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Physiology of Anti-Müllerian Hormone (AMH)
Physiology of Anti-Müllerian Hormone (AMH)
Anti-Müllerian hormone has also been called Müllerian inhibiting factor (MIF), Müllerian-
inhibiting hormone (MIH), and Müllerian-inhibiting substance (MIS), first detected in granulosa
cells in the 1980s. AMH is a member of the transforming growth factor-beta (TGF-β)
superfamily. includes more than 35 structurally related peptides, including activins, inhibins,
bone morphogenic proteins (BMPs) and growth differentiation factors. AMH is a homodimeric,
disulfide-linked glycoprotein with a molecular weight of 140 kDa. AMH works by interacting with
specific receptors on the surfaces of the cells of target tissues. The best-known and most
specific effect, mediated through the AMH type II receptors, includes programmed cell death
(apoptosis) of the target tissue (the fetal mullerian ducts). (Marca AL, 2010; Karkanaki A, 2011)
In the male, AMH is produced by Sertoli cells from 8 weeks gestation, causing
regression of the Mullerian ducts and allowing male development. In the female AMH
expression has been detected from 36 weeks gestation. AMH exerts its biological effects
through a transmembrane serine/ threonine kinase type II receptor (AMHRII), which is
specifically expressed in the gonads and in the mesenchymal cells adjacent to the Mullerian
ducts. In men, inadequate embryonal AMH activity can lead to the Persistent Müllerian duct
syndrome (PMDS), in which a rudimentary uterus is present and testes are usually
undescended. The AMH gene (AMH) or the gene (AMH-RII) for its receptor are usually
abnormal. AMH measurements have also become widely used in the evaluation of testicular
presence and function in infants with intersex conditions, ambiguous genitalia, and
cryptorchidism. (Ledger WL, 201)
In healthy females AMH is either just detectable or undetectable in cord blood at birth
and demonstrates a marked rise by 3 months of age; while still detectable it falls until 4 years of
age before rising linearly until 8 years of age remaining fairly constant from mid-childhood to
early adulthood, it does not change significantly during puberty and from 25 years of age, AMH
declines to undetectable levels at menopause.
AMH is produced by granulosa cells from pre-antral and antral follicles, restricting
expression to growing follicles, until they have reached the size and differentiation state at which
they are selected for dominance by the action of pituitary FSH. In the human this occurs in
antral follicles of size 4–6 mm. Neither AMH staining nor AMH mRNA expression was observed
in oocytes, corpus luteum, atretic follicles or theca cells in mice, rats or human ovaries,
confirming that the GCs are the only source of AMH in the ovary. (Weenen et al., 2004)
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Factors condition in female that influence AMH levels are :
A. Factors that decrease MIS/AMH • Increasing age
• Obesity
• Administration of gonadotropins
• Administration of chemotherapy or radiation
• Surgical removal of one or both ovaries
B. Factors that increase MIS/AMH
• Polycystic Ovarian Syndrome
C. Factors that do not influence MIS/AMH • Day of menstrual cycle
• GnRH agonists
• Birth Control Pills
• Pregnancy
The interpretation of the AMH levels is also subject to variation, as the levels which are
considered to be “normal”, are still not clarified and agreed on by the experts. Also, different
current commercial assays do not give equivalent results. AMH levels do not change
significantly throughout the menstrual cycle and decrease with age. Healthy women, below 38
years old, have AMH levels of 2.0 – 6.8 ng/ml (14.28 – 48.55 pmol/L). Other clasify, the levels
between 1-3 ng/ml are considered to be normal, 0.7-0.9 ng/ml to be low normal, 0.3-0.6 ng/ml to
be low and less than 0.3 to be very low. The levels above 3.0 ng/ml are considered to be high.
High levels are found in patients with PCOD dan obsese women have significantly lower
AMH levels (>65%) compare to normal weight women of similar age. But, there is a large
subjective variation in the clinical interpretation.
AMH is that there are at least 2 scales out there and innumerable clinic definitions of
what is "normal", it depends on which assay they use and which study. One scale is ng/ml and
one is pmol/l. The pmol/l scale runs from 0 to about 48; the ng/ml runs from about 0-10. On the
ng/ml scale, less than 2 ng/ml is considered to be low.
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THE ROLE OF AMH IN REPRODUCTIVE MEDICINE
The main physiological role of AMH in the ovary seems to involve in the regulation of
folliculogenesis. AMH seems to inhibition the early stages of follicular development, since both
in vivo and in vitro experiments have indicated that the transition from primordial into growing
follicles becomes enhanced in absence of AMH, leading to early exhaustion of the primordial
follicle pool. It has been suggested that follicles are more sensitive to FSH in the absence of
AMH. AMH continues to be expressed in the growing follicles in the ovary until they have
reached the size and differentiation state at which they may be selected for dominance.
(Durlinger et al., 2002).
The inhibitory effect of AMH on FSH sensitivity of follicles could play a role in the
process of selection. A low expression of AMH within the follicle would diminish the threshold
level for FSH, allowing these follicles to continue growth and to ovulate in the next estrous cycle.
(Marca AL, 2010). AMH attenuates the FSH-dependent increase in aromatase activity and LH
receptor expression. (Durlinger, 2001)
Figure 2. AMH is secreted by pre-antral and antral follicles and role of AMH in
folliculogenesis
It seems to inhibit initial follicle recruitment and FSH-stimulated follicle growth. The role of AMH in the two main compartments of normal ovarian follicle
development (the red centre represents the oocyte, the grey area represents the granulosa cell layer and the white area represents follicle fluid in the
antrum). AMH is expressed in small and large pre-antral follicles (broken arrows) and in small antral follicles (whole arrow), and the latter mainly
contributes to serum levels. Initial recruitment takes place as a continuous process, whereas cyclic recruitment is driven by a rise in FSH serum levels
at the end of a previous menstrual cycle. The inhibitory effects of AMH are shown (a) on the initial recruitment of primary follicles from the resting
primordial follicle pool and (b) on the sensitivity of antral follicles for FSH. (Broekmans st al., 2008)
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AMH levels do not vary with the menstrual cycle and can be measured independently of
the day of the menstrual cycle. Recently, many studies have been performed to measure the
AMH level in many situation correlation to ovarian function, as conclusion is AMH could predict
and marker for :
1. Ovarian Reserve
2. Predictor age of menopause
3. Marker of Premature ovarian failure (POF)
4. Evaluating fertility potential and ovarian response in ovarian stimulation in assisted
reproductive technique (ART)
5. Polycystic ovary (PCO)
6. Tumour marker
7. As a chemotherapeutic agent for epithelial ovarian cancer
8. As predictor post-threatment ovarian function in ovarian cancer
1. Ovarian Reserve
Ovarian reserve comprises two elements: the size of the stock of primordial follicles and
the quality of the oocytes. From the primordial follicle pool, primary follicles will start a
maturation process and develop through secondary (preantral) follicles into the pool of antral
follicles from which the monthly follicle to be ovulated is selected (Fauser and Van Heusden,
1997). Ovarian reserve tests can be divided into 2 types depending on the methods used. 1).
Biochemical tests use assays of basal or stimulated hormones including basal AMH, FSH, LH,
estradiol, and inhibin B. 2) Biophysical tests using transvaginal ultrasound include Doppler
studies of the blood-flow in the ovaries, ovarian volume, and antral follicle count (AFC). It is well
known that with increasing age there is a decline in female reproductive function due to the
reduction in the ovarian follicle pool and the quality of the oocytes.
The quantitative aspect of ovarian reserve is reflected by the size of the primordial
follicle pool. Direct measurement of the primordial follicle pool is impossible. However, the
number of primordial follicles is indirectly reflected by the number of growing follicles (Scheffer
et al. 1999). AMH is expressed by growing follicles will reflect the size of the primordial follicle
pool. Serum AMH levels show a reduction throughout reproductive life. Importantly, a strong
correlation of serum AMH levels with AFC was observed. This positive correlation was later
confirmed by Fanchin et al. (2003), who showed a strong correlation between serum AMH
levels and AFC.
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Study by Kelsey TW, et al (2011) demonstrates that serum AMH levels peak at age 18-
20. This is consistent with a study published in 2002 by de Vet A et al, that shows AMH
decreasing after age 20, however van Disseldorp (2008) and Soto N (2009) have reported peak
AMH at age 31-33. Undetectable AMH levels after spontaneous menopause have been
reported. AMH was the only marker of ovarian reserve showing a mean longitudinal decline
over time both in younger women (< 35 years) and in women over 40 years. (Marca AL and
Volpe A, 2006)
One potential advantage of using an AMH test as a marker of ovarian reserve, is that it
does not seem to change over the course of the menstrual cycle (FSH, inhibin B on the other
hand, must be measured on day 2 or day 3 of the menstrual cycle) (Durlinger et al., 1999), and
is not regulated by gonadotrophic hormones (Durlinger et al., 1999). In the study by van Rooij et
al. (2002) found that AMH levels did not change in response to an acute endogenous rise in
FSH and LH. As expected, production of E2 and inhibin B are under direct regulation of FSH as
indicated by the changes after GnRH agonist administration (Winslow et al., 1991; Elting et al.,
2001). Serum AMH levels are tightly related to early AFC, with a relationship that was
remarkably more intense than those obtained with serum levels of inhibin B, E2, FSH and LH. It
has become clear that AMH gives the best measure of ovarian reserve of all the basal tests.
(Ledger WL, 2010)
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whereas the prediction of late menopause would open options for preventive management of
breast and intestinal cancer.
The rationale for the predictive value of AMH for menopause timing is based on the age-
related decline in follicle number. Serum AMH levels have been shown to strongly correlate with
the number of antral follicles. For long term follow-up of ovarian reserve status in
normoovulatory (11 years) by Broer et al (2011) found that AMH is highly predictive for timing of
menopause, so demonstrated that AMH capable of predicting future age of menopause for
given woman. Because only AMH showed significant added value to age, a nomogram of age
and AMH for prediction of age at menopause was contracted using a Weilbull model. (Broer et
al, 2011). For the AFC, a cross-sectional study has suggested a possible relation with the timing
of menopause. In the present study, as well as in the earlier report by van Rooij et al. (34),
however, the AFC as well as basal SH failed to show a significant capacity in predicting age at
menopause compared with prediction on the basis of age alone.
Table. Age-specific AMH and corresponding percentiles for AMH and predicted age at
menopause
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3. Marker of Premature ovarian failure (POF)
Premature ovarian failure (POF) is a syndrome defined as the cessation of ovarian
function before the age of 40 and characterized by amenorrhoea associated with elevated
gonadotrophin levels. The etiology of POF includes genetic disorders, autoimmune disease, and
iatrogenic causes such as chemotherapy or radiotherapy. Serum AMH measurement may have
a role in identifying incipient ovarian failure in young eumenorrheic women with moderate
hypergonadotropism. Incipient ovarian failure, may precede the onset of cycle irregularity
(transitional ovarian failure) and hence the menopausal transition by 3–10 years. In a recent
study, serum levels of AMH were able to discriminate between incipient and transitional ovarian
failure, defined as elevated follicular phase FSH levels along with a regular menstrual cycle or
cycle disturbances, respectively. In women with incipient failure, levels were below the 5th
percentile of normo-ovulatory women in 25% and undetectable in 7%, compared with 66 and
52% in women with transitional ovarian failure (Knauff et al., 2008). This finding indicates that
AMH provide an accurate assessment of ovarian follicle pool in young hypergonadotropic
patients especially in the clinically challenging subgroups of patients with elevated FSH who do
not fulfil the strict definition of POF (Knauff et al., 2008).
Moreover, young sisters or daughters of women affected by POF, patients undergoing
ovarian surgery, and patients affected by Turner Syndrome may all benefit from the information
which AMH levels might provide in this context. This is illustrated in a recent report on the
fertility preservation in girls with Turner Syndrome. Forty-seven young girls with Turner
Syndrome underwent laparoscopy for ovarian tissue cryopreservation and 15 of them had
follicles in the tissue piece analyzed. When investigating which factors had the highest
predictive value for finding follicles, the most powerful were the presence of 46XX/XO
chromosomal mosaicism, serum FSH levels below 11 IU/l and serum AMH levels 0.28 ng/ml
(Borgstrom et al., 2008). AMH may therefore have a role in the diagnostic work-up and fertility
counselling of patients with Turner Syndrome.(Marca AL, 2009)
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and OHSS. Definition poor respone still not universally accepted. The number of developed
follicles and the number of retrieved oocytes are 2 of the most important criteria for defining
poor response. Number variation ranges from less than 3 - 5 dominant follicles on the day of
hCG, and from less than 3-5 retrieved oocytes (Tarlatzis et al., 2003). Poor responders have
definitely lower pregnancy rates compared with normal responders of similar age.
Studied by Marca AL (2007), Cut-off values for AMH of 0.7–0.75 ng/ml have been
proposed for the identification of poor responders by several groups with sensitivity and
specitifity 75%. Young women with AMH levels less than 0.7 ng/ml are better prognosis than
older. The patient at very high risk for cycle cancellation might be identified by serum AMH
levels lower than 0.1–0.35 ng/ml (Muttukrishna et al., 2004; Lekamge et al., 2007) and should
be refused threatment.
In the clinical setting it may be useful to correctly predict the occurrence of poor
response as this may lead to avoiding treatment in women destined not to respond to COS, thus
contributing to reducing the cycle cancellation rate, the treatment costs and psychological stress
for the couple. Finally improved counselling for the prediction of poor response may ameliorate
disappointment and distress.
Hyper-response if oocyte recovery more than 15. (Satwik R, 2011). The studies by Lee
et al. (2008) and Nardo et al. (2008) have independently calculated a similar performance of
AMH for the prediction of hyper-response and OHSS. The reported cut-off value is of about 3.5
ng/ml, above which hyper-response/OHSS may be anticipated. In the study by Lee et al. (2008).
Basal AMH levels predicted OHSS with a sensitivity of 90.5% and specificity of 81.3%.
Interestingly the cut-off value calculated (3.36 ng/ml) corresponded to the highest quartile of the
AMH values in their population, suggesting that hyper-response and OHSS may be caused by
gonadotrophin administration to women with enhanced ovarian reserve (Lee et al., 2008). In
conclusion, AMH measurement prior to gonadotrophin stimulation could provide useful
information to direct the application of mild patient-friendly stimulation protocols in order to avoid
OHSS. The key to preventing OHSS is the recognition of risk factors for OHSS leading to an
individualization of gonadotrophin starting dose which should be the minimum dose necessary
to achieve the therapeutical goal. Women with high AMH levels are considered to be at risk for
hyper-response and OHSS. A low FSH starting dose followed by the use of GnRH antagonists
have been shown to reduce the incidence of OHSS and may be proposed as a first line
treatment for patients with high serum AMH levels.
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5. AMH as a marker for PCO
Women with polycystic ovary syndrome (PCOS) show increased development of antral
follicles compared with normal women. On histological examination, polycystic ovaries (PCO)
exhibit a normal number of primordial follicles, whereas the number of developing follicles is
double compared with normal ovaries (Webber et al., 2003). Circulating AMH levels in women
with PCOS are 2-3 times higher than healthy controls.
In women with PCOS, increased AMH levels may not only be due to excessive
accumulation of antral follicle but also to increased granulosa cell AMH secretion (Mulders et al.,
2004). Indeed, levels of AMH are on average 75 times higher in granulosa cells from PCO,
compared with levels in granulosa cells from normal ovaries (Pellatt et al., 2007).
The mechanisms leading to PCOS are still poorly understood, the common denominator
is a disturbance in the selection of the dominant follicle resulting in anovulation. The defective
selection mechanism results in an accumulation of small antral follicles, which contribute
significantly to the production of AMH. AMH lowers the sensitivity of follicles to FSH (Durlinger
et al. 2001), possibly contributing to deranged follicle selection. It has been suggested that
aromatase activity in PCOS patients might be decreased because follicles from PCOS women
do not produce large amounts of E2. in PCOS women serum AMH levels were correlated with
antral follicle number. The two- to threefold increase in the number of growing follicles is
reflected by a two- to threefold increase in serum AMH level. Increasing in serum AMH levels is
not only due to an increase in the number of growing follicles, but may also result from
increased AMH production per follicle. In addition, androgens stimulate the proliferation of
granulosa and theca cells of growing follicles. It is possible that under these conditions follicles
may produce more AMH. Since AMH inhibits aromatase activity, local androgen concentrations
may be increased, possibly resulting in a positive feedback mechanism between AMH and
androgens. (Visser JA, et al, 2006)
AMH levels appear to be related to the severity of the syndrome, AMH is higher in
amenorrheic compared with oligomenorrheic or in anovulation campared with ovulation women
with PCOS (Marca AL, et al., 2004). High level values could reflecs a more evident impairment
in follicular development and granulosa cell function in the ovaries of amenorrhoeic and
oligomenorrhoeic PCOS women. Finally, AMH measurement has been found to offer a relatively
high specificity and sensitivity (92 and 67%, respectively) as a diagnostic marker for PCO (Pigny
et al., 2006). On this basis it has been proposed that in situations where accurate ultrasound
data are not available, AMH could be used instead of the follicle count as a diagnostic criterion
for PCOS (Pigny et al., 2006, Visser JA, 2006).
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Other than for diagnostic evaluation, AMH measurement may also be useful in the
therapeutic approach of PCOS patients. Overweight women with PCOS who respond to weight
loss with menstrual improvements have significantly reduced preweight-loss AMH levels,
indicating that baseline AMH may provide a potential clinical predictor of menstrual
improvements with weight loss in PCOS (Moran et al., 2007). Similarly, basal AMH level
evaluation may be useful in the prediction of ovarian response to clomiphene citrate (El-
Halawaty et al., 2007). Finally it has been shown that metformin administration in women
affected by PCOS is associated with a reduction in both AMH serum levels and antral follicles,
suggesting that the measurement of AMH could be used to evaluate the treatment efficacy with
insulin sensitizers (Piltonen et al., 2005).
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4. When bilateral ovariectomy is performed AMH must be undetectable in serum. Even very low
levels may be suggestive of residual disease.
5. A post-operative rise in serum AMH levels may precede the clinical recurrence. Hence, the
clinical examination and imaging should be anticipated.
6. AMH levels should be obtained every 6 months for at least 5 years after the surgery.
However, it should not be ignored that a late recurrence (up to 30 years after initial treatment)
has been reported in up to 33% of patients
7. Recurrences in juvenile GCTs occur within a year of initial diagnosis at a mean of 5–6
months. Hence, in juvenile GCT, AMH serum levels should be determined every month
following the surgery. (Marca AL, 2007)
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treatment was followed by a significant reduction in the graft size ratio indicating that AMH
delivered parenterally may cause inhibition of human cancer cell lines in vivo.
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of the growing follicle and AMH levels further decreased during continued treatment. (Anderson
RA, 2011) .
Rosendahl et al (2010) found that high pretreatment levels of AMH were associated with
a higher level of AMH 1 year after the end of treatment. Further, patients with pretreatment
levels of AMH above the median of the study group ( 2.2 np/ml) had a more favorable ovarian
function during recovery. These findings support data by Anderson et al (2011) who observed
higher pretreatment levels of AMH in patients with breast cancer who maintained menstrual
bleedings after chemotherapy.
The circulating level of AMH is to be a highly sensitive marker of ovarian reserve
because it is assumed to reflect the pool of resting primordial follicle. Patients with a higher
pretreatment AMH level would be able to endure more chemotherapy, because they have a
higher number of resting primordial follicles. Assesment circulating level of AMH in pretreatment
ovarian reserve may in future be used to individualize a patient’s risk of chemotherapy-induced
ovarian failure and hence offer a more patient-tailored plan for fertility preservation such as
cryopreservation of ovarian tissue
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