CLINICAL
Clinical Conference
Editorial
Therapeutic
THERAPEUTIC
CONFERENCE
Conference
Board
John C. Somberg, MD, Editor Hector Gomez, MD, Associate
Editor
Robert Piepho, PhD Andrew Whelton, MD Gilbert Mayor, MD Harold Neu, MD Atul Laddu, MD
O steoporosis
is better prevented than treated, and the prophylactic hormonal management of menopause may circumvent some of the symptoms experienced by patients. The mean age of menopause has not changed since classical times, and has remained at approximately 50 years. The female geriatric population has increased in size, however, as life expectancy has extended to beyond age 80. By the year 2025, there will be more than 58 million elderly United States citizens. Women will live one third of their lives in this age group, which will allow sufficient time for the effects of bone demineralization to significantly impact public health. The role of estrogen replacement therapy has expanded from treatment of atrophic vaginitis and symptomatic hot flashes, to include prevention of osteoporosis with knowledge that estrogen plays a pivotal role in the regulation of bone metabolism. As a review, the low-estrogen milieu of the climacteric is insufficient to sustain estrogen-dependent tissues of the reproductive tract. The uterus decreases in size, and endometrial atrophy induces menopause. Decreased glycogen within the vaginal epithelium causes thinning of the vaginal mucosa, atrophic vaginitis (e.g., bleeding, pruritis, monilial infection), and stenosis of the upper vagina, occasionally resulting in painful sexual relations, or dyspareunia. The urethra and skin of the external genitalia also are responsive to estrogen, and atrophy in these regions results in dysuria, vulvar pruritis, and diminished size of the labia minora. Tissues of the reproductive tract respond dramatically to estrogen supplementation. Vasomotor instability, or the hot flash, is defined as the sensation of heat over the face, neck, and
774
#{149} J Clin Pharmacol
1992;32:774-778
thorax, accompanied by reddening in these regions, and profuse sweating. It is the most common complaint of the climacteric, occurring in 50 to 76% of women with physiologic or surgical menopause. More than 85% of women with hot flashes continue to experience them 1 year later, although the flashes may diminish in intensity and frequency. The subjective symptoms of the hot flash last 0.5 to 5 minutes (mean, 4 minutes), and occur at irregular intervals, often being preceded by palpitations and headache. Hot flashes occurring at night are particularly symptomatic because they diminish rapid eye movement sleep, and lead to sleep deprivation, e.g. insomnia, irritability, and mood change. The physiologic changes accompanying the hot flash include peripheral vasodilation, sweating, elevated heart rate, and increased oxygen consumption. These events promote heat loss via redistribution of blood flow to the periphery, and reflect a change in the set point of the hypothalamic thermoregulatory center. Peripheral blood flow increases approximately 1.5 minutes before and continues for several minutes beyond the subjective symptoms of the hot flash. Perspiration, as measured by a change in skin conductance, begins 2.5 minutes later, and is accompanied by chills as core body temperature drops 0.2#{176}C. Hypothalamic norepinephrine may play a role in initiating vasomotor instability by stimulating sympathetic neurons within the cervical spinal cord that control regional vasodilation. This theory is supported by the fact that gonadectomy in animals increases hypothalamic norepinephrine, and enhances the activity of tyrosine hydroxylase, the enzyme responsible for catecholamine synthesis. Regardless of its cause, hot flashes also respond to estrogen replacement therapy.
MENOPAUSAL
DISCUSSION:CURRENT MANAGEMENT POSTMENOPAUSAL
OF
PERSPECTIVE MENOPAUSAL WOMEN
AND
IN
POSTMENOPAUSAL
THE
AND
Osteoporosis affects at least 20 million Americans, most of whom are postmenopausal women and elderly people. At least 1.2 million fractures related to osteoporosis occur in the United States annually, and vertebral fractures are present in one third of women older than age 65. By age 90, 33% of women and 17% of men will experience hip fractures, which will decrease expected survival by 5 to 20%.1 Fifty percent of women sustaining a hip fracture will be unable to ambulate normally after the fracture occurs. Osteoporosis is characterized by a decrease in bone density, and two types of this disease have been identified. This discussion focuses on type I osteoporosis, which is associated with accelerated bone loss in women during the menopausal years, and primarily affects trabecular bone, lending to vertebral and wrist fractures 15 to 20 years after ovarian failure. Type 2 osteoporosis is associated with slow, progressive bone loss in both sexes, and leads to fractures after the age of 70. Bone is a dynamic tissue, with resorption, formation, and remodeling occurring throughout life. Osteoporosis results when there is an imbalance between bone resorption and formation, with a chronic negative calcium balance causing mobilization of calcium from trabecular bone. Estrogen deficiency is a significant factor in the development of osteoporosis, and has been associated with a transient increase in serum calcium, a compensatory decrease in serum parathyroid hormone levels, hypercalciuria (negative calcium balance), and increased urinary loss of phosphorus and hydroxyproline. The rate of trabecular bone loss is 4 to 8% annually in the 5 to 8 years after menopause, and women lose 35% of their cortical bone and 50% of their trabecular bone through life.2 Estrogen exerts a protective effect on bone, in part by inhibiting bone reabsorption. Although the complex mechanisms of estrogen action on bone may be indirect, estrogen receptors have been identified on osteoblasts, and these cells appear to increase collagen production after estrogen administration.3 In addition, local growth factors, including fibroblast growth factor, transforming growth factor, insulinlike growth factor, beta2-microglobulin, and platelet-derived growth factor are present in skeletal tissue, and may regulate bone metabolism under the influence of hormones. Christiansen et al.4 have demonstrated that menopausal women receiving estrogen therapy for 2 years maintain bone mass, whereas placebo-treated women exhibit a significant decline. The rate of
CLINICAL
THERAPEUTIC
CONFERENCE
WOMEN
bone loss increased to 2.3% after estrogen therapy was discontinued, whereas untreated women stopped losing bone when reassigned to estrogen therapy after 2 years. These data suggest that it is unlikely that a 78-year-old woman suffering from osteoporosis will benefit by estrogen, because most bone loss has already occurred. Estrogen administration early after menopause may have prevented her symptoms, but would require prolonged therapy to prevent bone loss over time. Long-term estrogen users have a decrease in the risk of spine, wrist, and hip fracture as compared with nonusers.56 Oral administration of conjugated equine estrogens (CEE; 0.625 mg daily) is commonly used in the United States as prophylaxis against osteoporosis. At the University of Wisconsin, we see several young women with hypoestrogenic conditions, including anorexia nervosa, hypothalamic amenorrhea, and premature loss of ovarian function, who are interested in prevention of osteoporosis, and ingest calcium supplements without estrogen therapy. We tell these patients that, although calcium metabolism is important for healthy bone, calcium supplementation alone does not seem to be effective in preventing osteoporosis. Riis et al.7 have shown that calcium intake of I to 2 g is not effective in preventing vertebral body bone loss in early menopause. When calcium supplementation (1500 mg daily) is combined with oral CEE (0.3 mg daily), however, protection against bone loss is achieved.8 We occasionally use this combination of low-dose estrogen therapy and calcium supplementation in women complaining of mastalgia, but follow all of these patients with radiologic assessment of bone density. The above notwithstanding, cardiovascular disease is the leading cause of death in women older than age 67 in the United States. Approximately 250,000 deaths occur annually in women with coronary heart disease (CHD), and I in 7 women between ages 45 and 64 have some form of heart disease. The pathogenesis of CHD is, in part, related to circulating cholesterol, which is transported in plasma by macromolecules called lipoproteins. Five major lipoprotein fractions exist: chylomicrons, very-low-density lipoprotein, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and intermediate-density lipoproteins. Chylomicrons transport dietary cholesterol and triglycerides from the intestine to body tissues, including the liver, where it is incorporated into bile acids and very-low-density lipoprotein. Very-lowdensity lipoprotein contains mostly exogenous triglycerides, and is a risk factor for coronary heart disease in women. It is converted by capillary lipoprotein lipase in adipose and muscle to intermediate-density lipoprotein, which subsequently is
775
DUMESIC
metabolized by the liver to LDL. Low-density lipoprotein carries 70% of total cholesterol to hepatic and extrahepatic cells for structural and metabolic requirements, and is atherogenic in both sexes. A 2% increase in the risk of myocardial infarction accompanies every 1% increase in total cholesterol level. High-density lipoprotein carries cholesterol from the arterial wall to the liver, e.g., reverse cholesterol transport, where it is metabolized and excreted via the bile duct; HDL levels, particularly those of the HDL2 subfraction, are inversely proportional to cardiovascular disease. The development of cardiovascular disease is related to several risk factors, including positive family history, age, obesity, hypertension, diabetes mellitus, and cigarette smoking. Menopause also appears be a risk factor because postmenopausal women are at greater risk of cardiovascular disease than agematched premenopausal women, and estrogen deficiency is accompanied by an elevation in circulating LDL and total cholesterol levels. Evidence that estrogen exerts a cardioprotective effect comes from demographic studies showing greater mortality rates in men than in premenopausal women, and an increased heart attack rate in women after menopause. Bilateral oophorectomy in premenopausal women also increases the frequency of heart disease. Oral administration of estrogen increases serum HDL2 concentrations, and decreases serum LDL and total cholesterol levels.9 These effects of exogenous estrogen on circulating lipoproteins may contribute to the reduction of CHD in postmenopausal women receiving estrogen therapy.’#{176} The lipid hypothesis, however, accounts for only 25 to 50% of the beneficial effect of estrogen on CHD, and, therefore, other estrogen actions on cardiovascular function must be operative. Estrogen increases arterial prostacyclin levels, potentially inhibiting local platelet aggregation, and also binds to specific receptors on myocardium and coronary arteries.11’12 A 50% reduction in the relative risk of CHD reported in some studies would have a significant impact on women’s healthcare in our society.1#{176} Estrogen stimulates endometrial mitogenesis, and promotes proliferation of epithelial and stromal cells. Therefore, it is not surprising to find that postmenopausal estrogen use increases the risk of developing endometrial carcinoma by fourfold to eightfold. Progestins antagonize estrogen action on the endometrium, so that their use has been successful in preventing estrogen-induced endometrial hyperplasia and carcinoma. Addition of a progestin for at least 13 days monthly reduces the incidence of endometrial hyperplasia to below that of the general population.13 Unfortunately, sequential administration of
776
#{149} J Clin Pharmacol
1992;32:774-778
medroxyprogesterone acetate (5 to 10 mg daily for 13 days per month) in combination with oral CEE (0.625 mg daily) is usually associated with inconvenient monthly menstruation. Continuous use of medroxyprogesterone acetate (2.5 mg daily) in conjunction with 0.625 mg CEE induces amenorrhea in most patients after 1 year, but causes irregular bleeding in one third of these individuals during the first months of therapy. Both sequential and continuous progestin regimens induce endometrial atrophy in women receiving postmenopausal estrogens, and do not interfere with the beneficial effects of estrogen on bone turnover. All menopausal women with an intact uterus should receive a progestin with estrogen replacement therapy, and should be advised to expect monthly menstruation and irregular spotting with the sequential and continuous use of progestin. Progestins used for postmenopausal hormone therapy are derived from either 19-nortestosterone (norethindrone, norethindrone acetate, levonorgestrel, lynestrenol, ethynodiol diacetate, and desogestrel), or 17-alpha hydroxyprogesterone (medroxyprogesterone acetate, megestrol acetate). The type and dose of progestin affects the action of estrogen on circulating lipoprotein levels. Derivatives of 19-nortestosterone are potent progestins, and reduce HDL levels. In contrast, the use of medroxyprogesterone acetate for the purpose of postmenopausal hormone replacement does not reverse the effect of estrogen on serum LDL levels, but does attenuate the estrogen-induced rise in HDL levels.14 Whether the beneficial effect of estrogen therapy on cardiovascular disease is antagonized by concomitant progestin use remains to be elucidated. Estrogens influence the growth of normal breast tissue. The observation that long-term use of exogenous estrogen increases the risk of endometrial carcinoma has led investigators to examine the effect of estrogen replacement therapy on the development of breast cancer. Breast cancer is a multifactorial disease, influenced by various factors, including advanced age, country of birth, family history of breast cancer, age at first full-term pregnancy, and age of menarche and menopause. Although the endocrinologic relationship between estrogen and breast cancer remains unclear, the relative risk of developing this disease probably increases after 5 to 10 years of estrogen use. A meta-analysis of 37 original studies by Sillero-Arenas et aL15 has shown that estrogen use for longer than 12 years increases the risk of breast cancer by 23%. Interestingly, the prognosis after breast cancer diagnosed in women exposed to exogenous estrogen may be better than in women not exposed to hormone therapy, although it is unclear whether this finding reflects estrogen action on
MENOPAUSAL
AND
POSTMENOPAUSAL
tumor induction, or close surveillance of women receiving hormone therapy.16 Therefore, I advise women that long-term estrogen therapy is required to prevent osteoporosis and decrease the incidence of CHD, and that it may increase slightly the risk of developing breast cancer. Although breast cancer affects one in every ten women, and is the leading female cancer in the United States, the reduction in morbidity and mortality rates from osteoporosis and CHD justifies the use of estrogen replacement therapy even if it is associated with a modest increase in breast cancer risk. Commonly used oral estrogen preparations for postmenopausal hormone replacement include CEE, estrone sulfate, and micronized 17f-estradiol. Recently, therapeutic blood levels of estradiol have been achieved in postmenopausal women receiving transdermal estradiol (TE). Nonhepatic markers of estrogen action respond similarly to the 50-zg TE patch and 0.625 mg CEE, and to the 100-gig TE patch and 1.25 mg CEE.17 Daily use of 50 ig TE by postmenopausal women has been shown to alleviate hot flashes and prevent postmenopausal bone loss.18 It is important to remember that percutaneous estrogen delivery stimulates endometrial proliferation, and administration of 100 zg TE for 96 weeks is associated with a 42% incidence of endometrial hyperplasia.’9 Consequently, the use of TE should be combined with progestin therapy when delivered to a postmenopausal woman with an intact uterus. Oral estrogens have a significant impact on hepatic lipoprotein regulation because they are delivered to the liver in high concentration by the enterohepatic circulation (first-pass liver effect). This phenomenon, however, can cause erratic circulating estrogen levels because of steroid metabolism and elevation in renin-substrate leading to hypertension. Transdermal absorption of estradiol avoids the enterohepatic circulation, which reduces steroid metabolism but also diminishes the action of estrogen on hepatic lipoprotein regulation. Transdermal estradiol administration for I month is not associated with the beneficial changes in circulating lipoprotein levels induced by oral estrogen.’7 Because estrogen’s cardioprotective actions are complex, and involve mechanisms other than that of cholesterol transport, the degree to which TE administration affects the risk of developing CHD remains to be elucidated. The recent observation, however, that serum LDL levels are significantly decreased after TE therapy for 6 months underscores the danger in predicting the effect of prolonged estrogen therapy on CHD by studies examining short-term estrogen action.2#{176} Whether all women approaching menopause should be offered hormone replacement therapy is
CLINICAL
THERAPEUTIC
CONFERENCE
WOMEN
controversial. Although the degree to which bone demineralization occurs varies with individuals, urinary calcium excretion is inversely related to serum levels of endogenous estrone and estradiol. The postclimacteric ovary produces little, if any, estrogen, because oophorectomy after menopause does not affect circulating levels of estradiol or estrone. Similarly, estrogen production by the adrenal is not significant. The source of estrogen in postdlimacteric women reflects steroid metabolism by adipose tissue, which aromatizes androstenedione to estrone, and then converts some of this estrone to estradiol. It is important to recognize that extraglandular aromatization is positively correlated with body mass, and this phenomenon may explain why postmenopausal women sustaining fractures have a mean body weight less than that of age-matched normal women. Conversely, obese postclimacteric women have elevated circulating estrogen levels and are at greater risk of developing estrogen-dependent carcinoma, e.g., breast and endometrial carcinoma, compared with asthenic individuals. Because a reliable method for predicting the rate of bone demineralization has not been established, we continue to offer hormone replacement therapy to most postmenopausal women. In conclusion, postmenopausal estrogen replacement therapy plays a significant role in the treatment of estrogen deficiency, and in the prevention of osteoporosis. Long-term estrogen therapy stimulates endometrial proliferation, so that estrogen-treated women with an intact uterus should receive concomitant progestin therapy to eliminate the risk of endometrial hyperplasia and cancer. Prolonged estrogen administration modestly increases the risk of breast cancer. Oral estrogen therapy appears to be cardioprotective, and this action is due, in part, to the firstpass liver effect, which induces a favorable influence on circulating lipoprotein concentrations. Transdermal estradiol delivery does not depend on initial absorption through the enterohepatic circulation, and its efficacy in the prevention of CHD remains to be determined. Mt. Sinai: I enjoyed your lecture very much. I would like to get your help on a case that I have had to deal with, and that I think is very difficult. I swear to you that I am not making up any of these facts. I have a patient who is in her mid-40s and is an immigrant from Germany. She has a very slight build, smokes cigarettes, and had an estrogen-receptor-positive breast cancer in her 30s. She underwent an angioplasty for stenosis of the superficial femoral artery, and currently is doing well. Her serum lipid levels are normal. After a hysterectomy and bilateral oo-
777
DUMESIC
phorectomy several years ago, her gynecologist placed her on estrogen/progesterone therapy. She and I were very nervous about this, and I searched the literature but could not find anything to help me advise her whether to continue or discontinue this treatment. We eventually discontinued it, but I wonder if you might have any input on this. Dumesic: Although there is no strong evidence that exogenous estrogen therapy increases the incidence of recurrent breast cancer, many physicians are reluctant to offer these women estrogen. A recent study by Dr. Richard Love at our institution has demonstrated that tamoxifen, a nonsteroidal antiestrogen used for breast cancer treatment, has an estrogenic effect on bone. Postmenopausal women receiving tamoxifen for 2 years had a significant decrease in bone turnover as compared with women receiving placebo. It would certainly be helpful for these individuals to have an agent that is antiestrogenic at the breast and estrogenic at the bone. Progestins induce endometrial atrophy, but we are reluctant to use them in breast cancer patients because they promote mammary epithelial proliferation in animal models. This woman obviously requires close surveillance, and should undergo serial mammography to watch for recurrent disease. REFERENCES Nickens HW: A review of fractures affecting the occurrence outcome of hip fractures, with special reference to psychosoissues. JAm Geriatr Soc 1983;31:166-170. 2. Kaplan FS: Osteoporosis: Pathophysiology and prevention. CIin Symp 1987; 39:1-32. 3. Eriksen EF, Colvard DS, Berg NJ, Graham ML, Mann KG, Spelsberg IC, Riggs BL: Evidence of estrogen receptors in normal human osteoblast-like cells. Science 1988; 241:84-86. 1.
and cial
4. Christiansen C. Christensen MS, Transbol I: Bone mass menopausal women after withdrawal of oestrogen/gestagen placement therapy. Lancet 1981; 1:459-461. 5. Ettinger B, Genant ment therapy prevents 1985; 102:319-324.
HK, Cann CE: Long-term bone loss and fracture.
778
I
B, Genant HK, Cann CE: Postmenopausal by treatment with low-dosage estrogen Med 1987;106:40-45.
J COn Pharmacol
1992;32:774-778
10. the
of estradiol on blood lipids and lipoprowomen. Obstet Gynecol 1988; 72:18S-
Knopp RH: The effects of postmenopausal incidence of artioscierotic vascular
1988;
estrogen therapy on disease. Obstet Gynecol
72:23S-30S.
11. Steinleitner A, Stanczyk FZ, Levin JH: Decreased in vitro production of 6-keto prostaglandin F2 alpha by uterine arteries from postmenopausal women. Am J Obstet Gynecol 1989;161:16771681. 12.
McGuill
cular
HC:
system.
Sex
hormone
steroid
Postgrad
Med
1989;
receptors
in the cardiovas-
April:64-69.
13. Studd JWW, Thom MH, Paterson MEL, Wade-Evans T: The prevention and treatment of endometrial pathology in postmenopausal women receiving exogenous estrogens, in Pasetto N, Paoletti R, Ambrus JL teds.): The Menopause and Post-menopause. Lancaster: MTP Press, 1979;127-139. 14. Hirvonen E, Malkonen M, Manninen V: Effects of different progestogens on lipoproteins during postmenopausal replacement therapy. N EngI J Med 1981;304:560-563. 15. Sillero-Arenas M, Delgado-Rodriguez M, Rodigues-Canteras R, Bueno-Cavanillas A, Galvez-Vargas R: Menopausal hormone replacement therapy and breast cancer: A meta-analysis. Obstet Gynecol
1992;
79:286-294.
16. Bergkvist L, Adami HO, Persson I, Bergstrom R, Krusemo UB: Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1989; 130:221-228. 17. Judd HL: Efficacy of transdermal estradiol. Am I Obstet Gynecol
1987;156:1326-1331.
18. Ribot C, Tremollieres F, Pouilles JM, Louvet JP, Peyron R: Preventive effects of transdermal administration of 17 beta-estradiol on postmenopausal bone loss: A 2-year prospective study. Gynecol Endocrinol 1989; 3:259-267. 19. HL: trial 201.
Clisham Long-term histology
PR,
Cedars MI, Greendale transdermal estradiol and bleeding patterns.
G, Fu YS, Gambone J, Judd therapy: Effects on endomeObstet Gynecol 1992; 79:196-
20. Crook DC, Cust MP, Gangar KF, Worthington M, Hillard TC, Stevenson JC, Whitehead MI, Wynn V: Comparison of transdermal and oral estrogen-progestin replacement therapy: Effects on serum lipids and lipoproteins. Am J Obstet Gynecol 1992; 166:950955.
in postre-
estrogen replaceAnn Intern Med
6. Kiel DP, Felson DT, Anderson JJ, wilson PWF. Moskowitz MA: Hip fracture and the use of estrogens in postmenopausal women: the Framingham study. N EngI J Med 1987;317:1169-1174. 7. Riis B, Thomsen K, Christiansen C: Does calcium supplementation prevent postmenopausal bone loss? A double-blind controlled clinical study. N Engi J Med 1987; 316:173-177. 8. Ettinger prevented Ann Intern
9. Fahraeus L: The effects teins in postmenopausal 22S.
bone loss is with calcium.
Discussant Daniel A. Dumesic, MD Associate Professor, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Wisconsin, Madison, Madison, WI. The
clinical
cal School
Therapeutic
as part
The editor for the support
thanks
of the
conferences Medical
CIBA-Geigy
of this conference.
Grand Corporation
are
held
Rounds
at the
Chicago
Medi-
Program.
for their
educational
grant
Clinical Conference
Editorial
Therapeutic
THERAPEUTIC
CONFERENCE
Conference
Board
John C. Somberg, MD, Editor Hector Gomez, MD, Associate
Editor
Robert Piepho, PhD Andrew Whelton, MD Gilbert Mayor, MD Harold Neu, MD Atul Laddu, MD
O steoporosis
is better prevented than treated, and the prophylactic hormonal management of menopause may circumvent some of the symptoms experienced by patients. The mean age of menopause has not changed since classical times, and has remained at approximately 50 years. The female geriatric population has increased in size, however, as life expectancy has extended to beyond age 80. By the year 2025, there will be more than 58 million elderly United States citizens. Women will live one third of their lives in this age group, which will allow sufficient time for the effects of bone demineralization to significantly impact public health. The role of estrogen replacement therapy has expanded from treatment of atrophic vaginitis and symptomatic hot flashes, to include prevention of osteoporosis with knowledge that estrogen plays a pivotal role in the regulation of bone metabolism. As a review, the low-estrogen milieu of the climacteric is insufficient to sustain estrogen-dependent tissues of the reproductive tract. The uterus decreases in size, and endometrial atrophy induces menopause. Decreased glycogen within the vaginal epithelium causes thinning of the vaginal mucosa, atrophic vaginitis (e.g., bleeding, pruritis, monilial infection), and stenosis of the upper vagina, occasionally resulting in painful sexual relations, or dyspareunia. The urethra and skin of the external genitalia also are responsive to estrogen, and atrophy in these regions results in dysuria, vulvar pruritis, and diminished size of the labia minora. Tissues of the reproductive tract respond dramatically to estrogen supplementation. Vasomotor instability, or the hot flash, is defined as the sensation of heat over the face, neck, and
774
#{149} J Clin Pharmacol
1992;32:774-778
thorax, accompanied by reddening in these regions, and profuse sweating. It is the most common complaint of the climacteric, occurring in 50 to 76% of women with physiologic or surgical menopause. More than 85% of women with hot flashes continue to experience them 1 year later, although the flashes may diminish in intensity and frequency. The subjective symptoms of the hot flash last 0.5 to 5 minutes (mean, 4 minutes), and occur at irregular intervals, often being preceded by palpitations and headache. Hot flashes occurring at night are particularly symptomatic because they diminish rapid eye movement sleep, and lead to sleep deprivation, e.g. insomnia, irritability, and mood change. The physiologic changes accompanying the hot flash include peripheral vasodilation, sweating, elevated heart rate, and increased oxygen consumption. These events promote heat loss via redistribution of blood flow to the periphery, and reflect a change in the set point of the hypothalamic thermoregulatory center. Peripheral blood flow increases approximately 1.5 minutes before and continues for several minutes beyond the subjective symptoms of the hot flash. Perspiration, as measured by a change in skin conductance, begins 2.5 minutes later, and is accompanied by chills as core body temperature drops 0.2#{176}C. Hypothalamic norepinephrine may play a role in initiating vasomotor instability by stimulating sympathetic neurons within the cervical spinal cord that control regional vasodilation. This theory is supported by the fact that gonadectomy in animals increases hypothalamic norepinephrine, and enhances the activity of tyrosine hydroxylase, the enzyme responsible for catecholamine synthesis. Regardless of its cause, hot flashes also respond to estrogen replacement therapy.
MENOPAUSAL
DISCUSSION:CURRENT MANAGEMENT POSTMENOPAUSAL
OF
PERSPECTIVE MENOPAUSAL WOMEN
AND
IN
POSTMENOPAUSAL
THE
AND
Osteoporosis affects at least 20 million Americans, most of whom are postmenopausal women and elderly people. At least 1.2 million fractures related to osteoporosis occur in the United States annually, and vertebral fractures are present in one third of women older than age 65. By age 90, 33% of women and 17% of men will experience hip fractures, which will decrease expected survival by 5 to 20%.1 Fifty percent of women sustaining a hip fracture will be unable to ambulate normally after the fracture occurs. Osteoporosis is characterized by a decrease in bone density, and two types of this disease have been identified. This discussion focuses on type I osteoporosis, which is associated with accelerated bone loss in women during the menopausal years, and primarily affects trabecular bone, lending to vertebral and wrist fractures 15 to 20 years after ovarian failure. Type 2 osteoporosis is associated with slow, progressive bone loss in both sexes, and leads to fractures after the age of 70. Bone is a dynamic tissue, with resorption, formation, and remodeling occurring throughout life. Osteoporosis results when there is an imbalance between bone resorption and formation, with a chronic negative calcium balance causing mobilization of calcium from trabecular bone. Estrogen deficiency is a significant factor in the development of osteoporosis, and has been associated with a transient increase in serum calcium, a compensatory decrease in serum parathyroid hormone levels, hypercalciuria (negative calcium balance), and increased urinary loss of phosphorus and hydroxyproline. The rate of trabecular bone loss is 4 to 8% annually in the 5 to 8 years after menopause, and women lose 35% of their cortical bone and 50% of their trabecular bone through life.2 Estrogen exerts a protective effect on bone, in part by inhibiting bone reabsorption. Although the complex mechanisms of estrogen action on bone may be indirect, estrogen receptors have been identified on osteoblasts, and these cells appear to increase collagen production after estrogen administration.3 In addition, local growth factors, including fibroblast growth factor, transforming growth factor, insulinlike growth factor, beta2-microglobulin, and platelet-derived growth factor are present in skeletal tissue, and may regulate bone metabolism under the influence of hormones. Christiansen et al.4 have demonstrated that menopausal women receiving estrogen therapy for 2 years maintain bone mass, whereas placebo-treated women exhibit a significant decline. The rate of
CLINICAL
THERAPEUTIC
CONFERENCE
WOMEN
bone loss increased to 2.3% after estrogen therapy was discontinued, whereas untreated women stopped losing bone when reassigned to estrogen therapy after 2 years. These data suggest that it is unlikely that a 78-year-old woman suffering from osteoporosis will benefit by estrogen, because most bone loss has already occurred. Estrogen administration early after menopause may have prevented her symptoms, but would require prolonged therapy to prevent bone loss over time. Long-term estrogen users have a decrease in the risk of spine, wrist, and hip fracture as compared with nonusers.56 Oral administration of conjugated equine estrogens (CEE; 0.625 mg daily) is commonly used in the United States as prophylaxis against osteoporosis. At the University of Wisconsin, we see several young women with hypoestrogenic conditions, including anorexia nervosa, hypothalamic amenorrhea, and premature loss of ovarian function, who are interested in prevention of osteoporosis, and ingest calcium supplements without estrogen therapy. We tell these patients that, although calcium metabolism is important for healthy bone, calcium supplementation alone does not seem to be effective in preventing osteoporosis. Riis et al.7 have shown that calcium intake of I to 2 g is not effective in preventing vertebral body bone loss in early menopause. When calcium supplementation (1500 mg daily) is combined with oral CEE (0.3 mg daily), however, protection against bone loss is achieved.8 We occasionally use this combination of low-dose estrogen therapy and calcium supplementation in women complaining of mastalgia, but follow all of these patients with radiologic assessment of bone density. The above notwithstanding, cardiovascular disease is the leading cause of death in women older than age 67 in the United States. Approximately 250,000 deaths occur annually in women with coronary heart disease (CHD), and I in 7 women between ages 45 and 64 have some form of heart disease. The pathogenesis of CHD is, in part, related to circulating cholesterol, which is transported in plasma by macromolecules called lipoproteins. Five major lipoprotein fractions exist: chylomicrons, very-low-density lipoprotein, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and intermediate-density lipoproteins. Chylomicrons transport dietary cholesterol and triglycerides from the intestine to body tissues, including the liver, where it is incorporated into bile acids and very-low-density lipoprotein. Very-lowdensity lipoprotein contains mostly exogenous triglycerides, and is a risk factor for coronary heart disease in women. It is converted by capillary lipoprotein lipase in adipose and muscle to intermediate-density lipoprotein, which subsequently is
775
DUMESIC
metabolized by the liver to LDL. Low-density lipoprotein carries 70% of total cholesterol to hepatic and extrahepatic cells for structural and metabolic requirements, and is atherogenic in both sexes. A 2% increase in the risk of myocardial infarction accompanies every 1% increase in total cholesterol level. High-density lipoprotein carries cholesterol from the arterial wall to the liver, e.g., reverse cholesterol transport, where it is metabolized and excreted via the bile duct; HDL levels, particularly those of the HDL2 subfraction, are inversely proportional to cardiovascular disease. The development of cardiovascular disease is related to several risk factors, including positive family history, age, obesity, hypertension, diabetes mellitus, and cigarette smoking. Menopause also appears be a risk factor because postmenopausal women are at greater risk of cardiovascular disease than agematched premenopausal women, and estrogen deficiency is accompanied by an elevation in circulating LDL and total cholesterol levels. Evidence that estrogen exerts a cardioprotective effect comes from demographic studies showing greater mortality rates in men than in premenopausal women, and an increased heart attack rate in women after menopause. Bilateral oophorectomy in premenopausal women also increases the frequency of heart disease. Oral administration of estrogen increases serum HDL2 concentrations, and decreases serum LDL and total cholesterol levels.9 These effects of exogenous estrogen on circulating lipoproteins may contribute to the reduction of CHD in postmenopausal women receiving estrogen therapy.’#{176} The lipid hypothesis, however, accounts for only 25 to 50% of the beneficial effect of estrogen on CHD, and, therefore, other estrogen actions on cardiovascular function must be operative. Estrogen increases arterial prostacyclin levels, potentially inhibiting local platelet aggregation, and also binds to specific receptors on myocardium and coronary arteries.11’12 A 50% reduction in the relative risk of CHD reported in some studies would have a significant impact on women’s healthcare in our society.1#{176} Estrogen stimulates endometrial mitogenesis, and promotes proliferation of epithelial and stromal cells. Therefore, it is not surprising to find that postmenopausal estrogen use increases the risk of developing endometrial carcinoma by fourfold to eightfold. Progestins antagonize estrogen action on the endometrium, so that their use has been successful in preventing estrogen-induced endometrial hyperplasia and carcinoma. Addition of a progestin for at least 13 days monthly reduces the incidence of endometrial hyperplasia to below that of the general population.13 Unfortunately, sequential administration of
776
#{149} J Clin Pharmacol
1992;32:774-778
medroxyprogesterone acetate (5 to 10 mg daily for 13 days per month) in combination with oral CEE (0.625 mg daily) is usually associated with inconvenient monthly menstruation. Continuous use of medroxyprogesterone acetate (2.5 mg daily) in conjunction with 0.625 mg CEE induces amenorrhea in most patients after 1 year, but causes irregular bleeding in one third of these individuals during the first months of therapy. Both sequential and continuous progestin regimens induce endometrial atrophy in women receiving postmenopausal estrogens, and do not interfere with the beneficial effects of estrogen on bone turnover. All menopausal women with an intact uterus should receive a progestin with estrogen replacement therapy, and should be advised to expect monthly menstruation and irregular spotting with the sequential and continuous use of progestin. Progestins used for postmenopausal hormone therapy are derived from either 19-nortestosterone (norethindrone, norethindrone acetate, levonorgestrel, lynestrenol, ethynodiol diacetate, and desogestrel), or 17-alpha hydroxyprogesterone (medroxyprogesterone acetate, megestrol acetate). The type and dose of progestin affects the action of estrogen on circulating lipoprotein levels. Derivatives of 19-nortestosterone are potent progestins, and reduce HDL levels. In contrast, the use of medroxyprogesterone acetate for the purpose of postmenopausal hormone replacement does not reverse the effect of estrogen on serum LDL levels, but does attenuate the estrogen-induced rise in HDL levels.14 Whether the beneficial effect of estrogen therapy on cardiovascular disease is antagonized by concomitant progestin use remains to be elucidated. Estrogens influence the growth of normal breast tissue. The observation that long-term use of exogenous estrogen increases the risk of endometrial carcinoma has led investigators to examine the effect of estrogen replacement therapy on the development of breast cancer. Breast cancer is a multifactorial disease, influenced by various factors, including advanced age, country of birth, family history of breast cancer, age at first full-term pregnancy, and age of menarche and menopause. Although the endocrinologic relationship between estrogen and breast cancer remains unclear, the relative risk of developing this disease probably increases after 5 to 10 years of estrogen use. A meta-analysis of 37 original studies by Sillero-Arenas et aL15 has shown that estrogen use for longer than 12 years increases the risk of breast cancer by 23%. Interestingly, the prognosis after breast cancer diagnosed in women exposed to exogenous estrogen may be better than in women not exposed to hormone therapy, although it is unclear whether this finding reflects estrogen action on
MENOPAUSAL
AND
POSTMENOPAUSAL
tumor induction, or close surveillance of women receiving hormone therapy.16 Therefore, I advise women that long-term estrogen therapy is required to prevent osteoporosis and decrease the incidence of CHD, and that it may increase slightly the risk of developing breast cancer. Although breast cancer affects one in every ten women, and is the leading female cancer in the United States, the reduction in morbidity and mortality rates from osteoporosis and CHD justifies the use of estrogen replacement therapy even if it is associated with a modest increase in breast cancer risk. Commonly used oral estrogen preparations for postmenopausal hormone replacement include CEE, estrone sulfate, and micronized 17f-estradiol. Recently, therapeutic blood levels of estradiol have been achieved in postmenopausal women receiving transdermal estradiol (TE). Nonhepatic markers of estrogen action respond similarly to the 50-zg TE patch and 0.625 mg CEE, and to the 100-gig TE patch and 1.25 mg CEE.17 Daily use of 50 ig TE by postmenopausal women has been shown to alleviate hot flashes and prevent postmenopausal bone loss.18 It is important to remember that percutaneous estrogen delivery stimulates endometrial proliferation, and administration of 100 zg TE for 96 weeks is associated with a 42% incidence of endometrial hyperplasia.’9 Consequently, the use of TE should be combined with progestin therapy when delivered to a postmenopausal woman with an intact uterus. Oral estrogens have a significant impact on hepatic lipoprotein regulation because they are delivered to the liver in high concentration by the enterohepatic circulation (first-pass liver effect). This phenomenon, however, can cause erratic circulating estrogen levels because of steroid metabolism and elevation in renin-substrate leading to hypertension. Transdermal absorption of estradiol avoids the enterohepatic circulation, which reduces steroid metabolism but also diminishes the action of estrogen on hepatic lipoprotein regulation. Transdermal estradiol administration for I month is not associated with the beneficial changes in circulating lipoprotein levels induced by oral estrogen.’7 Because estrogen’s cardioprotective actions are complex, and involve mechanisms other than that of cholesterol transport, the degree to which TE administration affects the risk of developing CHD remains to be elucidated. The recent observation, however, that serum LDL levels are significantly decreased after TE therapy for 6 months underscores the danger in predicting the effect of prolonged estrogen therapy on CHD by studies examining short-term estrogen action.2#{176} Whether all women approaching menopause should be offered hormone replacement therapy is
CLINICAL
THERAPEUTIC
CONFERENCE
WOMEN
controversial. Although the degree to which bone demineralization occurs varies with individuals, urinary calcium excretion is inversely related to serum levels of endogenous estrone and estradiol. The postclimacteric ovary produces little, if any, estrogen, because oophorectomy after menopause does not affect circulating levels of estradiol or estrone. Similarly, estrogen production by the adrenal is not significant. The source of estrogen in postdlimacteric women reflects steroid metabolism by adipose tissue, which aromatizes androstenedione to estrone, and then converts some of this estrone to estradiol. It is important to recognize that extraglandular aromatization is positively correlated with body mass, and this phenomenon may explain why postmenopausal women sustaining fractures have a mean body weight less than that of age-matched normal women. Conversely, obese postclimacteric women have elevated circulating estrogen levels and are at greater risk of developing estrogen-dependent carcinoma, e.g., breast and endometrial carcinoma, compared with asthenic individuals. Because a reliable method for predicting the rate of bone demineralization has not been established, we continue to offer hormone replacement therapy to most postmenopausal women. In conclusion, postmenopausal estrogen replacement therapy plays a significant role in the treatment of estrogen deficiency, and in the prevention of osteoporosis. Long-term estrogen therapy stimulates endometrial proliferation, so that estrogen-treated women with an intact uterus should receive concomitant progestin therapy to eliminate the risk of endometrial hyperplasia and cancer. Prolonged estrogen administration modestly increases the risk of breast cancer. Oral estrogen therapy appears to be cardioprotective, and this action is due, in part, to the firstpass liver effect, which induces a favorable influence on circulating lipoprotein concentrations. Transdermal estradiol delivery does not depend on initial absorption through the enterohepatic circulation, and its efficacy in the prevention of CHD remains to be determined. Mt. Sinai: I enjoyed your lecture very much. I would like to get your help on a case that I have had to deal with, and that I think is very difficult. I swear to you that I am not making up any of these facts. I have a patient who is in her mid-40s and is an immigrant from Germany. She has a very slight build, smokes cigarettes, and had an estrogen-receptor-positive breast cancer in her 30s. She underwent an angioplasty for stenosis of the superficial femoral artery, and currently is doing well. Her serum lipid levels are normal. After a hysterectomy and bilateral oo-
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phorectomy several years ago, her gynecologist placed her on estrogen/progesterone therapy. She and I were very nervous about this, and I searched the literature but could not find anything to help me advise her whether to continue or discontinue this treatment. We eventually discontinued it, but I wonder if you might have any input on this. Dumesic: Although there is no strong evidence that exogenous estrogen therapy increases the incidence of recurrent breast cancer, many physicians are reluctant to offer these women estrogen. A recent study by Dr. Richard Love at our institution has demonstrated that tamoxifen, a nonsteroidal antiestrogen used for breast cancer treatment, has an estrogenic effect on bone. Postmenopausal women receiving tamoxifen for 2 years had a significant decrease in bone turnover as compared with women receiving placebo. It would certainly be helpful for these individuals to have an agent that is antiestrogenic at the breast and estrogenic at the bone. Progestins induce endometrial atrophy, but we are reluctant to use them in breast cancer patients because they promote mammary epithelial proliferation in animal models. This woman obviously requires close surveillance, and should undergo serial mammography to watch for recurrent disease. REFERENCES Nickens HW: A review of fractures affecting the occurrence outcome of hip fractures, with special reference to psychosoissues. JAm Geriatr Soc 1983;31:166-170. 2. Kaplan FS: Osteoporosis: Pathophysiology and prevention. CIin Symp 1987; 39:1-32. 3. Eriksen EF, Colvard DS, Berg NJ, Graham ML, Mann KG, Spelsberg IC, Riggs BL: Evidence of estrogen receptors in normal human osteoblast-like cells. Science 1988; 241:84-86. 1.
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4. Christiansen C. Christensen MS, Transbol I: Bone mass menopausal women after withdrawal of oestrogen/gestagen placement therapy. Lancet 1981; 1:459-461. 5. Ettinger B, Genant ment therapy prevents 1985; 102:319-324.
HK, Cann CE: Long-term bone loss and fracture.
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of estradiol on blood lipids and lipoprowomen. Obstet Gynecol 1988; 72:18S-
Knopp RH: The effects of postmenopausal incidence of artioscierotic vascular
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11. Steinleitner A, Stanczyk FZ, Levin JH: Decreased in vitro production of 6-keto prostaglandin F2 alpha by uterine arteries from postmenopausal women. Am J Obstet Gynecol 1989;161:16771681. 12.
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13. Studd JWW, Thom MH, Paterson MEL, Wade-Evans T: The prevention and treatment of endometrial pathology in postmenopausal women receiving exogenous estrogens, in Pasetto N, Paoletti R, Ambrus JL teds.): The Menopause and Post-menopause. Lancaster: MTP Press, 1979;127-139. 14. Hirvonen E, Malkonen M, Manninen V: Effects of different progestogens on lipoproteins during postmenopausal replacement therapy. N EngI J Med 1981;304:560-563. 15. Sillero-Arenas M, Delgado-Rodriguez M, Rodigues-Canteras R, Bueno-Cavanillas A, Galvez-Vargas R: Menopausal hormone replacement therapy and breast cancer: A meta-analysis. Obstet Gynecol
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16. Bergkvist L, Adami HO, Persson I, Bergstrom R, Krusemo UB: Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1989; 130:221-228. 17. Judd HL: Efficacy of transdermal estradiol. Am I Obstet Gynecol
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18. Ribot C, Tremollieres F, Pouilles JM, Louvet JP, Peyron R: Preventive effects of transdermal administration of 17 beta-estradiol on postmenopausal bone loss: A 2-year prospective study. Gynecol Endocrinol 1989; 3:259-267. 19. HL: trial 201.
Clisham Long-term histology
PR,
Cedars MI, Greendale transdermal estradiol and bleeding patterns.
G, Fu YS, Gambone J, Judd therapy: Effects on endomeObstet Gynecol 1992; 79:196-
20. Crook DC, Cust MP, Gangar KF, Worthington M, Hillard TC, Stevenson JC, Whitehead MI, Wynn V: Comparison of transdermal and oral estrogen-progestin replacement therapy: Effects on serum lipids and lipoproteins. Am J Obstet Gynecol 1992; 166:950955.
in postre-
estrogen replaceAnn Intern Med
6. Kiel DP, Felson DT, Anderson JJ, wilson PWF. Moskowitz MA: Hip fracture and the use of estrogens in postmenopausal women: the Framingham study. N EngI J Med 1987;317:1169-1174. 7. Riis B, Thomsen K, Christiansen C: Does calcium supplementation prevent postmenopausal bone loss? A double-blind controlled clinical study. N Engi J Med 1987; 316:173-177. 8. Ettinger prevented Ann Intern
9. Fahraeus L: The effects teins in postmenopausal 22S.
bone loss is with calcium.
Discussant Daniel A. Dumesic, MD Associate Professor, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Wisconsin, Madison, Madison, WI. The
clinical
cal School
Therapeutic
as part
The editor for the support
thanks
of the
conferences Medical
CIBA-Geigy
of this conference.
Grand Corporation
are
held
Rounds
at the
Chicago
Medi-
Program.
for their
educational
grant
