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AMH

Muellerian-inhibiting factor precursor (Anti-Muellerian hormone) (AMH) (Muellerian-inhibiting substance) (MIS) [MIF]

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Beyond premature ovarian insufficiency: Staging reproductive aging in adolescent and young adult cancer survivors.

While stages of reproductive aging for women in the general population are well described by STRAW 10 criteria, this is largely unknown for female adolescent and young adult cancer survivors (AYA survivors). To evaluate applying STRAW 10 criteria in AYA survivors using bleeding patterns with and without endocrine biomarkers, and assess how cancer treatment gonadotoxicity is related to reproductive aging stage. The sample (n=338) included AYA survivors from the Window Study cohort. Menstrual bleeding data and dried blood spots for AMH and FSH measurements (Ansh DBS ELISAs) were utilized for reproductive aging stage assessment. Cancer treatment data were abstracted from medical records. Among participants, mean age 34.0±4.5 and at a mean of 6.9±4.6 years since cancer treatment, the most common cancers were lymphomas(31%), breast(23%), and thyroid(17%). Twenty-nine percent was unclassifiable by STRAW 10 criteria, occuring more frequently in the first 2 years from treatment . Most unclassifiable survivors exhibited bleeding patterns consistent with the menopausal transition, but had reproductive phase AMH and/or FSH levels. For classifiable survivors (48% peak reproductive, 30% late reproductive, 12% early transition, 3% late transition, 7% post-menopause), endocrine biomarkers distinguished among peak, early and late stages within the reproductive and transition phases. Gonadotoxic treatments were associated with more advanced stages. We demonstrate a novel association between gonadotoxic treatments and advanced stages of reproductive aging. Without endocrine biomarkers, bleeding pattern alone can misclassify AYA survivors into either more or less advanced stages. Moreover, a large proportion of AYA survivors exhibited combinations of endocrine biomarkers and bleeding patterns that do not fit STRAW 10 criteria, suggesting the need for modified staging for this population.


Keywords

  • STRAW
  • adolescent and young adult cancer
  • menopausal transition
  • premature ovarian insufficiency
  • reproductive aging


Correlates and Timing of Reproductive Aging Transitions in a Global Cohort of Midlife Women With Human Immunodeficiency Virus: Insights From the REPRIEVE Trial.

Reproductive aging may contribute to cardiometabolic comorbid conditions. We integrated data on gynecologic history with levels of an ovarian reserve marker (anti-müllerian hormone [[[AMH]])] to interrogate reproductive aging patterns and associated factors among a subset of cisgender women with human immunodeficiency virus (WWH) enrolled in the REPRIEVE trial. A total of 1449 WWH were classified as premenopausal (n = 482) (menses within 12 months; AMH level ≥20 pg/mL; group 1), premenopausal with reduced ovarian reserve (n = 224) (menses within 12 months; AMH <20 pg/mL; group 2), or postmenopausal (n = 743) (no menses within12 months; AMH <20 pg/mL; group 3). Proportional odds models, adjusted for chronologic age, were used to investigate associations of cardiometabolic and demographic parameters with reproductive aging milestones (AMH <20 pg/mL or >12 months of amenorrhea). Excluding WWH with surgical menopause, age at final menstrual period was summarized for postmenopausal WWH (group 3) and estimated among all WWH (groups 1-3) using an accelerated failure-time model. Cardiometabolic and demographic parameters associated with advanced reproductive age (controlling for chronologic age) included waist circumference (>88 vs ≤88 cm) (odds ratio [OR], 1.38; 95% confidence interval, 1.06-1.80; P = .02), hemoglobin (≥12 vs <12 g/dL) (2.32; 1.71-3.14; P < .01), and region of residence (sub-Saharan Africa [1.50; 1.07-2.11; P = .02] and Latin America and the Caribbean [1.59; 1.08-2.33; P = .02], as compared with World Health Organization Global Burden of Disease high-income regions). The median age (Q1, Q3) at the final menstrual period was 48 (45, 51) years when described among postmenopausal WWH, and either 49 (46, 52) or 50 (47, 53) years when estimated among all WWH, depending on censoring strategy. Among WWH in the REPRIEVE trial, more advanced reproductive age is associated with metabolic dysregulation and region of residence. Additional research on age at menopause among WWH is needed. NCT0234429.


Keywords

  • Cardiometabolic Risk
  • HIV
  • Menopause
  • Reproductive Aging
  • Sex
  • Women


Decreased Anti-Müllerian hormone and Anti-Müllerian hormone receptor type 2 in hypothalami of old Japanese Black cows.

Cow fertility decreases with age, but the hypothalamic pathomechanisms are not understood. Anti-Müllerian hormone (AMH) stimulates gonadotropin-releasing hormone (GnRH) neurons via AMH receptor type 2 ([[AMHR2]]), and most GnRH neurons in the preoptic area (POA), arcuate nucleus (ARC), and median eminence (ME) express AMH and [[AMHR2]]. Therefore, we hypothesized that both protein amounts would differ in the anterior hypothalamus (containing the POA) and posterior hypothalamus (containing the ARC and ME) between young post-pubertal heifers and old cows. Western blot analysis showed lower (P<0.05) expressions of AMH and [[AMHR2]] in the posterior hypothalamus, but not in the anterior hypothalamus, of old Japanese Black cows compared to young heifers. Therefore, AMH and [[AMHR2]] were decreased in the posterior hypothalami of old cows.


Keywords

  • Müllerian inhibiting substance
  • female reproductive senescence
  • gonadotropin-releasing hormone neuron
  • preoptic area
  • ruminant


Epigenetic clock measuring age acceleration via DNA methylation levels in blood is associated with decreased oocyte yield.

To investigate how biologic age (phenotypic age at which your body functions) greater than chronologic age, (age acceleration (AgeAccel)), correlates with oocyte yield. Thirty-nine women undergoing ovarian stimulation, inclusive of all infertility diagnoses, were included in this pilot study. Methylome analysis of peripheral blood was utilized to determine biologic age. AgeAccel was defined as biologic age > 2 years older than chronologic age. A negative binomial model was used to obtain the crude association of AgeAccel with number of oocytes. A parsimonious adjusted model for the number of oocytes was obtained using backwards selection (p < 0.05). Measures of age were negatively correlated with number of oocytes (chronological age Pearson ρ = - 0.45, biologic age Pearson ρ = - 0.46) and AMH was positively correlated with number of oocytes (Pearson ρ = 0.91). Patients with AgeAccel were noted to have lower AMH values (1.29 ng/mL vs. 2.29, respectively (p = 0.049)) and lower oocyte yield (5.50 oocytes vs. 14.50 oocytes, respectively (p = 0.0030)). A crude association of a 7-oocyte reduction in the age-accelerated group was found (- 6.9 oocytes (CI - 11.6, - 2.4)). In a model with AMH and antral follicle count, AgeAccel was associated with a statistically significant 3.3 reduction in the number of oocytes (- 3.1; 95% CI - 6.5, - 0.1; p = 0.036). In this small pilot study, AgeAccel is associated with a lower AMH and lower oocyte yield providing preliminary evidence that biologic age, specifically AgeAccel, may serve as an epigenetic biomarker to improve the ability of predictive models to assess ovarian reserve.


Keywords

  • Aging
  • DNA methylation
  • Epigenetic clock
  • Epigenetics
  • Infertility
  • Methylome
  • Ovarian aging


Modeling Variation in the Reproductive Lifespan of Female Adolescent and Young Adult Cancer Survivors Using AMH.

Many female survivors of adolescent and young adult cancers (AYA survivors) have shortened reproductive lifespans. However, the timing and duration of ovarian function after cancer treatment are largely unknown. To model the trajectory of ovarian function over two decades following cancer treatment and evaluate how trajectories vary by treatment gonadotoxicity and age. In a prospective cohort, AYA survivors aged 18-39 at variable times since cancer treatment completion provided dried blood spots (DBS) every 6 months for up to 18 months. Anti-Müllerian hormone (AMH) levels were measured using the Ansh DBS AMH enzyme-linked immunosorbent assay. The mean AMH trajectory was modeled for the entire cohort and separately by treatment gonadotoxicity and age using functional principal components analysis. 763 participants, mean (standard deviation) enrollment age 33.3 (4.7) and age at cancer diagnosis 25.9 (5.7) years, contributed 1905 DBS samples. The most common cancers were breast (26.9%), lymphoma (24.8%), and thyroid (18.0%). AMH trajectories differed among survivors by treatment gonadotoxicity (low, moderate, or high) (P < 0.001). Following low or moderately gonadotoxic treatments, AMH levels increased over 2-3 years and plateaued over 10-15 years before declining. In contrast, following highly gonadotoxic treatment, AMH levels were lower overall and declined shortly after peak at 2-3 years. Younger age at treatment was associated with higher trajectories, but a protective effect of younger age was not observed in survivors exposed to highly gonadotoxic treatments (Pinteraction < 0.001). In this large AYA survivor cohort, timing and duration of ovarian function strongly depended on treatment gonadotoxicity and age at treatment. The findings provide novel, more precise information to guide reproductive decision-making.


Keywords

  • AMH
  • adolescent and young adult cancer
  • functional principal components analysis
  • ovarian reserve
  • reproductive lifespan


Improving Prediction of Age at Menopause Using Multiple Anti-Müllerian Hormone Measurements: the Tehran Lipid-Glucose Study.

Several statistical models were introduced for the prediction of age at menopause using a single measurement of anti-müllerian hormone (AMH); however, individual prediction is challenging and needs to be improved. The objective of this study was to determine whether multiple AMH measurements can improve the prediction of age at menopause. All eligible reproductive-age women (n = 959) were selected from the Tehran Lipid and Glucose Study. The serum concentration of AMH was measured at the time of recruitment and twice after that at an average of 6-year intervals. An accelerated failure-time model with Weibull distribution was used to predict age at menopause, using a single AMH value vs a model that included the annual AMH decline rate. The adequacy of these models was assessed using C statistics. The median follow-up period was 14 years, and 529 women reached menopause. Adding the annual decline rate to the model that included single AMH improved the model's discrimination adequacy from 70% (95% CI: 67% to 71%) to 78% (95% CI: 75% to 80%) in terms of C statistics. The median of differences between actual and predicted age at menopause for the first model was -0.48 years and decreased to -0.21 in the model that included the decline rate. The predicted age at menopause for women with the same amount of age-specific AMH but an annual AMH decline rate of 95 percentiles was about one decade lower than in those with a decline rate of 5 percentiles. Prediction of age at menopause could be improved by multiple AMH measurements; it will be useful in identifying women at risk of early menopause.


Keywords

  • Tehran Lipid and Glucose Study (TLGS)
  • anti-müllerian hormone (AMH)
  • menopause
  • reproductive aging


Antimullerian Hormone and Impending Menopause in Late Reproductive Age: The Study of Women's Health Across the Nation.

A test that helps predict the time to the final menstrual period (FMP) has been sought for many years. To assess the ability of antimullerian hormone (AMH) measurements to predictions the time to FMP. Prospective longitudinal cohort study. The Study of Women's Health Across the Nation. AMH and FSH were measured in 1537 pre- or early perimenopausal women, mean age 47.5 ± 2.6 years at baseline, then serially until 12 months of amenorrhea occurred. AMH was measured using a 2-site ELISA with a detection limit of 1.85 pg/mL. Areas under the receiver operating curves (AUC) for AMH-based and FSH-based predictions of time to FMP, stratified by age. Probabilities that women would undergo their FMP in the next 12, 24, or 36 months across a range of AMH values were assessed. AUCs for predicting that the FMP will occur within the next 24 months were significantly greater for AMH-based than FSH-based models. The probability that a woman with an AMH <10 pg/mL would undergo her FMP within the next 12 months ranged from 51% at h<48 years of age to 79% at ≥51 years. The probability that a woman with an AMH >100 pg/mL would not undergo her FMP within the next 12 months ranged from 97% in women <48 years old to 90% in women ≥51 years old. AMH measurement helps estimate when a woman will undergo her FMP, and, in general, does so better than FSH.


Keywords

  • aging
  • female reproductive endocrinology
  • gonadotropins
  • inhibin/activin/follistatin/AMH
  • menopause
  • ovaries


Basal characterization and in vitro differentiation of putative stem cells derived from the adult mouse ovary.

Lately, stem cell approaches have provided new information on reproductive organ function and additionally recommended novel treatment possibilities. The type(s) and differentiation potential of stem cells present in the mammalian ovary are largely unknown; while oogonial stem cells have been reported, we explored the possibility that multipotent stem cells may reside in the ovary and have wide differentiation potential. In this experimental study, homogenates of whole mouse ovaries were sorted using the stem cell surface markers stem cell antigen-1 and stage specific embryonic antigen-1/CD15. Viable double-positive cells 3-10 μm in diameter were evaluated immediately after sorting and after culture using differentiation conditions. Ovarian-derived stem cells were differentiated into the three main cell types: adipocytes, chondrocytes, or osteocytes. The subsequent culture was performed in media containing bone morphogenetic protein 4 (BMP-4) and/or retinoic acid (RA). RA, BMP-4 or the two agents in combination, consistently stimulated germ cell gene expression. RA treatment strongly stimulated germline gene expression and also the development of cells that were morphologically reminiscent of oocytes. The germ cell genes Dazl, Ddx4, Figla, Gdf-9, Nobox, Prdm9, and Sycp-1 were all detected at low levels. Remarkably, treatment with BMP-4 alone significantly increased protein expression of the granulosa cell product anti-Müllerian hormone (AMH). We have shown that an inclusive isolation protocol results in the consistent derivation of multipotent stem cells from the adult ovary; these cells can be differentiated towards the germ cell fate (RA alone), somatic ovarian cell fate as indicated by AMH production (BMP-4 alone), or classical mesenchymal cell types. Taken together, these data suggest the presence of multipotent mesenchymal stem cells in the murine ovary.

MeSH Terms

  • Aging
  • Animals
  • Anti-Mullerian Hormone
  • Antigens, Ly
  • Cell Differentiation
  • Cell Shape
  • Female
  • Lewis X Antigen
  • Membrane Proteins
  • Mice, Inbred C57BL
  • Ovary
  • Stem Cells

Keywords

  • BMP-4
  • Multipotent
  • Ovary
  • Retinoic acid
  • Stem cells


Serum anti-Müllerian hormone concentration and follicle density throughout reproductive life and in different diseases-implications in fertility preservation.

How do anti-Müllerian hormone (AMH) serum concentrations and follicle densities (FDs) change with age and disease and what are the implications for fertility preservation? AMH concentrations and FD do not correlate in young women, and AMH but not FD is reduced in some diseases, limiting the value of AMH as a predictive parameter of ovarian tissue transplantation. AMH is widely used as a parameter to estimate the ovarian reserve. However, the reliability of AMH to predict total number of follicles and the FD is questionable. Women with lymphoma and leukaemia have been shown to have reduced AMH concentrations, but it is unknown if the FD is also reduced. In fertility preservation it is essential to estimate the correct total number of follicles and the FD, as ovarian tissue should only be cryopreserved if ovarian reserve is high. Furthermore, the amount of tissue to be transplanted should be based on the estimation of the real FD. This retrospective observational study included 830 women (mean ± SD age, 28.2 ± 6.81 years; range, 4-43 years) with malignant (n = 806) and benign (n = 24) diseases who cryopreserved tissue in a single centre as part of a national fertility preservation programme. Females with ovarian surgery or known predispositions for a reduced ovarian reserve were excluded. AMH concentrations and FD were evaluated from March 2011 to September 2016. AMH concentrations were analysed before gonadotoxic therapies. Standardized biopsies, obtained from different areas of ovarian cortex, were collected. FD was analysed after tissue digestion and calcein staining and was expressed as average number of primordial and primary follicles count per 3 mm biopsy and per cubic millimeter tissue. AMH concentrations and FD were analysed in relation to age and diagnosis group. Both parameters were age adjusted, and associations between the different diagnosis groups and AMH versus FD were assessed. Mean ± SD AMH concentration was 3.1 ± 2.81 g/ml, mean FD per 3 mm biopsy was 137 ± 173.9 and 19.4 ± 24.60 per mm3. Maximum AMH concentrations were found in children and teenagers at the age of 6-10 years (5.71 ng/ml) and in adults at the age of 21-25 years (3.33 ng/ml). FD was highest in young children up to an age of 15 years and decreased with increasing age. AMH and FD were not correlated in women ≤20 years and weakly to moderately correlated in women 21-40 years (r = 0.24-0.39). Age-adjusted correlations between AMH and FD were demonstrated in several diagnosis groups such as breast cancer, leukaemia, sarcoma, gastrointestinal cancer and gynaecological cancer but not in the groups exhibiting Hodgkin's and non-Hodgkin's lymphoma, cerebral cancer, other types of malignancies and other types of benign diseases. Further statistical analysis supported the finding that, in some diagnosis groups such as Hodgkin's lymphoma and in gynaecological cancer, AMH concentrations but not FDs are reduced, questioning the prognostic accuracy of AMH for the FD in these diseases. Even though biopsies were taken from different sites, heterogenous distribution of follicles might have had some effect on the accuracy of the analysis. AMH should be used with care to estimate the total ovarian reserve and FD of cancer patients in young women in some diseases. Therefore, calculating the amount of ovarian tissue to be transplanted based solely on AMH might be inaccurate whereas FD might be a better parameter. The study did not receive any exterior funding.

MeSH Terms

  • Adolescent
  • Adult
  • Aging
  • Anti-Mullerian Hormone
  • Child
  • Child, Preschool
  • Female
  • Fertility Preservation
  • Humans
  • Ovarian Follicle
  • Retrospective Studies
  • Young Adult

Keywords

  • anti-Müllerian hormone
  • cancer
  • fertility preservation
  • ovarian reserve
  • ovarian tissue
  • primary follicle
  • primordial follicle


Do BRCA1 and BRCA2 gene mutation carriers have a reduced ovarian reserve? Protocol for a prospective observational study.

BRCA1/2 gene mutations increase risk of breast and/or ovarian cancer and may have implications for reproductive health. Indirect biomarkers of the ovarian primordial follicle pool (anti-Müllerian hormone (AMH)) and one small study in female cadavers suggest that ovarian reserve may be reduced in BRCA mutation carriers, but findings are conflicting and association between circulating AMH and primordial follicle number is not established. The aim of this study is to measure primordial follicle density in premenopausal ovarian tissue samples from women with BRCA1/2 gene mutations versus age-matched comparison group. Prospective observational study measuring associations between BRCA gene mutation status, premenopausal ovarian primordial follicle density and serum AMH concentrations versus age-matched premenopausal women from the general population. Primordial follicle density will be measured in cortical sections from ovarian tissue collected at the time of risk-reducing bilateral salpingo-oophorectomy (RRBSO) in 88 BRCA1 gene mutation carriers, 65 BRCA2 gene mutation carriers and 157 non-mutation carriers. Primordial follicle density will be determined by counting follicles in a known volume of ovarian cortical tissue using light microscopy. Follicles will be identified by immunohistochemical staining for oocyte marker mouse vasa homologue. To inform the mechanisms underlying reduced ovarian reserve, the proportion of follicles containing oocytes with DNA damage will be determined by immunohistochemical staining for phosphorylated histone H2AX and terminal deoxynucleotidyl transferase dUTP nick end labelling assay to identify apoptotic cells. Follicle density will be correlated with circulating AMH concentrations quantified in the same cohort, using an electrochemiluminescence immunoassay on an automated platform. Ethics approval has been granted by Peter MacCallum Cancer Centre to access biobanks, including; The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab-HREC#97_27) and the What Happens after Menopause? (HREC12PMCC24-12/90) and Melbourne IVF.

MeSH Terms

  • Adolescent
  • Adult
  • Aging
  • BRCA1 Protein
  • BRCA2 Protein
  • Female
  • Germ-Line Mutation
  • Heterozygote
  • Humans
  • Immunohistochemistry
  • Middle Aged
  • Observational Studies as Topic
  • Ovarian Follicle
  • Ovarian Reserve
  • Prospective Studies
  • Research Design
  • Young Adult

Keywords

  • BRCA
  • DNA repair
  • fertility
  • follicle
  • germline mutation
  • oocyte


Associations Between Anti-Mullerian Hormone and Cardiometabolic Health in Reproductive Age Women Are Explained by Body Mass Index.

The relationship between reproductive and cardiometabolic aging is unclear. It is unknown if the relationship differs across different clinical populations. To determine whether markers of ovarian reserve are associated with cardiometabolic risk in reproductive aged women with unexplained infertility (UI), polycystic ovary syndrome (PCOS), and regularly cycling women (OVA). Cross-sectional data from 8 US-based academic centers. Women aged 25-40 from 3 clinical populations: 870 with UI, 640 with PCOS, and 921 community-based OVA. Multivariable linear regression models were used to relate anti-mullerian hormone (AMH) and antral follicle count with cardiometabolic parameters including body mass index (BMI), waist circumference (WC), fasting glucose and insulin, homeostasis model assessment-insulin resistance (HOMA-IR), lipids, and C-reactive protein. In age and study site-adjusted models, AMH inversely related to BMI in the UI and OVA groups (P = 0.02 and P < 0.001). Among women with PCOS, AMH inversely related to BMI (P < 0.001), and also to WC (P < 0.001), fasting insulin (P < 0.01), HOMA-IR (P < 0.01), triglycerides (P = 0.04), and C-reactive protein (P < 0.001) and directly related to higher total (P = 0.02), low-density lipoprotein (P < 0.01), and high-density lipoprotein cholesterol (P < 0.01). In OVA, AMH also varied inversely with WC (P < 0.001), fasting insulin (P = 0.02), and HOMA-IR (P = 0.02). Adjustment for BMI eliminated associations in the OVA group but in PCOS, the relationship of AMH to total (P = 0.03) and low-density lipoprotein cholesterol (P = 0.003) remained. Associations observed between AMH and cardiometabolic indices are largely explained by BMI in women with and without PCOS. (J Clin Endocrinol Metab XX: 0-0, 2019).

MeSH Terms

  • Adult
  • Anti-Mullerian Hormone
  • Biomarkers
  • Body Mass Index
  • Cardiovascular Diseases
  • Case-Control Studies
  • Cross-Sectional Studies
  • Female
  • Follow-Up Studies
  • Humans
  • Incidence
  • Infertility, Female
  • Polycystic Ovary Syndrome
  • Prognosis
  • United States

Keywords

  • anti-mullerian hormone (AMH)
  • cardiometabolic health
  • cardiovascular risk
  • ovarian aging
  • ovarian reserve markers
  • reproductive aging


Relationships between antral follicle count, blood serum concentration of anti-Müllerian hormone and fertility in mares.

The anti-Müllerian hormone (AMH) plays an inhibitory role during folliculogenesis by regulating the number of follicles entering the growing pool. Antral follicle counts (AFC) are highly correlated with serum AMH concentrations and both appear to be related to the ovarian reserve in several species. Few data on AMH and AFC in mares exist, especially with regard to fertility. Therefore, the objective of the current study was to investigate the interrelationship between antral follicle count, serum AMH concentrations and fertility outcome in mares. One hundred and twenty-seven mares were enrolled in the study and grouped according to their reproductive status. Around time of estrus, serum AMH concentrations and AFC before and after ovulation were determined. Mares were artificially inseminated and pregnancy diagnosis was performed 14 to 18 days later. A high inter-individual variability in AFC and AMH concentration and a positive relationship between AMH and AFC for follicles ≤ 30 mm in diameter were observed, with a stronger correlation in mares older than 18 years. A high correlation between AFC measurements before and after ovulation was identified. The AFC after ovulation was higher than AFC before ovulation. AMH concentrations were neither related to the mares' reproductive status nor to age, number of cycles needed for pregnancy and pregnancy outcome. Excepted for a higher AFC in the middle-aged mares (9-18 years) compared to the younger mares (< 9 years), no associations between AFC and age, reproductive status as well as fertility of mares were found. This study confirms the relationship between AFC and AMH and a high degree of reproducibility of AFC measurements. However, based on our findings, neither AFC nor AMH are useful predictors of fertility in mares.

MeSH Terms

  • Aging
  • Animals
  • Anti-Mullerian Hormone
  • Female
  • Fertility
  • Horses
  • Ovarian Follicle
  • Ovulation

Keywords

  • AMH
  • Anzahl Follikel
  • Ovar
  • Pferd
  • Ultraschall
  • compte folliculaire
  • conta dei follicoli
  • ecografia
  • equine
  • equini
  • follicle count
  • ovaia
  • ovaire
  • ovary
  • reproductive status
  • stato riproduttivo
  • ultrasonography
  • ­Reproduktionsstatus
  • échographie
  • équin
  • état reproducteur


Single xenotransplant of rat brown adipose tissue prolonged the ovarian lifespan of aging mice by improving follicle survival.

Prolonging the ovarian lifespan is attractive and challenging. An optimal clinical strategy must be safe, long-acting, simple, and economical. Allotransplantation of brown adipose tissue (BAT), which is most abundant and robust in infants, has been utilized to treat various mouse models of human disease. Could we use BAT to prolong the ovarian lifespan of aging mice? Could we try BAT xenotransplantation to alleviate the clinical need for allogeneic BAT due to the lack of voluntary infant donors? In the current study, we found that a single rat-to-mouse (RTM) BAT xenotransplantation did not cause systemic immune rejection but did significantly increase the fertility of mice and was effective for more than 5 months (equivalent to 10 years in humans). Next, we did a series of analysis including follicle counting; AMH level; estrous cycle; mTOR activity; GDF9, BMP15, LHR, Sirt1, and Cyp19a level; ROS and annexin V level; IL6 and adiponectin level; biochemical blood indices; body temperature; transcriptome; and DNA methylation studies. From these, we proposed that rat BAT xenotransplantation rescued multiple indices indicative of follicle and oocyte quality; rat BAT also improved the metabolism and general health of the aging mice; and transcriptional and epigenetic (DNA methylation) improvement in F0 mice could benefit F1 mice; and multiple KEGG pathways and GO classified biological processes the differentially expressed genes (DEGs) or differentially methylated regions (DMRs) involved were identical between F0 and F1. This study could be a helpful reference for clinical BAT xenotransplantation from close human relatives to the woman.

MeSH Terms

  • Adipose Tissue, Brown
  • Animals
  • Cellular Senescence
  • Female
  • Longevity
  • Male
  • Mice
  • Ovarian Follicle
  • Ovary
  • Rats
  • Rats, Sprague-Dawley
  • Transplantation, Heterologous

Keywords

  • aging
  • brown adipose tissue (BAT)
  • lifespan
  • mice
  • ovary
  • rat
  • xenotransplant


Amyloid-like substance in mice and human oocytes and embryos.

To identify and characterize amyloid-like substance (ALS) in human and mouse oocytes and preimplantation embryos. An experimental prospective pilot study. A total of 252 mouse oocytes and preimplantation embryos and 50 immature and in vitro matured human oocytes and parthenogenetic human embryos, from 11 consenting fertility patients, ages 18-45. Fluorescence intensity from immunofluorescent staining and data from confocal microscopy were quantified. Data were compared by one-way analysis of variance, with the least square-MEANS post-test, Pearson correlation coefficients (r), and bivariate analyses (t tests). ALS morphology was verified using transmission electron microscopy. Immunostaining for ALS appears throughout the zona pellucida, as well as in the cytoplasm and nucleus of mouse and human oocytes, polar bodies, and parthenogenetic embryos, and mouse preimplantation embryos. In mouse, 2-cell embryos exhibited the highest level of ALS (69000187.4 ± 6733098.07). Electron microscopy confirmed the presence of ALS. In humans, fresh germinal vesicle stage oocytes exhibited the highest level of ALS (4164.74088 ± 1573.46) followed by metaphase I and II stages (p = 0.008). There was a significant negative association between levels of ALS and patient body mass index, number of days of ovarian stimulation, dose of gonadotropin used, time between retrieval and fixation, and time after the hCG trigger. Significantly higher levels of ALS were found in patients with AMH between 1 and 3 ng/ml compared to < 1 ng/ml. We demonstrate for the first time the presence, distribution, and change in ALS throughout some stages of mouse and human oocyte maturation and embryonic development. We also determine associations between ALS in human oocytes with clinical characteristics.

MeSH Terms

  • Adolescent
  • Adult
  • Amyloid
  • Animals
  • Blastocyst
  • Body Mass Index
  • Female
  • Humans
  • In Vitro Oocyte Maturation Techniques
  • Metaphase
  • Mice
  • Microscopy, Fluorescence
  • Middle Aged
  • Oocyte Retrieval
  • Oocytes
  • Ovulation Induction
  • Parthenogenesis
  • Pilot Projects
  • Prospective Studies
  • Young Adult
  • Zona Pellucida

Keywords

  • Amyloid
  • Oocyte quality
  • Reproductive aging
  • female fertility


Is in utero exposure to maternal socioeconomic disadvantage related to offspring ovarian reserve in adulthood?

Because the ovarian follicle pool is established in utero, adverse exposures during this period may be especially impactful on the size and health of the initial follicle endowment, potentially shaping trajectories of ovarian follicle loss and the eventual onset of menopause. Building on a robust literature linking socioeconomic status (SES) and menopausal timing, the current study examined adverse prenatal exposures related to maternal SES, hypothesizing that greater maternal socioeconomic disadvantage would be associated with lower ovarian reserve in the adult offspring. In a healthy, community-based sub-sample ([i]n[/i] = 350) of reproductive age participants in the OVA Study (2006-2011), prenatal maternal SES was examined in relation to two biomarkers of ovarian reserve, antimullerian hormone (AMH) and antral follicle count (AFC). Prenatal maternal SES was assessed indirectly using maternal addresses abstracted from participant birth certificates, geocoded, and linked to US Census-derived variables, including neighborhood-level characteristics: education (% of individuals with a HS diploma); poverty (% of families below the poverty line); unemployment (% of individuals > 16 years who are unemployed); and income (median family income). In separate covariate-adjusted linear regression models (following the backward elimination of main effects with [i]P[/i] > .10), greater maternal neighborhood education was related to higher ovarian reserve as marked by higher levels of offspring AMH (beta = .142, [i]P[/i] < .001) and AFC (beta = .092, [i]P[/i] < .10) with models accounting for 19.6% and 21.5% of the variance in AMH and AFC, respectively. In addition, greater maternal neighborhood poverty was related to lower ovarian reserve as marked by lower offspring AMH (beta = -.144, [i]P[/i] < .01), with the model accounting for 19.5% of the variance in AMH. Maternal socioeconomic disadvantage measured indirectly at the neighborhood level was associated with lower ovarian reserve among the adult offspring, independently of offspring SES and other potential confounding factors. This suggests SES-related adversity exposures may have a detrimental impact on the size or health of the initial follicle endowment, leading to accelerated follicle loss over time.


Keywords

  • Antimullerian hormone (AMH)
  • Antral follicle count (AFC)
  • Menopause
  • Neighborhood
  • Ovarian aging
  • Ovarian reserve
  • Poverty
  • Socioeconomic status (SES)


Physiology and endocrinology symposium: Anti-Müllerian hormone: a biomarker for the ovarian reserve, ovarian function, and fertility in dairy cows.

This review summarizes studies we conducted to test the hypothesis that size of the ovarian reserve (number of healthy follicles and oocytes in ovaries) positively impacts ovarian function and fertility in cattle. Key results, primarily in Bos taurus dairy cattle, show that antral follicle count (AFC) during follicular waves is highly variable between individuals, but very highly repeatable within individuals. Cycling heifers with low (≤15 follicles ≥3 mm, ~20% of a herd) vs. a high AFC (≥25, ~20% of a herd) have a smaller ovarian reserve, higher FSH but lower anti-Müllerian hormone (AMH), androstenedione, estradiol, and progesterone concentrations. Moreover, cattle with low AFC have a thinner endometrium, decreased response of granulosal, thecal, or luteal cells to FSH or LH and a poorer response to superovulation compared to cattle with high AFC. Interestingly, cows with a very high AFC as heifers have reduced fertility, fewer lactations, and shorter herd longevity, whereas cows with a low vs. intermediate AFC have reduced fertility, fewer lactations, and shorter herd longevity. Anti-Müllerian hormone concentrations are static within individuals but highly positively correlated with AFC, but fertility is not correlated with circulating AMH concentration in heifers and dairy cows with low vs. a higher AMH as heifers have reduced fertility and a shorter herd longevity. Anti-Müllerian hormone concentrations in dairy heifers are a moderately heritable trait (36%), and negatively impacted by inadequate maternal nutrition during early pregnancy or high maternal somatic cell count. We conclude that genetic or environmental manipulations of AMH could enhance size of the ovarian reserve and ovarian function, thereby improving fertility, response to superovulation, and longevity in dairy cows.

MeSH Terms

  • Androstenedione
  • Animals
  • Anti-Mullerian Hormone
  • Biomarkers
  • Cattle
  • Estradiol
  • Female
  • Fertility
  • Lactation
  • Longevity
  • Oocytes
  • Ovarian Follicle
  • Ovarian Reserve
  • Ovary
  • Pregnancy
  • Progesterone
  • Reproduction

Keywords

  • anti-Müllerian hormone
  • dairy cows
  • ovarian reserve


Genome-wide association study of anti-Müllerian hormone levels in pre-menopausal women of late reproductive age and relationship with genetic determinants of reproductive lifespan.

Anti-Müllerian hormone (AMH) is required for sexual differentiation in the fetus, and in adult females AMH is produced by growing ovarian follicles. Consequently, AMH levels are correlated with ovarian reserve, declining towards menopause when the oocyte pool is exhausted. A previous genome-wide association study identified three genetic variants in and around the AMH gene that explained 25% of variation in AMH levels in adolescent males but did not identify any genetic associations reaching genome-wide significance in adolescent females. To explore the role of genetic variation in determining AMH levels in women of late reproductive age, we carried out a genome-wide meta-analysis in 3344 pre-menopausal women from five cohorts (median age 44-48 years at blood draw). A single genetic variant, rs16991615, previously associated with age at menopause, reached genome-wide significance at P = 3.48 × 10-10, with a per allele difference in age-adjusted inverse normal AMH of 0.26 standard deviations (SD) (95% confidence interval (CI) [0.18,0.34]). We investigated whether genetic determinants of female reproductive lifespan were more generally associated with pre-menopausal AMH levels. Genetically-predicted age at menarche had no robust association but genetically-predicted age at menopause was associated with lower AMH levels by 0.18 SD (95% CI [0.14,0.21]) in age-adjusted inverse normal AMH per one-year earlier age at menopause. Our findings provide genetic support for the well-established use of AMH as a marker of ovarian reserve.

MeSH Terms

  • Adult
  • Age Factors
  • Anti-Mullerian Hormone
  • Base Sequence
  • Female
  • Gene Expression
  • Gene Expression Regulation
  • Genetic Association Studies
  • Genetic Variation
  • Genome-Wide Association Study
  • Haplotypes
  • Humans
  • Longevity
  • Menarche
  • Middle Aged
  • Mitochondria
  • Ovarian Follicle
  • Ovary
  • Polymorphism, Single Nucleotide
  • Premenopause
  • Reproduction
  • Sequence Analysis, DNA
  • Transcriptome


Low MFN2 expression related to ageing in granulosa cells is associated with assisted reproductive technology outcome.

Is low MFN2 expression associated with ageing in granulosa cells as well as assisted reproductive technology (ART) outcome, and what is the underlying mechanism of action of MFN2? In a prospective study, fresh granulosa cells were obtained from 161 women aged 20-40 years who underwent IVF with embryo transfer and who were divided into two groups: the diminished ovarian reserve (DOR) group (n = 51) and the control group (n = 110). Patient characteristics including age, infertility duration, body mass index, FSH, anti-Müllerian hormone (AMH), antral follicle count (AFC) and husband's semen parameters and granulosa cell MFN2 expression levels, cell apoptosis, mitochondrial membrane potential (ΔΨm) and ATP levels were analysed. There were no significant differences between the DOR and control groups in terms of age, infertility duration and husband semen parameters; however, significant (P< 0.05) changes were found between the two groups in FSH, AMH and AFC levels. MFN2 expression was remarkably lower in granulosa cells from the DOR group and decreased in both groups as age increased. Furthermore, among young patients, MFN2 levels significantly increased in patients with pregnancy. MFN2 protein levels and cell apoptosis were lower in the MFN2 knockdown (MFN2-siRNA) group than in the control (Cy3-siRNA) group. ΔΨm and ATP levels were reduced in the MFN2-siRNA group compared with the Cy3-siRNA group. Low MFN2 expression levels in granulosa cells were related to ageing, which may be involved in the clinical outcome of ART by promoting cell apoptosis and affecting mitochondrial function.

MeSH Terms

  • Adult
  • Aging
  • Apoptosis
  • Body Mass Index
  • Embryo Transfer
  • Female
  • Fertilization in Vitro
  • GTP Phosphohydrolases
  • Granulosa Cells
  • Humans
  • Infertility, Female
  • Male
  • Mitochondria
  • Mitochondrial Proteins
  • Ovarian Follicle
  • Ovarian Reserve
  • Prospective Studies
  • Semen Analysis
  • Treatment Outcome
  • Young Adult

Keywords

  • ART outcome
  • Ageing
  • Granulosa cells
  • IVF
  • MFN2
  • Mitochondria


Differential Rates of Change in Measures of Ovarian Reserve in Young Cancer Survivors Across the Reproductive Lifespan.

Recent studies have examined level and rate of change of anti-Müllerian hormone (AMH) for predicting time to menopause. Limited prospective, longitudinal data exists evaluating measures of ovarian reserve (MOR) in cancer survivors. Determine the rate of change of MOR in survivors (15 to 39 years) compared with similar-aged controls and compared with late reproductive-aged controls (40 to 50 years). Prospective cohort. Quaternary university hospital. Survivors at least 1 year from therapy completion, similar-aged controls, and late reproductive-aged controls. Annual visits with early follicular-phase hormone analysis and ultrasound. Changes in AMH and antral follicle count (AFC) were modeled using random effects linear regression. Cancer survivors (170) and 135 similar-aged controls had annual visits for an average of 38 months; 71 late reproductive-aged controls were followed for an average of 24 months. In models adjusted for body mass index, time since cancer therapy (for survivors), and exogenous hormone use, the geometric mean AMH and AFC levels were lower in the survivors than similar-aged controls at all ages. After age 24.5 AMH and AFC declined in both groups at rates that were similar (P = 0.78 for AMH, P = 0.37 for AFC). Late reproductive-aged controls declined at a much more precipitous rate of 30% per year for AMH and 16% per year for AFC (P < 0.01 compared with survivors). Although survivors had lower levels of AMH and AFC at the time of enrollment, the rate of change of AMH and AFC is not significantly different than similar-aged controls.

MeSH Terms

  • Adolescent
  • Adult
  • Anti-Mullerian Hormone
  • Cancer Survivors
  • Case-Control Studies
  • Female
  • Follow-Up Studies
  • Humans
  • Longevity
  • Longitudinal Studies
  • Neoplasms
  • Ovarian Reserve
  • Ovary
  • Prognosis
  • Prospective Studies
  • Reproduction
  • Young Adult

{{medline-entry |title=Establishment of a Mouse Model of Premature Ovarian Failure Using Consecutive Superovulation. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30537739 |abstract=This study investigated the effect of consecutive superovulation on the ovaries and established a premature ovarian failure (POF) model in mice. The mouse POF model was induced by 5-15 consecutive superovulation treatments with pregnant mare serum gonadotropin (PMSG), human chorionic gonadotropin (HCG) and prostaglandin F2α (PGF2α). Normal adult mice were compared with mice displaying natural ovarian aging. The following serum biochemical parameters were measured: including follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), estradiol (E2), inhibin B (INH B), malondialdehyde (MDA), total superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels. Follicles were counted using H

Источник — https://transhumanist.ru/index.php?title=AMH&oldid=5874