Lower anti-Müllerian Hormone Levels Research Articles

History of infertility and anti-Müllerian hormone levels among participants in the Nurses' Health Study II.

To better understand whether history of infertility is associated with anti-Müllerian hormone (AMH) levels later in life, outside of reproduction. Among 1,758 premenopausal women in the Nurses' Health Study II with measured AMH, we used multivariable generalized linear models to compare log-transformed plasma AMH for women with a history of infertility compared with fertile women. We investigated AMH levels by cause of infertility and effect modification by menstrual cycle regularity. Lastly, we investigated AMH levels by history of primary and secondary infertility and age at reported infertility. Mean age at blood collection was 40 years. We observed no association between overall history of infertility and AMH levels (% difference AMH: -8.1% [CI, -19.4 to 4.8]). The association between overall infertility and AMH was strongest among women who first reported infertility at >30 years (-17.7% [CI, -32.1 to -0.3]). Overall, we observed no association between the history of infertility and AMH levels later in life. However, specific subgroups of women with a history of infertility may have lower AMH levels throughout life compared with fertile women. This association was observed among subgroups, such as those who first experienced infertility at >30 years. These findings have implications for mechanisms through which infertility may be associated with premature menopause and chronic disease risk.

P-521 Inter-individual variation in gonadotoxicity in female childhood cancer survivors – a genome-wide association study: results from the PanCareLIFE study

Abstract Study question To identify new variants associated with alkylating agent (AA) induced gonadotoxicity among adult female childhood cancer survivors (CCS) using a genome-wide association study approach (GWAS). Summary answer Upon meta-analysis of two independent cohorts, the variant rs78861946 was associated with lower AMH levels in CCS, but not separately in the smaller replication cohort. What is known already Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Study design, size, duration A genome-wide association study (GWAS) approach was used to discover new variants associated with AA-induced gonadotoxicity among adult female CCS. The discovery cohort included adult female CCS from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, CNS, total body irradiation, or stem cell transplantation. Results were replicated in the USA-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years) and combined in a meta-analysis. Participants/materials, setting, methods Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in both the discovery and replication cohort. A GWAS was performed using a linear regression model adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study. Main results and the role of chance Three genome-wide significant (<5.0x10E-8 ) and 16 genome-wide suggestive (<5.0x10E-6 ) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. Based on effect allele frequency (EAF) (>0.01 if not genome-wide significant), p-value (<5.0 × 10E−6 ), and biological relevance, 15 SNPs were selected for replication in the independent replication cohort of the St. Jude Lifetime Cohort. None of the SNPs were statistically significantly associated with AMH levels in this smaller cohort. A meta-analysis indicated thatrs78861946 was associated at borderline genome-wide statistical significance (reference/effect allele: C/T;EAF: 0.04, Beta (SE): −0.484 (0.091), p-value= 9.39 × 10E−8). While the sample size of both the discovery and replication cohorts are large for CCS cohorts, they are very small compared to GWASs in the general population. The limited power is likely one of the reasons the identified SNPs were not statistically significant in our replication cohort of SJLIFE. Limitations, reasons for caution While AMH is a valuable surrogate marker for ovarian reserve, it remains a proxy for ovarian reserve and low AMH levels may still coincide with fertility potential and pregnancy. Wider implications of the findings Identification of risk-contributing variants such as rs78861946 may prove useful to better identify patients who are specifically susceptible for alkylating agent-induced gonadal toxicity. Future polygenic risk scores may aid individualized counselling regarding the treatment-related risk of gonadotoxicity and fertility preservation options for female childhood cancer survivors. Trial registration number not applicable

Reproductive Health Assessment and Reports of Fertility Counseling in Pediatric and Adolescent Patients with Sickle Cell Disease After Hematopoietic Cell Transplantation

Conditioning regimens for hematopoietic cell transplant (HCT) in patients with sickle cell disease (SCD) place patients at risk for reproductive health issues. The purpose of this study was to assess reproductive health and reports of fertility counseling in patients with SCD who received a transplant. This was a secondary analysis of gonadal hormone production, future infertility risk assessment, and parent-proxy/patient reports of fertility counseling in SCD transplant recipients who are currently pubertal and were enrolled in the Atlanta sites of the Sickle Cell Transplant Evaluation of Long-term and Late Effects Registry (STELLAR) between May 2017 and October 2023. Clinical information was abstracted from medical records and reproductive health survey data from the STELLAR database. Descriptive statistics were reported as median (interquartile range [IQR]) or percentages. There were 20 females and 12 males in the study population. Females were median (IQR) 19.6 (9.4) years old and males 20.8 (11.4) years old at the time of the study. Transplants most commonly occurred in the decade 2010 to 2019 at 10.7 (4.8) years old for females and 11.1 (4.1) years old for males. Most participants received bone marrow stem cells (95.0% females, 100.0% males) from matched sibling donors (90.0% females, 100.0% males). Participants received one of seven HCT conditioning regimens with cyclophosphamide equivalent doses ranging from 3388 to 9706 mg/m2. The majority of females (90.0%) had diminished ovarian reserve with low anti-Mullerian hormone levels, and 61.1% had premature ovarian insufficiency with two follicle-stimulating hormone levels (FSH) ≥40 mIU/mL post-HCT. All males had normal testosterone levels, but 63.6% had elevated FSH levels suggestive of impaired spermatogenesis post-HCT. Parent proxies (for patients <18 years old) and patients ≥18 years old completed surveys 9.0 years (5.2) and 7.9 years (9.3) since HCT in females and males respectively. Twenty-five percent of parent proxies and 45% of patients reported that they had not been informed by a healthcare provider of the risk of infertility post-transplant. There are high rates of gonadal dysfunction post-HCT, but many parent proxies and patients do not recall being told of the risk for future infertility. More effective methods of education are warranted to ensure SCD patients and their families clearly understand the risk for reproductive health issues post-HCT.

The Relationship Between Anti-Mullerian Hormone Levels and Pregnancy Outcomes in Patients with Recurrent Unexplained Miscarriage

Background: This study aimed to assess the correlation between serum levels of anti-Mullerian hormone (AMH), basal follicle-stimulating hormone (FSH), basal luteinizing hormone (LH), and basal estradiol with pregnancy outcomes. Methods: Conducted at Shariati Hospital in Tehran from 2020 to 2021, this prospective cohort study included women under 38 years old with idiopathic recurrent miscarriage (IRM). Individuals with AMH levels below 1 ng/mL were classified as the poor responder group. All participants with IRM received a daily combination of 20 mg prednisolone and 200 mg progesterone vaginal suppositories from the beginning of pregnancy until 12 weeks, along with aspirin and folic acid. Pregnancy was monitored until 36 weeks, and outcomes were evaluated over two years using univariate and multiple logistic regression, with P-values &lt; 0.05 considered significant. Results: The study comprised 128 individuals with a mean age of 36.4 ± 3.9 years. Of these, 80 became pregnant, while 48 did not. Among the pregnant individuals, 34 had terminations before 26 weeks (13 ongoing and 21 clinical), while 46 had pregnancies lasting 26 weeks or longer. Maternal age (RR = 1.23, 95% CI: 1.10 - 1.90, P = 0.001), history of abortion (RR = 1.262, 95% CI: 1.052 - 1.327, P = 0.008), and low serum AMH level (RR = 0.752, 95% CI: 0.227 - 0.934, P = 0.035) were significantly associated with the probability of subsequent pregnancies. Maternal age (RR = 1.108, 95% CI: 1.05 - 1.350, P = 0.025) and history of abortion (RR = 1.097, 95% CI: 1.02 - 1.161, P = 0.042) were the only factors associated with the risk of non-pregnancy. Conclusions: The study findings suggest that AMH levels in women with IRM significantly influence pregnancy outcomes, including abortion and live births at 26 weeks or more. The univariate analysis revealed significant correlations between age, serum AMH levels, previous history of abortion, and the risk of abortion. Additionally, AMH levels were found to relate to follicle storage rather than egg quality, indicating that AMH does not predict live birth after IVF. Overall, this prospective study underscores the importance of maternal age, AMH level, and previous abortion history in predicting pregnancy outcomes.

The impact of treatment for childhood classical Hodgkin lymphoma according to the EuroNet-PHL-C2 protocol on serum anti-Müllerian Hormone.

What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)? Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL. Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol. This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021. Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses. A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years. The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2-5 years post-diagnosis. The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol. The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K., D.K., W.H.W., D.H., M.C., A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest. N/A.

The association between leptin, adiponectin levels and the ovarian reserve in women of reproductive age.

Reproduction ability requires a certain amount of body fat that is necessary for ovulation, menstruation and pregnancy. Fat tissue represents an endocrine organ with high metabolic activity as it produces adipokines such as leptin and adiponectin. Our aim is to examine potential associations between women of reproductive age's ovarian reserves and their levels of leptin and adiponectin. 74 women between 19 and 40 years of age consented to take part. Based on the patterns of their ovarian reserves, the women were divided into three main groups: women with adequate ovarian reserves (AOR - Group A, n=30), women with polycystic ovary syndrome (PCOS - Group B, n=31) and women with depleted ovarian reserves (DOR - Group C, n=13). Among these groups, several biochemical and demographic parameters were statistically compared. Compared to the other two groups, women with DOR had statistically higher age and follicle stimulation hormone (FSH) levels. For estradiol (E2) and thyroid-stimulating hormone (TSH), no statistically significant difference was seen between the groups. In addition, women with PCOS had higher body mass index (BMI), luteinizing hormone (LH), total testosterone (TT), 17 hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHEA), anti-Mullerian hormone (AMH), and antral follicle count (AFC) than the other two groups. In line with expectations, women with DOR also had lower levels of AMH and AFC than the other two groups. Women with PCOS had higher leptin levels than the other two groups, but there was no statistically significant difference. Women with PCOS had lower levels of adiponectin than the other groups, however the difference was not statistically significant. The way we classified women in our study according to their ovarian reserves is completely consistent with what has been published internationally. The ovarian reserve in women of reproductive age is not strongly correlated with leptin and adiponectin levels. For safe conclusions, more research including a greater number of samples is required.

Follicle-Stimulating Hormone Receptor and Estrogen Receptor Gene Polymorphisms in Women With Discordant Follicle-Stimulating Hormone and Anti-Mullerian Hormone Levels.

Objective This study aimed to investigate follicle-stimulating hormone receptor (FSHR) polymorphisms(Thr307Ala and Asn680Ser), estrogen receptor 1 (ESR1) polymorphisms (PvuII and XbaI), and ESR2 polymorphisms (RsaI and AluI) in Turkish women with follicle-stimulating hormone (FSH) and anti-Mullerian hormone (AMH) discordance. Method Genotyping was performed in 60 patients aged 21-35 with FSH-AMH discordance and/or low ovarian reserve and 20 age-matched controls with normal FSH and AMH levels. The patients were investigated in four groups of 20 women according to their FSH and AMH levels. Groups 1, 2, 3, and 4 were as follows: normal FSH and low AMH levels, normal AMH and high FSH levels, high FSH and low AMH levels, and normal FSH and AMH levels. Genomic DNA was obtained from 3 cc peripheral blood, and polymorphisms were analyzed using TaqMan genotyping assays. Relations between groups of categorical variables were analyzed with a chi-square test. Differences between the groups were assessed using a student's t-testor Mann-Whitney U test. Results Women with discordant FSH and AMH levels (group 1 and group 2) were not statistically different from women with concordant FSH and AMH levels (group 3 and group 4) in terms of FSHR, ESR1, and ER2 single nucleotide polymorphisms (SNPs). Body mass index (BMI) was statistically significant between groups 1 and 2 as well as groups 2 and 3 (p = 0.004). Conclusions This study showed that FSHR, ESR1, and ESR2 SNPs have not had any effect on AMH-FSH discordance in reproductive age Turkish women.

A Study to Determine the Impact of Diminished Oocyte Reserve (DOR) on Pregnancy Outcome in Women of Advanced Reproductive Age

Background: Both advancing age and diminished oocyte reserve (DOR) have a negative impact on fecundity. Objective: To determine what effect diminished oocyte reserve (DOR), as determined by low anti-Mullerian hormone levels, has on live delivered pregnancy rates following in vitro fertilization embryo transfer (IVF-ET) in women aged-40-42. Design: This was a retrospective study. Materials and Methods: A retrospective study was performed in women aged 40-42 undergoing IVF-ET with DOR or normal ovarian reserve (NOR). The women were divided into two groups based on egg reserve: DOR (anti-mullerian hormone (AMH) level &lt;1 ng/ml) and normal oocyte reserve (NOR) (serum AMH ≥ 1ng/ml). A type of mild ovarian stimulation protocol, known as the FSH receptor up-regulation technique, was used for women with DOR. Setting: University-associated private practice IVF center. Results: The live delivered pregnancy rate (LDPR) was 12.6% for the DOR group and 12.9% for normal oocyte reserve (NOR). Conclusion: Since the LDPRs were the same for women aged 40-42 with DOR compared to NOR, a low serum AMH should not be a deterrent for performing IVF-ET in women aged 40-42. If this LDPR is not acceptable, then one could consider the use of donor eggs.

The Relationship Between Anti-Müllerian Hormone and Body Composition Components in Patients With Polycystic Ovary Syndrome of Reproductive Age.

To investigate and analyze the relationship between body composition components, including Body Mass Index (BMI), body fat percentage, waist-to-hip ratio, and visceral fat index, and Anti-Müllerian Hormone (AMH) levels in patients diagnosed with Polycystic Ovary Syndrome (PCOS), The study aims to provide a comprehensive understanding of how various aspects of body composition impact AMH levels. This study enrolled 167 women with PCOS of reproductive age. Serum AMH level and body composition were measured, and the correlation between body composition elements and AMH levels was analyzed. AMH level was negatively correlated with body weight, BMI, fat-free mass, body fat percentage, waist-hip ratio, and visceral fat level (P < 0.01). And negatively correlated with skeletal muscle ratio ( P= 0.003). AMH level remained significantly associated with BMI (P = 0.028), body fat percentage (P = 0.040), waist-hip ratio (P= 0.003), and visceral fat level ( P= 0.040) after age was included and a multiple linear regression model was established. After adjusting for age, BMI was still significantly associated with AMH (P = 0.029). At the same time, there was no obvious linear correlation between BSA and AMH. The results showed that AMH levels were significantly different among the three groups (9.53 ± 5.12 vs 6.98 ± 3.35 vs 6.38 ± 3.38, P < 0.001; ng/mL). The level of AMH in the non-central obesity group was higher than that in the central obesity group (9.68 ± 5.22vs7.09 ± 3.83, P < 0.001; ng/mL). In PCOS patients, those who are more obese have lower AMH levels, indicating poorer Ovarian Reserve. BMI may independently affect AMH levels, apart from age, BSA, and other factors. Ovarian function in centrally obese patients is poorer than in those with non-central obesity.

Pharmacological Protection of Ovaries During Program Drug Chemotherapy in Classical Hodgkin Lymphoma and Non-Hodgkin Lymphoma Patients

Aim. To assess the efficacy of ovarian protection and options for fertility preservation with the use of gonadotropin-releasing hormone agonists (a-GnRH) in patients with classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphomas (NHLs) during program drug chemotherapy.&#x0D; Materials &amp; Methods. The study enrolled 247 female patients (187 with cHL and 60 with NHLs) undergoing program drug chemotherapy from 2019 to 2023. The patients were aged 13–42 years (median 24 years). Prior to chemotherapy and after it was completed, the serum anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and estradiol levels were measured. Besides, antral follicle count was estimated by pelvic ultrasound. To provide ovarian protection during chemotherapy, a-GnRH was administered to 67 (27 %) out of 247 patients. Ovarian reserve was assessed based on ultrasound and AMH, FSH, and estradiol levels in 2–3 months after completing the program of drug chemotherapy or after spontaneous menstrual recovery.&#x0D; Results. Menstrual cycle recovered in 194 (78.5 %) out of 247 patients, regardless of lymphoid malignancy variant. Among them, there were 79.7 % (n = 149) of cHL patients and 75 % (n = 45) of NHL patients. Accordingly, ovarian function was lost in 20.3 % (n = 38) of cHL patients and 25 % (n = 15) of NHL patients. Predictors of ovarian function recovery appeared to be age ≤ 28 years and AMH level &gt; 2.45 ng/mL. Pharmacological protection of ovaries did not impact the probability of menstrual cycle recovery. Regardless of immunomorphological variant of lymphoid malignancy, a regular menstrual cycle was completely restored in 48 (71.6 %) out of 67 a-GnRH recipients and in 146 (81.1 %) out of 180 patients without a-GnRH treatment.&#x0D; Conclusion. Most of cHL and NHL patients of early reproductive age (≤ 30 years) have a fair chance of menstrual cycle recovery after completing the program drug chemotherapy similar to BEACOPP, EACODD(PP)-14, R-CHOP, R-Da-EPOCH and other regimens. Ovarian reserve cannot be preserved by means of a-GnRH administration during chemotherapy. High baseline FSH and low baseline AMH levels indirectly indicate evidence of impaired ovarian reserve. Patients belonging to this category are those who, if intensive combined cytostatic therapy regimens are planned, should undergo prior oocyte/embryo retrieval with subsequent cryopreservation due to the risk of premature loss of ovarian function.

A novel antimüllerian gene mutation in a woman with high antral follicle count and extremely low serum antimüllerian hormone levels

To report a case with a distinct difference between the ovarian reserve parameters of antimüllerian hormone (AMH) levels, antral follicle count (AFC), and follicle-stimulating hormone levels caused by a novel homozygous missense variant in the exon 1 of the AMH gene [NM_000479.4:c259G>A, p.(Val87Met)]. Case report. Tertiary referral invitro fertilization clinic. A 33-year-old woman, G4P4A0E0L4, with a BMI of 25.33 kg/m2, high AFC, and repeated extremely low systemic AMH levels, was detected and measured using multiple enzyme-linked immunosorbent assays. Antimüllerian hormone analysis with multiple assays, whole exome sequencing through next generation sequencing to diagnose the missense variant, and inhibin B measurement. Genetic counseling and two subsequent ovarian stimulations for successful fertility preservation. Detection of the [NM_000479.4:c259G>A, p.(Val87Met)] variant in the AMH gene. Retrieval and cryopreservation of four euploid blastocysts and 26 metaphase II oocytes. AMH gene mutations can lead to the absence of systemic AMH levels and might be discordant to other ovarian reserve markers like AFC, follicle-stimulating hormone, and inhibin B, without affecting the ovarian response to ovarian stimulation. Clinicians should not rely exclusively on AMH levels for ovarian stimulation. When severely reduced AMH levels are found in patients with high AFC, AMH variants should be suspected, and fertility treatments should be tailored adequately.

Brca2(p.T1942fs/+) dissipates ovarian reserve in rats through oxidative stress in follicular granulosa cells

Pathogenic variants of BRCA1/2 constitute hereditary breast and ovarian cancer (HBOC) syndrome, and BRCA1/2 mutant is a risk for various cancers. Whereas the clinical guideline for HBOC patients has been organized for the therapy and prevention of cancer, there is no recommendation on the female reproductive discipline. Indeed, the role of BRCA1/2 pathogenic variants in ovarian reserve has not been established due to the deficiency of appropriate animal models. Here, we used a rat model of Brca2(p.T1942fs/+) mutant of Sprague-Dawley strain with CRISPR-Cas9 editing to evaluate ovarian reserve in females. Fertility and ovarian follicles were evaluated and anti-Müllerian hormone (AMH) was measured at 8–32 weeks of age with a comparison between the wild-type and the mutant rats (MUT). MUT revealed a significantly smaller number of deliveries with fewer total pups. Furthermore, MUT showed a significant decrease in primordial follicles at 20 weeks and a low AMH level at 28 weeks. RNA-sequencing of the ovary at 10 weeks detected acceleration of the DNA damage repair pathway, which was accompanied by oxidative stress-induced DNA double-strand breaks, a decrease in PTEN, and an increase in mTOR in follicular granulosa cells. In conclusion, Brca2(p.T1942fs/+) dissipates primordial follicles via early activation of granulosa cells through oxidative stress, leading to earlier termination of fertility.

Age-Related Changes in Low Serum Anti-Müllerian Hormone Levels in Female Adolescents: A Single-Center Retrospective Pilot Study

Study ObjectiveAvailable data on the clinical significance of low serum anti-Müllerian hormone (AMH) levels in female adolescents are limited. The aim of this study was to elucidate age-related changes in low serum AMH levels in adolescents and to identify predictive factors for AMH progression. MethodsA retrospective review was conducted on a series of female adolescents aged 11-19 years with low serum AMH levels (<1.19 ng/mL) who underwent additional AMH tests at least 1 year apart. Participants who showed an increase in the subsequent AMH test (>1.6 ng/mL) (Group 1) were compared with those who did not (Group 2). ResultsAmong 1655 adolescents who underwent AMH testing at least once from 2010 to 2022, 75 participants (4.5%) exhibited low AMH levels (<1.19 ng/mL), excluding primary ovarian insufficiency. A notable increase in serum AMH levels (>1.6 ng/mL) was confirmed in 7 (30.4%) of 23 female adolescents who underwent relevant follow-up testing. Group 1 had higher initial AMH levels and lower initial follicle-stimulating hormone levels than Group 2 (1.0 vs 0.59 ng/mL, P = .001 and 4.4 vs 9.8 mIU/mL, P = .015, respectively). Ovarian volume did not differ between the groups (3.8 vs 4.4 cm3, P = .465). None of the participants with initial AMH levels under 0.75 ng/mL showed an increase in AMH levels during follow-up. ConclusionThese findings suggest that low serum AMH levels in adolescents may have other explanations in addition to being indicative of a low ovarian reserve. Prospective studies involving a larger number of participants will aid in predicting AMH improvement in adolescents.

Serum concentrations of anti-Müllerian hormone modulate ovarian response to different doses of follicle-stimulating hormone in Japanese Black donors.

Anti-Müllerian hormone (AMH) is a marker for predicting embryo production in cows subjected to superovulation; however, it remains to be established as a reliable predictor of reproductive performance. We hypothesized that the serum AMH concentration of donors affects the ovarian response to follicle-stimulating hormone (FSH) treatment during superovulation. Herein, we retrospectively investigated the association between different FSH doses and AMH concentrations in donor Japanese Black cows in a superovulation program and analyzed the number of total and transferable embryos recovered. The number of transferable embryos recovered from donors with high AMH levels was significantly higher than that recovered from donors with low AMH levels. Additionally, it increased further with a reduction in the FSH dose. These results illustrate that the AMH concentration is a useful marker for predicting embryo production after superovulation, and donors with high AMH levels produce more transferable embryos at low FSH doses than at high doses.

Correlation of Serum TSH with Ovarian Reserve in Patient of Infertility. A Retrospective Study

Background: Various hormones have different impact in fertility either to predict, to investigate or to treat infertility. Due to hindrance in follicular growth, embryo development, implantation and placental formation thyroid dysfunction affects fertility. Studies suggest that thyroid disorder affecting follicular process is associated with ovarian reserve. Similarly serum FSH is directly related to AMH depicting strong correlation of age with each other. This study was conducted to see the association between thyroid dysfunction and serum Anti Mullerian Hormone (AMH) level. Methods: All the female having infertility between age of 20 to 45 were included in the study. Those who did not undergo hormonal assay were excluded from study. All the data were taken from Opd record and their serum Thyroid Stimulating Hormone, AMH and Day2 Follicle Stimulating Hormone Luteinizing Hormone, Prolactin, Estradiol and Progesterone were evaluated. Result: A total of 292 patients visited infertility clinic at our institution over a period of 1.5 yrs and of them only 80 had undergone all hormonal assay. Majority of women enrolled for the study were in the age group 21-30 and the mean age was 29.98±5.4 yrs. Hypothyroidism was seen in 27.5% (n=22) females while we found no cases of hyperthyroidism in our study. Though 35% of females had TSH &lt;2.5. Low serum AMH levels (&lt;1.6 ng/ml) were noted in 25% (n=20). Among women of age less than 35 yrs and low AMH (&lt;1.6) mean TSH was 7.27±6.93 and with normal AMH (&gt;1.6) mean TSH was 3.61±1.73 which was statistically significant (p-value &lt;0.001). Similarly mean FSH in women with low AMH (&lt;1.6) was 8.66±2.89 and with normal AMH (&gt;1.6) was 5.81±1.36 which was statistically significant (p-value &lt;0.001). Conclusion: TSH and FSH level is inversely related to ovarian reserve infertile women.

Elevated Thyroglobulin Antibody Level is Associated with Decreased Anti-Müllerian Hormone in Women of Reproductive Age.

Women with Hashimoto's thyroiditis (HT) have an increased risk of ovarian insufficiency. However, whether thyroid antibodies affect the ovarian reserve remains controversial. The aim of this study was to explore the possible relationship between anti-Müllerian hormone (AMH) and thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) levels in women of reproductive age. A total of 483 women between 18 and 45 years old who had their TPOAb, TgAb, thyroid-stimulating hormone (TSH), free thyroxine (FT4), and AMH levels measured on the same day were enrolled in this study. The levels of TSH, FT4, TPOAb, and TgAb, the prevalence of overt and subclinical hypothyroidism, and the positive rate of TPOAb and TgAb were compared between patients with low (below the 10th percentile), normal (10th to 90th percentile), and high (higher than the 90th percentile) AMH levels. The median AMH level was 1.72 (0.33-4.27) ng/mL. A total of 9.9% of patients had low AMH levels. The TgAb levels and the prevalence of TgAb positivity were higher in the low AMH group (37.62 (13.10-232.68) IU/mL, 35.42%) than in the normal (12.46 (10.0-67.04) IU/mL, 19.59%) and high (13.61 (10.0-95.74) IU/mL, 23.4%) AMH groups (p=0.001, p=0.040, respectively). Serum AMH levels were inversely correlated with TgAb levels (r = -0.114, p=0.013). The AMH of women of reproductive age is affected by HT. Furthermore, women with the lowest AMH level had higher levels of TgAb and a positive rate of TgAb, and high TgAb levels may cause autoimmune damage to the ovaries.

Cumulative cyclophosphamide dose and serum anti-Mullerian hormone levels in adolescent cancer survivors in Indonesia

Background As both the prevalence and survival rates of cancer in children and adolescents has risen, longer-term effects of cancer treatment must be investigated. High-risk gonadotoxic chemotherapeutic agents such as cyclophosphamide may affect the ovarian reserve and impact female adolescent fertility. Anti-Mullerian hormone is a reliable marker to assess ovarian reserve.&#x0D; Objective To assess for a possible correlation between the cumulative dose of cyclophosphamide and serum anti-Mullerian hormone (AMH) levels among adolescent cancer patients.&#x0D; Methods This cross-sectional study included 12-18-year-old adolescent female cancer patients who had experienced menarche and received cyclophosphamide therapy. We recorded the patients’ full history, including menstrual history, computed the cumulative dose of cyclophosphamide received, and measured serum AMH levels. The correlation test was performed to evaluate for a possible correlation between the cumulative dose of cyclophosphamide and ovarian reserve as represented by AMH levels.&#x0D; Results Out of 12 female adolescent cancer patients, three complained of disturbances in their menstrual cycles. Low levels of AMH (&lt;1.5 ng/mL) were noted in five patients. Median cumulative cyclophosphamide dose was 1,000 mg/m2 (range 1,000 to 5,250 mg/m2). Cumulative cyclophosphamide dose was negatively correlated with serum AMH levels, but this correlation was not statistically significant (r=-0.316, P=0.318).&#x0D; Conclusion This study has not been able to show a correlation between cumulative cyclophosphamide dose and serum AMH level. Regular evaluation of fertility and involvement of fertility team is recommended in adolescents receiving high-risk gonadotoxic chemotherapeutic agents.

Mechanism of protective effect of resveratrol on poor ovarian response in mice

This study aims to investigate the therapeutic effects and potential mechanisms of resveratrol(Res) on poor ovarian response(POR) in mice. The common target genes shared by Res and POR were predicted by network pharmacology, used for Gene Ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment, and then validated by animal experiments. The mice with regular estrous cycle after screening were randomized into normal, POR, and low-and high-dose(20 and 40 mg·kg~(-1), respectively) Res groups. The normal group was administrated with an equal volume of 0.9% sodium chloride solution by gavage, and the mice in other groups with tripterygium glycosides suspension(50 mg·kg~(-1)) by gavage for 2 weeks. After the modeling, the mice in low-and high-dose Res groups were treated with Res by gavage for 2 weeks, and the mice in normal and POR groups with an equal volume of 0.9% sodium chloride solution by gavage. Ovulation induction and sample collection were carried out on the day following the end of treatment. Vaginal smears were collected for observation of the changes in the estrous cycle, the counting of retrieved oocytes, and the measurement of ovarian wet weight and ovarian index. The enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of anti-mullerian hormone(AMH), follicle-stimulating hormone(FSH), estradiol(E_2), and luteinizing hormone(LH) in the serum. The ovarian tissue morphology and granulosa cell apoptosis were observed by hematoxylin-eosin(HE) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL), respectively. Western blot was employed to determine the protein levels of phosphatidylinositol 3-kinase(PI3K), protein kinase B(AKT), forkhead box O(FOXO) 3a, hypoxia-inducible factor(HIF)-1α, B-cell lymphoma-2(Bcl-2), and Bcl-2-associated X protein(Bax). A total of 222 common targets shared by Res and POR were collected. GO annotation indicated that these targets were mainly involved in oxidative stress response. KEGG enrichment analysis revealed that Res can intervene in POR via PI3K/AKT, HIF-1, and FOXO signaling pathways. Animal experiments showed that the model group had higher rate of estrous cycle disorders, lower number and poorer morphology of normally developed follicles at all levels, more atretic follicles, higher apoptosis of ovarian granulosa cells, lower number of retrieved oocytes, lower ovarian wet weight and ovarian index, higher serum levels of FSH and LH, lower levels of AMH and E_2, higher expression levels of HIF-1α, FOXO3a and Bax, and lower expression levels of PI3K, AKT, and Bcl-2 in the ovarian tissue than the normal group. Compared with the POR group, low-and high-dose Res decreased the rate of estrous cycle disorders, improved the follicle number and morphology, reduced atretic follicles, promoted the apoptosis of ovarian granulosa cells, increased retrieved oocytes, ovarian wet weight and ovarian index, and lowered serum FSH and LH levels. Moreover, Res down-regulated the expression levels of HIF-1α, FOXO3a and Bax, and up-regulated the expression levels of PI3K, AKT and Bcl-2 in the ovarian tissue. In summary, Res can inhibit apoptosis and mitigate poor ovarian response in mice by regulating the PI3K/AKT/FOXO3a and HIF-1α pathways.

Kaempferol exerts antioxidant effects in age-related diminished ovarian reserve by regulating the HSP90/NRF2 pathway.

Kaempferol is the active ingredient of Er-Xian decoction (EXD), a traditional Chinese medicine formula used clinically to treat ovarian dysfunction, but the mechanism of kaempferol relieving age-related diminished ovarian reserve (AR-DOR) is still unclear. In this study, 36 volunteers and 78 DOR patients (37 patients with EXD treatment) were enrolled in the clinical research. Meanwhile, 32-week-old female mice were used to establish the AR-DOR model, and these model mice were intragastrically administered with 100 mg/kg kaempferol in the presence or absence of 200 mg/kg geranylgeranylacetone (GGA) or 1 mg/kg geldanamycin (GDA). The effects of kaempferol on serum hormone levels and oxidative stress-related indexes were detected by enzyme-linked immunosorbent assay. Antral follicle count (AFC) was determined by hematoxylin-eosin staining. The protein levels of HSP90 and nuclear factor erythroid 2-related factor 2 (NRF2) were assayed by Western blot. This study displayed that the serum anti-Mullerian hormone (AMH) level in DOR patients with EXD treatment was higher than that in DOR patients without EXD treatment. Kaempferol treatment reversed the low levels of AMH, estradiol (E2), AFC, superoxide dismutase (SOD), and catalase (CAT), as well as the high levels of follicle-stimulating hormone (FSH), reactive oxygen species (ROS), and malonaldehyde (MDA). The results showed that HSP90 was predicted to have high affinity with kaempferol, and its expression was inhibited by kaempferol, while the expression of NRF2, the target of HSP90, was up-regulated by kaempferol. However, the above effects of kaempferol were reversed by GGA. On the contrary, GDA enhanced the therapeutic effects of kaempferol on AR-DOR mice. Moreover, the treatment of kaempferol resulted in a reduction in the phosphorylation level of heat shock factor 1 (HSF1), the transcription factor associated with HSP90, and an increase in the phosphorylation level of Src, a client protein of HSP90. In summary, kaempferol exerts an antioxidant effect on AR-DOR by inhibiting HSP90 expression to up-regulate NRF2 expression. This study provides a theoretical basis for the clinical application of kaempferol in AR-DOR.

Frequency of diminished ovarian reserve in women with multiple sclerosis in Chile: An exploratory study

IntroductionMultiple Sclerosis (MS) is a chronic disease affecting around 2.8 million people worldwide. Two-thirds are women, and the mean age at diagnosis is about 30 years old. Social trends are moving towards older age at first pregnancy, both in women with and without MS. ObjectivesTo determine the frequency of diminished ovarian reserve (DOR) through anti-Mullerian Hormone (AMH) measurement in women with MS at fertile age and Healthy Females (HF) in Chile. MethodsCase-control, multicentric, cross-sectional study including relapsing-remitting people with MS (pwMS) between 18 and 40 years and sex and age-matched HF. We obtained a blood sample to determine AMH levels. We defined DOR as AMH <1.5 ng/mL and very-low AMH levels as <0.5 ng/mL. Also, we performed questions regarding reproductive decision-making. ResultsWe included 79 sex and age-matched HF and 92 pwMS, median age 32(19–40) years, median disease duration 6 (1–17)years, median EDSS 1.0 (0–6), 95% were receiving disease-modifying therapy (DMT), 70% high-efficacy DMT and 37% with a treatment that contraindicates pregnancy. DOR was observed in 24% (n = 22) of the pwMS, compared to 14% (n = 11) of the HF (p = 0.09), while very-low AMH levels were observed in 7.6% (n = 7) of pwMS and none of the HF (p = 0.0166). We observed an inverse correlation between age and AMH levels. Age was the only significant risk factor for low AMH levels in pwMS (OR 1.14 95%CI(1.00–1–31), p = 0.04), including smoking, body mass index (BMI), hormonal contraception, autoimmune comorbidity, high/low-moderate efficacy DMT, and active disease as covariables. We did not find statistically significant differences in age at diagnosis, BMI, disease duration, EDSS, autoimmune comorbidity, use of hormonal contraception, or percentage of active disease between MS women with normal vs DOR. Over 70% of pwMS desired to become pregnant in the future, while 60% considered that the diagnosis of MS was a limitation for pregnancy planning. ConclusionsNo differences in DOR, measured by levels of AMH, were observed between pwMS MS and HF in Chile. As expected, AMH levels were correlated only with ageing. This information may be evaluated early during the disease course to help patients and neurologists with fertility counselling and family planning considerations regarding DMT use.