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Follicle-stimulating hormone (and luteinizing hormone) in ovarian stimulation: Does the dose matter for cycle success?

Kuokkanen, Satu; Pal, Lubna
In this review, we have summarized the evolution in our understanding of a relevance of gonadotropin dosing for cycle outcomes in women attempting to conceive through the utilization of the in vitro fertilization technology.
PMID: 36529184
ISSN: 1556-5653
CID: 5418882

RACIAL DISPARITIES IN OUTCOMES OF PREGNANCIES RESULTING FROM PGT-A SINGLE BLASTOCYST TRANSF [Meeting Abstract]

Pal, L; Akerman, M; Kuokkanen, S
Objective: To examine if pregnancy outcomes following transfer of thawed single genetically tested (PGT-A) blastocysts differ by race & ethnicity.
Material(s) and Method(s): SARS CORS data on autologous single embryo transfer (ET) PGT-A cycles were analyzed. Recurrent pregnancy loss, gestational carrier, donor egg & donor ET cycles were excluded. Racial categories available in SART CORS are: White (W), Black (B), Asian (As), Pacific Islander (PI) & Unknown (Unk). Ethnic categories are Hispanic (H) & non-Hispanic (nH). SART specified pregnancy outcomes include preterm birth (PTB), stillbirth (SB), ectopic pregnancy (EP) & live birth (LB). Term birth (TB, birth at gestation >=37 weeks), early loss (EL, loss at gestation<13 weeks) & late loss (LL, loss between>=13 and <20 weeks) were computed. Multivariable analysis examined relationship between race & ethnicity with specified outcomes, after adjusting for age, BMI, smoking, endometrial thickness (mm), infertility diagnoses of uterine & tubal factor & AMH (linked with fresh cycle).
Result(s): Of the 79,416 FET single ET cycles meeting eligibility criteria, racial & ethnic representations were: W: 35, 654 (45%), B: 2,255 (2.8%), As: 10.015 (12.6%), PI: 115 (0.14%), Unk (31,378 (39.5%), H: 3,168 (4.0%). Outcomes of pregnancies resulting from single genetically tested ET were significantly compromised in women of non-W race & of H ethnicity compared to W & non-H women (Table). EP & EL were unrelated to race or ethnicity (p>0.05). [Formula presented]
Conclusion(s): Concerning racial & ethnic differentials in pregnancy outcomes of IVF PGT-A cycles utilizing transfer of single thawed blastocysts were noted. Impact Statement: Among women of color achieving pregnancy following transfer of genetically tested single embryos in the US, Black women are at a disproportionately higher risk for concerning obstetric outcomes including late PL, PTB & SB. Systemic racism as underpinning to the observed associations is a plausible consideration that merits attentiveness. Support: None
Copyright
EMBASE:2020860510
ISSN: 1556-5653
CID: 5367012

PREGNANCY OUTCOMES OF SINGLE PGT-A (PREIMPLANTATION GENETIC TESTING FOR ANEUPLOIDY) TESTED FROZEN EMBRYO TRANSFER CYCLES IN WOMEN WITH PC [Meeting Abstract]

Kuokkanen, S; Akerman, M; Pal, L
Objective: To determine pregnancy outcomes in women with PCOS compared to those with other infertility diagnoses following frozen-thawed embryo transfer (FET) of a single preimplantation genetically tested (PGT-A) blastocyst.
Material(s) and Method(s): Retrospective cohort analysis of the SART CORS database 2016-2018. Autologous single embryo transfer cycles of PGT-A tested blastocysts were included. Exclusion criteria were recurrent pregnancy loss, gestational carrier and cycles using donor oocytes or embryos. We examined pregnancy outcomes in women with PCOS compared to those without PCOS diagnosis for the SART specified outcomes: biochemical pregnancy (BP), pregnancy loss (PL, loss at 5 to <20 weeks), preterm birth (PTB), stillbirth (SB), ectopic pregnancy (EP) and live birth (LB). Term birth (TB) was defined as live birth at >=37 weeks. Univariate and multivariable analysis were performed using STATA V13.0. Covariates adjusted for included age, BMI, race/ethnicity, smoking, endometrial thickness, uterine factor and AMH. The data are presented as odds ratios (OR) and 95% CI.
Result(s): 79,416 FET cycles of single PGT-A tested embryos met eligibility criteria, of these 12,230 (15%) were in women with PCOS. Compared to the other infertility diagnoses, the diagnosis of PCOS was significantly associated with greater likelihood of BP, PL and PTL, and lower likelihood of LB (Table). The outcomes of SB and EP were unrelated to the PCOS diagnosis.
Conclusion(s): We found that compared to other infertility etiologies, the diagnosis of PCOS is associated with adverse outcomes in pregnancies following transfer of a single PGT-A tested blastocyst. Our results suggest that other factors than embryo aneuploidy are contributors to attenuated pregnancy success in women with PCOS. Impact Statement: In women with PCOS, pregnancy outcomes are compromised following transfer of a single genetically tested embryo. Intensified pregnancy surveillance may be warranted in women with PCOS. The future research needs to confirm the observed adverse pregnancy outcomes in women with PCOS and explore the underlying mechanisms. [Formula presented] Support: None.
Copyright
EMBASE:2020861270
ISSN: 1556-5653
CID: 5367252

The selective progesterone receptor modulator, telapristone acetate, is a mixed antagonist/agonist in the human and mouse endometrium and inhibits pregnancy in mice

McAvey, Beth; Kuokkanen, Satu; Zhu, Liyin; Pollard, Jeffrey W
OBJECTIVE:To investigate the effect of the selective progesterone receptor modulator, telapristone acetate (CDB-4124), on endometrial biology and reproductive outcomes. Ovariectomized and hormone-treated CD1 female mice, CD1 female mice with xenotransplants of reconstructed human endometrial tissue, mated wildtype female mice, and cultured human endometrial stromal cells (hESCs) were treated with CDB-4124, followed by the assessment of endometrial cell deoxyribonucleic acid (DNA) proliferation, stromal decidual response, and embryo implantation. DESIGN:Experimental study. SETTING:Academic research laboratory. PATIENTS:Healthy volunteer women from the community were recruited for endometrial biopsies. ANIMALS:CD1 out-bred mice (Charles River Laboratories) and nude mice, NU/J (Jackson Laboratories, Bar Harbor, ME). INTERVENTION:Treatment of mice and hESCs with CDB-4124. MAIN OUTCOME MEASURE:The effect of CDB-4124 on endometrial cell morphology and DNA synthesis, decidual response, and mouse embryo implantation. RESULTS:CDB-4124 inhibited estradiol-induced epithelial DNA synthesis in the mouse uterus and xenotransplanted human endometrium. This antiproliferative effect was less than that of progesterone (P4) and was observed when CDB-4124 was administered alone or concomitantly with P4. In the uterine epithelium, CDB-4124 acted as a P4 agonist and partial antagonist. In contrast, CDB-4124 acted as a complete P4 antagonist in the uterine stroma, where it blocked P4's action to induce a decidual response in the pseudopregnant mouse uterus and wildtype mouse uterus after copulation. In mated female mice, CDB-4124 impaired embryo implantation. Similarly, CDB-4124 inhibited the morphological and biochemical transformations of hESCs to decidual cells in vitro. CONCLUSION:CDB-4124 exerts mixed P4 antagonistic/agonistic effects in the human and mouse endometrium, which result in failed embryo implantation because of the absence of stromal decidualization.
PMID: 35559765
ISSN: 2666-335x
CID: 5247622

Xenografted tissue models for the study of human endometrial biology

Kuokkanen, Satu; Zhu, Liyin; Pollard, Jeffrey W
The human endometrium undergoes extensive morphological, biochemical and molecular changes under the influence of female sex steroid hormones. Besides the fact that estrogen stimulates endometrial cell proliferation and progesterone inhibits this proliferation and induces differentiation, there is limited knowledge about precise molecular mechanisms underlying human endometrial biology. The importance of paracrine signaling in endometrial physiology explains why in vitro culture of endometrial cells has been challenging. Researchers, therefore, have developed alternative experimental in vivo models for the study of endometrial biology. The objective of this review is to summarize the recent developments and work on these in vivo endometrial research models. The in vivo recombinant tissue models in which wild-type endometrial cells are combined with endometrial cells from a gene-targeted mouse strain followed by xenografting to host mice have been critical in confirming the significance of paracrine signaling between the epithelium and stroma in the growth regulation of the endometrium. Additionally, these studies have uncovered differences between the mouse and human, emphasizing the need for the development of experimental models specifically of the human endometrium. Recently, xenotransplants of human endometrial fragments into the subcutaneous space of host mice and endometrial xenografts of dissociated and recombined epithelial and stromal cells beneath the kidney capsule of immunodeficient host mice have proven to be highly promising tools for in vivo research of endometrial functions. For the first time, the latter approach provides an immense opportunity for the application of genome engineering, such as targeted ablation of endometrial genes for example by using CRISPR/CAS9 system. This research will begin to elucidate the functional role of specific genes in this complex tissue. Another advantage of xenotransplantation and xenograft models of the human endometrium is their use to investigate endometrial effects of new compounds and drugs without needing to give them to women. Underpinning the molecular mechanisms underlying endometrial functions is critical to ultimately advance our understanding of endometrial pathophysiology and develop targeted therapies to prevent and cure endometrial pathologies as well as enhance endometrial function when it is desired for fertility.
PMCID:5726894
PMID: 29156254
ISSN: 1432-0436
CID: 3646212

Thin endometrium after radiation therapy as an unresolved treatment challenge: a case report [Case Report]

Kudesia, Rashmi; Kuokkanen, Satu
Receptive endometrium is essential for successful implantation and ongoing pregnancy. Significant health issues and associated therapies, especially oncologic therapies, have potential to negatively impact future fertility in young women. Irradiation and chemotherapeutic alkylating agents are known to cause ovarian failure in most females; however, less well is characterized the impact of irradiation on uterine development and integrity. With an increasing number of cancer survivors, women are seeking infertility treatment after such therapies. Here, we present a young woman who developed ovarian failure after the treatment of acute myeloid leukemia with bone marrow transplant and preceding irradiation and chemotherapy and who was diagnosed with thin endometrial lining while seeking infertility therapy.
PMID: 27129096
ISSN: 1473-0766
CID: 3646192

Corpus luteum as a novel target of weight changes that contribute to impaired female reproductive physiology and function

Kuokkanen, Satu; Polotsky, Alex J; Chosich, Justin; Bradford, Andrew P; Jasinska, Anna; Phang, Tzu; Santoro, Nanette; Appt, Susan E
UNLABELLED:Obesity and malnutrition are associated with decreased fecundity in women. Impaired reproductive capacity in obese women is often attributed to anovulation. However, obese women with ovulatory cycles also have reduced fertility, but the etiology of their impaired reproduction is only partially understood. Accumulating evidence suggests that obesity directly impairs oocyte and embryo quality as well as endometrial receptivity. In obese women, urinary progesterone metabolite excretion is decreased, but in excess of what can be explained by suppressed gonadotropin secretion, suggesting that apart from its central effect obesity may directly affect progesterone (P4) production. These observations have led to the novel hypothesis that obesity directly affects corpus luteum (CL) function. Similarly, we hypothesize that weight loss may contribute to luteal dysfunction. Here, we propose a non-human primate model, the vervet monkey, to examine the effect of weight gain and loss on menstrual cycle parameters and CL gene expression. In this model, weight gain and loss did not significantly alter menstrual cyclicity; however, both induced alterations in the CL transcriptome. In the weight gain monkey, we observed that impaired mid-luteal P4 secretion was associated with downregulation of steroidogenic pathways in CL. Collectively, these preliminary findings support our hypothesis that weight gain and loss may contribute to CL dysfunction. The vervet model described and preliminary observations provide a basis for a larger study to address this important question. Understanding the mechanisms by which weight gain and loss contribute to reproductive dysfunction can assist in the development of targeted treatments to enhance women's reproductive capability when it is desired. ABBREVIATIONS/BACKGROUND:CL: corpus luteum; P4: progesterone; E2: estradiol; PDG: pregnanediol 3-glucoronide; LH: luteinizing hormone; FSH: follicle-stimulating hormone; GnRH: gonadotropin releasing hormone; BMI: body mass index; qrtPCR: quantitative real-time PCR; PGR: progesterone receptor; ART: assisted reproductive technology; IVF: in vitro fertilization; HPO: hypothalamic-pituitary-ovarian axis; MMPs: matrix metalloproteinases Gene symbols: LH receptor (LHGCR); cholesterol side-chain cleavage enzyme (CYP11A1); 3 beta-hydroxysteroid dehydrogenase type II (HSD3B2); steroidogenic acute regulatory protein (STAR); LDL receptor (LDLR); scavenger receptor B1 (SCARB1); ATP-binding cassette sub-family A member 1 (ABCA1); ATP-binding cassette sub-family G member 1 (ABCG1); apolipoprotein A (APOA1); 24 dehydrocholesterol reductase (DHCR24); 3-hydroxy-3-methylglytaryl-CoA reductase (HMGCR); vascular endothelial growth factor A (VEGFA); vascular endothelial growth factor C (VEGFC); vascular endothelial growth factor receptor 1 (VEGFR1); and TIMP metallopeptidase inhibitor 1 (TIMP1); amphiregulin (AREG); epiregulin (EREG); CCAAT/enhancer binding protein alpha (CEBPBA); cAMP responsive element binding protein 3-like 1 (CREB3L1); ADAM metallopeptidase with thrombospodin type 1 motif 1 (ADAMTS1); matrix metallopeptidase 9 (MMP9); cytochrome b-245 beta polypeptide (CYBB or NOX2); NADH oxidase (NCF2 or NOXA2); Fc fragment of IgG receptor IIb (FCGR2B); Fc fragment of IgG receptor IIb (FCGR2C); ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1); RAB27A member RAS oncofamily (RAB27A); hydroxyprostaglandin dehydrogenase (HPGD); prostaglandin-endoperoxidase synthase 1 (PTGS1); integrin B2 (ITGB2); leukotriene A4 hydrolase (LTA4H); radixin (RDX); ezrin (EZR); nuclear receptor subfamily 5 group A member 2 (NR5A2).
PMCID:4996623
PMID: 27187064
ISSN: 1939-6376
CID: 3646202

Mir-204-5p Regulates ROR2 (Thyrosine-Protein Kinase Transmembrane Receptor) and Other Genes Involved in the Functions of the Human Endometrial Epithelium. [Meeting Abstract]

Kuokkanen, Satu; Pollard, Jeffrey W.
ISI:000372879200922
ISSN: 1933-7191
CID: 3646272

Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17β is mediated by a PKC-ERK1/2-mTOR signaling pathway

Wang, Yuxiang; Zhu, Liyin; Kuokkanen, Satu; Pollard, Jeffrey W
The uterine epithelium of mice and humans undergoes cyclical waves of cell proliferation and differentiation under the regulation of estradiol-17β (E2) and progesterone (P4). These epithelial cells respond to E2 with increased protein and DNA synthesis, whereas P4 inhibits only the E2-induced DNA synthetic response. Here we show that E2 regulates protein synthesis in these epithelial cells through activating PKC that in turn stimulates ERK1/2 to phosphorylate and thereby activate the central regulator of protein synthesis mechanistic target of rapamycin (mTOR). This mTOR pathway is not inhibited by P4. Inhibitor studies with an estrogen receptor (ESR1) antagonist showed the dependence of this mTOR pathway on ESR1 but that once activated, a phosphorylation cascade independent of ESR1 propagates the pathway. E2 also stimulates an IGF1 receptor (IGF1R) to PI3 kinase to AKT to GSK-3β pathway required for activation of the canonical cell cycle machinery that is inhibited by P4. PKC activation did not stimulate this pathway nor does inhibition of PKC or ERK1/2 affect it. These studies therefore indicate a mechanism whereby DNA and protein synthesis are regulated by two ESR1-activated pathways that run in parallel with only the one responsible for the initiation of DNA synthesis blocked by P4. Inhibition of mTOR by rapamycin in vivo resulted in inhibition of E2-induced protein and DNA synthesis. Proliferative diseases of the endometrium such as endometriosis and cancer are common and E2 dependent. Thus, defining this mTOR pathway suggests that local (intrauterine or peritoneal) rapamycin administration might be a therapeutic option for these diseases.
PMCID:4371960
PMID: 25733860
ISSN: 1091-6490
CID: 3646172

Joint MiRNA/mRNA expression profiling reveals changes consistent with development of dysfunctional corpus luteum after weight gain

Bradford, Andrew P; Jones, Kenneth; Kechris, Katerina; Chosich, Justin; Montague, Michael; Warren, Wesley C; May, Margaret C; Al-Safi, Zain; Kuokkanen, Satu; Appt, Susan E; Polotsky, Alex J
Obese women exhibit decreased fertility, high miscarriage rates and dysfunctional corpus luteum (CL), but molecular mechanisms are poorly defined. We hypothesized that weight gain induces alterations in CL gene expression. RNA sequencing was used to identify changes in the CL transcriptome in the vervet monkey (Chlorocebus aethiops) during weight gain. 10 months of high-fat, high-fructose diet (HFHF) resulted in a 20% weight gain for HFHF animals vs. 2% for controls (p = 0.03) and a 66% increase in percent fat mass for HFHF group. Ovulation was confirmed at baseline and after intervention in all animals. CL were collected on luteal day 7-9 based on follicular phase estradiol peak. 432 mRNAs and 9 miRNAs were differentially expressed in response to HFHF diet. Specifically, miR-28, miR-26, and let-7b previously shown to inhibit sex steroid production in human granulosa cells, were up-regulated. Using integrated miRNA and gene expression analysis, we demonstrated changes in 52 coordinately regulated mRNA targets corresponding to opposite changes in miRNA. Specifically, 2 targets of miR-28 and 10 targets of miR-26 were down-regulated, including genes linked to follicular development, steroidogenesis, granulosa cell proliferation and survival. To the best of our knowledge, this is the first report of dietary-induced responses of the ovulating ovary to developing adiposity. The observed HFHF diet-induced changes were consistent with development of a dysfunctional CL and provide new mechanistic insights for decreased sex steroid production characteristic of obese women. MiRNAs may represent novel biomarkers of obesity-related subfertility and potential new avenues for therapeutic intervention.
PMCID:4530955
PMID: 26258540
ISSN: 1932-6203
CID: 3646182