Anti-Mullerian Hormone (AMH) in Female Reproduction Part 1

Anti-Mullerian Hormone (AMH) in Female Reproduction (Part 1)
Essay Submitted by: Mohamed D. Mansy
Specialist of Obstetrics and Gynecology
Ministry of Health & Population (MOHP) Port Said
2009

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.

Introduction

At the early stages of development in mammals, fetuses of both sexes have two pairs of ducts: the Wollfian and the Müllerian ducts. In the 1940s, Alfred Jost showed that a testicular product different from the testosterone was responsible for the regression of Müllerian ducts in the male fetus.

This product was called 'hormone inhibitrice'. Twenty three years ago the human gene for anti-Müllerian hormone (AMH) was isolated and sequenced.
(Cate, et al., 1986)

There is considerable individual variation in the age of menopause and, subsequently, also in the age of subfertility. Hence, chronological age is a poor indicator of reproductive aging, and thus of the ovarian reserve.
(teVelde and Pearson 2002)

To assess an individual's ovarian reserve, early follicular phase serum levels of FSH, inhibin B and estradiol (E₂) have been measured. Inhibin B and E₂ are produced by early antral follicles in response to FSH, and contribute to the classical feedback loop of the pituitary-gonadal axis to suppress FSH secretion.

• So far, assessment of the number of antral follicles by ultrasonography, the antral follicle count (AFC), best predicts the quantitative aspect of ovarian reserve (Scheffer, et al., 2003)

• However, measurement of the AFC requires an additional transvaginal ultrasound examination during the early follicular phase.

Therefore, a serum marker that reflects the number of follicles that have made the transition from the primordial pool into the growing follicle pool, and that is not controlled by gonadotropins, would benefit both patients and clinicians. In recent years, accumulated data indicate that anti-Müllerian hormone (AMH) may fulfill this role. (Visser, et al., 2006)

AIM OF THE WORK

To review the update in Anti-Müllerian
Hormone in Female Reproduction.

Subjects and Method

This review depends on searching trusted websites as, Cochrane library, RCOG site, Green Top guideline, ACOG, Pub Med, Obgyn.net, etc. and most recent obstetrics and gynecology (national and international) books, journals and editorials.

Review of Literature

Review of Literature
AMH and Its Expression in the Ovary

AMH is a member of the transforming growth factor-beta (TGF-β) superfamily. AMH is a homodimeric disulfide-linked glycoprotein with a molecular weight of 140kDa (kilo Dalton, which is atomic mass unit). The gene is located on the short arm of chromosome 19 in humans, band 19p 13-3 (Al-Qahtani, et al., 2005)

• AMH, produced by the Sertoli cells of the fetal testis, induces the regression of the Müllerian ducts, the anlagen of the female reproductive tract (Josso, et al., 1993).
• In the absence of AMH, Müllerian ducts of both sexes develop into the uterus, the Fallopian tubes and the upper part of the vagina (Behringer, et al., 1994).

• However, after birth, this sex-dimorphic expression pattern is lost and AMH is also expressed in granulosa cells of growing follicles in the ovary.

• Expression in the ovaries has been observed as early as 36 weeks' gestation in humans.
• Expression also is highest in granulosa cells of preantral and small antral follicles, and gradually diminishes in the subsequent stages of follicle development.

• AMH is no longer expressed during the FSH-dependent final stages of follicle growth. In addition, AMH expression disappears when follicles become atretic.

Interestingly, two major regulatory steps of folliculogenesis,
1. initial follicle recruitment.
2. cyclic selection for dominance.
(McGee, and Hsueh, 2000)

• In women, AMH expression can first be observed in granulosa cells of primary follicles, and expression is strongest in preantral and small antral follicles (4mm). AMH expression disappears in follicles of increasing size and is almost lost in follicles larger than 8 mm, where only very weak staining remains, restricted to the granulosa cells of the cumulus. (Weenen, et al., 2004)

• This expression pattern suggests that, also in man, AMH may play a role in initial recruitment and in the selection of the dominant follicle (Visser, 2003).

• The results of a sturdy by Modi D, et al. (2006) in both human and monkeys strongly favor the regulatory roles of MIS in the folliculogenesis particularly in the process of follicular growth and differentiation.

• Based on the expression profiles and the results of some in vitro studies, it seems likely that the roles of MIS in ovarian functions in the rodents and primates may differ.

• AMH in the primate ovary may exert its effects in a larger temporal window initiating from the primordial follicle growth to terminal granulosa cell differentiation.

• The presence of MIS in the granulosa cells and a small subset of oocytes in the fetal ovary, point towards its additional role during fetal ovarian development that needs to be explored. (Modi, et al., 2006)

Figure (2): Expression of Mullerian inhibiting substance (MIS) mRNA in the developing human ovary.

Figure (3): Mullerian inhibiting substance (MIS) mRNA in the neonatal ovary.
(A) Newborn human ovary containing primordial follicles showing MIS expression in the granulosa cells of primordial follicles. (B) Expression of MIS in the growing follicles in a...

Figure (4): Cellular localization of Mullerian inhibiting substance (MIS) transcripts during folliculogenesis in the human ovary.

It has been demonstrated that oocytes from early preantral, late preantral and preovulatory follicles up-regulate AMH mRNA levels in granulosa cells, in a fashion that is dependent upon the developmental stage of the oocyte. (Salmon, et al., 2004)

The pattern of MIS expression during fetal life and in adulthood suggests its roles in follicular formation and the autocrine/paracrine regulation of adult folliculogenesis. (Modi, et al., 2006)

Review of Literature
Receptors for AMH

• AMH uses a heteromeric receptor system consisting of a single membrane spanning serine threonine kinase receptors called type I and type II. The type II receptor (AMHRII) imparts ligand binding specificity and the type I receptor mediates downstream signalling when activated by the type II receptor.

• The human gene for AMHRII was isolated in 1995 (Imbeaud, et al., 1995). It is located on chromosome 12 and is made up of 11 exons spread over more than 8 kbp (kilo Base pair).
• The AMHRII messenger is expressed by AMH target organs, namely the Müllerian ducts, and the gonads.

• Loss of function mutations in the type II receptor as well as the AMH ligand itself are causes of persistent Müllerian duct syndrome in humans. (Imbeaud, et al., 1994).

Review of Literature
The Role of AMH in Ovarian Physiology

• The activation of primordial follicles and the pace of follicular development are regulated by both positive and negative factors. AMH is considered as a negative regulator of the early stages of follicular development.

Figure (7): Role of AMH in human folliculogenesis.
Progressing stages of folliculogenesis are depicted. AMH is produced by the small growing (primary and preantral) follicles in the postnatal ovary and has two sites of action. It inhibits initial follicle recruitment (1) and inhibits FSH-dependent growth and selection of preantral and small antral follicles (2).

• Studies suggests that, the presence of AMH acts as a brake on the activation of primordial follicles and the growth of preantral follicles. Both in vitro and in vivo studies have shown that follicles are more sensitive to FSH in the absence of AMH.

• The presence of AMH in the granulosa cells and a small subset of oocytes in the fetal ovary, point towards its additional role during fetal ovarian development. (Modi, et al., 2006)

Review of Literature
Clinical Utility of AMH Measurement

• AMH levels in women are lower than in men throughout life. In women, AMH serum levels can be almost undetectable at birth. (Rajpert-De Meyts, et al., 1999)

• Evaluating Fertility Potential - Serum AMH levels correlate with the number of early antral follicles with greater specificity than Inhibin B, Oestradiol, Follicle Stimulating Hormone and Luteinizing Hormone on cycle day 3. Thus, serum AMH may reflect ovarian follicular status better than these hormone markers.
Measuring Ovarian Aging - Diminished ovarian reserve, associated with poor response to IVF, is signaled by reduced baseline serum AMH concentrations. AMH would appear to be a useful marker for predicting ovarian aging and the potential for successful IVF.

• Predicting Onset of Menopause - The duration of the menopausal transition can vary significantly in individuals and reproductive capacity may be seriously compromised prior to clinical diagnosis. AMH can predict the occurrence of the menopausal transition.
Assessing Polycystic Ovary Syndrome - Serum AMH levels are elevated in patients with polycystic ovary syndrome and may be useful as a marker for the extent of the disease.

Review of Literature
AMH as a Marker of Ovarian Reserve in Aging Women

It is well known that with increasing age there is a decline in female reproductive function due to the reduction in the ovarian follicle pool and the quality of the oocytes.

• Many studies suggest AMH as a novel measure of ovarian reserve. Serum AMH levels show a reduction throughout reproductive life.
• Undetectable AMH levels after spontaneous menopause have been reported (LaMarca, et al., 2005a).

• Ovariectomy in regularly cycling women is associated with disappearance of AMH in 3-5 days, demonstrating that circulating AMH is exclusively of ovarian origin. (Long, et al., 2000 & LaMarca, et al., 2005a).

• Eighty one, women were prospectively studied for 4 years (mean age 39-6 and 43-6 at the beginning and at the end of the study, respectively). It was found that AFC did not change over time whereas AMH, FSH and inhibin B changed significantly. (Scheffer, et al., 1999).

• The quantitative aspect of ovarian aging is reflected by a decline in the size of the primordial follicle pool. Direct measurement of the primordial follicle pool is impossible. However, the number of primordial follicles is indirectly reflected by the number of growing follicles. (Scheffer, et al., 1999)

• Hence, a factor primarily secreted by growing follicles will reflect the size of the primordial follicle pool. Since AMH is expressed by growing follicles up to selection (Durlinger, et al., 2002a), and can be detected in serum (Lee, et al., 1996), it is a promising candidate.

• In young normal ovulatory women, early follicular phase hormone measurements at 3-year intervals revealed that serum AMH levels decline significantly whereas serum levels of FSH and inhibin B and the number of antral follicles do not change during this interval. (deVet, et al., 2002)

• Changes in serum AMH levels occur relatively early in the sequence of events associated with ovarian aging. Substantially elevated serum levels of FSH are not found until cycles have already become irregular. (Burger et al., 1999)

• Furthermore, compared to other ovarian reserve markers, only serum AMH level showed a mean longitudinal decline over time. Taken together, these data strongly suggest that serum levels of AMH can be used as a marker of ovarian aging.

• The usefulness of serum AMH levels as a measure of the ovarian reserve was recently shown in young women after treatment for childhood cancer.

• With respect to other known markers, AMH seems to better reflect the continuous decline of the oocyte/follicle pool with age (VanRooij, et al., 2004).

• However, AMH was the only marker of ovarian reserve showing a mean longitudinal decline over time both in younger women (< 35 years) and in women over 40 years.

• The decrease in AMH with advancing age may be present before changes in currently known ageing-related variables, indicating that serum AMH levels may be the best marker for ovarian ageing and menopausal transition (Hale and Burger, 2008).

Thank you