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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1066
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 10 4064-4069
Copyright © 2006 by The Endocrine Society

Estradiol and Regulation of Anti-Müllerian Hormone, Inhibin-A, and Inhibin-B Secretion: Analysis of Small Antral and Preovulatory Human Follicles’ Fluid

Claus Yding Andersen 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, 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: In ovaries surgically removed for fertility preservation, hormone concentrations in fluid from small antral follicles were determined. Levels were compared with those found in preovulatory follicular fluid.

Objective: The objective of this study is to measure intrafollicular concentrations of anti-Müllerian hormone (AMH), inhibin-A, inhibin-B, estradiol, and progesterone.

Setting: The study was set in a university hospital.

Patients: Patients were 22 women suffering from a cancer disease and 16 women undergoing assisted reproduction.

Interventions: Fluid from 35 follicles (diameter, 3–8 mm) was included and compared with that of 32 preovulatory follicles.

Main Outcome Measures: The main outcome measures were intrafollicular concentrations of the measured hormones and their possible correlation.

Results: Concentrations of AMH in small antral follicles were almost three orders of magnitude higher than in follicle fluid of preovulatory follicles, 790 ± 95 vs. 1.17 ± 0.14 ng/ml (mean ± SEM), respectively. There was a significant negative correlation between estradiol and AMH in fluid from small antral follicles, whereas inhibin-A and inhibin-B were correlated positively with estradiol concentrations. Progesterone showed a similar correlation to levels of AMH but only in fluid of preovulatory follicles.

Conclusions: The high expression of AMH in granulosa cells of small antral follicles actually translates into very high follicle fluid AMH concentrations. This most likely explains the correlation between serum AMH levels and the number of small antral follicles as previously demonstrated. The negative correlation between estradiol and AMH suggests that FSH down-regulates AMH expression. Thus, the microenvironment of the follicle shows profound changes with developmental stage and highlights the importance of studies to understand the mechanisms that regulate follicular growth and development during antral stages of development.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE FOLLICULAR COMPARTMENT maintains an environment that is different from that of other follicles and from that of circulation. Granulosa cells and the oocyte interact, and the follicle fluid (FF) composition from antral follicles is unique to each individual follicle. In addition, during the course of follicular growth and development, the composition of FF changes is expressed especially in the steroid content and that of some growth factors like EGF (1, 2). Based on steroid measurements, early studies in humans suggested that the microenvironment of the follicle reflects its health and its subsequent possibilities for further growth and maturation (3, 4). In connection with assisted reproduction, numerous studies were undertaken in which the steroid content and content of various other factors in preovulatory fluid were evaluated in search of prognostic parameters that allowed selection of the most viable oocyte with the greatest likelihood of resulting in a successful implantation. Most of these studies concentrated on preovulatory FF obtained in connection with oocyte aspiration and assisted reproduction. Although follicles to some degree could be classified as containing an oocyte with a pregnancy potential (e.g. the FF androgen to estrogen ratio), the precision has remained too low for applying such parameters clinically (4). However, preovulatory FF only reflects the very final stages of follicle development shortly before ovulation, which is a very dynamic period in which all the changes induced by the midcycle surge of gonadotropins occur for transition to the luteal phase to take place.

During recent years there has been an increased interest in understanding the mechanisms that regulate follicular growth during earlier stages of development. This interest has been initiated partly by the increased use of in vitro maturation of human oocytes for clinical use and partly by a number of studies that highlighted the importance of various growth factors on follicular development such as anti-Müllerian hormone (AMH). Granulosa cell expression of AMH is turned on simultaneously with onset of early follicular growth and abates in granulosa cells of preovulatory follicles (5, 6). The exact physiological mechanism of AMH in the ovary is not yet clear, and there are only limited experimental data to suggest how AMH expression is becoming down-regulated as the follicle reaches more advanced stages of development (5).

In contrast to inhibin-A and inhibin-B that occur in concentrations several orders of magnitude higher in FF from preovulatory follicles than in circulation (7, 8), FF concentrations of AMH remain almost similar to that of the circulation being around a few nanograms per milliliter (9), probably reflecting the low expression in preovulatory follicles. It has been suggested that AMH acts as an aromatase inhibitor and induces refractoriness to FSH-stimulated granulosa cell differentiation and, therefore, might be involved in the pathogenesis of polycystic ovary syndrome (PCOS) (5, 10).

The aim of the present study was to characterize FF from small antral follicles with a diameter of 3–8 mm with respect to content of AMH, inhibin-A, and inhibin-B to describe the environment that oocytes are exposed to before the preovulatory stage. Furthermore, it was our intention to compare the intrafollicular concentrations with that of preovulatory follicles and to relate these growth factor concentrations to that of estradiol and progesterone to gain a better understanding of the mechanisms that control production.


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

Follicular fluid samples of individual small antral follicles were obtained by aspiration from laparoscopically recovered ovaries removed for fertility preservation. Due to a cancer disease where adequate chemotherapy and/or radiation treatment posed a high risk of destroying all ovarian follicles and rendering the woman infertile, the cortex of one entire ovary was cryopreserved before therapy. Samples were obtained in 22 women, aged 14–34 yr (median, 28 yr) at a random time during their menstrual cycle. Diagnosis for ovarian cryopreservation included mammary cancer (8), Hodgkin’s disease (3), acute lymphatic lymphoma (2), and various others (9) and did not relate in any case to an endocrinological (e.g. polycystic ovarian syndrome) and/or ovarian disease.

The follicular fluid samples were collected immediately after recovery of the ovary before isolation of the ovarian cortex. Antral follicles visible on the surface of the ovary or observed during preparation of cortex were each 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 [mean number of follicles ± SEM (range): 2.2 ± 0.3 (1, 2, 3, 4, 5, 6)] 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, each sample was stored at –80 C until assayed for hormones. The ethical committee of the municipalities of Copenhagen and Frederiksberg approved the project.

Patients and collection of preovulatory follicular fluid

Details on patient characteristics and the hormonal treatment given have previously been published (8, 11). In brief, normogonadotropic women receiving in vitro fertilization or intracytoplasmic sperm injection treatment followed an antagonist protocol and received stimulation with recombinant human FSH (150–200 IU per day) (Puregon; Organon, Skovlunde, Denmark) from cycle d 2 and until the day of ovulation induction. Once the leading follicle had reached a size of 15 mm, prevention of a premature LH peak was secured by cotreatment with the GnRH antagonist ganirelix (Orgalutran; Organon), 0.25 mg/d. Administration of the GnRH antagonist continued up to and including the day of ovulation induction. When at least three follicles had reached a size of 17 mm, ovulation induction was done with either a single bolus of 0.5 mg buserelin sc (Suprefact; Hoechst, Hørsholm, Denmark), or 10,000 IU of human chorionic gonadotropin sc (Pregnyl; Organon), and oocyte retrieval was performed 35 h later.

At oocyte retrieval, two follicular fluid samples from each patient were collected; the first follicle was aspirated from either of the two ovaries. After removal of potential oocytes for treatment, the fluid was centrifuged (500 x g) to eliminate granulosa cells and to monitor the contamination of red blood cells. Only women in whom both samples were without visible contamination of red blood cells were included. Thus, a total of 16 women (median age, 31.6 yr; range, 25.7–39.1 yr) contributed a total of 32 FF samples. Samples were stored at –20 C until analysis.

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 (small antral follicles) or 1:1000 (preovulatory follicles) in steroid-free serum just before measurement.

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, whereas FF samples from preovulatory follicles were tested undiluted.

Inhibin-B and inhibin-A were measured using a specific ELISA kit according to the manufacturer’s instructions (The Oxford Bio-innovation kit; Biotech-IgG, Copenhagen, Denmark). Before measurement, all FF samples irrespective of whether they derived from small antral or preovulatory follicles were diluted 1:100 or 1:500 (inhibin-B) and 1:200 (inhibin-A) in serum obtained from a pool of five postmenopausal women (who had neither inhibin-B nor inhibin-A activity). The FF were pretreated with SDS, 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 (coefficient of variation < 10% and 7% for inhibin-A and -B, respectively).

Statistics

Comparison of hormone levels between subgroups (n > 2) were analyzed with an ANOVA test. Comparison of two independent groups was done using Student’s t test. 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
 
Follicular fluid was aspirated from a total of 35 small antral follicles in 22 women undergoing ovarian cryopreservation. The aspirated volume ranged from 40–300 µl (median 100 µl) corresponding to follicular diameters from around 3–4 to 7–9 mm. In the smaller follicles, all aspirated fluid was used to monitor the five hormone concentrations that were measured. In Table 1Go the average concentrations of each of these five hormones are given. As expected, concentrations of estradiol and progesterone increase one or two orders of magnitude compared with that of preovulatory follicles. Concentrations of AMH were high in FF from small antral follicles and showed a substantial decrease in preovulatory follicles, being two or three orders of magnitude lower in FF from preovulatory follicles (P < 0001). Also, concentrations of inhibin-B show a highly significant decline in fluid of preovulatory follicles compared with that of small antral follicles (P < 0.001). On the contrary, levels of inhibin-A were augmented by more than one order of magnitude in FF of preovulatory follicles compared with levels of small antral follicles (P < 0.001).


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

 
A possible correlation between levels of estradiol and AMH, inhibin-B, and inhibin-A in fluid from small antral follicles was evaluated by dividing estradiol concentrations into four intervals creating four approximately similar sized groups (Table 2Go). Concentrations of AMH showed a highly significant inverse correlation with the levels of estradiol, being almost 20 times higher in the group with estradiol levels less than 5 nM compared with the group with estradiol concentrations above 100 nM (ANOVA, P < 0.001). In contrast, concentrations of inhibin-A and inhibin-B showed a highly significant positive correlation with intrafollicular concentrations of estradiol (ANOVA, P < 0.001) (Table 2Go). Linear regression coefficients were evaluated for all five hormones measured in small antral FF (Table 3Go). Follicular fluid from preovulatory follicles showed a similar inverse correlation with estradiol (Table 4Go). However, this correlation only reached borderline significance (0.05 < P < 0.10).


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  		TABLE 2. Small antral follicles: FF content of AMH, inhibin-B, and inhibin-A in relation to the estradiol concentration

 

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  		TABLE 3. Linear regression coefficients and P values between hormonal markers in fluid from small antral follicles

 

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  		TABLE 4. Preovulatory follicles: FF content of AMH in relation to the estradiol and the progesterone concentration

 
When levels of AMH, inhibin-A, and inhibin-B were related to levels of progesterone in fluid of small antral follicles, no significant correlation between AMH and progesterone was observed, whereas levels of inhibin-A and inhibin-B were correlated significantly positively to levels of progesterone (Table 5Go). In preovulatory FF, concentrations of progesterone showed a significant positive inverse correlation with concentrations of AMH (Table 4Go).


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  		TABLE 5. Small antral follicles: FF content of AMH, inhibin-B, and inhibin-A in relation to the progesterone concentration

 
Dividing the follicular volume of small antral follicles into three groups showed a significant inverse relation with AMH [volumes <100 µl, 101–200 µl, >200 µl were (mean ± SEM) 926 ± 223, 454 ± 150, 211 ± 99 ng/ml, respectively], whereas that of inhibin-A and inhibin-B did not show a correlation with volume (data not shown). The individual intrafollicular concentrations of AMH in small antral follicles are shown in Fig. 1Go. In 10 of the women, two or more follicles were included in the study. The concentration of AMH showed a pronounced variability within each patient ranging from almost similar levels to differences exceeding one order of magnitude.


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.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
To our knowledge, this study is the first to measure AMH in fluid from human small antral follicles with diameters from 3–8 mm, and the study demonstrates that concentrations of AMH are two to three orders of magnitude higher than that seen in circulation (5, 9) and in fluid from large preovulatory follicles. Thereby this study confirms that the strong AMH expression in granulosa cells of small antral follicles actually translates into secretions of this growth factor. As for other granulosa cell-derived hormones (e.g. estradiol, inhibin-A, and inhibin-B), it can be expected that AMH produced in the follicles enters circulation. The very high concentration of AMH in FF from small antral follicles in contrast to those of preovulatory follicles is thus likely to have a profound impact on the concentration measured in circulation. Therefore, the present results corroborate the many observations, which have found a positive correlation between the circulatory concentrations of AMH and the number of antral follicles in both normal women (9, 12, 13, 14) and women with PCOS (15, 16). Thus, being a substance expressed in high concentrations in small antral follicles decreasing to relatively low levels in preovulatory follicles, the present study confirms and extends the value of AMH as a measure of the pool of growing small antral follicles and the ovarian reserve.

Moreover, this study demonstrates a highly significant inverse correlation between concentrations of AMH and estradiol in FF from small antral follicles, a tendency that was also observed in preovulatory FF. This strong correlation suggests a close interdependent regulation between AMH and estradiol in small antral follicles below a diameter of 8 mm possibly reaching into the preovulatory phase. As to whether estradiol negatively regulates AMH expression or whether AMH negatively affects expression of aromatase and, thereby, estradiol production cannot be determined by the present study. However, it seems unlikely that the massive amounts of estradiol in preovulatory FF should be affected by relative low concentrations of AMH. In contrast, the negative correlation between AMH and estradiol levels in small antral follicles may reflect a higher FSH sensitivity that leads to aromatase expression and estradiol secretion. Thus, the present study suggests that FSH acts locally as a negative regulator of AMH expression, possibly through its stimulatory effect of estradiol secretion. One study reported an inverse correlation between serum AMH and serum estradiol levels in PCOS patients (15), and several studies have shown a negative correlation between AMH and FSH serum levels in both normal and PCOS women and suggested that FSH acts as negative regulator of AMH (9, 12, 13). Also, studies in adult rats have reported that FSH down-regulates ovarian AMH and AMH type II receptor expression (17).

However, other studies suggested that AMH inhibits FSH action in the ovary (18). This suggestion was based on studies showing that AMH decreased aromatase activity in the fetal ovary (19) and that follicles from AMH knockout mice were more sensitive to FSH than those of wild-type mice (20). It has also been shown that AMH suppresses steroidogenesis in both human granulosa cells (21, 22) and mouse Sertoli cells (23), and an alternative explanation may be that this inhibition by AMH is overcome by the suppression of AMH synthesis by factors other than FSH and possibly estradiol.

The present study also demonstrated a correlation between estradiol and inhibin-A and inhibin-B expression and thus a negative correlation between AMH and the inhibins. It is possible that the inhibins interact with AMH expression in follicles with a diameter of less than 8 mm and, in this way, affect follicular FSH responsiveness. In any case, the presence of AMH in concentrations one order of magnitude higher than the inhibins warrants a number of studies looking into the specific roles of AMH and the regulation of its expression within the follicle. Furthermore, there is considerable variation in particular follicular AMH concentration of individual follicles but also of the inhibins, suggesting that these growth factors have pronounced intrafollicular effects and are probably related to the health status of the follicle. Furthermore, the almost constant levels of AMH throughout the menstrual cycle further indicate that AMH actions occur at a local level either within the ovary or indeed within the follicle itself. In addition, it could be interpreted that follicles determining circulating AMH levels are almost constant and are likely to consist of small antral follicles just a few millimeters in diameter.

A previous study found a correlation between levels of progesterone and AMH in preovulatory FF obtained in connection with assisted reproduction (24). A similar correlation was found in the present study looking at preovulatory FF. However, this observation did not extend into the small antral follicles. The present study also found a borderline significant correlation between preovulatory estradiol and AMH levels, enforcing that the intrafollicular concentration of AMH, also at the preovulatory level, seems to be closely linked to the steroid concentrations.

The preovulatory FF used in the present study derives from women who underwent ovarian stimulation, and it cannot be excluded that levels of AMH are affected by the exogenous administration of gonadotropins. Ideally a comparison of AMH levels from small antral follicles should be performed with preovulatory FF from natural cycles.

The concentrations of inhibin-B in fluid from small antral follicles was almost double the concentration in preovulatory FF and was almost one order of magnitude higher than inhibin-A in the small follicles. Both inhibin-B and inhibin-A showed a pronounced positive correlation with intrafollicular concentrations of estradiol and progesterone. This suggests that follicles acquire a high sensitivity toward inhibin expression during their development from a follicle with only little steroid hormone production to a gonadotropin-dependent follicle with augmented production. Because FSH controls granulosa cell inhibin production, follicles with high inhibin content may express enhanced sensitivity toward FSH or they may be stimulated with FSH isoforms that preferentially enhance inhibin expression. Actually, it has been shown that {alpha}-inhibin mRNA is preferentially expressed by granulosa cells when stimulated with acidic FSH isoforms compared with less acidic isoforms, being the only known substance hitherto that acidic isoforms express in higher amount compared with that of less acidic isoforms (25). During the natural menstrual cycle, the recruitable follicles of around 2–6 mm in diameter in the early follicular phase are actually exposed to relatively high levels of acidic FSH isoforms (25). This recruitable pool of follicles resembles the size of follicles used in the present study, and the results suggest that such follicles are sensitive to inhibin production perhaps especially in response to stimulation with acidic FSH isoforms.

Furthermore, the high concentration of inhibin-B in fluid of small antral follicles and the highly significant positive correlation with the estradiol concentration support the findings of inhibin-B as having an important paracrine function by enhancing theca cell androgen production in the synergy with LH (26), and thereby provide substrate for an augmented estradiol production.

In conclusion, the present study demonstrates that the microenvironment of small antral follicles is highly variable with regard to its content of AMH, inhibin-A, and inhibin-B and that these growth factors are present in concentrations very different from those found in preovulatory FF. Concentrations of AMH are very high in FF from small antral follicles, which confirms that serum levels of AMH do reflect the pool of small antral follicles present in the ovaries of a woman and enforce the use of AMH as marker of the ovarian reserve. In addition, AMH shows a pronounced negative correlation with concentrations of estradiol, suggesting that FSH may govern down-regulation of AMH expression possibly via estradiol synthesis. The present study suggests that AMH may undertake yet undisclosed functions within the growing follicles and underlines that elucidating the regulatory mechanisms in the developing follicle may provide insight into how follicular health is regulated.


   Acknowledgments
 
We acknowledge the excellent technical assistance by Tiny Roed. 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). Peter Humaidan and the Skive Fertility Clinic are thanked for collecting preovulatory follicular fluid samples.


   Footnotes
 
Cryopreservation of ovarian tissue would not have been possible without support from the Danish Cancer Foundation Grant (DP05112).

Disclosure summary: The authors have nothing to disclose.

First Published Online August 8, 2006

Abbreviations: AMH, Anti-Müllerian hormone; FF, follicle fluid; PCOS, polycystic ovary syndrome.

Received May 16, 2006.

Accepted July 31, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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  3. McNatty KP, Smith DM, Makris A, Osathanondh R, Ryan KJ 1979 The microenvironment of the human antral follicle: interrelationships among the steroid levels in antral fluid, the population of granulosa cells, and the status of the oocyte in vivo and in vitro. J Clin Endocrinol Metab 49:851–860[Medline]
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S. Catteau-Jonard, P. Pigny, A.-C. Reyss, C. Decanter, E. Poncelet, and D. Dewailly
Changes in Serum Anti-Mullerian Hormone Level during Low-Dose Recombinant Follicular-Stimulating Hormone Therapy for Anovulation in Polycystic Ovary Syndrome
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M. E. Kevenaar, A. P.N. Themmen, J. S.E. Laven, B. Sonntag, S. L. Fong, A. G. Uitterlinden, F. H. de Jong, H. A.P. Pols, M. Simoni, and J. A. Visser
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D. S. Wachs, M. S. Coffler, P. J. Malcom, and R. J. Chang
Serum Anti-Mullerian Hormone Concentrations Are Not Altered by Acute Administration of Follicle Stimulating Hormone in Polycystic Ovary Syndrome and Normal Women
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