By Katherine Rivlin, MD, MSc
Associate Professor, Department of Obstetrics and Gynecology, University of Chicago
SYNOPSIS: In this multi-site, community-based study, anti-Müllerian hormone levels did not decline more rapidly among patients who underwent hysterectomy with ovarian conservation compared to patients who experienced natural menopause.
SOURCE: Santoro N, Flyckt R, Davis A, et al. Anti-Müllerian hormone level decline in patients undergoing hysterectomy with and without oophorectomy compared with natural menopause. Obstet Gynecol 2023;141:331-340.
Menopause is clinically defined as 12 consecutive months of amenorrhea as the result of depletion of ovarian follicles and the subsequent drop in estrogen. Determining time of menopause after hysterectomy brings challenges, given the absence of menses as a clinical marker. Follicle-stimulating hormone (FSH), the traditional serum marker of menopause, varies throughout the menstrual cycle, which makes its interpretation difficult. Anti-Müllerian hormone (AMH) derives from granulosa cells and, therefore, provides a more direct measure of ovarian function compared to FSH, with minimal fluctuation across a menstrual cycle.
A newer AMH marker recently has been validated as predictive of the final menstrual period, or menopause, as part of the Study of Women’s Health Across the Nation (SWAN) study.1 Santoro et al used this new assay to determine time to undetectable AMH levels among patients in the SWAN study who underwent hysterectomy compared to those who underwent natural menopause. The authors hypothesized a shorter time to undetectable AMH levels among those patients who underwent hysterectomy with ovarian preservation compared to those who underwent natural menopause. Secondarily, they hypothesized an immediate reduction in AMH among those who underwent bilateral salpingo-oopherectomy (BSO) at the time of hysterectomy. The data were obtained from the SWAN study, a multi-site, racially and ethnically diverse, community-based study of 3,302 patients followed through the transition to menopause. Patients were aged 42-52 years, had a uterus, and in the prior three months had had at least one period, were not pregnant or lactating, and had not used reproductive hormones.
Participants completed a monthly menstrual calendar and a monthly questionnaire about final menses and hysterectomy. The study asked for consent to obtain medical records for those patients undergoing hysterectomy. Fasting AMH levels were obtained on cycle days 2-5 for menstruating participants. Participants who had undergone a hysterectomy had AMH levels collected before surgery and during the 90-day window following surgery, and then annually until levels were undetectable. Among the natural menopause cohort, AMH was measured at least once prior to and at least once after the final menstrual period until levels were undetectable. The team compared AMH levels for both cohorts, as well as participant characteristics.
The study included 232 participants who underwent hysterectomy with or without ovarian conservation. Of these, 159 underwent BSO, 16 underwent a unilateral salpingo-oopherectomy (USO), and 60 conserved both ovaries. It did not include participants undergoing adnexal surgery only, such as BSO. The natural menopause cohort included 1,428 participants for a final analytic sample of 1,660. Participants undergoing natural menopause were more likely to be older, have a lower body mass index, and were less likely to have fibroids. Patients undergoing BSO were older than the group who retained both ovaries. The team found an immediate reduction in AMH to an undetectable level among the BSO cohort. On Kaplan-Meier curves, the hysterectomy with ovarian conservation cohort and the natural menopause cohort had similar age at undetectable AMH level (age 51 years, P = 0.31), which was significantly later than the BSO cohort (P < 0.001) and USO group.
AMH was significantly lower in the BSO and USO cohorts, but it was not significantly different in the hysterectomy with ovarian conservation cohort compared to those in the natural menopause cohort. After adjusting for baseline covariates, the differences in AMH between USO and natural menopause no longer were statistically significant. All other associations did not change significantly after adjustment for baseline covariates.
COMMENTARY
This study indicates that patients undergoing hysterectomy with ovarian preservation or USO have similar AMH levels postoperatively compared to patients experiencing natural menopause. This finding contradicts the study’s hypothesis, prior published literature, and current provider counseling patterns. Previous studies using FSH as an indicator of menopause have concluded that hysterectomy with ovarian conservation hastens time to ovarian failure, compared to natural menopause, by as many as two years.2
Providers have incorporated these findings into their counseling and anticipatory guidance for patients considering hysterectomy. This study indicates that such counseling may be inaccurate, since FSH may be an insufficient measure of menopause. FSH varies significantly throughout the menstrual cycle, which makes timing its measurement after hysterectomy challenging. Additionally, no universally agreed upon FSH concentration that defines menopause exists, which poses challenges both in answering this research question and to patients and providers seeking to measure menopause when cessation of menses as a clinical marker is insufficient or not feasible.
Prior studies also have used AMH to detect menopause but with enzyme-linked immunoassay measurements inadequately sensitive to detect differences at the end of reproductive life. Additionally, some studies have not followed AMH levels for sufficient time periods post-operatively to detect changes.3,4 This study also includes newer surgical techniques, given recent trends toward minimally invasive approaches to hysterectomy. Perhaps laparoscopic techniques pose lower risks to ovarian reserve, although prior data on surgical approach have yielded conflicting results. Clear research gaps still exist on surgical approach and ovarian reserve.
Instead of routinely counseling that hysterectomy with ovarian conservation hastens menopause, clinicians can incorporate this study’s findings into their counseling to encourage informed consent. Additionally, more sensitive AMH levels can allow providers to measure ovarian failure more accurately in patients following hysterectomy, since menopause can bring symptomatic implications, as well as risks to bone and cardiovascular health.
REFERENCES
- Finkelstein JS, Lee H, Karlamangla A, et al. Antimullerian hormone and impending menopause in late reproductive age: The Study of Women’s Health Across the Nation. J Clin Endocrinol Metab 2020;105:e1862-e1871.
- Moorman PG, Myers ER, Schildkraut JM, et al. Effect of hysterectomy with ovarian preservation on ovarian function. Obstet Gynecol 2011;118:1271-1279.
- Trabuco EC, Moorman PG, Algeciras-Schimnich A, et al. Association of ovary-sparing hysterectomy with ovarian reserve. Obstet Gynecol 2016;127:819-827.
- Welsh P, Smith K, Nelson SM. A single-centre evaluation of two new anti-Mullerian hormone assays and comparison with the current clinical standard assay. Hum Reprod 2014;29:1035-1041.
