Introduction

Blood levels of Anti-Müllerian Hormone (AMH), which declines by age, represent one of the key markers to determine the menopausal status of women.

Why do we use MenoCheck picoAMH Testing to measure menopause?

Women are born with a finite number of follicles/oocytes that decline over age. Anti-Müllerian Hormone, which is produced from growing follicles, inhibits the growth of primordial follicles to maintain the ovarian reserve. Levels of AMH decline to non-detectable after menopause. AMH has shown promise as a biomarker of ovarian reserve but the current commercially available assays are not sensitive enough to allow assessment of low ovarian reserve or low AMH in women in menopausal transition. Ansh Labs has developed picoAMH, a novel ELISA test with an unequivocal sensitivity of 6 pg/mL. 

Branded as MenoCheck, the picoAMH ELISA kit has been FDA cleared as an aid in the determination of menopausal status in women between 42 and 62 years. The MenoCheck picoAMH reference ranges and menopause categories were determined in the longitudinal, multi-center SWAN study (Study of Women’s Health Across the Nation). 

Blood AMH levels fall steadily from 44 years to 55 years over the menopausal transition:

Figure 1. Steady Decline of AMH levels over menopausal transition

Age-stratified expected values for serum AMH is presented for ostensibly healthy women > 5 years from their final menstrual period (FMP), < 5 years from FMP, and at FMP or later in their menopausal transition.

Figure 2. Menopausal categories, years from Final Menstrual Perid and picoAMH concentration

The final menstrual period (FMP) for each woman in the SWAN Study were assigned retrospectively after 12 months of amenorrhea (the clinical definition of natural menopause). Menopausal categories for assigning status were based on the approximate time to the final menstrual period (FMP). Three menopausal categories were defined based on the time to final menstrual period (TTFMP).  Serum AMH measurements, with picogram-level sensitive assays, allow for the categorization of menopausal status and calculation of time to FMP thus providing valuable additional information to support physician’s efforts to determine a woman’s menopausal status and management.

Assessing peri-menopause and menopause status

Menstrual cycle changes are the best indicator of menopause stage. 

Hormone measurements to determine menopause status are not routinely indicated but Follicle Stimulating Hormone (FSH) and Anti-Müllerian Hormone (AMH) levels can be a useful adjunct to menopause staging if this is requested by the patient or the clinician.  This is more important if menopause symptoms are atypical or are occuring at an early age. In these instances hormonal measurements are essential as a part of a clinical evaluation to confirm what may be happening.

FSH and Oestrogen levels do vary as menopause approaches. The number and quality of ovarian follicles diminish after 40 years causing a decline in oestrogen production and fewer ovulations. However oestrogen levels vary widely - either dropping precipitously or spiking higher than normal. FSH levels rise to attempt to push the ovaries into producing more oestrogen. 

Figure 3. Decline of FSH and Oestradiol levels over menopausal transition

Although a high FSH level can be a sign of early peri-menopause, a single FSH reading is not a reliable indicator because day-to-day hormone levels fluctuate dramatically though the cycle. While oestradiol measurements are reasonably well suited to the diagnosis and management of infertility they are simply not precise enough to estimate menopause and peri-menopausal status. In the SWAN study, average oestradiol levels did not decrease until 2.03 years before the final menstrual period and this was using a very sensitive immunoassay with a lower limit of detection of 1 pg/mL. Most commercial oestradiol assays cannot accurately measure levels below 20pg/mL which is the level needed in postmenopausal women. 

In contrast, AMH levels steadily decrease without the month to month variation that happens with oestradiol and FSH levels. With the MenoCheck picoAMH assay the sensitivity is 1000's of times greater than other commercial AMH tests and so has been clinically validated to be able to accurately estimate the time to a woman's final menstrual period and thus reliably confirm whether symptoms being experienced  are due to peri-menopause or not.

In summary, it is only MenoCheck picoAMH that has been clinically validated  to reliably give an accurate estimate of the time to the final menstrual period.

Clinical Studies

Clinical StudiesKey FindingsConclusion
Anti-Mullerian Hormone and Impending Menopause in Late Reproductive AgepicoAMH measurement helps estimate when a woman will undergo her final menstrual period (FMP), and, in general, does so better than FSH. This paper evaluated the ability of AMH to predict the FMP, using a new, ultrasensitive AMH assay (picoAMH ELISA, Ansh Labs, Webster, TX) which has a lower limit detection than prior AMH assays. The ability to predict the FMP accurately and precisely has long been a "Holy Grail" of menopause research. However using menstrual bleeding patterns, serum FSH levels, or previous AMH assays, The FMP can only be predicted within a window of approximately 4 years, a time window that is too great to be clinically useful. Using [MenoCheck] it is now possible to predict the FMP within a window of 12 - 24 months in late reproductive aged women.
picoAMH & Trans-Menopausal Bone LossIn multivariable linear regression adjusted for age, BMI, smoking, race/ethnicity, and study site each 75% (or four-fold) decrement in AMH level was associated with 0.15% per year faster decline in spine BMD (p<0.001) and 0.13% per year faster decline in femoral neck BMD (p=0.005).Serum levels of picoAMH in women going through the MT can indeed predict the rate of trans-menopausal bone loss and help identify the women at risk of most loss. AMH levels appear to provide information about the rate of bone loss beyond that provided by serum levels of estradiol and FSH.
picoAMH & Onset of Menopausal Vasomotor SymptomsAMH remained significantly associated (p<.001) with incident frequent VMS after adjusting for menopause status (adjusted HR 0.29, 95% CI 0.22 – 0.39), for estradiol (adjusted HR 0.36, 95% CI 0.27 – 0.50), and for FSH (adjusted HR 0.55, 95% CI 0.42 – 0.71).AMH is useful for predicting incidence of VMS, particularly frequent VMS, independent of other key markers of menopause stage based on menstrual bleeding or other reproductive hormones.
picoAMH & Menopausal Lipids ChangeIn unadjusted models, lower premenopausal AMH levels and greater declines in AMH over the MT were significantly associated with higher levels of all lipids [per 1 log unit decrease in premenopausal AMH: Cholesterol β(se): 2.76(0.38) , log Triglycerides: 0.01(0.01), LDL-C: 1.86(0.35), apoB: 1.45(0.31), HDL-C: 0.54(0.17), apoA-1: 0.83(0.30), P values <0.006; per 1 log unit decline in AMH over MT: Cholesterol β(se): 2.80(0.15) , log Triglycerides: 0.01(0.002), LDL-C: 2.12(0.13), apoB: 1.09(0.12), HDL-C: 0.46(0.05), apoA-1: 2.44(0.16), P values <0.0001].Women with less ovarian reserve as reflected by lower premenopausal AMH levels and greater declines in AMH over the MT had a worse lipid profile, with the exception that apoA-1, were unexpectedly higher. Measuring AMH earlier in the MT could help identify premenopausal women at increased risk of later CVD.
picoAMH & New-Onset of Sleep DisturbanceAMH was significantly negatively associated with new-onset sleep disturbance (hazard ratio [HR] 0.90, 95% CI 0.82–0.998, p=0.047) and awakenings (HR 0.90, 95% CI 0.81–0.995, p=0.040) after adjusting for all covariates except VMS. AMH predicts the development of sleep disturbance in general, and awakenings, during the menopause transition, but this association is mediated by VMS, which appears to drive the association between declining AMH levels and new-onset sleep problems.
picoAMH & Early MenopauseIn multivariable conditional logistic regression models adjusting for matching factors, body mass index, smoking, parity, oral contraceptive use, and other factors, each 0.10 ng/mL decrease in AMH was associated with a 14% higher risk of early menopause (95% confidence interval (CI) 1.10 to 1.18; P < 0.001). This is the first prospective study to evaluate whether AMH levels are associated with early menopause. These findings support the utility of AMH as a clinical marker of early menopause in otherwise healthy women.

References:

  1. The North American Menopause Society Recommendations for Clinical Care of Midlife Women. https://www.menopause.org
  2. Santoro N  J Women’s Health (Larchmt). 2016 Apr 1; 25(4): 332–339
  3. Perimenopause: Rocky road to menopause.  https://www.health.harvard.edu/womens-health/perimenopause-rocky-road-to-menopause
  4. Rosner et al, 2013 J Clin Endocrinol Metab. 2013 Apr; 98(4): 1376–1387.
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  6. Robertson et al, 2014. Menopause; 21(12):1277-86.
  7. https://www.swanstudy.org/
  8. Finkelstein et al, Utility of Anti-Mullerian Hormone (AMH) for Predicting the Time to the Final Menstrual Period: The Study of Women’s Health Across the Nation (SWAN). Presented at 98th Annual Endocrine Society Meeting; 2016 Apr 1-3; Boston, MA
  9. Karlamangla et al, Anti-Mullerian Hormone and Prediction of Trans-Menopausal Bone Loss. Presented at 98th Annual Endocrine Society Meeting; 2016 Apr 1-3; Boston, MA
  10. Crawford et al, Predicting Onset of Menopausal Vasomotor Symptoms with Anti-Mullerian Hormone in the Study of Women’s Health Across the Nation (SWAN) Presented at 98th Annual Endocrine Society Meeting; 2016 Apr 1-3; Boston, MA
  11. El Khoudary et al, Associations of Anti-Mullerian Hormone Premenopausal Levels and Their Changes over the Menopausal Transition with Lipids: The Study of Women′s Health Across the Nation (SWAN). Presented at 98th Annual Endocrine Society Meeting; 2016 Apr 1-3; Boston, MA
  12. Joffe et al, Vasomotor Symptoms Mediate the Association Between Anti-Mullerian Hormone Levels and New-Onset Sleep Disturbance in Women during the Menopause Transition: Study of Women’s Health Across the Nation (SWAN). Presented at 98th Annual Endocrine Society Meeting; 2016 Apr 1-3; Boston, MA
  13. Bertone‐Johnson et al, Anti‐Müllerian hormone levels and incidence of early natural menopause in a prospective study. Hum Reprod. 2018 Jun 1;33(6):1175‐1182.
  14. Finkelstein et al, AntiMullerian Hormone and Impending Menopause in Late Reproductive Age: The Study of Women's Health Across the Nation. J Clin Endocrinol Metabol. 2020 Jan