Appraisal of Experimental Methods to Manage Menopause and Infertility: Intraovarian Platelet-Rich Plasma vs. Condensed Platelet-Derived Cytokines.

The first published description of intraovarian platelet-rich plasma (PRP) appeared in mid-2016, when a new experimental technique was successfully used in adult human ovaries to correct the reduced fertility potential accompanying advanced maternal age. Considering the potential therapeutic scope of intraovarian PRP would likely cover both menopause and infertility, the mainstream response has ranged from skeptical disbelief to welcome astonishment. Indeed, reports of intraovarian PRP leading to restored menses in menopause (as an alternative to conventional hormone replacement therapy) and healthy term livebirths for infertility patients (from IVF or as unassisted conceptions) continue to draw notice. Yet, any proper criticism of ovarian PRP applications will be difficult to rebut given the heterogenous patient screening, varied sample preparations, wide differences in platelet incubation and activation protocols, surgical/anesthesia techniques, and delivery methods. Notwithstanding these aspects, no adverse events have thus far been reported and ovarian PRP appears well tolerated by patients. Here, early studies guiding the transition of 'ovarian rejuvenation' from experimental to clinical are outlined, with mechanisms to explain results observed in both veterinary and human ovarian PRP research. Current and future challenges for intraovarian cytokine treatment are also discussed.

First data on in vitro fertilization and blastocyst formation after intraovarian injection of calcium gluconate-activated autologous platelet rich plasma.

Platelets modulate clinically relevant yet incompletely understood tissue regeneration processes, and platelet rich plasma (PRP) has been previously used with some success in various non-reproductive medical contexts. Here, we extended PRP application to ovarian tissue with a view to document impact on ovarian reserve among women attending for infertility treatment. PRP was freshly isolated from patients (n= 4) with diminished ovarian reserve as determined by at least one prior IVF cycle canceled for poor follicular recruitment response or estimated by serum AMH and/or FSH, no menses for ≥1 year. Immediately following substrate isolation and activation with calcium gluconate, approximately 5 mL of autologous PRP was injected into each ovary under direct transvaginal sonogram guidance. For each study subject, AMH, FSH, and serum estradiol data were recorded at two-week intervals post-PRP and compared to baseline (pre-PRP) values. In this pilot group, mean (±SD) patient age was 42 ± 4 years with infertility duration reported as 60 ± 25 months. Following this protocol of intraovarian PRP administration, increases in serum AMH (p = .17), decreases in FSH (p < .01), or both, were observed in all cases, sufficient to permit retrieval of 5.3 ± 1.3 MII oocytes. IVF occurred 78 ± 22 (range = 59-110) days after activated PRP injection, and results appeared independent of patient age, infertility duration, baseline platelet concentration or pretreatment antral follicle count. Each patient had at least one blastocyst suitable for cryopreservation. While autologous PRP has been successfully applied therapeutically to various tissues to accelerate healing and wound repair, this is the first description of direct injection of activated PRP into the human ovary of poor prognosis IVF patients. Evidence of improved ovarian function was noted in all who received intraovarian PRP, possibly as early as two months after treatment. Additional research is needed to clarify (and enhance) which PRP components are responsible for altered ovarian function, and to identify predictive characteristics for patients most likely to benefit from this intervention.

Surgical Management After Hysteroscopic Sterilization: Minimally Invasive Approach Incorporating Intraoperative Fluoroscopy for Symptomatic Patients with >2 Essure® Devices.

OBJECTIVE: To describe a non-hysterectomy surgical technique for symptomatic patients with >2 Essure® (Bayer Healthcare, Whippany, New Jersey) devices. DESIGN: Patients (n=4) presented with sharp pelvic pain, irregular vaginal bleeding, dyspareunia, weight gain, hair loss, fatigue, and/or diffuse skin rash, all of which were absent before undergoing hysteroscopic sterilization (HS). Hysterosalpingogram obtained before surgical excision of contraceptive tubal implants confirmed more than two Essure® devices in all patients. Except for HS-associated complaints, all patients were in otherwise good general health and none had any history of prior pelvic pathology. Hysteroscopy was followed by 5mm triple-port laparoscopic cornual dissection, modified partial bilateral salpingectomy, and foreign body removal under fluoroscopy and/or radiographic guidance. RESULTS: In this group, mean±SD patient age was 41±8yrs and interval between HS and device removal was 6.4±2.7yrs. At the conclusion of each case (mean±SD operative time=179±11min), imaging studies were reviewed by an attending radiologist and verified no retained metal in the abdomen. Conversion to laparotomy, hysterectomy, or blood transfusion was unnecessary for any patients, and all were discharged home within three hours. Their postoperative course continues to be satisfactory. CONCLUSION: Patients with more than two Essure® devices comprise an unusual group with a complex pelvic foreign body presentation. This is the first report on surgical management for such patients, underscoring the importance of localizing these contraceptive devices with careful imaging before, during, and after surgery. Moreover, hysterectomy is not absolutely mandatory in this setting and intraoperative fluoroscopy/radiography can facilitate complete, safe removal of all implants on an out-patient basis. Creation of ICD-10 modifiers for various post-HS complaints would allow for improved surveillance of the Essure® phenomenon.

A decade of health assessments in Appalachia.

Purpose The purpose of this paper is to describe standardized clinical process of care and quality performance metrics at Roane Medical Center (RMC) and compare data from 2005 to 2015. Design/methodology/approach Information was extracted from a nationwide sample of short-term acute care hospitals using the Hospital Quality Alliance (HQA) database, evaluating multiple parameters measured at RMC. HQA data from RMC were matched against state and national benchmarks; findings were also compared with similar reports from the same facility in 2005. Findings Information collected by HQA expanded substantially in ten years and queried different parameters over time, thus exact comparisons between 2005 and 2015 cannot be easily calculated. Nevertheless, analysis of process of care data for 2015 placed RMC at or above state- and national-average performance in 64.9 percent (24 of 37) and 56.5 percent (26 of 46) categories, respectively. RMC registered superior process of care scores in heart failure care, pneumonia care, thrombus prevention and care, as well as stroke care. While RMC continues to perform favorably against state and national reference groups, the differences between RMC vs state and RMC vs national averages using current reporting metrics were both statistically smaller in 2015 compared to 2005 ( p<0.05). Research limitations/implications Perhaps the most significant interval health event for the RMC service area since 2005 was a coal ash spill at the nearby Tennessee Valley Authority facility in December 2008. Although reports on environmental and health effects following one of the largest domestic industrial toxin releases reached a number of important conclusions, the consequences for RMC in terms of potential added clinical burden on emergency services and impact on chronic health conditions have not been specifically studied. This could explain data reported on emergency department services at RMC but additional research will be needed to establish causality. Practical implications While tracking of care processes at all US hospitals will be facilitated by refinements in HQA tools, longitudinal evaluations for any specific unit will be more meaningful if the assessment instrument undergoes limited change over time. Social implications Appalachia remains one of several regions in the USA often identified as medically underserved. Hospitals here have confronted the challenge of diminished reimbursement, high expenses, limited staffing and other financial hardships in a variety of ways. Since the last published report on RMC, a particularly severe global recession has placed additional stress on organizations offering crucial health services in the region. Originality/value As a follow-up study to track potential changes which have been registered in the decade 2005-2015, this is the first report to provide original, longitudinal analysis on RMC, an institution operating in a rural and underserved area.

Gestational surrogacy and the role of routine embryo screening: Current challenges and future directions for preimplantation genetic testing.

Preimplantation genetic screening (PGS) is a component of IVF entailing selection of an embryo for transfer on the basis of chromosomal normalcy. If PGS were integrated with single embryo transfer (SET) in a surrogacy setting, this approach could improve pregnancy rates, minimize miscarriage risk, and limit multiple gestations. Even without PGS, pregnancy rates for IVF surrogacy cases are generally satisfactory, especially when treatment utilizes embryos derived from young oocytes and transferred to a healthy surrogate. However, there could be a more general role for PGS in surrogacy, since background aneuploidy in embryos remains a major factor driving implantation failure and miscarriage for all infertility patients. At present, the proportion of IVF cases involving GS is limited, while the number of IVF patients requesting PGS appears to be increasing. In this report, the relevance of PGS for surrogacy in the rapidly changing field of assisted fertility medicine is discussed.

Serum estradiol:oocyte ratio as a predictor of reproductive outcome: an analysis of data from >9000 IVF cycles in the Republic of Ireland.

PURPOSE: The purpose of this study was to evaluate the serum estradiol (E2) per oocyte ratio (EOR) as a function of selected embryology events and reproductive outcomes with IVF. METHODS: This retrospective analysis included all IVF cycles where oocyte collection and fresh transfer occurred between January 2001 and November 2012 at a single institution. Patients were divided by three age groups (<35, 35-39, and ≥40 years) and further stratified into nine groups based on EOR (measured in pmol/L/oocyte). Terminal serum E2 (pmol/mL) was recorded on day of hCG trigger administration, and fertilization rate, cleavage rate, number of good quality embryos, and reproductive outcomes were recorded for each IVF cycle. RESULTS: During the study interval, 9109 oocyte retrievals were performed for 5499 IVF patients (mean = 1.7 cycles/patient). A total of 63.4 % of transfers were performed on day 3 (n = 4926), while 36.6 % were carried out on day 5 (n = 2843). Clinical pregnancy rates were highest in patients with EOR of 250-750 and declined as this ratio increased, independent of patient age. While the odds ratio (OR) for clinical pregnancy where EOR = 250-750 vs. EOR > 1500 was 3.4 (p < 0.001; 95 % CI 2.67-4.34), no statistically significant correlation was seen in fertilization, cleavage rates or number of good quality embryos as a function of EOR. CONCLUSIONS: Predicting reproductive outcomes with IVF has great utility both for patients and providers. The former have the opportunity to build realistic expectations, and the latter are better able to counsel according to measured clinical parameters. A better understanding of follicular dynamics and ovarian response to gonadotropin stimulation could optimize IVF treatments going forward.

Patient Outcomes Following Injury from Hysteroscopic Sterilization.

OBJECTIVE: We present clinical data on two patients who underwent hysteroscopic sterilization (HS) 11 years apart using the Essure® (Bayer Inc., Whippany, NJ) device. MATERIALS AND METHODS: Symptoms and resolution are described for symptomatic Essure® patients. RESULTS: Case 1 (G3P1) underwent HS in 2004 at age 21. Performed in a physician's office without anesthesia, HS involved placement of >2 Essure® devices which was followed by severe, unrelenting pelvic pain. Confirmatory hysterosalpingogram (HSG) three months after HS revealed five devices. Surgical costs for laparoscopic assisted vaginal hysterectomy (LAVH) were fully reimbursed by the device manufacturer seven months later. Case 2 (G8P4) underwent HS in 2015 at age 32. One year earlier, the patient's right fallopian tube was removed due to ectopic pregnancy. Essure® devices were placed bilaterally in a physician's office without anesthesia; HS was accompanied by sharp pelvic pain. The patient obtained HSG three weeks after HS due to constant discomfort. Bilateral tubal occlusion was verified, but abnormal device loop configuration suggesting myometrial penetration was noted on the right. At laparoscopy, the left Essure® device was excised intact but the right coil could not be located. Thus far, there has been no offer in Case 2 from the device manufacturer to offset medical expenses. CONCLUSIONS: While HS has been FDA approved for use in the United States since 2002, this is the first description of clinical sequela when FDA labeling for the Essure® procedure is ignored. These cases illustrate the importance of proper physician training in HS and underscore the need for improved tracking of Essure® associated symptoms.

Referrals for complications following hysteroscopic sterilisation: characteristics associated with symptomatic patients after the Essure procedure.

OBJECTIVE: This report summarises recent experience with a series of symptomatic Essure® patients with an emphasis on clinical presentation, preoperative imaging, surgical intervention, and outcome. METHODS: This case series presents Essure® patients (n = 7) who sought medical consultation for various complications. This retrospective analysis is based on consultations during a six-month interval beginning in April 2015. RESULTS: In this sample, mean (± SD) patient age was 35.9 ± 3.4 yrs. The gravida/parity status was 3.6 ± 1.1 and 2.4 ± 1.4, respectively. Average duration of exposure to Essure® coils among these patients was 25.6 ± 24.5 (range 5-67) months. Except for one woman, these patients had hysteroscopic sterilisation (HS) either with heavy sedation or under general anaesthesia. More than two Essure® devices were implanted in two women. Complications reported after HS included device migration, coil fragmentation, tissue perforation, and vaginal expulsion of Essure® fragment. Three of seven women have required hysterectomy. CONCLUSION: The current series offers evidence of migration of contraceptive coils as well as Essure® inserts perforating tissue and being spontaneously expelled. Evaluation of symptomatic HS patients should include determining how many devices have been implanted, as some women have more than two.

Can laparoscopic removal of Essure device before embryo transfer correct poor reproductive outcome pattern in IVF? A case report.

OBJECTIVE: This report describes a successful surgical approach to multiple in vitro fertilization (IVF) failures in the setting of hydrosalpinges, which had been previously treated with Essure inserts. MATERIALS AND METHODS: A non-smoking 33-year-old Caucasian G2 P0020 (body mass index: BMI = 22) attended for second opinion. Her history was significant for bilateral hydrosalpinges having been noted on hysterosalpingogram two years earlier. This was managed by hysteroscopic placement of Essure inserts bilaterally. One year later, and now with Essure in situ, the patient completed three IVF cycles elsewhere. Her first and third IVF attempts resulted in biochemical pregnancy, while human chorionic gonadotropin (hCG) was negative after the second cycle. Upon presentation at the authors' center and before beginning a fourth IVF cycle, further testing and surgical removal of the Essure devices was recommended. RESULTS: Repeat hysteroscopy was unremarkable; laparoscopic bilateral salpingectomy and extirpation of Essure implants was accomplished without difficulty. Following menses, the patient initiated IVF with three embryos transferred. At day 60, a single intrauterine pregnancy was identified with positive cardiac activity (rate > 100/min). Her obstetrical course was uneventful; a healthy 4,195 gram male infant was delivered (breech) by Cesarean at 40 weeks' gestation. CONCLUSION: Essure inserts comprise inner fibers of polyethylene terephthalate, a stainless steel coil, and a nickel-titanium coil. The product received FDA approval as a contraceptive in 2002 although its use for hydrosalpinx remains off-label. While successful outcomes with IVF following Essure placement have been reported, this is the first description of pregnancy and delivery from IVF after Essure removal. Essure may be considered for sterilization when laparoscopy is contraindicated, but experience with its use specifically for treating hydrosalpinges before IVF is limited. This observed association between prior poor IVF outcomes and Essure with subsequent delivery after surgical Essure removal is the first of its kind to be reported, and warrants further investigation.

Population Dynamics, Plasma Cytokines and Platelet Centrifugation: Technical and Sociodemographic Aspects of 'Ovarian Rejuvenation'.

While advanced reproductive technologies have attained remarkable increases in sophistication, success, and availability since the 1980s, clinicians always meet a therapeutic impasse when the ovarian reserve reaches exhaustion. Irrespective of fertility aspirations, the decline in and eventual collapse of ovarian estrogen output means that menopause arrives with tremendous physiologic changes and reduced overall productivity. Because more women are gaining in longevity or delaying the age at pregnancy, the number of affected patients has never been larger. As concerns regarding standard hormone replacement therapy and the limitations of IVF are confronted, a workable path to enable primordial germ cell recruitment and de novo oocyte development would be welcome. Proof-of-concept case reports and clinical studies on autologous activated platelet-rich plasma (PRP) or its condensed cytokine derivatives suggest a way to facilitate these goals. However, ovarian PRP faces vexing challenges that place 'ovarian rejuvenation' under caution as it enters this therapeutic space. Here, we review key features of experimental human ovarian stem cell isolation/handling and reaffirm the need to harmonize laboratory protocols. Recognizing the regenerative science borrowed from other disciplines, specimen centrifugation, platelet processing, and condensed plasma cytokine enrichment are highlighted here. As the refinement of this rejuvenation approach would promise to reprogram adult ovarian physiology, the disruption of established treatment paradigms for infertility, menopause, and perhaps overall women's health seems likely. Emerging roles in reproductive biology and clinical practice are thus placed in a broader social and demographic context.

Multichannel Recovery Potential with Activated Autologous Intraovarian Platelet-Rich Plasma and Its Derivatives.

Platelet-rich plasma (PRP) is an 'orthobiologic' with recognized roles in plastic surgery, musculoskeletal disorders, dentistry, dermatology, and more recently, 'ovarian rejuvenation'. Intraovarian PRP involves a complex secretome discharged after platelet activation, comprising multiple cytokine mediators delivered surgically to older or inactive ovarian tissue. Loss of oocyte meiotic fidelity and impaired fertilization accompanying advanced maternal age are already managed by IVF, but only with eggs provided by younger donors. However, if the observed effect of rectifying embryo ploidy error can be proven beyond case reports and small series, activated PRP (or its condensed plasma cytokines) would deliver a welcome therapeutic disruption that is difficult to overstate. Because shortcomings in ovarian function are presently addressed mainly by pharmacological approaches (i.e., via recombinant gonadotropins, GnRH analogs, or luteal support), autologous PRP would represent an unusual departure from these interventions. Given the diversity of platelet cargo proteins, the target response of intraovarian PRP is probably not confined to oocytes or follicles. For example, PRP manipulates signal networks driving improved perfusion, HOX regulation, N-glycan post-translational modification, adjustment of voltage-gated ion channels, telomere stabilization, optimization of SIRT3, and ribosome and mitochondria recovery in older oocytes. While multichannel signals operating on various pathways are not unique to reproductive biology, in intraovarian PRP this feature has received little study and may help explain why its standardization has been difficult. Against this background, our report examines the research themes considered most likely to shape clinical practice.

Neuroendocrine tumor chromogranin A response following synthetic somatostatin analog (lanreotide): Early observations from an isolated duodenal neoplasm .

Neuroendocrine tumors (NETs) of duodenal origin are an unusual subset among all NETs, comprising only about 3% of this neoplasm class. In general, NETs are characterized by overexpression of somatostatin receptors and carry an excellent prognosis with early diagnosis and intervention. Chromogranin A (CgA), a protein originating in secretory vesicles of neurons and endocrine cells, has gained wide usage in NET diagnosis and surveillance. Lanreotide is a synthetic octapeptide somatostatin analog with potent anti-proliferative action which has been approved by the FDA (U.S.) and EMA (E.U.) for NET treatment. It is known for its inhibitory effects on growth hormone, serotonin, CgA, and other markers. Here we describe a 56yr-old female with functional NET of duodenal origin, where serum CgA was successfully reduced from 3636 to <100 ng/mL after multidose lanreotide within five months. Of note, no metastatic spread was identified on positron emission tomography/computed tomography with 64Cu-labeled somatostatin analog tracer. Surgical resection of distal antrum, pylorus, and proximal duodenum was completed without complication. Histology revealed well-differentiated tumor cells with characteristic neuroendocrine features and clear surgical margins; low proliferation index (2%) was noted on Ki-67 staining. While select laboratory and imaging modalities are available for diagnosis and monitoring of duodenal NET, this is the first reported therapeutic use of lanreotide in this NET setting. The observed serum chromogranin A attenuation, even before surgery, supports its effectiveness in management of primary nonmetastatic duodenal NET after resection.

mTOR Inhibition via Low-Dose, Pulsed Rapamycin with Intraovarian Condensed Platelet Cytokines: An Individualized Protocol to Recover Diminished Reserve?

No major breakthroughs have entered mainstream clinical fertility practice since egg donation and intracytoplasmic sperm injection decades ago, and oocyte deficits secondary to advanced age continue as the main manifestation of diminished ovarian reserve. In the meantime, several unproven IVF 'accessories' have emerged including so-called ovarian rejuvenation which entails placing fresh autologous platelet-rich plasma (PRP) directly into ovarian tissue. Among cellular responses attributed to this intervention are reduced oxidative stress, slowed apoptosis and improved metabolism. Besides having an impact on the existing follicle pool, platelet growth factors might also facilitate de novo oocyte recruitment by specified gene upregulation targeting uncommitted ovarian stem cells. Given that disordered activity at the mechanistic target of rapamycin (mTOR) has been shown to exacerbate or accelerate ovarian aging, PRP-discharged plasma cytokines combined with mTOR suppression by pulsed/cyclic rapamycin represents a novel fusion technique to enhance ovarian function. While beneficial effects have already been observed experimentally in oocytes and embryos with mTOR inhibition alone, this proposal is the first to discuss intraovarian platelet cytokines followed by low-dose, phased rapamycin. For refractory cases, this investigational, tailored approach could amplify or sustain ovarian capacity sufficient to permit retrieval of competent oocytes via distinct but complementary pathways-thus reducing dependency on oocyte donation.

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.

Intrathecal autologous thrombin-activated condensed platelet cytokines in chronic neurodegenerative disease: A hypothesis for anti-inflammatory and regenerative response.

Choroid plexus insufficiency or glymphatic stasis are often classified as prequels to harmful accretion of toxic proteins in neurodegenerative disease. Cognitive decline and disordered neuronal signaling subsequently become cardinal features of Alzheimer's disease (AD), typically progressing with amyloid-ß and tau protein accumulation. For Parkinson's disease (PD), α-synuclein deposits and dopamine depletion are linked to impaired movement, resting tremor, and rigidity. Importantly, both diagnoses feature hyperinflammation and intrathecal cytokine changes. Thus far, numerous clinical trials have produced nothing effective for AD or PD, yet the anti-inflammatory and regenerative potential of autologous platelet-rich plasma (PRP) remains largely unexamined in this context. Our report explores a proposed Phase I study on intrathecal condensed plasma growth factors processed from thrombin-activated PRP as monotherapy for AD or PD. The concept gains support from related work where cytokines of platelet origin successfully lowered inflammation, corrected background fibrosis, deactivated abnormal cells, and recovered local tissue function-all desirable outcomes in AD and PD. While PRP-mediated effects on membrane potentials, cellular signaling, electrolyte balance, and water clearance are less well characterized, experimental data suggest these pathways could likewise influence glymphatic drainage to ameliorate proteinopathies. As a well-tolerated 'orthobiologic' with no hypersensitivity risk, intrathecal PRP and its derivatives bring advantages over synthetic pharmaceuticals. If age-associated neuroinflammation in AD and PD is an upstream event inciting or contributing to neural disruption, then dampening local oxidative stress by a patient's own platelet cytokines (successful in other contexts) could offer therapeutic relevance to these neurodegenerative conditions as well.

Balancing selected medication costs with total number of daily injections: a preference analysis of GnRH-agonist and antagonist protocols by IVF patients.

BACKGROUND: During in vitro fertilization (IVF), fertility patients are expected to self-administer many injections as part of this treatment. While newer medications have been developed to substantially reduce the number of these injections, such agents are typically much more expensive. Considering these differences in both cost and number of injections, this study compared patient preferences between GnRH-agonist and GnRH-antagonist based protocols in IVF. METHODS: Data were collected by voluntary, anonymous questionnaire at first consultation appointment. Patient opinion concerning total number of s.c. injections as a function of non-reimbursed patient cost associated with GnRH-agonist [A] and GnRH-antagonist [B] protocols in IVF was studied. RESULTS: Completed questionnaires (n = 71) revealed a mean +/- SD patient age of 34 +/- 4.1 yrs. Most (83.1%) had no prior IVF experience; 2.8% reported another medical condition requiring self-administration of subcutaneous medication(s). When out-of-pocket cost for [A] and [B] were identical, preference for [B] was registered by 50.7% patients. The tendency to favor protocol [B] was weaker among patients with a health occupation. Estimated patient costs for [A] and [B] were $259.82 +/- 11.75 and $654.55 +/- 106.34, respectively (p < 0.005). Measured patient preference for [B] diminished as the cost difference increased. CONCLUSIONS: This investigation found consistently higher non-reimbursed direct medication costs for GnRH-antagonist IVF vs. GnRH-agonist IVF protocols. A conditional preference to minimize downregulation (using GnRH-antagonist) was noted among some, but not all, IVF patient sub-groups. Compared to IVF patients with a health occupation, the preference for GnRH-antagonist was weaker than for other patients. While reducing total number of injections by using GnRH-antagonist is a desirable goal, it appears this advantage is not perceived equally by all IVF patients and its utility is likely discounted heavily by patients when nonreimbursed medication costs reach a critical level.

Why might ovarian rejuvenation fail? Decision analysis of variables impacting reproductive response after autologous platelet-rich plasma.

Experience with platelet-rich plasma (PRP) has accumulated from use in dental restoration, postinfarct myocardial repair, tendon surgery, pain management, and aesthetic enhancements. Reproductive medicine joined this arena in 2016, beginning with reports of menopause reversal and fertility recovery after autologous PRP for senescent ovaries. Although recent publications have highlighted benefits of "ovarian rejuvenation," the absence of randomized placebo-controlled clinical trial data has limited its acceptance. Because selection bias tends to underreport negative outcomes, reliable estimates cannot be calculated for how often intraovarian PRP is unsuccessful. However, ample information is available to permit an operational root-cause analysis when failures are considered. This assessment uses a PRP treatment care path with a decision theory model to critique pre-intake screening, baseline audit, sample processing, ovarian tissue placement method, equipment selection, and follow-up monitoring. These branched choice points enable interventions likely to determine outcome. Specimen handling for intraovarian PRP merits particular scrutiny, since enormous variation in platelet protocols already exists across unrelated clinical areas. As a new addition to fertility practice, intraovarian PRP requires validation of safety and efficacy to gain wider support. Borrowing PRP knowledge from other domains can facilitate this goal, ideally with appreciation of aspects unique to intraovarian use.

Ovarian recovery via autologous platelet-rich plasma: New benchmarks for condensed cytokine applications to reverse reproductive aging.

Health and life expectancy gains have pushed the overall number of menopausal patients to record levels. Because maternal age at first pregnancy also continues to rise, it is unsurprising that reduced birth rates are consistently reported across many populations. Both trends severely strain national demographics and present a socioeconomic challenge for which no satisfactory solution currently exists. Symptomatic menopause and infertility/miscarriage are met with standard therapies like hormone replacement therapy (HRT) and in vitro fertilization, respectively. Although these accepted interventions do supply some cover, both are expensive, low yield, and not without controversy. Meanwhile, ovarian steroid output and competent oocyte availability approach unrecoverable loss beyond age ~35 years, irrespective of treatment. Received wisdom holds that postnatal oogenesis in humans is impossible, a tenet which until recently encountered little serious confrontation. Reassessing this paradigm is overdue given proof-of-concept work on native sex steroid rejuvenation, de novo euploid oogenesis, ovulation, blastocyst development, fetal growth, and healthy term livebirths-all apparently possible with intraovarian insertion of platelet-rich plasma (PRP). Discrete functional analysis of the full platelet-derived cytokine array carried with PRP unfortunately for now, is incomplete. Here, selected platelet releasate constituents and measured effects are framed to address advances in wellness and women's health. Emphasis is on cytokines best positioned to enable recovery of senescent ovarian function sufficient to suspend synthetic HRT dependency and/or permit egg retrieval and pregnancy. Whereas the chronicle of progress in other clinical fields does invite generalization of fresh platelet applications to reproductive endocrinology, basic mechanistic questions remain open.

Phenotype from SAMD9 Mutation at 7p21.2 Appears Attenuated by Novel Compound Heterozygous Variants at RUNX2 and SALL1.

Sterile α motif domain-containing protein 9 (SAMD9) is a regulatory protein centrally involved in cell proliferation and apoptosis. Mapped to 7p21.2, variants in SAMD9 have been reported in <50 pediatric cases worldwide, typically with early lethality. Germline gain-of-function SAMD9 variants are associated with MIRAGE syndrome (myelodysplasia, infection, restricted growth, adrenal hypoplasia, genital anomalies, and enteropathy). Spalt like transcription factor 1 (SALL1) is a zinc finger transcriptional repressor located at 16q12.1 where only two transcript variants in SALL1 are known. RUNX2 (6p21.1) encodes a nuclear protein with a Runt DNA-binding domain critical for osteoblastic differentiation, skeletal morphogenesis, and serves as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. RUNX2 and SALL1 are thus both "master regulators" of tissue organization and embryo development. Here, we describe exome sequencing and copy number variants in two previously unknown mutations-R824Q in SAMD9, and Q253H in SALL1. A multiexon 3' terminal duplication of RUNX2 not previously encountered is also reported. This is the first known phenotype assessment for an intersection of all three variants in a healthy 46,XX adult. Focusing on developmental progress, ultrastructural renal anatomy, and selected reproductive aspects, we describe this unique genotype diagnosed incidentally during coronavirus disease 2019 (COVID-19) illness. Individually, disruption in SAMD9, RUNX2, or SALL1 would be expected to give a bleak prognosis. However, this variant convergence appears to dampen severe pathology perhaps by cross-gene silencing of effects normally deleterious when such changes occur alone.

Growth factors, gene activation, and cell recruitment: From intraovarian condensed platelet cytokines to de novo oocyte development.

BACKGROUND: Interest in decelerating or reversing reproductive aging is unlikely to diminish in the era of molecular genetics. For the adult human ovary, meeting the challenge of menopause without synthetic hormone replacement has now moved beyond proof-of-concept, as shown from treatments validated with standard metabolic markers and ovarian reserve estimates. However, without proper recruitment and differentiation of oocytes, such outcomes would be impossible. The full inventory of factors required for such folliculogenesis is not yet final, but growth differentiation factor-9, transforming growth factor-beta1, vascular endothelial growth factor, and insulin-like growth factor-1 are consistently identified as relevant. Platelet-derived growth factor and, more recently, bone morphogenic proteins are also central to cell migration, vascular support, and general ovarian function. Interestingly, when cells secreting these moieties are surgically grafted near undifferentiated oocyte stem precursors, the latency phase transitions to delineate follicle development and restoration of reproductive capacity. Direct intraovarian injection of condensed platelet-derived cytokines (a platelet-rich plasma/PRP product) likewise enables return of menses, ovulation, and term live birth. AIM: This report extends our previous work on the proangiogenic effects of intraovarian PRP by connecting clinical responses to specific cytokine-dependent gene activation pathways likely needed to induce oocyte differentiation. RELEVANCE FOR PATIENTS: Ovarian rejuvenation is a promising new application for platelet-rich plasma and/or condensed plasma cytokines of platelet origin, which are injected into older ovarian tissue.