Loss of Ovarian Hormones and Accelerated Somatic and Mental Aging

Abstract

Bilateral oophorectomy in premenopausal women is a unique condition causing the abrupt and premature loss of ovarian hormones, primarily estrogen. Bilateral oophorectomy causes an alteration of several fundamental aging processes at the cellular, tissue, organ, and system levels, leading to multimorbidity, frailty, and reduced survival. However, many questions remain unanswered.

FIGURE 1.

Illustration of the most important organs and systems under the influence of estrogen in women

FIGURE 2.

Cumulative incidence of 18 chronic conditions considered separately in women with and without bilateral oophorectomy Cumulative incidence of 18 chronic conditions considered separately in women with (red line) and without bilateral oophorectomy (black line). The analyses were restricted to women who underwent bilateral oophorectomy before age 46. The 18 graphs are grouped in 5 mental health conditions (yellow background), 7 cardiovascular or metabolic conditions (white background), and 6 other somatic conditions (blue background). The curves were adjusted using inverse probability weights derived from a logistic regression model including all 18 chronic conditions present at baseline, years of education (≤12, 13–16, >16), race (white vs. nonwhite), body mass index (<30 kg/m² vs. ≥30 kg/m²), cigarette smoking (current or former vs. never), and age and calendar year at baseline (continuous). The number of women at risk varied across conditions because we excluded women with that specific condition on the index date. The HRs and corresponding 95% confidence intervals were calculated using Cox proportional hazards models, with age as the time scale and adjusted using inverse probability weights. Note the different scales used for the y-axis to better show differences. Therefore, the magnitude of the differences cannot be compared visually across conditions (e.g., schizophrenia vs. hyperlipidemia). CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease.

FIGURE 3.

Possible interpretations of the findings A: genetic variants in estrogen synthesis or responsiveness pathways, or behavioral and environmental risk factors are the true causes of both accelerated aging, leading to multimorbidity and increased mortality, and of the gynecological conditions prompting hysterectomy with bilateral oophorectomy. In this scenario, the oophorectomy is completely innocent and does not have any effect on aging. This scenario is called confounding in the epidemiological literature. B: bilateral oophorectomy has a direct causal effect on accelerated aging, leading to multimorbidity and increased mortality. In this scenario, genetic variants in estrogen synthesis or responsiveness pathways or behavioral and environmental risk factors may be effect modifiers of the causal pathway; however, oophorectomy is the major driver of the harmful effects. C: this is a more complex scenario in which bilateral oophorectomy is linked to accelerated aging both via a confounding mechanism and via a genuine causal effect. Even though genetic variants in estrogen synthesis or responsiveness pathways, or behavioral and environmental risk factors are the true causes of the preexisting accelerated aging manifesting as gynecological conditions that prompted hysterectomy with bilateral oophorectomy, the oophorectomy does have an incremental biological effect on the aging processes further accelerating a preexisting abnormal aging condition.

FIGURE 4.

Conceptual model of the possible relationship between bilateral oophorectomy, premature loss of estrogen, and accelerated aging The central part of the figure was derived from figures in Refs. and . Although in our model we postulate that estrogen plays a major role, the link between bilateral oophorectomy and accelerated aging may be mediated completely or in part by the loss of other ovarian hormones (e.g., premature loss of progesterone, testosterone, or inhibin, or disruption of the hypothalamus-pituitary-ovarian axis). Hormone therapy, primarily estrogen therapy, can attenuate the harmful effects of the premature loss of ovarian hormones caused by the oophorectomy. The minus sign indicates an antagonistic effect against accelerated aging (protective effect against aging). The genetic variants in the estrogen synthesis or responsiveness pathway may increase or decrease the effects of the hormonal loss (plus and minus sign). Similarly, behavioral or environmental risk factors may increase or decrease the effects of the hormonal loss (plus and minus sign). In this scenario, hormonal therapy, genetic factors, and non-genetic factors play a role as effect modifiers (interaction variables). COPD, chronic obstructive pulmonary disease.