Molecular and Cellular Endocrinology 347 (2012) 7884

Contents lists available at ScienceDirect

Molecular and Cellular Endocrinology

journal homepage: www.elsevier.com/locate/mce

Review

Inhibins and activins in blood: Predictors of female reproductive health?

David M. Robertson
Prince Henrys Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia

a r t i c l e

i n f o

Article history:
Available online 1 June 2011
Keywords:
FSH
Ovarian follicle reserve
Menopause transition
Down syndrome
Preeclampsia
Ovarian cancer

a b s t r a c t
Inhibins A and B are gonadal factors which are important in fertility. Their use as predictors of female
reproductive health has centred on their application to ovarian cancer, Anorexia Nervosa, Down Syndrome and preeclampsia. Inhibin B also provides an index of the endocrine feedback relationship
between the ovary and pituitary particularly when the ovarian follicle reserve is low. These applications
are relevant in monitoring the onset of the menopause transition, ovarian recovery following chemotherapy and disturbances in pubertal development. Currently, these applications have only found widespread
use in Down Syndrome and ovarian cancer. Activins, on the other hand, appear to have a limited
application.
2011 Elsevier Ireland Ltd. All rights reserved.

Contents
1.
2.
3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The physiology of inhibin in women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Role of inhibins in follicular function and ovarian reserve assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Inhibin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Inhibin B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.
Menopause transition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.
Ovarian function in assisted reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.
Inhibin and female infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.
Premature ovarian failure (POF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.
Anorexia Nervosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.
Polycystic ovarian syndrome (PCOS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.
Puberty. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5.
Monitoring ovarian function following chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.
Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1.
Down Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.
Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.
Ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.
Activins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

Abbreviations: AMH, anti-Mullerian hormone; POF, premature ovarian failure;

IOF, incipient ovarian failure; PCOS, polycystic ovarian syndrome.
Tel.: +61 3 95947901.
E-mail address: david.robertson@princehenrys.org
0303-7207/$ - see front matter 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.mce.2011.05.016

The objective of the present review is to update the reader on

advances in the physiology and clinical application of inhibins
and activins in human female reproduction. A number of reviews
(Laven and Fauser, 2004; Robertson et al., 2004; Tong et al.,

D.M. Robertson / Molecular and Cellular Endocrinology 347 (2012) 7884

2003; Welt, 2002) have been previously published which the reader can refer to for details of earlier studies.
2. The physiology of inhibin in women
The role of inhibin in reproductive endocrinology differs from
that of many of the other members of the TGFb growth factor family as its existence had been postulated from earlier in vivo observations. These studies showed that steroids were insufcient to
adequately suppress pituitary FSH secretion in contrast to LH,
and that additional gonadal factors were involved. This hypothesis
was based on in vivo studies whereby administration of proteinaceous gonadal extracts was successful in suppressing serum FSH. In
due course, inhibins A and B were isolated as active ingredients
from these extracts and these factors conform in most aspects to
the FSH suppressing factor which is central to the inhibin
hypothesis.
Inhibin, a dimeric glycoprotein consists of a and either bA or bB
subunits. They are produced as precursors and cleaved both intracellularly and extracellularly to produce the 30k mature form,
although precursor forms where one or both subunits remain intact are also secreted. These partially processed dimers are biologically active in vitro.
In addition, the b subunits can dimerise (bAbA and bBbB) to
form activin (A and B). Its biological activity is distinct from inhibin
with additional actions in non-reproductive systems, in particular,
development and inammation (recent review by Xia and Schneyer, 2009). It is unclear if activin in normal physiological situations
exhibits an endocrine role as it is bound strongly in serum to follistatin which neutralises its bioactivity. The observation that follistatin in turn exhibits FSH suppressing activity led to the
conclusion that activin acts via an autocrine/paracrine mechanism
within the pituitary to stimulate FSH synthesis which is then
antagonised by circulating inhibin. Thus inhibins endocrine role,
at least within the pituitary was to neutralise activins action. Activins mechanism of action, consistent with other TGFb family
members, is to facilitate the interaction between the Activin Type
II and Type I receptors leading to an activation of the intracellular
Smad pathway. Inhibins mode of action is thus to inhibit this
process.
It is now recognised that inhibins mechanism of action requires
an initial interaction with the accessory binding protein, betaglycan. This inhibin:betaglycan complex interacts with several Type
2 receptors (e.g. activin and BMP) inhibiting the subsequent interaction and activation of the appropriate Type 1 receptor. However
it is clear that the inhibinbetaglycan complex can, in principle, inhibit any TGFb ligand that interacts with these Type II receptors,
e.g. activin A, activin B, TGFb2, BMP2, 4, 6, 7, GDF9, GDF11, myostatin (Wiater et al., 2009). Thus from a mechanistic point of view,
inhibin can inhibit the actions of a range of TGFb family members.
Inhibins action is best recognised for
(a) its action in inhibiting activin and other TGFb family members such as BMPs, myostatin, GDF9, stimulation of FSH
secretion by the pituitary as part of the gonadal feedback
regulation of pituitary FSH secretion;
(b) a role in suppressing granulosa cell tumours and muscle and
liver cachexia as observed in inhibin a subunit null mice.
The action of inhibin appears in part to limit the overproduction of activin responsible for the cachexia. Activins role in
the initiation of ovarian cancers is less readily understood;
(c) suppressing the development of adrenal tumours in
gonadectomised inhibin a subunit null mice by inhibiting
the action of TGFb2 on adrenocortical cell proliferation
(Looyenga et al., 2010). This observation is particularly
novel. It had been previously conjectured that overproduc-

79

tion/secretion of activin as a mitogen was the factor responsible for the tumours. However a more complex pathway
was identied involving the gonadectomy-induced upregulation of TGFb2 by LH and an elevation in the levels of betaglycan normally inhibited by inhibin. Thus inhibins action
was to suppress the levels of betaglycan and thus hindering
the mitogenic action of TGFb2;
(d) as a possible inhibitory factor in bone turnover resulting in
an increase in osteoporosis in women during the menopause
transition. Inhibin A rather than inhibin B was the better
predictor of both bone formation and bone resorption (Perrien et al., 2006, 2007);
(e) a role in ovarian folliculogenesis through modication of
steroid production; in vitro data only is available (Drummond, 2005).
In clinical terms inhibin is best known as a marker of ovarian
follicle activity at puberty, during reproductive life and approaching menopause, and in granulosa cell and mucinous ovarian cancers, Down Syndrome and preeclampsia.
3. Role of inhibins in follicular function and ovarian reserve
assessments
The physiology of inhibin is better understood in relation to its
feedback role in regulating FSH secretion.
3.1. Inhibin A
Inhibin A is primarily the product of the developing dominant
follicle and corpus luteum in the human menstrual cycle, with circulating levels increasing across the follicular phase, falling sharply
in the vicinity of the midcycle LH peak and then increasing and
decreasing across the luteal phase in parallel with the biphasic pattern of plasma progesterone. Attempts to show a reciprocal relationship between serum inhibin A and FSH across either the
follicular or luteal phases of the cycle (Robertson et al., 2009) has
been unsuccessful. However, a reciprocal relationship between serum inhibin A and FSH has been shown (Welt et al., 1997) across the
lutealfollicular transition. It should be noted that this relationship
is observed at the intersection between the regression of the corpus luteum of the previous cycle with the development of ovulatory follicles in the latter and thus the observed reciprocal
relationship is likely to be due to the overlap of inhibitory and
stimulatory effects across this region of the menstrual cycle.
Later in the menstrual cycle, inhibin A levels closely parallel
those of plasma estradiol in the follicular phase and progesterone
in the luteal phase, reecting the numbers of developing dominant
follicles and corpora lutea. These associations suggest that serum
inhibin A is a marker of follicle number or activity as its serum levels, like estradiol, increase with FSH stimulation however there
does not appear to be any evidence of feedback activity on the
pituitary secretion of FSH or LH. This conclusion is surprising since
inhibin A administration to rats (Makanji et al., 2009), sheep (Tilbrook et al., 1993) and monkeys (Molskness et al., 1996) does result in suppression of FSH secretion. Why is inhibin A seemingly
inactive in vivo as an inhibitor of FSH secretion in the human?
One possibility is that the circulating levels of inhibin A in the
follicular phase are quantitatively less than inhibin B, however
when inhibin A and B levels are related to puried inhibin A and
B calibrators their levels when measured by immunoassay were
similar (Makanji et al., 2009). Another possibility is that inhibin
A is less bioactive than inhibin B. In vitro and in vivo studies do
show that the mature form of (30k) inhibin B is more bioactive
than 30k inhibin A, however the differences in in vivo bioactivity

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D.M. Robertson / Molecular and Cellular Endocrinology 347 (2012) 7884

at least in rats (Makanji et al., 2009) is not sufciently large (50%)

to explain this difference. As a third possibility, that human inhibin
As mechanism of action differs compared to inhibin B. However
there is little evidence at this point to support this possibility.
3.2. Inhibin B
Inhibin B in contrast, is the product of follicles in early development (follicles with diameters <2 mm in size). Its levels are elevated early in the follicular phase of the menstrual cycle
decreasing across the follicular, ovulatory and luteal phases of
the cycle. However, in contrast to inhibin A, an inverse relationship
between circulating inhibin B and FSH particularly in the follicular
phase was observed (Robertson et al., 2009; Welt, 2002). It is believed that as part of this feedback mechanism, FSH initially stimulates the ovary during the luteal phase of the preceding menstrual
cycle to promote more developing follicles. These follicles under
FSH stimulation produce more inhibin B during the follicular phase
of the following cycle which acts by an endocrine mechanism at
the pituitary level to inhibit FSH. Then FSH starts to fall in the late
follicular phase and with this reduction in FSH, inhibin B levels fall.
This decrease in FSH will result in an increase in the number of
non-dominant follicles being directed along the atretic pathway
leaving mainly one dominant follicle to proceed to ovulation.
4. Menopause transition
Studies investigating the changes in reproductive hormone levels approaching menopause have provided some useful insights
into the roles of both inhibins A and B and their relationship to
both FSH and LH (Burger, 2008; Hale et al., 2007; Robertson
et al., 2008, 2009; Sowers et al., 2008; Welt, 2002). These analyses
provide an assessment of the change in reproductive hormones as
the ovarian supply of follicles and the inuence of ovarian feedback
factors diminish. In one study (Hale et al., 2007; Robertson et al.,
2008, 2009) reproductive hormone levels were determined in
blood samples collected every 3 days across ovulatory menstrual
cycles from women in the 2535 year and 4555 year age group.
The hormone patterns were classied into four cycle types. The
rst cycle type consisted of cycle proles which showed no significant changes across the menstrual cycle between the two aged
groups in serum levels of FSH, LH, estradiol, progesterone, inhibin
A, inhibin B. AMH, in contrast, showed a marked age-related decline. The second cycle type identied in within this 4555 year
age group consisted of ovulatory cycles where there was a signicant decrease in inhibin B and a corresponding rise in FSH, with a
further fall in AMH. Meanwhile, estradiol, inhibin A, progesterone,
and LH remained unchanged. The further fall in AMH is attributed
to a further reduction in follicle number, in parallel with a fall in
inhibin B. These ndings reinforce previous observations (Burger,
2008; Klein et al., 2004; Knauff et al., 2009; Welt et al., 1999) of reciprocal changes in the serum inhibin B and FSH levels in ovulatory
cycles across mid to late reproductive life. One presumes that the
inhibin B levels have fallen below a critical level due to the reduction in follicle number resulting in a reduced capacity to suppress
FSH which as a consequence of reduced feedback inhibition, starts
to rise. In contrast, the proles of inhibin A, estradiol and progesterone remain the same reecting the apparent independent development of the dominant follicle and normal luteolysis in the luteal
phase with the formation of a normal corpus luteum. A third cycle
type was identied whereby although ovulatory cycles was evident with elevated luteal phase progesterone levels, inhibin B levels decrease further, while FSH and now LH start to rise markedly.
AMH remains unchanged. Meanwhile, follicular phase inhibin A
and E2 follow similar patterns to that seen with the early cycle

types. Klein et al. (2004) noted that in addition during the menstrual cycle in this latter aged group, inhibin A actually increased
at midcycle while inhibin B was reduced in the follicular phase.
Klein et al. (2004) investigated the age-related changes of serum activin A as part of their characterisation of hormonal patterns across the menstrual cycle. While a decrease in inhibin B
and a rise in inhibin A was noted with age, no signicant changes
in serum activin A across the menstrual cycle or with age was
identied.
These changes in hormone patterns associated with the menopause transition are thus characterised by a decline in follicle number including a decrease in follicle products (inhibin B and AMH)
and the ongoing and relatively unchanging process of folliculogenesis as reected in relatively unchanged estradiol, inhibin A and
progesterone as products of the developing follicle and corpus luteum, respectively.
With the depletion of follicles, serum AMH continuously declines (although there are caveats to this process (Robertson
et al., 2011)) while inhibin B falls at a later stage. A number of studies (Sowers et al., 2008; van Rooij et al., 2004, 2005) now suggest
that serum AMH levels may be useful early marker of menopause
based on its continuing close association with follicle number. Another approach to study the relationship between FSH and inhibin
B as a measure of the pituitary:gonadal feedback, is to express this
data as a ratio of FSH and inhibin B (Robertson et al., 2008). This
ratio is not signicantly different between the 2135 year group
and Type 1 cycles in the 4555 year group, however this ratio subsequently changes in parallel with the decrease in inhibin B and increases in FSH in Type 2 cycles. This transition or demarcation
would suggest that Type 2 cycles are likely to be hormonally
compromised.
A comparison between AMH and FSH:inhibin B ratio with age
and through the menopause transition showed a close linear relationship (Fig. 1, r = 0.83, p < 0.001). This analysis enabled the identication of Type 2 cycles which can be readily distinguished from
normal reproductive (Type 1) cycles based on AMH, FSH and inhibin B levels. For example, in Fig. 1, an AMH level of 0.2 ng/ml and a
FSH:inhibin B ratio of 0.2 as determined in the early follicular
phase demarcated this transition. We conjecture that this cut-off
point may be useful in predicting the onset of irregular ovarian
and menstrual activities in the menopause transition as this may
indicate an increase in cycle irregularity and the possibility of
impending menopause. This approach may be useful in other
settings such premature ovarian failure, reproductive capacity
following chemotherapy where knowledge of the normal ovarian:pituitary axis would be important.
5. Ovarian function in assisted reproduction
Inhibins A and B are primarily products of the ovarian granulosa
cell and responsive to FSH treatment (Eldar-Geva et al., 2005; Hee
et al., 1993; Welt, 2002) and as such have been considered as plasma markers in assisted reproduction methodologies. However, the
clinical interest in these hormones has centred more on predicting
ovarian reserve in terms of follicle number or number of oocytes
retrieved than the quality of the follicles produced. Inhibin A, as
discussed above, is a marker of the tertiary follicles and not the antral and preantral follicular pool. Inhibin B is unlikely to be a good
marker of follicle number since serum inhibin B does not change
with age until the perimenopausal period despite the fact that
the ovarian antral follicle complement falls dramatically. Furthermore, studies show a limited or no relationship between basal inhibin B levels and subsequent IVF outcome in contrast to other
endpoints (serum AMH or antral follicle count (Jayaprakasan
et al., 2010; Kwee et al., 2008; Muttukrishna et al., 2004)).
Currently, plasma AMH and/or antral follicle count are the better

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D.M. Robertson / Molecular and Cellular Endocrinology 347 (2012) 7884

10.00

Cycle Type 1
Cycle Type 2
Cycle Type 3

r=0.83

MRA

AMH (ng/ml)

1.00

0.10

0.01
0.01

0.10

1.00

10.00

FSH/Inhibin B ratio
Fig. 1. Regression plot between FSH:inhibin B ratios and AMH levels in the early follicular phase of ovulatory cycles from mid reproductive age (2135 years, MRA) and
women in late reproductive age (4555 years, Cycle Types 13). The dotted lines represent potential upper and lower cut-off points of FSH:inhibin B ratio (0.25) and AMH
(0.25 ng/ml) as a means to distinguish Type 1 from Type 2 and 3 cycles (correlation coefcient r = 0.83, p < 0.001). See text and Robertson et al. (2008) for more details.
(Printed with permission from Menopause.)

6. Inhibin and female infertility

whereby the ovary responds to FSH. This is reected in the increase

in inhibin B/FSH ratio from low values to approach normal values
found in the control group.
In a separate study, inhibin B, FSH, estradiol and AMH levels
were assessed as predictors of recovery of ovarian function in
young women with Anorexia Nervosa (van Elburg et al., 2007). Inhibin B, FSH and AMH were shown to be independent predictors of
recovery in support of the importance of these hormones in ovarian recovery.

6.1. Premature ovarian failure (POF)

6.3. Polycystic ovarian syndrome (PCOS)

A recent study was undertaken to assess the clinical value of inhibin B, antral follicle count and AMH in assessing ovarian function
in women with POF (Knauff et al., 2009). These women were categorised into women <40 years with an elevated FSH and either normal menstrual cycles (incipient ovarian failure, IOF),
oligomenorrhoea or amenorrhoea. The authors concluded that
AMH levels were better correlated with POF clinical status,
although it was noted that normal AMH levels were also associated
with IOF. Serum inhibin B levels did not differ between controls
and IOF while the corresponding AMH levels fell 10-fold.

It was anticipated that higher levels of circulating inhibins

would be associated with polycystic ovaries in women, however
the ndings to date have been inconclusive. Serum inhibin B has
been shown to be elevated in some but not all studies however
the elevated inhibin B levels now have been attributed to the effects of obesity and diabetes, conditions often associated with
PCOS (Codner et al., 2007; Welt, 2002). In order to obtain an understanding of inhibin production by follicles in women with PCOS, Inhibin A and B levels were determined in follicular uid from
follicles from normal women and women with PCOS (Welt et al.,
2005). Both inhibins were reduced in concentration in the PCOS
group raising the question that this decrease may be associated
more with follicular arrest which typies PCOS.

diagnostic markers of IVF outcome although their clinical utility

overall is still questioned (Jayaprakasan et al., 2010; Muttukrishna
et al., 2004). AMH is produced by preantral and small antral follicles with lower levels produced by either primordial or dominant
follicles. AMH levels correlate with antral follicle number and its
blood levels do not appear to be hormonally sensitive as its levels
remain relatively unchanged across the menstrual cycle.

6.2. Anorexia Nervosa

Inhibin B, FSH, LH, estradiol and leptin were determined in
young women with Anorexia Nervosa following treatment and
the patient hormone patterns divided into those who remained
amenorrhoea and those who gained weight with and without the
return of menstrual cyclicity (Popovic et al., 2004). Inhibin B increased from low to intermediate values with women who gained
optimal weight, reaching control values, i.e. those identied in women with normal menstrual cycles. There was a signicant correlation between inhibin B and BMI (r = 0.47) and inhibin B and
leptin (r = 0.45). These data suggest that normalising of inhibin B
levels was associated with the return of cyclicity and this return
was not related to weight gain. One explanation is that inhibin B
is a marker of ovarian reproductive health reecting the process

6.4. Puberty
Serum inhibin B, estradiol and FSH are initially elevated in the
rst 2 years of life, decreasing during the prepubertal period before
increases at puberty. Inhibin A levels are largely undetectable until
late puberty (Chada et al., 2003; Crofton et al., 2003). Serum inhibin B is positively correlated (r = 0.460.86) with serum FSH, LH
and estradiol in the rst 2 years of life and again through early
puberty (Tanner Stages I ) III) with a reduced correlation in Tanner Stages IV ) V (Chada et al., 2003) presumably as the feedback
regulation of FSH in response to the increasing inhibin B takes effect. Using FSH and inhibin B levels as markers of ovarian function,

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D.M. Robertson / Molecular and Cellular Endocrinology 347 (2012) 7884

a study (Crofton et al., 2005) was undertaken to differentiate between normal pubertal girls, girls with central precocious puberty
and those with premature thelarche (isolated breast development
in young girls). Inhibin B and FSH in girls with central precocious
puberty and premature thelarche were elevated compared to
age-matched controls but matched with normal pubertal girls for
the same breast stage, however these markers were unable to differentiate between premature thelarche which is a benign disease
and central precocious puberty.
6.5. Monitoring ovarian function following chemotherapy
There is an increased interest in establishing the ovarian status
of women who have undergone chemotherapy for breast and other
cancers. A study (Anders et al., 2008) of biomarkers for the prediction of women with chemotherapy-related amenorrhoea with
early stage breast cancer concluded that of the reproductive hormones studied AMH and inhibin B levels prior to treatment were
the best predictors. The risk of amenorrhoea was greatest in women with the lowest pre-chemotherapy inhibin B and AMH. Similar ndings (Su et al., 2010) were found in women in late stage
breast cancer where pretreatment levels of inhibin B and AMH
were signicantly lower in the women who developed chemotherapy-related amenorrhoea.
7. Pregnancy
7.1. Down Syndrome
Previous reviews (Tong et al., 2003) have highlighted the role of
inhibin A as a diagnostic marker for Down Syndrome in 2nd trimester pregnancy. The most efcient screening procedure currently
available, termed the full integrated test consists of a combination
of ultrasound and biochemical markers covering the 1st and 2nd trimesters (Wald et al., 1999). PAPPA and nuchal translucency was assessed in the 1st trimester with alpha foetal protein (AFP) urinary
estriol, hCG and inhibin A in th 2nd trimester. Several large studies
(Lambert-Messerlian et al., 2006; MacRae et al., 2010; Wald et al.,
2006; Weisz and Rodeck, 2006) have shown that the integrated test
has a false positive value of <5% and an accuracy of >90% which
meets the guidelines for prenatal screening recommended in the
USA, Canada and UK. The contribution of inhibin A to the triple test
of AFP, urinary estriol and hCG in the 2nd trimester reduced the
false positive rate from 8.9% to 5.2% (MacRae et al., 2010).
Attempts have been made to establish if these markers can be
used to detect Down Syndrome in the 1st trimester. A promising
grouping of markers was observed with the combination of serum
inhibin A, PAPPA, bhCG and nuchal translucency in the rst trimester (Ramos-Corpas and Santiago, 2008) giving comparable false positive values to that obtained with the integrated test.
Additional associations were made between Down Syndrome
markers and aneuploidies other than Down Syndrome (Breathnach
et al., 2007) with the conclusion that the majority of non-Down
Syndrome aneuploidies also can be detected. In relation to other
congenital anomalities, signicant associations were observed
(Hoffman et al., 2008) between inhibin A and/or hCG, and PAPPA with multicystic dysplastic kidney, two-vessel cord and hydrocele suggesting that Down Syndrome markers are also potentially
useful in these conditions. It is still unclear why inhibin A is elevated in Down Syndrome.
7.2. Preeclampsia
Preeclampsia, particularly in the early stages of pregnancy is
associated with uterine growth restriction and subsequent

hypertension disorders. Inhibin A is elevated in women with preeclampsia (review by Akolekar et al., 2009a) and in conjunction
with other markers (PAPPA, PP13, ADAM12) and uterine artery
Doppler, provides a promising test for preeclampsia (sensitivity
6080% and false detection rate of <20%) in low risk groups
(Giguere et al., 2010). Inhibin A in combination with other markers (placental growth factor) and endoglin (Lambert-Messerlian
et al., 2009) in the 2nd trimester also provides a sensitive test
(sensitivity 50%, false positive rate of 2%) for early onset
preeclampsia.
An assessment of markers in the 1st trimester (1113 weeks,
Akolekar et al., 2009a) showed that inhibin A and uterine artery
pulsatility index adjusted for maternal factors gave a detection
rate of 85% with false positive rate of 5%. Serum activin A
(Akolekar et al., 2009b) when assessed in the same time period
were elevated in preeclampsia. However, no associations were
observed with uterine artery pulsatility index or TNF-R1 which
are markers of this disease. Other studies in the 2nd trimester
have noted similar increases in activin A in women with preeclampsia (Muttukrishna et al., 2000) however the specicity:
sensitivity characteristics were viewed as unsuitable for a
screening test.
The basis for the elevated inhibin A levels in preeclampsia is unknown. The inhibin a and bA subunits are synthesised by the syncytiotrophoblast layer and their expression is increased in
preeclampsia. Attempts to link elevated inhibin A levels with placental hypoxia (Akolekar et al., 2009a) or increased leakage into
the maternal circulation have been questioned.
8. Ovarian cancer
Early studies noted that ovarian granulosa cell tumours produce
inhibin (Lappohn et al., 1992) which has been used as a histological
and plasma marker of this disease. Inhibin levels in the circulation
are negligible in healthy women after menopause providing a low
control baseline in any potential ovarian cancer test. In addition to
granulosa cell tumours, ovarian mucinous tumours produce inhibin (Healy et al., 1993).
Granulosa cell tumours secrete inhibin A, B and the free a subunit (pro-aC) while ovarian mucinous tumours secrete primarily
the free a subunit (Robertson et al., 2004). To develop a test which
will detect both cancers, a total inhibin assay has been developed
which detects the presence of the a subunit common to all forms
of inhibin (Robertson et al., 2002). This serum test was successful
in detecting these ovarian cancers but less successful with serous,
endometrioid and other ovarian cancers, although in one study
with this test (Tsigkou et al., 2007), serous cancers were more
readily detected. A combination of the total inhibin test with another ovarian cancer marker, CA125 which is effective in detecting
serous, endometrioid and other ovarian cancers, showed an improved detection of all ovarian cancers. The combined test showed
95% sensitivity and 95% specicity for detection of ovarian cancer
in women after menopause with non-detectable values in breast
and colon cancers. More recently, a large cohort of healthy postmenopausal women (n = 500) were investigated (Bell et al., 2009;
Healy et al., 2008) and the inclusion of these results from this control group increased the sensitivity and specicity of the combined
total inhibinCA125 test to 98% and 98%, respectively. This test has
been useful in the detection of ovarian cancers in postmenopausal
women at high risk and following treatment. The test has not been
applied as a screening procedure in asymptomatic women as the
sensitivity: specicity indices are not sufciently high to be effective. The total inhibin test can be used to detect granulosa cell tumours during the reproductive life in women in contrast to ovarian
mucinous tumours as the inhibin levels are sufciently elevated
above baseline to be a useful diagnostic.

D.M. Robertson / Molecular and Cellular Endocrinology 347 (2012) 7884

83

9. Activins

Acknowledgements

Attempts to identify the clinical utility of activins in female

reproduction have been largely unsuccessful. Circulating activins
are produced by many tissues with serum levels remaining unchanged following gonadectomy and after menopause. Furthermore, it is believed that in normal situations circulating activins
are complexed to follistatin and are thus biologically inactive.
Serum activin A levels are unchanged over the menstrual cycle
but do increase following FSH stimulation (Klein et al., 2004).
No changes were observed in ovarian cancer (Robertson et al.,
2004). Activin is increased to some extent in serum from women
with Down Syndrome but it is less sensitive than inhibin A as a
diagnostic marker (Akolekar et al., 2009b). Activin A is also elevated in preeclampsia (Akolekar et al., 2009b; Muttukrishna
et al., 2000). The reader is referred to the review by Tong et al.
(2003) for the role of activin A as a diagnostic marker in aspects
of pregnancy including parturition and foetal wellbeing. Further
details of the in vitro actions of activins in the process of folliculogenesis are presented in the reviews of Knight and Glister
(2006) and Drummond (2005).

This study was supported by a research grants from the NHMRC

of Australia Program Grant (#241000) and Research Fellowship
(D.M.R.) #169201 and by the victorian Governments Operational
Infrastructure Support Program.

10. Conclusions
The predictive roles of inhibins in female reproductive health
fall into three categories.
(a) Providing a measure of ovarian follicular reserve. Inhibins A
and B are poor predictors of ovarian follicular reserve in
contrast to other markers (e.g. AMH). This applies in
the assessment of oocyte retrieval and pregnancy outcome in IVF programs and assessment of follicular reserve
in the menopause transition, premature ovarian failure,
Anorexia Nervosa and during pubertal development.
While inhibin B in particular, shows some correlation
with follicle number, its use as a diagnostic test is dictated by its variability over the menstrual cycle and its
regulation by FSH as part of the ovarian:pituitary feedback mechanism.
(b) As a biomarker of Down Syndrome, preeclampsia and ovarian
cancer. The basis for the elevation of inhibins in each of these
clinical conditions is unknown.
(c) As an assessment of follicle quality and reproductive capacity. In the assessment of women with suspected poor fertility, e.g. premature ovarian failure, Anorexia Nervosa
and following chemotherapy or during pubertal development, some knowledge of reproductive status of the
patient and her follicle/oocyte quality may be important
in determining treatment. This reviewer suggests that a
comparison of FSH/inhibin B ratio which provides a measure of the ovarianpituitary feedback status and serum
AMH which provides a measure of follicle number may
be able to describe the reproductive status of the individual with more accuracy. This analysis would be similar to
that shown in the menopause studies above as presented
in Fig. 1. For example, the Type 2 cycle group of women
classied in the menopause transition (Fig. 1) may equate
to the incipient ovarian failure group in the premature
ovarian failure study of Knauff et al. (2009). This
approach may also provide some indication of a return
to fertility following chemotherapy, for example monitoring the FSH:inhibin B ratio as it returns into the normal
range. Depending on the response, an appropriate clinical
treatment can be developed.

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