Gentle ovarian stimulation protocols, such as ‘mini-IVF’, have several potential advantages over conventional IVF protocols, including less medication and fewer injections, producing fewer eggs, but eggs of higher quality. The particular ‘mild’ stimulation protocol called ‘mini-IVF’ is described. This protocol requires a reliable and cheap method for embryo cryopreservation such as vitrification, because of the negative impact of clomiphene citrate on the endometrium and since cryopreserved embryo transfers with this protocol have yielded much higher pregnancy rates than fresh transfers. In this series, patients were not denied treatment based on their day-3 FSH value or ovarian reserve. Yet very acceptable pregnancy rates were achieved (20% for fresh embryo transfers and 41% for cryopreserved embryo transfers). These results strengthen the argument for a mini-IVF protocol and vitrification as an alternative to standard conventional IVF stimulation protocols. Now a randomized control trial with cryopreserved single-embryo transfer is required.
Gentle ovarian stimulation protocols have several potential advantages over conventional IVF protocols, including less medication and fewer injections, producing fewer eggs, but eggs of higher quality. ‘Mini-IVF’ is safe, patient friendly and physiologically more natural. It may be more cost effective if results are comparable to conventional protocols. Vitrification of embryos allows the transfer of warmed embryos in subsequent cycles when the endometrium is more receptive. In this series, patients were not denied treatment based on their day-3 FSH value or ovarian reserve. Yet very acceptable pregnancy rates were achieved (20% for fresh embryo transfers and 41% for cryopreserved embryo transfers). These results strengthen the argument for gentle stimulation protocols and vitrification in preference to standard conventional IVF stimulation protocols. Now a randomized control trial with cryopreserved single-embryo transfer is required.
Introduction
The ‘mini-IVF’ protocol evolved with the intention of providing more natural stimulation for IVF. In this unusual protocol, clomiphene citrate, a competitive inhibitor of oestradiol, was used to stimulate the ovary by elevating FSH secretion of the pituitary gland. Continuation of clomiphene citrate beyond the usual 5 days was also able to inhibit the LH surge (Teramoto and Kato, 2007). Thus, a longer stimulation was achieved with clomiphene citrate and premature LH surge was prevented by the anti-oestrogen effect of clomiphene on the pituitary when the oestradiol began to rise. A very low supplemental dose of FSH was administered every other day from day 8. Once adequate follicle development was noted, a nasal spray of gonadotrophin-releasing hormone agonist (GnRHa) was administered to trigger an LH surge for the final maturation of oocytes.
Gentle ovarian stimulation protocols have been shown to have many advantages over conventional ovarian stimulation protocols. There have been several reports of improved egg quality in IVF protocols with less medication (Baart et al., 2007, Collins, 2009, de Jong et al., 2000, Devreker et al., 1999, Fauser et al., 1999, Heijnen et al., 2007, Pelinck et al., 2007, Polinder et al., 2008, Van der Gaast et al., 2006, Verberg et al., 2008, Verberg et al., 2009a, Verberg et al., 2009b). Gentle ovarian stimulation protocols use fewer injections of drugs, thus reducing pain from multiple daily injections and dramatically reducing drug costs (Sophonsritsuk et al., 2005). With conventional stimulation, patients tend to drop out from treatment cycles due to the inability to tolerate the pain from 2–3 weeks of daily drug injections and the cost component of the medications (Verberg et al., 2008). Mini-IVF is less expensive than conventional IVF for other reasons as well. With less follicles to aspirate and less eggs for the laboratory to manage, many more procedures can be performed with less effort and less cost (Check, 2007, Heijnen et al., 2007, Polinder et al., 2008, Teramoto and Kato, 2007). The question is whether the already-demonstrated improvement in percentage of good-quality embryos with a mild stimulation protocol is sufficient to outweigh the larger number of embryos obtained with conventional stimulation (Devreker et al., 1999, Verberg et al., 2009a, Verberg et al., 2009b). The aim of the present study was to evaluate retrospectively the outcomes of patients who underwent Mini-IVF using clomiphene citrate and also to evaluate the efficacy of vitrification for embryo cryopreservation in such a programme.
Section snippets
Study subjects and protocol
These study patients include women who underwent a mini-IVF protocol from 2006 to 2009 in New Hope Fertility Center, NY, USA. Clomiphene citrate 50 mg (Clomid; PAR Pharmaceutical, USA) was initiated orally each day, beginning on day 3 for ovarian stimulation and continued until the follicles were developed sufficiently for ovulation triggering. Subcutaneous administration of 150 IU human menopausal gonadotrophin (Menopur; Ferring Pharmaceuticals, Tarrytown, NY, USA) every 48 h was begun on day 5
Results
A total of 2516 patients (1580 patients with day-3 FSH ⩽15 IU/l, 998 patients with day-3 FSH >15 IU/l) underwent IVF treatment using a mini-IVF protocol. A total of 2957 cycles were initiated with 2741 retrieval cycles, 577 fresh transfer cycles and 926 cryopreserved transfer cycles. A total of 496 pregnancies were achieved, of which 380 pregnancies were from cryopreserved embryo transfer. For day-3 FSH ⩽15 IU/l and >15 IU/l, the average number of oocytes per retrieval was 2.3 ± 2.2 and 2.1 ± 2.1 (a
Discussion
Gentle ovarian stimulation protocols were developed for patients desiring a less stressful and less expensive mode of IVF treatment to achieve a pregnancy. The question is whether such a protocol has acceptable pregnancy rates. The concept of the mini-IVF protocol described here is based on the continued secretion of FSH by abolishing the negative feedback of oestradiol on the pituitary with clomiphene citrate.
For this purpose, a small dose of oral clomiphene citrate was initiated from day 3
Acknowledgements
The authors wish to thank all the patients who participated in this study, the entire staff at New Hope Fertility Center New York, and Sharon Fuller for her assistance in preparation of this manuscript.
2021, Computer Methods and Programs in Biomedicine
Frozen-thawed embryo transfer (FET) is now widely used for the treatment of infertility. For many couples and clinicians, concerns over the probability and how to increase the chance of a successful birth are very common. Currently, there is not a single model to predict the live birth outcomes for FET. To estimate the probability of live birth (PLB) in FET and to provide advice on potential treatment options by a data-driven predictive (DDP) model.
2,189 FET cycles from Jan 2012 to Dec 2015 were recruited in a single center. 815 cycles of FET outcomes were live births and 1,374 cycles of FET outcomes failed. To verify the consistency of the DDP model, we carried out 10-fold cross-validation, and the mean and standard deviation of the accuracy were measured. Moreover, the performance of this model was evaluated by the mean and standard deviation of receiver operating characteristic curve and area under the curve (AUC).
Nine dominant factors, including age, BMI, HOMA-IR, basal follicle stimulating hormone, basal luteinizing hormone, basal estradiol, endometrial thickness, the number of embryo transfers and the total number of embryos, were automatically extracted from 28 candidate factors. The accuracy of our prediction model is 76.9%±1.6%, and the AUC is 0.83. Then, the PLB is estimated by the random forest algorithm. On this basis, the DDP model can comprehensively traverse and dynamically visualize the impact of several factors on live birth outcomes. Finally, optimal suggestions for the treatment of patients before FET are attempted to be made by the genetic algorithm.
The DDP model can not only provide satisfactory performance for predicting live birth outcomes in FET but also offer a visual estimation and simulation tool for clinicians to make treatment plans.
The current ovarian cycle paradigm postulates that ovulation is triggered by a critically sustained elevation of estradiol. However, an in-depth look into the published data reveals considerable uncertainty about the relative roles of progesterone and estradiol in the ovulation process.This review provides compelling evidences that the role of estradiol in ovulation has been misinterpreted and that the true physiological trigger of ovulation is a luteinizing hormone–independent preovulatory progesterone surge in the circulation to approximately 0.5 ng/mL. Furthermore, the current work reconciles the ability of progesterone to trigger ovulation, with its well-established ability to block ovulation during pregnancy, or when administered in the form of a synthetic progestin in birth control formulations and with experimental data that estradiol benzoate triggers ovulation in the complete absence of progesterone.
Prolonged embryo culture is increasingly used as a way of improving pregnancy rates, especially in the context of single embryo transfer. So far, only a handful of studies examined the relation between implantation potential and time-lapse parameters extracted from later stages (morula and blastocyst) of embryo development. For this retrospective study all 285 single vitrified-thawed blastocyst transfers (SVBT) from all consecutive unselected patients whose fertilized oocytes were submitted to time-lapse monitoring (TLM) from a two-year cohort were analysed. Two different statistical models were created; a hierarchical one including the two strongest live birth (LB) predictors (t2 and texpB2) and a more complex model based on principal component analysis (PCA) and logistic regression methods. The first, four-category, hierarchical model effectively distinguished between blastocysts of increasing LB rates (8, 30, 40, 53%). For the second data-mining model quartiles of the created Sc parameter had increasing LB rates (12, 19, 40, 49%). AUC values were comparable for both models (0.723, 95CI%:0.66–0.79 versus 0.717, 95CI%:0.65–0.78). The combination of cleavage- and blastocyst-stage variables through hierarchical or data mining-based algorithms was used successfully to predict live birth. However, due to the lack of internal / external validation the predictive capacities of this model could differ largely in different datasets.
To evaluate the effect of adding clomiphene citrate (CC) in the mid-to-late follicular phase as an adjuvant to gonadotropins to suppress luteinizing hormone (LH) surge in women undergoing intracytoplasmic sperm injection (ICSI).
Prospective non-randomized study of 108 women undergoing ICSI and subjected to ovarian stimulation with gonadotropins with addition of CC (50 mg 3 times per day) when a leading follicle reached 14 mm in diameter and continued till the day of human chorionic gonadotropin (HCG) administration. Women subjected to controlled ovarian stimulation (COS) with the gonadotropin-CC protocol (n = 50) were compared with a group of women were to COS with the flexible gonadotropin releasing hormone antagonist (GnRH-ant) protocol (n = 58).
Serum LH level on day HCG administration was significantly higher in CC group than in GnRH-ant group and the incidence of LH surge was higher in CC group than in GnRH-ant group (10% vs 3.4%, respectively) but without statistically significant difference (P = .246). The oocyte maturation and fertilization rates, the biochemical and clinical pregnancy rates, the implantation rate and the ongoing pregnancy rate were comparable in both groups.
Adding CC in the mid-to-late follicular phase as an adjuvant to gonadotropins represents a less costly COS which is effective in eliminating the occurrence of premature LH surge without compromising the cycle outcomes in women undergoing ICSI.
Is minimal ovarian stimulation (MOS) as effective as conventional ovarian stimulation (COS) in ovarian response and embryo quality in the same 46 poor-responder patients according to the Bologna criteria?
An intra-patient comparison of patients undergoing both protocols. Ovaries were stimulated with either a gonadotrophin-releasing hormone antagonist protocol and a combination of recombinant FSH and highly purified human menotrophin (HP-HMG) daily (COS), or with the use of clomiphene citrate 50 mg daily and 150 IU of HP-HMG or recombinant FSH every other day from simulation day 4 (MOS).
After MOS, significantly more good-quality embryos (1.0 ± 1.2 versus 0.3 ± 0.6) (P = 0.002), oocytes (3.2 ± 1.9 versus 2.0 ± 1.8) (P = 0.002), and mature (metaphase II) oocytes (2.6 ± 1.7 versus 1.6 ± 1.7) (P = 0.001) were obtained. In COS cycles, a significantly higher total gonadotrophin dose was needed per good-quality embryo (+2194 IU; 95% CI 618 to 3170).
In poor responder patients, MOS is a good alternative when COS has failed, or even as a first-line treatment. It offered a significantly greater number of good-quality embryos as well as a higher number of oocytes, using significantly lower doses of gonadotrophins per oocyte and embryo obtained.
For many years, assisted conception technologies were characterized by a limited efficiency that was in some was compensated for by aggressive ovarian stimulation aimed at obtaining large number of oocytes. However, this approach placed a considerable burden of cost, side effects, and risk of complications on the patient. Recognition of this, and of the potentially detrimental effects of gamete and endometrial exposure to supra-physiological levels of gonadotrophins and estrogens, and concern as to the viability of the oocytes thus obtained led to the development of milder stimulation protocols, and increased use of natural cycle IVF. In this article, the principles behind mild stimulation and natural cycle IVF are outlined, and the published data relating to their respective efficacy, advantages, and disadvantages are reviewed.
Dr John Zhang graduated in 1984 from Zhejiang University School of Medicine in China. He was awarded his PhD from Cambridge University for his IVF studies in 1991. In addition, he also has a Masters degree in male infertility from Birmingham University, UK. He is a reproductive endocrinology and infertility specialist whose academic training includes residency training in obstetrics and gynaecology and a fellowship in Reproductive Endocrinology and Infertility in 2004 from New York University School of Medicine. Dr Zhang is the director and founder of New Hope Fertility Center, an independent IVF facility in New York.
