Thyroid Autoimmunity Is Not Associated with Embryo Quality or Pregnancy Outcomes in Euthyroid Women Undergoing Assisted Reproductive Technology in China.

Background: Studies have shown that thyroid autoimmunity (TAI) is associated with increased risks of adverse pregnancy outcomes. The aim of this study was to investigate the associations between TAI and embryo quality in euthyroid women undergoing in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI). Methods: This retrospective cohort study included euthyroid infertile women with and without TAI (defined as a serum thyroperoxidase concentration ≥34 IU/mL or a thyroglobulin concentration ≥115.0 IU/mL) who underwent their first complete IVF/ICSI treatment cycles at a tertiary referral center between April 2016 and February 2022. Embryo quality measurements and clinical outcomes were compared between women with (TAI positive) and without TAI (TAI negative). The high-quality cleavage embryo rate and cumulative live birth rate (cLBR) were the primary outcomes. Results: A total of 499 TAI-positive and 2945 TAI-negative women were included in this study, and their mean (standard deviation) ages were 31.6 (4.5) and 30.9 (4.4) years, respectively (p = 0.001). The overall analysis showed no significant differences between TAI-negative and TAI-positive women in the high-quality cleavage embryo rate (n/N: 11,139/22,553 vs. 1971/3820; adjusted rate: 52.8% vs. 53.4%, p = 0.66) and cLBR (1917/2945 vs. 327/499; 53.4% vs. 56.2%, p = 0.31). Moreover, no significant differences were observed between TAI-negative and TAI-positive women in the rates of oocyte retrieval (35,078/51,978 vs. 5853/8628; 69.1% vs. 69.4%; p = 0.65), fertilization (23,067/34,197 vs. 3902/5728; 61.1% vs. 62.2%, p = 0.34), embryo utilization (18,233/22,553 vs. 3156/3820; 80.2% vs. 80.8%, p = 0.61), blastocyst formation (7051/13,721 vs. 1192/2330; 48.5% vs. 48.4%, p = 0.97), and high-quality blastocysts (4819/13,721 vs. 799/2330; 29.9% vs. 29.4%, p = 0.73). Furthermore, no significant differences were observed between TAI-negative and TAI-positive women in the clinical pregnancy rate (1524/2808 vs. 248/482; 46.7% vs. 44.6%, p = 0.40), early pregnancy loss rate (156/1524 vs. 23/248; 13.5% vs. 11.5%, p = 0.44), and LBR (1338/2808 vs. 218/482; 37.4% vs. 36.0%, p = 0.55) of the first transfer cycle. Conclusions: This study demonstrated that TAI in women was not associated with embryo quality or the cLBR following IVF/ICSI. Future large studies are warranted to confirm these findings.

Subclinical Hypothyroidism and Sperm DNA Fragmentation: A Cross-sectional Study of 5401 Men Seeking Infertility Care.

CONTEXT: Our previous study showed that paternal subclinical hypothyroidism (SCH) had a detrimental effect on the clinical outcomes of assisted reproductive technologies. However, it remains to be determined whether paternal SCH affects sperm DNA integrity. OBJECTIVE: To investigate the association between SCH and sperm DNA fragmentation in men seeking infertility care. METHODS: This cross-sectional study included 4983 men with euthyroidism and 418 men with SCH seeking infertility treatment in a tertiary care academic medical center between January 2017 and December 2021. The outcome measures were the absolute DNA fragmentation index (DFI) and the risk of abnormal DFI (defined as DFI ≥ 25% or ≥ 30%). RESULTS: The mean (SD) age of men with euthyroidism and men with SCH was 34.20 (5.97) and 35.35 (6.48) years, respectively (P < 0.001). The difference in DFI was not statistically significant (adjusted mean: 19.7% vs 18.9% in the SCH and euthyroidism groups, respectively; P = 0.07) after confounder adjustment. A DFI ≥25% was significantly more frequent in men with SCH (20.57%) than in men with euthyroidism (14.49%) after confounder adjustment [odds ratio (OR) 1.43 (95% CI 1.09-1.88)]. DFI ≥ 30% was also significantly more common in men with SCH (11.72%) than in men with euthyroidism [6.74%; OR 1.84 (95% CI 1.34-2.52)]. In addition, thyroid-stimulating hormone concentration was significantly associated with an increased risk of having a DFI ≥25% (P < 0.001) or ≥30% (P = 0.011). CONCLUSION: SCH was significantly associated with an increased risk of an abnormal DFI.

Paternal Subclinical Hypothyroidism Affects the Clinical Outcomes of In Vitro Fertilization/Intracytoplasmic Sperm Injection.

Background: Maternal subclinical hypothyroidism (SCH) is a risk factor for adverse pregnancy outcomes. However, it is still unclear whether SCH affects male fertility. The aim of this study was to determine the association between paternal SCH and clinical outcomes after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Methods: This retrospective study included 2511 couples with paternal euthyroidism (n = 2282) or SCH (n = 229) who visited our clinic for infertility treatment between April 1, 2017, and September 30, 2019. The primary outcomes were the fertilization rate and clinical pregnancy rate; the secondary outcomes were the good-quality embryo rate, blastocyst formation rate, implantation rate, and early miscarriage rate. These outcomes were compared between the euthyroid and the SCH groups after adjusting for various potential confounders. Results: The mean paternal ages in the euthyroid and SCH groups were 34.5 and 36.0 years, respectively (p = 0.002). Semen parameters and sperm DNA fragmentation index were similar between the two groups (all p > 0.05). The adjusted fertilization (0.69 vs. 0.71, p = 0.30), good-quality embryo (0.49 vs. 0.52, p = 0.31), blastocyst formation (0.51 vs. 0.53, p = 0.57), and early miscarriage (0.11 vs. 0.10, p = 0.81) rates were also similar between the two groups. There was a significantly decreased adjusted clinical pregnancy rate [confidence interval, CI] and implantation rate [CI] in the paternal SCH group compared with the euthyroid group (0.32 [0.26-0.40] vs. 0.42 [0.40-0.45], p = 0.009 for the clinical pregnancy rate; 0.24 [0.19-0.29] vs. 0.29 [0.27-0.31], p = 0.037 for the implantation rate). Stratified analysis indicated that these differences were only significant in men aged ≥35 years (p = 0.009 and 0.022, respectively) and not in men <35 years (p = 0.39 and 0.45, respectively). Conclusions: Paternal SCH was associated with worse clinical outcomes after IVF/ICSI, whereas this detrimental impact was only present in males ≥35 years old. Prospective studies and basic research are warranted to confirm these results and to clarify the mechanisms underlying these associations, respectively.

Subclinical Hypothyroidism Is Associated with Lower Ovarian Reserve in Women Aged 35 Years or Older.

Background: Overt thyroid diseases have been identified as risk factors for female infertility. However, it remains largely unclear whether subclinical hypothyroidism (SCH), a very common thyroid disorder, is associated with female infertility. This study aimed to investigate the potential association between SCH and the ovarian reserve in women seeking infertility treatment. Methods: This retrospective study included 2568 women with normal thyroid function (n = 2279) or SCH (n = 289) who visited our clinic for infertility treatment. Ovarian reserve markers, including follicle-stimulating hormone (FSH) concentrations on days 2-4, the antral follicle count (AFC), and anti-Müllerian hormone (AMH) concentration, were compared between euthyroid women and those with SCH. Multiple linear and Poisson regression analyses were used to estimate the associations of SCH with ovarian reserve markers. These analyses were repeated separately in women aged <35 (n = 1349) and ≥35 years (n = 1219). Results: In the total study population, women with SCH had significantly lower AMH concentrations (median: 2.05 vs. 2.51 ng/mL, p = 0.015) and AFCs (median: 10.0 vs. 11.0, p = 0.013), compared with euthyroid women. In linear and Poisson regression analyses, SCH was significantly associated with a higher basal FSH concentration (mean difference = 1.13 mIU/mL [95% confidence interval (CI) 0.97 to 1.29 mIU/mL], p < 0.001), lower AMH concentration (mean difference = -0.27 ng/mL [CI -0.43 to -0.12 ng/mL], p = 0.001), and lower AFC (mean difference = -0.7 [CI -1.3 to -0.2], p = 0.005). In women aged ≥35 years, SCH was significantly associated with FSH (mean difference = 1.74 mIU/mL, p < 0.001) and AMH concentrations (mean difference = -0.40 mg/mL, p < 0.001) and AFC (mean difference = -0.8, p < 0.001). In women <35 years old, SCH was significantly associated with a higher FSH concentration (mean difference = 0.30 mIU/mL, p < 0.001), but not with AMH or AFC concentrations (p = 0.84 and 0.06, respectively). Thyroperoxidase antibody (TPOAb) positivity was not associated with measures of ovarian reserve. Conclusions: The data suggest that SCH is associated with decreased ovarian reserve during later reproductive age. TPOAb positivity was not associated with ovarian reserve. Future research is necessary to investigate the underlying molecular mechanisms regulating the diminished ovarian reserve in women with SCH and to evaluate whether levothyroxine supplementation may improve the ovarian function of women with SCH.

Effect of levothyroxine supplementation on pregnancy loss and preterm birth in women with subclinical hypothyroidism and thyroid autoimmunity: a systematic review and meta-analysis.

BACKGROUND: Subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes such as pregnancy loss and preterm birth. However, the ability of levothyroxine (LT4) supplementation to attenuate the risks of these outcomes remains controversial. OBJECTIVE AND RATIONALE: This systematic review and meta-analysis was conducted to determine the effect of LT4 supplementation on pregnancy loss rate (PLR) and preterm birth rate (PBR) among pregnant women with SCH and TAI. SEARCH METHODS: A systematic literature search of the PubMed, EMBASE, Web of Science and Cochrane Controlled Trials Register databases and Clinicaltrials.gov was performed to identify all relevant English studies published up to April 2018. The following terms were used for the search: [subclinical hypothyroidism OR thyroid autoimmunity OR thyroperoxidase antibody (TPO-Ab) OR thyroglobulin antibodies (Tg-Ab)] AND (levothyroxine OR euthyrox) AND [pregnancy outcome OR miscarriage OR abortion OR pregnancy loss OR preterm birth OR premature delivery OR early labo(u)r]. The reference lists of the relevant publications were also manually searched for related studies. Published manuscripts were included if they reported data on pregnancy loss, preterm birth or both. We separately analysed the pooled effects of LT4 supplementation on PLR and PBR in women with SCH and TAI. OUTCOMES: Overall, 13 eligible studies including 7970 women were included in the meta-analysis. Eight and five of these studies were randomized controlled trials (RCTs) and retrospective studies, respectively. The pooled results indicated that LT4 supplementation significantly decreased the PLR [relative risk (RR) = 0.56, 95% confidence interval (CI): 0.42-0.75, I2 = 1%, 12 studies] and PBR (RR = 0.68, 95% CI: 0.51-0.91, I2 = 21%, eight studies) in women with SCH and/or TAI. We further found that LT4 supplementation significantly decreased the risk of pregnancy loss (RR = 0.43, 95% CI: 0.26-0.72, P = 0.001, I2 = 0%) but not of preterm birth (RR = 0.67, 95% CI: 0.41-1.12, P = 0.13, I2 = 0%) in women with SCH. Furthermore, LT4 supplementation significantly decreased the risks of both pregnancy loss (RR = 0.63, 95% CI: 0.45-0.89, P = 0.009, I2 = 0%) and preterm birth (RR = 0.68 95% CI: 0.48-0.98, P = 0.04, I2 = 46%) in women with TAI. These results were consistent when only RCTs were included in the analysis. Further, in women with SCH, LT4 supplementation reduced the risk of pregnancy loss in pregnancies achieved by assisted reproduction (RR = 0.27, 95% CI: 0.14-0.52, P < 0.001, I2 = 14%) but not in naturally conceived pregnancies (RR = 0.60, 95% CI: 0.28-1.30, P = 0.13, I2 = 0%). By contrast, in women with TAI, LT4 supplementation reduced the risks of both pregnancy loss (RR = 0.61, 95% CI: 0.39-0.96, P = 0.03, I2 = 0%) and preterm birth (RR = 0.49, 95% CI: 0.30-0.79, P = 0.003, I2 = 0%) in naturally conceived pregnancies but not in pregnancies achieved by assisted reproduction (RR = 0.68, 95% CI: 0.40-1.15, P = 0.15, I2 = 0% for pregnancy loss and RR = 1.20, 95% CI: 0.68-2.13, P = 0.53, I2 not applicable for preterm birth). WIDER IMPLICATIONS: This meta-analysis confirmed the beneficial effects of LT4 supplementation, namely the reduced risks of pregnancy loss and preterm birth, among pregnant women with SCH and/or TAI. The different effects of LT4 supplementation on naturally conceived pregnancies and pregnancies achieved by assisted reproduction in women with SCH and/or TAI suggest that these women should be managed separately. Due to the limited number of studies included in this meta-analysis, especially in the subgroup analysis, further large RCTs and fundamental studies are warranted to confirm the conclusions and better clarify the molecular mechanism underlying these associations.

Nucleoside reverse transcriptase inhibitor-induced rat oocyte dysfunction and low fertility mediated by autophagy.

Low fertility is one of the most common side effects caused by nucleoside reverse transcriptase inhibitors (NRTIs), whereas the molecular mechanism underlying this process were largely unclear. This study was conducted to investigate whether autophagy plays a role in NRTIs-induced oocyte dysfunction and low fertility in female rat. Both in vivo and in vitro experiments were conducted. For the in vivo experiment, female adult Sprague-Dawley rats were subjected to zidovudine (AZT) and lamivudine (3TC) intragastric treatment for 3, 6, 9, and 12 weeks; a control was also set. Oocytes were collected for maturation evaluation, in vitro fertilization and mitochondrial function assays, and apoptosis and autophagy analysis. For the in vitro experiment, oocytes were collected and assigned to the control, 3-methyladenine (3-MA, an effective autophagy inhibitor), AZT, AZT+3-MA, 3TC, and 3TC+3-MA groups. The oocytes were cultured with the abovementioned drugs for 24, 48, and 72 h and then, subjected to the same assays as in the in vivo study. The results showed a significant time-dependent decrease in oocyte maturation-related maker levels, oocyte cleavage rate, blastocyst formation rate, mitochondrial DNA copy number and adenosine triphosphate level, and apoptosis, and a significant increase in the reactive oxygen species levels (all P-values < 0.05), in both the in vivo and the in vitro experiments. These changes, except for the changes in the oocyte maturation-related markers, were partially attenuated by 3-MA. In conclusion, we demonstrated that NRTIs can cause rat oocyte dysfunction and low fertility, and this damage was, at least partially, mediated by autophagy.

Imprinting alterations in sperm may not significantly influence ART outcomes and imprinting patterns in the cord blood of offspring.

An increase in imprinting disorders in children conceived though assisted reproductive technologies (ARTs) has been the subject of several reports. The transmission of imprinting errors from the sperm of infertile fathers is believed to be a possible reason for the increased occurrence of these disorders. However, whether the imprinting alterations in sperm affect ART outcomes and the imprinting of offspring is unclear. In the current study, we analyzed the methylation of H19, SNRPN and KCNQ1OT1 by pyrosequencing sperm samples from 97 infertile patients and 31 proven fertile males as well as cord blood samples from 13 infantswho were conceived by infertile parents through intracytoplasmic sperm injection (ICSI) and 30 healthy newborns who were conceived naturally. After four cases were excluded owing to the lack of a sequencing signal, the infertile patients were subgrouped into normal (69 cases) and abnormal (24 cases) imprinting groups according to the reference range set by the control group. Between the groups, there were no significant differences in ART outcomes. Significantly different levels of methylation were detected in H19, but none of the imprinted genes were determined to be outside of the methylation reference range set by the values derived from the naturally conceived controls. Three CpG loci were found to be significantly hypomethylated in the maternally imprinted gene KCNQ1OT1 in two patients from the abnormal imprinting group, none of which were caused by sperm imprinting errors. In addition, the paternal H19 gene exhibited discrepant methylation patterns between the sperm controls and the cord blood controls. Our data suggest that increased imprinting errors in the sperm of infertile patients do not have an obvious influence on ART outcomes or the imprinting of offspring.

Comparisons of GnRH antagonist versus GnRH agonist protocol in supposed normal ovarian responders undergoing IVF: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness and safety of GnRH antagonist and GnRH agonist in supposed normal ovarian responders undergoing IVF. METHODS: Data from 6 databases were retrieved for this study. The RCTs of GnRH agonist and GnRH antagonist use during IVF-EF therapy for patients with supposed normal ovarian response were included. A meta-analysis was performed with Revman 5.1software. RESULTS: Twenty-three RCTs met the inclusion criteria. The number of stimulation days (mean difference (MD): -0.66, 95% confidence interval (CI): -1.04∼-0.27), Gn amount (MD: -2.92, 95% CI: -5.0∼-0.85), E2 values on the day of HCG (MD: -330.39, 95% CI: -510.51∼-150.26), Number of oocytes retrieved (MD: -1.33, 95% CI: -2.02∼-0.64), clinical pregnancy rate (odds ratio (OR): 0.87, 95% CI: 0.75-1.0), and ovarian hyperstimulation syndrome (OHSS) incidence (OR: 0.59, 95% CI: 0.42∼0.82) were significantly lower in GnRH antagonist protocol than GnRH agonist protocol. However, the endometrial thickness on the day of HCG (MD: -0.04, 95% CI: -0.23∼0.14), the ongoing pregnancy rate (OR: 0.87, 95% CI: 0.74∼1.03), live birth rate (OR: 0.89, 95% CI: 0.64∼1.24), miscarriage rate (OR: 1.17, 95% CI: 0.85∼1.61), and cycle cancellation rate (OR: 1.11, 95% CI: 0.90∼1.37) did not significantly differ between the 2 groups. CONCLUSIONS: During IVF treatment for patients with supposed normal responses, the incidence of OHSS were significantly lower, whereas the ongoing pregnancy and live birth rates were similar in the GnRH antagonist compared with the standard long GnRH agonist protocols.