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Anti-mullerian Hormone (AMH) and it's relevance to the "Biological Clock"

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In recent years, anti-mullerian hormone (AMH) has been the subject of much research pertaining to its biological purpose and clinical relevance. However, the value of AMH as an accurate indicator of reproductive functionality varies according to the presence of certain physiological characteristics or pathologies in different female sub-populations. 

Another aspect which has been the subject of some investigation is the potential influence of exogenous factors including diet, medications, smoking and stress on AMH levels. This article discusses what is currently understood regarding the role of AMH in the body and the potential clinical implications. 

What is Anti-Mullerian Hormone?

AMH is a homodimeric glycoprotein belonging to the transforming growth factor beta family of hormones and growth factors.[1,2] Following the cleavage of AMH, it binds to the AMH type 2 receptors (AMHR2), which are expressed on the ovarian granulosa cells and one of either the activin A type 1 (ACVR1), bone morphogenetic protein type 1A or 1B (BMPR1A or BMPR1B) receptors.[2-4] Along with ovarian cells, AMH receptor expression has also been detected in brain, placental, endometrial and uterine tissues.[2-4

AMH expression by the granulosa cells is initiated following follicular activation, increasing during the pre- and early-antral phases (2-8mm) and decreasing as the antral follicles grow to the follicle stimulating hormone (FSH)-dependent phase of growth (8-10mm).[2,3

It is important to note that AMH fluctuations throughout the menstrual cycle are minimal, which is considered to be a benefit in relation its longitudinal clinical measurement.[3,5] This contrasts with the normal fluctuation of other ovarian hormones including FSH, oestradiol and inhibin B.[3

What does AMH tell us about health?

What is currently known regarding the physiological role of AMH in the body relates to its involvement in cellular growth and differentiation, and primordial follicle recruitment selection, activation and inhibition.[3,4,6] Specific mechanisms underlying these roles include modulating primordial follicle granulosa cell sensitivity to FSH and inhibiting growth factors required for recruitment, including KIT-ligand and basic fibroblast growth factors, thereby inhibiting the follicular activation.[2,3,7] A key role of AMH is proposed to be the prevention of premature ovarian reserve depletion via such inhibitory activity.[2,3,7

Currently it is understood that the overall size of the follicular pool is both a primary antecedent to systemic AMH levels and regulator of non-follicular cell AMH receptivity and responsiveness.[2

While AMH levels have been observed to vary significantly between individuals across the female population, they are generally observed to be maximal, at around 25 years of age, followed by a gradual, non-linear decrease that accelerates after 40 years of age until it reaches a non-detectable level at menopause.[3,8

This was demonstrated in a 2016 population-based study involving 3326 women observed over a 20-year period.[8] In the Doetinchem Cohort Study, women with a baseline age range of 20-59 years had their AMH levels, and several reproductive, lifestyle and general health parameters, assessed every 5 years to determine the pattern of AMH decline and the influence of baseline AMH levels on its trajectory. The main findings of this long-term study were that the decline in AMH levels across the population occurred in a non-linear, non-uniform pattern, but followed a consistent trajectory within individuals correlating to age, the significant variation in AMH levels between individuals and time to menopause, and the more rapid decline in AMH levels between 40-55 years of age. 

The current clinical uses of AMH include the evaluation of ovarian function and reserve to determine reproductive potential, likely responsiveness to fertility treatment, prediction of reproductive lifespan, evaluation of polycystic ovarian syndrome (PCOS), as a marker of ovarian tumours and in the presence of testicular abnormalities in infants.[6,7

However, the clinical accuracy and relevance of AMH for such uses is variable due to a number of factors including its lack of validity in relation to oocyte quality, the influence of certain physiological characteristics and pathologies on AMH levels, and the need for further evidence to confirm its applicability for some such uses.[3,6,8-11]

Is AMH a reliable predictor of fertility potential?

The value of using AMH to predict reproductive potential in women without infertility has been questioned in a recent study reported in JAMA.[11] In a prospective cohort of 981 women with no fertility issues, aged 30-44 years who had been trying to conceive for no more than 3 months, the correlation between ovarian reserve markers (AMH and FSH) and reproductive potential was assessed. The main outcomes were cumulative probability of conception following 6 and 12 cycles of attempt and probability of conception in a menstrual cycle. No significant difference in predicted probability of conception by 6 or 12 cycles of attempt was observed between women with low (<0.7 ng/mL, n=84) or high (n=579) AMH levels or high versus normal FSH levels, after adjustment for age, body mass index (BMI), smoking status and recent oral contraceptive pill (OCP) use. The study authors concluded that in women aged 30-44 years with no fertility issues, urinary or blood AMH and FSH levels did not accurately predict fertility potential and pregnancy outcomes.

The evidence regarding the value of AMH as a predictor of pregnancy outcomes in women receiving assisted reproductive treatment (ART) is mixed, with earlier studies concluding AMH could not accurately predict pregnancy following ART in this population.[12,13] However more recent evidence has observed an association between AMH levels and pregnancy outcomes in sub-fertile patients.[1,14

In a 2014 retrospective study, the influence of serum AMH levels on pregnancy rates in 637 women aged <35 years of age doing their first stimulated IVF procedure was assessed.[1] The primary outcomes were cycle results according to AMH percentiles (<25th, 25-75th and >75th) based on age. It was observed that women in the <25th percentile AMH group (<0.46ng/mL) were more likely to have a cancelled cycle, and less likely to have an embryo transfer, frozen embryos and ongoing pregnancies regardless of their age, compared to women in the 25th-75th AMH percentile. 

Similar results were observed in a separate cross-sectional study in 240 women aged >35 years of age undergoing ART.[14] AMH was found to be an independent predictor of clinical pregnancy rates, with median levels in pregnant women higher than in non-pregnant women (3.20 versus 1.15 ng/mL). AMH levels were also found to be significantly correlated with the number of oocytes retrieved. 

The clinical value of AMH as a credible parameter for assessing ovarian reserve and potential responsiveness to stimulation has also been demonstrated in several other studies, with the overall evidence demonstrating a strong correlation between basal serum AMH levels and ovarian reserve and number of oocytes retrieved.[6,7,15

Several diseases or states of physiological imbalance have been associated with variable AMH levels compared to healthy populations, including breast cancer (pre- and post-treatment), thyroid imbalance, endometriosis and PCOS.[7,10,16,17,20-22]

In women with breast cancer, AMH levels have been observed to be lower both pre- and post-cancer treatment compared to levels in healthy women.[7] A 2015 meta-analysis concluded that along with age, serum AMH can reliably predict post-treatment ovarian activity in breast cancer patients, particularly in women aged <40 years of age, indicating it may be a valid clinical marker for treatment-induced follicular loss.[7,16

Similarly, levels of AMH in women with endometriosis are lower compared with non-endometriosis patients both before and after surgery.[10,17] As well as being a valid marker for ovarian reserve in this population, AMH may be involved in endometriosis etiology, with several factors including the AMH expression in normal endometrial tissue, its elevated expression in endometrial tissue samples from women with deep endometriosis compared to healthy tissue with no difference in serum AMH levels, and its known involvement in cellular differentiation and growth suggesting potential involvement.[4,18,19

Conversely, AMH levels in women with both overweight/obese and lean phenotype PCOS have been persistently observed to be elevated, which given the correlation between AMH and the size of the follicular pool, and the ovarian physiology of PCOS is unsurprising.[3,20] From a clinical perspective, AMH, along with other diagnostic parameters, is increasingly being used to diagnose PCOS when levels are >4-5ng/mL.[1,3

Suboptimal thyroid hormone levels are also associated with AMH levels and ovarian function in infertile women.[21,22] Two separate studies demonstrated an inverse correlation between AMH and TSH levels in infertile women aged <40 years of age. TSH levels >3.0 μIU/mL were associated with significantly lower AMH levels (0.8+ 1.8ng/mL) demonstrating a reduced functional ovarian reserve. This evidence highlights the interdependent relationship between AMH, thyroid hormones and ovarian function. 

Along with the variable influence of endogenous physiological factors on AMH levels, the potential impact of exogenous factors including diet, medications, smoking and stress has been the subject of some investigations, though further assessment is needed before definitive correlations can be confirmed. 

In a recent randomised, controlled study involving overweight/obese PCOS phenotypes, subjects followed either a low calorie DASH or low-calorie control diet (n=30 for both) for 12 weeks, with the DASH diet having high intakes of fruits and vegetables, wholegrains, low-fat dairy products and grains.[23] Compared to the control group, subjects following the DASH-diet had significant decreases in AMH (-1.1+ 3.1 vs +0.3+0.7ng/mL), along with insulin, HOMA-IR, free androgen index and malondialdehyde, and significant increases in insulin sensitivity and sex hormone-binding globulin. 

In a nested prospective case-control study from the National Cancer Institute’s Biological Markers Project, a range of data including AMH levels, and demographic, anthropometric, behaviourial, age, height, weight, reproductive history and lifestyle factors were recorded between 1977-1987 and subsequently followed up in 1999-2004 in 135 women aged >45 years of age.[24] After adjusting for age, AMH levels were observed to be significantly different between women using the oral contraceptive pill (3.0pmol/L) compared to non-users (4.57pmol/L). AMH was not significantly correlated with other factors measured including BMI and smoking status. 

These results contrasted with the results of a large cross-sectional study involving 50,884 women aged 35-54 years of age as part of the Sister Study Cohort, with the primary outcome measures being serum AMH levels in relation to use of tobacco, marijuana and indoor heating and cooking sources.[25] Exposure to indoor heating for more than 10 times annually, smoking more than 20 cigarettes daily or being exposed to environmental tobacco smoke for more than 10 years were all associated with reduced levels of AMH compared to those not exposed at these levels. 

An association between elevated stress and AMH levels has also been observed in a cross-sectional study involving 576 infertile women aged 23-45 years of age receiving ART.[26] High levels of psychological stress as assessed by salivary alpha-amylase levels was significantly correlated with decreased AMH levels. 

The use of dehydroepiandrosterone (DHEA) has been shown to enhance AMH levels in women with poor ovarian response undergoing IVF or intracytoplasmic sperm injection procedures, as demonstrated in a systematic review and meta-analysis.[27] Pretreatment with DHEA increased levels of AMH and oocyte yield, as well as clinical pregnancy and live birth rates, rate of implantation and antral follicle counts. 

What is the take home message?

Currently the overall evidence points to AMH being potentially relevant when used with other clinical assessments for estimating ovarian reserve, likely responsiveness to ART, pregnancy outcomes and PCOS. However, the impact of endogenous and exogenous factors need to be considered in relation to its accuracy in determining certain diagnoses or treatment plans. Further research is necessary to confirm the most appropriate clinical application of AMH, its role in ovarian and reproductive physiology and functionality, and if increasing the levels of AMH with will result in clinically relevant outcomes. 


References

  1. Lehmann P, Velez MP, Saumet J, et al. Anti-mullerian hormone (AMH): a reliable biomarker of occyte quality in IVF. J Assist Reprod Genet 2014;31(4):493-498. [Full Text]
     
  2. Pankhurst MW. A putative role for anti-mullerian hormone (AMH) in optimizing ovarian reserve expenditure. J Endocrinol 2017;233(1):R1-R13. [Full Text]
     
  3. Jamil Z, Fatima SS, Ahmed K, et al. Anti-mullerian hormone: above and beyond conventional ovarian reserve markers. Hindawi Publishing Corporation Disease Markers, 2016;Article ID 5246217. [Full Text
     
  4. Signorile PG, Petraglia F, Baldi A. AMH is expressed by endometriosis tissues and induces cell cycle arrest and apoptosis in endometriosis cells. J Exp Clin Canc Res 2014;33(1):46. [Full Text]
     
  5. Lee JE, Yoon SH, Kim HO, et al. Correlation between serum luteinizing hormone to follicle stimulating hormone ratio and the anti-mullerian hormone levels in normo-ovulatory women. J Korean Med Sci 2015;30(3):296-300. [Full Text]
     
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  15. Nelson SM, Klein BM, Arce JC. Comparison of anti-mullerian hormone levels and antral follicle count as predictor of ovarian response to controlled ovarian stimulation in good-prognosis patients at individual fertility clinics in two multi-centre trials. Fertil Steril 2015;103(4):923-930. [Full Text]
     
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georgia.marrion's picture
Georgia Marrion
Georgia is a naturopath and nutritionist of more than 12 years in the complementary medicine industry, with experience in areas including clinical practice, practitioner consultant, writing, lecturing, product development and regulatory affairs. With a Masters in Human Nutrition, her main interest areas are gastrointestinal and women's health, and she is passionate about providing information to people to help them optimise their overall health.