and thawing cycles. The total FSH dose and the peak estradiol level were significantly lower in the "mild" protocol, whereas the retrieved oocytes, fertilization rate, number and quality of embryos, pregnancy and implantation rates, cumulative "fresh plus thaw" success rate, and incidence of severe ovarian hyperstimulation syndrome were comparable with the two regimens. In young, normoovulatory patients with good ovarian responsiveness undergoing IVF the "mild" stimulation protocol has effectiveness and risks comparable to the "long" protocol with low FSH starting dose, even when thawing cycles are included in the comparison.

Gonadotropin-releasing hormone agonist versus hCG for oocyte triggering in mild ovarian stimulation cycles in patients with diminished ovarian reserve

Gonadotropin-releasing hormone agonist versus hCG for oocyte triggering in mild ovarian stimulation cycles in patients with diminished ovarian reserve

A short narrative review of the feasibility of adopting mild ovarian stimulation for IVF as the current standard of care

Mild ovarian stimulation has been conceived, proposed and implemented in clinical practice as a safer and cheaper alternative to conventional strategies of controlled ovarian hyperstimulation in preparation for in vitro fertilization (IVF). Our aim was to summarize the key evidence on this topic and explore its possible role as the standard treatment option for women undergoing IVF. A short narrative review of the existing literature, with emphasis on mild ovarian stimulation clinical and cost effectiveness, as well as treatment limitations. Numerous studies highlight mild ovarian stimulation's favorable characteristics with respect to oocyte/embryo quality, reduced patient risk, and ease of intervention. There is, however, a need for high-quality laboratory environment. Limitations regarding poor responders, older women, or those seeking ovarian stimulation for non-infertility indications should also be considered. Finally, outcomes on the cumulative success rates and the cost effectiveness of mild ovarian stimulation remain inconclusive. Mild ovarian stimulation protocols for IVF should currently be implemented only in carefully selected populations. Further research is needed to clarify the remaining controversies in this IVF approach.

Mild ovarian stimulation in women with poor ovarian response undergoing IVF and ICSI

Mild ovarian stimulation in women with poor ovarian response undergoing IVF and ICSI

A Comparison of Pregnancy Rates Following In Vitro Fertilization-Embryo Transfer (IVF-ET) Using Mild Ovarian Stimulation in Women With Decreased Vs. Normal Oocyte Reserve

A Comparison of Pregnancy Rates Following In Vitro Fertilization-Embryo Transfer (IVF-ET) Using Mild Ovarian Stimulation in Women With Decreased Vs. Normal Oocyte Reserve

Pregnancy Rates Per Single Embryo Transfer According to the Number of Blastomeres in Day 3 Frozen-Thawed Embryos

A previous study using mild ovarian stimulation of single fresh embryo transfer into women with diminished oocyte reserve evaluated the fertility potential according to the number of blastomeres of day 3 embryos. The clinical pregnancy rates per transfer were as follows: 4-cell – 3.8%, 5-cell – 9.5%, 6-cell – 38%, 7-cell – 40%, and 8-cell – 42.4%.

A case–control pilot study of low-intensity IVF in good-prognosis patients

Low-intensity IVF (LI-IVF) is rapidly gaining in popularity. Yet studies comparing LI-IVF to standard IVF are lacking. This is a case–control pilot study, reporting on 14 first LI-IVF and 14 standard IVF cycles in women with normal age-specific ovarian reserve under age 38, matched for age, laboratory environment, staff and time of cycle. LI-IVF cycles underwent mild ovarian stimulation, utilizing clomiphene citrate, augmented by low-dose gonadotrophin stimulation. Control patients underwent routine ovarian stimulation. LI-IVF and regular IVF patients were similar in age, body mass index, FSH and anti-Müllerian hormone. Standard IVF utilized more gonadotrophins (P<0.001), yielded more oocytes (P<0.001) and cryopreserved more embryos (P<0.001). With similar embryo numbers transferred, after ethnicity adjustments, standard IVF demonstrated better odds for pregnancy (OR 7.07; P=0.046) and higher cumulative pregnancy rates (63.3% versus 21.4%; OR 6.6; P=0.02). Adjustments for age, ethnicity and diagnosis maintained significance but oocyte adjustment did not. Cost assessments failed to reveal differences between LI-IVF and standard IVF. In this small study, LI-IVF reduced pregnancy chances without demonstrating cost advantages, raising questions about its utility. In the absence of established clinical and/or economic foundations, LI-IVF should be considered an experimental procedure.Low-intensity IVF (LI-IVF) is increasingly propagated as an alternative to standard IVF. LI-IVF has, however, never been properly assessed in comparison to standard IVF. Such a comparison is presented in the format of a small pilot study, matching LI-IVF cycles with regular IVF cycles and comparing outcomes as well as costs. The study suggests that LI-IVF, at least in this setting, is clinically inferior and economically at best similar to standard IVF. LI-IVF should, therefore, as of this point not be offered as routine IVF treatment but only as an experimental procedure.

INVO Procedure: Minimally Invasive IVF as an Alternative Treatment Option for Infertile Couples

Intravaginal culture (IVC), also called INVO (intravaginal culture of oocytes), is an assisted reproduction procedure where oocyte fertilization and early embryo development are carried out within a gas permeable air-free plastic device, placed into the maternal vaginal cavity for incubation. In the present study we assessed the outcome of the INVO procedure, using the recently designed INVOcell device, in combination with a mild ovarian stimulation protocol. A total of 125 cycles were performed. On average 6.5 oocytes per cycle were retrieved, and a mean of 4.2 were placed per INVOcell device. The cleavage rate obtained after the INVO culture was 63%. The procedure yielded 40%, 31.2%, and 24% of clinical pregnancy, live birth, and single live birth rates per cycle, respectively. Our results suggest that the INVO procedure is an effective alternative treatment option in assisted reproduction that shows comparable results to those reported for existing IVF techniques.

Les stimulations ovariennes modérées pour fécondation in vitro constituent-elles un réel progrès en assistance médicale à la procréation ?

Growing evidence indicates that mild ovarian stimulation for in vitro-fertilization-embryo transfer may be an interesting approach to reduce the incidence and severity of complications, the number of treatment days, cost, patient discomfort and number of patient drop-outs. However, the heterogeneity of FSH-sensitive follicles, presumably requires multiple follicular growth to improve oocyte-embryo selection. In addition, whether the acceptability probably is similar between standard ovarian stimulation and mild stimulation, per-treatment pregnancy rates with conventional stimulation is superior to mild stimulation in unselected populations. Hence, some specific indications tend to emerge such as alterations of the ovarian follicular reserve in women of less than 38 years, bad embryo qualities and implantation failure after conventional stimulation, patients with previous history of hyperstimulation syndrome or contraindications to hyperoestrogenia (estrogeno-related cancers and thromboembolic diseases). However, no randomized trials have ever been performed to compare the results of mild versus conventional stimulation in young patients and good responders. Therefore, there is insufficient scientific evidence to shift from standard stimulation to mild stimulation for all patients. Cultural standards have to be considered in the choice of the type of stimulation.

A programmed schedule of oocyte retrieval using mild ovarian stimulation (clomiphene citrate and recombinant follicle-stimulating hormone).

The purpose was to establish a mild ovarian stimulation protocol that would help assisted reproductive technology (ART) units to avoid scheduling on weekends. This protocol directed patients to take 50 mg/day of clomiphene citrate between days 3 and 7 of the menstrual cycle: 225 IU of recombinant follicle-stimulating hormone (rec-FSH) were administered on days 3, 5 and 7; human chorionic gonadotropin (hCG) was administered on day 9; and, oocyte pick-up (OPU) was planned for day 11. From October 2008 through October 2009, 514 women underwent ART treatment with mild stimulation at the Sugiyama Clinic, and we evaluated whether OPU was accomplished on the planned day. Of all the treatment cycles, 419 (81.5%) underwent OPU on day 11 (scheduled group). Additional rec-FSH administration was needed in 83 cycles, in which case OPU was performed on day 12 or later. In 12 cycles, OPU was canceled. The unscheduled group (n = 95) consisted of delayed OPU cycles and canceled cycles. Of all treatment cycles, 332 cycles in the scheduled group and 68 cycles in the unscheduled group underwent embryo transfer, with 81 and 16, respectively, resulting in pregnancies. Using this protocol, OPU was performed on the scheduled day in about 80% of the cycles. Most weekend scheduling of OPU can be avoided using this mild stimulation.

Mild ovarian stimulation for women with poor ovarian response undergoing IVF/ICSI treatment cycles; randomized controlled study

To evaluate the efficacy of mild ovarian stimulation strategy, based on the combined administration of oral clomiphene citrate (CC) plus HMG from cycle day 7, and GnRH antagonist administration (fixed protocol) for poor responders elected for ART compared with the outcome of a standard ovarian stimulation strategy.

Mild vs conventional ovarian stimulation in intrauterine insemination. a prospective randomized study

Our aim was evaluate a mild ovarian stimulation protocol starting the gonadotropin administration after natural follicular recruitment and compared with conventional ovarian stimulation as ovulation induction to intrauterine insemination. A prospective randomized study of two different protocols of ovarian stimulation. Patients with less than three attempts of IUI, younger than 41 years old, with body mass index lower than 35 Kg/m2 and regular menstrual cycles were randomized to start 75 IU per day of HP-HMG (Menopur, Ferring, Spain) from the day 2 of menstrual period (conventional stimulation: CS) or after the leader follicle reaches 11 mm of mean diameter (mild stimulation: MS). A single intrauterine insemination was performed 36 hours after hCG administration. Ethical committee of our institution approved the present study. From January 2008 to February 2011, 39 patients underwent to 54 cycles of IUI were included. No differences were found between patients of CS compared with MS in age (34.3 ± 3 vs 34.5 ± 2.6 years), levels of estradiol, FSH and progesterone on days 0 or 6 of ovarian stimulation. The number of follicles with mean diameter between 15 to 17 mm on hCG day was similar (CS: 1.8 ± 3 follicles, MS: 1.1 ± 0.3 follicles) and also similar number of follicles of 18 mm or more diameter were found in both groups (p: 0.158). Similar male factor was documented between groups.Significant differences were found in estradiol level on day 4 of stimulation (113.4 ± 53 vs 63.8 ± 55.5 pg/mL), days of stimulation (9.83 ± 2.5 vs 5.94 ± 2.1) and amount of gonadotropins (635.37 ± 263.1 vs 396.3 ± 191) between CS compared with MS group (P< 0,05). No difference was found in pregnancy rate per cycle in CS group (12,5%) compared with MS group (22.2%) (p:0.473). Mild stimulation protocol needs fewer amounts of gonadotropins, fewer days of ovarian stimulation and it reaches similar pregnancy rate than conventional ovarian stimulation in intrauterine insemination.

Follicular Phase Endocrine Characteristics during Ovarian Stimulation and GnRH Antagonist Cotreatment for IVF: RCT Comparing recFSH Initiated on Cycle Day 2 or 5

Strategies involving mild ovarian stimulation protocols for in vitro fertilization (IVF) might lessen discomfort to the patient and substantially lower complication rates. The objective of the study was to compare the follicular-phase endocrine characteristics and follicular development in patients who started recombinant FSH (recFSH) on cycle day (CD) 2 or CD5 in IVF treatment, using GnRH antagonist as comedication. This was a prospective randomized controlled trial in two university centers in Belgium and The Netherlands. Seventy-six IVF/intracytoplasmic sperm injection patients were included in the study. The control group (CD2) received a standard treatment with 150 IU recFSH from CD2, whereas in the study group (CD5), stimulation was started on d 5 of the cycle. The GnRH antagonist was administered daily from CD6 onward in both treatment arms. Endocrine follicular phase profile during ovarian stimulation was measured. Follicular-phase patterns of gonadotropin and steroid concentrations were found to be comparable in both treatment groups, except for serum estradiol being significantly higher in the CD2 group on d 6 of the cycle (295.6 ± 202.5 ng/liter in the CD2 vs. 102.5 ± 47.9 ng/liter in the CD5 group; P < 0.01) and LH being significantly higher in the CD5 group on d 6 of the cycle (1.7 ± 0.7 IU/liter in the CD2 vs. 5.0 ± 2.1 IU/liter in the CD5 group; P < 0.01). With regard to follicular development, there was no difference in the numbers of small follicles (<10 mm), intermediate follicles (10-12 and > 12-14 mm) and large follicles (>14 mm) in both groups. This study shows that the administration of recFSH starting on d 2 or d 5 of the cycle in a GnRH antagonist protocol for IVF/intracytoplasmic sperm injection patients yields a comparable endocrine profile and follicular development. Future studies should focus on the design of more patient-tailored ovarian stimulation protocols.

Preconception Folic Acid Use Modulates Estradiol and Follicular Responses to Ovarian Stimulation

Background: Folate is a methyl donor. Availability of folate affects DNA methylation profiles and thereby gene expression profiles. We investigated the effects of low-dose folic acid use (0.4 mg/d) on the ovarian response to mild and conventional ovarian stimulation in women. Methods: In a randomized trial among subfertile women, 24 and 26 subjects received conventional and mild ovarian stimulation, respectively. Blood samples were taken during the early follicular phase of the cycle prior to treatment and on the day of human chorionic gonadotropin administration for determination of serum total homocysteine, anti-Müllerian hormone (AMH), estradiol, and folate. Folic acid use was validated by questionnaire and serum folate levels. Preovulatory follicles were visualized, counted, and diameters recorded using transvaginal ultrasound. The relation between folic acid use and ovarian response was assessed using linear regression analysis. Results: Folic acid use modified the ovarian response to ovarian stimulation treatment. The estradiol response was higher in nonfolic acid users receiving conventional treatment [βinteraction = 0.52 (0.07–0.97); P = 0.03], and this effect was independent of serum AMH levels and the preovulatory follicle count. In the conventional treatment, the mean follicle number was also greater in nonusers compared with the users group (14.1 vs. 8.9, P = 0.03). Conclusion: Low-dose folic acid use attenuates follicular and endocrine responses to conventional stimulation, independent of AMH and follicle count. The nature of this observation suggests that the effect of folic acid is most prominent during early follicle development, affecting immature follicles. Deleterious effects of folate deficiency, like DNA hypomethylation and oxidative stress, can help to explain our observations.

Comparison of mild ovarian stimulation with conventional ovarian stimulation in poor responders

ObjectiveTo compare the IVF outcomes of mild ovarian stimulation with conventional ovarian stimulation in poor responders.MethodsFrom 2004 to 2009, 389 IVF cycles in 285 women showed poor responses (defined as either a basal FSH level ≥12 mIU/mL, or the number of retrieved oocytes ≤3, or serum E2 level on hCG day <500 pg/mL) were analyzed, retrospectively. In total, 119 cycles with mild ovarian stimulation (m-IVF) and 270 cycles with conventional ovarian stimulation (c-IVF) were included. Both groups were divided based on their age, into groups over and under 37 years old.ResultsThe m-IVF group was lower than the c-IVF group in the duration of stimulation, total doses of gonadotropins used, serum E2 level on hCG day, the number of retrieved oocytes, and the number of mature oocytes. However, there was no significant difference in the number of good embryos, the number of transferred embryos, the cancellation rate, or the clinical pregnancy rate. In the m-IVF group over 37 years old, the clinical pregnancy rate and live birth rate were higher when compared with the c-IVF group, but this result was not statistically significant.ConclusionIn poor responder groups, mild ovarian stimulation is more cost effective and patient friendly than conventional IVF. Therefore, we suggest that mild ovarian stimulation could be considered for poor responders over 37 years old.