The Impact of Mmu17 Non-Hsa21 Orthologous Genes in the Ts65Dn Mouse Model of Down Syndrome: The Gold Standard Refuted.

BACKGROUND: Despite successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome, translation to humans has failed. This raises questions about the appropriateness of the Ts65Dn mouse as the gold standard. We used the novel Ts66Yah mouse that carries an extra chromosome and the identical segmental Mmu16 trisomy as Ts65Dn without the Mmu17 non-Hsa21 orthologous region. METHODS: Forebrains from embryonic day 18.5 Ts66Yah and Ts65Dn mice, along with euploid littermate controls, were used for gene expression and pathway analyses. Behavioral experiments were performed in neonatal and adult mice. Because male Ts66Yah mice are fertile, parent-of-origin transmission of the extra chromosome was studied. RESULTS: Forty-five protein-coding genes mapped to the Ts65Dn Mmu17 non-Hsa21 orthologous region; 71%-82% are expressed during forebrain development. Several of these genes are uniquely overexpressed in Ts65Dn embryonic forebrain, producing major differences in dysregulated genes and pathways. Despite these differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in commonly dysregulated disomic genes and pathways. Delays in motor development, communication, and olfactory spatial memory were present in Ts66Yah but more pronounced in Ts65Dn neonates. Adult Ts66Yah mice showed milder working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved. CONCLUSIONS: Our findings suggest that triplication of the non-Hsa21 orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may explain why preclinical trials that used this model have unsuccessfully translated to human therapies.

Clarifying the relationship between total motile sperm counts and intrauterine insemination pregnancy rates.

OBJECTIVE: To study the relationship between postwash total motile sperm count (TMSC) and intrauterine insemination (IUI) outcomes. DESIGN: Retrospective review SETTING: Large fertility clinic PATIENT(S): A total of 92,471 insemination cycles from 37,553 patients were included in this study. INTERVENTION(S): All stimulated clomiphene citrate, letrozole, and/or injectable gonadotropin IUI cycles performed at a single institution from 2002 through 2018 were reviewed. Generalized estimating equations (GEE) analysis was used to account for multiple cycles by individual patients and to adjust for female partner age, body mass index, and stimulation protocol. MAIN OUTCOME MEASURE(S): Successful clinical pregnancy was defined as ultrasound confirmation of an intrauterine gestational sac with fetal cardiac activity. RESULT(S): A total of 92,471 insemination cycles were available to evaluate the relationship between postwash TMSC and clinical pregnancy. Pregnancy rates were highest with TMSC of ≥9 × 106 and declined gradually as TMSC decreased. Complete data for the adjusted GEE analysis were available for 62,758 cycles. Adjusted GEE analysis among cycles with TMSC of ≥9 × 106 (n = 46,557) confirmed that TMSC in this range was unrelated to pregnancy. Conversely, TMSC was highly predictive of pregnancy (Wald χ2 = 39.85) in adjusted GEE analysis among cycles with TMSC of <9 × 106 (n = 16,201), with a statistically significant decline. CONCLUSIONS: IUI pregnancy is optimized with TMSC of ≥9 × 106, below which the rates gradually decline. Although rare, pregnancies were achieved with TMSC of <0.25 × 106. Since the decline in pregnancy is gradual and continuous, there is no specific threshold above which IUI should be recommended. Rather, these more specific quantitative predictions can be used to provide personalized counseling and guide clinical decision making.

Endometriosis does not impact live-birth rates in frozen embryo transfers of euploid blastocysts.

OBJECTIVE: To determine whether subfertility in patients with endometriosis is due to impaired endometrial receptivity by comparing pregnancy and live-birth outcomes in women with endometriosis versus two control groups without suspected endometrial factors: noninfertile patients who underwent assisted reproduction to test embryos for a single-gene disorder and couples with isolated male factor infertility. DESIGN: Retrospective cohort. SETTING: Multicenter private practice. PATIENT(S): All patients aged 24 to 44 years undergoing euploid frozen blastocysts transfer from January 2016 through March 2018. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth, clinical pregnancies, pregnancy losses, and aneuploid rates in preimplantation genetic testing for aneuploidy cycles. RESULT(S): The analysis included 459 euploid frozen embryo transfer cycles among 328 unique patients. There were no differences in clinical pregnancy, pregnancy loss, or live-birth rates in patients with endometriosis compared with both control groups. The aneuploidy rates were lowest in the preimplantation genetic testing for monogenic disorders cohort, and the endometriosis patients had aneuploidy rates similar to those of the male factor infertility patients. CONCLUSION(S): It is unclear whether endometriosis primarily affects in vitro fertilization outcomes via oocyte quality or the endometrium. By controlling for embryo quality using euploid frozen embryo transfer cycles, we found no difference in pregnancy outcomes in patients with endometriosis compared with patients undergoing treatment for male factor infertility and noninfertile patients.

Forty years of IVF.

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field.

Diminished ovarian reserve as measured by means of baseline follicle-stimulating hormone and antral follicle count is not associated with pregnancy loss in younger in vitro fertilization patients.

OBJECTIVE: To assess the relationship between diminished ovarian reserve and pregnancy outcomes in a large cohort of women achieving pregnancy through in vitro fertilization (IVF). We evaluated antral follicle count (AFC) and baseline FSH as a measure of ovarian reserve. Secondarily, we assessed whether diminished ovarian reserve was associated with aneuploidy among spontaneous abortions. DESIGN: Retrospective cohort study. SETTING: Multicenter private practice. PATIENT(S): All patients aged 21-44 years undergoing fresh autologous IVF cycles during 2009-2013 that resulted in positive serum hCG with recorded baseline FSH levels. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live births per early pregnancy, biochemical pregnancies, clinical pregnancy losses, and aneuploidy rates in products of conception among pregnancy losses. RESULT(S): A total of 9,489 cycles among 8,214 patients were analyzed. There was no association between live birth and ovarian reserve among pregnant IVF patients under the age of 35 years. Among patients 35 years of age and older, elevated baseline FSH was associated with a higher risk of pregnancy loss, which increased with increasing age. AFC was not significantly associated with pregnancy loss at any age. No associations were found between ovarian reserve measures and aneuploidy in products of conception in age-adjusted analyses, although the power to effectively evaluate this was limited. CONCLUSION(S): Diminished ovarian reserve is not associated with an increase in miscarriage among younger women achieving pregnancy through IVF. Elevated FSH is associated with a higher risk of IVF pregnancy loss among older patients. We found no evidence to confirm that diminished ovarian reserve is associated with increased aneuploidy among spontaneous abortions.

Management of Chronic Pelvic Pain.

The management of chronic pelvic pain poses a significant challenge to both physicians and patients. Patients should be evaluated for both gynecologic and nongynecologic conditions, and >1 source may be identified. Treatment involves medical as well as surgical options, and it is important to set realistic goals with patients. Treatment may not be curative, but should improve the patient's quality of life.

A case of recurrent hyperreactio luteinalis in three spontaneous pregnancies.

Hyperreactio luteinalis is a rare condition in pregnancy characterized by enlarged ovaries with multiple theca luteal cysts, and recurrence of disease has seldom been documented in the literature. This is a case report of a woman who developed recurrent hyperreactio luteinalis with three spontaneous pregnancies. Endocrine evaluation was performed and revealed hyperandrogenism. Ultrasonography was used to assess the ovaries throughout each pregnancy. The ovarian cysts required drainage in the first pregnancy due to severe distention and shortness of breath. Cyst resolution occurred in the post-partum period following each pregnancy. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:502-505, 2016.