AMH: Marker of Ovarian Reserve and More
September 1, 2014
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SPECIAL FEATURE
AMH: Marker of Ovarian Reserve and More
By Michael A. Thomas, MD
Professor, Reproductive Endocrinology and Infertility, Director, Division of Reproductive Endocrinology and Infertility, University of Cincinnati College of Medicine
Dr. Thomas reports no financial relationships relevant to this field of study.
Serum anti-Mullerian hormone (AMH) has been well-established as an accurate marker of ovarian reserve. It is solely produced in the human ovary by the granulosa cells.1 The expression of AMH starts in the primary follicles as soon as recruitment is initiated from the primordial follicle pool. The expression is strongest during the early antral stage of follicle growth, but stops when the recruited follicle reaches a diameter between 8-10 mm. AMH shows little variation during the menstrual cycle, is unaffected by hormonal contraceptives, and reflects the number of early developing follicles in the ovary. Thus, AMH serves as a proxy for the size of the primordial follicle pool. Most fertility centers use an AMH level of >1 ng/mL as an acceptable value for a normal ovarian reserve. In addition, investigators have confirmed a strong correlation between the measurement of AMH and antral follicle count performed by ultrasound.2,3
To confirm the potential correlation of AMH with age, researchers from The Netherlands performed a longitudital study that followed 804 girls or women from infancy to the end of reproductive life.4 All subjects had stored serum from previous studies. None of the eumenorrheic females were pregnant or on any hormonal agents. During the study, it was noted that AMH inversely correlated with age (r = -0.24; P < 0.001). Maximum AMH levels occurred at age 15.8 years, then remained stable until 25.0 years. The inverse relationship with AMH started after 25 years of age, which implies that AMH is only useful as a predictor of ovarian reserve after the age of 25.
To date, serum AMH primarily has been used as a marker of diminished ovarian reserve, which is a predictor of poor ovarian response to controlled ovarian hyperstimuation during ovulation induction for timed intercourse, intrauterine insemination, or in vitro fertilization (IVF). AMH is thought to be a better marker than age, serum follicle-stimulating hormone (FSH), or serum inhibin B.5,6 This indirect knowledge of the remaining ovarian primordial follicle reserve helps physicians select an ovarian stimulation protocol that would be most helpful to obtain oocytes for freezing or fertilization. However, more recent studies have utilized AMH to help in the diagnosis of polycystic ovary syndrome (PCOS), predict which patients are at higher risk of ovarian hyperstimulation syndrome (OHSS) when undergoing IVF, and determine potential ovarian function after the use of chemotherapy agents in cancer patients.
PREDICTOR OF PCOS
The majority of clinicians use the Rotterdam criteria to aid in making the diagnosis of PCOS.7 This diagnostic classification states that a patient can be diagnosed with PCOS if she has two of the following three signs: hyperandrogenism (HA), oligomenorrhea/anovulation, and/or polycystic-appearing ovaries on ultrasound (> 12 antral follicles). However, this "easy-to-use" method in defining PCOS has not been readily accepted by some researchers, even a few who were part of the Rotterdam "consensus." These anti-Rotterdam folks strongly feel that hyperandrogenism MUST be part of a diagnosis of PCOS or else it is something else.8 No clear agreement has been established as to whether HA is required at this point, but two studies have argued that serum AMH > 5 ng/mL should replace ultrasound to define ovarian morphology.9,10
In the first paper, a French group retrospectively documented 240 women who were referred to their center to evaluate hyperandrogenic symptoms.9 They were divided into three separate groups: non-PCOS without HA and ovulatory cycles (Group 1), PCOS diagnosis with either HA or oligo-anovulation (Group 2), and PCOS with both HA and oligo-anovulation (Group 3). Analysis of ultrasound in each group demonstrated that patients with PCOS were more likely to have an AMH > 5 ng/mL than > 12 antral follicles. From these patients, the investigators concluded that serum AMH was more sensitive than follicle count to diagnose PCOS and that AMH should replace ultrasound morphology as part of the diagnostic classification.
The second paper observed 56 women who met Rotterdam criteria and 44 who met criteria set forth by the Androgen Excess-PCOS Society (which includes HA in all subjects).10 They concluded that AMH (> 3 ng/mL) was a better determinant of PCOS ovarian morphology than follicle number. However, they felt that AMH could not be used alone to make this diagnosis, but in conjunction with HA and oligo-anovulation.
Overall, these studies both highlight that the use of ultrasound to count follicles and determine morphology may be very subjective. Serum AMH >5 ng/mL, a biochemical measure, appears to be a better and more consistent substitute.
PREDICTOR OF OHSS
OHSS is one of the most serious complications of controlled ovarian hyperstimulation with exogenous gonadotropins. This condition can develop during ovulation induction for timed intercourse, intrauterine insemination, or IVF. It is subcategorized as mild, moderate, or severe with symptoms that range from mild post-hCG bloating to pulmonary compromise from ascites or pleural effusions that may require hospitalization or, at worse, result in death. Risk factors for OHSS include younger age (< 35 years), lean habitus, signs of PCOS, the presence of multiple (total > 35) small or intermediate follicles, and excessively high levels of estradiol on the day of hCG administration (> 4000 pg/mL).11 Despite these known risk factors, 100% prediction of OHSS is difficult. Because patients have developed OHSS with an older age, high body mass index (BMI), and low estradiol levels, other ways to predict OHSS are needed.
Chinese investigators measured serum AMH levels prospectively in 262 IVF cycles.12 The incidence of OHSS in this group of subjects was 7.7%, which correlates with previously published rate of 8%. They used a receiver operating characteristic (ROC) curve analysis to estimate the cutoff values of the measured variables that increased the risk of OHSS (AMH, estradiol, BMI, age, number of follicles measured, and number of follicles retrieved). Pre-cycle AMH levels > 3.36 ng/mL best correlated with risk of OHSS. The second variable that weakly correlated with AMH to increase OHSS risk was when the estradiol concentration was > 1613 pg/mL.
Fertility specialists who observe patients undergoing an IVF cycle who have AMH levels > 3.3 ng/mL, despite estradiol levels that are < 4000 pg/ml, still need to consider OHSS as a consequence and, therefore, give appropriate precautions to the patient.
PREDICTOR OF POST-CHEMOTHERAPY OVARIAN RESERVE
Cancer therapies, particularly use of chemotherapy agents, have an adverse effect on short- and long-term reproductive function by increasing the risk of early menopause and infertility. However, continuous improvement of survival rates and potential resurgence of ovarian function after treatment presents the clinician and patient with important quality-of-life issues. Chemotherapy regimens, particularly those that include alkylating agents, are toxic to ovarian germ cells by damaging follicles whether they are primordial, preantral, or antral. Factors that cause this damage include apoptotic processes, cortical fibroisis, and blood vessel compromise.13,14
Two prospective studies have determined that AMH should be obtained before chemotherapy treatment and then after these ovarian-toxic agents are completed to determine future reproductive potential.15,16
Anderson and colleagues found that all 33 patients undergoing chemotherapy for early stage breast cancer were noted to have a decrease in AMH (1.29 ng/mL vs 0.09 ng/mL), inhibin B (58.2 pg/mL vs 22.9 pg/mL), and estradiol (297 pg/mL vs 101 pg/mL) with an increase in FSH (10.4 mIU/mL vs 25.5 mIU/mL) 5 years after initial treatment.15 Over this time frame, these same patients were compared to 14 patients who did not take chemotherapy and were found to have a significant difference when observing all measures of ovarian reserve. When dividing the chemotherapy-using patients who had return of menses to those who developed amenorrhea after 5 years, those with normal menses had a higher AMH concentration (0.16 ng/mL vs 0.06 ng/mL) compared to those who were amenorrheic.
In the second study, 46 adolescent and young adult women were given alkylating chemotherapy for several cancers.16 When comparing AMH levels 12 months after treatment, patients who had pretreatment AMH levels > 2 ng/mL were noted to have progressively increasing levels with a recovery rate of 11.9% per month. However, if pretreatment AMH levels were < 2 ng/mL, the recovery rate for AMH was only 2.6% per month.
Both of these papers demonstrate pretreatment AMH levels, particularly if > 2 ng/mL, help predict the potential for return of ovarian function after the use of chemotherapeutic alkylating agents.
CONCLUSION
Although AMH is used most often in the clinical setting to judge the fertility reserve of an older reproductive woman, it may have value outside this arena. AMH allows both patients and clinicians to help predict the extent of primordial follicles remaining in the ovaries for many reasons. If there are too many follicles, patients may have a diagnosis of PCOS or may be at risk for OHSS. If there are too few, patients may have issues with their future fertility because of age or because of exogenous agents that directly destroy germ cells. Future applications for AMH may include a role in predicting when to safely stop oral contraceptives in the perimenopausal woman or whether ovarian shielding during radiation for cancer treatment truly has a protective effect.
REFERENCES
- Weenen C, et al. Anti-Mullerian hormone expression pattern in the human ovary: Potential implications for initial and cyclic recruitment. Mol Hum Reprod 2004;10:77-83.
- van Rooij IA, et al. Serum anti-Mullerian hormone levels: A novel measure of ovarian reserve. Hum Reprod 2002;17:3965-3971.
- Pigny P, et al. Serum anti-Mullerian hormone as a surrogate marker for antral follicle count for definition of the polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:941-945.
- Lie Fong S, et al. Serum anti-Mullerian hormone levels in healthy females: a nomogram ranging from infancy to adulthood. J Clin Endolcrinol Metab 2012;97:4650-4655.
- Fanchin R, et al. Serum anti-Mullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 2003;18:323-327.
- van Rooij IA, et al. Serum anti-Mullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: A longitudinal study. Fertil Steril 2005; 83:979-987.
- Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41-47.
- Azziz R, et al. Positions statement: Criteria for defining polycystic ovary syndrome as a predominately hyperandrogenic syndrome: An Androgen Excess Society guideline. J Clin Endocrinol Metab 2006;91:4237-4245.
- Dewailly D, et al. Diagnosis of polycystic ovary syndrome (PCOS): Revisiting the threshold values of follicle count on ultrasound and of the serum AMH level for the definition of polycystic ovaries. Hum Reprod 2011;26:3123-3129.
- Eilertsen TB, et al. Anti-Mullerian hormone in the diagnosis of polycystic ovary syndrome: Can morphology description be replaced? Hum Reprod 2012;27:2494-2502.
- Navot D, et al. Ovarian hyperstimulation syndrome in novel reproductive technologies: Prevention and treatment. Fertil Steril 1992;58:249-261.
- Lee T-H, et al. Serum anti-mullerian hormone and estradiol levels are predictors of ovarian hyperstimulation syndrome in assisted reproduction technology cycles. Hum Reprod 2008;23:160-167.
- Marcello MF, et al. Structural and ultrastructural study of the ovary in childhood leukemia after successful treatment. Cancer 1990;66:2099-2104.
- Meirow D, et al. Cortical fibroisis and blood vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury. Hum Reprod 2007;22:1626-1633.
- Anderson RA, Cameron DA. Pretreatment serum anti-Mullerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab 2011;96:1336-1343.
- Dillion KE, et al. Pretreatment antimullerian hormone levels determine rate of posttherapy ovarian reserve recovery: Acute changes in ovarian reserve during and after chemotherapy. Fertil Steril 2012;99:477-483.
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