madman
Super Moderator
Sex Hormones and Cardiovascular Disease in Relation to Menopause (2023)
Catherine Kim, MD, MPH, Melissa Wellons, MD, MHS
INTRODUCTION
Natural menopause is defined as the cessation of menstruation among women who have not undergone a hysterectomy or bilateral oophorectomy. The cessation of menstruation results from the depletion of the functional ovarian follicle pool, which is commonly believed to be fixed at birth.1 With the depletion of this pool, the ovaries decrease the production of estradiol (E2), and the pituitary increases the production of follicle-stimulating hormone (FSH).2 The term “perimenopause” is often loosely applied to the several years flanking the final menstrual period (FMP) but technically is defined by menstrual irregularity according to the International Stages of Reproductive Aging Workshop (STRAW) consortium.3 According to STRAW criteria, women begin perimenopause when their menses vary by ≥7 days between consecutive cycles.3 Women are then classified as postmenopausal when a year has passed without a menstrual period. Women who have cessation of menses due to hysterectomy or bilateral oophorectomy cannot be staged according to STRAW criteria.
Humans and several whale species are among the few species that undergo cessation of menses years before death.4 Thus, menopause represents a milestone of aging that is unique to humans and also universal for women. In this review, the authors outline how this milestone relates to cardiovascular disease (CVD) risk. Specifically, the authors discuss shared antecedents of menopause and cardiovascular disease as well as the changes in sex hormone levels and CVD risk factors during the menopausal transition. The authors also review the trials of exogenous estrogen for modification of CVD risk and current guidelines for the use of such therapies in these populations.
*DETERMINANTS OF MENOPAUSE
*AGE AT MENOPAUSE AND CARDIOVASCULAR RISK
*SEX HORMONE CHANGES DURING MENOPAUSE
Women who undergo natural menopause experience declines in E2 and increases in FSH during the transition.35 The Study of Women’s Health Across the Nation (SWAN) s a multiracial cohort study that noted that these hormonal changes may vary in speed (Fig. 2).35 Several trajectories of hormone changes were identified among women who did not undergo gynecologic surgery.35,36 Approximately one-third of women experienced a slight increase in E2 before the FMP, followed by steep declines, whereas about one-fourth of women experienced more gradual declines in E2. These trajectories were mirrored by trajectories in FSH, where some women experienced sharp increases in FSH, whereas others experienced more gradual increases. Obese women were more likely to have gradual changes in hormone levels.35Although other sex steroids also change during the menopausal transition, the fluctuation in levels is generally less dramatic than that observed with E2 and FSH.37,38 Androgen levels, including testosterone (T), androstenedione (A4), and dehydroepiandrosterone sulfate (DHEAS), are relatively stable as compared with E2 during the natural menopause transition. With the marked decline in ovarian E2 production after the FMP, the adrenal gland becomes a particularly important source of sex steroids, particularly DHEAS, which can be aromatized to A4, which in turn is converted to estrone (E1), the predominant circulating estrogen after the FMP. DHEAS modestly increases in perimenopause, with constant levels of T and minimal declines in A4, regardless of BMI (Fig. 3).39 The resulting postmenopausal hormonal milieu is more androgenic than the premenopausal milieu.
Not surprisingly, women who undergo oophorectomy have lower total and unbound E2 and T postoperatively compared with preoperative levels,40 consistent with the fact that the ovaries are an important source of T as well as E2 production. The postsurgical milieu is characterized by lower absolute androgen levels due to the loss of T from the ovary,41–43 although the environment is predominantly androgenic due to the loss of E2 production and continued androgen production by the adrenal glands.
*CHANGES IN CARDIOVASCULAR RISK FACTORS DURING MENOPAUSE AND CARDIOVASCULAR RISK AFTER MENOPAUSE
*IMPACT OF EXOGENOUS ESTROGEN ON CARDIOVASCULAR DISEASE
Overall, in postmenopausal women generally, combined continuous estrogen and progesterone therapy increases rather than decreases the risk of coronary events although on a magnitude of several cases per thousand users, as well as thromboembolic events, breast cancer, dementia, and gallbladder disease.58,66 Thus, the use of such therapy for preventive purposes is limited. These recommendations are similar for women who undergo hysterectomy and/or oophorectomy; among the women who experience surgical menopause in the WHI, estrogen therapy did not impact CVD events, although women aged 50 to 59 years seemed to derive some mortality benefit.68
*IMPACT OF EXOGENOUS ANDROGENS ON CARDIOVASCULAR DISEASE
Overall, CVD event rates are low in the existing studies of T therapy, reflecting study designs that have likely excluded women at high risk of CVD.70 Of note, polycystic ovary syndrome is characterized by high endogenous T levels and is not associated with a lower risk of CVD.71
*ESTROGEN THERAPY IN POSTMENOPAUSAL WOMEN
Estrogen therapy can mitigate menopausal hot flashes or the genitourinary syndrome of menopause which includes vaginal itching, dryness, dyspareunia, and urinary symptoms. Contraindications to estrogen therapy include breast cancer, gallbladder disease, hypertriglyceridemia, and a history of thrombosis as well as a history of CVD or elevated risk of CVD. Several CVD risk calculators, including the commonly used prospective diabetes study (UKPDS) engine72 and the Pooled Cohort Equations risk engine73, can be used to calculate CVD risk in women. Despite variations in the weighting of particular factors, the classification of persons at medium versus high risk is fairly consistent across calculators. Women with a high risk of CVD events due to suboptimal levels of risk factors, family history, or age should not receive estrogen therapy. Usually, this includes women who are older than 60 years of age, more than 10 years from their last menses, and have abnormal risk factor levels.74 Women with a significantly elevated risk of breast cancer because of unfavorable family or reproductive histories should not receive estrogen therapy, and women considering estrogen therapy should also be willing to engage in mammographic imaging and routine follow-up.
If women and their clinicians at low risk for CVD events and breast cancer choose to initiate estrogen therapy, transdermal or oral estrogen therapy can be initiated. E2, specifically 17-beta-E2, may offer a hypothetical benefit over conjugated equine estrogen as estradiol is released by the ovary, whereas conjugated equine estrogen is not identical. Transdermal E2 is generally preferred, as oral E2 may adversely affect inflammation and coagulation profiles 75 and thromboembolic risk to a greater extent than transdermal E2.55 If oral E2 is initiated, 10-year CVD risk should be low, and oral E2 should be avoided in women at moderate or high risk.76 In general, the lowest dose for relief of symptoms should be given, along with progesterone to reduce the risk of uterine cancer in women who have a uterus. Transdermal forms include E2-only patches (applied once or twice weekly, at E2 doses ranging from 0.025 to 0.14 mg per day), E2–progestin patches (applied once or twice weekly), gels (ranging from 0.25 to 0.75 mg per applicator), intravaginal creams (0.1 mg E2 per gram or Premarin given daily), and vaginal suppositories (10 mcg per tablet, usually inserted twice a week). Rings are available both in higher dose formulations for hot flash relief (ranging from 0.05 to 0.1 mg per day over 3 months) to formulations targeting genitourinary syndromes of menopause (7.5 mcg per day over 3 months). Oral E2 forms range from 0.5 mg per day to 2 mg per day, and oral E2–progestin formulations are also available for women who have uteruses.
Such therapy is usually tapered after 4 to 5 years of use, due to the observation in the WHI that breast cancer risk increased after 5 years of use. However, due to the duration of hot flashes, women may opt to continue therapy with repeated efforts at gradual tapers over a period of 6 months or even longer. Although about one-quarter of women have relatively mild hot flashes or VMS that subside several years after the FMP, approximately another quarter have persistent VMS even a decade after the FMP (Fig. 5).77 Although estrogen therapy is typically not recommended for women over the age of 60 years, the figure suggests that estrogen therapy could potentially is of use in this subpopulation at younger ages. Women were more likely to have persistent VMS if they had greater alcohol intake, higher depressive and anxiety symptoms, and poorer health status.77
Among women who experience menopause at younger ages, particularly before the age of 40 years, estrogen therapy is usually prescribed primarily for the preservation of bone health or cardiovascular health.78 Although randomized trial data are currently lacking, there are currently studies underway to detect benefits.79 In the meantime, 17-beta-E2 (and progesterone, if women retain their uteruses) is usually given at higher doses than in older women. Combined estrogen–progestin contraceptive pills provide higher doses of E2 than the doses of E2 typically given among older perimenopausal women. Oral contraceptive pills have the added benefit of providing contraception should ovarian activity resume. Such therapy is typically continued until the age of 50 years, although the length of use is primarily based on average at the FMP rather than trials examining the length of use.
*TESTOSTERONE THERAPY IN POSTMENOPAUSAL WOMEN
Hyposexual desire disorder is the sole evidence-based indication for T therapy in postmenopausal women, although it is not a Food and Drug Administration (FDA) approved therapy. The ability of clinicians to balance this benefit against long-term chronic disease risk is limited by the lack of long-term randomized studies. In addition, for postmenopausal women who desire supplemental T, no FDA-approved T preparation exists that is formulated to restore premenopausal T levels. Although oral estrogen and T-containing products exist in the marketplace (eg, esterified estrogens and methyltestosterone-containing tablets), the known negative effects of oral T on lipid metabolism limit enthusiasm for its use. Off-label use of male T preparations may be considered with the caveat that there is minimal evidence of the effect of these preparations on women’s cardiovascular health.69 Currently, there are no biochemical criteria for what constitutes low androgens in women (regardless of menopausal state), but levels of total T greater than 2.8 nmol/L (70 ng/dL) should raise concerns about pathological processes.
Data regarding postmenopausal supplementation of other androgen formulations, particularly DHEA, are even more sparse than for T. In 2014, the Endocrine Society recommended against the use of DHEA for women with low androgen levels as are commonly found in adrenal insufficiency, surgical menopause, hypopituitarism, or other conditions due to the lack of data noting improved symptoms or signs with therapy as well as the lack of long-term data on risk.80 Other medical professional societies such as the North American Menopause Society have also recommended against the routine use of DHEA, with the exception of vaginal formulations for genitourinary symptoms. This 2022 position has been endorsed by an international consortium of menopause societies.76
SUMMARY
The implications of menopause management are particularly important with the aging of the population and increasing awareness of the importance of midlife risk on longevity. Our understanding of the relationships between reproductive milestones and CVD continues to evolve particularly regarding shared determinants of health. The life course approaches that examine in-utero, childhood, and early adult exposures on milestones such as menopause and CVD risk are needed to better understand when to intervene and which risk factors need to be targeted to improve downstream determinants of health.
In the interim, clinicians should engage in shared decision-making regarding the use of estrogen therapies for the mitigation of menopausal symptoms. Low-dose oral or transdermal formulations can improve quality of life and are safe among the majority of women who undergo surgical menopause or natural menopause.
Catherine Kim, MD, MPH, Melissa Wellons, MD, MHS
INTRODUCTION
Natural menopause is defined as the cessation of menstruation among women who have not undergone a hysterectomy or bilateral oophorectomy. The cessation of menstruation results from the depletion of the functional ovarian follicle pool, which is commonly believed to be fixed at birth.1 With the depletion of this pool, the ovaries decrease the production of estradiol (E2), and the pituitary increases the production of follicle-stimulating hormone (FSH).2 The term “perimenopause” is often loosely applied to the several years flanking the final menstrual period (FMP) but technically is defined by menstrual irregularity according to the International Stages of Reproductive Aging Workshop (STRAW) consortium.3 According to STRAW criteria, women begin perimenopause when their menses vary by ≥7 days between consecutive cycles.3 Women are then classified as postmenopausal when a year has passed without a menstrual period. Women who have cessation of menses due to hysterectomy or bilateral oophorectomy cannot be staged according to STRAW criteria.
Humans and several whale species are among the few species that undergo cessation of menses years before death.4 Thus, menopause represents a milestone of aging that is unique to humans and also universal for women. In this review, the authors outline how this milestone relates to cardiovascular disease (CVD) risk. Specifically, the authors discuss shared antecedents of menopause and cardiovascular disease as well as the changes in sex hormone levels and CVD risk factors during the menopausal transition. The authors also review the trials of exogenous estrogen for modification of CVD risk and current guidelines for the use of such therapies in these populations.
*DETERMINANTS OF MENOPAUSE
*AGE AT MENOPAUSE AND CARDIOVASCULAR RISK
*SEX HORMONE CHANGES DURING MENOPAUSE
Women who undergo natural menopause experience declines in E2 and increases in FSH during the transition.35 The Study of Women’s Health Across the Nation (SWAN) s a multiracial cohort study that noted that these hormonal changes may vary in speed (Fig. 2).35 Several trajectories of hormone changes were identified among women who did not undergo gynecologic surgery.35,36 Approximately one-third of women experienced a slight increase in E2 before the FMP, followed by steep declines, whereas about one-fourth of women experienced more gradual declines in E2. These trajectories were mirrored by trajectories in FSH, where some women experienced sharp increases in FSH, whereas others experienced more gradual increases. Obese women were more likely to have gradual changes in hormone levels.35Although other sex steroids also change during the menopausal transition, the fluctuation in levels is generally less dramatic than that observed with E2 and FSH.37,38 Androgen levels, including testosterone (T), androstenedione (A4), and dehydroepiandrosterone sulfate (DHEAS), are relatively stable as compared with E2 during the natural menopause transition. With the marked decline in ovarian E2 production after the FMP, the adrenal gland becomes a particularly important source of sex steroids, particularly DHEAS, which can be aromatized to A4, which in turn is converted to estrone (E1), the predominant circulating estrogen after the FMP. DHEAS modestly increases in perimenopause, with constant levels of T and minimal declines in A4, regardless of BMI (Fig. 3).39 The resulting postmenopausal hormonal milieu is more androgenic than the premenopausal milieu.
Not surprisingly, women who undergo oophorectomy have lower total and unbound E2 and T postoperatively compared with preoperative levels,40 consistent with the fact that the ovaries are an important source of T as well as E2 production. The postsurgical milieu is characterized by lower absolute androgen levels due to the loss of T from the ovary,41–43 although the environment is predominantly androgenic due to the loss of E2 production and continued androgen production by the adrenal glands.
*CHANGES IN CARDIOVASCULAR RISK FACTORS DURING MENOPAUSE AND CARDIOVASCULAR RISK AFTER MENOPAUSE
*IMPACT OF EXOGENOUS ESTROGEN ON CARDIOVASCULAR DISEASE
Overall, in postmenopausal women generally, combined continuous estrogen and progesterone therapy increases rather than decreases the risk of coronary events although on a magnitude of several cases per thousand users, as well as thromboembolic events, breast cancer, dementia, and gallbladder disease.58,66 Thus, the use of such therapy for preventive purposes is limited. These recommendations are similar for women who undergo hysterectomy and/or oophorectomy; among the women who experience surgical menopause in the WHI, estrogen therapy did not impact CVD events, although women aged 50 to 59 years seemed to derive some mortality benefit.68
*IMPACT OF EXOGENOUS ANDROGENS ON CARDIOVASCULAR DISEASE
Overall, CVD event rates are low in the existing studies of T therapy, reflecting study designs that have likely excluded women at high risk of CVD.70 Of note, polycystic ovary syndrome is characterized by high endogenous T levels and is not associated with a lower risk of CVD.71
*ESTROGEN THERAPY IN POSTMENOPAUSAL WOMEN
Estrogen therapy can mitigate menopausal hot flashes or the genitourinary syndrome of menopause which includes vaginal itching, dryness, dyspareunia, and urinary symptoms. Contraindications to estrogen therapy include breast cancer, gallbladder disease, hypertriglyceridemia, and a history of thrombosis as well as a history of CVD or elevated risk of CVD. Several CVD risk calculators, including the commonly used prospective diabetes study (UKPDS) engine72 and the Pooled Cohort Equations risk engine73, can be used to calculate CVD risk in women. Despite variations in the weighting of particular factors, the classification of persons at medium versus high risk is fairly consistent across calculators. Women with a high risk of CVD events due to suboptimal levels of risk factors, family history, or age should not receive estrogen therapy. Usually, this includes women who are older than 60 years of age, more than 10 years from their last menses, and have abnormal risk factor levels.74 Women with a significantly elevated risk of breast cancer because of unfavorable family or reproductive histories should not receive estrogen therapy, and women considering estrogen therapy should also be willing to engage in mammographic imaging and routine follow-up.
If women and their clinicians at low risk for CVD events and breast cancer choose to initiate estrogen therapy, transdermal or oral estrogen therapy can be initiated. E2, specifically 17-beta-E2, may offer a hypothetical benefit over conjugated equine estrogen as estradiol is released by the ovary, whereas conjugated equine estrogen is not identical. Transdermal E2 is generally preferred, as oral E2 may adversely affect inflammation and coagulation profiles 75 and thromboembolic risk to a greater extent than transdermal E2.55 If oral E2 is initiated, 10-year CVD risk should be low, and oral E2 should be avoided in women at moderate or high risk.76 In general, the lowest dose for relief of symptoms should be given, along with progesterone to reduce the risk of uterine cancer in women who have a uterus. Transdermal forms include E2-only patches (applied once or twice weekly, at E2 doses ranging from 0.025 to 0.14 mg per day), E2–progestin patches (applied once or twice weekly), gels (ranging from 0.25 to 0.75 mg per applicator), intravaginal creams (0.1 mg E2 per gram or Premarin given daily), and vaginal suppositories (10 mcg per tablet, usually inserted twice a week). Rings are available both in higher dose formulations for hot flash relief (ranging from 0.05 to 0.1 mg per day over 3 months) to formulations targeting genitourinary syndromes of menopause (7.5 mcg per day over 3 months). Oral E2 forms range from 0.5 mg per day to 2 mg per day, and oral E2–progestin formulations are also available for women who have uteruses.
Such therapy is usually tapered after 4 to 5 years of use, due to the observation in the WHI that breast cancer risk increased after 5 years of use. However, due to the duration of hot flashes, women may opt to continue therapy with repeated efforts at gradual tapers over a period of 6 months or even longer. Although about one-quarter of women have relatively mild hot flashes or VMS that subside several years after the FMP, approximately another quarter have persistent VMS even a decade after the FMP (Fig. 5).77 Although estrogen therapy is typically not recommended for women over the age of 60 years, the figure suggests that estrogen therapy could potentially is of use in this subpopulation at younger ages. Women were more likely to have persistent VMS if they had greater alcohol intake, higher depressive and anxiety symptoms, and poorer health status.77
Among women who experience menopause at younger ages, particularly before the age of 40 years, estrogen therapy is usually prescribed primarily for the preservation of bone health or cardiovascular health.78 Although randomized trial data are currently lacking, there are currently studies underway to detect benefits.79 In the meantime, 17-beta-E2 (and progesterone, if women retain their uteruses) is usually given at higher doses than in older women. Combined estrogen–progestin contraceptive pills provide higher doses of E2 than the doses of E2 typically given among older perimenopausal women. Oral contraceptive pills have the added benefit of providing contraception should ovarian activity resume. Such therapy is typically continued until the age of 50 years, although the length of use is primarily based on average at the FMP rather than trials examining the length of use.
*TESTOSTERONE THERAPY IN POSTMENOPAUSAL WOMEN
Hyposexual desire disorder is the sole evidence-based indication for T therapy in postmenopausal women, although it is not a Food and Drug Administration (FDA) approved therapy. The ability of clinicians to balance this benefit against long-term chronic disease risk is limited by the lack of long-term randomized studies. In addition, for postmenopausal women who desire supplemental T, no FDA-approved T preparation exists that is formulated to restore premenopausal T levels. Although oral estrogen and T-containing products exist in the marketplace (eg, esterified estrogens and methyltestosterone-containing tablets), the known negative effects of oral T on lipid metabolism limit enthusiasm for its use. Off-label use of male T preparations may be considered with the caveat that there is minimal evidence of the effect of these preparations on women’s cardiovascular health.69 Currently, there are no biochemical criteria for what constitutes low androgens in women (regardless of menopausal state), but levels of total T greater than 2.8 nmol/L (70 ng/dL) should raise concerns about pathological processes.
Data regarding postmenopausal supplementation of other androgen formulations, particularly DHEA, are even more sparse than for T. In 2014, the Endocrine Society recommended against the use of DHEA for women with low androgen levels as are commonly found in adrenal insufficiency, surgical menopause, hypopituitarism, or other conditions due to the lack of data noting improved symptoms or signs with therapy as well as the lack of long-term data on risk.80 Other medical professional societies such as the North American Menopause Society have also recommended against the routine use of DHEA, with the exception of vaginal formulations for genitourinary symptoms. This 2022 position has been endorsed by an international consortium of menopause societies.76
SUMMARY
The implications of menopause management are particularly important with the aging of the population and increasing awareness of the importance of midlife risk on longevity. Our understanding of the relationships between reproductive milestones and CVD continues to evolve particularly regarding shared determinants of health. The life course approaches that examine in-utero, childhood, and early adult exposures on milestones such as menopause and CVD risk are needed to better understand when to intervene and which risk factors need to be targeted to improve downstream determinants of health.
In the interim, clinicians should engage in shared decision-making regarding the use of estrogen therapies for the mitigation of menopausal symptoms. Low-dose oral or transdermal formulations can improve quality of life and are safe among the majority of women who undergo surgical menopause or natural menopause.
