Human reproduction (Oxford, England), 29(8), 1764-1772, 2014
Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women
Kissell KA , Kerri Kissell , M. R. Danaher
Enrique F Schisterman, K A Ahrens, Neil J Perkins, J Weck, Sunni L Mumford, Karen C Schliep, Lindsey A Sjaarda, Jean Wactawski-Wende
Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), MSC 751...
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentROR
Department of Epidemiology and Environmental Health, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY.ROR
Does serum anti-Müllerian hormone (AMH) vary significantly throughout both ovulatory and sporadic anovulatory menstrual cycles in healthy premenopausal women?
Summary Answer
Serum AMH levels vary statistically significantly across the menstrual cycle in both ovulatory and sporadic anovulatory cycles of healthy eumenorrheic women.
What Is Known Already
Studies to date evaluating serum AMH levels throughout the menstrual cycle have conflicting results regarding intra-woman cyclicity. No previous studies have evaluated an association between AMH and sporadic anovulation.
Study Design, Size, Duration
We conducted a prospective cohort study of 259 regularly menstruating women recruited between 2005 and 2007.
Participants/Materials, Setting, Methods
Women aged 18-44 years were followed for one (n = 9) or two (n = 250) menstrual cycles. Anovulatory cycles were defined as any cycle with peak progesterone concentration ≤5 ng/ml and no serum LH peak on the mid or late luteal visits. Serum AMH was measured at up to eight-time points throughout each cycle.
Main Results and the Role of Chance: Geometric mean AMH levels were observed to vary across the menstrual cycle (P < 0.01) with the highest levels observed during the mid-follicular phase at 2.06 ng/ml, decreasing around the time of ovulation to 1.79 ng/ml and increasing thereafter to 1.93 (mid-follicular versus ovulation, P < 0.01; ovulation versus late luteal, P = 0.01; mid-follicular versus late luteal, P = 0.05). Patterns were similar across all age groups and during ovulatory and anovulatory cycles, with higher levels of AMH observed among women with one or more anovulatory cycles (P = 0.03).
Limitations, Reasons for Caution
Ovulatory status was not verified by direct visualization. AMH was analyzed using the original Generation II enzymatically amplified two-site immunoassay, which has been shown to be susceptible to assay interference. Thus, absolute levels should be interpreted with caution, however, patterns and associations remain consistent and any potential bias would be non-differential.
Wider Implications of the Findings
This study demonstrates a significant variation in serum AMH levels across the menstrual cycle regardless of ovulatory status. This variability, although statistically significant, is not large enough to warrant a change in current clinical practice to time AMH measurements to cycle day/phase.
Study Funding/Competing Interests
This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD (Contracts # HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001). The authors have no conflicts of interest to declare.
PMID 24925522 24925522 DOI 10.1093/humrep/deu142 10.1093/humrep/deu142 Kissell et al. 2014, Kissell 2014
Cite this article
Kissell, K. A., Danaher, M. R., Schisterman, E. F., Wactawski-Wende, J., Ahrens, K. A., Schliep, K., Perkins, N. J., Sjaarda, L., Weck, J., & Mumford, S. L. (2014). Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women. Human reproduction (Oxford, England), 29(8), 1764-1772. https://doi.org/10.1093/humrep/deu142
Kissell KA, Danaher MR, Schisterman EF, Wactawski-Wende J, Ahrens KA, Schliep K, et al. Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women. Hum Reprod. 2014;29(8):1764-1772. doi:10.1093/humrep/deu142
Kissell, K. A., et al. "Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women." Human reproduction (Oxford, England), vol. 29, no. 8, 2014, pp. 1764-1772.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
A CrMS-synchronized hormone sampling protocol is detailed in which progesterone, estradiol, and other reproductive hormones are drawn at cycle-phase-specific time points defined by the charted Peak Day rather than by fixed cycle day, producing a targeted hormone profile that accurately reflects luteal and follicular function. This Peak Day-referenced approach substantially improves the diagnostic sensitivity for luteal phase deficiency, follicular dysfunction, and other endocrine abnormalities that fixed-day sampling routinely misclassifies.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Normal estradiol and progesterone reference ranges in NaProTECHNOLOGY are derived from fertile, ovulatory cycles with confirmed CrMS Peak days and sonographic ovulation, with blood sampling timed to Peak-anchored days (pre-ovulatory P-days for estradiol, P+3 through P+11 for luteal hormones) rather than to calendar cycle days. These day-specific normative values allow detection of subtle deficiencies -- such as a blunted progesterone rise at P+5 or inadequate pre-ovulatory estradiol -- that are clinically actionable for diagnosing follicular and luteal phase disorders but are invisible to standard mid-luteal or phase-independent reference intervals.
Women who experience pregnancy loss are especially prone to high stress, though the effects of stress on reproductive outcomes in this vulnerable population are unknown. We assessed relationships between perceived stress and hormones, anovulation, and fecundability among women with prior loss. One thousand two hundred fourteen women with 1-2 prior losses were followed for ≤6 cycles while attempting pregnancy and completed end-of-cycle stress assessments. For cycles 1 and 2, women also collected daily urine and completed daily perceived stress assessments. We assessed anovulation via. an algorithm based on human chorionic gonadotropin (hCG), pregnanediol-3-glucuronide (PdG), luteinizing hormone (LH), and fertility monitor readings. Pregnancy was determined via. hCG. Adjusted weighted linear mixed models estimated the effect of prospective phase-varying (menses, follicular, periovulatory, and luteal) perceived stress quartiles on estrone-1-glucuronide (E1G), PdG, and LH concentrations. Marginal structural models accounted for time-varying confounding by hormones and lifestyle factors affected by prior stress. Poisson and Cox regression estimated risk ratios and fecundability odds ratios of cycle-varying stress quartiles on anovulation and fecundability. Models were adjusted for age, race, body mass index (BMI), parity, and time-varying caffeine, alcohol, smoking, intercourse, and pelvic pain. Women in the highest versus lowest stress quartile had lower E1G and PdG concentrations, a marginally higher risk of anovulation [1.28; 95% confidence interval (CI) = 1.00, 1.63], and lower fecundability (0.71; 95% CI = 0.55, 0.90). Preconception perceived stress appears to adversely affect sex steroid synthesis and time to pregnancy. Mechanisms likely include the effects of stress on ovulatory function, but additional mechanisms, potentially during implantation, may also exist.
Natural family planning (NFP) methods have served many generations well, and in particular, the symptothermal or symptohormonal methods. The comparison of daily mucus and temperature records for individual cycles with daily hormone measurements, which is now possible, shows that some of the assumptions underlying NFP may not be completely accurate. The various methods are inadvertently depending on an element of chance, which, of course, cannot be known by the NFP user. However, it is statistically inevitable that such errors will result eventually in an unexpected pregnancy, and these discrepancies are the likely reason for the method failures. Further research and integration of home hormone measurements with NFP symptoms are needed.
Traditional NFP methods, based on the observations of temperature, mucus, and luteinizing hormone, can work well. However, these data are sometimes difficult to interpret, and significant changes in the variables are sometimes "missing" from some cycles. Changes in these variables are elicited by the estrogen and progesterone released from the ovaries. It follows that the direct measures of events in the ovaries are the levels of estrogen and progesterone or their derivatives in blood or urine. Measurements of urinary derivatives of estrogen and progesterone can be used to monitor the ovaries directly and are clearer indicators than traditional NFP methods.