Scholarly article on topic 'Anti-mullerian hormone in the management of infertility'

Anti-mullerian hormone in the management of infertility Academic research paper on "Health sciences"

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Academic research paper on topic "Anti-mullerian hormone in the management of infertility"

Middle East Fertility Society Journal (2014) 19, 1-7

Middle East Fertility Society Middle East Fertility Society Journal

www.mefsjournal.org www.sciencedirect.com

Middle East Fertility Society Journal , :

REVIEW

Anti-mullerian hormone in the management cm*

of infertility

Mohamed Aboulghar *

Faculty of Medicine, Cairo University, Egypt

Received 17 March 2014; accepted 17 March 2014 Available online 13 April 2014

Contents

1. Introduction............................................................................ 1

2. The roles of AMH in ovarian physiology........................................................ 1

3. AMH changes in normal women.............................................................. 2

4. AMH and outcome of ART................................................................. 2

5. Comparison of AMH with other tests to assess ovarian reserve........................................ 3

6. AMH in the assessment of ovarian response..................................................... 3

7. AMH and assessment of poor and hyper response................................................. 3

8. AMH in the assessment and follow up of cancer in young females...................................... 4

9. Assay of AMH.......................................................................... 5

10. AMH in relation to race................................................................... 5

11. Conclusion ............................................................................. 5

12. Conflict of interest........................................................................ 5

References ............................................................................. 5

1. Introduction

AMH is a dimeric glycoprotein, a member of the transforming growth factor (TGF)-b superfamily (1), which acts on tissue growth and differentiation. In women, AMH is produced by the granulosa cells (GC) in the preantral and antral follicles (2). Because serum AMH levels reflect the ovarian follicular

pool, any reduction in the number of small, growing follicles may be followed by a reduction in circulating AMH (3).

Age clearly remains the primary determinant of the probability of a live birth after assisted conception, but for any given age, women with higher ovarian reserves and therefore higher circulating AMH levels have a higher success rate than their counterparts with lower AMH (4).

2. The roles of AMH in ovarian physiology

AMH is specifically expressed in granulosa cells of small growing follicles. In rodents, expression is initiated as soon as primordial follicles are recruited to grow, and highest

* Address: 10 Geziret El Arab St., Mohandessin 12411, Cairo, Egypt.

Tel.: +20 2 27498488.

E-mail address: gharmd@gmail.com.

Peer review under responsibility of Middle East Fertility Society.

1110-5690 © 2014 Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society. http://dx.doi.Org/10.1016/j.mefs.2014.03.002

expression is observed in pre-antral and small antral follicles. AMH is no longer expressed by mural granulose cells during the FSH-dependent stages of follicular growth, nor is it expressed in atretic follicles (5). However, expression persists in the cumulus cells of pre-ovulatory follicles (6). AMH has also been suggested to exert a physiological effect on antral follicles in the human ovary before final selection. There exists a fine-tuned and delicate balance between estradiol (E2) (and inhibin) output by the pre-ovulatory follicle and gonadotropin secretion by the pituitary to ensure that ovulation is triggered exactly at the right time (7). Recently, it has been suggested that AMH may exert a physiological role in down-regulating the aromatizing capacity of granulosa cells until the time of follicular selection (8).

In a prospective study based on 20 women, Sowers et al. (9) described two different patterns for AMH dynamics throughout the menstrual cycle. The 'younger ovary' pattern had higher mean AMH and significant variations in AMH levels throughout the cycle. This contrasted with an 'ageing ovary' pattern with low mean AMH, shorter menstrual cycle lengths, and very low variation in AMH levels.

Recently, a cohort study based on 863 women (228 OC-users and 504 non-users) reported that AMH serum levels were 29.8% lower in OC users than controls (10).

3. AMH changes in normal women

Relationship of serum anti-mullerian hormone concentration to age at menopause.

AMH levels were measured in 144 fertile normal volunteers and used to determine an estimate of mean AMH as a function of age. Data on the onset of menopause were obtained from the population-based prospective investigation. Predictions of age at menopause follow an individual woman's AMH pattern. Results showed a good conformity between the observed distribution of age at menopause and that predicted from declining AMH levels. The similarity between observed and predictive distributions of age at menopause supports the hypothesis that AMH levels are related to the onset of menopause. Results of this study suggest that AMH is able to specify a woman's reproductive age more realistically than chronological age alone (11).

Age-specific serum AMH values for 17120 women presenting to fertility centres within the United States showed that both median and mean AMH values decreased steadily in a manner highly correlated with advancing age. The average yearly decrease in the median serum AMH value was 0.2 ng/ mL/year through age 35 and then diminished to 0.1 ng/mL/ year after age 35. The rate of decline in mean AMH values was 0.2 ngmL/year through age 40 and then diminished to 0.1 ng/mL/year thereafter. Such data may be of value to physicians and their patients who are considering reproductive options (12).

Normogram for the decline in serum AMH in a population of 9601 infertility patients showed that circulating AMH concentrations decline with increasing reproductive age. This validated age-related AMH normogram will enable counselling of infertility patients regarding reproductive performance (13).

Serum AMH levels have been measured at frequent timepoints during the menstrual cycle, suggesting the complete absence of fluctuation. A study included 48 women attending the IVF/ICSI programme. Blood withdrawal for AMH

measurement was performed in all the patients independently of the day of the menstrual cycle. For the first time, clinicians may have a reliable serum marker of ovarian response that can be measured independent of the day of the menstrual cycle (14).

Serum levels of AMH as a marker of ovarian function was assessed in 926 healthy females from birth to adulthood. AMH was undetectable in 54% (38 out of 71) of cord blood samples (<2;<2-15 pmol/l) (median; 2.5th to 97.5th percentile) and increased in all (37 of 37) infants from birth to 3 months (15; 4.5-29.5 pmol/l). From 8-15 years, AMH levels were stable (19.9; 4.7-60.1 pmol/l), with the lower level of the reference range clearly above the detection limit. The conclusion was AMH seems to be a promising marker of ovarian function in healthy girls (15).

Serum AMH levels remained stable throughout the menstrual cycle and after oral or vaginal administration of synthetic sex steroids. Twenty-four young, healthy volunteer women with regular cycles who had received no hormonal contraception for at least 3 months before the study. They received oral of vaginal oestrogen/progestogen contraception from day 5 to 25 of a menstrual cycle versus no contraception. AMH levels remained steady during the menstrual cycle and indicated that they are unaffected by exogenous sex steriods used for contraception whether administered orally or vaginally (16).

4. AMH and outcome of ART

La Marca et al. (17) analysed their data base between 2005 and 2008 and demonstrated long logistic regression that success of IVF depends mainly on age and AMH level.

Reproductive data were collected from 769 women; 346 women using conventional stimulation protocols; 423 women treated under new AMH-tailored protocols. ET rates increased significantly (P = 0.002) after the introduction of AMH-tai-lored stimulation protocols. Pregnancy rate per cycle started and live birth rate also increased significantly (P = 0.002 and 0.007 respectively. The incidence of the ovarian hyperstimulation syndrome fell significantly (6.9-2.3%, P = 0.002) and failed fertilization fell from 7.8% to 4.5%. The cost of fertility drug treatment fell by 29% (18).

AMH, independent of age, has some association with predicting live birth after assisted conception and may be helpful when counselling couples before undergoing fertility treatment. However, its predictive accuracy is poor (19).

AMH is strongly associated with live-birth rates after IVF/ ICSI. AMH may therefore serve as a prognostic factor for the chance of a pregnancy and live birth. Treatment outcome was superior in patients with polycystic ovaries. The findings also indicate that AMH may partially comprise information about oocytes quality (20).

In a prospective controlled study for subfertile women (aged 6 40 years) treated by IVF/ ICSI in 2011 (n = 4,960), it was hypothesized that women with a diagnosis of unexplained infertility or endometriosis, women with a history of ovarian surgery and women between the ages of 37 and 40 years would be at a higher risk of having a poor ovarian reserve. Routine AMH was performed for all patients (3).

The routine use of AMH levels before IVF/ICSI in patients considered at a higher risk for cycle cancellation significantly reduced the incidence of cycle cancellation and stress, compared with a control group with no AMH assays.

5. Comparison of AMH with other tests to assess ovarian reserve

A comparison of the predictive value of AMH, FSH inhibin B and age by assessment of menstrual cycle day 3 serum samples in 123 IVF cycles was done and compared with IVF records. The study showed that AMH values correlated the best with the number of retrieved cycles (r = 0.539; P < 0/001) relative to age (r = -0/323; P < 0.1) FSH (r = -0.317; P < 0.01), and inhibin B (P > 0.05). AMH correlates better than age, FSH, LH, inhibin B and estradiol with the number of retrieved oocytes (21).

AMH correlates better than age, FSH, and inhibin B with the number of retrieved oocytes. Serum basal AMH may offer a better prognostic value for clinical pregnancy than other currently available markers of IVF outcome in our preliminary study (22).

To compare the inter- and intra-cycle stability of antral follicle count (AFC) and AMH, age-adjusted intra-class correlation coefficients (ICCs) were used. Data were prospectively collected from 77 regularly cycling infertile women aged 24-40. AMH and AFC values were measured on cycle day 3. Data were used from a prospective cohort study of 44 regularly cycling volunteers, aged 25-46 years and AMH was measured and AFC (2-10 mm) assessed every 1-3 cycle days. Serum AMH demonstrated less individual intra- and inter-cycle variation than AFCs and may therefore be considered a more reliable and robust means of assessing ovarian reserve in subfertile women (11).

AMH is the most informative serum marker of ovarian reserve. It is both more convenient and informative than basal FSH and can be assessed at any point in the cycle. It is the most useful serum method of determining ovarian reserve, which guides pretreatment counselling, choice of infertility treatment, and avoidance of ovarian hyperstimulation. The future role of basal FSH testing is in doubt (23).

AMH can predict the ovarian response to hyperstimulation (24). AMH is superior to female age in assessing the quantitative aspects of the ovarian reserve but its value is much more limited in the prediction of ongoing pregnancy.

Inter-individual variability of AMH is high, mainly due to the very high variability in the number of antral follicles within groups of subjects of similar age (25-27). There also seems to be ethnic variation, with African-American (28,29) and Hispanic (28) women having lower serum AMH levels than those found in Caucasian women, which may indicate a discrepancy between ovarian follicle number and AMH production. Some studies have indicated a negative relationship between BMI and AMH (30,31) but this has not been consistent (32).

6. AMH in the assessment of ovarian response

Serum anti-mullerian hormone and FSH: prediction of live birth and extremes of response in stimulated cycles-implications for individualization of therapy. Plasma AMH is a superior predictor for live birth and anticipated oocytes yield compared with FSH and age, facilitating individualization of therapy prior to first ART cycle (33).

Circulating AMH has the ability to predict excessive and poor response to stimulation with exogenous gonadotropins. Overall, this biomarker is superior to basal FSH and AFC,

and has the potential to be incorporated into work-up protocols to predict patient's ovarian response (34).

As AMH may permit the identification of both the extremes of ovarian stimulation, a possible role for its measurement may be in the individualization of treatment strategies in order to reduce the clinical risk of ART along with optimized treatment burden. It is fundamental to clarify the cost/benefit of its use in ovarian reserve testing (35).

To investigate the role of AMH as predictor of reproductive outcome in subfertile women with elevated basal FSH, a prospective observational cohort study was conducted on subfertile women with a regular menstrual cycle, basal FSH concentrations P12.3IU/L, and younger than 40 years old was conducted. The results showed a cumulative live birth rate of 63.5% during a median follow-up of 3.3 years (n = 85). The AMH level was significantly associated with live birth. There was evidence of a nonlinear prediction pattern, with an increase in chances of live birth until an AMH level of 1 ig/L. These findings suggested applicability of AMH determination as a marker for actual fertility in subfertile women with elevated basal FSH levels (36).

Based on current evidence, it appears that the use of AMH serum concentrations to predict ovarian response and optimize treatment strategies is a promising approach for improving pregnancy outcomes in women undergoing ovarian stimulation. However, prospective randomized controlled trials evaluating this approach are needed before any firm conclusions can be drawn (37).

According to the Italian national assisted reproduction technique (ART) register 4500 cycles are cancelled every year due to an abnormal response to stimulation with gonadotro-pins. The main objective of individualization of treatment in IVF is to offer every single woman the best treatment tailored to her unique characteristics, thus maximizing success, eliminating iatrogenic risks, such as OHSS, and minimizing the risk of cycle cancellation (38).

7. AMH and assessment of poor and hyper response

Prediction of poor response is vital for the counselling and management of these women in clinical practice (39) on the basis of a low AFC or reduced levels of AMH (37).

Cut-off levels of AMH values for poor ovarian response reported in the literature vary between 0.1 and 2.97 ng/ml, which is within the range of normal values for AMH in healthy women (38).

The two largest prospective studies published to date have included 340 and 356 women, respectively (39,40). In Nelson et al. (39) the best cut-off value for AMH was 5 pmol/l (0.7 ng/ml) (DSL assay), which was associated with a sensitivity of 75% and specificity of 91%. Al-Azemi et al. (40) found an AMH value of 1.36 ng/ml (9.7 pmol/l) (IBC assay) to be associated with 75.5% sensitivity and 74.8% specificity. According to published data a cut-off value of AMH ranging between 0.7-1.3 ng/ml may be considered acceptable for the prediction of poor response in IVF.

With regard to a refusal of IVF treatment for women who have been predicted as poor responders, it is commonly agreed not to exclude anyone from their first IVF attempt only on the basis of the ovarian reserve test, as the accuracy of these tests can be poor for the prediction of pregnancy (41,42).

Moreover, even though the possibility of pregnancy is reduced, pregnancy rates in younger poor responders are still considered acceptable (43).

It is of great importance to accurately predict women who are likely to have a high response to COS as it is the main risk factor for OHSS (44).

Markers of ovarian reserve, in particular AMH and AFC, once again allow for considerable enhancement in identifying women who are likely to show a high response to COS (38).

Not only is prediction of a high response prior to an IVF cycle useful in counselling patients on the risk of OHSS but it also gives a real possibility of modifying the stimulation protocol and reducing the incidence of a high response and OHSS. Recent studies have demonstrated that the use of antagonists is associated with a reduction of the occurrence of a high response and a significant reduction in the incidence of OHSS or of cycle cancellation because of the risk of OHSS (45).

Regarding the use and efficacy of serum AMH levels in tailored treatment, two studies have been published reporting simple models for gonadotropin dose selection (46,47). In both the models the daily dose of gonadotropin was tailored according to the pretreatment AMH levels independently of the age or other characteristics of the woman (46,47).

AMH seems to be a better marker in predicting ovarian response to controlled ovarian stimulation than age of the patient, FSH, estradiol and inhibin B. A similar performance for AMH and antral follicular count has been reported. In clinical practice, AMH measurement may be useful in the prediction of poor response and cycle cancellation and also of hyper-response and ovarian hyperstimulation syndrome.

In the male, the wide overlap of AMH values between controls and infertile men precludes this hormone from being a useful marker of spermatogenesis.

As AMH may permit the identification of both the extremes of ovarian stimulation, a possible role for its measurement may be in the individualization of treatment strategies in order to reduce the clinical risk of ART along with optimized treatment burden. It is fundamental to clarify the cost/benefit of its use in ovarian reserve testing. Regarding the role of AMH in the evaluation of infertile men, AMH as a single marker of spermatogenesis does not seem to reach a satisfactory clinical utility (35).

Recognition of the linear relationship of AMH with oocyte yield was a critical step forward (31,25). That AMH can predict ovarian response accurately (48) enables clinicians to avoid iatrogenic complications and to choose the optimal stimulation strategy.

Serum AMH is 2-4-fold higher in women with PCOS than in healthy women (49,50). This increase in serum AMH was thought to reflect the increased number of small antral follicles in which AMH production is highest. However, when production of AMH per granulosa cell was compared between normal ovaries, ovulatory and anovulatory PCOs (51), AMH production was on average 75 times higher per granulosa cell from anovulatory PCOs and 20 times higher from ovulatory PCOs than healthy ovaries. This indicates that the increase in AMH is due to an intrinsic property of granulosa cells in PCOs, a property that persists even after stimulation for IVF (52). These increased AMH concentrations are also found in the follicular fluid (53).

Given its strong involvement in the pathophysiology of PCOS, serum AMH is a subject of special interest for clinicians

involved in this field. There is considerable interest in whether it might become part of the diagnostic criteria for the condition, although this is at present premature.

8. AMH in the assessment and follow up of cancer in young females

The impact of cancer therapy on the reproductive potential of patients is increasingly recognized because survival rates of patients have clearly improved in recent years. A case-control study in which female patients who were diagnosed with hae-matological malignancies and treated with chemotherapy and/or radiotherapy were compared with age-matched controls in terms of ovarian reserve, as measured by ultrasound examination and hormonal status. By stratifying patients for gonado-toxicity of the therapy received and time elapsed from the end of the therapy, the authors reported that patients treated with low gonadotoxic therapies, while being similar to age-matched controls in their ovarian reserve when evaluated within a few years from the end of the therapy, show a clear impairment over longer times. AMH is the most sensitive hormonal parameter in detecting changes in ovarian reserve when compared with FSH of inhibin B. The study stressed the importance of accurate counselling at the time of diagnosis of cancer and emphasized the risks of infertility with low gonadotoxic therapies that may reduce the reproductive window of survivors (54).

Forty-two women received (neo-) adjuvant chemotherapy for breast cancer, continuing menses 4-5 years after diagnosis closely reflected ovarian activity as assessed by a range of serum markers, including estradiol, inhibin B, FSH, and AMH. Pretreatment serum AMH, FSH, AFC, and age predicated late ovarian activity by univariate analysis. However, only AMH was predictive in a multivariate logistic regression (odds ratio = 13.0; 95% confidence interval = 2.5-66.7); 0.71 ng/ml gave a peak likelihood ratio of 7.0 with 54% sensitivity and 92% specificity. Bone mineral density fell over 4-5 years after diagnosis with greater loss in women with lower ovarian activity. Higher pretreatment AMH was associated with lower bone mineral density at both lumbar spine and hip at 5 years (P < 0.02). In conclusion, measurement of AMH at cancer diagnosis predicts long-term ovarian function after haemother-apy. Use of this in clinical practice may allow better prediction of chemotherapy-related risk to further fertility (55).

Assessment of ovarian reserve in adult childhood cancer survivors using anti-mullerian hormone was studied in a total cohort of 185 survivors compared with 42 control subjects. The median follow-up time was 18.1 years (range 4.143.2 years). Median AMH concentrations in the analysed cohort were not different from controls. However, AMH levels were lower than the 10th percentile of normal values in 27% (49/182) of our survivors. AMH can be used to identify subgroups of childhood cancer survivors at risk for decreased fertility or premature ovarian failure. In these survivors, options for fertility preservation should be considered prior to starting treatment since they may be at risk for poor chances of pregnancy after assisted reproductive treatment (56).

The relationship between serum AMH and the number of small growing and indeed primordial follicles has made it a prime potential tool for the investigation of gonadotoxicity of cancer therapy and loss of the ovarian reserve from ovarian surgery (57).

9. Assay of AMH

There has been an evolution of AMH assays from the laboratory versions (58-60), through to the commercially available Diagnostic Systems Lab (DSL) and Immunotech Beckman Coulter (IBC) assays, and published studies have used either the DSL assay or the IBC assay. As these assays utilize two different antibodies against AMH, the values reported by different authors have varied substantially with the IBC assay giving values for AMH that are higher than with the DSL assay. Issues regarding different AMH assays have now been resolved with Beckman Coulter purchasing the patents for all previous versions and establishing the AMH Generation II assay (61).

There have been studies questioning the stability of AMH upon storage, sample handling and sample diluting, either prior to or by sequential addition to the microtitre plate, which might all affect serum AMH values (62). In contrast, stable serum AMH values were reported upon long-term storage at 2208 0C with the previous DSL assay (63).

Concerns about the robustness of the AMH Gen II assay have been fuelled by recent safety notices and technical update letters from Beckman-Coulter, indicating not only that undiluted samples may give falsely low values due to interference from complement, but also that some samples diluted prior to addition to the plate may give falsely elevated values. Therefore, results published so far with the AMH Gen II assay have to be taken with caution and will probably need to be revisited once the technical issues are resolved (57).

10. AMH in relation to race

Accumulating evidence suggests that reproductive potential and function may be different across racial and ethnic groups.

Racial differences have been demonstrated in pubertal timing, infertility, outcomes after assisted reproductive technology (ART) treatment, and reproductive ageing. Recently, racial differences have also been described in serum antimtillerian hormone (AMH), a sensitive biomarker of ovarian reserve, supporting the notion that ovarian reserve differs between racial/ethnic groups. The existence of such racial/ethnic differences in ovarian reserve, as reflected by AMH, may have important clinical implications for reproductive endocrinolo-gists. However, the mechanisms which may underlie such racial differences in ovarian reserve are unclear.

Various genetic factors and environmental factors such as obesity, smoking, and vitamin D deficiency which have been shown to correlate with serum AMH levels and also display significant racial/ethnic variations are discussed in this review. Improving our understanding of racial differences in ovarian reserve and their underlying causes may be essential for infertility treatment in minority women and lead to better reproductive planning, improved treatment outcomes, and timely interventions which may prolong the reproductive lifespan in these women (64).

11. Conclusion

There is a vast amount of recent data which suggests that the physiological role of AMH has been clarified. The changes in the levels of AMH during the life span of the female are

studied and discussed in detail. The relation between AMH assay and the prediction of ovarian response and the determination of the required dose of FSH have been evaluated. The role of AMH in the follow up of ovarian reserve after chemotherapy for young females was found to be useful. Standardization of testing ahead of the AMH level was an important step for a universal agreement on the AMH level.

It is clear that the AMH assay is becoming the most important hormonal test in infertility patients before starting treatment.

12. Conflict of interest

There is no conflict of interest to declare.

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