Ultrasound Imaging in Reproductive Medicine: Advances in Infertility Work-up, Treatment, and ART

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However, it failed to demonstrate favorable results in the setting of Asherman's syndrome, a condition characterized by the presence of uterine synechiae. These investigators have successfully applied this treatment in 2 women noted to have inadequate endometrium after surgical resection of uterine synechiae. Both patients had a history of a post-partum uterine curettage with subsequent secondary infertility. Asherman's syndrome was surgically demonstrated and treated in both patients. Post-operatively, both patients were noted to have a thin endometrium and failed to conceive despite fertility treatment.

Subsequently, these women achieved pregnancy in the 1st treatment cycle with vaginal sildenafil citrate. Using trans-vaginal ultrasound, endometrial thickness was noted to improve when sildenafil citrate was administered. It is suspected that this medication causes selective vasodilatation, resulting in improved endometrial development. Malinova et al noted that evaluation of endometrial receptivity remains a challenge in clinical practice.

Ultrasound evaluation of endometrial thickness and texture and measurement of uterine artery blood flow has been used for endometrial assessment. These researchers investigated the role of combination of sildenafil citrate and serophene on endometrial thickness, endometrial volume, endometrial FI and VFI on angiohistogram, RI and PI to a. A total of 42 patients were selected randomly who had anovulatory infertility. In the sildenafil citrate plus serophene group Group I , patients got 25 mg sildenafil citrate Silden vaginally and serophene to mg orally, and in serophene group Group II , to mg of serophene was given orally.

Mean endometrial thickness and endometrial volume was There was significant decrease in PI and RI to a. The authors concluded that combination of sildenafil citrate and serophene is an effective agent as a first-line of treatment for ovulation induction. This was a relatively small study, and its findings were confounded by the combined use of sildenafil and serophene. Soliman and colleagues developed and characterized in-situ thermos-sensitive gels for the vaginal administration of sildenafil as a potential treatment of endometrial thinning occurring as a result of using clomiphene citrate for ovulation induction in women with type II eugonadotrophic anovulation.

Advances in Infertility Work-up, Treatment, and ART

While sildenafil has shown promising results in the treatment of infertility in women, the lack of vaginal pharmaceutical preparation and the side effects associated with oral sildenafil limit its clinical effectiveness. Sildenafil citrate in-situ forming gels were prepared using different grades of Pluronic PF and PF Muco-adhesive polymers as sodium alginate and hydroxyethyl cellulose were added to the gels in different concentrations and the effect on gel properties was studied.

The formulations were evaluated in terms of viscosity, gelation temperature Tsol-gel , muco-adhesion properties, and in-vitro drug release characteristics. Selected formulations were evaluated in women with clomiphene citrate failure due to thin endometrium Clinicaltrial. Increasing Pluronic concentration increased gel viscosity and muco-adhesive force but decreased drug release rate.

Clinical results showed that the in-situ sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow with no reported side effects. Further, these results were achieved at lower frequency and duration of drug administration. The authors concluded that sildenafil thermos-sensitive vaginal gels might result in improved potential of pregnancy in anovulatory patients with clomiphene citrate failure due to thin endometrium.

These preliminary findings need to be validated by well-designed studies. Successful germ cell transplants can be achieved from mouse to mouse, rat to rat, and rat to immune-compromised mouse. Recently, successful ectopic xenografts of testis from a number of species including primates into mice have allowed studies of drugs and toxicants on spermatogenesis without having to administer the agent to the species. These observations suggest that germ cell transplantation or cultured testicular stem cells may become a treatment for male infertility and for genetic diseases in men that can be corrected and eradicated in germ cell lines.

Craciunas and colleagues examined if intra-uterine intra-cavity administration of hCG IC-hCG around the time of ET improves clinical outcomes in sub-fertile women undergoing assisted reproduction. These investigators performed searches on January 9, using Cochrane methods. Two review authors independently selected studies, assessed risk of bias, extracted data from studies, and attempted to contact study authors when data were missing.

They performed statistical analysis using Review Manager 5. Primary outcomes were live-birth and miscarriage; secondary outcomes were clinical pregnancy rate and complications. Common problems were unclear reporting of study methods and lack of blinding. The main limitations for evidence quality were high risk of bias and serious imprecision.

Exploration for sources of heterogeneity revealed 2 key pre-specified variables as important determinants: stage of ET cleavage versus blastocyst stage and dose of IC-hCG less than international units IU versus greater than or equal to IU. They performed meta-analyses within subgroups defined by stage of embryo and dose of IC-hCG. Live-birth rates among women having cleavage-stage ET with an IC-hCG dose of less than IU compared to women having cleavage-stage ET without IC-hCG showed no benefit of the intervention and would be consistent with no substantive difference or disadvantage of indeterminate magnitude risk ratio RR 0.

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Evidence for clinical pregnancy among women having cleavage-stage ET with an IC-hCG dose of less than IU showed no benefit of the intervention and would be consistent with no substantive difference or disadvantage of indeterminate magnitude RR 0. These researchers were uncertain whether miscarriage was influenced by intra-uterine hCG administration RR 1. Reported complications were ectopic pregnancy 4r RCTs; 1, participants; 4 events overall , heterotopic pregnancy 1 RCT; participants; 1 event , intra-uterine death 3 RCTs; 1, participants; 22 events , and triplets 1 RCT; 48 participants; 3 events.

Events were few, and very low-quality evidence was insufficient to permit conclusions to be drawn. The authors concluded that there was moderate quality evidence that women undergoing cleavage-stage transfer using an IC-hCG dose of greater than or equal to IU had an improved live-birth rate. There was insufficient evidence for IC-hCG treatment for blastocyst transfer. There should be further trials with live-birth as the primary outcome to identify the groups of women who would benefit the most from this intervention.

Events were too few to allow conclusions to be drawn with regard to other complications. DuoStim has two steps.

Step one includes stimulation, aspiration, fertilization and freeze of the embryos. Step two occurs after aspiration in step one and involves stimulation of any follicles that were too small to aspirate in step one. This second crop of follicles go to aspiration and fertilization. Massin noted that the advent of embryo and oocyte vitrification today gives reproductive specialists an opportunity to consider new strategies for improving the practice and results of in-vitro fertilization IVF attempts.

As the freezing of entire cohorts does not compromise, and may even improve, the results of IVF attempts, it is possible to break away from the standard sequence of stimulation-retrieval-transfer. The constraints associated with ovarian stimulation in relation to the potential harmful effects of the hormonal environment on endometrial receptivity can be avoided. This review examined the new stimulation protocols where progesterone is used to block the LH surge. Thanks to 'freeze all' strategies, the increase in progesterone could actually be no longer a cause for concern. There are 2 ways of using progesterone, whether it be endogenous, as in luteal phase stimulation, or exogenous, as in the use of progesterone in the follicular phase i.

These investigators performed a literature search until September on Medline.

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The following text words were utilized to generate the list of citations: progestin primed ovarian stimulation, luteal phase stimulation, luteal stimulation, DuoStim, double stimulation, random start. Articles and their references were then examined in order to identify other potential studies. All of the articles were reported in this review. The use of progesterone during ovarian stimulation is effective in blocking the LH surge, whether endogenous or exogenous, and it does not affect the number of oocytes collected or the quality of the embryos obtained.

Its main constraint is that it requires total freezing and delayed transfer. A variety of stimulation protocols can be derived from these 2 methods, and their implications were discussed, from fertility preservation to ovarian response profiles to organization for the patients and clinics. These new regimens enable more flexibility and are of emerging interest in daily practice.

However, their medical and economic significance remains to be demonstrated.

The authors concluded that the use of luteal phase or follicular phase protocols with progestins could rapidly develop in the context of oocyte donation and fertility preservation not related to oncology. Their place could develop even more in the general population of patients in IVF programs. The strategy of total freezing continues to develop, thanks to technical improvements, in particular vitrification and PGS on blastocysts, and thanks to studies showing improvements in embryo implantation when the transfer take place far removed from the hormonal changes caused by ovarian stimulation.

Vaiarelli et al stated that the management and treatment of patients with poor ovarian response is still a controversial issue in IVF.

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Increasing evidences demonstrate that the number of oocytes retrieved after a controlled ovarian stimulation COS greatly influences the clinical outcome in terms of cumulative live-birth per started cycle. For this reason, any COS should aim to optimize the number of oocytes according to the ovarian reserve of the patient.


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Gonadotrophins cannot compensate for the absence of follicles in the ovary, therefore, COS in poor responders may benefit from the exploitation of multiple follicular waves within a single ovarian cycle, for instance, through luteal phase stimulation or double stimulation follicular plus luteal in the same ovarian cycle DuoStim protocols. The authors concluded that many strategies have been proposed to manage poor responder patients, however, a consensus upon which is the most beneficial has not been yet reached; and DuoStim is the most promising approach to increase the number of oocytes collected in a single ovarian cycle; however, more embryological and clinical data is needed, as well as an analysis of its cost-effectiveness.

Yet, a clear characterization of this crucial biological process for human reproduction is missing. Recent advances implemented in IVF, such as blastocyst culture, aneuploidy testing and vitrification, have encouraged clinicians to maximize the exploitation of the ovarian reserve through tailored stimulation protocols, which is crucial especially for poor prognosis patients aiming to conceive after IVF. Luteal phase stimulations LPS has been already successfully adopted to treat poor prognosis or oncological patients through DuoStim, LPS-only or random-start ovarian stimulation approaches.

Nevertheless, little, and mainly retrospective, evidence has been produced to support the safety of LPS in general. In a case-control study, these researchers determined if the mean numbers of blastocysts obtained from sibling cohorts of oocytes recruited after follicular phase stimulation FPS and LPS in the same ovarian cycle are similar.

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This trial was carried out with paired follicular phase- and luteal phase-derived cohorts of oocytes collected after stimulations in the same ovarian cycle DuoStim at 2 private IVF clinics between October and December This study included poor prognosis patients undergoing DuoStim with pre-implantation genetic testing for aneuploidies PGT-A ; FPS and LPS were performed with the same daily dose of recombinant-gonadotrophins in an antagonist protocol.

Blastocyst culture, trophectoderm biopsy, vitrification and frozen-warmed euploid single blastocyst transfers were performed. Mean blastulation and euploidy rates were monitored, along with the number of oocytes, euploid blastocysts and clinical outcomes.