Does Unilateral Oophorectomy Lead to Early Menopause?
Abstact& Commentary
By Jeffrey T. Jensen, MD, Editor
Synopsis: In a large Norwegian population-based cohort study, women with a history of unilateral oophorectomy experienced a slightly earlier onset of menopause compared to women with both ovaries, but this finding does not suggest a clinically important effect.
Source: Bjelland EK, et al. Is unilateral oophorectomy associated with age at menopause? A population study (the HUNT2 Survey).
Hum Reprod 2014;29:835-841.
To determine whether removal of one ovary is associated with an early onset of menopause, Bjelland et al performed a retrospective cohort study of 23,580 Norwegian women who were included in the population-based HUNT2 Survey. All individuals ≥ 20 years of age living in Nord Trøndelag County, Norway, during the years 1995-1997, were invited to participate in the survey. Data on gynecologic surgery and age of menopause were collected at enrollment using two self-administered questionnaires. Cox proportional hazard models were used to estimate relative risks of menopause according to unilateral oophorectomy status with and without adjustment for birth cohort, parity, smoking, body mass index (BMI), and age at menarche.
Overall, women in the unilateral oophorectomy cohort were about 1 year younger at menopause (mean, 49.6 years; 95% confidence interval [CI], 49.2-50.0) than women without unilateral oophorectomy (mean, 50.7 years; CI, 50.6-50.8). The crude relative risk of menopause was 1.28 (CI, 1.15-1.42) and remained elevated after adjustment for potential confounders (relative risk aversion [RRa], 1.27; CI, 1.14-1.41). To put this risk in perspective, the impact of unilateral oophorectomy was similar to that of nulliparity (49.7 vs 50.7 years; RRa, 1.25; CI, 1.16-1.36) and greater than that attributable to smoking (1.18; CI, 1.13-1.24). In contrast, there was a modest increase in the age of menopause associated with increasing BMI (RRa, 0.88; CI, 0.82-0.94) for BMI ≥ 30 kg/m2 compared to BMI < 25 kg/m2.
Given that the overall effect of unilateral oophorectomy on age at onset of menopause is small, and similar to other established risk factors like smoking and nulliparity, the authors concluded that mechanisms must exist that compensate for the large loss of follicles with ovarian surgery.
Commentary
This is a nice study because the authors put the findings into real clinical perspective. The main result that unilateral oophorectomy increases the risk of early menopause by 27% could make for a great alarmist headline. Although the tight confidence interval around the relative risk estimate demonstrates statistical significance, the finding is clearly not clinically important. Although large database and retrospective cohort studies are capable of producing impressive small confidence intervals, the clarity of the statistical results should not cloud the interpretation of the clinical relevance of these results. In general, risk estimates that do not exceed a minimum threshold of 2.0 (or 0.5 for protection) are highly suspect, and should be largely ignored.1 In addition, the authors of this study acknowledge inherent weakness of the study design (e.g., self-reported outcomes, misclassification bias) that should reduce confidence in the strict interpretation of the findings. Nevertheless, we can still learn from this study.
Since the age of menopause has reproductive and health implications for women, research addressing factors that might influence the onset is a legitimate area of inquiry. Results from well-designed studies can be useful to clinicians counseling their patients. The findings of Bjelland et al illustrate a principle of mammalian reproductive biology. Menopause occurs due to the loss of ovarian follicles. This process begins in fetal life and accelerates through the reproductive years. Although many environmental and genetic conditions likely contribute to the age of menopause, the process of follicle atresia and apotosis occurs rather steadily in most women until the pool of oocytes is exhausted.2 Radiation therapy and chemotherapy during cancer treatment accelerate the loss of follicles and are associated with an early onset of menopause, and the same effect has been noted on a population consisting of atomic bomb survivors.3 But treatment with hormonal contraceptives that block ovulation does not prevent follicular atresia or postpone the age of menopause.4 Thus, the loss of follicles occurs slowly and steadily throughout life, with ovarian failure occurring in the early 50s for most women.
If the timing of menopause was related only to follicle number, the effect of oophorectomy should be substantial, as surgery results in loss of approximately half the remaining ovarian follicles. Given that women are born with a finite number of follicles, Faddy and Gosden estimated that if the absolute rate of follicle atresia remained the same after oophorectomy, the age of menopause should be 5-10 years earlier.5 Since the epidemiologic data do not support this hypothesis, other explanations must exist. Some experts believe that the ovary is capable of producing new primordial follicles. There have been recent reports of mitotically active germ cells in the ovaries of women capable of producing new "oocyte-like structures."6 However, these findings are highly speculative and have not been confirmed.7
The most likely explanation for the stable age of menopause after oophorectomy is that the rate of follicle atresia is relatively constant in each ovary and independent of ovulation. In other words, each ovary has an independent clock and fate. Although the two ovaries influence each other to favor maturation and ovulation of a single oocyte each cycle, the background rate of follicle loss occurring in each ovary is independent of ovulation. When one ovary is missing, the other does not speed up the rate of follicle loss. Consider two blocks of ice side by side. Removal of one block may slightly influence the rate of melting of the other, but to a large extent, they melt independently.
So the clinical message from this report is reassuring for women facing the decision regarding a unilateral oophorectomy. Among women desiring future fertility, every effort should be made to conserve ovarian tissue. However, if unilateral oophorectomy is indicted, consideration of menopause should not factor into the clinical decision making. I don’t see the value in performing a difficult ovarian cystectomy procedure on a 40-year-old woman who is not interested in future pregnancies.
References
- Schulz KF, Grimes DA. The Lancet Handbook of Essential Concepts in Clinical Research. New York: Elsevier; 2006.
- Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility. 8th Ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.
- Sakata R, et al. Radiat Res 2011;176:787-795.
- Pokoradi AJ, et al. Am J Obstet Gynecol 2011;205:34.e1-13.
- Faddy MJ, Gosden RG. Hum Reprod 1996;11:1484-486.
- Tilly JL, Sinclair DA. Cell Metab 2013;17:838-850.
- Hanna CB, Hennebold JD. Fertil Steril 2014;101:20-30.
