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1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78en . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79ion and. . . . . .. . . . . .. . . . . .duction. . . . . .(POF) . .. . . . . .e (PCO. . . . . .

1. Introduction

The objective of the present review is to update the reader onadvances in the physiology and clinical application of inhibinsand activins in human female reproduction. A number of reviews(Laven and Fauser, 2004; Robertson et al., 2004; Tong et al.,

Abbreviations: AMH, anti-Mullerian hormone; POF, premature ovarian failure;IOF, incipient ovarian failure; PCOS, polycystic ovarian syndrome. Tel.: +61 3 95947901.

Molecular and Cellular Endocrinology 347 (2012) 7884

Contents lists availab

Molecular and Cellu

journal homepage: www.elsevier .com/locate /mceE-mail address: david.robertson@princehenrys.org6.5. Monitoring ovarian function following chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

7.1. Down Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827.2. Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

8. Ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829. Activins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8310. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 832. The physiology of inhibin in wom3. Role of inhibins in follicular funct

3.1. Inhibin A . . . . . . . . . . . . . .3.2. Inhibin B . . . . . . . . . . . . . .

4. Menopause transition . . . . . . . . .5. Ovarian function in assisted repro6. Inhibin and female infertility . . .

6.1. Premature ovarian failure6.2. Anorexia Nervosa . . . . . . .6.3. Polycystic ovarian syndrom6.4. Puberty. . . . . . . . . . . . . . . .0303-7207/$ - see front matter 2011 Elsevier Irelandoi:10.1016/j.mce.2011.05.016ovarian reserve assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Contentsreeclampsiavarian cancer 2011 Elsevier Ireland Ltd. All rights reserved.ause transitionyndrome

use in Down Syndrome and ovarian cancer. Activins, on the other hand, appear to have a limitedapplication.eywords:SHvarian follicle reserveenop

between the ovary and pituitary particularly when the ovarian follicle reserve is low. These applicationsare relevant in monitoring the onset of the menopause transition, ovarian recovery following chemother-apy and disturbances in pubertal development. Currently, these applications have only found widespreadi c l e i n f o

history:le online 1 June 2011

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 femalereproductive health has centred on their application to ovarian cancer, Anorexia Nervosa, Down Syn-drome and preeclampsia. Inhibin B also provides an index of the endocrine feedback relationshipenrys Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australianhibins and activins in blood: Predictors of female reproductive health?

avid M. Robertson Reviewd Ltd. All rights reserved.le at ScienceDirect

lar Endocrinology

tern of plasma progesterone. Attempts to show a reciprocal rela-

pus luteum of the previous cycle with the development of ovula-

lular2003; Welt, 2002) have been previously published which the read-er can refer to for details of earlier studies.

2. The physiology of inhibin in women

The role of inhibin in reproductive endocrinology differs fromthat of many of the other members of the TGFb growth factor fam-ily as its existence had been postulated from earlier in vivo obser-vations. These studies showed that steroids were insufcient toadequately suppress pituitary FSH secretion in contrast to LH,and that additional gonadal factors were involved. This hypothesiswas based on in vivo studies whereby administration of proteina-ceous gonadal extracts was successful in suppressing serum FSH. Indue course, inhibins A and B were isolated as active ingredientsfrom these extracts and these factors conform in most aspects tothe FSH suppressing factor which is central to the inhibinhypothesis.

Inhibin, a dimeric glycoprotein consists of a and either bA or bBsubunits. They are produced as precursors and cleaved both intra-cellularly and extracellularly to produce the 30k mature form,although precursor forms where one or both subunits remain in-tact are also secreted. These partially processed dimers are biolog-ically active in vitro.

In addition, the b subunits can dimerise (bAbA and bBbB) toform activin (A and B). Its biological activity is distinct from inhibinwith additional actions in non-reproductive systems, in particular,development and inammation (recent review by Xia and Schney-er, 2009). It is unclear if activin in normal physiological situationsexhibits an endocrine role as it is bound strongly in serum to fol-listatin which neutralises its bioactivity. The observation that fol-listatin in turn exhibits FSH suppressing activity led to theconclusion that activin acts via an autocrine/paracrine mechanismwithin the pituitary to stimulate FSH synthesis which is thenantagonised by circulating inhibin. Thus inhibins endocrine role,at least within the pituitary was to neutralise activins action. Acti-vins mechanism of action, consistent with other TGFb familymembers, is to facilitate the interaction between the Activin TypeII and Type I receptors leading to an activation of the intracellularSmad pathway. Inhibins mode of action is thus to inhibit thisprocess.

It is now recognised that inhibins mechanism of action requiresan initial interaction with the accessory binding protein, betagly-can. This inhibin:betaglycan complex interacts with several Type2 receptors (e.g. activin and BMP) inhibiting the subsequent inter-action and activation of the appropriate Type 1 receptor. Howeverit is clear that the inhibinbetaglycan complex can, in principle, in-hibit any TGFb ligand that interacts with these Type II receptors,e.g. activin A, activin B, TGFb2, BMP2, 4, 6, 7, GDF9, GDF11, myost-atin (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 mem-bers such as BMPs, myostatin, GDF9, stimulation of FSHsecretion by the pituitary as part of the gonadal feedbackregulation of pituitary FSH secretion;

(b) a role in suppressing granulosa cell tumours and muscle andliver cachexia as observed in inhibin a subunit null mice.The action of inhibin appears in part to limit the overproduc-tion of activin responsible for the cachexia. Activins role inthe initiation of ovarian cancers is less readily understood;

(c) suppressing the development of adrenal tumours ingonadectomised inhibin a subunit null mice by inhibiting

D.M. Robertson /Molecular and Celthe action of TGFb2 on adrenocortical cell proliferation(Looyenga et al., 2010). This observation is particularlynovel. It had been previously conjectured that overproduc-tory follicles in the latter and thus the observed reciprocalrelationship is likely to be due to the overlap of inhibitory andstimulatory effects across this region of the menstrual cycle.

Later in the menstrual cycle, inhibin A levels closely parallelthose of plasma estradiol in the follicular phase and progesteronein the luteal phase, reecting the numbers of developing dominantfollicles and corpora lutea. These associations suggest that seruminhibin A is a marker of follicle number or activity as its serum lev-els, like estradiol, increase with FSH stimulation however theredoes not appear to be any evidence of feedback activity on thepituitary secretion of FSH or LH. This conclusion is surprising sinceinhibin A administration to rats (Makanji et al., 2009), sheep (Til-brook et al., 1993) and monkeys (Molskness et al., 1996) does re-sult in suppression of FSH secretion. Why is inhibin A seeminglyinactive in vivo as an inhibitor of FSH secretion in the human?

One possibility is that the circulating levels of inhibin A in thefollicular phase are quantitatively less than inhibin B, howeverwhen inhibin A and B levels are related to puried inhibin A andB calibrators their levels when measured by immunoassay weresimilar (Makanji et al., 2009). Another possibility is that inhibintionship between serum inhibin A and FSH across either thefollicular or luteal phases of the cycle (Robertson et al., 2009) hasbeen unsuccessful. However, a reciprocal relationship between ser-um inhibin A and FSH has been shown (Welt et al., 1997) across thelutealfollicular transition. It should be noted that this relationshipis observed at the intersection between the regression of the cor-tion/secretion of activin as a mitogen was the factor respon-sible for the tumours. However a more complex pathwaywas identied involving the gonadectomy-induced upregu-lation of TGFb2 by LH and an elevation in the levels of beta-glycan normally inhibited by inhibin. Thus inhibins actionwas to suppress the levels of betaglycan and thus hinderingthe mitogenic action of TGFb2;

(d) as a possible inhibitory factor in bone turnover resulting inan increase in osteoporosis in women during the menopausetransition. Inhibin A rather than inhibin B was the betterpredictor of both bone formation and bone resorption (Per-rien et al., 2006, 2007);

(e) a role in ovarian folliculogenesis through modication ofsteroid production; in vitro data only is available (Drum-mond, 2005).

In clinical terms inhibin is best known as a marker of ovarianfollicle activity at puberty, during reproductive life and approach-ing menopause, and in granulosa cell and mucinous ovarian can-cers, Down Syndrome and preeclampsia.

3. Role of inhibins in follicular function and ovarian reserveassessments

The physiology of inhibin is better understood in relation to itsfeedback role in regulating FSH secretion.

3.1. Inhibin A

Inhibin A is primarily the product of the developing dominantfollicle and corpus luteum in the human menstrual cycle, with cir-culating levels increasing across the follicular phase, falling sharplyin the vicinity of the midcycle LH peak and then increasing anddecreasing across the luteal phase in parallel with the biphasic pat-

Endocrinology 347 (2012) 7884 79A is less bioactive than inhibin B. In vitro and in vivo studies doshow that the mature form of (30k) inhibin B is more bioactivethan 30k inhibin A, however the differences in in vivo bioactivity

blood samples collected every 3 days across ovulatory menstrual

terone remain the same reecting the apparent independent devel-

lularopment of the dominant follicle and normal luteolysis in the lutealphase with the formation of a normal corpus luteum. A third cycletype was identied whereby although ovulatory cycles was evi-dent with elevated luteal phase progesterone levels, inhibin B lev-cycles from women in the 2535 year and 4555 year age group.The hormone patterns were classied into four cycle types. Therst cycle type consisted of cycle proles which showed no signif-icant changes across the menstrual cycle between the two agedgroups in serum levels of FSH, LH, estradiol, progesterone, inhibinA, inhibin B. AMH, in contrast, showed a marked age-related de-cline. The second cycle type identied in within this 4555 yearage group consisted of ovulatory cycles where there was a signi-cant decrease in inhibin B and a corresponding rise in FSH, with afurther fall in AMH. Meanwhile, estradiol, inhibin A, progesterone,and LH remained unchanged. The further fall in AMH is attributedto a further reduction in follicle number, in parallel with a fall ininhibin B. These ndings reinforce previous observations (Burger,2008; Klein et al., 2004; Knauff et al., 2009; Welt et al., 1999) of re-ciprocal changes in the serum inhibin B and FSH levels in ovulatorycycles across mid to late reproductive life. One presumes that theinhibin B levels have fallen below a critical level due to the reduc-tion in follicle number resulting in a reduced capacity to suppressFSH which as a consequence of reduced feedback inhibition, startsto rise. In contrast, the proles of inhibin A, estradiol and proges-at least in rats (Makanji et al., 2009) is not sufciently large (50%)to explain this difference. As a third possibility, that human inhibinAs mechanism of action differs compared to inhibin B. Howeverthere 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 develop-ment (follicles with diameters

diagnostic markers of IVF outcome although their clinical utility

Inh

ollicpresn co

lularoverall is still questioned (Jayaprakasan et al., 2010; Muttukrishnaet al., 2004). AMH is produced by preantral and small antral folli-cles with lower levels produced by either primordial or dominantfollicles. AMH levels correlate with antral follicle number and itsblood levels do not appear to be hormonally sensitive as its levelsremain relatively unchanged across the menstrual cycle.0.01

0.10

1.00

10.00

0.01 0.10

FSH/

AM

H (n

g/m

l)

r=0.83

Fig. 1. Regression plot between FSH:inhibin B ratios and AMH levels in the early fwomen in late reproductive age (4555 years, Cycle Types 13). The dotted lines re(0.25 ng/ml) as a means to distinguish Type 1 from Type 2 and 3 cycles (correlatio(Printed with permission from Menopause.)

D.M. Robertson /Molecular and Cel6. Inhibin and female infertility

6.1. Premature ovarian failure (POF)

A recent study was undertaken to assess the clinical value of in-hibin B, antral follicle count and AMH in assessing ovarian functionin women with POF (Knauff et al., 2009). These women were cate-gorised into women

(Lambert-Messerlian et al., 2006; MacRae et al., 2010; Wald et al.,

lular2006;Weisz and Rodeck, 2006) have shown that the integrated testhas a false positive value of 90% whichmeets the guidelines for prenatal screening recommended in theUSA, Canada and UK. The contribution of inhibin A to the triple testof AFP, urinary estriol and hCG in the 2nd trimester reduced thefalse positive rate from 8.9% to 5.2% (MacRae et al., 2010).

Attempts have been made to establish if these markers can beused to detect Down Syndrome in the 1st trimester. A promisinggrouping of markers was observed with the combination of seruminhibin A, PAPPA, bhCG and nuchal translucency in the rst trimes-ter (Ramos-Corpas and Santiago, 2008) giving comparable false po-sitive values to that obtained with the integrated test.

Additional associations were made between Down Syndromemarkers and aneuploidies other than Down Syndrome (Breathnachet al., 2007) with the conclusion that the majority of non-DownSyndrome aneuploidies also can be detected. In relation to othercongenital anomalities, signicant associations were observed(Hoffman et al., 2008) between inhibin A and/or hCG, and PAPP-A with multicystic dysplastic kidney, two-vessel cord and hydro-cele suggesting that Down Syndrome markers are also potentiallyuseful in these conditions. It is still unclear why inhibin A is ele-vated in Down Syndrome.

7.2. Preeclampsiaa study (Crofton et al., 2005) was undertaken to differentiate be-tween normal pubertal girls, girls with central precocious pubertyand those with premature thelarche (isolated breast developmentin young girls). Inhibin B and FSH in girls with central precociouspuberty and premature thelarche were elevated compared toage-matched controls but matched with normal pubertal girls forthe same breast stage, however these markers were unable to dif-ferentiate between premature thelarche which is a benign diseaseand central precocious puberty.

6.5. Monitoring ovarian function following chemotherapy

There is an increased interest in establishing the ovarian statusof women who have undergone chemotherapy for breast and othercancers. A study (Anders et al., 2008) of biomarkers for the predic-tion of women with chemotherapy-related amenorrhoea withearly stage breast cancer concluded that of the reproductive hor-mones studied AMH and inhibin B levels prior to treatment werethe best predictors. The risk of amenorrhoea was greatest in wo-men with the lowest pre-chemotherapy inhibin B and AMH. Simi-lar ndings (Su et al., 2010) were found in women in late stagebreast cancer where pretreatment levels of inhibin B and AMHwere signicantly lower in the women who developed chemother-apy-related amenorrhoea.

7. Pregnancy

7.1. Down Syndrome

Previous reviews (Tong et al., 2003) have highlighted the role ofinhibin A as a diagnostic marker for Down Syndrome in 2nd trimes-ter pregnancy. The most efcient screening procedure currentlyavailable, termed the full integrated test consists of a combinationof ultrasound and biochemicalmarkers covering the 1st and 2nd tri-mesters (Wald et al., 1999). PAPPA and nuchal translucency was as-sessed in the 1st trimester with alpha foetal protein (AFP) urinaryestriol, hCG and inhibin A in th 2nd trimester. Several large studies

82 D.M. Robertson /Molecular and CelPreeclampsia, particularly in the early stages of pregnancy isassociated with uterine growth restriction and subsequenthypertension disorders. Inhibin A is elevated in women with pre-eclampsia (review by Akolekar et al., 2009a) and in conjunctionwith other markers (PAPPA, PP13, ADAM12) and uterine arteryDoppler, provides a promising test for preeclampsia (sensitivity6080% and false detection rate of

regulation by FSH as part of the ovarian:pituitary feed-back mechanism.

(b) As a biomarker of Down Syndrome, preeclampsia and ovarian

stimulation of immunoreactive inhibin secretion during the follicular phase ofthe human menstrual cycle. J. Clin. Endocrinol. Metab. 76, 13401343.

lularcancer. The basis for the elevation of inhibins in each of theseclinical conditions is unknown.

(c) As an assessment of follicle quality and reproductive capac-ity. In the assessment of women with suspected poor fer-tility, e.g. premature ovarian failure, Anorexia Nervosaand following chemotherapy or during pubertal develop-ment, some knowledge of reproductive status of thepatient and her follicle/oocyte quality may be importantin determining treatment. This reviewer suggests that acomparison of FSH/inhibin B ratio which provides a mea-sure of the ovarianpituitary feedback status and serumAMH which provides a measure of follicle number maybe able to describe the reproductive status of the individ-ual with more accuracy. This analysis would be similar tothat shown in the menopause studies above as presentedin Fig. 1. For example, the Type 2 cycle group of womenclassied in the menopause transition (Fig. 1) may equateto the incipient ovarian failure group in the prematureovarian failure study of Knauff et al. (2009). Thisapproach may also provide some indication of a returnto fertility following chemotherapy, for example monitor-9. Activins

Attempts to identify the clinical utility of activins in femalereproduction have been largely unsuccessful. Circulating activinsare produced by many tissues with serum levels remaining un-changed following gonadectomy and after menopause. Further-more, it is believed that in normal situations circulating activinsare complexed to follistatin and are thus biologically inactive.Serum activin A levels are unchanged over the menstrual cyclebut 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 womenwith Down Syndrome but it is less sensitive than inhibin A as adiagnostic marker (Akolekar et al., 2009b). Activin A is also ele-vated in preeclampsia (Akolekar et al., 2009b; Muttukrishnaet 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 aspectsof pregnancy including parturition and foetal wellbeing. Furtherdetails of the in vitro actions of activins in the process of follicu-logenesis are presented in the reviews of Knight and Glister(2006) and Drummond (2005).

10. Conclusions

The predictive roles of inhibins in female reproductive healthfall into three categories.

(a) Providing a measure of ovarian follicular reserve. Inhibins Aand B are poor predictors of ovarian follicular reserve incontrast to other markers (e.g. AMH). This applies inthe assessment of oocyte retrieval and pregnancy out-come in IVF programs and assessment of follicular reservein the menopause transition, premature ovarian failure,Anorexia Nervosa and during pubertal development.While inhibin B in particular, shows some correlationwith follicle number, its use as a diagnostic test is dic-tated by its variability over the menstrual cycle and its

D.M. Robertson /Molecular and Celing the FSH:inhibin B ratio as it returns into the normalrange. Depending on the response, an appropriate clinicaltreatment can be developed.Hoffman, J.D., Bianchi, D.W., Sullivan, L.M., Mackinnon, B.L., Collins, J., Malone, F.D.,Porter, T.F., Nyberg, D.A., Comstock, C.H., Bukowski, R., Berkowitz, R.L., Gross,S.J., Dugoff, L., Craigo, S.D., Timor-Tritsch, I.E., Carr, S.R., Wolfe, H.M., DAlton,M.E., 2008. Down syndrome serum screening also identies an increased riskfor multicystic dysplastic kidney, two-vessel cord, and hydrocele. Prenat. Diagn.28, 12041208.

Jayaprakasan, K., Campbell, B., Hopkisson, J., Johnson, I., Raine-Fenning, N., 2010. Aprospective, comparative analysis of anti-Mullerian hormone, inhibin-B, andthree-dimensional ultrasound determinants of ovarian reserve in the predictionAcknowledgements

This study was supported by a research grants from the NHMRCof Australia Program Grant (#241000) and Research Fellowship(D.M.R.) #169201 and by the victorian Governments OperationalInfrastructure Support Program.

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Inhibins and activins in blood: Predictors of female reproductive health?1 Introduction2 The physiology of inhibin in women3 Role of inhibins in follicular function and ovarian reserve assessments3.1 Inhibin A3.2 Inhibin B

4 Menopause transition5 Ovarian function in assisted reproduction6 Inhibin and female infertility6.1 Premature ovarian failure (POF)6.2 Anorexia Nervosa6.3 Polycystic ovarian syndrome (PCOS)6.4 Puberty6.5 Monitoring ovarian function following chemotherapy

7 Pregnancy7.1 Down Syndrome7.2 Preeclampsia

8 Ovarian cancer9 Activins10 ConclusionsAcknowledgementsReferences