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Changes in Serum Anti-Müllerian Hormone Level during Low-Dose Recombinant Follicular-Stimulating Hormone Therapy for Anovulation in Polycystic Ovary Syndrome

Departments of Endocrine Gynaecology and Reproductive Medicine (S.C.-J., A.-C.R., C.D., D.D.), and Radiology (E.P.), Hôpital Jeanne de Flandre, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France; and Laboratory of Endocrinology (P.P.), Parc Eurasanté, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France

Address all correspondence and requests for reprints to: Didier Dewailly, Department of Endocrine Gynaecology and Reproductive Medicine, Hôpital Jeanne de Flandre, Avenue Eugène Avinée, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France. E-mail: ddewailly{at}chru-lille.fr.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: We previously hypothesized that the excess of anti-müllerian hormone (AMH) at the level of selectable follicles could be involved in the follicular arrest of polycystic ovary syndrome (PCOS), mainly through inhibition of FSH effect on aromatase expression.

Objective: In this study, we investigated whether a decrease in the serum AMH level was concomitant to the appearance of a dominant follicle induced by administration of mild amounts of exogenous FSH in women with PCOS.

Design: A total of 30 women with PCOS in whom anovulation was resistant to clomiphene citrate received recombinant FSH using the low-dose step-up protocol during only one cycle. Serum levels of estradiol, AMH, LH, FSH, inhibin B, and ultrasound parameters were assessed twice a week until 3 d after the appearance of one or more dominant follicle(s).

Results: The day of dominance (d 0) was defined by the appearance of at least one follicle more than 10 mm growing 2 mm/d. From d –14 before dominance to d +3, the mean serum AMH level and the 2- to 5-mm follicle number at ultrasound declined steadily, although not significantly by ANOVA. Mean AMH relative values (100% being the value at d 0) declined significantly (P = 0.04), from 125 ± 32% at d –14 to 105 ± 15% at d –4. Within the same time lag, the mean FSH relative values increased from 91 ± 17% to 107 ± 19% (P = 0.013). In the 87 samples obtained from d –14 to –4, absolute values of AMH were positively and negatively associated with those of LH and FSH, respectively, in an independent manner (P = 0.009 and P = 0.03, respectively). In the 55 samples collected at d 0 and +3, they were negatively correlated to those of estradiol (r = –0.272; P < 0.05).

Conclusions: These data suggest that in anovulatory women with PCOS, gently increasing the serum FSH level reduces the AMH excess, thus relieving the inhibition from the latter on aromatase expression by selectable follicles and allowing the emergence of a dominant follicle.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
POLYCYSTIC OVARY syndrome (PCOS) is the most common cause of oligo-anovulation (OA), infertility, and hyperandrogenism in women, affecting between 5 and 10% of women of reproductive age worldwide (1). In the PCOS, the follicle abnormality responsible for OA is 2-fold (2). First, polycystic ovaries (PCO) are endowed with an abnormally rich pool of growing follicles from classes 1–5 (until 5 mm) (3), probably due to intraovarian hyperandrogenism that promotes excessive early follicular growth. Second, the selection of one follicle from the increased pool of selectable follicles and its further maturation to a dominant follicle does not occur, an abnormality that is called "follicular arrest" (FA). The reasons for this last phenomenon are unknown, although inhibition of the local effects of FSH seems pivotal (4). Both follicle abnormalities may be linked since we recently reported a negative correlation between the small (2–5 mm) and larger (6–9 mm) antral follicle number (FN) at ultrasound (5). In our opinion, this could reflect an inhibitory mechanism exerted by the selectable follicles on their further maturation, putatively involving the anti-müllerian hormone (AMH).

AMH, a member of the transforming growth factor ß-superfamily, is expressed and secreted by human granulosa cells (GCs) of growing follicles from the primary to the large antral follicle stage (6). From experimental data mainly obtained in rodents, the proposed functions of AMH are inhibition of the initial recruitment of primordial follicles (7), inhibition of aromatase activity in GCs (8, 9), and decrease of FSH-stimulated follicle growth in the mouse, both in vitro and in vivo (10). Together, these data suggest that AMH is a negative regulator of follicle growth and reduces follicle sensitivity to FSH. Therefore, this effect is supposed to recede in the early follicular phase, when the cohort of selectable follicles is constituted under the effect of the intercycle FSH peak (4). Accordingly, immunocytochemical data in the normal human ovary indicate that AMH expression is maximal in small antral follicles and then declines in larger follicles (6). Recently, it has been suggested from data in human follicular fluid that FSH exerts a negative influence on AMH secretion in these follicles (11).

Such a sequence might be disturbed in anovulatory PCOS. In these patients, the serum AMH level is markedly increased in close relationship with the degree of menstrual disorder (12) and with the excess in the 2- to 5-mm FN at ultrasonography (13, 14). Therefore, we previously hypothesized that the AMH excess could be involved in the FA of PCOS through inhibition of FSH effects on the cohort of selectable follicles (2). In particular, it could be involved in the lack of FSH-induced aromatase activity that characterizes the FA of PCOS (15). In agreement, a negative correlation between serum AMH and estradiol (E2) levels has been reported in nonstimulated anovulatory women with PCOS (16). Because such a negative relationship has also been observed in follicular fluid from small antral follicles collected in normal women (11), the lack of FSH-induced aromatase activity in PCOS due to AMH excess could represent the exaggeration of a physiological phenomenon.

That a decrease of the AMH excess coincides with the resumption of the terminal follicle growth under exogenous FSH in anovulatory women with PCOS would further support this hypothesis. Therefore, we verified in a group of infertile women with PCOS whether the appearance of a dominant follicle induced by administration of mild amounts of exogenous FSH was preceded by changes in the serum AMH level, along with other hormonal and ultrasound changes.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

This prospective study included 30 oligo-ovulatory women aged 20–38 yr willing a pregnancy who were resistant to clomiphene citrate, i.e. no ovulation at 150 mg/d or no pregnancy after six ovulatory cycles. The sperm analysis and hysterosalpingography were normal in all patients. According to the Rotterdam criteria (17), the diagnosis of PCOS was based on the association of at least two of three following criteria: 1) ovulatory disturbance, mainly oligomenorrhea or amenorrhea; 2) hyperandrogenism, as defined either clinically by hirsutism (modified Ferriman and Gallway score > 6), or severe acne/seborrhea, and/or biologically by a testosterone serum level greater than 0.6 ng/ml and/or -4-androstenedione greater than 2.2 ng/ml; and 3) more than 12 follicles in the 2- to 9-mm range in each ovary at ultrasound and/or an ovarian volume higher than 10 ml.

All patients gave informed consent before their inclusion in this study. This study was approved by the institutional Review Board of the University Hospital of Lille.

Design

All women were investigated during only one cycle and received recombinant FSH (recFSH) (Puregon; Organon Laboratories, Saint-Denis, France) using the low-dose step-up protocol (18), starting from d 2 or 3 after the menstrual period, until the mean diameter of one or two follicles became more than 17 mm. The ovulation was then triggered by an injection of 5000 IU human chorionic gonadotropin (hCG), except in the presence of three or more dominant follicles. The last menstrual period was either spontaneous or induced by the administration of dydrogesterone (10 mg/d for 7 d). The starting dose of recFSH was 50 IU/d. In the absence of criteria for dominance (see next sentence) after 14 d at 50 IU/d, the recFSH dose was increased by 25 IU/d every 7 d until dominance was achieved. Dominance was defined by the appearance of at least one follicle more than 10 mm growing at least 2 mm/d and serum E2 more than 100 pg/liter. Serum levels of E2, inhibin B, AMH, LH, FSH, and ultrasound parameters (follicle count with distinction between diameters of 2–5, 6–9, 10–15, and >15 mm, ovarian area and volume, endometrial thickness) were assessed twice a week from the first day of stimulation until 3 d after dominance was achieved. The time lag between FSH injections and blood sampling was 16–17 h in every patient at each visit.

Ultrasound examination was performed with a 7-MHz transvaginal transducer (Sonoline Elegra; Siemens, Cheshire, CT). Ultrasound measurements were taken in real time, according to a standardized protocol, as previously described (19).

Hormonal immunoassays

Serum AMH levels were assessed using the second generation enzyme immunoassay AMH-EIA (ref A16507) provided by Immunotech Beckman Coulter (Marseille, France). Intraassay and interassay coefficients of variation were less than 12.3 and 14.3%, respectively. The functional sensitivity (i.e. lowest AMH concentration measurable with an interassay coefficient of variation less than 20%) was 2.5 pmol/liter (Taeib, J., and P. Pigny, unpublished data). LH and FSH were measured using chemiluminescent two-site immunoassays on a multiparameter system (Axsym; Abbott Laboratories, Rungis, France). E2, inhibin B, and total testosterone were measured prospectively by immunoassays as described previously (20).

Statistical methods

ANOVA with post hoc analysis using the Bonferroni correction was used to detect any significant variation of the tested parameters during the considered time periods. Multiple linear regression analysis was used to search for an independent association among a set of variables. All statistical procedures were run on SPSS 11.5 (SPSS Inc., Chicago, IL).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
General findings and treatment outcome

The main pretreatment clinical, hormonal, and ultrasound data in the 30 patients are presented in Table 1. Ultrasound data fitted with the Rotterdam definition of PCO (21) in all patients. In addition to OA that was present in all patients, hyperandrogenism (i.e. Ferriman and Gallway score 6 and/or serum total testosterone level 0.6 ng/ml) was observed in 24 (80%) patients.

Presentation of dynamic data

Because the treatment time varied widely between patients, gathering the patients according to the time elapsed once FSH treatment was started (i.e. d +4, +7, +11, etc... .)would have yield a heterogeneous cohort in regard to changes putatively occurring when dominance was approaching. For instance, d +7 would have been very close to dominance for some patients but very far for others. Therefore, the day of dominance was considered as d 0, and the other days of sampling were expressed backward as d –4 to –46 and forward as d +3 (see Patients and Methods for treatment protocol). Figure 1 shows the cumulative number of patients that were studied at each visit. We decided using only data from d –14 to d +3 because the population samples from d –18 to –46 were small (n 10) and too distant from dominance to be pertinent. Therefore, the size of our patient population at each visit varied from 14 at d –14 to 30 at d –4 and 0 (Fig. 1).

View larger version (13K): [in this window] [in a new window]   FIG. 1. Cumulative number of patients included at each visit. Each day is expressed relatively to the day of dominance (d 0).

As shown in Fig. 2, the mean serum FSH level first increased and peaked at d –7. It then decreased from d –4 to +3, presumably because of the negative feedback exerted by the increasing serum inhibin B and E2 levels (Fig. 2). Meanwhile, the mean serum AMH level and the 2- to 5-mm FN declined steadily from d –14 to +3. The mean serum LH level declined steadily from d –14 to 0 and then increased sharply at d +3. This was explained by the fact that four patients had a premature LH surge with an increase of serum level more than 300% between d 0 and +3. ANOVA, including data from d –14 to +3, indicated significant changes for E2 (P < 0.0001), inhibin B (P < 0.0001), and LH (P < 0.006). Statistical significance was not reached for changes in FSH (P = 0.83), AMH (P = 0.32), and 2- to 5-mm FN (P = 0.15). As indicated by the span of SEMs on Fig. 2, these last parameters suffered from a wide interindividual variability.

View larger version (19K): [in this window] [in a new window]   FIG. 2. Mean (±SE) values of serum FSH, E2, inhibin B, LH, and AMH, and mean (±SE) values of the 2- to 5-mm FN from d –14 to +3. Note that the number of patients sampled each day was variable. See Fig. 1. To convert E2 in pmol/liter, multiply by 3.671.

Relative values were used to analyze the evolution of these parameters under FSH treatment. To do so, each absolute value at any day was divided by the value at d 0 and multiplied by 100. The d 0 value (100% for every patient) was not used in the ANOVA, and the four patients who were not sampled earlier than d –4 (Fig. 1) were excluded from this analysis. From d –14 to –4 before dominance, the mean AMH relative value declined significantly from 125 ± 32% to 105 ± 15%, respectively (P = 0.04) (Fig. 3). Two by two comparisons with post hoc analysis using the Bonferroni correction indicated a significant difference between d –14 and –4 (P = 0.0054; minimum P value required = 0.0083). Within the same time lag, the mean FSH relative values increased from 91 ± 17% to 107 ± 19% (P = 0.013) (Fig. 3). No two by two comparison was significant. The mean relative number of 2- to 5-mm follicles at ultrasound also declined between d –14 and –4, although not significantly.

View larger version (9K): [in this window] [in a new window]   FIG. 3. Mean (±SE) relative values (d 0 value = 100%) of serum AMH (empty squares) and FSH (filled squares) from d –14 to 0. Note that the number of patients sampled each day was variable. See Fig. 1.

Simple regression analysis using the data from the 87 samples obtained from d –14 to –4 indicated that the absolute values of AMH were tightly and positively related to the 2- to 5-mm FN (r = 0.73; P < 0.0001) and the inhibin B values (r = 0.29; P < 0.01). They were positively and negatively associated with those of LH and FSH, respectively (r = 0.28, P = 0.009 and r = –0.24, P = 0.03, respectively). E2 values were not related to those of AMH (P = 0.7) and LH (P = 0.14), whereas they were strongly and positively associated with those of FSH and inhibin B (P < 0.0001 for both). LH and FSH values were not related to each other (P = 0.13). After multiple linear regression analysis with AMH as a dependent variable and LH, FSH, inhibin B, and 2- to 5-mm FN as independent variables, all relationships with AMH remained significant (P < 0.05), with regression coefficients of 0.158, –0.145, 0.251, and 0.648, respectively.

Simple regression analysis using the data from the 55 available samples obtained at d 0 and +3 (five patients could not be sampled at d +3) indicated that the absolute values of AMH were negatively related to those of E2 (r = –0.272; P < 0.05) but were not related to those of inhibin B.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
With the use of low doses of recFSH in our patients with PCOS, we were able to mimic a typical pattern of the FSH window as it occurs in the early follicular phase of normal nonstimulated cycles (4). In the first part of this phenomenon (from d –14 to –4), the significant increase of serum FSH level was accompanied by a significant AMH decrease when values were expressed relatively to d 0. Moreover, individual absolute values of both parameters were negatively and significantly related during this period of time, independently from other variables. Although such an association does not necessary mean causality, it agrees with studies in adult rats reporting that FSH down-regulates ovarian AMH and AMH type II receptor expression (23). Moreover, it has been shown recently that in vitro FSH treatment significantly reduced AMH expression in cultured GCs from patients with PCOS (24). Therefore, we suggest that in our patients with PCOS, the serum AMH decrease that preceded the establishment of dominance was the consequence of the serum FSH increase under treatment. Because this effect took several days to be perceived, our assertion is not contradictory with the recent finding that an acute 24-hr FSH infusion had no effect on serum AMH level in women with PCOS and in controls (25). Conversely, it disagrees with the hypothesis that the FSH effects upon AMH expression are mediated through E2 within the GCs (11, 25) since the AMH level started to decline far before the E2 increase.

That the progressive decline in the serum AMH level occurred before E2 increased and a follicle became dominant suggests that induction of aromatase activity and terminal follicle growth by FSH was possible once the AMH excess was partially reduced in our patients with PCOS. Although this assertion remains speculative, it agrees, however, with others’ experimental animal and human data indicating that AMH may play an important negative role in aromatase expression during the selection process (8, 16) and with our hypothesis that such a role is amplified in PCOS (5). However, because of the lack of sensitivity of our E2 assay, the demonstration of a negative association between AMH and E2 was only possible once serum E2 level was > 50 pg/ml (i.e. later than d –4). Another explanation could be that the lowering of AMH under FSH was the consequence of the shift of small antral follicles to larger ones expressing less AMH and not yet aromatase.

One could argue that the degree of AMH decrease before dominance was too modest to be instrumental, averaging only 25%. However, it must be reminded that the selectable follicles contribute only for a part of the total serum AMH content (14, 26, 27). One could speculate that the AMH decrease was more important at the selectable follicle level in our patients and that it was even normalized, thus allowing dominance to occur. This may also explain why our data disagree at first sight with the absence of significant change in the AMH plasma level during the follicular phase of the spontaneous menstrual cycle in normal ovulatory women (27, 28). Presumably, in this situation with less selectable follicles and lower serum AMH levels, this decrease is too subtle to be perceived in peripheral blood. Conversely, during controlled ovarian hyperstimulation for in vitro fertilization (IVF) in normal women, three studies have reported a marked serum AMH decline (>50%) in close relationship with the diminution of the small antral FN and the establishment of multifollicular dominance (28, 29, 30). Such discrepancy could indicate that, in serum, the decrease of the AMH level can be seen only in a situation of small antral follicle excess that occurs either spontaneously, as in PCOS, or under controlled ovarian hyperstimulation, as in normal women undergoing IVF. This decrease would result from the evolution of the nonselected follicles to atresia (28). Accordingly, a contemporary decrease in the small FN was observed at ultrasound in the IVF study by Fanchin et al. (29) as well as in the present study, although the P value of our ANOVA remained slightly above the threshold for significance.

Indeed, in this dynamic study, we found a tight relationship between the AMH values and the 2- to 5-mm FN, as previously reported in nonstimulated patients with PCOS (13, 14). The concomitant decline of both AMH level and FN raises the question about which of both is putatively the prerequisite to the establishment of dominance. We have recently shown that the FA of PCOS strongly depends on the excess of small antral follicles (5). This agrees also with our previous statement that the AMH excess in PCOS is secondary to the increase in the FN (12). Putatively, this excess would occur within the follicle environment by cumulative effect, and would inhibit the small antral follicle function and growth through follicle-follicle interactions (2). Conversely, Pellatt et al. (24) argued that an intrinsic AMH dysregulation at the GC level could be the primum movens of the FA of PCOS. They found a mean AMH level many times higher in GC-conditioned media from PCO than from normal ovaries. Clearly, in vivo studies using follicular fluid are necessary to solve the controversial issue as to whether the AMH production per follicle is increased or not in PCO.

In the present study, we observed a significant decrease of serum LH level before dominance, a phenomenon that has been known for a long time to occur in spontaneous or stimulated uni-ovulatory cycles (18). Here, we show that it is significantly related to the AMH decrease, independently from FSH and E2 variations. Laven et al. (14) also reported a positive correlation between AMH and LH baseline serum levels in nonstimulated normogonadotropic anovulatory infertile women, a population we can assimilate to PCOS. These data could indicate that LH controls positively the ovarian AMH secretion, at least in PCOS. Accordingly, Pellatt et al. (24) observed that, when incubated with LH, GCs from normal follicles more than 10 mm increased slightly their AMH secretion, whereas the increase was 4-fold in GCs from follicles collected in PCO. Conversely, some experimental data indicate that AMH could regulate positively the pituitary LH secretion (31). Consequently, the decrease in AMH secretion could participate in the decrease of LH level before dominance. Obviously, more investigations are necessary to explain this mysterious relationship between LH and AMH.

To conclude, these data lead us to speculate that the AMH excess secondary to the increased FN is involved in the FA of the PCOS, probably through aromatase inhibition. Increasing the serum FSH level may reduce the AMH excess, thus relieving its inhibition on the follicular function and growth, and allowing the emergence of a dominant follicle. However, further experimental data are necessary to confirm such a role of AMH and follicle excess.

	Acknowledgments

 
We thank the staffs of the Laboratoire de Biochimie et Hormonologie, Parc Eurasanté, and of the Service de Radiologie, Hôpital Jeanne de Flandre, Centre Hospitalier Régional Universitaire de Lille, for their excellent technical help. We also thank Ms. Laure Decoster and Marion Farasse for collecting the clinical data and Mrs. Lydie Lombardo and Sylvie Vanoverschelde for collecting the blood samples.

	Footnotes

 
This work was supported by a grant from the Fonds d’Aide à la Recherche Organon, Organon Laboratories, France.

The clinical trial number registered on clinicaltrials.gov is CP03/102.

Disclosure Statement: The authors have nothing to disclose.

First Published Online August 14, 2007

Abbreviations: AMH, Anti-Müllerian hormone; E2, estradiol; FA, follicular arrest; FN, follicle number; GC, granulosa cell; hCG, human chorionic gonadotropin; IVF, in vitro fertilization; OA, oligo-anovulation; PCO, polycystic ovaries; PCOS, polycystic ovary syndrome; recFSH, recombinant FSH.

Received April 18, 2007.

Accepted August 6, 2007.

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