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Essay Submitted by Mohamed D. Mansy Specialist of Obstetrics and Gynecology Ministry of Health Population MOHP Port S

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Essay Submitted by Mohamed D. Mansy Specialist of Obstetrics and Gynecology Ministry of Health Population MOHP Port S

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    1. 08 ????? ??????? 11 dr_mansy@hotmail.com 1 Essay Submitted by Mohamed D. Mansy Specialist of Obstetrics and Gynecology Ministry of Health & Population (MOHP) Port Said 2009

    2. 08 ????? ??????? 11 dr_mansy@hotmail.com 2 Under supervision of Prof. Dr: Mahmoud Farouk Midan Professor and Head of Obstetrics and Gynecology Department Faculty of medicine, Al-Azhar university, Damietta. Dr.: Khattab Abd Elhalem Omar Khattab Assist. Professor of Obstetrics and Gynecology Faculty of medicine, Al-Azhar university, Damietta. Dr. Rashed Mohamed Rashed lecturer in Obstetrics and Gynecology Faculty of medicine, Al-Azhar university, Damietta.

    3. 08 ????? ??????? 11 dr_mansy@hotmail.com 3

    4. 08 ????? ??????? 11 dr_mansy@hotmail.com 4 In women undergoing treatment for infertility, ovarian aging is characterized by decreased ovarian responsiveness to exogenous gonadotropin administration and poor pregnancy outcome.

    5. 08 ????? ??????? 11 dr_mansy@hotmail.com 5 On the one hand, correct identification of poor responders by assessment of their ovarian reserve before entering an in vitro fertilization (IVF) program is important.

    6. 08 ????? ??????? 11 dr_mansy@hotmail.com 6 On the other hand, assessment of the ovarian reserve may also benefit patients that would generally be excluded from IVF programs because of advanced age.

    7. 08 ????? ??????? 11 dr_mansy@hotmail.com 7 Several studies have shown that AMH is an excellent marker to determine ovarian responsiveness also in an IVF program.

    8. 08 ????? ??????? 11 dr_mansy@hotmail.com 8 Hormone measurements in the early follicular phase (day 3 of spontaneous cycle), retrospectively or in a group of unselected patients, revealed that AMH levels are lower in patients with poor ovarian response than in women with normal response. )Seifer, et al., 2002 and vanRooij et al., 2002)

    9. 08 ????? ??????? 11 dr_mansy@hotmail.com 9 ovarian responsiveness being defined as the number of oocytes retrieved, or as cancellation due to impaired or absent follicular growth.

    10. 08 ????? ??????? 11 dr_mansy@hotmail.com 10 AMH serum levels were shown to be highly correlated with the number of antral follicles before treatment and number of oocytes retrieved upon ovarian stimulation (vanRooij, et al., 2002).

    11. 08 ????? ??????? 11 dr_mansy@hotmail.com 11 serum AMH levels had a better predictive value than serum levels of FSH, inhibin B and E2, and that the predictive values for AMH and AFC were almost identical (ROCAUC 0.85 vs 0.86)

    12. 08 ????? ??????? 11 dr_mansy@hotmail.com 12 To achieve a reliable predictive outcome, one single hormone measurement for AMH seems sufficient (Fanchin, et al., 2005a). The absence of regulation of AMH by gonadotropins was shown in both rodents and man. AMH acts as a paracrine rather than a systemic factor.

    13. 08 ????? ??????? 11 dr_mansy@hotmail.com 13 Treatment of IVF patients with a single, high dose of gonadotropin-releasing hormone (GnRH) agonist, resulting in a rise of endogenous FSH and LH, does not affect AMH serum levels (vanRooij, et al., 2002).

    14. 08 ????? ??????? 11 dr_mansy@hotmail.com 14 Similarly, in conditions where FSH levels are suppressed, such as pregnancy, AMH levels remain constant (LaMarca, et al., 2005a) Thus, AMH is not influenced by the gonadotropic status and reflects only the follicle population.

    15. 08 ????? ??????? 11 dr_mansy@hotmail.com 15 However, from a clinical point of view, poor responders should be identified before treatment; therefore, it is more useful to determine serum AMH levels during a spontaneous cycle.

    16. 08 ????? ??????? 11 dr_mansy@hotmail.com 16 Throughout the controlled ovarian hyperstimulation protocol, serum AMH levels correlated well with the decrease in number of small antral follicles (12 mm) (Fanchin, et al., 2003a) reflecting the complete conversion of small antral follicles into large antral follicles in response to FSH stimulation.

    17. 08 ????? ??????? 11 dr_mansy@hotmail.com 17 Indeed, no correlation with the number of growing follicles (> 12 mm) was observed, in line with the low expression of AMH in these follicles (Weenen, et al., 2004).

    18. 08 ????? ??????? 11 dr_mansy@hotmail.com 18 In the days following hCG treatment, AMH serum levels initially declined, possibly as a result of the luteinization of granulosa cells upon hCG treatment that also causes a decline in E2 levels.

    19. 08 ????? ??????? 11 dr_mansy@hotmail.com 19 During the midluteal phase, AMH serum levels slightly increased, probably as a result of the presence of newly developed, small antral follicles (Fanchin, et al., 2005b).

    20. 08 ????? ??????? 11 dr_mansy@hotmail.com 20 All combined these studies strongly support a role of serum AMH level as a marker for ovarian responsiveness. However, the application of AMH to predict ongoing pregnancy seems limited, although day 3 serum AMH levels are higher in patients that become pregnant after IVF treatment than in those who do not. (Hazout, et al., 2004).

    21. 08 ????? ??????? 11 dr_mansy@hotmail.com 21 Therefore, it is likely that the quantitative aspect of AMH as a marker of the ovarian reserve has contributed predominantly to the association with pregnancy outcome.

    22. 08 ????? ??????? 11 dr_mansy@hotmail.com 22 Indeed, other studies did not observe a predictive value of AMH serum levels for ongoing pregnancy after IVF treatment (Penarrubia, et al., 2005). Moreover, the decrease in AMH in FSH-treated women might be the result of a growth stimulation by FSH of the follicles that enlarge, thereby losing their AMH expression.

    23. 08 ????? ??????? 11 dr_mansy@hotmail.com 23 Small follicles (8-12 mm in diameter) secreted AMH at levels that were approximately three times as high as those of large follicles (16-20 mm in diameter) (Fanchin, et al., 2005c). Serum AMH levels correlated strongly with the AFC, the number of follicles retrieved, age, inhibin B and FSH.

    24. 08 ????? ??????? 11 dr_mansy@hotmail.com 24 AMH assessment was shown to predict ovarian reserve with a sensitivity of 80% and a specificity of 85% (Tremellen, et al., 2005). AMH levels have also been shown to be 10-fold lower in the cancelled cycles compared with patients who had a completed IVF cycle. In about 75% of cancelled cycles, AMH levels were below the detection limit (Muttukrishna, et al., 2004).

    25. 08 ????? ??????? 11 dr_mansy@hotmail.com 25 For the first time, clinicians may have a reliable serum marker of ovarian response that can be measured independently of the day of the menstrual cycle (LaMarca, et al., 2007).

    26. 08 ????? ??????? 11 dr_mansy@hotmail.com 26 Recently, Raziehi, et al., (2008) concluded that, it appears that AMH serum levels are associated with ovarian response in ART cycles and can be served as a novel marker for ovarian reserve. Riggs, et al., (2008) cocluded that Anti-Müllerian hormone correlates better than age, follicle-stimulating hormone, luteinizing hormone, inhibin B, and E2 with the number of retrieved oocytes.

    27. 08 ????? ??????? 11 dr_mansy@hotmail.com 27 AMH is a predictor of ovarian response and suitable for screening. Levels =1.26 ng/ml are highly predictive of reduced ovarian reserve and should be confirmed by a second line antral follicle count. Measurement of AMH supports clinical decisions, but alone it is not a suitable predictor of IVF success (Gnoth, et al., 2008).

    28. 08 ????? ??????? 11 dr_mansy@hotmail.com 28 The AFC and AMH are the most significant predictors of poor response to ovarian stimulation during ART. The AMH and AFC, either alone or in combination, demonstrate a similar predictive power but are not predictive of nonconception, which is dependent on the woman's age (Jayaprakasan , et al., 2008).

    29. 08 ????? ??????? 11 dr_mansy@hotmail.com 29 The AMH and inhibin B levels on the day of oocyte retrieval are correlated to reproductive outcome (Wunder, et al., 2008).

    30. 08 ????? ??????? 11 dr_mansy@hotmail.com 30

    31. 08 ????? ??????? 11 dr_mansy@hotmail.com 31 In the human, follicle development to the antral stage continues throughout life until depletion of follicles at the menopause, even in the presence of conditions under which endogenous gonadotrophin release is substantially diminished. (Richardson and Nelson, 1990)

    32. 08 ????? ??????? 11 dr_mansy@hotmail.com 32 AMH serum levels have been measured in women affected by hypergonadotrophic amenorrhoea (premature ovarian failure, POF) or by hypogonadotrophic amenorrhoea (functional hypothalamic amenorrhoea). AMH serum levels have been found to be normal in women with hypogonadotrophic amenorrhoea and to be undetectable in 83% of women with hypergonadotrophic amenorrhoea (POF). The remaining 17% of patients had very low AMH serum levels.

    33. 08 ????? ??????? 11 dr_mansy@hotmail.com 33 AMH measurement could provide information on ovarian reserve when women with secondary amenorrhoea are investigated and initial follicle recruitment is not abolished in hypogonadotrophic hypogonadism. (LaMarca, et al., 2006)

    34. 08 ????? ??????? 11 dr_mansy@hotmail.com 34 Premature ovarian failure (POF) is generally irreversible. However, developing follicles up to the antral stage are reported in POF and anti-Müllerian hormone (AMH) might be a good indicator of follicular presence.

    35. 08 ????? ??????? 11 dr_mansy@hotmail.com 35 The dysfunction of AMH production in the antral follicles of POF women observed in their series of ovarian biopsies suggests the possibility of the presence of a defect in antral follicular development, particularly concerning the granulosa cells.

    36. 08 ????? ??????? 11 dr_mansy@hotmail.com 36 A decreased antral granulosa cell AMH production could alter the mechanism of follicular recruitment in these patients. AMH could be useful in discriminating POF patients with a sizable follicular population from patients with no or few ovarian follicles, with a lesser potential for ovulation and pregnancy (Méduri, et al., 2007)

    37. 08 ????? ??????? 11 dr_mansy@hotmail.com 37 PCOS is one of the most common endocrine disorders in women of reproductive age (Franks, 1995) It is characterized by anovulation manifested as oligo- or amenorrhea, elevated levels of circulating androgens, and polycystic ovaries as visualized by ultrasound. The diagnosis is based on the presence of at least two of the described characteristics, as defined by the Rotterdam Consensus (2004)

    38. 08 ????? ??????? 11 dr_mansy@hotmail.com 38 AMH production is reported to increase in women with polycystic ovary syndrome (PCOS) compared to controls (Fallat, et al., 1997, Cook, et al., 2002 and Laven, et al., 2004) This may be the result of aberrant activities of the granulosa cells in the polycystic ovaries (Mulders, et al., 2004) AMH measurement can offer a high specificity and sensitivity (92% and 67%, respectively) as a marker for PCOS.

    39. 08 ????? ??????? 11 dr_mansy@hotmail.com 39 On this basis it has been proposed that in situations where accurate ultrasonography data are not available, AMH could be used instead of the follicle count as a diagnostic criterion for PCOS. (Pigny, et al., 2006)

    40. 08 ????? ??????? 11 dr_mansy@hotmail.com 40 AMH levels in amenorrhoeic is higher than in oligomenorrhoeic women with PCOS, which could indicate a role for AMH in the pathogenesis of PCOS-related anovulation. Alternatively, high AMH values could reflect a more evident impairment in follicular development and granulosa cell function in the ovaries of amenorrhoeic than oligomenorrhoeic PCOS women. (LaMarca, et al., 2004b)

    41. 08 ????? ??????? 11 dr_mansy@hotmail.com 41 Anovulation in PCOS could be the result of excessive pituitary LH secretion and inhibin production by multiple, small follicles that inhibit FSH secretory dynamics. Increased ovarian AMH production may exert a paracrine negative control on follicle growth, sufficient to prevent selection of a dominant follicle.

    42. 08 ????? ??????? 11 dr_mansy@hotmail.com 42 Pellatt, et al. (2007) concluded The reduction of AMH in follicles greater than 9mm from normal ovaries appears to be an important requirement for the selection of the dominant follicle. AMH production per GC was 75 times higher in anovPCOs, compared with normal ovaries. This increase in AMH may contribute to failure of follicle growth and ovulation seen in polycystic ovary syndrome.

    43. 08 ????? ??????? 11 dr_mansy@hotmail.com 43 It is important to bear in mind that these raised levels could be misleading if used as a marker of ovarian reserve. The overproduction of AMH could have important implications for the mechanism of anovulation in these women.

    44. 08 ????? ??????? 11 dr_mansy@hotmail.com 44 The reduction in serum level of AMH in PCOS patients was lower than in the controls. The authors concluded that this may indicate a sustained reproductive lifespan in these patients. (Cook, et al., 2002)

    45. 08 ????? ??????? 11 dr_mansy@hotmail.com 45 On histological examination, polycystic ovaries exhibit the same number of primordial follicles, whereas the number of developing follicles is doubled compared with normal ovaries (Webber, et al., 2003) Hence, it may be proposed that the process of ovarian ageing is delayed in women with PCOS as high AMH levels may inhibit the primordial follicle pool depletion. (Cook, et al., 2002 )

    46. 08 ????? ??????? 11 dr_mansy@hotmail.com 46 Serum AMH level can be used as a marker for the number of growing follicles. Besides being a marker for a diminishing follicle pool, serum AMH level can also serve as a marker in ovarian pathophysiology, in which the antral follicle pool is enlarged.

    47. 08 ????? ??????? 11 dr_mansy@hotmail.com 47 In a study by Eldar-Geva, et al,. (2005), categorization of PCOS women by presence or absence of hyperandrogenism showed that AMH levels were significantly different between groups. Both groups had increased AMH levels compared to control women, but levels in women with PCO and hyperandrogenism were even further elevated. These results suggest that the nonvisible pool of follicles may be further increased in the presence of increased androgen levels.

    48. 08 ????? ??????? 11 dr_mansy@hotmail.com 48 The increased insulin levels in some PCOS women can, in part, account for the hyperandrogenism, because insulin acts synergistically with LH to enhance androgen production by theca cells. However, serum AMH levels do not seem to correlate with BMI and insulin levels (Fleming, et al., 2005).

    49. 08 ????? ??????? 11 dr_mansy@hotmail.com 49 In contrast, in a small study, LaMarca, et al., (2004b) observed a positive correlation between serum AMH levels and the Homeostatic model assessment (HOMA) index .

    50. 08 ????? ??????? 11 dr_mansy@hotmail.com 50 In a study of obese PCOS women, metformin treatment suppressed androstenedione levels and ovulation rate although androgen levels were still above the upper limit of the normal range. Metformin administration also resulted in a small but significant reduction of serum AMH levels after 8 months of treatment, whereas the follicle number did not change significantly. (Fleming, et al., 2005)

    51. 08 ????? ??????? 11 dr_mansy@hotmail.com 51 In a smaller study, metformin treatment for 6 months also decreased serum AMH levels only slightly, and levels remained strongly elevated compared to controls. (Piltonen, et al., 2005)

    52. 08 ????? ??????? 11 dr_mansy@hotmail.com 52 Future challenges comprise the availability of a well standardized assay and the development of AMH agonists and antagonists as possible tools to manipulate ovarian function for contraception or ovarian longevity. (Broekmans, et al., 2008)

    53. 08 ????? ??????? 11 dr_mansy@hotmail.com 53

    54. 08 ????? ??????? 11 dr_mansy@hotmail.com 54 AMH expression is limited to ovarian granulosa cells, hence it has been proposed to use AMH as a marker of granulosa cell tumours (GCTs). It has been shown that AMH serum levels are increased in women affected by GCTs. (Rey, et al., 2000)

    55. 08 ????? ??????? 11 dr_mansy@hotmail.com 55 The mean AMH level was 190.3 ng/ml (range 2-1124 ng/ml) in patients with GCTs in one study. (Lane, et al., 1999) In patients in whom serial measurements were made following initial tumour resection, the length of time that an elevation in AMH levels preceded clinical detection of a recurrence was 16 months. (Long, et al., 2000)

    56. 08 ????? ??????? 11 dr_mansy@hotmail.com 56 AMH seems to be superior to alpha-inhibin and oestradiol in the follow-up of GCT. It is largely recognized that AMH and alpha-inhibin exhibit a higher degree of sensitivity than oestradiol in progressive GCT. Indeed, oestradiol production by GCT is widely variable (Lappohn, et al., 1989)

    57. 08 ????? ??????? 11 dr_mansy@hotmail.com 57 In the follow-up, AMH seems to be a marker of comparable value to alpha-inhibin. However, AMH is elevated only in GCT, while inhibin may be elevated in different types of cancer (Healy, et al., 1993)

    58. 08 ????? ??????? 11 dr_mansy@hotmail.com 58 Based on the published studies it is possible to elaborate the following recommendations for the use of AMH as a marker of GCT: High serum AMH levels are found in 76–93% of patients with GCT. Serum AMH levels should normalize within few days following surgery. Persistent AMH levels are indicative of residual disease. When bilateral ovariectomy is performed AMH must be undetectable in serum. Even very low levels may be suggestive of residual disease. A post-operative rise in serum AMH levels may precede the clinical recurrence. Hence, the clinical examination and imaging should be anticipated. AMH levels should be obtained every 6 months for at least 5 years after the surgery. However, it should not be ignored that a late recurrence (up to 30 years after initial treatment) has been reported in up to 33% of patients (Stenwig, et al., 1979). Recurrences in juvenile GCTs occur within a year of initial diagnosis at a mean of 5–6 months. Hence, in juvenile GCT, AMH serum levels should be determined every month following the surgery.

    59. 08 ????? ??????? 11 dr_mansy@hotmail.com 59 Several authors have also hypothesized a role for recombinant AMH in the treatment of epithelial ovarian cancer Based on the physiological inhibiting role of AMH on the mullerian ducts, researchers have demonstrated that AMH inhibits epithelial ovarian cancer cell in vitro. (Stephen, et al., 2001, 2002)

    60. 08 ????? ??????? 11 dr_mansy@hotmail.com 60 The administration of recombinant AMH in immunosuppressed mice with human epithelial ovarian cancer implants has been followed by reduced dimensions of the graft (Stephen et al., 2002). This of course will be the basis for future research aiming to investigate the possible clinical role of AMH as neo-adjuvant or most probably adjuvant therapy for ovarian cancer (LaMarca and Volpe, 2007)

    61. 08 ????? ??????? 11 dr_mansy@hotmail.com 61 Table (4): Modifications in Markers of Ovarian Function (Oestradiol, Inhibin B and AMH) During a Woman's Life and in Some Pathological Conditions.

    62. 08 ????? ??????? 11 dr_mansy@hotmail.com 62

    63. 08 ????? ??????? 11 dr_mansy@hotmail.com 63 Summary: Anti-Müllerian hormone (AMH) is a dimeric glycoprotein, a member of the transforming growth factor (TGF) superfamily. It is produced exclusively in the gonads, and is involved in the regulation of follicular growth and development. In the ovary AMH is produced by the granulosa cells of early developing follicles and seems to be able to inhibit the initiation of primordial follicle growth and FSH-induced follicle growth. A clearer understanding of its role in ovarian physiology may help clinicians to find a role for AMH measurement in the field of reproductive medicine.

    64. 08 ????? ??????? 11 dr_mansy@hotmail.com 64 As AMH is largely expressed throughout folliculogenesis, from the primary follicular stage towards the antral stage, serum levels of AMH may represent both the quantity and quality of the ovarian follicle pool. Compared to other ovarian tests, AMH seems to be the best marker reflecting the decline of reproductive age. AMH measurement could be useful in the prediction of the menopausal transition. It could also be used to predict poor ovarian response and possibly the prognosis of in vitro fertilization (IVF) cycles.

    65. 08 ????? ??????? 11 dr_mansy@hotmail.com 65 AMH has been shown to be a good surrogate marker for polycystic ovary syndrome (PCOS). Also, its use as a marker for granulosa cell tumours has been proposed. The administration of recombinant AMH in immunosuppressed mice with human epithelial ovarian cancer implants has been followed by reduced dimensions of the graft. This of course will be the basis for future research aiming to investigate the possible clinical role of AMH as neo-adjuvant or most probably adjuvant therapy for ovarian cancer.

    66. 08 ????? ??????? 11 dr_mansy@hotmail.com 66 Conclusions: AMH is a very sensitive indicator of ovarian ageing and for ovarian response to controlled ovarian stimulation. Compared with the other ovarian tests, AMH seems to be the best marker for reflecting the oocyte/follicle pool. Also, serum levels of AMH are a good candidate for inclusion in standard diagnostic procedures to assess ovarian dysfunctions, such as premature ovarian failure.

    67. 08 ????? ??????? 11 dr_mansy@hotmail.com 67 AMH can be measured at any time during the cycle, which is a great advantage in clinical practice. However, complementary studies in various clinical situations are necessary to attest the superiority of this compared to the other markers.

    68. 08 ????? ??????? 11 dr_mansy@hotmail.com 68 There seems to be little doubt that research on AMH will continue in the years to come. A clearer understanding of its role in ovarian physiology may help clinicians to find a role for AMH measurement in the field of reproductive medicine.

    69. 08 ????? ??????? 11 dr_mansy@hotmail.com 69

    70. 08 ????? ??????? 11 dr_mansy@hotmail.com 70 In order to determine whether serum AMH level has prognostic value, additional prospective studies in a normal population are necessary to provide definite proof for this concept.

    71. 08 ????? ??????? 11 dr_mansy@hotmail.com 71 The positive correlation between serum AMH levels and number of antral follicles is also observed in women with PCOS. The elevated levels of AMH in these women strongly suggest that serum AMH levels may also be used in the diagnosis of PCOS.

    72. 08 ????? ??????? 11 dr_mansy@hotmail.com 72 The difference in serum levels of AMH between subgroups of PCOS women suggests that AMH might also be used to establish a subclassification of this heterogeneous syndrome. However, more studies, preferably prospective, with thoroughly analyzed patient cohorts are necessary to define cutoff values. In addition, studies are necessary to determine whether serum AMH levels are also indicative of improved ovarian function upon treatment of PCOS women.

    73. 08 ????? ??????? 11 dr_mansy@hotmail.com 73 Genetic studies of well-defined population cohorts would also provide more knowledge about the role of AMH in ovarian physiology.

    74. 08 ????? ??????? 11 dr_mansy@hotmail.com 74

    75. 08 ????? ??????? 11 dr_mansy@hotmail.com 75

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