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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2342
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 6 2344-2349
Copyright © 2008 by The Endocrine Society

Concentration of Anti-Müllerian Hormone and Inhibin-B in Relation to Steroids and Age in Follicular Fluid from Small Antral Human Follicles

Claus Yding Andersen, Mikkel Rosendahl and Anne Grete Byskov

Laboratory of Reproductive Biology, The Juliane Marie Centre for Women, Children, and Reproduction, University Hospital of Copenhagen, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Claus Yding Andersen, D.M.Sc., Laboratory of Reproductive Biology, Section 5712, University Hospital of Copenhagen, Blegdamsvej 9, Rigshospitalet, DK-2100 Copenhagen, Denmark. E-mail: yding{at}rh.dk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Ovaries surgically removed for fertility preservation served as a source of follicle fluid from human small antral follicles.

Objective: The objective of the study was to measure intrafollicular concentrations of anti-Müllerian Hormone (AMH), inhibin-B, progesterone, androstenedione, testosterone, estradiol, and IGF binding protein-4.

Setting: The study was conducted at a university hospital.

Patients: Patients included 43 women having one ovary removed prior to receiving gonadotoxic treatment due to malignant disease.

Interventions: Fluid from 100 follicles (diameter of 3–9 mM) were included.

Main Outcome Measures: Intrafollicular concentrations of the measured hormones, their possible intercorrelation, and correlation with age were measured.

Results: Concentrations of AMH were unrelated to follicular fluid concentrations of androstenedione and testosterone. There was a significant negative correlation between estradiol, inhibin-B, progesterone, and AMH. In four age groups spanning 11–37 yr, levels of AMH, estradiol, androstenedione, testosterone and inhibin-B remained constant, whereas progesterone showed significant variations. IGF binding protein-4 was unrelated to any other measured hormone.

Conclusions: This study was unable to confirm a stimulatory effect of androgens on AMH secretion but did enforce a close intimate correlation between AMH and estradiol expressions in the developing human follicle. The insignificant variation of the AMH concentration with age, even in prepubertal girls, suggests that AMH expression is unrelated to menstrual cycle FSH cyclicity.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
In the progression of human follicle growth various growth factors related to the TGFβ superfamily have been shown to exert functions on their own and to interact with gonadotropin induced signals (1, 2). Especially growth factors locally produced by granulosa cells, like anti-Müllerian hormone (AMH) and inhibin-B, seem to be intimately involved in follicular growth and development (2). AMH is expressed beginning at the primary follicle until the small antral stage during which expression ceases, and expression seems to be absent in late antral and preovulatory follicles (3). This expression pattern is reflected in the follicular fluid (FF) of small antral follicles, which are 2–3 orders of magnitude higher than in preovulatory follicles (4, 5). In line with this, circulating levels of AMH representing the collective release from the pool of small follicles in the ovaries has been shown to correlate strongly with the number of antral follicles in both normal women and women with polycystic ovaries (PCOs) (6, 7, 8). In corollary, serum levels of AMH decline with advancing age in parallel with the decreasing number of antral follicles (9). Indeed, serum levels of AMH have been suggested to represent both the quantity and quality of the ovarian follicle pool and may represent the best marker to show biological aging of the ovaries (10).

However, the precise role of AMH in folliculogenesis and especially in small antral follicles is far from being understood. The current dogma states that AMH decreases granulosa cell sensitivity to FSH stimulation to limit the number of follicles that develop to the preovulatory stage (3, 5). This hypothesis is mainly based on studies in AMH null mice in which it was shown that follicles from AMH knockout mice were more sensitive to FSH than those of wild-type mice (11, 12). In line with this hypothesis, an inhibitory effect on AMH was observed on proliferation and progesterone production in human granulosa-luteal cells in vitro (13) and a reduced expression of aromatase and LH receptors in cultured granulosa cells of rat and porcine immature ovaries (14).

Contrary to what would be expected from the hypothesis on AMH action in small antral follicles, it has recently been shown that FSH does not have an effect on AMH secretion from human granulosa cells from small antral follicles during culture (5). Another recent study was unable to observe any acute effect of FSH administration on AMH serum concentrations in women (15). Other recent results also seem to argue against the proposed hypothesis because AMH levels in fluid from preovulatory follicles were highest in those with the highest likelihood of implanting, suggesting that these follicles expressed a good FSH sensitivity (16). Furthermore, sensitivity toward FSH in granulosa cells from women with PCO is higher than those from normal women (17), and contrary to what the hypothesis predicts, granulosa cells from small antral follicles from women with either ovulatory or anovulatory PCOs showed a much higher AMH production per granulosa cell than in normal women (5). Actually, it was suggested that androgens, being elevated in PCO women, was the cause of the increased AMH production in women with PCOs (5). In supporting this assumption, it has been found that serum AMH levels correlate positively with serum levels of both androstenedione and testosterone in both normal women and women with PCOs (8, 18, 19).

However, other studies have suggested that a close interrelationship between AMH and estradiol expression exists. A recent study based on AMH and AMH type II receptor polymorphism found a correlation between the AMH concentration and the follicular phase estradiol level and suggested that AMH regulates estradiol levels via modulation of FSH sensitivity in the human ovary (20). These data support our previous study in which we found a strong inverse correlation between follicular fluid levels of AMH and estradiol in small antral human follicles (4).

To examine the role of AMH in small antral follicles, the aim of the present study was to characterize FF from 100 small antral follicles with respect to content of AMH and inhibin-B in relation to steroids including estradiol, progesterone, androstenedione, and testosterone. For comparison, measurements of IGF binding protein (IGFBP)-4 was also included, which is not a specific granulosa cell product but has been shown to affect granulosa cell steroidogenesis in vitro and could be of importance for follicular development (21, 22). Furthermore, it was our intention to evaluate possible age-related changes in the expression of these follicular markers.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and collection of small antral FF

FF samples of individual small antral follicles were obtained by aspiration from ovaries removed for fertility preservation. Due to a disease in which adequate treatment (e.g. chemo- and/or radiation therapy) posed a high risk of destroying all ovarian follicles and rendering the woman sterile, the cortex of one entire ovary was cryopreserved before therapy.

A total of 100 FF samples were obtained in 43 women, aged 11–37 yr (median 27.6 yr) at a random time during their menstrual cycle. Diagnosis for ovarian cryopreservation included mammary cancer (17), Hodgkin’s and non-Hodgkin’s disease (8), Ewing and other sarcoma (4), acute lymphatic lymphoma and other lymphoma (5), and various others (9), which did not relate to an endocrinological (e.g. polycystic ovarian syndrome) and/or ovarian disease. All ovaries appeared normal by visual inspection in connection with the cryopreservation procedure and by subsequent microscopic evaluation of histological sections from a small piece of the ovarian cortex. Regular menstrual cycles was recorded in 17 patients, eight used oral contraceptives, six had irregular cycles (including one girl at 14 yr of age and 3 women above the age of 35 yr), and no information was available in 12 cases.

The FF samples were collected immediately after recovery of the ovary before isolation of the ovarian cortex. Each antral follicle visible on the surface of the ovary or observed during preparation of cortex was aspirated with a 1 ml syringe with a 26-gauge needle (Becton Dickinson, Brøndby, Denmark). FF was collected from one to six antral follicles per patient (one FF, 20 patients; two FF, six patients; three FF, seven patients; four FF, five patients; five FF, three patients; six FF, two patients), and only those with an aspirated volume exceeding 40 µl were included in the study. The volume of each FF was determined in the syringe and after centrifugation the supernatant of each sample was stored at –80 C until assayed for hormones. Seventeen antral FF included in our previous study (4) were also included in this study because they contained enough fluid for measurements of androgens and IGFBP4. The ethical committee of the municipalities of Copenhagen and Frederiksberg approved the project.

Hormone measurements

Estradiol and progesterone were measured using commercially available RIA kits (DSL-43100 and DSL-3400; Diagnostic System Laboratories, Webster, TX). Samples for both assays were diluted 1:50 in steroid-free serum just before measurement. Androstenedione was measured using RIA kit (DSL-3800; Diagnostic System Laboratories) with samples being diluted 1:200 in steroid-free serum and testosterone using RIA kit (DSL-4000; Diagnostic System Laboratories) diluted 1:100 in steroid-free serum.

AMH was measured using a specific ELISA kit according to the manufacturer’s instructions (DSL-10–14400; Diagnostic System Laboratories). FF samples from small antral follicles were diluted either 1:500 or 1:3000 in the zero standard provided by the manufacturer. Interassay variation of a sample containing 7.6 ng AMH per milliliter was 4.4% (n = 12) and intraassay variation was 3.3% (n = 5) of sample containing 0.45 ng/ml. Dilution curves of FF samples proved parallel to the standard curve.

Inhibin-B was measured using a specific ELISA kit according to the manufacturer’s instruction (Oxford Bio-Innovation kit; Biotech-IgG, Copenhagen, Denmark). Before measurement, all FF samples were diluted 1:100 or 1:500 in serum obtained from a pool of five postmenopausal women (who had no inhibin-B activity). The FF samples were pretreated with sodium dodecyl sulfate, heated, and exposed to hydrogen peroxide before they were applied to the wells of the plate and incubated overnight at room temperature. Subsequently the plates were washed and incubated with detection antibody for 3 h at room temperature. Substrate solution was applied and incubated for 1 h. The amplifier solution was added, and the plates were read with an ELISA reader at 490 nm with its reference at 620 nm (CV < 7%).

IGFBP4 was measured using a commercially available ELISA kit (R&D Diagnostic Systems, Minneapolis, MN; DY804 using substrate DY999) according to manufacturer’s instructions. Each FF sample was tested in a dilution of 1:50 using 5% Tween 20 in PBS for dilution. Intra- and interassay variations of a sample containing 179 ng/ml IGFBP4 were 7 and 8.5%, respectively.

Statistics

For comparison of levels of AMH and testosterone with the other measured hormones, each FF was treated as an individual observation because intrapatient variation was high, as shown in Fig. 1Go. Thus, hormone levels between subgroups (n > 2) were analyzed with ANOVA test. Comparison of two independent groups was done using Student’s t test.


Figure 1
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  		FIG. 1. Concentration of AMH in individual follicular fluid samples from small antral follicles given for each individual patient.

 
For evaluating a possible relation between age and hormone levels, the hormonal levels of each patient were determined as the mean level of the FF samples obtained from each patient. When only one FF sample was obtained the hormonal levels of this single sample represented the patient level. This data reduction was done to investigate possible associations between hormonal levels, without overestimating the number of independent observations. Least square linear regression analyses using SPSS 12 (SPSS Inc., Chicago, IL) was also used.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The aspirated volume in small antral follicles ranged from 40 to 350 µl (median 70 µl) corresponding to follicular diameters from around 3 to 9 mM.

The average hormone concentrations in FF are given in Table 1Go. The concentration of AMH was 582 ng/ml and ranged 2 orders of magnitude from 25 to 2213 ng/ml. In patients in which more than one follicles was analyzed, the AMH levels was mostly seen to vary as much as between patients (Fig. 1Go). Within-patient variation often reached 1 order of magnitude with a maximum of more than 20 times. The remaining variability was related to between-patient variation (Fig. 1Go). The other granulosa cell-derived hormones showed a range similar to that of AMH spanning 2–3 orders of magnitude.


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  		TABLE 1. Concentrations of AMH, inhibin-B, IGFBP4, and steroids in fluid from small antral follicles

 
FF concentrations of AMH in small antral follicles showed a strong negative linear regression correlation with inhibin-B, estradiol, and progesterone (P < 0.0001 for all), whereas FF levels of testosterone, androstenedione, and IGFBP4 were unrelated (Table 2Go). Using the recorded volume of each follicle, which may underestimate the real follicular volume because not all fluid may be aspirated, a significant inverse correlation between AMH concentration and volume was found (P < 0.05, r2 = 0.22). The mean AMH concentration in the group of the smallest follicles (<50 µl) was 721 ± 91 ng/ml (mean ± SEM), compared with 385 ± 87 ng/ml in the largest group of follicles (>200 µl).


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  		TABLE 2. Follicular fluid content of AMH in relation to inhibin-B, IGFBP4, and steroids

 
Concentrations of testosterone showed a strong significant correlation to those of inhibin-B and androstenedione. Levels of progesterone also correlated significantly to testosterone concentrations, whereas concentrations of estradiol, AMH and IGFBP4 were not (Table 3Go).


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  		TABLE 3. Follicular fluid content of AMH, inhibin-B, IGFBP4, and steroids in relation to the testosterone concentration

 
Levels of estradiol and progesterone showed a strong linear regression correlation (P < 0.0001, r2 = 0.43) as did levels of testosterone and androstenedione (P < 0.0001, r2 = 0.41). No significant linear regression correlations were found between IGFBP4 and any of the other hormones.

A possible age-related effect on hormone concentrations in FF from small antral follicles was evaluated in four age groups using the mean hormone concentration per patient (Table 4Go). Concentrations of FF AMH, inhibin-B, IGFBP4, estradiol, androstenedione, and testosterone were unrelated to age, whereas levels of progesterone showed a significant positive correlation with age. The FF ratio of estradiol to testosterone was also unrelated to age (data not shown).


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  		TABLE 4. Small antral follicles: mean FF concentration per patient of AMH, inhibin-B, IGFBP4, and steroids in relation to age

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The present study demonstrated that levels of AMH in fluid from small antral follicles were unrelated to those of androstenedione and testosterone. This study was therefore unable to establish a link between androgens and AMH expression in small antral follicles. However, this study does extend and confirm a strong inverse correlation between FF AMH levels and estradiol, inhibin-B, and progesterone as previously observed on a smaller number of FF samples (4). The secretion of both estradiol and inhibin-B in small antral follicles are specific granulosa cell FSH-stimulated actions, and this study enforces a strong interrelation between FSH stimulation and AMH. However, the mechanism by which this dependence is effected is not clear; does AMH affect FSH action or conversely, does FSH, perhaps indirectly, inhibit AMH expression?

The present study found insignificant changes in FF AMH levels with age. Markedly, the age group younger than 18 yr remained similar to the older groups. The young age group included five young prepubertal girls between the ages of 11 and 13 yr. Eleven FF samples from these girls showed a concentration of AMH similar to that of older women (data not shown), suggesting that AMH levels in antral follicles exposed to only low tonic levels of FSH as seen before puberty are similar to those of women with menstrual cycles and who therefore experience higher concentrations of FSH. Thus, it appears that lack of FSH stimulation does not affect AMH secretion. Stimulation with FSH, on the other hand, also does not seem to affect AMH secretion (5, 16). Collectively, strong evidence now suggests that FSH itself does not affect AMH secretion.

The inverse correlation between AMH and several important FSH-induced secretions like estradiol, inhibin-B, and progesterone as observed in the present study may suggest that AMH and FSH instead interact indirectly through one or more of these substances. The strong inverse correlation between AMH and estradiol of the present study may reflect a direct interaction (4) mediated indirectly through FSH stimulation of granulosa cells. In fact, an early study support this notion and reported that AMH reduced aromatase and LH receptor expression in rat granulosa cells in culture (14). Furthermore, recent studies on human preovulatory FF found a significant inverse correlation between AMH and both estradiol and progesterone (16, 23), confirming our previous observation on preovulatory FF but on a small number of samples (4). It has also been shown that AMH suppresses steroidogenesis in human granulosa cells (21, 22) and affects androgen synthesis at the transcriptional level (24).

Collectively, these results suggest a close interrelation between AMH and estradiol, which may operate through a direct inhibitory effect of AMH on aromatase expression and possibly LH receptor expression in small human antral follicles.

Perhaps AMH prevents the cohort of growing follicles before the recruitable stage (i.e. 4–6 mM in diameter) from expressing aromatase and granulosa cell LH receptors, thereby reducing their estradiol production. The reduced estradiol synthesis may result in higher intrafollicular levels of androgens, which augment FSH receptor expression (25, 26). The group of small antral follicles may therefore slowly acquire more FSH sensitivity, which in connection with the FSH rise seen in the early follicular phase of the menstrual cycle overcomes the negative impact on follicular growth and aromatase expression resulting in preovulatory follicular development.

The original hypothesis of AMH inhibiting FSH action in the follicle was based on studies in mice (11, 12). However, the action of estradiol differs in mice and man. Whereas estradiol has been found to be a potent stimulation of granulosa cell proliferation in rodents (27), estradiol does not have the same function in women (28). Therefore, a closer evaluation of AMH expression in response to estradiol exposure in mouse and man may be warranted.

Previously, in vitro experiments have suggested that inhibin-B interacts synergistically with LH to enhance theca cell-derived androgen production (29). The results of the present study in which a significant positive correlation were found between testosterone and androstenedione on one hand and inhibin-B on the other may reflect that inhibin-B also acts in vivo to augment theca cell-derived androgen production in a paracrine manner.

The present study also found no correlation with FF levels of estradiol and inhibin-B in relation to age. This showed that the reduced levels of inhibin-B and AMH in circulation of older women (30) are likely to be caused by a reduced number of antral follicles rather than a decreased production per follicle. It is surprising that progesterone shows a significant correlation with age. The underlying mechanism cannot readily be explained.

The health status of the follicles of the present study has not been assessed and it is presently unknown whether a correlation to AMH levels exist. This would potentially be interesting to evaluate because intrafollicular concentrations of estradiol in small human antral follicles has been shown to be positive related to follicular health (31). In the context of the present study, this would imply that low levels of AMH is indicative of a healthy follicle. The granulosa cells aspirated from small antral follicles could provide a measure of the health status of the follicle and maintain the FF for hormone measurements (31).

In conclusion, the present study demonstrates a close interdependence between AMH and estradiol in fluid from small human antral follicles, whereas there does not appear to be any correlation between intrafollicular levels of androgens and AMH. Levels of AMH remain constant in FF in different age groups of women, even in young girls before circulating levels of FSH. It is suggested that AMH interact with estradiol production rather than exerting a desensitizing effect on granulosa cells to FSH action.


   Acknowledgments
 
The excellent technical assistance by Tiny Roed and Maria Westfall is gratefully acknowledged. Cryopreservation of ovarian tissue would not have been possible without support from the Danish Cancer Foundation Grant (DP05112), which is hereby acknowledged. Cryopreservation of ovarian tissue is performed in a much appreciated collaboration with the following: Anders Nyboe Andersen (The Fertility Clinic, University Hospital of Copenhagen, Copenhagen, Denmark); Erik Ernst (Skejby University Hospital, Aarhus, Denmark); and Lars G. Westergaard (Odense University Hospital, Odense, Denmark).


   Footnotes
 
Disclosure Summary: The authors have nothing to disclose.

First Published Online April 1, 2008

Abbreviations: AMH, Anti-Müllerian hormone; FF, follicular fluid; IGFBP, IGF binding protein; PCO, polycystic ovary.

Received October 22, 2007.

Accepted March 26, 2008.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals