We wish to report the first live births from genetically screened human euploid blastocysts obtained by uterine lavage. The embryos transferred to infertile women were previously obtained using a novel fully automated uterine lavage catheter and fluid recovery device developed for this indication. The objective of this portion of the research was to confirm embryo implantation and live births with these unique in vivo conceived blastocysts obtained by uterine lavage. In vivo conceived embryos recovered by uterine lavage 5 days after intrauterine insemination were available for embryo donation. In vivo embryos were the result of prior controlled ovarian stimulation cycles in oocyte donors and intrauterine insemination with donor sperm. An observational case series of nine embryo transfer procedures was performed at an outpatient fertility center. One to two embryos were transferred to eight infertile women since one woman had two separate embryo transfer procedures. Nine embryo transfer procedures were performed with 14 blastocysts in eight women resulting in a blastocyst implantation rate of 36

.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . Corrigendum. First PGT-A using human in vivo blastocysts recovered by uterine lavage: comparison with matched IVF embryo controls Santiago Munné*, Steven T. Nakajima, Sam Najmabadi, Mark V. Sauer, Marlane J. Angle, José L. Rivas, Laura V. Mendieta, Thelma M. Macaso, Sarthak Sawarkar, Alexander Nadal, Kajal Choudhary, Camran Nezhat, Sandra A. Carson, and John E. Buster CooperGenomics, Livingston, NJ, USA Overture Life, Madrid, Spain Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, New Haven, CT, USA Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA Center for Reproductive Health and Gynecology, Beverly Hills, CA, USA Punta Mita Fertility Center/Center for Reproductive Health and Gynecology, Punta Mita Hospital, Nayarit C.P., Mexico Department of Obstetrics, Gynecology and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA Laurel Fertility Care, San Francisco, CA, USA Previvo Genetics, Inc, San Carlos, CA, USA Center for Special Minimally Invasive and Robotic Surgery, Palo Alto, CA, USA Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Providence, RI, USA

Abstract Supplementation with adjuvant therapies, including growth hormone (hGH), is commonly used to improve fertility treatment outcomes. hGH is important for normal female fertility; low hGH has been associated with causes of infertility and impaired fertility, including polycystic ovarian syndrome (PCOS), endometriosis, diminished ovarian reserve (DOR), and advanced maternal age. A novel, low dose, orally administered amino acid blend has been previously shown in a double-blind, randomized, placebo-controlled, crossover clinical trial to produce a statistically significant increase in endogenous hGH secretion. In this clinical case series, we report outcomes in 7 women with infertility or impaired fertility and conditions associated with low hGH who administered the amino acid blend during fertility treatment (n=5) or timed intercourse/spontaneous pregnancy (n=2). Medical history included conditions associated with impaired fertility and low hGH: endometriosis (n=3), PCOS (n=2), and poor response to ovarian stimulation/history of failed in vitro fertilization (IVF) (n=3). The amino acid blend (containing 2.9 g of L-lysine, L-arginine, oxo-proline, N-acetyl-L-cysteine, L-glutamine, and schizonepeta) was administered daily on an empty stomach. Outcomes included embryo quality and success of embryo transfer (for IVF) and successful pregnancy/live births. Mean±SD age was 33±5 years (range 27-38) and BMI was 27±7 kg/m2 (range 21-37). Time to pregnancy ranged from 1 week to 9 months (median 3 months) prior to egg retrieval for IVF (n=4), intrauterine insemination (n=1), or timed intercourse/spontaneous pregnancy (n=2). For women with a history of failed IVF (n=3), there was an improvement in oocyte retrieval, a higher fertilization rate, and a greater number of high-quality embryos compared to previous IVF attempts. There were 2 twin pregnancies (both following IVF). All 7 pregnancies resulted in live births. Consistent with previous studies, the amino acid blend was well tolerated; no adverse events were observed. We report a case series of successful pregnancy in 7 women with conditions associated with low hGH including PCOS, endometriosis, and poor response to ovarian stimulation/history of failed IVF who administered the amino acid blend concomitant with fertility treatment or who reported spontaneous pregnancy. This may represent a potential low-risk and cost-effective treatment to improve IVF success and increase pregnancy rates in individuals with infertility or impaired fertility.

Introduction Early work performed by Buster et al. (1985) demonstrated the recovery of embryos from the uteri using uterine lavage. The advancement in embryo cryopreservation, blastocyst culture and the development of comprehensive methods of PGT-A have refocused attention on uterine lavage as a possible nonsurgical minimally invasive approach for fertile individuals who desire PGT-A without utilization of in vitro fertilization (IVF). Materials and Methods Gonadotropin induced ovarian stimulation and insemination were performed followed by uterine lavage to recover the in vivo conceived embryos. Recovered embryos were characterized morphologically using the Gardner Scale, underwent trophectoderm (TE) biopsy, were then vitrified and stored in liquid nitrogen. Biopsies were analyzed using next-generation sequencing (NGS) technique. Results were compared with in vitro conceived embryos from other cycles of the same patients. Results Uterine lavage performed after insemination successfully recovered blastocysts providing a reliable and consistent means to capture in vivo conceived embryos. Results to date from this ongoing study (134 of 500 planned lavage cycles completed) show consistent improvement in successive cohorts with respect to the ability of the lavage system to recover embryos. Embryos of many stages were recovered in 42% (56/134) of the cycles, out of which, 71% (96/136) embryos were blastocyst stage embryos representing a most advanced stage of embryogenesis. The 63% of in vivo conceived embryos were euploid or low-mosaic (<40% abnormal), which was similar to that of IVF conceived embryos (64%). High-mosaicism rate (11% vs 9%), complex abnormal rates (8% vs 10%) and aneuploidy rates (19% vs 17%) were also similar. Three blastocysts were not identified and left out of the analysis. A 73.7% (70/95, 1 blastocyst not graded) of recovered in vivo embryos were of good quality as determined by the Gardner Scale of Morphology compared to 178 of controls. Conclusions Although a nascent technology, studies indicate that Uterine Lavage may have the potential to provide a new tool to acquire genetic information on in vivo conceived embryos. The procedure has the potential to provide a low cost, minimally invasive, reproducible and effective way to acquire in-vivo conceived embryos. Uterine Lavage provides an alternative option to IVF for fertile couples who want to be proactive in the health of their future children. It offers a platform for genetic testing (PGT-A) prior to the establishment of pregnancy as well as the diagnosis and identification of genetic indications. From a research perspective, the study of in-vivo conceived embryos when compared to IVF-derived embryos may provide new scientific insights into embryo science by characterizing any difference between embryos conceived within and outside the uterus.

Does exogenous gonadotropin stimulation increase the risk of aneuploidy for in vivo blastocysts? We performed 134 stimulated uterine lavage cycles to evaluate the safety and efficacy of a new lavage system (Previvo Genetics, Inc., San Carlos, CA). Patients gave their written informed consent. All lavages were performed in Punta Mita, Mexico from August 2017 to June 2018. Subjects were followed for 30-days post-lavage to monitor for complications. Following completion of this series, retrospective data analysis was performed. Subjects were pretreated with oral contraceptives and stimulated with gonadotropins. After ovulation was triggered, an intrauterine insemination (IUI) was performed 36 hours after trigger. Uterine lavage occurred 4-6 days after the insemination. Subjects had an endometrial biopsy and given GnRH antagonist after lavage to cause lysis of the corpora lutea. Recovered embryos underwent trophectoderm biopsy, vitrified and stored in liquid nitrogen. Biopsies were analyzed using Next Generation Sequencing (NGS). In 134 uterine lavage cycles, 46 (34%) resulted in recovery of one blastocyst. Mean age and BMI of the subgroup were 26 years and 24.2 kg/m2, respectively. Subjects were stimulated for an average of 9.4 days with a mean total gonadotropin dosage of 1789 IU, mean total hMG dose of 888 IU. At the time of trigger, subjects had a mean maximum E2 of 2613 pg/mL (range 394-6377 pg/mL) and 9.6 follicles 16mm. A total of 96 blastocysts were recovered and biopsied. After the initial biopsy, 37% (33/89) were euploid, 63% (56/89) aneuploid, and 7 blastocysts had no determination. Due to the high rate of aneuploidy, a second biopsy was performed in 64% (61/96) of the blastocysts (10 euploid, 48 aneuploid, 3 no determination). The second biopsy result was used to determine the euploid status of the blastocysts for this analysis resulting in a euploid rate of 53% (49/92), 47% (43/92) aneuploid, and 4 no determinations. In 8.2% (11/134) of the cycles, positive hCG was present 13 days after IUI. The hCG levels in all cycles resolved spontaneously, or after curettage with or without methotrexate. A logistical regression was performed to determine whether there was any correlation between covariates (days of stimulation, mean total gonadotropins, mean total hMG, mean maximum estradiol and follicles 16mm at trigger) and euploid status. No significant associations were found between any of the variables and euploid status. This study reinforces existing IVF data that imply gonadotropin stimulation is not associated with higher rates of aneuploidy but now performed in an in vivo data set. These findings support the continued use of stimulation in the process of uterine lavage. However, the sample size is small, and the lavage system is not fully optimized to recover all embryos.

Purpose: In this paper we describe a novel uterine lavage system for the recovery of in vivo preimplantation embryos. Currently, no other method exists to retrieve preimplantation embryos except for in vitro fertilization (IVF). Methods: A single center, prospective feasibility study was conducted to test a novel uterine lavage system for the recovery of in vivo preimplantation embryos in egg donors and patients seeking pregnancy. Subjects were placed on controlled ovarian hyperstimulation followed by intrauterine insemination (IUI) and uterine lavage performed approximately 4-6 days after IUI. Subjects were followed up for 30 days after the procedure to monitor for safety events. Results: A total of 134 uterine lavage cycles were performed on 81 subjects (average: 1.7 cycles/subject). Ova (oocytes or embryos) were collected in 53% (71/134) of the cycles with steady improvement of recovery efficiency over the course of the study, and embryos collected in 42% (56/134) of cycles. Embryos of many stages were collected, but 71% (96/136) of embryos collected were blastocyst stage embryos which are at the most advanced stage of embryogenesis. Embryos recovered were of good quality based on blastocyst gradings in which 74% (70/95, 1 blastocyst not graded) of the blastocysts were good quality as determined by the Gardner Scale of Morphology. The procedure was well tolerated with minor side effects. In 8% of cycles a positive hCG was observed after the lavage indicating some embryos were not recovered by the lavage system. Conclusion: Through this work the system has been shown to recover embryos from the uterus in a safe and effective manner, thus opening the possibility that uterine lavage may serve as an alternative to IVF where patient indications allow.

To report the chromosomal characterization of in vivo conceived embryos utilizing a FAST-SeqS NGS-based PGT-A assay Reported rates of euploidy per oocyte age differ amongst fertility programs. The most striking range reported, with a relatively homogenous group of oocyte donors, suggests that stimulation, culture conditions and manipulation may impact ploidy.1 IVF/PGT-A reduces the transfer of abnormal embryos but may be cost prohibitive even with minimal stimulation. A preliminary report demonstrated success with retrieving in vivo created embryos for PGT-A using a patented uterine lavage system2. In vivo culture would reduce the financial burden and the potential untoward effects of the in vitro environment. Twenty women underwent ovulation induction and donor insemination, with uterine lavage 5 days later, as previously described.2 The study had IRB approval and oversight by the Ministry of Health. TE biopsy was performed after lavage or following in vitro culture. Biopsies were analyzed using Invitae's FAST-SeqS NGS/bioinformatics pipeline which detects whole chromosome and segmental aneuploidies (≥10 MB). Whole genome uniparental isodisomy (WG-UPiD or haploidy), all forms of triploidy, and most single chromosome UPiD are also leveraged from SNP data.3-5 Thirty-five viable embryos were recovered from 15 patients. Five blasts were biopsied on day 5 and 13 biopsied on day 6 from 10 patients total. Mean egg age for the resulting biopsied embryos was 26 (range 21-30). In all (n=18), 12 embryos (67%) were euploid, 4 were aneuploid (22%) and 2 mosaic (5.7%). Of interest, all 5 embryos biopsied on day 5 were euploid regardless of grade; the day 6 aneuploidy rate was 46%.Tabled 1Study IDTotal # embryos at lavage (day 5)Day 5 Grade6 (Recovery)Day 6 Grade6 (24hr in vitro culture)Bx DayInterpretationMisc Result18646 cell frag3CC6Aneuploiddel(1)(q41)187114AA6AA6Normal4AA6AA6Normal9cell3CC6Normal4BA5BA6Normal6 cell vac3CC6AneuploidMonosomy 8192312 cell, vac4AB6Mosaictrisomy 22(mos)8 cell, vac2 (early)6Aneuploid53,X,+1,+2,+3,+8,+9,+17,+20,+2119743AB4AB6Normalmorula3CC6Mosaicdel(4)(q32) (mos)193110 cell, vac3CC6Normal18522 (early)6BB6AneuploidMonosomy 131964morula3CC6Normal2005AA5Normal6AA5Normal3CC5Normal20226CC5Normal19915BB5Normal Open table in a new tab In this small sample, the higher aneuploidy rate in day 6 biopsies was consistent with Invitae's previous report7. Additionally, the euploid rate for egg age (<= 30) and the mosaic rate are consistent with Invitae's internal data (68% and 5-7%, respectively). Uterine lavage is an effective alternative to IVF for the recovery of viable embryos for PGT-A. Additional studies are planned to confirm these findings.

Healthy female sexual functioning is driven by sexual desire. Sexual desire, traditionally defined as sexual thoughts and fantasies, is a natural life force and an art form affecting all aspects of a woman’s interpersonal and professional life. Virtually, all diagnostic categories of female sexual dysfunction, including arousal disorder, anorgasmia, and sexual pain disorder are linked to, caused by, or aggravated by loss of sexual desire. Decreased sexual desire is a diagnosis (hypoactive sexual desire disorder, HSDD) with its own International Classification of Diseases code (F52.0).. Impact is often subtle. HSDD may express as seemingly unrelated emotional disturbances that degrade life quality in family relationships, in the workplace, or both. For some women, it is severely distracting. The diagnosis of HSDD is made when symptoms are sufficient to cause distress. In older women, HSDD is heavily impacted by menopause-associated withdrawal of reproductive hormones, particularly testosterone and estradiol. HSDD greatly improves with transdermal replacement of these steroids. Side effects of transdermal hormones are minimal but response can be gratifying. In premenopausal women, HSDD behaves more as a psychoendocrine disorder that is responsive in some patients to flibanserin, a nonhormonal 5-HT1A receptor agonist. Side effects of flibanserin are significant but manageable. This review contains 12 figures, 6 tables, and references. Key Words: estradiol, flibanserin, hypoactive sexual desire disorder, menopause, selective serotonin reuptake inhibitors, sexual desire, sexuality, testosterone, transdermal, women

The purpose of this observational survey study is to assess genetic knowledge in reproductive-aged women and to determine the role played by their obstetricians in their education. A 31-item survey was distributed via an internet survey service to women between the ages of 18 and 45. The survey included subject demographics, a query regarding the source of subjects’ knowledge of genetics, and 6 question genetics quiz with 3 fundamental questions and 3 advanced questions. Subjects were divided into parous and nulliparous groups, and responses were compared using student’s t-test for continuous variables and chi square for proportions. Participants included 207 parous and 221 nulliparous women. There were no differences in demographic characteristics including age and education. Parous women scored significantly higher than nulliparous women on the fundamental genetics quiz (71 vs 61 %, p = 0.03). This difference remained but was no longer significant when the 3 advanced questions were included (48 vs 42 %). Only 39 % of parous and 8 % of nulliparous subjects listed their physician as one of their main sources of genetic information. 78 % of all subjects stated that they would prefer to receive genetic information from their physicians over other sources. Recently parous women scored higher on a genetics assessment quiz than did their nulliparous counterparts, but the majority did not cite their obstetrician gynecologists as a main source of information. As genetic counseling and testing are becoming increasingly important aspects of obstetrical care, obstetricians should play a more substantial role in educating their patients.

Surveillance is a triennial worldwide compendium of national rules and regulations for assisted reproductive technology. It was last published in 2010.

Develop a novel device for the safe recovery of in vivo human derived embryos by nonsurgical uterine lavage for pre-implantation genetic screening and diagnosis. Pre-Clinical Laboratory Test of New Medical Device. The Previvo catheter was fabricated by Previvo Genetics LLC, San Jose, CA and consists of a co-axial uterine catheter, a distal supply port attached to a supply line that is regulated by an electrical controller managing a consistent flow and withdrawal of lavage fluid. The Previvo catheter was tested using a series of experiments to verify its ability to recover blastocysts. (1) 350 lavages were conducted using a simulated silicon uterus to test variable settings on the catheter for optimal fluid dynamics to prevent fluid loss. The lavage cycle included fluid supplied and vacuumed in alternating pulse cycles of approximately 0.5 to 4.0 sec using low flow and vacuum conditions with a total volume of liquid of 100-300 ml per lavage cycle. (2) 24 uterine lavages were conducted in 12 extirpated human uteri to assess that the device will not cause harm to the uterine anatomy. After two lavage cycles, each uterus was bisected and inspected for mechanical damage. (3) 129 mouse blastocysts were placed in silicon uteri and lavages were performed to recover the blastocysts, which were then cultured and scored for cell divisions and morphology. 98% of lavage fluid was recovered from the silicon uterus models. (2) No visible tissue abrasion, pinching or puncture occurred after 2 lavage cycles in the extirpated uteri. (3) 96.7% of lavage-recovered mouse blastocysts were viable one day after the lavage cycle as indicated by ongoing cell divisions and morphological assessment. The Previvo catheter successfully recovers blastocysts non-surgically without damage to the embryos or uterus. These results indicate the device is ready for human trials for recovery of human embryos derived in vivo to afford the opportunity for pre-implantation genetic diagnosis without undergoing IVF.

Female sexual dysfunction, though reputedly intractable and difficult, can be managed very successfully if caregivers will ask their patients about it.

Female sexual dysfunctions (FSDs) range from short-term aggravations to major emotional disturbances adversely affecting family and workplace. This review highlights diagnosis and management of the four most widely diagnosed FSDs. It initially focuses on hypoactive sexual desire disorder (HSDD) as a driving force at the heart of all other FSDs; nothing happens without sexual desire. Successful resolution of HSDD frequently facilitates resolution of other disorders. Central to understanding HSDD is the impact of aging female sexual endocrinology and its effect on both prevalence and expression patterns of FSD. Advances in this field have enabled introduction of some the most effective treatments yet described for HSDD. Sexual arousal disorder, though commonly affected by the same factors as HSDD, is heavily associated with psychotropic drugs and mood elevators. Orgasmic disorder is frequently the downstream result of other sexual dysfunctions, particularly HSDD, or the result of a major psychosexual trauma. Successful management of the underlying disorder often resolves orgasmic disorder. Sexual pain disorder is frequently the result of a gynecologic disorder, such as endometriosis, that can be substantially managed through successful treatment of that disorder. This article ends with the article's most important note: how to initiate the conversation.

To determine if phthalates and bisphenol A accumulate in human follicular fluid after brief exposure to medical plastics during an IVF cycleProspective collection of follicular fluid from five infertile women undergoing oocyte retrieval at a University IVF laboratory and analysis of Phthalate & Bisphenol A levels.All phthalate levels were detected at levels less than 15 ng/mL and Bisphenol A levels were undetectable in all five samples. The concentrations of phthalates are 200-1000 fold less than the minimum levels reported to cause reproductive toxicity in vitro to cumulus-oocyte complexes of laboratory animals.In reproductive age women undergoing infertility treatments there is little transfer or accumulation of phthalates, phthalate metabolites or bisphenol A into the microenvironment of the human preovulatory oocyte and the levels are not clinically significant. Further investigation of phthalate and bisphenol A accumulation in vivo in human follicular fluid may not be productive.

OBJECTIVE:To report for the first time a case of postmenopausal endometrial hyperplasia caused by nonclassic 21-hydroxylase deficiency (NC21OHD). The specific combination of mutations associated with this case has never before been reported. DESIGN:Case report. SETTING:Private academic practice. PATIENT(S):A 67-year-old woman with uterine bleeding due to endometrial hyperplasia was found to have premenopausal gonadotropins with elevated estrogens. Endocrine workup revealed increased 17-hydroxyprogesterone (17-OHP), which led to molecular testing to establish a diagnosis of NC21OHD. INTERVENTION(S):Trial of suppression with low-dose oral dexamethasone. MAIN OUTCOME MEASURE(S):Resolution of postmenopausal bleeding. RESULT(S):Total estrogens normalized with treatment, and the endometrial stripe became normal. CONCLUSION(S):This is an unusual case of NC21OHD in which the sole presentation was persistent endometrial hyperplasia, with bleeding past the normal age for menopause. In women with unusual endometrial hyperplasias of this type, we suggest endocrine testing before proceeding to hysterectomy.

Hypoactive sexual desire disorder (HSDD) is the most common female sexual dysfunction (FSD) and is thus frequently encountered in the primary care provider and OB/GYN practices. Causes of low sexual desire may be hormonal, neurologic, vascular, psychologic, or a result of illness/surgery or medications. The condition is often left untreated because both women and clinicians feel embarrassed to bring up the topic and believe that there is no available treatment. The use of short, validated questionnaires, such as the Decreased Sexual Desire Screener, to be completed in the waiting room, can open up discussion between provider and patient. In addition, 2 other algorithms are designed for clinicians who are not specifically trained in FSD and can help in diagnosing and managing a broad range of conditions related to FSD. Treatment for low desire consists primarily of patient education and counseling, as well as treatment of underlying comorbid conditions, such as diabetes, obesity, or cancer. While testosterone products are approved in Europe for use in surgically postmenopausal women with HSDD, in the United States, no pharmacologic treatments are approved for the treatment of HSDD or any FSD. Testosterone products are being used off-label, but questions remain about their efficacy and safety in pre- and postmenopausal women. This article gives an overview of HSDD in clinical practice and provides 3 case descriptions to illustrate the treatment of low sexual desire in women with diverse histories.