Anti-Müllerian hormone

The ovary is one of the major organs of the female reproductive system. Two of the key functions of the ovary are to produce sex hormones and to generate mature gametes. Both of these two functions cease during the reproductive stage known as menopause, which is characterized by the cessation of menstruation, or the regular monthly period. Menopause generally occurs in women between the ages of 45 and 50. Around ten years prior to menopause (that is, around 30 years of age), the capacity of a female to conceive children, also known as fertility, decreases. In medical clinics, a woman’s ovulatory function is often determined by measuring the levels of sex hormones that circulate in the body, as well gonadotrophins that are produced by the pituitary gland. In addition to measuring these hormones, the number of ovarian follicles may also be determined using another hormone, the anti-Mullerian hormone (AMH).

Background

The AMH, also known as Mullerian-inhibiting substance (MIS) or factor (MIF), was first characterized in the 1980s from bovine testicular tissue, mainly by extracting messenger RNA (mRNA) and producing a cDNA library out of this. By using the cDNA as a template for blotting experiments, researchers determined that AMH was produced not only in adult ovaries in females, but also in fetal testicular tissues. The AMH was then determined to work on both males and females. In males, AMH allows the development of male genitalia and the prostate gland, as well as disrupt the appearance of Mullerian ducts.

Another study on AMH in the 1980s included the isolation of the gene that encodes this particular hormone. The isolated gene was determined to be located in the short arm of chromosome 19, and encodes a protein that is 560 amino acids in length. Further studies on the AMH protein showed that it was highly similar to the human transforming growth factor-beta, which plays a major role in tissue regeneration, cell differentiation, and the maintenance of the immune system. The AMH protein is also similar to the porcine protein, inhibin, which prevents the production of ovarian follicles.

Subsequent studies on the AMH in the 1990s focused on determining the association between this particular hormone and the testicular status of pre-adolescent boys who did not have palpable gonads, also known as undescended testes. It then appeared that a low level of AMH was strongly associated with poor male reproductive development or inferior testicular integrity. AMH was then also used in determining intersex conditions, which included conditions in which an individual presented ambiguous genitalia. Low AMH levels in a chromosomally determined male (46, XY) would often show poor testicular development and low testosterone levels. On the other hand, a chromosomally determined female (46, XX) with a high AMH level develops testicular tissue. Based on the findings of these experiments, it was established that AMH levels may be utilized as an indicator of intersex states, facilitating the identification of defects in male reproductive development, which includes the establishment of testes and the secretion of testosterone.

Impact

Although the AMH was isolated and characterized in the 1980s, it’s most significant contribution to clinical study was only realized in late 2008, when the correlation between this hormone and the reproductive phase of menopause was established. One of the pioneering studies led by observed that the AMH levels of fertile women declined over age, particularly those who were approaching the menopausal stage. Another breakthrough using AMH in the clinical setting was in the evaluation of the response of women to superovulation during an in vitro fertilization (IVF) cycle. Because AMH directly reflects the number of egg cells (oocytes) that are collected during an IVF procedure, this hormone is thus considered a valuable indicator for an over-response in a particular female patient. More importantly, monitoring the AMH level of women undergoing an IVF procedure may prevent the occurrence of ovarian hyperstimulation syndrome (OHSS).

OHSS pertains to a woman’s response to injectable hormones that are administered during an IVF procedure. The injected hormones are mainly used as fertility medications that induce the ovaries to develop oocytes. The amount of fertility medications a woman requires to stimulate egg development is difficult to determine and thus an assumed low, yet effective dose is injected. When an excessive amount of fertility medications is administered to a woman, this may result in OHSS, which is characterized by swelling of the ovaries combined with abdominal pain, shortness of breath, vomiting, and sudden gain in weight. The occurrence of OHSS among women who have received fertility medications during an IVF procedure is relatively small. Based on the risk of OHSS, some women are given oral fertility treatment, which is associated with a low prevalence of this particular syndrome.

Studies have also shown that the levels of AMH are a better discriminator for a woman’s response to fertility drugs than another sex hormone, namely, follicle-stimulating hormone (FSH). Therefore, AMH is employed as a tool to determine the number of follicles that have developed (ovarian reserve) after administering fertility medications. Because the entire process of recruiting follicles after fertility treatment takes approximately two weeks, these are relatively well advanced in terms of growth. The term ovarian reserve thus more accurately pertains to the collection of non-growing (primordial) follicles produced by the ovary. Histological studies have confirmed the correlation between the level of AMH in the blood and the number of primordial follicles in a woman.

Because AMH is generated by primordial follicles, its number is directly reflected by the concentration of AMH in the blood. However, the level of AMH generally decreases during aging. AMH is therefore also used as a predictor of the remaining number of reproductive years of a female. In turn, this may also facilitate calculating the approximate age when menopause would occur. However, additional studies in establishing the relationship between age and menopause should be conducted, particularly since women reach this reproductive stage at varying ages.

Bibliography

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Clark, Christine A., Carl A. Laskin, and Kenneth Cadesky. "Anti-Mullerian Hormone: Reality Check." Human Reproduction 29.1 (2014): 184–5. Print.

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Leader, B., and V. L. Baker. "Maximizing the Clinical Utility of Antimüllerian Hormone Testing in Women’s Health." Current Opinion in Obstetrics and Gynecology 26.4: 226–36. Print.

Lindhardt Johansen, M., et al. "Anti-Müllerian Hormone and Its Clinical Use in Pediatrics with Special Emphasis on Disorders of Sex Development." International Journal of Endocrinology 2013: 198698. Print.

Monniaux, D., et al. "The Ovarian Reserve of Primordial Follicles and the Dynamic Reserve of Antral Growing Follicles: What Is the Link?" Biology of Reproduction 90.4 (2003): 85. Print.

van Disseldorp, J. L., et al. "Relationship of Serum Antimüllerian Hormone Concentration to Age at Menopause." Journal of Clinical Endocrinology and Metabolism 93.6 (2008): 2129–34. Print.