|Year : 2015 | Volume
| Issue : 3 | Page : 104-126
3rd World Congress on Ovulation Induction and Ovarian Stimulation Protocols, Seychelles, 3rd to 6th September 2015
|Date of Web Publication||8-Dec-2015|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
. 3rd World Congress on Ovulation Induction and Ovarian Stimulation Protocols, Seychelles, 3rd to 6th September 2015. IVF Lite 2015;2:104-26
|How to cite this URL:|
. 3rd World Congress on Ovulation Induction and Ovarian Stimulation Protocols, Seychelles, 3rd to 6th September 2015. IVF Lite [serial online] 2015 [cited 2022 Jan 18];2:104-26. Available from: http://www.ivflite.org/text.asp?2015/2/3/104/171217
Outcome of ovarian drilling in women with polycystic ovary syndrome
Dr. Singh Test Tube Baby Centre, Meerut, Uttar Pradesh, India,
Polycystic ovary syndrome (PCOS) is a relatively common clinical disorder that affects 5–10% of women in the reproductive age group Problems in inducing ovulation in PCOS are well-recognized and range from a brisk response to no response at all. Obesity, even of moderate degree (body mass index >27 kg/m2) is associated with a reduced likelihood of ovulation. Thus, exercise and calorie restriction to reduce weight is necessary to optimize the success rate with medical therapy. The drug of choice to induce ovulation is clomiphene citrate (CC). Failure to ovulate after 2–3 successive cycles of CC at the maximal dose is usually an indication to consider treatment with gonadotrophins. Surgical Therapy: Bilateral ovarian wedge resection was first introduced as treatment for patients with anovulatory PCOS. The ovulation rates were high, but pregnancy rates (PRs) were much lower, probably because of the high incidence of postsurgical periadnexal adhesion formation which converted an endocrinological problem to a mechanical one. Laparoscopic Ovarian Drilling: This technique was first described in 1984 and involved the creation of 8–15 holes, each one 2–4 mm deep on the surface and stroma of each ovary using a unipolar electrode. Mechanism of Action of Laparoscopic Ovarian Drilling: The mechanism of action is unknown but is believed to be related to endocrine changes that result from the procedure. Potential Risks and Complications of Laparoscopic Ovarian Drilling: It is rare and includes avulsion of utero-ovarian ligament from excessive traction and bleeding from the holes drilled in the ovary. Other risks are associated with the laparoscopy procedure itself. Another potential complication is premature ovarian failure. Comparative Efficacy of Ovarian Drilling and Gonadotropin Stimulation: Very few comparative studies are available. However, it is evident that gonadotrophin stimulation has more success than ovarian drilling in ovulation and PR.
One step ultrasound assessment of the infertile woman
Department of Obstetrics and Gynecology, Women's Health and Assisted Reproduction Center, American Hospital of Istanbul, Istanbul, Turkey, E-mail: firstname.lastname@example.org
Ultrasound examination is essential in the first step of assessment of infertility. One stop transvaginal ultrasound provides detailed information of the pelvic structures, targeting to address issues concerning fertility potential. The main objective of this speech is to demonstrate how to use transvaginal ultrasound to evaluate the uterus, ovaries, and tubes. Regarding uterine evaluation, assessment of endometrial receptivity, endometrial polyp, fibroid, adenomyosis, intrauterine adhesions, and anatomical abnormalities will be discussed. Concerning ovarian evaluation, ovarian reserve assessment and effect of endometriomas on fertility will be debated. Ultrasound assessment of tubal status, hydrosalpinx and tubal patency will be discussed. Three-dimensional ultrasonography provides additional benefit to the patient's fertility management. One step ultrasound assessment gives important information in fertility evaluation and saves valuable time for couples and physicians.
Anti-Müllerian hormone and in vitro fertilization Stimulation Protocols
University of Rochester Medical Center, Rochester, NY, USA,
Appropriate stimulation of the ovaries for in vitro fertilization remains a challenge. Inadequate stimulation leads to poor outcomes and MERiT and MEGASET trials have shown that excessive stimulation leads to poor outcomes as well. In addition, the health of the patient can be compromised with excessive stimulation of the ovaries. It would be ideal if we could predict the ovarian response and tailor, the stimulation protocol for individual patients. Maternal age, early follicular phase follicle stimulating hormone (FSH) levels, PCOS status of patient, anti-Müllerian hormone (AMH) levels, and antral follicle count are some of the tools at our disposal to predict ovarian response to stimulation. Of these, AMH levels and antral follicle count (AFC) are most promising tools available today. Measurement of AMH levels has been plagued with problems initially, but the latest method has improved its reproducibility. It is cycle independent and does not suffer from interobserver variability. It is better at predicting excessive ovarian response than at predicting poor response. Comparison of AMH to AFC has shown that they are very similar in efficacy although AFC suffers from interobserver variability. Models have been created to predict ovarian response and tailor, the stimulation protocol based on the AMH levels. Studies from the UK and Vietnam support these models, and an Italian group has designed a nomogram to determine the starting dose of FSH based on AMH, patient's age, and early follicular FSH levels. Based on these studies, it is apparent that an antagonist protocol is best for patients with low or high AMH levels in determining a better outcome by decreasing cycle cancelation, decreasing ovarian hyperstimulation syndrome, increasing pregnancy rate in hyper-responders, and by decreasing cycle cost. Because of the variation in the AMH levels from laboratory to laboratory, it is advisable for individual centers to establish their own norms for low-, normal-, and high-FSH levels.
Is Estrogen Priming in the Poor Responder a Resource or a Gimmick?
University of Rochester Medical Center, Rochester, NY, USA,
Many protocols have been advocated for the optimal management of a poor responder to in vitro fertilization (IVF) stimulation. There is weak evidence favoring either agonist or antagonist protocols to improve outcome in these patients. Estrogen priming in the luteal phase of the cycle leading to the IVF cycle has been proposed to improve outcome based on the theoretical advantage of decreasing luteal follicle stimulating hormone levels thereby decreasing lead follicle development and improving formation of a cohort of follicles. Fischer et al. first introduced this concept with a complex protocol, named AACEP (agonist/antagonist conversion with estrogen priming protocol) and showed a pregnancy outcome of 25–28%. Ye et al. published the results of a randomized controlled trial (RCT) that compared luteal estrogen priming in antagonist cycles with long agonist cycles that did not have estrogen priming. There was no difference in pregnancy rates (PRs) between the two protocols, but the live birth rates were very good at 34–37% which makes one question the diagnosis of poor responder. Durnerin et al. performed a similar study and came to the conclusion that estrogen priming does not improve the pregnancy outcome. A meta-analysis by Reynolds et al. concluded that the PRs are not improved but risk for cycle cancelation may be improved with estrogen priming. Cakmak et al. introduced a modification to the estrogen priming protocol by following the estrogen priming with 7 days of antagonist before starting stimulation with gonadotropins (delayed start protocol) and showed an improved outcome. A RCT by Maged et al. compared conventional antagonist protocol with delayed start protocol and showed a significant improvement in clinical PRs of 30% compared with 10%. In summary, although estrogen priming sounds promising in theory, it has not shown to be useful in practice. Delayed start protocol may hold prom.
Management of Fluid in the Endometrial Cavity During in vitro fertilization Cycles
University of Rochester Medical Center, Rochester, NY, USA,
Fluid accumulation is noted with reasonable frequency during in vitro fertilization (IVF) stimulation cycles. The evidence that this is detrimental to pregnancy is confusing at best. The reason for this confusion may be in part due to size of the studies, which are frequently small and in part due to study design, which is frequently poorly controlled. A study by Chien et al. showed a significant decrease in pregnancy rates (PRs) in the presence of endometrial fluid whereas Lee et al. showed no difference in PRs and live birth rates. The reason for this discrepancy may be due to a lack of discrimination of the etiology for the endometrial fluid accumulation. Akman et al. compared PRs in women with tubal pathology and fluid accumulation with those with polycystic ovary syndrome (PCOS). They showed that clinical PRs were significantly decreased if there was tubal pathology compared with PCOS. Drainage of tubal fluid alone does not improve pregnancy outcomes (Sowter) whereas proximal tubal occlusion or salpingectomy improves pregnancy outcomes (Surrey, Arora). Recently, it has been reported that endometrial fluid in the presence of cesarean scar defect (isthmocele) decreases PRs and correction of this defect improve the outcome (Gubbini). In conclusion, endometrial fluid in the presence of tubal disease or isthmocele is detrimental to PRs after IVF and removal or proximal occlusion of fallopian tubes or resection of isthmocele restores PRs. In the absence of pathology, fluid may be aspirated, or embryo transfer performed in the presence of fluid.
Strategies to Improve Endometrial Thickness
University of Rochester Medical Center, Rochester, NY, USA,
Poor endometrial development with resultant thin endometrium observed during ultrasound monitoring of in vitro fertilization stimulation is a frustrating problem faced by all clinicians. This is secondary to the long held belief and observation that thin endometrium is accompanied by poor pregnancy rates (PRs). A recent systematic review showed that thin endometrium is a poor predictor of PRs. However, it has also been shown that thicker the endometrium results in better the PRs. Therefore, although one should not cancel a cycle as a result of thin endometrium, it may be worthwhile to increase the endometrial thickness to improve the chances of success. The first step in addressing thin endometrium is to evaluate the endometrium by performing a hysteroscopy and removing any adhesions if present. After this step, increasing the dose and duration of estradiol has been documented to be most successful in achieving a thicker endometrium. If this fails, sildenafil, pentoxifylline, tocopherol, luteal gonadotrophin releasing hormone agonist, luteal human chorionic gonadotropin, and intrauterine granulocyte colony-stimulating factor have all been advocated. The evidence for the effectiveness of any of these adjunct agents is poor at best and more, better-designed studies need to be conducted to evaluate their usefulness.
Management Of Endometrioma In Reproductive-Aged Women; Balancing Harm And Benefit
Baris Ata, Ayse Seyhan1
Department of Obstetrics and Gynecology, KOC University School of Medicine, 1Department of Obstetrics and Gynecology, Women's health and Assisted Reproduction Center, American Hospital of Istanbul, Istanbul, Turkey,
Endometriosis affects 1–2% of reproductive-aged women and 20–40% of them have endometriomas. Indications for surgical treatment are controversial, yet endometrioma excision is commonly performed. Suggested benefits of surgical treatment include: (i) Providing a definitive diagnosis and ruling out malignancy, (ii) treatment of anovulation, (iii) treatment of pain, (iv) improve chances of spontaneous conception, and (v) increase in vitro fertilization (IVF) success. The vast majority of endometriomas have typical ultrasound characteristics, and these include ground glass appearance, 1–4 locules, and the absence of vascularized papillary structures. Unusual ultrasound findings, the presence of concomitant symptoms suggesting a malignancy can trigger further investigation. Germ cell tumors are more common than epithelial ovarian cancers in young women. In contrast to endometriomas, they are characterized by rapid growth and serum markers alpha-fetoprotein, lactate dehydrogenase, and human chorionic gonadotropin can help diagnosis. Human epididymal protein 4 is rarely increased with endometriomas and would better assist for differential diagnosis between epithelial tumors and endometriomas than CA-125, which is also increased in endometriosis. Using a combination of appropriately selected markers and ultrasound features, surgery would be rarely needed to rule out malignancy, perhaps except for very large ones. A large study clearly shows endometriomas do not affect ovulation from the harboring ovary. Indeed, most patients with endometriosis are ovulatory. When postoperative hormone therapy is not used, pelvic pain frequently recurs following surgery in reproductive aged women. If the patient desires fertility, hormone treatment cannot be used, and effect of surgery on fecundity is controversial. Indeed, studies supporting a beneficial effect are usually uncontrolled and provide low-quality evidence. In contrast, there is high-quality evidence demonstrating declined ovarian reserve following endometrioma excision. Endometrioma excision does not improve IVF outcomes. Moreover, advanced endometriosis surgery is not complication free. Patients with endometriomas must be assessed in detail for their major complaints, and age, ovarian reserve, fertility desire, estimated time to menopause should be considered for balancing harm and benefit. These must be discussed with the patient in advance.
Effect of endometrioma and its excision on ovarian reserve
Baris Ata, Ayse Seyhan1
Department of Obstetrics and Gynecology, KOC University School of Medicine, 1Department of Obstetrics and Gynecology, KOC University School of Medicine, Istanbul, Turkey,
Endometriosis affects 1–2% of reproductive-aged women and 20–40% of them have endometriomas. Ovarian reserve is reproductive potential of a woman expressed as a function of quantity and quality of oocytes. Antral follicle count (AFC) as assessed by transvaginal ultrasound and serum anti-Müllerian hormone (AMH) level are commonly used markers of ovarian reserve. Number of oocytes collected in a stimulated in vitro fertilization (IVF) cycle also reflects ovarian reserve. Is the presence of an endometrioma associated with a decrease in ovarian reserve? Few retrospective studies compared AFC between women with endometrioma and infertile women, recruited as controls, and found AFC to be similar. However, these studies are biased with the selection of control groups. In a prospective study, we compared AFC between 30 women with endometrioma and 30 age-matched healthy controls and found AFC to be significantly decreased. In the same study, we also found significantly decreased AMH levels in women with endometrioma. Another retrospective study has corroborated our findings. A recent meta-analysis reported significantly less oocytes being collected from women with endometrioma and a significantly higher rate of cycle cancelation as compared to other women undergoing IVF. Although a recent meta-analysis report AFC to be similar before and after endometrioma excision, when the analysis is limited to the operated gonad AFC seems to be decreased. Several studies consistently demonstrate a permanent decline in AMH following endometrioma excision. Compared to unoperated gonads, ovaries yield significantly less oocytes following endometrioma excision, without an improvement in pregnancy rates. Several factors have been investigated as determinants of harm on ovarian reserve. While age does not seem to affect the rate of decline in ovarian reserve, women with bilateral endometriomas experience a higher loss. Women who have higher ovarian reserve before surgery also experience a relatively higher loss, but they may end up with reasonable ovarian reserve after surgery. Bipolar cauterization of the cyst bed harms ovarian reserve more than suturing or application of hemostatic sealant. In conclusion, endometrioma decreases ovarian reserve. Endometrioma excision causes a further decline.
What Not To Do In Infertility Practice
Department of Obstetrics and Gynecology, KOC University School of Medicine, Istanbul, Turkey,
Medical practice should be based on effective diagnostic and therapeutic interventions, as proven by proper studies. Expert opinions and general agreement on therapeutic intervention can prove right or wrong over time. Interventions that should be absolutely avoided would include simply irrational treatments and that are proven ineffective, alongside complications. Infertility is a couple's problem and treating one partner without properly assessing the other is simply irrational. An increasing number of tests are being introduced to clinical practice without proper background. Tests should only be ordered when their results are expected to alter couple's management. Several treatment strategies, which have high-quality evidence against effectiveness, are being used worldwide. The clinician is responsible with closely following the literature and acquiring the skills for critical appraisal of research papers. Ovarian hyperstimulation syndrome and multiple pregnancies are the most important complications of assisted reproductive technologies. In 2015, ovarian hyperstimulation syndrome could be almost completely eliminated with appropriate cycle monitoring and management. Multiple pregnancies are most often caused by uncontrolled ovarian stimulation and intrauterine insemination cycles, rather than in vitro fertilization (IVF). The number of growing follicles should be closely monitored, and cycles should be canceled without hesitation if needed. Single embryo transfer must be the aim in IVF cycles. Errors in the IVF laboratories can have dire consequences not only for the couple and the medical professionals but also for the children. Adequate quality control systems and standard operating procedures must be in place to avoid gamete and embryo mix-up.
Biosimilar products for Ovulation Induction
Al Ain Fertility Center, Al Ain, Abu Dhabi, UAE,
Biosimilar medicines are medical products whose active drug substance is made by or derived from a living organism by recombinant DNA or controlled gene expression. They have to meet high standards for comparability to the originator medicine and are approved for use in the same indications. Biosimilars are the biologic medicines, equivalent of chemical generics. A biosimilar is a copy version of an approved original biologic medicine whose data protection has expired. Since the implementation of a biosimilar approval pathway in 2005, several biosimilars have been licensed and become available in the European Union. These biological molecules are derived from living cells or organisms and consist of relatively large and often highly complex molecular entities that may be difficult to fully characterize. The amino acid sequence is expected to be the same, and only small differences in the microheterogeneity pattern of the molecule may be acceptable. As with generics, biosimilars are intended to be used at the same dose(s) and dosing regimen(s) for same indication(s) as their reference products. Therefore, the focus of biosimilar development is not to establish patient benefit per se, as this has already been done for the originator product, but to convincingly demonstrate high similarity to the reference product as basis for relying, in part, on its efficacy and safety experience. Major concerns about biosimilars will be discussed (pharmaceutical quality, safety, efficacy, and interchangeability with the originator product). First, biosimilar ready to be used in reproductive medicine is recombinant follicle stimulating hormone (r-FSH). The r-FSH preparations Gonal-f and Puregon have been commercially available since 1995 and 1996, respectively. Bemfola (Finox AG, Switzerland) is the first r-FSH biosimilar on the market that has been demonstrated to have similar physicochemical properties in preclinical studies and is intended for use in the same therapeutic indications as Gonal-f. Bemfola has similar nonclinical pharmacological, pharmacokinetic, and toxicological profiles to those of Gonal-f (European Public Assessment Report, Bemfola). In this presentation, we will review data showing the equivalence of Bemfola and the comparator product Gonal-f in ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection. Data coming from the Phase I clinical trial and the first MultiCenter Phase III study will be discussed.
Why The Education And Professional Status Of Embryologists Is Important
IVF Consultancy Services, UK,
The first live birth following clinical in vitro fertilization (IVF) was reported in the UK in 1978 by an embryologist (Bob Edwards) and a gynecologist (Patrick Steptoe). Since then, reproductive medicine and assisted conception have become a sophisticated multidisciplinary area of medicine. Assisted reproductive technology (ART) is globally accepted as a subspecialty for gynecologists, who are recognized as fertility specialists. However, the recognition for embryologists has been slower despite good laboratory skills being paramount to IVF success. From a survey of 1349 European clinics in 2012, over 7000 laboratory staff performed over 700,000 fresh and frozen ART cycles. This would not have been possible without trained embryologists. Despite the increasing demand for ART, clinical embryology is only recognized as an official profession in 3 out of 27 national health systems in Europe! To help gain recognition, the European Society of Human Reproduction and Embryology launched the Embryologist Certification for junior and senior clinical embryologists in 2008, with the first examinations taking place in 2009. A BSc degree in Natural Sciences with at least 3 years' hands-on experience is needed for entry into the junior clinical embryologist examination, while an MSc or PhD degree in Natural Sciences with at least 6 years' hands-on experience is needed for entry into the senior embryologist examination. This provides an international standard by which embryologists can demonstrate their knowledge and clinical experience. Certification was initially limited to Europe; however, due to increasing demand, examinations are now offered to nonEuropeans. This presentation will summarize the opportunities for training and education for embryologists in different countries. The aim is to highlight the need for proper training and recognition not only to provide optimal care and high success rates but also to protect people who are seeking ART.
Importance Of Cytoplasmic Granularity Of Human Oocytes In in vitro fertilization/intracytoplasmic sperm injection Treatments
IVF Consultancy Services, UK,
Oocyte quality can be initially assessed at the time of collection, and then assessed in more detail when the surrounding cumulus cells are removed. Oocyte maturity can then be assessed, by looking for the presence of a polar body, indicating that the oocyte is most likely at the metaphase II stage. Microscopic assessment of the oocyte appearance can also provide information about the quality of this gamete. Oocyte morphology impacts on fertilization, embryo quality, and implantation. Irregularities such as a large perivitelline space, presence of a smooth endoplasmic reticulum (SER) disc, or an unusual "color" of the cytoplasm should be recorded. The latter has often been linked to the term "granularity." Such granularity can affect the whole cytoplasm, or more usually, an oocyte may have a centrally located area of granularity, appearing darker than the rest of the cytoplasm. This presentation will focus on the impact of granularity on key performance indicators. Other aspects of oocyte appearance including the presence of SER discs will also be discussed. The ultrastructure of the oocyte will be examined in terms of metabolism. Most notably the role of calcium signaling will be discussed since this is critical to the activation process after sperm entry either by conventional in vitro fertilization insemination or via intracytoplasmic sperm injection.
Time-lapse in the in vitro fertilization-laboratory: how should assess potential benefits?
Preimplantation Genetics Diagnosis Laboratory, Institute Marques Clinic, Barcelona, Spain,
Selection of embryos with the highest probability of achieving and maintaining a pregnancy is the most important challenge in human assisted reproduction. The introduction of noninvasive time-lapse system in in vitro fertilization laboratories has enabled the continuous monitoring of embryo morphological and dynamic temporal data (morphokinetics) without the disturbance of culture requirements by avoiding daily removal from the incubator. This technology offers the possibility of a more accurate selection of those embryos with the greater implantation potential. Several algorithms have been proposed to attempt to find differences in morphokinetic variables between aneuploidy and euploid embryos as a potential tool to select viable embryos. The objectives of this work were to determine noninvasive predictive factors of chromosomal normality, designing a statistical model to achieve better selection of embryos those couples at risk of chromosomal abnormalities who do not consider preimplantation genetic diagnosis (PGD) due to ethical, religious, legal, or economic reasons. This was a retrospective study carried out at the Institute Marques Clinic (Barcelona) that analyzed time-lapse imaging data of human embryos biopsied and subject to PGD during in vitro growth until day 5. Embryos were cultured a time-lapse incubator system EmbryoScope (EmbryoScope; UnisenseFertiliTech), and images were acquired every 10 min through seven focal planes. Biopsies were performed on the day 3 embryos and Blastomeres were analyzed by fluorescent in situ hybridization-24 technique. A model obtained by multivariate logistic regression including s2, time to 3 cells, time to compaction, time to morula, time to expanded blastocyst, percentage of fragmentation on the day 2 and 3 (W3), location of fragmentation on the day 2, and morphokinetic score, predicts normal chromosomal content. Moreover, in PGD euploid embryos, time to pronuclei appearance, time to 3 cells, W3, and the location of fragmentation on the day 3 were significantly associated with successful pregnancy. In conclusion, a model that can be used to optimize embryo selection by increasing the chances of selecting euploid embryos for couples at chromosomal risk that for several reasons rejects PGD have been developed as well as a model that predicts the outcome of the transferred euploid embryo for couples that undergo PGD, as selection tool to increase chances of pregnancy.
in vitro fertilization-Lite in Poor Responders
Gautam N. Allahbadia, Goral Gandhi
Rotunda - The Center for Human Reproduction, Bandra, Mumbai, Maharashtra, India,
Despite the fact that in the last two decades, an enormous number of papers on the topic of poor ovarian response have been published in the literature, so far it has been impossible to identify any efficient treatment to improve the ovarian response and the clinical outcome of this group of patients. The incidence of poor ovarian responders among infertile women has been estimated at 9–24%; however, according to recent reviews, it seems to have slightly increased. Unfortunately, despite advances in stimulation protocols, recombinant formulations, application of preimplantation genetic screening/preimplantation genetic diagnosis, and newer techniques such as trophectoderm biopsy + next generation sequencing, the in vitro fertilization (IVF) success rates for poor responders have not improved. The only consistent good results have been from centers using vitrification and accumulation of embryos as their first-line treatments for this difficult group of patients. Consequently, with evolution of these patient-friendly Assisted Conception procedures, routine IVF is being challenged by simpler methodologies. These include natural cycle IVF, minimal stimulation IVF (msIVF), and IVF Lite (msIVF + vitrification + accumulation of embryos + remote embryo transfer) (msIVF + ACCUVIT + rET). IVF Lite requires a reliable 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 (PRs) than fresh transfers. In our series, patients were not denied treatment based on their day-3 follicle stimulating hormone value or ovarian reserve. Yet, very acceptable PRs were achieved. These results strengthen the argument for IVF Lite as an alternative to standard conventional IVF stimulation protocols. IVF Lite gives PRs comparable to conventional IVF in patients with a normal ovarian reserve. IVF Lite gives PRs much better than conventional IVF in older patients, patients with previous conventional IVF Failures, poor responders, and hyper-responders. Further prospective randomized studies are needed to compare cumulative PRs between the two protocols. In cost-conscious environments, IVF Lite is probably the type of IVF that is going to be the future.
Ovarian Stimulation Protocols For intrauterine insemination Cycles
Gautam Allahbadia, Goral Gandhi
Rotunda - The Center for Human Reproduction, Bandra, Mumbai, Maharashtra, India,
Intrauterine insemination (IUI) treatment requires ovarian stimulation to achieve the modest results, but the high multiple pregnancy rates (PRs) mean that it is no more than a poor substitute for in vitro fertilization treatment. More trials are needed on IUI treatment with mild stimulation and the order of IUI and other treatments. In 2009, the European Society of Human Reproduction and Embryology, Capri Workshop Group, reviewed controversies in IUI on the basis of the available evidence. They suggested that compared to expectant management, IUI with stimulation might lead to improved clinical outcomes. Particularly, ovarian stimulation with gonadotropin may have a moderate benefit compared to clomiphene citrate (CC) while still being associated with increased cost for the repeated injections, frequent monitoring, risk of multiple pregnancies, and development of ovarian hyperstimulation syndrome (OHSS) as a complication. Robust evidence is lacking, but based on the available results, gonadotropins might be the most effective drugs when IUI is combined with ovarian hyperstimulation. When gonadotropins are applied, it might be done on a daily basis. When gonadotropins are used for ovarian stimulation, low dose protocols are advised since PRs do not differ from PRs which result from high dose regimen, whereas the chances to encounter negative effects from ovarian stimulation such as multiples and OHSS are limited with low dose gonadotropins. The most desirable goal of ovulation induction for IUI is a higher PR with reduced complications. To achieve this goal, the use of minimal stimulation has been considered because it has been reported to reduce complications while maintaining overall PRs. The concept of minimal stimulation was first proposed by Kistner in 1972 who used CC followed by overlapping human menopausal gonadotropin (hMG) to increase the PR compared to the use of CC alone and to reduce the amount of hMG required for stimulation. Since then, research has continued using variable agents combined with various doses and types of gonadotropin. In spite of the heterogeneity of previous studies ranging from retrospective reviews to prospective randomized controlled studies investigating minimal stimulation, the clinical pregnancy rates (PRs) reported were equal or superior to those in gonadotropin-only regimens. Furthermore, the use of minimal stimulation resulted in fewer stimulation days and less gonadotropin use, suggesting that it is more cost-effective than gonadotropin-only cycles. If oral agents are used alone for ovulation induction, the global preferences are clomid (clomiphene) and femara (letrozole). These are inexpensive, easy to take and have few side effects (i.e., hot flushes, irritability, headaches) for most people. Each of these medications is taken daily for 5 days at the beginning of the menstrual cycle. When IUI is also performed at the time of ovulation, monthly PRs vary between 8% and 32% depending on the specific infertility etiology. Multiple PRs are approximately 8%.
Social Egg Freezing
Goral N. Gandhi, Gautam N. Allahbadia
Rotunda - Center for Human Reproduction, B Wing, Bandra West, Mumbai, Maharashtra, India,
All women share a common dream of becoming a mother. Female fertility begins declining in the late 20's, however conception rates remain high into the 30's. After age 35, the decline accelerates and reaches nearly zero pregnancy potential by the time the woman reaches age 45. In addition, women over 35 have an increased risk of miscarriage and/or genetic abnormalities in their children as a result of age-dependent changes in egg quality. Fertility preservation (FP) is a very fast emerging branch of reproductive medicine, involving the preservation of reproductive gametes and tissues. Cancer patients who are to start chemotherapy or undergo surgery, patients undergoing in vitro fertilization (IVF), women with other medical conditions leading to premature menopause and healthy women who wish to delay their fertility for social, educational, or professional reasons are the main beneficiaries of FP strategies. "Social Egg Freezing" is the term given to attempts at FP via egg freezing for nonmedical reasons. Last few years have seen tremendous advancements in the field of cryobiology, with special emphasis on oocyte vitrification. These advancements have greatly changed the way IVF centers operate. Until recently, egg freezing was offered to young, oncological female patients, who are facing chemotherapy or surgery. However, the American Society for Reproductive Medicine at the end of 2012 endorsed oocyte cryopreservation as a standard practice for FP. Some research has suggested that elective egg freezing is a cost-effective method for achieving a future live birth for women under age 39, compared to the possibility of undergoing IVF at a later time in life. The aim of this presentation is to explore the need and scope of social egg freezing, taking into account - (1) the biological, societal, and scientific background, (2) the evidence from the laboratory, and (3) the pros and cons. The concept of egg banking and FP or social egg freezing offers hope to all women who are concerned about their future fertility. It greatly increases a woman's potential to have children later in life.
Ovarian Reserve: Testing And Interpretation
Gouri Sultane Gupta, Varsha Chipkar1
Consultant Fertility and IVF Specialist, Department of Assisted Reproduction, Seven Hills Hospital, 1Laboratory Director, Department of Assisted Reproduction, Seven Hills Hospital, Mumbai, Maharashtra, India,
Introduction: Currently, there is no uniformly accepted definition of decreased ovarian reserve (DOR). It may refer to three related but distinctly different outcomes - oocyte quantity, oocyte quality, and reproductive potential. Available evidence is limited by small sample size, heterogeneous study designs, and lack of validated outcome measures. Various tests of ovarian reserve discussed and advantageous and limitations of each specified and compared. Summary evidence of DOR does not necessarily equate with inability to conceive. The use of screening test for DOR in a population at low risk for DOR will yield a large number of false positive results. Overall, follicle stimulating hormone is most frequently used screening test for DOR. However, antral follicle count (AFC) and anti-Müllerian hormone (AMH) exhibit less variability and therefore are promising predictors of ovarian reserve. There is fair evidence to suggest that low AMH levels (e.g., undetectable AMH) and low AFC (<6) have high specificity as a screening test for poor ovarian reserve but insufficient evidence to suggest its use to screen for failure to conceive. There is fair evidence against the use of basal inhibin B and ovarian volume as a screening test for DOR. Poor ovarian response to maximal stimulation during in vitro fertilization reflects DOR.
Conclusion: There is insufficient evidence to recommend that any ovarian reserve test now available should be used as a sole criterion for the use of ART. There is good evidence to support the conclusion that the number of false positive test results will increase when screening tests for DOR are used in the low-risk population.
Evidence-Based Management Of Unexplained Infertility
Department of Obstetrics and Gynecology, School of Medicine, Hacettepe University, Ankara, Turkey,
Unexplained infertility is defined as lack of a definable cause for a couple's failure to achieve pregnancy after 12 months of attempting conception despite a standard evaluation. The standard care for the infertile couple generally composed from evaluation of semen analysis, uterine cavity, tubal patency, and ovulation. The assessment of ovarian reserve might also be considered for the initial workup. According to available studies, expectant management might be preferred for duration of 6 months, when the female age is young, sperm analysis normal, and there is no suspicious of diminished ovarian reserve. Once expectant management fails, the subsequent strategy is not clear due to lack of consensus for the right treatment strategy. Particularly in women with advanced age or decreased ovarian reserve, in vitro fertilization (IVF) should be employed in order to shorten the period to pregnancy. For the couples with ≤3 years of infertility and total motile sperm count higher than 5 million, superovulation with intrauterine insemination (IUI) might be used before going further with IVF. Only superovulation with either clomiphene citrate (CC) or exogenous gonadotropin (GN) is superior to expectant management. Superovulation-only with or without timed intercourse and insemination-only approaches do not improve spontaneous pregnancy chance. For the comparison of CC and GN before IUI, the latter medication might be superior according to limited number of randomized controlled trials and their meta-analysis.
Can addition of clomiphene citrate/letrozole improve outcomes in poor responder patients?
Advanced Fertility and Gynae Centre, New Delhi,
Most studies have concluded that in poor responders, the addition of clomiphene citrate (CC) or letrozole (LZ) to gonadotropin treatment significantly enhanced the oocyte and embryo yield. The data suggest that the addition of LZ may be somewhat more efficacious than CC. There were higher estradiol levels in these cycles along with significantly higher number of retrieved oocytes, higher number of embryos transferred and also increased pregnancy rates. The cycle cancelation rate was also significantly lower. Addition of CC/LZ appears also to be a low-cost and better alternative to natural cycle in vitro fertilization patients in poor responders.
Mild ovarian stimulation for in vitro fertilization in poor responders
K. S. Kavitha Gautham
Director and Lead Clinician, Department of Obstetrics and Gynaecology, Bloom Fertility and Healthcare, Velachery, Chennai, Tamil Nadu, India,
Background: Mild ovarian stimulation for in vitro fertilization (IVF) in poor responders aims to achieve cost-effective, patient-friendly regimens, which optimize the balance between outcomes and risks of treatment. Methods: PubMed and Medline were searched up to the end of January 2015 for papers on ovarian stimulation protocols for IVF. Results: 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 (odds ratio = 0.86, 95% confidence interval = 0.72–1.02). Mild ovarian stimulation may be achieved with limited gonadotrophins or with alternatives such as antiestrogens 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 analyzed does not allow a meta-analysis to be performed. In addition, the implications of mild ovarian stimulation for embryo quality, endometrial receptivity, cost, and the psychological impact of IVF treatment are discussed. Conclusions: Evidence in favor of mild ovarian stimulation for IVF in poor responders 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, number of treatment days, medication used, cost, patient discomfort, and number of patient drop-outs in studies on IVF are encouraged.
Preventing Ovarian Hyperstimulation Syndrome By Predicting Hyper-responders (At Risk) Prior To Ovarian Stimulation
K. I. Onwuzurigbo
Advance Fertility Center of Kingswill Specialist Hospital, 3 Ayinuola Close, Apple Junction Roundabout, Amuwo-Odofin, Lagos, Nigeria, E-mail: email@example.com
Ovarian hyperstimulation syndrome (OHSS) is a dreaded complication associated with the use of fertility drugs. It occurs in some patients with excessive response to ovarian stimulation. Currently, no curative therapy is available. However, measures aimed at managing the condition exist. Predicting patients at risk of OHSS prior to commencing ovarian stimulation may enable the adoption of such measures and perhaps prevent the condition. Objective: To prevent OHSS by predicting hyper-responders at risk prior to commencing ovarian stimulation. Observation: We observed that all hyper-responders to ovarian stimulation in our clinic (from May 2014 to April 2015) who had OHSS were earlier diagnosed with polycystic ovarian syndrome (PCOS). However, other hyper-responders without PCOS did not have OHSS in any form (irrespective of the number of follicles or eggs obtained). Study Design: All patient requiring ovarian stimulation at Kingswill Specialist Hospital, Lagos, between June and August 2015 were screened for PCOS in the preceding cycle. Those that met the Rotterdam criteria for diagnosing PCOS were included in this study after obtaining an informed consent. A total of 10 patients were recruited. Controlled ovarian stimulation was achieved with recombinant follicle stimulating hormone (follitrope) and concomitant treatment with gonadotrophin-releasing hormone antagonist cetrorelix (cetrotide) for the prevention of premature luteinizing hormone surge. Ovulation was triggered using 0.2 mg of triptorelin (decapeptyl). Results: The average number of oocytes obtained was 15 of which 94% was metaphase II. None of the patients developed any sign or symptom of OHSS. Four clinical pregnancies (40%) were recorded. Conclusion: Predicting hyper-responders at risk prior to commencing superovulation may help in preventing OHSS. The efficacy of this approach needs to be established in comparative, randomized studies.
A Comparative Study Between Agonist And Antagonist Protocol For Ovarian Stimulation In assisted reproductive technique Cycles At A Rural Set Up In South Gujarat
Kishore Nadkarni, Purnima Nadkarni
Nadkarni Hospital and Test Tube Baby Centre, Killa Pardi, Valsad, Gujarat, India,
Modern infertility practice provides us with several protocols for controlled ovarian hyperstimulation for the assisted reproductive techniques (ARTs) cycles. The review summarizes the clinical characteristics of the protocols using Gonadotropin-releasing hormone agonists and antagonists emphasizing on the major clinical and laboratory outcomes with each protocol. A total of 322 cases undergoing ovarian stimulation with agonist and antagonist protocols in ART cycles at a rural set up at Killa Pardi in the year 2014 were studied and their laboratory and clinical outcomes were evaluated. Antagonist group had better outcomes in term of number of follicles (>16 mm) on the day of hCG, total number of retrieved oocytes, MII oocytes and pregnancy rate. Agonist group had also had a good pregnancy rate with maximum Grade I embryos. Taking all data together, it may be concluded that antagonists and minimal ovarian stimulation with antagonist protocols offer a new treatment regimen in ovarian stimulation that is short, safe, cost-effective, well tolerated, optimizing convenience for the patient.
Recent Advances in Ovulation Induction in Polycystic ovary syndrome
Kulvinder Kochar Kaur, Gautam N. Allahbadia1
Dr. Kulvinder's Centre For Human Reproduction, 721, GTB Nagar, Jalandhar, Punjab, India, 1Rotunda - The Centre For Human Reproduction, Mumbai, Maharashtra, India,
The definitions of polycystic ovary syndrome (PCOS) have changed from the classic National Institutes of Health definition to more inclusive Rotterdam's criteria (any two of the following three criteria after excluding etiologies such as hyperprolactinemia, clinical and/or biochemical androgen excess, oligo/anovulation, and polycystic morphology on ultrasonography). In 2009, the androgen excess society launched a new definition that considered PCOS primarily as a disorder of clinical and biochemical androgen excess plus either chronic anovulation and/or polycystic ovaries, still with exclusion of specific etiologies. Ovulation induction in PCOS (1) clomiphene citrate (CC) acts by increasing serum follicle stimulating hormone remains the first line of treatment. (2) Metformin commonly used as an oral hypoglycemic had been found to improve menstrual cyclicity by reducing insulin levels and altering the effects of insulin on androgen biosynthesis, also potentially inhibits through a direct effect on inhibiting ovarian gluconeogenesis. Further, allopregnanolone secretion is altered with no change in progesterone secretion in obese PCOS patients which gets corrected by metformin restoring normal steroid synthesis both from the ovary as well as the adrenal gland (Gennazzani). (3) aromatase inhibitors - letrozole (LZ)/anastrozole - banned in India, special interest was for getting monofolliculogenesis but Kasper et al. show how under the false impression as many as sixtuplets got born with third cycle of 7.5 mg LZ and hence careful monitoring is needed even when planning an intrauterine insemination. (4) Glucocorticoids such as dexamethasone have been used to induce ovulation by adding to CC in CC-resistant PCOS with normal DHEAS. Enthusiasm for their use is dampened, however, by their potential adverse effects on insulin sensitivity; therefore, prolonged use should be discouraged. (5) Gonadotropins - second line of action, main drawback - multiple folliculogenesis, OHSS (6) d-chiro-inositol is effective in restoring insulin sensitivity in obese hyperinsulinemics esp. with diabetic relatives. (7) Myo-inositol for correcting insulin resistance. In a study by Kamenov et al., after myo-inositol treatment, ovulation was present in 29 women (61.7%) and 18 (38.3%) were resistant. Of the ovulatory women, 11 became pregnant (37.9%). Of the 18 myo-inositol resistant patients after clomiphene treatment, 13 (72.2%) ovulated. Of the 13 ovulatory women, 6 (42.6%) became pregnant. During follow-up, a reduction of body mass index and HOMA index was also observed. (8) Treatment with exenatide/topiramate can be considered in severely obese. It significantly improves the regularity of periods in PCOS women. (9) Occasional extreme PCOS - >100 df /ovary - how successful osteogenesis imperfecta/pregnancy achieved is discussed.
Clomiphene Citrate VERSUS Aromatase Inhibitors in Intrauterine insemination cycles
Kundan V. Ingale
Medical Director, Nirmiti Clinic, A Centre for Assisted Reproduction, Pune, Maharashtra, India,
Clomiphene is still the first-line ovulation-inducting agent in the World Health Organization Cat II on ovulatory patients. Singleton live birth rate with clomiphene citrate (CC) is reduced by anti-estrogenic effects and fairly high miscarriage rates and multiple pregnancy rates. Aromatase inhibitors (AIs) such as letrozole (LZ) are not having negative effects on estrogen receptors due to which it produces higher ovulation rate and higher live birth rate. In comparison with clomiphene, AIs are acting for a shorter duration of time, due to which it results into monofollicular development. Higher singleton live rate is higher with AIs. CC is also associated with clomiphene resistance due to higher cancelation rates in clomiphene cycles, in which cases, AIs are inducing ovulation in >50% cases and pregnancy rate was 15%, live birth rates were in LZ versus clomiphene group; 27.5% versus 19.1%. In polycystic ovary syndrome (PCOS) patients with body mass index >30 kg/m2, LZ has given double live birth rate than clomiphene. Congenital malformation and chromosomal abnormality rates associated with LZ and clomiphene ovulation induction were 2.4% and 4.8%, respectively. The major congenital malformation rates for LZ and clomiphene were 1.2% and 3.0%, respectively. Incidence of congenital anomalies in natural conception, conception following LZ, and clomiphene is 2.9%, 2.5%, and 4.0%, respectively. In conclusion, LZ appears to be safer than natural conception and after use of CC. An abstract presentation at American Society for Reproductive Medicine 2005 suggested an increase in congenital malformations following LZ treatment. The attention generated by this publication resulted in the manufacturers (Novartis) declaring that use of LZ as an ovulation induction agent is contraindicated. Though there are data to critically analyze these findings, today LZ has still not received approval for use in fertility treatments in US, Europe, and in many parts of the world including India. However, there is a need for larger well-designed randomized trials to generate robust data to establish the true potential of LZ.
Endometrium preparation using the natural cycle with gonadotropin-releasing hormone agonist as luteal support compared with standard estrogen progesterone/endometrium preparation in donor egg recipients: a retrospective comparative Study from Spain
S. L. Canario Infertility Institute, Calle Leony Castillo, 284, 35005 Las Palmas de Gran Canaria, Spain,
Study Question: Is it possible that an endometrium preparation using the natural cycle and gonadotropin-releasing hormone (GnRH) agonist as luteal support may be as efficient as the standard estrogen/progesterone endometrium preparation in donor egg recipients in a routine in vitro fertilization (IVF) clinic in Spain? Study Design: In donor egg recipients, a total of 24 cycles of endometrium preparation in the natural cycle with GnRH agonist as luteal support were compared to 32 cycles of standard estrogen/progesterone endometrium preparation. All patients were treated in the same period and allocated to the different treatments on their own request. The study took place at Instituto Canario de Infertilidad, a private IVF clinic in Spain from 09/2014 to 05/2015. Materials and Methods: A retrospective comparative study data from patients admitted to egg donation at our clinic in the given period was compared. Only patients with spontaneous regular cycle were included. The patients decided on their own to go for endometrium preparation in the natural cycle where ovulation was triggered with 200 µg intranasal buserelin at follicle size 17/18 mm, followed by 100 µg every day up to 14 days of the luteal phase or standard endometrium preparation with 6 mg oral estradiol valerate for 10–12 days, followed by 600 mg vaginal micronized progesterone up to 6 weeks after embryo transfer (ET). Only elective fresh single ET in day 5 blastocyst stage was performed in all patients. In the natural cycle group, ET was performed 156 h after the first buserelin application and in the standard preparation group 120 hours after the first vaginal progesterone application. Results: No difference in endometrial thickness was found between the groups at the moment of trigger/start of vaginal progesterone (7.6 mm vs. 8.1 mm). The clinical pregnancy rate was found to be not significantly different between the natural cycle group and the standard preparation group (54.2% vs. 53.1%).
Low Ovarian Stimulation using Tamoxifen/ follicle stimulating hormone compared with Clomid/follicle stimulating hormone and follicle stimulating hormone/gonadotropin-releasing hormone - Antagonist: A Cohort Comparative Study from Kazakhstan
S. L. Canario Infertility Institute, Calle Leony Castillo, 284, 35005 Las Palmas de Gran Canaria, Spain,
Study Question: (1) Is it possible that a low stimulation protocol based on tamoxifen and follicle stimulating hormone may be as efficient as a conventional in vitro fertilization (IVF) program in a routine IVF clinic in Kazakhstan? (2) Is there a difference between tamoxifen and clomid in low stimulation protocols? Study Design: A total of 92 regular short antagonist IVF cycles were compared to 109 tamoxifen low stimulation IVF cycles. Then, the 109 tamoxifen low stimulation cycles were compared to 58 low stimulation cycles using clomid instead of tamoxifen. All patients were recruited in the same period and allocated to the different treatments on their own request. The first 58 patients in the minimal stimulation arm were treated with clomid; all subsequent patients received tamoxifen. The study took place in our clinic "Ecomed Plus" (Astana) from 01/2011 to 04/2013. Materials and Methods: In a cohort study including all patients admitted to IVF for unexplained infertility, male factor or tubal factor, the patients decided on their own to go for regular IVF using a short antagonist protocol with daily 225 IU human menopausal gonadotropin (hMG) or low stimulation using daily tamoxifen 40 mg + 150 IU hMG or daily clomid 50 mg + 150 IU hMG. Only elective fresh single embryo transfer in day 2 or day 3 stage was performed in all patients. Results: No differences in age and number of previous cycles were found in between the groups. The pregnancy rates per transfer and per started cycle were not significantly different between the protocols, although we found a tendency for a lower pregnancy rate per started cycle in the clomid group compared with the tamoxifen group, which was due to a higher cancelation rate because of thin endometrium. The mean number of hMG units used in conventional IVF was significantly higher than for low stimulation. The clinical pregnancy rate was found to be not significantly different between the tamoxifen-treated group and the conventional stimulation group (24.7% vs. 21.2%) as well as between the tamoxifen and the clomid group (24.7% vs. 17.1%).
Gonadotropin-releasing hormone aGONIST Trigger: Why, When, How?
Gelecek - The Center for Human Reproduction, Antalya, Turkey,
Human chorionic gonadotropin (hCG) has been traditionally used since mid-1970s for the trigger of final maturation of the oocytes in in vitro fertilization cycles. Although hCG provides oocyte maturation, follicular luteinization, and progesterone production, it is associated with excessive risk of ovarian hyperstimulation syndrome (OHSS), the incidence of which is 1–14%. hCG is thought to play a key role in the pathophysiological mechanism of OHSS by mediating the release of vascular endothelial growth factor (VEGF-A). VEGF-A, through its interactions with the VEGF receptor-2, promotes angiogenesis and vascular hyperpermeability. The hemoconcentration which ensues results in complications such as hypercoagulability and reduced end-organ perfusion. Certain risk factors including the presence of polycystic ovary syndrome, high number of antral follicles, and high serum estradiol (E2) levels increases the risk. Several prevention measures have been proposed, one of the methods is considering alternatives for triggering ovulation. With the introduction of gonadotropin-releasing hormone (GnRH) antagonist protocols, interest shifted back to the pioneering work with GnRH and GnRH agonist (GnRHa) simulation of the midcycle gonadotropin surge started in the 1970s. Its long half-life (2.32 days) however causes prolonged luteotrophic effects, multiple corpora luteal development, and higher luteal phase P4 and E2 concentrations. The GnRHa trigger may encompass the specific follicle stimulating hormone (FSH) effects in the process of final follicular maturation, leading to more physiologic oocyte maturation. It also significantly decreases the expression of VEGF and lowers the gene expression of enzymes that takes part in steroidogenesis of estrogen and progesterone. This protocol works because GnRHa have a greater affinity for the GnRH receptor than do GnRH antagonists. The GnRHa thus displaces the antagonist from the receptor and results in activation of luteinizing hormone and FSH release. Although early studies reported a significant reduction in pregnancy rates as compared with an hCG trigger, this was later found to be caused by a severely compromised luteal phase, which could be restored by low-dose hCG supplementation and adequate luteal P support GnRHa trigger provides a quick and reversible luteolysis. In conclusion, GnRHa use as a trigger injection is cost effective; excellent in oocyte donors, case reports of early OHSS, and theoretical risk of late OHSS have been reported. Although the results are promising, it is not recommended for routine use yet. The hCG trigger remains the gold standard today.
Outcome of vitrified-thawed embryo transfer in the gonadotropin-releasing hormone agonist versus antagonist protocols
Gelecek - The Center For Human Reproduction, Antalya, Turkey,
Since the mid-1980's, cryopreservation and storage of in vitro-derived cleavage stage embryos have been employed. The first successful pregnancy following FET was reported in 1983 in Australia followed by the first live birth following embryo cryopreservation was reported in 1984 in The Netherlands. The major advantages of frozen embryo transfer (ET) are increased cumulative PR after ovum pick-up, decreased multiple birth rate, decreased cost, and prevention of OHSS. Vitrification is an ultra-rapid method of cryopreservation whereby high concentrations of cryoprotectants together with rapid cooling rates are essential to cryopreserve embryos. This method combines rapid cooling rates and high cryoprotectant concentrations to invoke a glasslike solid phase and minimize cellular injuries due to ice crystal formation. Factors related to the outcome of frozen/thawed ETs are: Controlled ovarian hyperstimulation protocol, freezing protocol, selection of embryos for freezing and transfer, pregnancy in the fresh in vitro fertilization/intracytoplasmic sperm injection cycle from where the frozen embryos originated, increased female age at embryo freezing, the age of women undergoing FET, good quality before freezing - survival rate and are associated with a PR, thawed embryos resume cleaving, cryopreservation-associated damage, progesterone supplementation, hormonal substitution, antral follicle count, basal serum follicle stimulating hormone level, endometrial thickness, mean number of embryos transferred, mean number of good-quality embryos, reason for freezing, damaged blastomere, and observed compaction. The method of stimulation (agonist vs. antagonist) has not been rigorously evaluated so far. We retrospectively analyzed our own data on vitrification/thawing cycles [Table 1],[Table 2],[Table 3].
Post thaw parameters day 2–3
Post thaw parameters day 5
In conclusion, the method of stimulation (agonist vs. antagonist) has not been rigorously evaluated. In the present data, post-thaw embryo parameters and pregnancy outcome were very similar in vitrified-thawed ETs in agonist and antagonist cycles. This issue needs prospective randomized trials for strong evidence.
New Advancement In Infertility Treatment With Augment
M. R. Elshmoury, M. Fakih
IVF Laboratory Director, Fakih IVF,
Reproductive Medicine, Dubai, UAE,
Egg health is a key factor in fertility. Compromised egg health is common and it happens naturally as women age, and younger women can have poor egg health due to inherited reproductive disorders, environmental factors, or other medical conditions. Ovarian insufficiency and the associated poor oocyte quality are linked with impaired mitochondrial biogenesis. Mitochondrial dysfunction of the oocytes has been proposed as one of the causes of poor development and arrest of the preimplantation embryos generated using assisted reproductive technology (ART). Cytoplasmic transfer between human oocytes has been performed as a mean to restore normal growth of developmentally compromised oocyte and embryos and to improve the outcome of ART. Cytoplasmic transfer can lead to mitochondrial DNA heteroplasmy and the prospect of the mitochondrial heteroplasmy and its potential problems impose further studies. Egg precursor (EggPC) cells are immature egg cells found in the protective lining of the ovaries. The AUGMENT treatment uses the energy-producing mitochondria from patient's own EggPC cells to supplement the existing mitochondria in patient's eggs. This process is designed to boost patient eggs' and energy levels for embryo development and improve ART outcome.
Gonadotropin-releasing hormone agonist triggering and luteal phase support
M. A. Karimzadeh
Department of Obstetrics and Gynecology, Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran,
E-mail: Ma karimzadeh@ yahoo.com
Introduction: Gonadotropin-releasing hormone agonist (GnRHa) triggering is one of the strategies for ovulation triggering and final maturation of oocytes. So, luteal phase support should be noticed in these cycles. At first, it was began for prevention of severe OHSS, but it was associated with luteal phase problem and lower pregnancy rate due to luteolysis effects of GnRH agonists. Hence, two other alternative strategies have been suggested, the first was dual triggering with GnRH-a and low dose human chorionic gonadotropin (hCG) and the second was 1500 units of hCG on the day of oocyte pick-up to replace the actions of early luteal luteinizing hormone to sustain implantation and endogenous luteal ovarian steroidogenesis. Sometimes the physician avoids hCG injection and instead focuses on correcting the abnormal luteal steroid profile by providing intensive luteal-phase support with estradiol and progesterone. Although the pregnancy rate is lower in the fresh embryo transfer (ET), in donor recipient and frozen embryo cycles there were no significant differences between GnRHa triggering and hCG. It shows that the oocyte quality is not disturbed by GnRHa triggering. It may be associated to endometrial gene expression. The endometrial gene expression after the GnRHa trigger and a modified luteal phase support (with 1500 IU of hCG on the day of ovum pick-up was similar to the pattern seen after the hCG trigger and standard luteal phase support but it does not eliminate the risk of OHSS).
Conclusion: However, regarding the optimal results of segmental in vitro fertilization, it is recommended to use from GnRHa for ovulation triggering and postpone the ET to another cycle.
Comparison Of Cabergoline And Intravenous Albumin In The Prevention Of Ovarian Hyperstimulation Syndrome
Shanti Memorial Hospital and Assisted Conception Center, Uditnagar, Rourkela, Odissa, India,
Background: Ovarian hyperstimulation syndrome (OHSS) is a dangerous iatrogenic complication of assisted reproductive techniques (ART) which may cause severe morbidity and even mortality. OHSS typically is a result of ovarian expression of vascular endothelial growth factor (VEGF) which increases vascular permeability usage of dopamine agonist, cabergoline has been found to reduce the effects of VEGF without compromising pregnancy rate. Administration of intravenous albumin at the time of oocyte retrieval has been studied as a possible prevention strategy. Though short use of cabergoline for preventing OHSS represents no significant risk for women, long term data on its efficacy and safety require corroboration. The aim of this review is to evaluate the evidence from randomized controlled trials (RCTs) to determine whether cabergoline can reduce the incidence of moderate or severe OHSS. Objective: Comparison of cabergoline and intravenous albumin in the prevention of OHSS. Methods: Major medical databases were systemically searched for RCTS assessing the effect of cabergoline and intravenous albumin in preventing OHSS. RCTs which compared cabergoline with intravenous albumin considered for inclusion primary outcome measures included incidence of moderate or severe OHSS and live birth rate secondary end points were clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, and any other adverse efforts of the treatment. Results: A statistically significant reduction in OHSS was observed in the cabergoline-treated group. The number of severe OHSS cases in the HA group was significantly higher than the cabergoline group. Discussion: The studies have shown the increase in VEGF and VEGF receptor and (VEGFR-2) mRNA expressions as the fundamental role in vascular permeability and OHSS presentation. Dopamine agonists case inhibit phosphorylation of receptor VEGFR-2. Results have proven that patients who took Cabergoline manifested significant difference in the severity and also incidence of OHSS compared with there who took human albumin. Data and many currently studies support the suggestion that the intravenous albumin administration does not reduce the occurrence of severe OHSS. Despite the lower number of fertilization in the cabergoline group, treatment in both the groups resulted in similar ongoing pregnancy rate per started cycle; therefore, oral administration of cabergoline presented no adverse effects on ART outcome. HA and cabergoline groups had similar other ART outcomes in the terms of implantation and miscarriage rates. Conclusion: Prophylactic oral low dose cabergoline was more effective and less costly than intravenous human albumin in the prevention of OHSS in high-risk patients. Cabergoline administration for patients is costly and safer than iv administration of HA. However, further well-designed studies, especially about the best time and dare for the drug administration are needed.
Fertility In Turner Syndrome
NewLife Hospital, Varanasi, Uttar Pradesh, India,
Characteristic physical features and complete or partial absence of the second X chromosome define Turner syndrome (TS). The biological effects depend on the proportion of mosaic throughout the body. Most girls with TS undergo ovarian failure at a very early age. Up to 90% of girls lose most or all of their germ cells before completing puberty. A young woman with TS may be a candidate for fertility preservation by oocyte or ovarian cortex cryopreservation. The predictors for the presence of follicles are mosaic karyotype, low follicle stimulating hormone level, high anti-Müllerian hormone level, spontaneous onset of puberty and menarche. Only 2% of these subjects are reported to achieve a spontaneous pregnancy. in vitro fertilization may be an option for some women who have maintained ovarian function past adolescence, though pregnancy rates (PRs) would be expected to be limited by decreased ovarian reserve. For the vast majority of such women, being an egg recipient is the only way to become pregnant. Regarding the possible increased risk of fetal chromosomal abnormalities, women with TS who conceive with their own oocytes, whether cryopreserved or not, should be offered prenatal genetic screening. Several studies suggest that a 45, X karyotype confers increased risk of aortic dissection and rupture. In addition, these women have an elevated risk of pregnancy-induced hypertension, preeclampsia, eclampsia, gestational diabetes mellitus, and hypothyroidism. It is imperative that any woman with TS has only a single embryo transferred, as the risks during a multiple gestation are five times higher. Given the increased risks of serious complication, in 2012, the Practice Committee of the American Society for Reproductive Medicine recommended that TS be considered a relative contraindication to pregnancy. If additional risk factors for aortic dissection are present, pregnancy is contraindicated and that all women with TS can be counseled to consider gestational surrogacy and adoption as favorable alternatives. Several international bodies have recommended screening guidelines for women with TS who are considering pregnancy. A gestational carrier in combination with an oocyte donor would avoid the maternal and fetal risks. A multidisciplinary team of specialists in maternal-fetal medicine, cardiology, and endocrinology should follow closely women with TS.
The Serum Level Of C-Reactive Protein In Patients Undergoing Gonadotropin-Releasing Hormone Agonist Protocols For In Vitro Fertilization Cycles
Department of Obstetrics and Gynecology, Sant Parmanand Hospital, Civil Lines, New Delhi, India,
C-reactive protein (CRP) is part of acute phase immune response to injury or infection. It is a sensitive biomarker of inflammation of current infection and many chronic disease statuses. During the menstrual cycle, changes in endogenous estrogen and progesterone concentration are significantly and independently associated with changes in CRP concentration; endogenous estrogen decreases CRP, progesterone increases CRP, and menstruation increases CRP. The utility of CRP as a marker of events during the reproductive cycle is scantly explored. Controlled ovarian hyperstimulation (COH) during in vitro fertilization-embryo transfer (IVF-ET) evokes marked ovarian enlargement and there is massive systemic inflammatory cytokine response. In one study with gonadotropin-releasing hormone agonist long protocol, serum CRP levels on the day adequate luteinizing hormone suppression is obtained (Day-S) is much lower than the day human chorionic gonadotropin is administered human chorionic gonadotropin (Day-hCG) and CRP level on Day hCG is lower than the day of ovum pick-up (Day-OPU). No difference was observed between follicular and serum CRP levels on Day-OPU. No significant correlations were found between serum CRP to body mass index ratio and sex steroid levels or IVF treatment variables. In another study with short protocol, serum CRP on Day 2 < Day hCG < Day ET in both pregnant and nonpregnant group. In the non-pregnant group, the ratio of CRP on Day hCG/Day 2 and ET/hCG was significantly higher than the pregnant group. More research is needed to confirm these findings. CRP as a sensitive inflammatory marker, CRP ratio of Day ET/Day hCG could be a predictor of treatment outcome in COH.
Is There Still A Role For Injury To The Endometrium Before In Vitro Fertilization?
Department of Obstetrics and Gynecology, IVF Unit, Laboratory for Reproductive Immunology, Hillel Yaffe Medical Center, Faculty of Medicine, Technion - Israel Institute of Technology, Hadera, Israel,
The success of in vitro fertilization and embryo transfer (IVF-ET) is dependent on many factors, including patient profile, uterine pathology, stimulation protocols, culture conditions, embryo quality, and ET technique. Implantation is a process of embryonic attachment to the endometrium and subsequent invasion into the stroma of the uterine wall. It is a complex and multistage process involving a myriad of cytokines and growth factors as well as cross-talk between the embryonic tissue and the endometrium. Because implantation failure is frequent, and comprises a limiting step in IVF success, several methods have been suggested to improve implantation rates with inconsistent success rates. One of the most promising methods is local injury to the endometrium. In 2003, Barash et al. were the first to report that endometrial injury before IVF among women with repeated implantation failure was associated with increased rates of implantation, clinical pregnancy, and live birth. Nevertheless, subsequent studies resulted in conflicting results as to its beneficial effect on IVF success. The purpose of my talk will be to critically examine the association between endometrial injury and IVF success rates, to describe possible mechanisms for this effect, and to try and establish clinical guidelines for infertile couples in light of the current evidence.
Luteinizing Hormone Pretreatment As A Novel Strategy For Poor Responders
Department of Obstetrics and Gynecology, IVF Unit, Laboratory for Reproductive Immunology, Hillel Yaffe Medical Center, Faculty of Medicine, Technion - Israel Institute of Technology, Hadera, Israel,
Poor ovarian response to gonadotropins is one of the most challenging problems in assisted reproductive technology (ART). A variety of regimens have been proposed to improve poor responders' outcome, but results are often disappointing. Poor ovarian responders (PORs) exhibit both a quantitative reduction of their oocyte cohorts and a high risk of implantation failure suggesting compromised oocyte quality. PORs, as defined by the Bologna criteria (ESHRE 2011) tend to react in a similar way under all these suggested protocols. The use of androgens (testosterone and dehydroepiandrosterone) or androgen modulating agents (aromatase inhibitors, luteinizing hormone [LH], and human chorionic gonadotropin) represents an important and intriguing strategy to try to increase ovarian response. The rationale behind this strategy resides in findings that suggest that androgen priming may increase the number of recruitable follicles by subsequent follicle stimulating hormone stimulation. The purpose of my talk is to discuss the rationale, molecular basis, and scientific evidence of LH pretreatment as a new promising strategy to increase ovarian response.
Minimal Stimulation Protocols: A Pilot Study
Pankaj Gupta, Savita Gupta, Saroj Jain
Pribbgom Test Tube Baby Centre and Infertility Hospital, Alwar, Rajasthan, India,
Clomiphene citrate (CC) has been used since long as a first-line of stimulation in infertile women. However, anti-estrogenic effect leading to less thickness of endometrium and low pregnancy rate restricted it in all patients. In this study, we investigated the minimal stimulation protocols using administration of few different regimes: (1) Tamoxifen 80 mg alone, (2) tamoxifen 80 mg + anastrozole 1 mg, (3) tamoxifen 80 mg initially for 2–7 day, and later after endometrial thickness of >7 mm adding enclomiphene 200 mg alone or again with anstrazole-1 mg, (4) A new regime of administrating CC in the late follicular phase (instead in early follicular phase) of patients undergoing intrauterine insemination/in vitro fertilization (IUI/IVF), and (5) administrating human menopausal gonadotropin (hMG) 75 IU/150 IU only in very few patients and that in late follicular phase only. A total of 66 cycles from 57 healthy women (mean age 31.3 [range 22–38] years) were monitored, starting on day 2 by daily ultrasound and measurement of serum concentrations of estradiol, luteinizing hormone, follicle stimulating hormone, and progesterone. When plasma estradiol concentrations reached 100–150 pg/ml, with a lead follicle between 12 and 14 mm diameters, a single injection (s.c.) of 1 mg cetrorelix was administered (only in 15 cycles). hMG (hMG; 75/150 IU) was administered daily (only 11 cycles) at the time of the first injection of cetrorelix and repeated thereafter until human chorionic gonadotropin (hCG) administration. A total of 5 out of 57 cycles were canceled (9.0%). No decline in follicular growth or estradiol secretion was observed after cetrorelix administration. IUI was done in 42 cycles and IVF in 10 cycles. From IVF cycles, 37 oocytes were retrieved, resulting in 32 embryos. 16 embryo transfers were done with 2 embryos/transfer. In 3 cycles (30%), no oocyte was obtained. Fertilization failure occurred in one cycles (10%). In two patients, the embryo was arrested at the 2 pronuclear stage. A total of 12 clinical pregnancies 7 from IUI (16.6% per IUI) and 5 from IVF were obtained (31.25% per transfer), of which seven are ongoing. Thus, use of tamoxifen and anastrozole along with clomiphene administration in late follicular face with very few injections of hMG could represent a first-choice IUI and/or IVF treatment with none of the complications and risks of current controlled ovarian hyper stimulation protocols and an acceptable success rate.
Preimplantation Genetic Screening: A Clinician'S Point Of View
Kaali Institute IVF Center, Budapest, Hungary,
In in vitro fertilization, success rates are only slowly increasing and do not meet the expectations of the patients or providers either. One of the problems limiting success rates is the relatively high rate of aneuploidies in the embryos, while an abnormal chromosome copy number can be seen in young patients as well the incidence increases with maternal age. An embryo with abnormal chromosome content is unlikely to implant or if it does so will likely be lost early on. It therefore would be desired to replace euploid embryos only to improve implantation, pregnancy, and live-birth rates. Screening of embryos for abnormal chromosome copy count (preimplantation genetic screening [PGS]) has an over 20-year history by now. Since the incidence of aneuploidies increases with maternal age, PGS was initially recommended to couples with advanced maternal age. Subsequently, couples with recurrent pregnancy loss, repetitive implantation failure, or severe male factor infertility were believed to benefit too. Initial testing used fluorescent in situ hybridization and early reports indeed suggested improved clinical outcome. Results of randomized controlled trials however detected no improvement or in fact a negative effect on pregnancy rates. These findings have resulted in a decrease in PGS use and a search for alternative testing methods. Nowadays, there are multiple methods available that can perform 24-chromosome copy number analysis. These technologies were shown to improve outcome in young, high-responder patients based on small randomized controlled trials (RCTs) performed in the highest performing IVF labs in the world. Are we ready to generalize and recommend PGS routinely based on these results? There are experts who remained skeptical and caution against premature, widespread use of PGS. Several questions about PGS can be raised. What is the true benefit of PGS? Is it to improve clinical outcome? Is it to shorten the time to pregnancy? Is it to lower miscarriage risk? If the aim is to improve pregnancy rates then to whom should we offer the test? There is no available RCT data that supports such benefit in those with the classic indications. If the aim is to shorten the time to pregnancy, then again we need to show that there is a true benefit as the time may be less important to those who are young. Studies should test the cost-effectiveness of various approaches. In PGS cycles, one has to consider the extra expenses of PGS itself, elective cryopreservation, and the frozen-thawed cycle as well. During the presentation, I will discuss the current status of PGS through the eyes of a clinician.
The significance of premature progesterone rise during in vitro fertilization
Kaali Institute IVF Center, Budapest, Hungary,
Successful implantation requires a euploid embryo, a receptive endometrium, and proper timing. Implantation can only take place in the so-called "window of implantation;" 8–10 days after ovulation. Implantation is a critical step during in vitro fertilization (IVF) as well. Many aspects of the IVF treatment have improved significantly, but implantation rates are only slowly increasing and still are disappointingly low, around 20–40%. It has been hypothesized that the stimulation used during IVF may have negative effects on endometrial development. During controlled ovarian stimulation, multiple follicles grow simultaneously and much higher estradiol levels are achieved compared to a spontaneous cycle. This results in faster proliferation, early up-regulation of steroid hormone receptors, and altered steroidogenesis. In the pregonadotropin-releasing hormone (GnRH) analog era, premature luteinization was common and lead to early progesterone secretion. With the use of GnRH analogs, however, the luteinizing hormone secretion remains suppressed. Still, in variable proportion of cycles, a preretrieval progesterone elevation can be detected. Various cut-off values have been evaluated; most commonly a value >1.5 ng/ml on the day of human chorionic gonadotropin (hCG) injection is considered elevated. Most studies have found reduced implantation and pregnancy rates in these cycles. The impact seems to be less in high responder patients. Histologic evaluation of the endometrium shows advanced endometrial maturation and premature secretory changes in cycles with progesterone elevation. Studies evaluating endometrial gene expression also show altered up- and down-regulation of genes depending on progesterone levels. Further evidence supporting endometrial negative effect and no impact on egg and embryo quality comes from studies using donated eggs of frozen embryos. Eggs/embryos obtained in cycles with elevated progesterone levels have a similar chance to implant in a frozen-thaw cycle compared to eggs/embryos transferred in fresh cycles with low progesterone cycles. Various treatment options have been suggested. Use of mild stimulation, early trigger in high responders, using different follicle sizes with different stimulation protocols as the cut-off for the hCG trigger and elective embryo cryopreservation in cycles with high progesterone have been suggested. The presentation will discuss the physiology of implantation, the significance of premature progesterone rise, and proposed treatment modalities.
Stimulation protocols in cycles with preimplantation genetic screening
Kaali Institute IVF Center, Budapest, Hungary,
Assisted reproduction and in vitro fertilization (IVF) have undergone tremendous improvements over its close to four-decade history. The first successful treatment was reported in 1978 and by 2005 over 1 million treatment cycles have been reported worldwide. The number of infertile couples is on the rise, and therefore the need for assisted reproductive technology is continuously increasing as well. Furthermore, with the rapid technological developments indications for IVF change as well. With the availability of preimplantation genetic testing, couples with inherited diseases may now have healthy offsprings. As the technology develops, the expectations rise as well. Patients, providers, and insurance companies covering the expenses expect the quality of the care to improve. This does not just mean further improvements in the pregnancy and live birth rates, but a reduction in complications as well. There are several important steps during IVF; the use of stimulation to induce multi-follicular development is one of them. Cycles involving the use of preimplantation genetic diagnosis or screening are considered "special" as in these cases (depending on the nature of the genetic problem), it is known that certain proportion of the embryos will not be healthy regardless of the maternal age (e.g., in case of translocation carriers up to 2/3 of the embryos). Therefore, in these cases, there is even greater pressure to provide the embryologist with a proper number of oocytes. Patients differ significantly from each other and their treatment has to accommodate these differences. Stimulation protocols, medication type and dose therefore need to be individually determined. As a first step, we need to assess what response to stimulation to expect from the individual. In an ideal setting, we aim for around 15 oocytes. A patient is considered as poor responder if she produces less than 5 eggs; whereas the risk of hyperstimulation increases when more than 15 oocytes are collected. There are various hormonal (follicle stimulating hormone, estradiol, and anti-Müllerian hormone) and ultrasound (antral follicle count, ovarian volume) markers that are used to estimate the ovarian reserve. These results separately or combined will help the selection of the proper stimulation protocol and gonadotropin dose. During the presentation, it will be discussed how the stimulation phase of the IVF treatment can be personalized based on the results of screening tests.
Antibiotics Prior To Embryo Transfer (ET) In assisted reproductive technology
Specialist Gynecologist, Corniche Hospital, Abu Dhabi, UAE,
ET is a critical step in the assisted reproductive technology cycle. During an ET, the embryo(s) is passed through the cervix by means of a catheter. While many women will reach the stage of ET with embryos of adequate quality, few of these embryos will implant and even fewer will achieve a live birth. The success of ET may be affected by technical aspects of the ET procedure as well as by factors beyond operator control, such as embryo quality and uterine receptivity. Many variables affect the chance of pregnancy after ET, including embryo quality, uterine factors, and the embryo transfer (ET) technique. High levels of bacteria and other organisms in the upper genital tract have a detrimental effect on pregnancy rate after ET. Administration of antibiotics prior to ET may reduce the growth of these organisms and improve the outcomes of in vitro fertilization (IVF). While the clinical pelvic infection is relatively rare following ET, there is evidence to suggest that increased endocervical microbial colonization at the time of ET results in lower pregnancy rates. The effect of colonization on pregnancy rates depends on the organism and degree of colonization. The administration of antibiotics prior to or at the time of ET is hypothesized to alter the endocervical and vaginal flora and thereby reduce the likelihood of endometrial bacterial contamination by the ET catheter. Cochrane Systematic review in 2012 suggests that the administration of amoxycillin and clavulanic acid prior to ET reduced upper genital tract microbial contamination but did not alter clinical pregnancy rates. The effect of antibiotics on live birth is unknown. There are no data from randomized controlled trials to support or refute other antibiotic regimens in this setting. Based on the findings in few studies in the past, prophylactic co-amoxiclav cannot be recommended during ET. However, it is reasonable to propose that the clinician should try to ensure maximum catheter sterility while performing embryo transfer to improve the clinical pregnancy rate.
Clinical Applications Of Vitrification
P. S. R. Murthy, Sitamani Sahoo, R. Anitha, K. S. Dechamma, Merlin Vasanthkumar, P. Monica Murth, M. D. Kini
Miracle Advanced Reproductive Centre, Kilpauk, Chennai, Tamil Nadu, India,
Vitrification (from Latin vitreum, "glass" via French vitrifier) is the transformation of a substance into a glass. Usually, it is achieved by rapidly cooling a liquid through the glass transition. Certain chemical reactions also result in glasses. An important application is the vitrification of an antifreeze-like liquid in cryopreservation. Vitrification is characteristic for amorphous materials or disordered systems and occurs when bonding between elementary particles (atoms, molecules, and forming blocks) becomes higher than a certain threshold value. Thermal fluctuations break the bonds therefore the lower the temperature, the higher the degree of connectivity. Because of that amorphous materials have a characteristic threshold temperature termed as glass transition temperature (Tg): Below Tg amorphous materials are glassy whereas above Tg they are molten. In a wider sense, the embedding of material in a glassy matrix is also called vitrification. The inside story of vitrification would be discussed.
Poor Ovarian Reserve
Nadkarni Hospital and Test Tube Baby Centre, Killa Pardi, Valsad, Gujarat, India,
Ovarian reserve is the quantity and quality of the follicles left in the ovary at any given time. It is very important as it declines with age and predicts the ovarian response to stimulation and thus affects pregnancy rates. Poor responders are the women with low ovarian reserve as diagnosed by ovarian reserve tests and also by parameters such as age and previous response to stimulation. As age advances, there is a decline in antral follicle count, inhibin B, anti-Müllerian hormone, and a rise in follicle stimulating hormone. Poor responders can be so due to genetic causes, infections, smoking, adhesions, endometriosis, etc. The ovarian response in poor responders can be improved by (1) addition of luteinizing hormone prior to recombinant follicle stimulating hormone (2) use of testosterone and (3) dehydroepiandrosterone pretreatment (4) growth hormone administration. Hence, today we have many new options to retrieve good quality and adequate quantity of eggs from women with poor ovarian reserve, which is indeed a great challenge.
Effect Of gonadotropin-releasing hormone Antagonists On Clinical Pregnancy Rates In Ovulation Induction Protocols With Gonadotropins And Intrauterine insemination Therapy
Rajat Kumar Ray, Sunita Samal
Ray Hospital and Test Tube Baby Centre, Rourkela, Odisha, India,
Introduction: Effect of gonadotropin-releasing hormone (GnRH) antagonists on clinical pregnancy rates in ovulation induction protocols with gonadotropins and intrauterine insemination (IUI) therapy was studied. Methods: This study was conducted from January 1, 2015 and May 31, 2015, and involved a total of 304 patients. All were patients of primary infertility with failed IUI cycles stimulated with clomiphene. The patients were randomized into two groups–patients in Group A received human menopausal gonadotropin (hMG) + GnRH antagonist (n = 120), whereas those in Group B received only hMG (n = 184). Results: There was no significant difference in the mean age and body mass index (BMI) and the mean total hMG dose administered in both groups. On the human chorionic gonadotropin (hCG) trigger day, the mean number of follicles that were >16 mm was significantly higher in Group A (1.45 and 1.92, respectively; P < 0.05). There were no statistically significant differences in the number of canceled cycles due to premature luteinization (none in Group A vs. one in Group B) and the rate of clinical pregnancy (8.4% in Group A vs. 7.8% in Group B). Conclusion: No significant improvement in the clinical pregnancy rates was observed when GnRH antagonists were used in IUI cycles using gonadotropins.
Gonadotropin-releasing hormone agonist trigger for prevention of ovarian hyperstimulation syndrome
Reeta H. Biliangady
Department of Reproductive Medicine, Infertility Specialist at Cloudnine Hospital, Bengaluru, Karnataka, India,
Human chorionic gonadotropin (hCG) has been used as a surrogate for the mid-cycle luteinizing hormone (LH) surge for decades in fertility management. Due to structural and biological similarities with LH, hCG binds to and activates the common receptor, the LH/hCG receptor. In spite of the fact that hCG effectively secures final oocyte maturation and ovulation, its use as a surrogate for LH has several drawbacks–first and foremost a sustained luteotropic effect, often causing ovarian hyperstimulation syndrome (OHSS). With the introduction of the gonadotropin-releasing hormone (GnRH) antagonist for the prevention of a premature LH surge, final oocyte maturation can be triggered with a single bolus of a GnRH agonist (GnRHa) as an alternative to hCG. GnRHa is as effective as hCG for the induction of ovulation, and apart from the LH surge, a surge of follicle stimulating hormone is also induced, mimicking the natural mid-cycle surge of gonadotropins. However, the first randomized controlled trials reported a poor clinical outcome when GnRHa was used to trigger final oocyte maturation due to a luteal phase deficiency, despite standard luteal phase supplementation with progesterone and estradiol. GnRHa triggering possesses advantages over hCG triggering in terms of a reduced risk of OHSS, the retrieval of more mature oocytes, and a higher patient convenience. However, the challenge has been to rescue the luteal phase. At present, an increasing number of trials have successfully been performed, using a so-called modified luteal phase support after GnRHa trigger, resulting in a reproductive outcome comparable to that seen after hCG triggering and with either a significant reduction in or total elimination of OHSS. To optimize the in vitro fertilization outcome without OHSS individualized controlled ovarian stimulation should consider the follicular phase, the mode of triggering final oocyte maturation, and the luteal phase support used. It is necessary to differentiate between the high responder patient and the normo-responder. In an oocyte donor, use of GnRha trigger for final oocyte maturation reduces the cost and also the risk of OHSS. Research is needed to further fine-tune the optimal luteal support after GnRHa trigger. GnRHa triggering is now a valid alternative to hCG triggering with significant benefits. At cloudnine fertility, we have done 196 cases with GnRha trigger between January 2012 and December 2014. Almost 164 of them had fresh embryo transfer. We had a pregnancy rate of 37.80% as against overall pregnancy rate of 44.4% at the center. We had no OHSS, which needed hospitalization.
The Contribution Of Sildenafil (ViAgra)To Ovarian Stimulation With Gonadotropins
Rudolph Kantum Adageba
Fertility Specialist/OBGYN Specialist, Ruma Fertility and Specialist Hospital , Kumasi, Ghana,
The importance of the endometrium to successful in vitro fertilization (IVF) treatment has long been known. The morphological characteristics of an endometrium suitable for successful implantation include the thickness and morphological appearance. An endometrial thickness of more than 8 mm exhibiting a triple line (trilaminar) appearance has been shown to be associated with successful implantation and development of pregnancy. Several conditions may be associated with inadequate or poor endometrial development during IVF treatment. These include basal damage to the endometrium, endometrial resistance to estrogens, reduced blood flow to the endometrium in some cases of uterine fibroids or adenomyosis, and overexposure to testosterone. Several small studies have demonstrated better and improved endometrial development in cases of multiple IVF failures due to poor endometrial development with the addition of Sildenafil Citrate (Viagra) to stimulation protocols. The improved endometrial growth and development resulted in improved implantation and ongoing pregnancy rates in these women. Nitric oxide (NO), which is a well-known vasodilator, is present in both the endometrium and myometrium. Its action is mediated by cyclic guanyl monophosphate (c-GMP), which is degraded by type-5 phosphodiesterase (PDE-5). Sildenafil is a potent inhibitor of PDE-5, thereby preventing the degradation of c-GMP in the endometrium and myometrium. This action results in vasodilatation and improved blood flow to the uterus. The net effect is better and improved endometrial growth during ovarian stimulation with gonadotropins. Sildenafil can either be administered orally or vaginally during ovarian stimulation. Both routes of administration have been shown to be effective in promoting endometrial growth. It should be discontinued prior to or on the day of hCG administration because NO has been shown to mediate the release of cytokines such has tumor necrosis factor from activated natural killers cells that can interfere with implantation. Use of sildenafil can therefore be considered in cases of repeated IVF failures attributable to poor endometrial development. Larger randomized controlled studies are however needed to establish its efficacy and safety before its widespread use can be recommended.
Polycystic ovary syndrome and Antagonist Protocol
Sam P. Abraham
Abraham's Advanced Infertility Centre, Changanacherry, Kottayam, Kerala, India,
The polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in women of reproductive age. Controlled ovarian stimulation (COS) in patients with PCOS undergoing assisted reproductive techniques is are a great challenge. These patients have a high risk of developing ovarian hyperstimulation syndrome (OHSS). Gonadotropin-releasing hormone (GnRH) antagonists have been increasingly used for the prevention of premature luteinizing hormone (LH) surges in patients with PCOS undergoing controlled ovarian stimulation for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). GnRH antagonists offer several advantages over agonists for pituitary suppression. In contrast to GnRH agonists (GnRHa), antagonists produce rapid and reversible suppression of LH with no initial flare effect. Furthermore, antagonists are less likely than GnRHa to cause hypoestrogenic symptoms. There is increasing evidence showing that GnRH antagonist protocol can achieve a similar clinical pregnancy and ongoing pregnancy rates in patients with PCOS undergoing IVF, ICSI as compared with the GnRHa long protocol with a lower dose and shorter duration of gonadotropin stimulation and less risk of severe OHSS. In GnRH antagonists cycle, GnRHa can be used instead of human chorionic gonadotropin for final oocyte maturation. If an excessive ovarian response is encountered, GnRH antagonists protocols in COS cycles provides the option of triggering final oocyte maturation with GnRHa, followed by either a modified luteal phase support or a total freeze of embryos and transfer in subsequent thaw cycles. Both approaches ensure a good reproductive outcome with very little or no risk of OHSS development. For the PCOS patient undergoing ovarian stimulation with gonadotropins for IVF, the GnRH antagonist protocol should be the protocol of choice.
Stimulation With Tamoxifen Citrate: Rationale And Indications
Seema Hospital and Eva fertility Clinic n IVF Centre, Azamgarh, Uttar Pradesh, India,
Introduction: Though it is difficult to calculate the exact prevalence of infertility in developing countries due to lack of proper definition and studies, but it is said that around 8–12 million couples worldwide face difficulty in conceiving at some point of their lives. Thus, infertility affects roughly around 80 to 100 millions couples. This is also a fact that while some third world countries are fighting against population explosion at the same time few sub-Saharan African countries have one-third of their population suffering from infertility. While female infertility is the main focus of research, health care attention, social stigma, blame, and male factor infertility are the contributing factors in approximately fifty percent of cases. The overlooked need for an infertility program which includes assisted reproductive technology (ART) services as well is criticized on two grounds in these developing countries. First argument is about overfertility leading to overpopulation should be dealt with first rather than infertility and second is treating infertility through expensive ART treatment cannot be justified in these poor resource settings. Hence, as ART clinicians and health service providers, it is our duty to discover newer and modified ovulation stimulation protocols which could drastically cut the overall cost of ART treatment and at the same time does not compromise with the take-home baby rates. The tamoxifen citrate is a selective estrogen receptor modulator, which is used as an adjuvant therapy in the treatment of breast carcinoma patients. Similar to clomifene citrate (CC), tamoxifen citrate acts primarily by binding with estrogen receptors at the hypothalamus resulting in a significant drop in endogenous estrogen levels and leading to an endogenous rise in gonadotropin levels. However unlike clomifene, the action of tamoxifen on endometrium and vagina is as an estrogen agonist. Now through various studies, it is almost established that tamoxifen is a reliable ovulation induction agent, and it is almost as successful as CC, the additional benefit is of tamoxifen is in those cases where there is poor endometrium growth after CC or in cases of CC resistant polycystic ovary syndrome who cannot afford pure gonadotropin induction or ovarian drilling. The most significant use of tamoxifen in last few years was as an adjuvant in breast carcinoma patients who wanted to cryopreserve their oocytes or embryos and were estrogen receptor positive. Tamoxifen citrate can be used either alone or in combination with gonadotropin for ovarian stimulation. Though literature is sparse in terms of randomized controlled trials but enough literature is there to support that tamoxifen alone or in combination gives better oocyte and embryo yield than a natural cycle in vitro fertilization. On the abovementioned arguments, it was decided that if tamoxifen alone or in combination with minimal dose gonadotropins was used as a stimulation protocol and it would lead to an equally effective and cost-effective protocol as compared to fixed dose gonadotropins cost wise and CC plus gonadotropins efficacy wise. At the same time, the known complications of ART cycles such as multi-fetal gestation and ovarian hyper-stimulation syndrome would be avoided which puts further burden on any health service. Moreover looking at its endometrium-friendly behavior and decreased miscarriage rates tamoxifen citrate can be considered as an embryo and fetus friendly drug.
Conclusion: Tamoxifen citrate may prove to be an instrumental drug for minimal ovarian stimulation protocols where cost is also a limiting factor.
Recombinant luteinizing hormone In Poor In Poor Responders
T. S. Shanmugapriya
Kumbakonam Fertility Centre, Kumbakonam, Tamil Nadu, India,
The incidence of poor ovarian responders among infertility women has been estimated at 9–24%, but according to recent reviews, it seems to be slightly increased. Although the ideal treatment protocol for patients with a poor response to ovarian stimulation is yet to be identified, there is evidence to suggest that supplementation of recombinant human follicle stimulating hormone (r-hFSH) with recombinant luteinizing hormone (rLH) may be beneficial in this population of women. Hypothetically, this is attributed to the widespread use of protocols utilizing r-hFSH (with no LH activity) accompanied by observations of substantially lower LH concentrations than those observed with previously used protocols and during natural menstrual cycle. Data from a recently conducted meta-analysis including 43 studies and 6443 patients showed that the addition of r-hLH to r-hFSH were beneficial in poor responders resulting in 30% relative increase in clinical pregnancy rate compared to r-hFSH monotherapy. The supplementation of r-hLH in poor responders also led to a significant increase in no of oocyte retrieved and ongoing pregnancy rates. Despite these findings, the use of r-hLH supplementation during COS remains a topic of ongoing debate. It needs further randomized controlled trials (RCT) to confirm and end this point. "Efficacy and safety of pergovaris in ART trial is an ongoing phase III multicenter RCT to confirm the studies."
Can Endometrial Scratching Boost in vitro fertilization Success Rate
Infertility Specialist, Dr. Singh Test Tube Baby Centre, Meerut, Uttar Pradesh, India,
Implantation is a complex process in which embryo attaches to the endometrium and then invade in the stroma of the uterine wall. It is a process regulated by several gene expression, many cytokines, and growth factors as well as a dialog between the embryonic tissue and the endometrium. Implantation failure is frequent phenomena so several methods have been adopted to improve the implantation rate. However their results are inconsistent. According to the ESHRE data on assisted reproductive technology outcomes across Europe, only 32% of fresh embryo transfers resulted in clinical pregnancies, and implantation failure remains one of the major factors limiting success in vitro fertilization (IVF) treatment. To improve pregnancy results, preimplantation genetic screening and replacement of chromosomally normal embryos have tried but still implantation cannot be guaranteed. Studies were done by causing local injury to the endometrium as a means to improve implantation in women with recurrent implantation failure. The majority of the trials have demonstrated significant improvements in clinical pregnancy rates and live birth rates following endometrial injury performed in the preceding cycle. However, few small trials failed to detect any benefit. Endometrial injury is done by aspiration or curettage in the previous cycle, and it is postulated that this injury cause increase in the level of certain implantation factors and upregulation of specific genes causing improvement in implantation and pregnancy outcome.
Hematologıcal Malıgnancıes And Fertılıty
Sinem Civriz Bozdağ
Department of Hematology, School of Medicine, Ankara University, Ankara, Turkey,
Increasing survival rates in hematological malignancies led to an interest of long-term complications such as fertility. It has been proven that chemo/radiotherapy lead to ovarian damage. Destruction of oocytes, diminish in primordial follicle pool, and harm in the ovarian blood vasculature are the major effects of chemotherapy on ovaries. The intensity of chemo/radiotherapy can identify the risk of infertility. One of the major concerns of long-term hematopoietic stem cell transplantation survivors still remains to be fertility. Either the patients or the physicians do not have enough information about fertility preservation. Hence, the right timing to contact with a fertility expert is an important issue for quality of life of these patients.
Tackling Follicular Asynchrony in gonadotropin-releasing hormone Antagonist Cycles
S. Dash, B. Sindhu
Srishti Assisted Fertility and Advanced Laparoscopy Puducherry, India,
Since the advent of in vitro fertilization technique, the gold standard controlled ovarian stimulation regimen has been the long agonist protocol. With the advent of the gonadotropin-releasing hormone (GnRH) antagonist, it has been seen that more and more clinics have chosen to use the antagonist protocol, where triggering the final maturation of oocytes with a GnRH agonist (GnRHa) can virtually eliminate the life-threatening complication of Ovarian hyperstimulation syndrome. One of the disadvantages of the use of GnRH antagonist protocol is the development of follicular asynchrony, which could finally lead to a reduced oocyte yield. Long agonist protocol is known to yield a greater number of oocytes because the degree of follicular asynchrony is lesser. Luteal pretreatment with estradiol or administration of a GnRH antagonist leads to reduced follicle stimulating hormone levels before controlled ovarian hyperstimulation, leading on to a more synchronous growth of antral follicles. Luteal Estradiol administration or the administration of a GnRH antagonist reduces the pace of growth, improves size homogeneity of antralfollicles, and increases the number of follicles reaching maturation at the same time. This approach represents a potentially more physiological alternative to GnRHa or oral contraceptive pretreatment to synchronize multi-follicular development and improve COH results, without the attendant risks of OHSS.
Ultraviolet Air purification system for Healthcare Industry
Managing Director (The Middle East and Asia), SPC Heat Pipes FZC, UAE,
Healthcare Buildings are built tight and insulted to combat energy loss and as a result of that biological and chemical concentrations continually rise within the building's envelope. HealthCare facilities face a myriad of indoor air quality (IAQ) issues from not bringing in enough fresh air to replenish oxygen, not sterilizing the air and that leads to bacteria thriving in such environment and multiply exponentially. Ultraviolet Air Purification systems improve IAQ significantly and especially in the healthcare industry. Ultraviolet air purifiers will neutralize biological contaminants such as mold, bacteria, viruses, spores, allergens, all kind of odors, and thousands of other airborne contaminants. Ultraviolet (UV) energy disrupts the DNA of a wide range of microorganisms, rendering them harmless and eventually eradicating them from the air. UV germicidal lamps are low-pressure mercury lamps that emit UV energy at 254 nm, and when applied in ducts for some time it purifies the air and keeps the system germ free and at the same time keeps the equipment more energy efficient and reduces replacement costs.
Role of granulocyte colony stimulating factor in ART Cycles
Morpheus Lucknow Fertility Center, Lucknow, Uttar Pradesh, India,
Recurrent implantation failure is a major challenge to an ART clinician. Repeatedly failed cycles put lot of financial and psychological stress to the couple. An endometrial thickness less than 7mm is widely considered as suboptimal for effective embryo implantation. To improve endometrial thickness, many adjuvant therapies such as extended use of estrogen, vaginal sildenafil, lose dose aspirin, heparin, endometrial injury, low dose human chorionic gonadotropin, pentoxifylline, Vitamin E, and L-arginine have been used with variable success. Though the prevalence of unresponsive patients is less than 1%, chronically thin endometrium frequently results in cycle cancelation, unplanned cryopreservation of the embryos and need of gestational surrogacy. A new drug granulocyte colony stimulating factor (G-CSF) has been put to trial to improve implantation rates. G-CSF is a glycoprotein with growth factor and cytokine function. It is produced in different tissues and cells including endothelium. As early as in the year 2000, Wurfel et al. reported the use on the day of embryo transfer resulting in higher pregnancy rate. Successful use of G-CSF by Gleicher et al. on four patients of unresponsive thin endometrium lead to more randomized controlled trials. Few of such trails have been reported whereas many others are going on. Recently concluded one such randomized clinical trial of endometrial perfusion of G-CSF showed that it does not affect endometrial thickness, implantation rate, or chemical pregnancy rate, whereas another concluded that G-CSF has the potential to improve clinical pregnancy rates but fails to demonstrate the effect on endometrial thickness. More such studies are needed to determine the effectiveness, mode of administration, dosage pattern, and criteria for patient selection to firmly establish G-CSF in clinician's armamentarium to get higher implantation rates.
Dual triggering with gonadotropin-releasing hormone Agonist and human chorionic gonadotropin
Infertility and Obstetrics and Gynecology, Infertility and Reproductive Health Research Center, Shahid Beheshti Medical University, Tehran, Iran,
Introduction: Ovulation triggering after follicle stimulating hormone (FSH) stimulation of ovaries with antagonist or agonist is a very important step in standard protocols of controlled ovarian stimulation. Traditionally, urinary human chorionic gonadotropin (hCG) has been used for luteinizing hormone (LH) surge. Recently, gonadotrophin-releasing hormone (GnRH) antagonists have been used for down-regulation and GnRH agonist (GnRHa) triggering is a useful alternative for prevention of OHSS due to shorter half-life than hCG. The duration and profile of GnRH-induced surge of gonadotropins is different. Although oocyte maturation and oocyte release in hCG injection relies entirely on the LH activity of hCG but in the GnRHa triggering cycles both FSH and LH surge occurs that mimics the physiology process and shorter half-life. The pregnancy rate and implantation rate is compromised by GnRHa due to its luteolysis effect and needs to intensive luteal phase support. Hence, combination therapy with dual triggering with low dose hCG and GnRHa or only GnRHa and hCG injection at the oocyte pickup has been described. The recent researches showed combination therapy with dual triggering is associated with higher cumulus oocyte number and higher top quality embryos and also more embryos will be frozen. It seems GnRHa with an early flare-up of FSH and LH changes the preovulatory hormonal changes leads to appropriate maturation of oocyte in comparison with hCG by LH activity only. Although the number of oocytes and embryo freezing is higher in combination therapy, but the luteolysis effect of GnRHa, the implantation rate is less than hCG triggering. GnRHa triggering in donor oocyte cycles showed the implantation and pregnancy rate in recipient was not impaired. However, when the segmental in vitro fertilization was planned for the patient, it is better to use from the combination therapy for ovulation triggering instead of hCG or GnRHa only.
Dehydroepiandrosterone - Does it improve in vitro fertilization outcome in poor responder?
Sree Abirami Fertility Centre and Research Institute, Coimbatore, Tamil Nadu, India,
Dehydroepiandrosterone (DHEA) is being presented as a miracle-drug for the treatment of women responding poorly to gonadotropin stimulation whereas the debate on its actual effectiveness is still ongoing. Women with diminished ovarian reserve often respond poorly to controlled ovarian stimulation resulting in retrieval of fewer oocytes and reduced pregnancy rates. It has been proposed that prein vitro fertilization (IVF) DHEA adjuvant therapy may improve ovarian response and pregnancy rates in women with diminished ovarian reserve. Although more data on the DHEA effect on assisted reproduction are needed, results obtained over the last few years confirm the improvement of oocyte production and pregnancy rates. No significant side effects are reported, and those include mainly hirsuitism and acne to present the possible positive effect of DHEA administration in assisted reproduction and especially in poor responders, women with diminished ovarian reserve, premature ovarian failure, and premature ovarian aging in the course of ovarian stimulation protocols followed either by intrauterine insemination or IVF. We would like to present how insufficient the current evidence of acceptable quality is to warrant a conclusion that DHEA supplementation is an effective treatment for women with diminished ovarian reserve. We believe that large-scale, well-designed confirmatory studies are necessary to prove the efficacy of DHEA before it can be recommended for routine use.
Luteinizing hormone add-back: is it needed in controlled ovarian stimulation, and if so, when?
Leeds Centre for Reproductive Medicine, Seacroft Hospital, Leeds Teaching Hospitals, Leeds, LS14 6UH, United Kingdom,
The transition from primordial to the primary follicle; growth of the dominant follicle to ovulation is a complex interplay of regulatory factors,, direct-indirect dialogue between the oocyte, granulosa cells (GC), adjacent theca and the surrounding follicles., Autocrine-paracrine signaling establishes follicle's responsiveness to follicle stimulating hormone (FSH). At initiation, follicles do not require Gn although GCs possess FSH (FSHr), and theca cells luteinizing hormone receptors (LHr). Progression from primary to secondary stage requires oocyte expansion, GC proliferation, and LH-responsive theca. These steps are critically dependent on paracrine signaling from Transforming growth factor-β superfamily namely the anti-Müllerian hormone, activin in early, inhibin-A, and inhibin-B in the late stages. FSH-induced "Gap Junctions" between oocyte and granulosa and cumulus cells allow LH-induced paracrine theca signals to influence oocytes before and after the GCs express LHr. Follicular antrum formation and antral expansion are absolutely dependent on FSH. The principle requirement for LH is to sustain androgen synthesis, without which there is no estrogen synthesis. LH is also required to finalize pre-ovulatory follicular maturation and deliver a fully competent oocyte. In mid-late follicular phase, the "dominant" follicle also expresses LHr, responds to FSH and LH both, and maintains the development despite receding FSH., The LH surge/human chorionic gonadotropin injection induced closure of the "Gap Junctions" might be the mechanism leading to a resumption of meiosis. Exogenous Gn in controlled ovarian hyerstimulation (COH) may influence Gn independent stages. An inextricable link between peri-follicular blood flow, follicular oxygenation, and oocyte competence is suspected. LH-dependent oocyte and cumulus cell maturation is responsive to paracrine signaling, mostly involving GDF9 and BMP15. COH increases the number of oocytes available, but the oocyte quality may be compromised leading to chromosomal anomalies and interference with imprinting during preimplantation development, is expensive, time-consuming, and has a risk profile (ovarian hyperstimulation syndrome and possibly ovarian cancer). In conclusion, oocyte "quality" is finely programmed by local paracrine and autocrine signaling events that can be adversely affected by inappropriate Gn stimulation. Embryo's developmental potential is largely dependent on oocyte "quality," this in turn is influenced by the regulatory factors, such that they may in part be responsible for treatment outcome. Intelligent strategies for follicular priming with Gn and coasting with LH alone have been tested to see if oocyte-embryo quality after COH can be improved.
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[Table 1], [Table 2], [Table 3]