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Schematic representation of the study protocol. Subjects performed urinary luteinizing hormone (LH) tests at home. On the day of a positive LH test, randomization took place for either estradiol (E 2 ) (600 mg aerodiol every 3 h on the day of LH combined with 8 Fem 7 patches from day LH until LHC4); progesterone (P) (progestine on day of LHC4: 25 mg, LHC5: 100 and 150 mg, LHC6: 300 and 300 mg), E 2 CP (combination of the above-mentioned regimens) or controls (non-treatment, N) group. Blood was sampled every other day during the luteal phase.
Source publication
The luteal phase after ovarian hyperstimulation for in vitro fertilization (IVF) is insufficient. Therefore, luteal phase supplementation is routinely applied in IVF. It may be postulated that premature luteolysis after ovarian hyperstimulation is due to supraphysiological steroid levels in the early luteal phase. In the present study, high doses o...
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Various studies have reported a prevalence of polycystic ovaries (PCO) of approximately 20% in the 'normal' population. Our aim was to investigate the frequency of ovulation and pattern of luteal phase progesterone secretion in a group of women with PCO who reported regular cycles and in whom ovulation had been established on the basis of previous...
Citations
... Therefore, if the oocytes are not there, we cannot harvest them, regardless of the high doses of gonadotropins or types of GnRH analogues applied (12,48). The lack of evidence of a difference in PRs between low and high dosing of gonadotropins may be explained by a trade-off between the positive effects of low doses of gonadotropins on several biological processes, like improved embryo quality, enhanced implantation, an increased proportion of euploid embryos, and the negative effects caused by high doses of gonadotropins by supraphysiological steroid levels on endometrial receptivity (49)(50)(51)(52). ...
Objective:
To evaluate the effectiveness of low doses of gonadotropins and gonadotropins combined with oral compounds compared with high doses of gonadotropins in ovarian stimulation regimens in terms of ongoing pregnancy per fresh IVF attempt in women with poor ovarian reserve undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment.
Design:
A systematic review and meta-analysis of randomized controlled studies that evaluate the effectiveness of low dosing of gonadotropins alone or combined with oral compounds compared with high doses of gonadotropins in women with poor ovarian reserve undergoing IVF/ICSI treatment.
Setting:
Not applicable.
Patient(s):
Subfertile women with poor ovarian reserve undergoing IVF/ICSI treatment.
Intervention(s):
We searched the PubMed, EMBASE, Web of Science, the Cochrane Library, and the Clinical Trials Registry using medical subject headings and free text terms up to June 2016, without language or year restrictions. We included randomized controlled studies (RCTs) enrolling subfertile women with poor ovarian reserve undergoing IVF/ICSI treatment and comparing low doses of gonadotropins and gonadotropins combined with oral compounds versus high doses of gonadotropins. We assessed the risk of bias using the criteria recommended by the Cochrane Collaboration. We pooled the results by meta-analysis using the fixed and random effects model.
Main outcomes measure(s):
The primary outcome was ongoing pregnancy rate (PR) per woman randomized.
Result(s):
We retrieved 787 records. Fourteen RCTs (N = 2,104 women) were included in the analysis. Five studies (N = 717 women) compared low doses of gonadotropins versus high doses of gonadotropins. There was no evidence of a difference in ongoing PR (2 RCTs: risk rate 0.98, 95% confidence interval 0.62-1.57, I2 = 0). Nine studies (N = 1,387 women) compared ovarian stimulation using gonadotropins combined with the oral compounds letrozole (n = 6) or clomiphene citrate (CC) (n = 3) versus high doses of gonadotropins. There was no evidence of a difference in ongoing PR (3 RCTs: risk rate 0.90, 95% confidence interval 0.63-1.27, I2 = 0).
Conclusion(s):
We found no evidence of a difference in pregnancy outcomes between low doses of gonadotropins and gonadotropins combined with oral compounds compared with high doses of gonadotropins in ovarian stimulation regimens. Whether low doses of gonadotropins or gonadotropins combined with oral compounds is to be preferred is unknown, as they have never been compared head to head. A health economic analysis to test the hypothesis that an ovarian stimulation with low dosing is more cost-effective than high doses of gonadotropins is needed.
Prospero registration number:
CRD42016041301.
... The relative hyperestrinism suppresses hypophysal LH production and it is believed that this is possible trigger mechanism of premature luteolysis 13 . The mechanism of premature luteolysis is not known in detail but the studies point to an indirect influence of E on the corpus luteum 14,15 . The length of ovarian steroid production after controlled ovarian hyperstimulation (COH) is about two or three days shorter than in the natural cycles 4 . ...
Background and objective:
Luteal phase physiology is distorted by in vitro fertilization (IVF) cycles using gonadotropin-releasing hormone (GnRH) agonists and antagonists, Controlled ovarian hyperstimulation leads to luteal phase defect and for this reason, luteal phase support is now an integral part of IVF/ICSI-ET programs. The support is provided by hCG, progesterone or GnRH-a. This study compared the efficiency, safety and tolerance of two vaginal micronized progesterones, Utrogestan and Crinone 8%.
Methods:
111 women, 18-40 years old, FSH < 10 IU/L and normal uterus findings were included. The efficiency of the two preparations to provide luteal support was evaluated by the fertilization, implantation, pregnancy and take-home baby rates. The safety was compared through the results of vaginal findings and vaginal inflammation markers before and after treatment. Comparison of tolerance was made by evaluating 21 subjective patient questionnaire parameters.
Results:
There were no significant differences between the preparations in terms of efficiency or safety though Crinone 8% was better tolerated.
Conclusion:
The outcomes of this study suggest that a vaginal gel with micronized progesterone (Crinone 8%) is the optimal choice at this time for luteal support.
... Moreover, the endometrium could respond to embryonic signals such as hCG, to facilitate preparation for implantation. 6 International Journal of Reproductive Medicine The supporting evidence regarding a possible adverse effect of supraphysiological levels of steroids in endometrial receptivity [4,9], corpus luteum function [14,35], oocyte, and embryo quality [36] indicates that the response of limited ovarian stimulation may have a beneficial effect on the potential of implantation. ...
The ovarian stimulation has been applied in order to increase the number of oocytes to compensate for the poor results of in vitro fertilization, allowing the selection of one or more embryos to be transferred. Our aim is to compare the results obtained in IVF/ICSI cycles using the short protocol for controlled ovarian stimulation to the results from the modified mild protocol used in our department. A total of 240 cycles were conducted from January 2010 to December 2011. When comparing both protocols, it could be observed that there was a significant difference in the quantity of gonadotropins doses in the mild protocol and in the short protocol. No significant difference was observed regarding pregnancy rates per cycle, 22% and 26.2%, in short and mild protocols, respectively. The protocols of controlled ovarian stimulation are often associated with high risk of complications such as ovarian hyperstimulation syndrome, excessive emotional stress, high rates of treatment dropouts, and abdominal discomfort. With the data obtained in this study, one can conclude that there are less risks and complications for the patient when using the mild stimulation protocol. It was also observed that in this group there was a slightly higher rate.
... However, increased efficacy in IVF laboratories and the current tendency to limit the number of embryo transferred have reduced the needs to large number of oocytes. On the other hand, conventional long protocol for ovarian stimulation with GnRH agonist combined with a 'high dose' of gonadotrophins produces a superphysiological steroid levels which have a potential negative effect on endometrium receptivity, corpus luteum function, oocyte, and embryo quality [38][39][40]. These evidences could indicate that limited ovarian stimulation and response might have a beneficial effect upon implantation and clinical outcome. ...
Recently, an increased scientific interest was focused on mild approaches for ovarian stimulation in clinical practice. Milder stimulation aims to develop safer and more patient-friendly protocols which are more physiological, less drug use, less expensive and the risks of treatment are highly minimized.
To investigate the efficacy and safety of a mild ovarian stimulation protocol in patients at high risk of developing ovarian hyperstimulation syndrome (OHSS), compared to conventional long down-regulation protocol.
This a prospective, open, randomized study, included 349 infertile patients considered at high risk of developing OHSS, undergoing in vitro fertilization treatment in two private assisted reproduction centers. The patients were randomized into two groups: group A (n = 148) had a mild/minimal stimulation protocol of recombinant FSH (rFSH) combined with GnRH antagonist. Group B (n = 201) (control group) had a standard long protocol of rFSH combined with GnRH agonist.
There was no significant difference observed between the two groups regarding the mean number of oocytes retrieved per patient, mature metaphase II oocytes, fertilization rate, and embryo cleavage rate. Significantly higher implantation rate (21.5 vs 14.5 %) (p < 0.05), pregnancy rate (37.7 vs 23.4 %) (p < 0.05), and delivery rate (32.8 vs 20.1 %) (p < 0.05) were observed in favor of groups A compared to group B. Lower proportion of patients (4.7 %), though not statistically significant, has developed OHSS in group A compared to group B (8.4 %).
Our study shows that mild stimulation regimen is highly effective for ovarian stimulation of patients who have experienced OHSS complication without increasing the risk of OHSS.
... Also, to overcome the side effects caused by high doses of drugs milder stimulation protocols have been developed (Olivennes et al., 2002; Nargund and Frydman, 2007; Pennings and Ombelet, 2007; Ubaldi et al., 2007). The evidence regarding a potentially negative effect of supraphysiological steroid levels on endometrial receptivity (Simon et al., 1995; Devroey et al., 2004), corpus luteum function (Fauser and Devroey, 2003; Beckers et al., 2006), oocyte and embryo quality (Valbuena et al., 2001; Baart et al., 2007) indicate that limited ovarian stimulation and response might have a beneficial effect on implantation potential. ...
... Whether the high estrogen levels in the early luteal phase contribute to the suppression of LH is rather unlikely based on data showing that high serum estradiol concentrations induced by exogenous estradiol during the first half of the luteal phase did not suppress serum LH levels and did not affect the luteal phase (37). More recent data have confirmed this observation by demonstrating that only when estradiol was combined with progesterone LH concentrations were reduced for only one day, i.e. on day 6 following the endogenous LH surge but the luteal phase was not disrupted (39). This suggests that the LH levels should be suppressed for a longer period in order to induce luteal phase disruption. ...
Induction of multiple follicular development is a common practice in IVF programmes. Nevertheless, such an approach is not without implications. Apart from the high multiple pregnancy rate, marked changes in the secretion of pituitary and ovarian hormones take place. Estradiol and inhibin are produced in high amounts during the follicular phase and as a result the negative feedback mechanism is potentiated leading to the marked suppression of gonadotropin secretion from the pituitary. The secretion of LH is also reduced in down-regulated cycles as well as in women receiving a GnRH antagonist, while LH levels are maintained stable when a GnRH agonist is used in a short protocol. The suppression of LH secretion is also evident at midcycle with the endogenous LH surge being blocked or markedly attenuated due to the production of gonadotropin surge attenuating factor (GnSAF). Under these conditions, the LH surge is usually premature in relation to the size of the leading follicle resulting in premature luteinization, but can be prevented by the use of GnRH analogs. In IVF cycles, the luteal phase is disrupted due to the suppression of LH levels. Mild protocols might provide a better approach to the ovarian stimulation than conventional protocols resulting in a reasonable success rate of IVF treatment.
... However, increased efficacy of IVF laboratory procedures and the current tendency—in some parts of the world—to limit the number of embryos transferred, has reduced the need for large quantities of oocytes. Furthermore, supportive evidence regarding a potentially negative effect of supraphysiological steroid levels on endometrial receptivity (Simon et al., 1995; Devroey et al., 2004), corpus luteum function (Fauser and Devroey, 2003; Beckers et al., 2006), oocyte and embryo quality (Valbuena et al., 2001; Baart et al., 2007) indicate that limited ovarian stimulation and response might have a beneficial effect upon implantation potential. ...
Mild ovarian stimulation for in vitro fertilization (IVF) aims to achieve cost-effective, patient-friendly regimens which optimize the balance between outcomes and risks of treatment.
Pubmed and Medline were searched up to end of January 2008 for papers on ovarian stimulation protocols for IVF. Additionally, references to related studies were selected wherever possible.
Studies show that mild interference with the decrease in follicle-stimulating hormone levels in the mid-follicular phase was sufficient to override the selection of a single dominant follicle. Gonadotrophin-releasing hormone antagonists compared with agonists reduce length and dosage of gonadotrophin treatment without a significant reduction in the probability of live birth (OR 0.86, 95% CI 0.72-1.02). Mild ovarian stimulation may be achieved with limited gonadotrophins or with alternatives such as anti-estrogens or aromatase inhibitors. Another option is luteinizing hormone or human chorionic gonadotrophin administration during the late follicular phase. Studies regarding these approaches are discussed individually; small sample size of single studies along with heterogeneity in patient inclusion criteria as well as outcomes analysed does not allow a meta-analysis to be performed. Additionally, the implications of mild ovarian stimulation for embryo quality, endometrial receptivity, cost and the psychological impact of IVF treatment are discussed.
Evidence in favour of mild ovarian stimulation for IVF is accumulating in recent literature. However, further, sufficiently powered prospective studies applying novel mild treatment regimens are required and structured reporting of the incidence and severity of complications, the number of treatment days, medication used, cost, patient discomfort and number of patient drop-outs in studies on IVF is encouraged.
Ovarian stimulation is the starting point of reproductive medicine but the procedure can result in adverse reactions particularly the dangerous ovarian hyperstimulation syndrome. Fully revised in line with modern practice of ovarian stimulation, this new edition is divided into six sections that cover mild forms, non-conventional forms, IVF, complications and their management, alternatives, and the practicalities of procedures. All aspects of ovarian stimulation are discussed including the different stimulation protocols from which to choose, the management of poor responders and hyper-responders, as well as stimulation in patients with PCOS. Comprehensively reviewing the modern approach to ovarian stimulation, the alternative procedures are also described, both in IVF and other methods of assisted reproduction. Written by leading experts on reproductive health and fertility, this book will assist infertility specialists, gynecologists, reproductive endocrinologists and radiologists in determining successful treatment for their patients.
Office Care of Women covers a wide range of topics which are pertinent to the provision of excellent healthcare. Common gynecologic topics are discussed in depth, as well as non-gynecologic medical conditions which are frequently faced by female patients. This book is designed as a single source reference which covers the majority of topics seen by clinicians as they care for women patients in the office setting. The fifty chapters include topics unique to female patients but also include other health conditions which are affected by the patient's gender. The authors of this book span six specialties and three continents thereby giving the reader a comprehensive source of information to improve the healthcare of women.
Office Care of Women covers a wide range of topics which are pertinent to the provision of excellent healthcare. Common gynecologic topics are discussed in depth, as well as non-gynecologic medical conditions which are frequently faced by female patients. This book is designed as a single source reference which covers the majority of topics seen by clinicians as they care for women patients in the office setting. The fifty chapters include topics unique to female patients but also include other health conditions which are affected by the patient's gender. The authors of this book span six specialties and three continents thereby giving the reader a comprehensive source of information to improve the healthcare of women.
