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Insm2 deficiency results in female infertility by disturbing steroid pathway and decreasing ovarian reserve in mice.

ABSTRACT: The number and quality of oocytes in the ovarian reserve are related to fertility and reproductive lifespan in mammals. Some transcription factors have been demonstrated to determine oogenesis. The insulinoma-associated 2 (Insm2) gene is a member of the Snail transcriptional repressor superfamily. Recent studies have demonstrated Insm2 plays an essential role for insulin secretion and glucose intolerance in mice, but the functions of Insm2 in reproduction remain elusive. Here, by examination of Insm2 knockout mice, we found Insm2 was essential for female fertility. Loss of Insm2 resulted in female infertility with major defects in primordial follicle pool, ovarian folliculogenesis and ovulation. Transcriptomic profiling of ovaries suggests that loss of Insm2 caused defects in oocyte meiosis and steroid synthesis. Both oocyte- and granulosa cell-expressed genes were dysregulated, including Foxo1 and other known genes involved in primary ovarian insufficiency. Together, these studies show that Insm2 is required for oocyte development and their communication with ovarian somatic cells.

SUBMITTER: Li ZM

PROVIDER: S-EPMC9586662 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Insm2 deficiency results in female infertility by disturbing steroid pathway and decreasing ovarian reserve in mice.

Li Zhi-Ming ZM Li Yuan-Yuan YY Fei Cai-Feng CF Zhou Li-Quan LQ

Cell cycle (Georgetown, Tex.) 20220703 21

The number and quality of oocytes in the ovarian reserve are related to fertility and reproductive lifespan in mammals. Some transcription factors have been demonstrated to determine oogenesis. The insulinoma-associated 2 (Insm2) gene is a member of the Snail transcriptional repressor superfamily. Recent studies have demonstrated Insm2 plays an essential role for insulin secretion and glucose intolerance in mice, but the functions of Insm2 in reproduction remain elusive. Her ...[more]

PMID: 35786158

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Project description:Study questionAre urinary phthalate metabolites associated with reduced antral follicle growth among women in an infertility setting?Summary answerHigher urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites were associated with significant decreases in antral follicle count (AFC) among women seeking infertility care.What is known alreadyExperimental animal studies show that DEHP accelerates primordial follicle recruitment and inhibits antral follicle growth. Whether phthalates also reduce the growing antral follicle pool in humans remains unknown.Study design, size, durationWe examined the association between urinary phthalate metabolites and AFC using prospective data from 215 females recruited between 2004 and 2012 in the Environment and Reproductive Health (EARTH) study.Participants/materials, setting, methodsWe quantified the urinary concentrations of 11 phthalate metabolites. We estimated the geometric mean for all urine samples provided prior to unstimulated day 3 AFC assessment for each woman. We evaluated the association of AFC with ∑DEHP (molar sum of four DEHP metabolites) and individual phthalate metabolites using Poisson regression, adjusting for age, BMI and smoking.Main results and the role of chanceWe observed significant decreases in mean AFC for all higher quartiles of ∑DEHP as compared with the lowest quartile. Compared with women in the first quartile of ∑DEHP, women in the second, third and fourth quartiles had a -24% (95% confidence interval (CI): -32%, -16%), -19% (95% CI: -27%, -9%), and -14% (95% CI: -23%, -5%) decrease in mean AFC. The absolute mean AFC in the first quartile was 14.2 follicles (95% CI: 13.2, 15.2) compared with 10.7 follicles (95% CI: 9.9, 11.6) in the second quartile. We observed similar trends among the four individual DEHP metabolites. There was no consistent change in AFC among the remaining phthalate metabolite concentrations evaluated.Limitations, reasons for cautionWe demonstrated a negative association between DEHP and a well-established marker of ovarian reserve among a subfertile population. However these findings may not be generalizable to women without fertility concerns, and we cannot rule out co-exposure to other chemicals.Wider implications of the findingsEnvironmental chemicals that inhibit the size of the growing antral follicle pool can impair fertility and reduce fecundity. This study suggests evidence in need of further investigation on the impact of phthalates on the human oocyte and follicular development.Study funding/competing interestsWork supported by grants ES009718, ES022955, ES000002, and T32ES007069 from the National Institute of Environmental Health Sciences (NIEHS) and grant T32 DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). C.M. was supported by a post-doctoral training award from the Canadian Institutes of Health Research. There are no competing interests to declare.

Project description:Importance:Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential. Objective:To determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age. Design, Setting, and Participants:Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N?=?981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area. Exposures:Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH. Main Outcomes and Measures:The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result. Results:A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis. After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL [n?=?84]) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n?=?579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively). Women with high serum FSH values (>10 mIU/mL [n?=?83]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n?=?654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%], respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine [n?=?69]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively). Inhibin B levels (n?=?737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001). Conclusions and Relevance:Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.

Project description:BACKGROUND:While overt thyroid disease is a well known risk factor for infertility, the potential consequences of mild thyroid dysfunction or thyroid autoimmunity remain unknown. Experimental studies suggest a considerable role for thyroid hormone in the physiological mechanisms of ovarian reserve, but translation of such findings to human studies remains rare. A potential role for thyroid function in female reproduction could be especially relevant when the cause of infertility remains unknown, such as in women with diminished ovarian reserve (DOR) or unexplained infertility. The aims of this study were to investigate the association of thyroid function and autoimmunity with markers of ovarian reserve day 3 follicle-stimulating hormone (FSH) concentrations and antral follicle count (AFC), and to investigate whether thyroid function or autoimmunity may have different effects in women with DOR or unexplained infertility. METHODS:Thyrotropin, free thyroxine, thyroxine, free triiodothyronine (fT3), triiodothyronine, thyroid peroxidase antibodies (TPOAbs), and thyroglobulin antibodies (TgAbs), as well as AFC and the day 3 FSH concentration, were measured among women seeking fertility treatment at the Massachusetts General Hospital Fertility Center. Multiple linear or mixed regression models were used to study the association of thyroid function or autoimmunity with AFC or day 3 FSH. RESULTS:In the total study population (436 women, 530 AFC measurements), there was no association of thyroid function or TPOAb positivity with AFC. However, TgAb positivity was associated with a higher AFC (mean difference = 3.4 [95% confidence interval (CI) 1.8-5.1], p < 0.001). In women with DOR or unexplained infertility, lower fT3 and TPOAb positivity were associated with a lower AFC (fT3: continuous nonlinear association, p = 0.009; TPOAb positivity: -2.3 follicles [confidence interval -3.8 to -0.5], p = 0.01), while TgAb positivity was not associated with AFC. Neither thyroid function nor thyroid antibody positivity was associated with the day 3 FSH concentration. CONCLUSIONS:This study found that lower fT3 and TPOAb positivity are associated with a lower AFC in women with DOR or unexplained infertility. Future studies are required to replicate these findings and further elucidate the role of TgAbs and underlying mechanisms through which thyroid function and autoimmunity is associated with ovarian reserve.

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Insm2 deficiency results in female infertility by disturbing steroid pathway and decreasing ovarian reserve in mice.

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<i>Insm2</i> deficiency results in female infertility by disturbing steroid pathway and decreasing ovarian reserve in mice.

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