Undetectable anti-Müllerian Hormone Research Articles

Can evaluation of seminal plasma and serum anti-Müllerian hormone be useful in the diagnosis of male infertility? (Literature review)

Background. Anti-Müllerian hormone (AMH) is secreted in men by Sertoli cells and plays an important role in the development of the male reproductive organs. High expression of AMH during embryonic development contributes to the regression of the Müllerian (paramesonephric) ducts; in the absence of AMH, the Müllerian ducts develop into the female internal genital organs. In adulthood, the clinical value of measuring AMH in serum and seminal plasma remains controversial. It is assumed that AMH, as a marker of the functional state of Sertoli cells, can be useful in the diagnosis of male infertility.Aim. To determine the clinical value of measuring serum and seminal plasma AMH levels in the diagnosis of male infertility by examining the current evidence base in the world literature.Materials and methods. A search was made for publications devoted to the study of the role of AMH in the diagnosis of male infertility in the international database PubMed, in the scientific electronic library eLIBRARY.RU and in the Google Scholar search engine. There were no restrictions regarding the status and period of publication.Results and conclusion. The results of the analysis indicate the absence of a significant relationship between the parameters of the ejaculate and the serum concentration of AMH, which does not allow using this indicator to assess male fertility. Serum AMH is of no value in the differential diagnosis of obstructive and non-obstructive azoospermia, the prediction of assisted reproductive technologies outcomes, and the prediction of testicular biopsy outcomes in the general non-obstructive azoospermia patient population. It is likely that serum AMH may be useful in predicting testicular biopsy results in patients with Klinefelter’s syndrome and idiopathic non-obstructive azoospermia.The clinical application of measuring the level of AMH in seminal plasma is limited by the high variability of this indicator, probably due to the dependence on the volume of the ejaculate and exposure to semen proteolytic enzymes. This indicator may be useful for the differential diagnosis of obstructive and non-obstructive azoospermia. In obstructive azoospermia, AMH is not detected in seminal plasma, but undetectable AMH concentrations can also be observed in patients with non-obstructive azoospermia, which reduces the differential value of this indicator. A promising direction is the use of AMH concentration in seminal plasma to predict the recovery of sperm motility after cryopreservation.

Undetectable anti-Mullerian hormone and inhibin B do not preclude the presence of germ cell tumours in 45,X/46,XY or 46,XY gonadal dysgenesis.

Individuals with 45,X/46,XYor 46,XYgonadal dysgenesis are at increased risk of germ cell malignancies. Therefore, prophylactic bilateral gonadectomy is advised in girls and considered in boys with atypical genitalia for undescended, macroscopically abnormal gonads. However, severely dysgenetic gonads may not contain germ cells rendering gonadectomy unnecessary. Therefore, we investigate if undetectable preoperative serum anti-Müllerian hormone(AMH) and inhibin B can predict the absence of germ cells, (pre)malignant or otherwise. Individuals who had undergone bilateral gonadal biopsy and/or gonadectomy because of suspected gonadal dysgenesis in 1999-2019 were included in this retrospective study if preoperative AMH and/or inhibin B were available. Histological material was reviewed by an experienced pathologist. Haematoxylin and eosin and immunohistochemical stainings for SOX9, OCT4, TSPY and SCF (KITL) were used. Thirteen males and 16 females were included, 20 with 46,XYand 9 with 45,X/46,XY DSD. Threefemales had dysgerminoma alongside gonadoblastoma; twogonadoblastoma, one germ cell neoplasia in situ (GCNIS) and three males had pre-GCNIS and/or pre-gonadoblastoma. Gonadoblastoma and/or dysgerminoma were present in 3/11 individuals with undetectable AMH and inhibin B, one of whom also had non-(pre)malignant germ cells. Of the other 18, in whom AMH and/or inhibin B were detectable, only one had no germ cells. Undetectable serum AMH and inhibin B cannot reliably predict the absence of germ cells and germ cell tumours in individuals with 45,X/46,XYor 46,XYgonadal dysgenesis. This information should help in counselling about prophylactic gonadectomy, taking into account both the germ cell cancer risk and potential for gonadal function.

A Surgical and Clinical Approach to Persistent Müllerian Duct Syndrome: Laparoscopic, Histological, and Molecular Findings

Background: Persistent müllerian duct syndrome (PMDS) is characterized by the persistence of müllerian duct derivatives in otherwise normally virilized 46,XY males. Biallelic mutations of the anti-müllerian hormone (AMH) and AMH receptor type 2 (AMHR2) genes lead to PMDS type 1 and 2, respectively. Aim: The aims of the study were to report the clinical, hormonal, and genetic findings in a patient with PMDS and discuss surgical strategies to achieve successful orchidopexy. Results: A 4-year-old boy was evaluated after the incidental finding of müllerian derivates during laparoscopy for nonpalpable gonads. Karyotype was 46,XY and laboratory tests revealed normal serum gonadotropin and androgen levels but undetectable serum AMH levels. PMDS was suspected. Molecular analysis revealed a novel variant c.902_929del in exon 5 and a previously reported mutation (c.367C>T) in exon 1 of the AMH gene. Successful orchidopexy was performed in two sequential surgeries in which the müllerian duct structure was preserved and divided to protect the vascular supply to the gonads. Histological evaluation of the testicular biopsy showed mild signs of dysgenesis. Doppler ultrasound showed blood flow in both testes positioned in the scrotum 1.5 years after surgery. Conclusion: PMDS is a rare entity that requires a high index of suspicion (from surgeons) when evaluating a patient with bilateral cryptorchidism. Surgical treatment is challenging and long-term follow-up is essential. Histological evaluation of the testis deserves further investigation.

Anti-Müllerian Hormone Level Decline in Patients Undergoing Hysterectomy With and Without Oophorectomy Compared With Natural Menopause.

To evaluate the relationship between hysterectomy with and without ovarian conservation and the onset of ovarian failure using anti-müllerian hormone (AMH) levels and imputed final menstrual period (FMP). A total of 1,428 women with an observed FMP and 232 women who underwent hysterectomy (159 with bilateral salpingo-oophorectomy [BSO], 13 with one ovary conserved, and 60 with both ovaries conserved) and who had serial AMH measurements were included from SWAN (The Study of Women's Health Across the Nation), a multi-ethnic, multi-site, community-based study. Anti-müllerian hormone levels were sampled annually with at least one presurgery or pre-FMP measurement at least one postsurgery or post-FMP measurement. Surgery-related differences in patterns of AMH levels with respect to surgery date or FMP were estimated using piecewise linear mixed modeling; differences in age at first undetectable AMH level were estimated using survival analyses. Patients with conservation of one or both ovaries or natural menopause demonstrated similar patterns of decline in AMH levels when anchored to surgery or FMP. Patients with hysterectomy (all types) had a later counterfactual FMP (52.9±0.2 SEM) compared with the observed FMP in those with natural menopause (52.1±0.1 years, P =.002). Those undergoing BSO had an immediate reduction in AMH level to undetectable after surgery. Hysterectomy does not lead to a more rapid decline in AMH levels postoperatively compared with natural menopause. Patients undergoing BSO have a rapid loss of AMH, consistent with complete removal of the ovaries. These data suggest that hysterectomy as currently performed does not compromise ovarian reserve.

Gonadal Hormone Production after Hematopoietic Cell Transplant (HCT) in Patients with Sickle Cell Disease (SCD): A Stellar Study

Introduction HCT is the only therapy for SCD with curative intent, but the alkylator chemotherapies used in preparative regimens place patients at high risk for gonadal dysfunction. Adequate ovarian and testicular hormone production post-HCT is important for optimal health. Methods We enrolled children and adults with SCD ≥ 1-year post-HCT ("HCT") in the Sickle Cell Transplant Evaluation of Long-term and Late Effects Registry (STELLAR) and a control group of patients with SCD not treated with HCT ("non-HCT"). We obtained annual surveys of gonadal health using a web-based platform. Surveys were completed by proxies for individuals <18 years and were self-report for individuals ≥18 years. Markers of ovarian reserve or testicular function were measured, including follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH) in females and FSH and testosterone in males. The most recent survey was used for analysis when multiple surveys were available. The upper limit of normal (ULN) for age of pubertal onset was defined as 13 years in females and 14 in males, and the ULN for menarche was 15 years. Only females >13 years and males >14 years (ULN for activation of the hypothalamic pituitary gonadal axis) were included in the FSH analysis. Descriptive statistics were reported as median (Interquartile range [IQR]: 3rd quartile - 1st quartile), mean (min, max) or count (%). Statistical procedures involved a chi-squared test. The effect size was calculated using standard mean difference (SMD). Results Surveys were completed by 48 SCD HCT patients (30 females, 18 males) and 12 SCD control patients (8 females, 4 males). Median age (IQR) at survey completion was 14.8 years (11.8) for female HCT, 16.0 (10.4) for male HCT, 14.5 (11.6) for female non-HCT, and 21.0 (22.8) for male non-HCT. Median age (IQR) at HCT was 8.8 years (6.1) for females and 9.1 years (5.2) for males. Most patients underwent HCT in 2010-2020 (86.7% of females, 78.8% of males). Donor was predominantly matched related (90.0% of females, 94.4% of males) with bone marrow stem cell source (90.0% of females, 94.4% of males). Most patients received myeloablative conditioning (86.7% of females, 94.4% of males). Only female HCT patients (n=8, 32%) reported being told they might need hormones to enter puberty. In females who were ≥15 years, menarche was reported in 11 (78.6%) HCT and all of the non-HCT patients. Current menstruation was reported in 9 (64.3%) HCT and 3 (75.0%) of non-HCT patients, and 10 (71.4%) HCT and 1 (25%) non-HCT females reported ever having taken hormones, including birth control. P-values and SMD can be seen in Table 1. Hormone levels were measured in 68 HCT patients (41 female, 27 male). Most patients underwent HCT from 2010-2020 (82.9% of females; 74.1% of males) using matched related donor (90.2% of females, 92.6% of males) bone marrow (87.8% of females, 85.2% of males) following myeloablative conditioning (87.8% of females, 88.9% of males). For females, the median age at the time of AMH testing was 16.5 years (IQR 9.1) with a mean of 6.8 years (IQR 4.8) post-HCT. Based on the age and assay normal values, AMH levels were normal in 3 (7.3%), low but detectable in 7 (17.1%), and undetectable in 31 (75.6%) of patients. FSH was measured in 12 females who were >13 years and not on hormone therapy (Table 2). The median age at FSH testing was 18.0 years (IQR 5.1), with a mean of 8.7 years (IQR 3.5) post-HCT. FSH levels were normal in 7 (58.3%) and above the ULN in 5 (41.7%), 3 of which were menopausal (>30mIU/mL). Testosterone values were obtained in 15 males who were >14 years with a median age 18.9 years (IQR 5.9) and a mean of 6.9 years (IQR 5.1) post-HCT. The mean testosterone level was 365.8 ng/dl (range 152-592), 13 (86.7%) of which were in the normal range and 2 (13.3%) being low. FSH values in males >14 years were high in 4 (26.7%). Conclusions Nearly all females had diminished ovarian reserve post-HCT, with >75% having undetectable AMH levels. In addition, close to half of the females had elevated FSH levels, some in the menopausal range. However, females with normal FSH and normal or low AMH can consider post-HCT mature oocyte cryopreservation. Most males had normal testosterone levels, but >25% had elevated FSH levels which could be a signal of impaired spermatogenesis. These findings highlight the importance of studying the impact of HCT on gonadal function and the consideration of these outcomes when developing protocols for curative therapy in SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of antim\xfcllerian hormone with polycystic ovarian syndrome phenotypes and pregnancy outcomes of in vitro fertilization cycles with fresh embryo transfer

ObjectiveThe current study was undertaken to investigate the relationship between antimüllerian hormone (AMH) and polycystic ovarian syndrome (PCOS) phenotypes and to determine whether AMH is associated with pregnancy outcomes in infertile women undergoing their first in vitro fertilization (IVF) treatment.MethodsWe performed a retrospective cohort study of 2973 infertile women, including 418 women with PCOS undergoing their first IVF treatment at a private fertility center from January 2014 to March 2018. Women were stratified into three groups using cutoffs defined by the 25th and 75th percentiles of the serum AMH level: 746 women had AMH ≤ 2.25 ng/mL; 1486 women had AMH between 2.25 to 5.71 ng/mL; and 741 women had AMH > 5.71 ng/mL. Endocrine characteristics, PCOS phenotypes, stimulation outcomes, pregnancy outcomes were compared among these groups. When there were any statistical differences (P < 0.05) among the three groups, Bonferroni test was performed as post-hoc tests to determine where the statistical differences existed. To assess the relationships between AMH and pregnancy outcomes in total patients and PCOS patients, logistic regression analysis, adjusted for potential confounding covariates, were performed.ResultsWomen with high AMH had greater prevalence of hyperandrogenism (HA), polycystic ovarian morphology (PCOM) and amenorrhea than women with low or average AMH. The clinical pregnancy rate were significantly higher in the high-AMH group compared with low- and average-AMH groups (69.9% vs. 58.8% and 64.7% respectively; P < 0.001). The live birth rate was significantly lower in women with AMH ≤ 2.25 ng/mL compared with average- and high-AMH groups (47.6% vs. 55.2 and 59.5% respectively; P < 0.001). However, after controlling for maternal age, oocyte yield, as well as other confounders, AMH was no longer associated with a higher live birth rate (aOR 1.037, 95% CI 0.853–1.261, P = 0.717; aOR 1.099, 95% CI 0.858–1.408, P = 0.455, respectively) and clinical pregnancy rate (aOR 1.064, 95% CI 0.834–1.359, P = 0.617; aOR 1.181, 95% CI 0.875–1.595, P = 0.276, respectively). Moreover, pregnancy outcomes did not differ in PCOS women according to AMH quartiles.ConclusionIncreased AMH levels associated with PCOS severity and greater ovarian stimulation. However, AMH was not associated with clinical pregnancy rate and live birth rate after controlling for other confounders in women undergoing IVF. Thus, AMH should not be used to alter clinical decisions and exclude patients based on a low or even undetectable AMH value.

Anti-Müllerian hormone as a marker of ovarian reserve and premature ovarian insufficiency in children and women with cancer: a systematic review.

BACKGROUNDFemale patients undergoing anticancer treatment are at elevated risk of adverse ovarian outcomes including infertility and premature ovarian insufficiency (POI), which is associated with short- and long-term health risks. Anti-Müllerian hormone (AMH) is a key biomarker of ovarian reserve, but its role prior to and after cancer treatment is less well understood.OBJECTIVE AND RATIONALETo conduct a systematic review evaluating AMH as a biomarker of ovarian reserve and POI before and after anticancer treatment, which has become a pressing clinical issue in reproductive medicine. There are a large number of observational studies, but differences in patient groups, cancer diagnoses and study design make this a confusing field that will benefit from a thorough and robust review.SEARCH METHODSA systematic literature search for AMH in women with cancer was conducted in PubMed, Embase and Cochrane Central Register of Controlled Trials up to 1 April 2021. Bias review was conducted using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) protocol along with qualitative assessment of quality. Exploratory subgroups were established based on age, cancer type and length of follow-up.OUTCOMESNinety-two publications (N = 9183 patients) were included in this analysis after quality and bias review. Reduced/undetectable AMH was consistently identified in 69/75 studies (92%) following chemotherapy or radiotherapy, with reductions ranging from 42% to concentrations below the limit of detection, and many reporting mean or median declines of ≥90%. Where longitudinal data were analysed (42 studies), a majority (33/42 (79%)) of studies reported at least partial recovery of AMH at follow-up, however, effect estimates were highly variable, reflecting that AMH levels were strongly impacted by anticancer treatment (i.e. the chemotherapy regimen used and the number of treatment cycles need), with recovery and its degree determined by treatment regimen, age and pre-treatment AMH level. In 16/31 (52%) publications, oligo/amenorrhoea was associated with lower post-treatment AMH consistent with impending POI, although menstruation and/or pregnancy were reported in patients with low or undetectable AMH. Long-term (>5 years) follow-up of paediatric patients following cancer treatment also found significantly lower AMH compared with control groups in 14/20 (70%) of studies, with very variable effect sizes from complete loss of AMH to full recovery depending on treatment exposure, as in adult patients.WIDER IMPLICATIONSAMH can be used to identify the damaging effect of cancer treatments on ovarian function. This can be applied to individual women, including pre-pubertal and adolescent girls, as well as comparing different treatment regimens, ages and pre-treatment AMH levels in populations of women. While there was evidence for its value in the diagnosis of POI after cancer treatment, further studies across a range of diagnoses/treatment regimens and patient ages are required to clarify this, and to quantify its predictive value. A major limitation for the use of AMH clinically is the very limited data relating post-treatment AMH levels to fertility, duration of reproductive lifespan or time to POI; analysis of these clinically relevant outcomes will be important in further research.

Is ovarian recovery after chemotherapy in young patients with early breast cancer influenced by controlled ovarian hyperstimulation for fertility preservation or tumor characteristics? Results of a prospective study in 126 patients.

Young individuals, aged <40 years, represent 7% of all patients with early breast cancer (EBC), most of whom receive chemotherapy. Preserving future fertility in these patients has become a major concern. This prospective study assessed ovarian function during and after chemotherapy according to patient and tumor characteristics and evaluated the outcome of controlled ovarian hyperstimulation (COH). Ovarian reserve was evaluated in terms of amenorrhea duration and by longitudinal serum anti-Müllerian hormone (AMH) level variations measured at study entry, during treatment and until 24 months thereafter. COH has been proposed for patients receiving adjuvant chemotherapy. We studied the association between clinical factors and ovarian function using Cox models and logistic regression. In this young population (age < 38 years, median=32), 85 of 90 evaluable patients (94%) experienced chemo-induced amenorrhea, including six persistent amenorrhea and one chemotherapy-induced definitive ovarian failure. Overall, 33% of patients still had undetectable AMH values 12 months after the end of chemotherapy, although most had recovered spontaneous and regular menstrual function. No specific factor was associated with clinical or biological late ovarian dysfunction, except for age and baseline AMH value. Overall, 58 patients underwent COH. The mean number of total retrieved oocytes and metaphase II oocytes were of 11.7 and 6.9, respectively. Thus, our study confirms the importance of fertility preservation in young patients with EBC. Our findings indicate that sequential chemotherapy is associated with a higher risk of persistent amenorrhea. There was no significant association between tumor characteristics, fertility preservation or recovery of ovarian reserve.

Anti-Müllerian hormone (AMH) as a marker of ovarian reserve and premature ovarian insufficiency (POI) in children and women with cancer: A systematic review.

e24057 Background: Female patients undergoing anticancer treatment are at elevated risk of ovarian damage including development of POI. AMH is a key serum biomarker of ovarian reserve. However, its role to identify risk of POI in cancer patients prior to and after treatment is less well understood. Methods: A systematic literature search for AMH in women with cancer was conducted up to 30 August 2020, with formal bias assessment. We aimed at evaluating AMH as a biomarker of ovarian reserve and POI before and after anticancer treatment. Exploratory subgroups were based on age, cancer type and length of follow-up. Results: : Eighty publications (including 7,708 patients) were included in this analysis. All papers reporting AMH before and after treatment reported a large reduction in AMH following treatment, in both adult and paediatric populations. Effect sizes varied depending on the treatment and diagnosis, but ranged from 42% to below the limit of detection, and many reported declines of ≥90%. A majority (25/34, 74%) of studies also reported at least partial recovery of AMH at follow-up. Pre-treatment AMH correlated with post-treatment levels in all studies and younger patient age with higher post-treatment AMH in 21/29 (72%) studies. In 18/32 (58%) publications, oligo/amenorrhea correlated with lower post-treatment AMH. No studies reported correlations between post-treatment AMH and pregnancy, although pregnancy was reported in some patients with low or undetectable AMH. 70% of publications found that within-study variations in treatment (estimated by chemotherapy or radiotherapy type, dosage, duration and/or number of cycles) correlated with AMH reductions and degree of recovery, indicating its potential value as a marker of gonadotoxicity. In women with breast cancer, recovery of AMH was reported in some patients in 10/18 publications; however, AMH levels showed no recovery in many patients receiving alkylating agents or cyclophosphamide-based chemotherapies. In lymphoma, patients receiving ABVD-based regimens had at least partial post-treatment recovery of AMH at follow-up compared with those receiving cyclophosphamide-containing regimens. 16/20 (80%) publications in pediatric cancer patients showed significant reductions in AMH compared with pre-treatment levels or controls. The diagnostic value of post-treatment AMH for POI was supported in 5/5 (100%) studies. AMH levels measured 1–2 years after treatment appeared to be equally reliable at indicating longer-term menstrual outcomes as studies with longer followup. Conclusions: AMH levels were strongly impacted by anticancer treatment, with recovery in some women determined by treatment regimen, age, and pretreatment AMH level. There was evidence for its role in diagnosis of POI, nut further studies are required to clarify its value to assist in patient management.

Early-life Farm Exposure and Ovarian Reserve in a US Cohort of Women.

In a previous exploratory study, we reported lower concentrations of the ovarian reserve biomarker anti-Müllerian hormone (AMH) in adulthood with prenatal farm exposure. We now examine this association as well as childhood farm exposure using enrollment data from the Sister Study, a large US cohort of women. We collected prenatal and childhood farm exposure data by questionnaire and telephone interview. However, serum AMH data were available only for a nested subset: premenopausal women ages 35-54 subsequently diagnosed with breast cancer (n = 418 cases) and their matched controls (n = 866). To avoid potential bias from restricting analyses to only premenopausal controls, we leveraged the available cohort data. We used data from both premenopausal cases and controls as well as postmenopausal women ages 35-54 (n = 3,526) (all presumed to have undetectable AMH concentrations) and applied weights to produce a sample representative of the cohort ages 35-54 (n = 17,799). The high proportion of undetectable AMH concentrations (41%) was addressed using reverse-scale Cox regression. An adjusted hazard ratio (HR) <1.0 indicates that exposed individuals had lower AMH concentrations than unexposed individuals. Prenatal exposure to maternal residence or work on a farm was associated with lower AMH concentrations (HR 0.66; 95% confidence intervals [CI] = 0.48 to 0.90). Associations between childhood farm residence exposures and AMH were null or weak, except childhood contact with pesticide-treated livestock or buildings (HR 0.69; 95% CI = 0.40 to 1.2). Replication of the prenatal farm exposure and lower adult AMH association raises concern that aspects of prenatal farm exposure may result in reduced adult ovarian reserve.

Effect of radiotherapy for rectal cancer on female sexual function: a prospective cohort study.

Abstract Background Clinical experience and limited data show that female sexual function is influenced negatively by preoperative radiotherapy (RT) for rectal cancer. The aim of this prospective study was to investigate the impact of RT on sexual function and ovarian reserve measured by levels of anti-Müllerian hormone (AMH). Methods Women with stage I–III rectal cancer scheduled for surgery with or without preoperative (chemo)RT were included and followed for 2 years. Female Sexual Function Index (FSFI) questionnaire responses and blood samples for hormone analyses, including AMH in women aged 45 years or less, were collected at baseline and during follow-up. Results In the group of 109 women who received preoperative RT, median scores in all FSFI domains decreased over time, as did the total FSFI score (from 18·5 (range 2·0–36·0) at baseline to 10·8 (2·0–34·8) at 2 years; P &amp;lt; 0·001). In the group of 30 women who did not receive preoperative RT, only satisfaction declined over time (from 3·2 (0·8–6·0) to 1·8 (0·8–6·0); P = 0·012). In longitudinal regression analysis, the mean decline in FSFI total score was –9·33 (95 per cent c.i. –16·66 to –1·99; P = 0·013) for women who had preoperative RT compared with those who did not, with adjustment for age, Psychological General Well-being Index score and relationship with partner. A corresponding association was seen for arousal, lubrication, orgasm and pain. Five of six women aged 45 years or less with detectable serum levels of AMH at baseline had undetectable levels after RT. Conclusion Preoperative RT was associated with impairment in sexual function in women with rectal cancer. This needs to be considered when discussing choice of treatment and rehabilitation. In younger women, undetectable AMH levels after RT indicate an irreversible loss of ovarian follicles.

SAT-194 Correlation of Capillary and Venous Plasma Measurements of Anti-Müllerian Hormone

Anti-Müllerian Hormone (AMH) is a member of the transforming growth factor β superfamily which regulates gonadal development and differentiation. AMH is a biomarker for ovarian age and reserve used to assess fertility and predict ovulation induction outcome. It is also a marker for diagnosis and treatment of polycystic ovarian syndrome (PCOS), menopausal transition, and gonadal function. As diagnostic testing begins to expand into self-collection and point-of-care capabilities, there is a need to minimize sample volume requirements and include additional sample types. The TAP device, manufactured by Seventh Sense Biosystems (Medford, MA), is a small, easy to use, single push device that collects approximately 100 µL whole blood from the upper arm. As the blood travels through the channels of the device it is mixed with lithium heparin anticoagulant. The device collects capillary blood and is FDA approved for use in hemoglobin A1c measurements. In this study, AMH levels in venous and capillary plasma were compared. AMH was measured by an electrochemiluminescent immunoassay requiring only 40 µL plasma. The performance characteristics of the assay including accuracy, precision, linearity, and limits of quantitation were assessed. The stability of samples stored in the TAP device was also evaluated. Twenty-one female volunteers ages 24 to 67 donated paired venous and capillary blood samples. Venous plasma from donors with undetectable AMH levels was used as a matrix for spike and recovery studies to verify acceptable accuracy and precision across the analytical measurement range (AMR) and establish the lower (LLOQ) and upper (ULOQ) limits of quantitation. The ULOQ and LLOQ were 15 and 0.15 ng/mL, respectively. Accuracy was within 20% and precision within 15% across the AMR. Linearity was evaluated by serially diluting samples with high levels of AMH in AMH-negative pooled plasma. The maximum acceptable dilution was 8-fold. Correlation of venous and capillary results was excellent. A linear least square model resulted in a coefficient of determination (R2) of 0.998. Four capillary blood samples were collected from each of three donors for stability analysis. One was processed immediately and used as the baseline. The remaining three samples were stored at 2-8°C in the TAP device for 3, 5 and 7 days before processing. Plasma collected after 5 and 7-day storage in the TAP device was moderately hemolyzed and smaller volumes were retrieved. The hemolysis did not impact AMH measurement. AMH was stable at all time points tested with mean recovery of 104% compared to baseline values. This study shows that very small volumes of venous and capillary plasma can be used to accurately measure AMH levels. The ability to measure AMH in capillary blood via the TAP device allows for quick and reproducible blood collection, potentially outside the healthcare setting, improving access to diagnostic information.

Regulation of anti-Müllerian hormone (AMH) in males and the associations of serum AMH with the disorders of male fertility.

Anti-Müllerian hormone (AMH) is a functional marker of fetal Sertoli cells. The germ cell number in adults depends on the number of Sertoli cells produced during perinatal development. Recently, AMH has received increasing attention in research of disorders related to male fertility. This paper reviews and summarizes the articles on the regulation of AMH in males and the serum levels of AMH in male fertility-related disorders. We have determined that follicle-stimulating hormone (FSH) promotes AMH transcription in the absence of androgen signaling. Testosterone inhibits the transcriptional activation of AMH. The undetectable levels of serum AMH and testosterone levels indicate a lack of functional testicular tissue, for example, that in patients with anorchia or severe Klinefelter syndrome suffering from impaired spermatogenesis. The normal serum testosterone level and undetectable AMH are highly suggestive of persistent Müllerian duct syndrome (PMDS), combined with clinical manifestations. The levels of both AMH and testosterone are always subnormal in patients with mixed disorders of sex development (DSD). Mixed DSD is an early-onset complete type of disorder with fetal hypogonadism resulting from the dysfunction of both Leydig and Sertoli cells. Serum AMH levels are varying in patients with male fertility-related disorders, including pubertal delay, severe congenital hypogonadotropic hypogonadism, nonobstructive azoospermia, Klinefelter syndrome, varicocele, McCune-Albright syndrome, and male senescence.

Variation in levels of AMH among Maya and non-Maya women in Campeche, Mexico.

The purpose of this study was to examine anti-Müllerian hormone (AMH) levels among women of Maya and non-Maya ancestry in the city of Campeche, Mexico. Levels of AMH can potentially predict age at menopause. Previous studies have indicated an early mean age at menopause among the Maya. Women aged 40-60 (n = 97) participated in semistructured interviews, anthropometric measures, and blood samples. Maya/non-Maya ethnicity was determined by the last names, languages spoken, and birthplace of the woman, her parents, and her grandparents. AMH values were categorized as detectable (0.05-4.19 ng/mL) and undetectable (<0.05 ng/mL). Logistic regressions calculated odds ratios (OR) for undetectable AMH. Women were categorized as Maya (n = 44), not Maya (n = 39), or not able to be clearly defined (n = 14). In bivariate comparisons, women with detectable levels of AMH were younger, more likely to be pre-menopausal, and not Maya. Age, menopausal status, and ethnicity remained significant in a logistic regression models after controlling for age at menarche. Maya women were more than five times as likely to have nondetectable AMH levels as non-Maya women. Increasing age and progression through the menopausal transition were both associated with declining levels of AMH. The association between Maya ethnicity and a lower likelihood of detecting AMH is consistent with the early ages at menopause reported in previous studies. We considered a rapid life history model as an explanatory framework, and suggest, from an ecological perspective, that future research should consider measures of developmental stress that may compromise ovarian reserves.

The utility of anti-Müllerian hormone in the diagnosis and prediction of loss of ovarian function following chemotherapy for early breast cancer

AimChemotherapy results in permanent loss of ovarian function in some premenopausal women. Accurate identification in women with hormone-sensitive early breast cancer (eBC) would allow optimisation of subsequent endocrine treatment. We sought to assess whether analysis of anti-Müllerian hormone (AMH) using a sensitive automated assay could identify women who would not regain ovarian function after chemotherapy. MethodsData from women in the Ovarian Protection Trial in Premenopausal Breast Cancer Patients (OPTION) trial of goserelin (a gonadotrophin-releasing hormone (GnRH) analogue) for ovarian protection were analysed. Women were assessed for premature ovarian insufficiency (POI: amenorrhoea with elevated follicle-stimulating hormone (FSH)) at 24 months after diagnosis. The accuracy of AMH for the diagnosis of POI and its prediction from measurement at the end of chemotherapy was calculated. ResultsAMH below the level of detection showed good diagnostic accuracy for POI at 24 months (n = 73) with receiver operating characteristic (ROC) area under the curve of 0.86, sensitivity 1.0 and specificity 0.73 at the assay limit of detection. In women aged >40 at diagnosis who did not receive goserelin, AMH measured at end of chemotherapy also gave good prediction of POI at 24 months (area under the curve (AUC) 0.89 95% CI 0.75–1.0, n = 32), with sensitivity 0.91, specificity 0.82, diagnostic odds ratio (DOR) 42.8. FSH gave slightly lower AUC, and specificity was low at 0.55. Age but not tamoxifen impacted on AMH levels. ConclusionUsing this sensitive AMH assay, the finding of an undetectable AMH level in women aged >40 at the end of chemotherapy for eBC gave a good prediction that ovarian function would not return. This may allow alterations in post-chemotherapy endocrine management.

Anti-Müllerian hormone, follicle stimulating hormone, antral follicle count, and risk of menopause within 5 years

ObjectiveTo evaluate the ability of concentration of anti-Müllerian hormone (AMH), antral follicle count (AFC), and concentration of follicle stimulating hormone (FSH) to predict the onset of menopause. Study designThe Coronary Artery Risk Development in Young Adults Study (CARDIA) Women's Study was an ancillary study to CARDIA, a population-based study of adults aged 18–30 years followed for 3 decades. For this report, participants were women (n=426) who had attended the CARDIA year 15–16 (2000–2001) examination, had at least one ovary, were not pregnant, and underwent serum AMH and FSH measurement and transvaginal ultrasonography in 2002–2003. Main outcome measuresThe probability of menopause in 5 years based upon AMH, FSH, and AFC. ResultsThe mean age of the women at the time of AMH, FSH, and AFC assessment was 43 years. The cumulative incidence of menopause at 25 years (or follow-up) was 27% (n=426), and the incidence within 5 years was 13% (n=55). Among women aged 45–49 years, undetectable AMH concentrations were associated with a greater than 60% probability of menopause within 5 years, whereas approximately 1/3 of women with no or just one antral follicle experienced menopause within 5 years. Both low and high concentrations of FSH were associated with greater odds of menopause than intermediate concentrations. Models with multiple markers did not improve the prediction of menopause over that afforded by models with single markers. ConclusionThe ability to predict onset of menopause was improved with any of the three menopausal markers in addition to age. AMH concentrations were more closely associated with menopause than AFC or FSH.

Anti-Müllerian hormone concentrations and parity in fertile women: the model of oocyte donors

In France until the end of 2015, oocyte donors must have had at least one child and be aged 18–37 years. This population of fertile women was selected to examine whether serum anti-Müllerian hormone (AMH) concentration could be a reliable correlate of spontaneous pregnancy in women who had proven their fertility before. A cohort of 217 women followed between 2009 and 2015 for oocyte donation at the University Hospital of Lille comprised this retrospective study. In these egg donors, aged 20–37 (median: 32 years), the median serum AMH level was 22 pmol/l (5–95th percentiles: 4.9–61.8). No significant correlation was found between serum AMH level and the number of children or the youngest child's age. Among the 32 women with AMH <10 pmol/l, 9 and 3 were less than 30 and 25 years old, respectively. Six women (2.8%) had undetectable serum AMH, i.e. <3 pmol/l. In conclusion, serum AMH level measured in this fertile female cohort showed too much variability to be a good fertility index. Assessment of serum AMH should only be discussed for patients at risk of ovarian failure.

Utility of Ovarian Reserve Screening with Anti-Müllerian Hormone for Reproductive Age Women Deferring Pregnancy.

Ovarian reserve (OR) testing with serum anti-Müllerian hormone (AMH) can provide information about a woman's fertility potential. The aim of this study was to assess interest and knowledge about OR testing and investigate the utility of measuring AMH in women of reproductive age deferring pregnancy. Women ages 27-37 years currently delaying childbearing were invited to take a survey regarding attitudes and knowledge about OR testing before and after an AMH measurement with explanation of their results. Of 121 women who took the pre-test survey, 96% believed OR testing was beneficial. The median AMH of the 97 women who underwent testing was 3.3 ng/mL (IQR 1.9-5.4 ng/mL). Nineteen percent of women had AMH <10th percentile for age and 3% had an undetectable AMH. Although 83% of these women were using hormonal contraception, none had known risk factors for diminished ovarian reserve. Seventy-eight percent of women with low AMH levels for age planned to seek fertility preservation or pregnancy, while those with AMH levels within established age normograms were reassured. On the post-test survey, 100% reported benefit in knowing their AMH level. Follow-up testing, 6-8 months after the initial measurement, showed stable AMH levels for most participants. Women are interested in OR testing. Most women will be reassured by knowing their AMH level, whereas those with a lower AMH can be counseled on fertility preservation options or may attempt pregnancy earlier.

Usefulness of the Ultrasensitive Anti-Müllerian Hormone Assay for Predicting True Ovarian Reserve.

Serum concentration of anti-Müllerian hormone (AMH) is a useful marker for ovarian reserve. Measurement of AMH in clinical practice has gained widespread use to predict parameters such as the ovarian response, menopause, and recovery after chemotherapy. However, undetectable AMH levels assayed by conventional enzyme-linked immunosorbent assay (ELISA) kits fail to predict depletion of follicles because of low sensitivity of the kits. We investigated whether a recently developed ultrasensitive ELISA kit, picoAMH, would be more effective at detecting very low AMH levels in association with menstrual status. We analyzed 68 women with undetectable serum AMH levels using an ELISA kit, AMH Gen II. The AMH concentration of the same samples was detected in 36 samples using picoAMH; 32 samples were within the standard range, and 4 samples were out of the standard range but still detectable. Thirty-two women whose AMH levels were undetectable using the picoAMH all showed amenorrhea. We also found a significant correlation between the classes of serum AMH levels (undetectable, detectable under the limit of quantification, and measurable within the assay range) and menstrual status. Five of the 6 amenorrheic women with detectable AMH eventually achieved follicle growth. The present study demonstrated that very low AMH levels detectable using picoAMH correspond well to current and future ovulation status. This suggests that serum AMH levels can be useful for the assessment of ovarian reserve and follow-up of women with a declined ovarian reserve.

Reduced ovarian reserve relates to monocyte activation and subclinical coronary atherosclerotic plaque in women with HIV.

To investigate differences in subclinical coronary atherosclerotic plaque and markers of immune activation among HIV-infected and non-HIV-infected women categorized by degree of ovarian reserve and menopause status. Cross-sectional evaluation. Seventy-four women (49 HIV-infected, 25 non-HIV-infected) without known cardiovascular disease (CVD) were classified as premenopausal, premenopausal with reduced ovarian reserve, or postmenopausal based on menstrual history and anti-Müllerian hormone (AMH) levels. Participants underwent contrast-enhanced coronary computed tomography angiography and immune phenotyping. Comparisons in coronary atherosclerotic plaque burden and immune markers were made between the HIV-infected and non-HIV-infected women overall and within the HIV-infected and non-HIV-infected women by reproductive classification group. Among the overall group of HIV-infected women, the women with reduced ovarian reserve (undetectable AMH) had a higher prevalence of coronary atherosclerotic plaque (52 versus 6%, P = 0.0007) and noncalcified plaque (48 versus 6%, P = 0.002), as well as higher levels of log sCD163 (P = 0.0004) and log MCP-1 (P = 0.006), compared with the premenopausal women with measurable AMH. Furthermore, reduced ovarian reserve in the HIV-infected group related to noncalcified plaque, controlling for traditional CVD risk factors (P = 0.04) and sCD163 (P = 0.03). HIV-infected women with reduced ovarian reserve have increased subclinical coronary atherosclerotic plaque compared with premenopausal women in whom AMH is measurable. This relationship holds when controlling for CVD risk factors (including age) and immune activation. Our findings demonstrate that reduced ovarian reserve may contribute to CVD burden in HIV-infected women and support a comprehensive assessment of CVD risk prior to completion of menopause in this population.