Intraovarian condensed platelet cytokines for infertility and menopause-Mirage or miracle?

On a therapeutic landscape unchanged since the 1980's, oocyte donation with IVF still stands as the solitary medical answer to diminished reserve and premature ovarian insufficiency. In 2016, intraovarian platelet-rich plasma (PRP) crossed the horizon as a hopeful reply to these intertwined problems. The once remote mirage of platelet cytokine effects on gene regulation or telomere stabilization has been brought into sharper focus, with current work clarifying how PRP corrects oxidative stress, rectifies tissue hypoxia, downregulates apoptosis, and enhances cellular metabolism. Not yet ready for routine use, this innovative treatment has already offered at least one point of early consensus: How intraovarian PRP results should be classified-Patients are either responders or non-responders. From this it is intriguing that no published PRP protocol has ever reported a supranormal ovarian rebound or hyperstimulation effect. This might be explained by baseline age-related ovarian conditions prevalent among poor responders, but since dysregulated or malignant transformations are also missing in other tissue contexts following autologous PRP treatment, the contribution of some platelet product which intrinsically delimits regenerative action cannot be discounted. Here we summarize results with recent experimental and clinical platelet research, framing those most likely to help advance reproductive endocrinology practice.

Covid-19 and adolescent acute kidney injury: Renal recovery with combined enalapril and estrogen therapy.

Covid-19 in adolescence with multisystem inflammatory injury (MIS-C) is a newly described condition sharing key features with Kawasaki disease and toxic shock syndrome. A May 2020 United Nations WHO brief covering findings from North America and Europe drew notice to this acute post-viral illness characterized by severe, diffuse hyperinflammation leading to multiorgan failure. While females diagnosed with Covid-19 generally have more favorable outcomes than males, this protection is negated by a low estrogen state. This case reports on acute kidney injury/MIS-C with amenorrhea from ovarian insufficiency in childhood, itself an uncommon presentation of idiopathic hypogonadism. Three exon variants were previously identified in a healthy, phenotypically normal 46,XX adolescent who subsequently underwent whole genome sequencing (WGS). She had only two spontaneous menses with a provisional diagnosis of premature ovarian insufficiency made by age 15. Against this background, Covid-19 infection necessitated hospital admission where progressively reduced renal function was a prime component of MIS-C. Combined angiotensin-converting enzyme inhibitor plus transdermal estrogen replacement therapy resulted in normalized estimated glomerular filtration rate (eGFR) from baseline 43 to 68 ml/min/1.73 m2, post-treatment. Serum cystatin-C also improved during this interval from 1.69 to 1.19 mg/L. Among 7 Covid-19 high risk intron variants identified was rs3131294 (6p21), near NOTCH4. Another finding at rs8068318 (17q23) was associated with creatine level and eGFR. This is the first work to explore Covid-19 and associated kidney injury as a component of MIS-C at the intersection of rare multigene variants and functional ovarian loss. The context of transition from adolescence to adulthood is also considered, where successful recovery of renal function was achieved with combined enalapril and supplemental estrogen.

Bivariate analysis of basal serum anti-Müllerian hormone measurements and human blastocyst development after IVF.

BACKGROUND: To report on relationships among baseline serum anti-Müllerian hormone (AMH) measurements, blastocyst development and other selected embryology parameters observed in non-donor oocyte IVF cycles. METHODS: Pre-treatment AMH was measured in patients undergoing IVF (n = 79) and retrospectively correlated to in vitro embryo development noted during culture. RESULTS: Mean (+/- SD) age for study patients in this study group was 36.3 ± 4.0 (range = 28-45) yrs, and mean (+/- SD) terminal serum estradiol during IVF was 5929 +/- 4056 pmol/l. A moderate positive correlation (0.49; 95% CI 0.31 to 0.65) was noted between basal serum AMH and number of MII oocytes retrieved. Similarly, a moderate positive correlation (0.44) was observed between serum AMH and number of early cleavage-stage embryos (95% CI 0.24 to 0.61), suggesting a relationship between serum AMH and embryo development in IVF. Of note, serum AMH levels at baseline were significantly different for patients who did and did not undergo blastocyst transfer (15.6 vs. 10.9 pmol/l; p = 0.029). CONCLUSIONS: While serum AMH has found increasing application as a predictor of ovarian reserve for patients prior to IVF, its roles to estimate in vitro embryo morphology and potential to advance to blastocyst stage have not been extensively investigated. These data suggest that baseline serum AMH determinations can help forecast blastocyst developmental during IVF. Serum AMH measured before treatment may assist patients, clinicians and embryologists as scheduling of embryo transfer is outlined. Additional studies are needed to confirm these correlations and to better define the role of baseline serum AMH level in the prediction of blastocyst formation.

Recipient screening in IVF: first data from women undergoing anonymous oocyte donation in Dublin.

BACKGROUND: Guidelines for safe gamete donation have emphasised donor screening, although none exist specifically for testing oocyte recipients. Pre-treatment assessment of anonymous donor oocyte IVF treatment in Ireland must comply with the European Union Tissues and Cells Directive (Directive 2004/23/EC). To determine the effectiveness of this Directive when applied to anonymous oocyte recipients in IVF, we reviewed data derived from selected screening tests performed in this clinical setting. METHODS: Data from tests conducted at baseline for all women enrolling as recipients (n = 225) in the anonymous oocyte donor IVF programme at an urban IVF referral centre during a 24-month period were analysed. Patient age at programme entry and clinical pregnancy rate were also tabulated. All recipients had at least one prior negative test for HIV, Hepatitis B/C, chlamydia, gonorrhoea and syphilis performed by her GP or other primary care provider before reproductive endocrinology consultation. RESULTS: Mean (±SD) age for donor egg IVF recipients was 40.7 ± 4.2 yrs. No baseline positive chlamydia, gonorrhoea or syphilis screening results were identified among recipients for anonymous oocyte donation IVF during the assessment interval. Mean pregnancy rate (per embryo transfer) in this group was 50.5%. CONCLUSION: When tests for HIV, Hepatitis B/C, chlamydia, gonorrhoea and syphilis already have been confirmed to be negative before starting the anonymous donor oocyte IVF sequence, additional (repeat) testing on the recipient contributes no new clinical information that would influence treatment in this setting. Patient safety does not appear to be enhanced by application of Directive 2004/23/EC to recipients of anonymous donor oocyte IVF treatment. Given the absence of evidence to quantify risk, this practice is difficult to justify when applied to this low-risk population.

A descriptive study of selected oocyte, blood and organ/tissue donation features among fertility patients in Ireland.

OBJECTIVE: Anonymous oocyte donation and participation in organ and blood/tissue donation programmes were studied specifically among Irish fertility patients. METHODS: An anonymous questionnaire measured patient perceptions of, and participation in, blood/organ/tissue donor programmes, and to record opinion on anonymous donor oocyte compensation. RESULTS: A total of 337 patents were sampled; 56.7% had no children. None had participated in a donor oocyte programme either as donor or recipient. At baseline, 19.6% had previous in vitro fertilisation experience, more than one-third (35.9%) had donated blood anonymously, 19.9% were organ/tissue donors and 52.2% indicated that anonymous oocyte donors should receive some compensation. We found patients with infertility for extended periods were more likely to view oocyte donation favourably, compared to those with infertility of shorter durations (p = 0.022, by Krusksal-Wallis Rank Sum test). Average recommended compensation for anonymous oocyte donor was euro 2177 (range euro 200-euro 9500), and most (77.2%) favoured confidential protections for recipient and donor identity. CONCLUSION: This is the first investigation of blood and organ/tissue donation features among fertility patients in Ireland; the rate of blood donation in this group was more than 10 times higher than in the general Irish population. Protection of anonymity for both donors and recipients was supported by most patients, even opponents of compensated anonymous donation. Further studies should clarify patient perceptions about oocyte donation as a function of involvement in organ/tissue procurement programmes and blood banks.

National birth rate, IVF utilisation and multiple gestation trends: findings from a 6-year analysis in the Republic of Ireland.

PURPOSE: The impact of the advanced reproductive technologies on multiple gestation has been well documented in several large populations, but only infrequently in smaller countries, where its effects may be different. This study estimated domestic in vitro fertilisation (IVF) use and multiple gestation rate in Ireland based on two data-reporting platforms. METHODS: The number of IVF cycles completed in Ireland was extrapolated from statistics reported to the central European fertility registry (ESHRE) between 1999 and 2004. Multiple gestation data during this period were obtained from the National Perinatal Reporting System (NPRS). These datasets were interlocked to offer a method to track the impact of IVF activity on background multiple gestation rate in Ireland. RESULTS: Total Irish births registered increased from 54,307 in 1999 to 62,406 in 2004, and multiple gestation rate (per 1,000) fluctuated non-linearly from 27.2 to 31.4 during this time. Reported IVF activity increased from 972 in 1999 to 1,705 in 2004. Annual incidence of multiple gestation appeared strongly correlated with annual number of ETs although statistical significance was not reached (unadjusted Spearman correlation coefficient = 0.6; p = 0.21). CONCLUSION: Although IVF providers must continue to reduce multiple births by limiting the number of embryos transferred, this study places national IVF activity in the context of multiple gestations recorded in the general Irish population. These datasets suggest the number of patients undergoing IVF increased steadily in Ireland from 1999 to 2004, but a similar increase in multiple gestation was not observed in the overall Irish population during our study interval. While it is reassuring that increased use of IVF in Ireland did not significantly influence the multiple gestation rate, the absence of a formal data collection method hampers direct and comprehensive monitoring of this phenomenon here.

Clinical Presentation and Conservative Management of Tympanic Membrane Perforation during Intrapartum Valsalva Maneuver.

Background. Tympanic membrane perforation may occur when ear pressures are excessive, including valsalva maneuver associated with active labor and vaginal delivery. A pressure differential across the eardrum of about 5 psi can cause rupture; the increased intraabdominal pressure spikes repeatedly manifested by "pushing" during second-stage labor easily approach (and may exceed) this level. Material and Method. We describe a healthy 21-year old nulliparous patient admitted in active labor at 39-weeks' gestational age. Results. Blood appeared asymptomatically in the left ear canal at delivery during active, closed-glottis pushing. Otoscopic examination confirmed perforation of the left tympanic membrane. Complete resolution of the eardrum rupture was noted at postpartum check-up six weeks later. Conclusion. While the precise incidence of intrapartum tympanic membrane rupture is not known, it may be unrecognized without gross blood in the ear canal or subjective hearing loss following delivery. Only one prior published report on tympanic membrane perforation during delivery currently appears in the medical literature; this is the first English language description of the event. Since a vigorous and repetitive valsalva effort is common in normal vaginal delivery, clinicians should be aware of the potential for otic complications associated with the increased intraabdominal pressure characteristic of this technique.

Novel ETHE1 mutation in a carrier couple having prior offspring affected with ethylmalonic encephalopathy: Genetic analysis, clinical management and reproductive outcome.

Ethylmalonic encephalopathy (EE) is an autosomally recessive inherited disorder with a relentlessly progressive decline in neurological function, usually fatal by the age of ten. It is characterised by generalised hypotonia, psychomotor regression, spastic tetraparesis, dystonia, seizures and, eventually, global neurological failure. Approximately 50 reports have been published worldwide describing this devastating disease, most involving patients of Mediterranean or Arab origin. The fundamental defect in EE likely involves the impairment of a mitochondrial sulphur dioxygenase coded by the ETHE1 gene responsible for the catabolism of sulphide, which subsequently accumulates to toxic levels. A diagnosis of EE should initiate careful genetic evaluation and counselling, particularly if the parents intend to have additional offspring. The present report describes the diagnosis of EE in a reproductive endocrinology context, where both members of a non-consanguineous couple were confirmed to be carriers of an identical A↷G mutation. This previously unknown mutation at nucleotide position c.494 resulted in an amino acid substitution, p.Asp165Gly. Although consideration was given to in vitro fertilisation, embryo biopsy and single gene pre-implantation genetic diagnosis, the couple decided to first utilise a less aggressive therapeutic approach with donor sperm insemination. Pregnancy with a low risk of EE was indeed achieved; however, the infant was affected with a different anomaly (hypoplastic left heart). As this case demonstrates, prior to the initiation of fertility therapy, genetic analysis may be used to provide a confirmatory diagnosis when EE is suspected.

Ovarian reserve screening in infertility: practical applications and theoretical directions for research.

The concept of ovarian reserve describes the natural oocyte endowment and is closely associated with female age, which is the single most important factor influencing reproductive outcome. Fertility potential first declines after the age of 30 and moves downward rapidly thereafter, essentially reaching zero by the mid-40s. Conceptions beyond this age are exceedingly rare, unless oocytes obtained from a younger donor are utilised. How best to estimate ovarian reserve clinically remains controversial. Passive assessments of ovarian reserve include measurement of serum follicle stimulating hormone (FSH), oestradiol (E(2)), anti-Müllerian hormone (AMH), and inhibin-B. Ultrasound determination of antral follicle count (AFC), ovarian vascularity and ovarian volume also can have a role. The clomiphene citrate challenge test (CCCT), exogenous FSH ovarian reserve test (EFORT), and GnRH-agonist stimulation test (GAST) are provocative methods that have been used to assess ovarian reserve. Importantly, a patient's prior response to gonadotropins also provides highly valuable information about ovarian function. Regarding prediction of reproductive outcome, in vitro fertilisation (IVF) experience at our centres and elsewhere has shown that some assessments of ovarian reserve perform better than others. In this report, these tests are discussed and compared; we also present practical strategies to organise screening as presently used at our institutions. Experimental challenges to the long-held tenet of irreversible ovarian ageing are also introduced and explored. While pregnancy rates after IVF are influenced by multiple (non-ovarian) factors including in vitro laboratory conditions, semen parameters, psychological stress and technique of embryo transfer, predicting response to gonadotropin treatment nevertheless remains an important aim in the evaluation of the couple struggling with infertility.

Ovarian serous adenocarcinoma identified during IVF: diagnostic approach, surgical management, and reproductive outcome.

BACKGROUND: To present a diagnostic evaluation and treatment strategy for serous adenocarcinoma of the ovary discovered during an in vitro fertilisation (IVF) sequence, and report on reproductive outcome after tumour resection and embryo transfer. CASE PRESENTATION: Cycle monitoring in IVF identified an abnormal ovarian lesion which was subjected to ultrasound-guided needle aspiration. Cytology suggested malignancy, and unilateral oophorectomy was performed after formal staging. After surgery, the patient underwent an anonymous donor oocyte IVF cycle which established a viable twin intrauterine pregnancy. No recurrence of cancer has been detected in the >72 month follow-up interval; mother and twin daughters continue to do well. CONCLUSION: Suspicious adnexal structures noted during controlled ovarian hyperstimulation for IVF warrant assessment, and this report confirms the role of aspiration cytology in such cases. If uterine conservation is possible, successful livebirth can be achieved from IVF if donor oocyes are utilised, as described here.

Who's asking? Patients may under-report postoperative pain scores to nurses (or over-report to surgeons) following surgery of the female reproductive tract.

OBJECTIVE: To determine if postoperative pain reporting via standardised visual analogue scale (VAS) is affected by which member of the healthcare team collects the information. MATERIALS AND METHODS: A standardised ten-point VAS measured postsurgical pain level among patients (n = 60) undergoing laparotomy via Pfannenstiel incision. All study patients received the same patient-controlled analgesia and uniform post-operative orders were used. VAS data were gathered from patients by surgeons (MD) and nurses (RN) 6 h and 24 h after surgery; RNs and MDs independently recorded patients' VAS pain scores in variable order. RESULTS: When assessed 6 h after surgery, the average pain level reported by patients to RNs was significantly lower than that reported to MDs (3.3 +/- 2.8 vs. 4.0 +/- 2.4; P = 0.02). Average patient pain levels remained lower when reported to RNs 24 h post-operatively compared to that reported to MDs, although this difference was not significant (1.9 +/- 2.1 vs. 2.1 +/- 2.1; P = 0.39). Whenever post-surgical patients provided different VAS scores for pain level to RNs and MDs, the higher pain reading was always reported to the MD. CONCLUSION: This study identified important variances in subjective pain reporting by patients that appeared to be influenced by who sampled the data. We found patients gave lower VAS pain scores to RNs compared to MDs; the reverse pattern was never observed. Post-surgical patients may communicate pain information differently depending on who asks them, particularly in the early post-operative period. Accordingly, patient pain data gathered over time by a care team with a heterogeneous composition (i.e., RNs, MDs) may not be fully interchangeable. Patient projections of pain severity and/or intensity appear to vary as a function of who evaluates the patient.

Clinical features and reproductive outcomes for embryos undergoing dual freeze-thaw sequences followed by blastocyst transfer: critique of 14 consecutive cases in IVF.

These data suggest that the physiologic stress associated with two consecutive freeze-thaw processes is likely minor. Dual freeze-thaw of embryos does not appear to adversely impact delivery rate in IVF; a livebirth delivery rate of 35.7% per transfer was observed in our population.

The GPR54-Kisspeptin complex in reproductive biology: neuroendocrine significance and implications for ovulation induction and contraception.

KISS1 encodes the kisspeptin (KP) family of peptides which were originally characterised as potent antimetastatic agents in breast cancer and malignant melanoma cells. One member of this family of arginine-phenylalanine amide peptides, KP-54, was subsequently identified as the natural ligand for the G-protein coupled receptor-54 (GPR54). In addition to its importance as a metastatic suppressor, KP has been found to play a major neuroregulatory role in governing endogenous gonadotropin release by its modulation of the hypothalamic-pituitary-gonadal (HPG) axis. In humans, KISS1 mRNA has been localised to the hypothalamic anteroventral periventricular nucleus and arcuate nucleus. Although GPR54 is expressed in human pituitary cells, it is not presently known if gonadotrope cells themselves are targets for significant KP activity. It was recently shown that full disruption of the KP/GPR54 complex resulted in hypogonadotropic hypogonadism. Indeed, evidence now suggests that KP/GPR54 signalling during gestation is necessary for sexual differentiation and implicates activation of the KP/GPR54 complex as the single most important upstream event regulating GnRH release. Several compelling studies have placed KP as the leading candidate molecule responsible for initiating puberty, making this receptor-ligand complex of fundamental importance to the neuroendocrinology of reproduction. Here, we discuss key KP/GPR54 discovery events and present an evolution of KP biology in the context of recent animal and human experimental work. With evidence pointing to proper KP/GPR54 signalling as the principal trigger for activation of GnRH neurons and subsequent ovulation, elucidation of how this pathway is modulated is likely to bring novel pharmacologic strategies for fertility treatment (and contraception) within reach. Because the physiological significance KP is now acknowledged to extend well beyond cancer biology (and may also contribute to the pathophysiology of pre-eclampsia), KP represents an exciting research theme in human reproductive biology and neuroendocrinology.

Ovarian hyperstimulation syndrome and prophylactic human embryo cryopreservation: analysis of reproductive outcome following thawed embryo transfer.

OBJECTIVE: To review utilisation of elective embryo cryopreservation in the expectant management of patients at risk for developing ovarian hyperstimulation syndrome (OHSS), and report on reproductive outcome following transfer of thawed embryos. MATERIALS AND METHODS: Medical records were reviewed for patients undergoing IVF from 2000-2008 to identify cases at risk for OHSS where cryopreservation was electively performed on all embryos at the 2 pn stage. Patient age, total number of oocytes retrieved, number of 2 pn embryos cryopreserved, interval between retrieval and thaw/transfer, number (and developmental stage) of embryos transferred (ET), and delivery rate after IVF were recorded for all patients. RESULTS: From a total of 2892 IVF cycles undertaken during the study period, 51 IVF cases (1.8%) were noted where follicle number exceeded 20 and pelvic fluid collection was present. Elective embryo freeze was performed as OHSS prophylaxis in each instance. Mean (+/- SD) age of these patients was 32 +/- 3.8 yrs. Average number of oocytes retrieved in this group was 23 +/- 8.7, which after fertilisation yielded an average of 14 +/- 5.7 embryos cryopreserved per patient. Thaw and ET was performed an average of 115 +/- 65 d (range 30-377 d) after oocyte retrieval with a mean of 2 +/- 0.6 embryos transferred. Grow-out to blastocyst stage was achieved in 88.2% of cases. Delivery/livebirth rate was 33.3% per initiated cycle and 43.6% per transfer. Non-transferred blastocysts remained in cryostorage for 24 of 51 patients (46.1%) after ET, with an average of 3 +/- 3 blastocysts refrozen per patient. CONCLUSION: OHSS prophylaxis was used in 1.8% of IVF cycles at this institution; no serious OHSS complications were encountered during the study period. Management based on elective 2 pn embryo cryopreservation with subsequent thaw and grow-out to blastocyst stage for transfer did not appear to compromise embryo viability or overall reproductive outcome. For these patients, immediate elective embryo cryopreservation and delay of ET by as little as 30 d allowed for satisfactory conclusion of the IVF sequence, yielding a livebirth-delivery rate (per ET) >40%.