Download The role of anti‐müllerian hormone as a predictor of ovarian function

DOI: 10.1111/j.1744-4667.2012.00112.x
2012;14:161–166
Review
The Obstetrician & Gynaecologist
http://onlinetog.org
The role of anti-müllerian hormone as a predictor of
ovarian function
Priya Bhide
MD MRCOG,
a,
* Amit Shah
MD MRCOG,
b
Anil Gudi
MD MRCOG,
b
Roy Homburg
b
FRCOG
a
Homerton Fertility Centre, Homerton University Hospital NHS Foundation Trust, Homerton Row, London E9 6SR, UK
Homerton Fertility Centre, London, UK
*Correspondence: Priya Bhide. Email: [email protected]
b
Key content
Levels of anti-müllerian hormone (AMH), which is secreted by
the granulosa cells of the ovary, indicate the size of the antral
follicle pool.
Along with other predictors, AMH levels can predict the
quantitative response to treatment in women undergoing assisted
reproductive therapy.
The aim of AMH testing in assisted reproductive therapy is mainly
to individualise treatment protocols with a view to achieving the
optimal ovarian response and oocyte yield.
AMH has not shown sufficient predictive value for pregnancy
outcome to be used in routine practice for either spontaneous
pregnancy or following assisted reproductive therapy.
AMH serves a diagnostic and prognostic role in the management
of women with polycystic ovary syndrome.
To identify the role of AMH as a predictor of fertility and
ovarian reserve.
To understand the role of AMH in assisted reproductive therapy.
Ethical issues
Is it ethical to make decisions about refusing treatment based
on AMH levels?
Can women be reassured that they can delay childbearing on
the basis of their AMH levels?
Keywords antral follicle count / assisted reproductive therapy /
clinical pregnancy rates / follicle-stimulating hormone / in vitro
fertilisation / ovarian hyperstimulation syndrome / polycystic ovary
syndrome
Learning objectives
To understand the physiology of AMH and its role in reproductive
function.
Please cite this paper as: Bhide P, Shah A, Gudi A, Homburg R. The role of anti-müllerian hormone as a predictor of ovarian function. The Obstetrician &
Gynaecologist 2012;14:161–166.
Introduction
Physiology
Changing lifestyles and social trends have led to delayed
childbearing in many couples. This trend has resulted in an
increased incidence of age-related subfertility and a greater
demand for assisted reproductive therapy.
Reproductive performance is clearly inversely related to
chronological age.1 However, this relationship is not absolute,2
and hence there is a need for other markers of ovarian
function. Serum levels of follicle-stimulating hormone (FSH),
ovarian volume and antral follicle count are commonly used as
indicators, with high FSH levels, low ovarian volume and low
antral follicle count all pointing to reduced reproductive
potential. Since 2005 measurement of serum levels of antimüllerian hormone (AMH) has emerged as another powerful
tool in the armamentarium available to the clinician.
The aim of this article is to summarise the current available
evidence for the measurement of AMH in different clinical
settings and to suggest a management plan based on current
best evidence.
AMH is a glycoprotein belonging to the transforming growth
factor b family. In the male fetus it is expressed in the Sertoli
cells of the testes, which leads to müllerian regression. In the
female fetus it is expressed by the granulosa cells of the ovary
from as early as 36 weeks of gestation3 and production
continues until the menopause. It is expressed mainly by the
pre-antral and small antral follicles,4 declining in dominant
follicles and with equivocal expression in atretic follicles,
corpus luteum and primordial follicles. AMH is thus a good
indicator of the size of the ovarian antral follicle pool.
The primary physiological function of AMH in the ovary is
inhibition of the recruitment of primordial follicles into the
antral follicle pool.5 AMH also reduces the sensitivity of the
growing follicles to FSH.6
AMH shows non-significant intracycle and intercycle
variation.7,8 This is an important advantage of AMH over
FSH, as it can be reliably measured at any stage of the
menstrual cycle. AMH levels remain unchanged in the first
ª 2012 Royal College of Obstetricians and Gynaecologists
161
Predicting ovarian function
trimester of pregnancy, but show a decline in the second and
third trimesters, with a return to pre-pregnancy levels early in
the puerperium. The levels during pregnancy, however, do not
become undetectable, indicating that follicular development is
not completely abolished.9,10 There is also a non-significant
variation in AMH levels during short-term oral
contraceptive use and short-term gonadotrophin-releasing
hormone analogue administration.11,12 Long-term use (for
more than 1 year) of oral contraceptives and gonadotrophinreleasing hormone analogues can reversibly reduce AMH
concentrations.10 These studies confirm the presence of
continuous ovarian activity independent of FSH stimulation.
The AMH assay
The lack of a single standardised assay for the measurement
of AMH has led to much confusion over interpretation and
comparison of results. There are two assays that have been
used for AMH, with differing values and units. These are:
the Diagnostic Systems Laboratories (DSL)
the Immunotech–Beckman.
Studies comparing the two assays showed AMH levels to
be five to seven times lower with the DSL assay than with the
Immunotech-Beckman assay. However, a single unified assay
is now being produced by one company (Beckman Coulter),
which will solve the logistical and methodological problems
that have been encountered.
AMH values should be interpreted according to the
reference ranges of each individual laboratory. Values below
the optimal range indicate a low antral follicle pool and hence
impaired reproductive capacity. Values above the optimal
range are suggestive of polycystic ovary syndrome (PCOS)
and a high antral follicle count.
AMH as a test of fertility and ovarian
reserve
It is well known that reproductive capacity is closely but
variably related to chronological age.1 Reproductive capacity
is dictated by biological ovarian age/ovarian reserve but this
is not always equivalent to chronological age. Reduced
ovarian reserve results from a decline in the ovarian pool of
follicles. A marker of ovarian reserve which would reliably
predict reproductive capacity and the time of onset of
menopause would be a significant clinical tool with which to
assist women to plan childbearing.
Currently, a combination of age, serum markers (AMH,
basal FSH, basal estradiol and basal inhibin), ultrasound
markers and challenge tests are used to assess ovarian reserve.
Several studies have shown AMH levels to decline normally
with increasing chronological age in a non-linear, quadratic
manner.13–15 This has led to the development of age-specific
162
reference values and normograms. AMH values have shown
wide variation at individual ages, with a tendency to be
skewed to the left, with the skew increasing with age and
median values consistently lower than the mean.14 Two large
studies13,14 have used the same assay and shown very similar
results. A third study15 showed differing results: this may be
because a different assay was used. The authors14
acknowledge that the role of factors such as ethnicity and
body mass index on these normograms needs evaluation.
Further consensus, standardisation and validation of these
normograms are needed before they can be put into universal
routine clinical practice.
As mentioned before, ovarian reserve may not always match
chronological age, leading to deviations from the normogram.
These variations may be due to genetic, autoimmune or
environmental factors and may or may not be reversible.
Decreased AMH levels are indicative of a reduced antral
follicle pool and hence reduced ovarian reserve, independent
of age. High levels of AMH are suggestive of polycystic
ovaries.
Most studies correlating AMH with reproductive outcome
and pregnancy have been in the setting of fertility/in vitro
fertilisation (IVF) clinics rather than an unselected
population. Although AMH concentrations at the extremes
of the scale give a reliable indication of fertility potential,16
other values are less reliable for planning pregnancy or
predicting the age of menopause.
The use of age-specific reference values and deviations
from them should be used with caution in predicting
individual reproductive outcome and span.
AMH is shown to be comparable to antral follicle count as
a marker of ovarian reserve,17,18 but is superior to FSH and
inhibin B.19,20 AMH (along with antral follicle count) has
shown better correlation with the ovarian primordial follicle
pool as assessed by histology than markers such as FSH and
inhibin.21
FSH values >10 u/l on days 2–5 of the menstrual cycle,
antral follicle counts of less than a total of 3 from both
ovaries, and ovarian volume < 3 cm3 have been found to be
associated with reduced ovarian reserve.18 Ovarian volume
and antral follicle count are accurate markers but have the
limitation of needing specialised equipment and skilled
operators.
Although there is a good correlation between the age at
actual menopause and that predicted by AMH levels, the
added predictive effect of the combination of AMH levels and
current age of improving the predictive value of age alone is
probably its most useful application in this respect at
present.22,23
In conclusion, AMH shows the potential to be a reliable
marker of ovarian reserve and reproductive performance. We
await further standardisation of normograms and studies
correlating AMH values with reproductive performance in
ª 2012 Royal College of Obstetricians and Gynaecologists
Bhide et al.
the unselected population rather than those attending fertility
clinics. This would allow AMH to be used to predict
individual reproductive span independent of age in the
general population.
AMH and response to fertility treatment
Several studies show a strong positive correlation between
basal serum AMH levels and the number of retrieved oocytes
in women undergoing controlled ovarian stimulation for
IVF.24–28 In the setting of an IVF clinic, therefore, AMH can
be used as a predictor of quantitative ovarian response. Poor
or over-response may lead to suboptimal outcome in terms
of pregnancy rates. AMH is thus useful in individualising the
stimulation protocols for controlled ovarian stimulation in
order to optimise the response during IVF. The choice of
protocol (long, antagonist, flare and so on) and starting
dosages of FSH may be decided based on AMH values.
Women with low AMH levels should be started on a higher
dosage of FSH than usual for that age; conversely, women
with high levels of AMH should have lower dosages than the
usual for that age.29,30
AMH has been shown to be a better predictor of
quantitative response than age, basal FSH, estradiol and
inhibin.24,26,27 AMH and antral follicle count have similar
predictive value.27
Approximately 10% of women show a poor response
(usually defined as fewer than four oocytes retrieved at egg
collection) to controlled ovarian hyperstimulation during
IVF,31 which can result in cycle cancellation. Lower pregnancy
rates are seen in women showing a poor response than in
women of the same age with a normal response.32,33
The effectiveness of AMH as a predictor of poor response
has been assessed.25,32,33 In several studies the sensitivity and
specificity range between 40–90% and 40–100%, respectively.
Most studies show specificities >85%, which makes AMH a
good indicator, as it gives few false positive results. Values
ranging between 0.1–1.4 ng/ml have been suggested in
different studies as a cut-off for predicting a poor response
to ovarian stimulation.
The use of AMH in predicting poor response is not
without its shortcomings. The predictive value of AMH and
the cut-off levels below which poor response can be expected
varies in different studies, depending on the study population
recruited and the very variable definition of poor response
used. AMH has been shown to have similar predictive values
as antral follicle count in the prediction of poor response.28
Although women with a poor response generally have
lower pregnancy rates than women with a normal response,
many poor responders, especially young women, do achieve
pregnancies.36,37
On balance, AMH is a good predictor of poor response,
independent of age and FSH levels. Prediction of poor
ª 2012 Royal College of Obstetricians and Gynaecologists
response allows the individualisation of stimulation regimens
in order to increase/optimise the number of oocytes
retrieved. Several strategies can be employed for this, which
are beyond the scope of this article. Prediction of poor
response is also useful for the appropriate counselling of
couples regarding the response to treatment, thus avoiding
distress and disappointment.
There are enormous implications to refusing treatment to
a couple based on estimated AMH values as a predictor of
poor response. Current evidence has not yet yielded cut-off
values below which treatment can be judged as being futile,
therefore AMH should not be used as an indicator for
refusing fertility treatment to women until further data
become available.
Ovarian hyperstimulation syndrome
Between 15–20% of women undergoing controlled ovarian
hyperstimulation for IVF have mild to moderate ovarian
hyperstimulation syndrome (OHSS) and 1–3% have severe
OHSS requiring hospitalisation.38
OHSS is distressing for the woman and can progress to a
severe form which requires hospitalisation: this is potentially
fatal and can result in serious complications such as deep
vein thrombosis, pulmonary embolism, pleural effusions
and renal failure. Pregnancy can exacerbate the symptoms,
hence a fresh embryo transfer may be avoided in that cycle
in order to facilitate recovery; this, however, is a suboptimal
outcome in terms of pregnancy, as subsequent frozen
embryo transfers have lower pregnancy rates than fresh
embryo transfers.
OHSS may be avoided or its severity decreased by several
strategies used to manipulate the stimulation regimen. Some
of these include changing the antagonist protocol and
lowering the starting dosage of gonadotrophins in women
with a high potential for developing OHSS.
OHSS may be predicted by several risk factors, the most
important being PCOS, young age and low body mass
index.38 About 20% of women undergoing controlled
ovarian hyperstimulation have polycystic ovaries and,
therefore, the potential for OHSS.39,40
The role of AMH levels and over-response/OHSS has been
investigated in studies which show high basal AMH levels to
be a strong predictor of over-response. These studies have
also reported cut-off levels of AMH above which overresponse and OHSS may be predicted with high sensitivity
and specificity. Values in the range of 3.5–5.0 ng/ml have
been quoted in different studies.27,34,41
AMH is a predictor of OHSS independent of age and
PCOS and is reported to be superior to age and body mass
index. Its practical application is in altering the stimulation
protocol in women with a high potential for developing
OHSS, with the possibility of preventing it and achieving an
optimal pregnancy outcome.
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Predicting ovarian function
The relationship between AMH and pregnancy rates
The role of AMH in predicting the qualitative response to
treatment and its value in the prediction of pregnancy
remains unclear. Prospective studies have shown a positive
correlation between serum AMH levels and clinical
pregnancy rates.26,27,35,42 Some of these studies had small
numbers, therefore the findings need to be corroborated by
larger studies. Also, the improved pregnancy rates associated
with high AMH levels positively correlated with a higher
yield of oocytes in these women. Studies were unable to show
a positive relationship between serum AMH and pregnancy
rates following IVF treatment when considered
independent of the oocyte yield.43 Levels of follicular
fluid AMH have been shown to correlate positively with
pregnancy rates.44,45
In conclusion (see Box 1), the relationship between AMH
and pregnancy rates may be indirect and due to the strong
and positive correlation between AMH and the number of
oocytes retrieved. Current evidence does not allow AMH to
be used as an independent predictor for pregnancy and
further studies are needed.
Box 1. Applications of anti-müllerian hormone in
fertility practice
Predicting over-response to controlled ovarian hyperstimulation/
OHSS
Altering stimulation protocols to prevent/minimise the chance of
OHSS
Predicting poor response to controlled ovarian hyperstimulation
Altering stimulation protocols to optimise oocyte yield in predicted
poor response
Counselling couples about poor response to avoid distress/
disappointment
AMH and polycystic ovary syndrome
Polycystic ovaries are characterised by an increased number
of follicles and altered folliculogenesis from very early stages.
Several studies46,47 have clearly demonstrated that women
with PCOS have high levels of basal AMH, which can be used
as an independent diagnostic indicator for PCOS, especially
where facilities for ultrasound and antral follicle count are
not available.48 Raised AMH levels in PCOS were initially
thought to be due only to greater antral follicle numbers, but
studies have shown greater AMH production per granulosa
cell and per antral follicle.49
The cause of increased AMH production by individual
granulosa cells in the polycystic ovary is still unknown,
with several mechanisms having been proposed, including
excess androgens or insulin, or simply an intrinsic dysfunction.
In women with PCOS, high androgen levels are seen in
association with high AMH concentrations, as opposed to the
164
normal androgen levels in women with normal AMH
levels.42,47 However, a reduction in androgen levels does
not appear to lower AMH levels.50
Some investigators have found a correlation between
insulin insensitivity and AMH levels,51 which has not been
confirmed by others.42,47 A therapeutic reduction in insulin
levels failed to reduce AMH levels.50
The intrinsic overexpression of the AMH gene has been
suggested, but the cause of increased levels of AMH remains
elusive.
In women with PCOS, AMH can be used as:
a diagnostic marker for PCOS
a prognostic marker for ovulation induction and fertility
treatment.
Women with PCOS can be subdivided into two distinct
groups, which do not overlap, based on AMH levels:49
Anovulatory women, who have very high AMH levels,
associated with high androgens and insulin insensitivity.
These women are more likely to respond poorly to
clomifene citrate or FSH stimulation during ovulation
induction treatments and have a poorer prognosis for
these treatments.
Women with lower levels of androgens and better insulin
sensitivity. They are often ovulatory, respond better to
ovulation induction treatments and have comparatively
lower levels of AMH.
Conclusion
AMH shows the potential to be a reliable marker of ovarian
reserve and reproductive performance. It is a good predictor of
poor response to fertility treatment, which can allows the
individualisation of stimulation regimens; it can also be used to
alter the stimulation protocol in women with a high potential
for developing OHSS. Current evidence does not allow AMH
to be used as an independent predictor for pregnancy and
further studies are needed. In women with PCOS, AMH can be
used as a diagnostic marker and as a prognostic marker for
ovulation induction and fertility treatment.
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ª 2012 Royal College of Obstetricians and Gynaecologists