The antiestrogenic effect of cigarette smoking in women

Current Development

The antiestrogenic effect of cigarette smoking in women John A. Baron, MD: Carlo La Vecchia, MD: and Fabio Levi, MDc Hanover, New Hampshire, Milan, Italy, and Lausanne, Switzerland Epidemiologic results indicate that women who smoke cigarettes are relatively estrogen-deficient. Smokers have an early natural menopause, a lowered risk of cancer of the endometrium, and an increased risk of some osteoporotic fractures . Moreover, women who smoke may have a reduced risk of uterine fibroids, endometriosis, hyperemesis gravidarum, and benign breast disease. Several possible mechanisms for these effects have been identified. Smoking does not appear to be clearly related to estradiol levels, at least in postmenopausal women, although levels of adrenal androgens are increased. Moreover, smoking appears to alter the metabolism of estradiol, leading to enhanced formation of the inactive catechol estrogens. (AM J OBSTET GVNECOL 1990;162:502-14.)

Key words: Cigarette smoking, breast cancer, endometrial cancer, estrogens, androgens

The harmful effects of cigarette smoking are not limited to tissues having direct smoke contact. For example, smokers have increased risks of cancer of the esophagus, kidneys, and bladder, presumably from swallowed or absorbed cigarette products. I·' Some hormonal effects of smoking, such as acute catecholamine and corticosteroid release, appear to be due to stimulation of the adrenal medulla or of the hypothalamus, with subsequent adrenocorticotropic hormone secretion!-I' Less well explained are the increased risks of infertility, ischemic heart disease, and cancer of the pancreas among smokers. 1-'. 13 Certain other effects at organs lacking direct smoke contact appear to follow an important pattern; in many ways women who smoke cigarettes behave as though they are relatively estrogen-deficient. Such an antiestrogenic effect of smoking would of course lead to an exacerbation of estrogen-deficiency problems, such as osteoporosis, but would also have unexpected beneficial effects on diseases caused by estrogen excess, such as endometrial cancer. This review summarizes the relationship between cigarette smoking and such estrogenrelated diseases and processes in women, in the context of available epidemiologic, clinical, and laboratory data.

From the Center, "Mario Institut

Department of Medicine, Dartmouth-Hitchcock Medical Hanover," the Instituto di Ricerche Farmacologtche, Negn," Milan,' and the Registre Vaudois des Tumeurs, Universitaire de Medecme Sociale et Preventive, Lau-

sannt'.C

Reprint requests: John A. Baron, MD, Dartmouth Medical School, Hinman Box 7927, Hanover, NH 03756. 6/1115587

502

Cancers of the breast and endometrium Cancers of the endometrium and breast are the malignancies of women most closely associated with reproductive hormones. Of these two, cancer of the endometrium is more directly associated with estrogenic stimuli" 14. 15and this difference is reflected in the relationships of these malignancies to smoking. More than 30 studies from 10 countries have considered breast cancer in relation to cigarette smoking. ' 6-54 In most, there was no substantial association. * Several of the studies reported moderately lowered risks among smokers, t although many of these results were not statistically significant, and other studies found some evidence of a positive association.* Analyses within age or menopausal groups have revealed no consistent effects,§ and there do not appear to be relationships between smoking and either estrogenreceptor-positive or estrogen-receptor-negative breast cancer. 51 . 52 Thus, overall, cigarette smoking does not appear to affect the risks of human breast cancer very strongly. In contrast, rats exposed to cigarette smoke develop fewer mammary tumors than those unexposed,54.5; although this may be due to differences in weight or survival. Mammary cancer in rodents is prolactindependent,56 and the lower risk of tumors may reflect a lowering of prolactin levels from long-term smoke exposure.'7. 58 Whatever the mechanism, the *References 49. tReferences :j:References §References

16, 18, 19, 25, 27, 28, 32, 33, 36, 39, 44,4617, 20, 22-24, 26, 29, 34, 37,41, 42. 21, 30, 31, 35, 38, 40, 43, 45, 50. 22, 29, 32, 35, 38, 40-43, 50, 53.

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Table I. Cigarette smoking and the incidence of endometrial cancer Study

Smith et aJ." Tyler et aJ.6' Franks et aJ. 66 Von Lau et aJ.60 Lesko et aJ. 63 Baron et aJ. 39 Zemla et aJ. 64 Lawrence et aJ.65

No. of cases/No. of controls and locale of study

70/612 Community 437/3,200 Community 79/416* Community 407/450 Clinic 510/727 Hospital 476/2128 Hospital 173/346 Hospital 200/200* Community

Lawrence et aJ. 69

84 / 16811 Community

Levi et aJ. 67 Stockwell and Lyman"

35711122 Hospital 1374/3921 Community

Koumantaki et aJ. 68

83/164 Hospital

Contrast

Continuous smoker vs. nonsmoker Current smoker vs. never-smoker Current smoker vs. nonsmoker Current smoker vs. never-smoker Current smoker vs. never-smoker 2: 15 pack year smoker vs. nonsmoker

Relatwe risk estimates

0.8 0.8 0.5t 0.6t 0.7t 0.6t

No consistent association across smoking strata Current smoker :sl pack/day >1 pack/day vs. never-smoker Current smoker :sl pack/day >1 pack/day vs. never-smoker Current smoker vs. never-smoker Current smoker <20/day 20-40/day >40/day vs. nonsmoker 20 yr of smoking vs. never-smoker

0.7§ 0.5§ 0.6 0.9 0.5t 0.9t 0.7 0.6 0.5*

*Postmenopausal women only. tStatistically different from I (p < 0.05). Early-stage cases. § Linear trend statistically significant (p < 0.025). II Late-stage cases.

*

absence of an effect of parenteral nicotine on nnitrosomethylurea-induced mammary tumors suggests that nicotine is not the smoke constituent responsible .'9 Of course, these results must be considered in light of the uncertain relationship between mammary tumors in rodents and human breast cancer. Data are more consistent regarding the effects of smoking on the endometrium. Among current cigarette smokers there may be a modest decrease in the risk of endometrial hyperplasia (Krieger N. Personal communication), and investigation of incident cases of endometrial cancer has repeatedly found currently smoking women to have a risk as low as half that of never-smokers (Table I). * A gradient of decreasing risk with increasing amounts smoked has been noted in several studies,'"39. 43 . 65 although not in others!1.6•. 66.67 The effect was generally more pronounced in postmenopausal than in premenopausal women,,,··3 6'.63.66.68 a

*References 22, 23, 27, 33, 39, 43. 53. 60-69.

pattern that requires further confirmation. Investigation of endometrial cancer mortality or advanced stage incidence has not been consistently related to smoking, 17.22. ' 5. 69 possibly because of the association of smoking with poor health practices that would delay treatment of this malignancy of generally low fatality. There are still uncertainties regarding the possible interactions of smoking with estrogen replacement and obesity. Several reports have found that smoking has particularly pronounced effects in high-risk groups such as the obese or those who take exogenous estrogens.' " 61. 64. 65·67 Also, it is not established whether exsmokers maintain a lower risk and, if so, for how long.

Benign neoplasms of the reproductive organs and other non-malignant processes Cigarette smoking is also related to other conditions of the female reproductive organs and pregnancy (Table II). Four studies found the risk of uterine fibroids to be modestly reduced among smoking

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Table II. Smoking and selected gynecologic conditions Study Uterine fibroids

Ross et aUI

Parazzini et al. 70 Wyshak et al. 72 E ndometnos!S

No. of cases/ No. of controls and locale of study

535 /535 Family planning clinic 275/722 Hospital Cohort study 520 Cases

Cramer et al. 7<

268/3794 I nfertility clinic

Hiller et aU5

293/312 Hospital! clinic 114/1127 Hospital

Parazzini et al. 76 Hyperemem gravidarum

Depue et al. 79

Klebanoff et aU8 Little and Hook" Weigel and Weigel80 Vellacott et al. 81

Contrast

419 /836 Perinatal Project centers 4517/3502 Perinatal Project centers 210t Health Maintenance Organization prenatal clinic 78/742 Clinic 500t Prenatal clinic

Relat!ve risk estimates

lO/day vs. nonsmoker

0.8*

Current vs. never-smoker

0.6*

Ever vs. never-smoker

0.8

Current vs. never-smoker 2: 1 pack / day before age 17 vs. never-smoker Current vs never-smoker

0.9 0.5* 0.4

Ever vs. never-smoker

1.0

Current vs. nonsmoker

0.6*

Smoker vs. nonsmoker

0 .7*

Smoker vs. nonsmoker

0 . 3*~

Recent vs. never-smoker

0.9

Smoker vs. never-smoker

0.5*~

*Statistically different from 1 (P < 0.05). tTotal number of subjects in the sample surveyed. ~ Derived from data given in reference.

women;" 70·72 and an investigation of terminated myomatous pregnancies supported these findings, though it did not control for age." Investigations of endometriosis conducted in infertility clinics have found that women who smoke cigarettes have a lowered risk/4 • 75 but endometriosis associated with other pelvic symptoms or limited to ovarian cysts appears to be less affected. 75 . 76 Hyperemesis gravidarum and vomiting of pregnancy are estrogen-related processes that also have generally been found to be inversely related to smoking."·81 Finally, women who smoke have been reported to have more symptoms that are possibly related to estrogen deficiency, such as irregular menses, menopausal complaints, and hirsutism. 82.9• Infertility is also more common among women who smoke, 13.95 but this appears to be largely due to fallopian tube dysfunction, perhaps related to pelvic infections. 13.96 Benign breast diseases are a heterogeneous diagnostic group and are strongly influenced by ovarian hormones.9 ' The available data relating them to smoking are rather inconsistent. 27 • '2.98-\03 Berkowitz et al.,IOO analyzing data from a large hospital-based study, found that postmenopausal current smokers were at significantly reduced risk of both fibrocystic disease and fibroadenoma. Pastides et al. 102 reported similar results for fibrocystic disease, and Wyshak et al.72 103 reported

an inverse relationship between smoking and fibrocystic disease ignoring menopausal status. Other published work, however, has generally shown no substantial association.98. 99. 101 These conflicting results may be due to the difficulties of identifying women with, and without, benign breast disease. In most studies the case series consisted of women seen for biopsy or removal of a breast mass, a group not necessarily representative of all women with the condition. In this situation both hospital and population-based controls may be an inadequate comparison. Age at natural menopause

Data from a variety of populations and study designs have showed that menopause typically occurs about 1 to 1.5 years earlier in current smokers than in neversmokers.38. 53. 83. 104·113 This hastening of the cessation of regular menstrual cycling could, in itself, exert an antiestrogenic influence, and the early menopause in smokers therefore may be a mechanism by which smoking exerts an antiestrogenic effect. The consistency of the finding, the absence of important covariate effects, and the presence of apparent dose-effect relationships with the number of cigarettes smoked'S. 10·•• 109. III indicate that the relation between

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current smoking and earlier natural menopause is probably causal. However, the interaction between smoking, weight, and menopause is not fully understood. In one large study, for instance, relative weight was inversely related to menopausal age among current smokers but not among exsmokers. 111 Further, it is not completely established whether natural menopause occurs earlier in exsmokers than in never-smokers. Various studies'" 83 I.... 107-1"". III reported menopausal rates for exsmokers that are intermediate between neversmokers and current smokers, generally much closer to those of never-smokers. An absence of a long-term effect would be at variance with the hypothesis that smoking advances menopause through a destruction of oocytes caused by the polycyclic aromatic hydrocarbons contained in cigarette smoke." ' Osteoporotic fractures

Since the initial reports of an association between cigarette smoking and osteoporotic fractures, 114 '" several other analyses have addressed that relationship." O-1.' Investigations of spinal fractures,l15 lIM. '2 0 though relatively informal, suggest a threefold or greater increase in risk for smokers. However, forearm fractures may be related to smoking only among thin, older women who never took menopausal estrogens. "7.120 There are more extensive data regarding fracture of the hip in women after menopause." 6 11 7. 11 9- '24 Three case-control studies" 6 . 11 7. '24 suggest that smokers have approximately a twofold increase in risk. Other investigations found no significant association with smoking or only a small increase in risk, 121. ,n '25 though they may have had poor power to detect an effect. Three other studies also reported only small increases in risk for smokers, but one was the only case-control study that used hospital controls,"9 another was a populationbased cross-sectional survey of fracture history, '20 and a third presented only combined data for men and women.,n In each of these, an effect of smoking in women could have been obscured. Thus, on balance, an association between cigarette smoking and postmenopausal fracture of the hip may well exist but appears modest. Finally, one study of fracture of the forearm or hip (reported together) among women 35 to 63 years old found no association of fracture risk with smoking." " Another study in men reported a n increased risk of vertebral fractures in smokers. IZ7 In investigations of the bones themselves (largely the radius or calcaneus), post-menopausal women who smoke often have been found to have lower bone mineral content (or smaller cortical width, etc.).' 15. I.". m-Ll4 Moreover, bone mass may fall at a higher rate in smokers. "o 133. 13. However, in these studies the differences

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505

between smokers and nonsmokers generally were not large (up to about 10%) and may be partially explained by body weight. 120 '30.132 Studies of men '28 131.137. 'lO. 141 or both sexes combined'··' '43 have typically shown lower bone density measures in smokers, although among premenopausal or perimenopausal women the differences have tended to be smaller." 5. ,.9 1:17.139 144-'47 Together, these data suggest that smoking is associated with osteoporosis and osteoporotic fractures in postmenopausal women, but the relationship may vary with age and the type of bone. Trabecular bone (which predominates in the spine and distal radius) is generally thought to be more susceptible to metabolic influences than cortical bone (which is relatively more important in the hip).148 Thus the spine and forearm would be more affected than the hip by smoking, and the epidemiologic results are more or less consistent with this pattern. There are several possible explanations for an association between cigarette smoking and osteoporosis besides an antagonism of estrogenic support of bone. Diet and alcohol use are potentially important covariates, and studies that controlled for them showed only small associations between smoking and hip fracture risk or bone mass.' 2'. 122 ' 33 '14 Other proposed mechanisms include changes in vitamin D levels or vitamin C levels and consequences of smoking-associated lung disease such as acidosis or aminophylline therapy." Commentary on the epidemiologic data

The pattern of relationships described above indicates that cigarette smoking is associated with effects in women that can be considered antiestrogenicreduced risks of problems associated with estrogen excess and increased risks for processes related to estrogen deficiency. Also, smoking tends to counteract estrogenic influences such as obesity and exogenous estrogens in relation to the risks of endometrial cancer, early menopause, and osteoporosis.53 The risk of breast cancer is not related to cigarette smoking, probably because for this malignancy the causal role of estrogens is weaker than for the other diseases. '4. '5 Alternatively, at this site, an indirect hormonal effect on the breast might be counterbalanced by a direct carcinogenic effect. The epidemiologic results have physiologic implications. For endometrial cancer, the effects of smoking may be more pronounced in postmenopausal women, presumably reflecting a greater influence on sex hormone systems that are less tightly regulated. Also, exsmokers may have only a modestly increased risk of early menopause. Assuming a substantial lifetime consumption, this implies that the effects of smoking on menopause are reversible. There is also some infor-

506 Baron, La Vecchia, and Levi

mation available regarding the risks of endometrial cancer, endometriosis, or uterine fibroids among those who have stopped smoking.43.63.65.67.70.75 In general, the risks are quite close to those of never-smokers, but there may be a residual effect for endometrial cancer and endometriosis. It might be expected that for endometrial cancer the impact of prolonged periods of relative estrogen deprivation would be permanent, as are the effects of an early menopause and oral contraceptives. 3. 148 The same might be predicted for osteoporosis with regard to postmenopausal smoking, but there are no published data 011 fillllltT ~lIlokers to document this. The role of age of menopause deserves comment. Early menopause is both a consequence of smoking and a causative or protective risk factor for many of the disorders considered here. 3. 70. 71. 95. 148 Thus an antiestrogenic effect of smoking in postmenopausal women might be partially explained by its hastening of the menopause. However, at least for endometrial cancer, it is only a small part of the effect; even after control for age at menopause, postmenopausal women who smoke cigarettes retain a substantially lowered risk.33. 63. 66. 67 Since exposure to cigarette smoking is relatively easy to assess, the major uncertainties of the epidemiologic data center around possible co variates and bias. Obesity tends to exert an estrogenic influence in postmenopausal women,149. 150 and the lower weight of smokers in comparison to never-smokers or exsmokers l51 may explain some of the relationships studied. In fact, if one assumes that smoking causes a lower body weight, then alteration of body habitus should be seen as a mechanism through which smoking acts. Diet and alcohol use are other possible covariates. Another important potential source of artifact is the choice of control groups in case-control studies. In hospital-based investigations, the controls would have an artifactually high smoking prevalence if smokers are admitted to hospital more than non-smokers or stay longer once admitted. This would lead to an underestimation of deleterious effects of smoking and exaggeration of "protective" ones. Population-based studies tend to avoid these potential problems. Ascertainment of disease is another potential difficulty in investigations of any design, since in certain settings factors associated with being diagnosed may appear to be etiologic. For example, if cigarette smokers seek health care more avidly than non-smokers, then cigarette smoking might appear to be associated with diseases that are only variably diagnosed. This is unlikely to be an issue for cancers or fractures, but it may distort findings regarding such problems as fibroids, menopausal symptoms, or mild endometriosis. Screening of defined groups is the best way to resolve this

February 1990 Am J Obstet Gynecol

issue and would be especially rewarding for investigation of benign breast disease, since the data regarding this condition are particularly variable. Clinical and laboratory data

Epidemiologic data thus suggest that women who smoke cigarettes behave physiologically as though they are relatively estrogen-deficient. However, investigation of hormone levels has yielded inconsistent results. MacMahon et al. 152 reported that premenopausal women who smoked had lower luteal phase urinary excretion of estrone, estradiol, and estriol than neversmokers. Exsmokers did not show this pattern, nor were there differences during the follicular phase. Similar results in both the follicular and luteal phase have been reported,153 though in postmenopausal women Trichopoulous et al. 154 found no differences between smokers and nonsmokers. There are important limitations of these analyses l55 ; the measured hormones account for less than half of the total metabolites of estradiol'''' 156 and it is the circulating hormones that are relevant for tissues. Levels of estrone and total estradiol have repeatedly been found to be similar in postmenopausal smokers and nonsmokers. "3. 138. 157-161 However, recently postmenopausal women who take oral estradiol and who smoke appear to have lower estradiol and estrone levels than similar nonsmoking women. 133,138 This implies that cigarette smoking affected the absorption, distribution, or metabolism of the estradiol. Pregnant women who smoke have lower circulating or urinary estriol levels compared with those of nonsmokers, as well as lower estradiol levels and subnormal conversion of dehydroepiandrosterone sulfate (DHEAS) to estradioI.162-166 However, these effects may simply be nonspecific, since other fetoplacental hormones also are depressed in smokers. 164. 166-168 Baron et al. 169 have used vaginal cytologic testing as an in-built "bioassay" of hormone effect in postmenopausal women. Even after consideration of weight, women who smoked cigarettes had a substantially higher maturation index and especially an increased proportion of intermediate cells. Since these results are consistent with an androgenic influence, they may reflect increases in the androgens androstenedione, dehydroepiandrosterone (DHEA), DHEAS, and testosterone that have been found in smoking postmenopausal women.157-159 However, except for testosterone, these hormones have little intrinsic androgenic potency. Their significance lies in the potential for conversion to more active forms such as testosterone or dihydrotestosterone. 170 DHEA, DHEAS, and (to a large extent) androstenedione are adrenal cortical hormones, and their asso-

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Table III. Possible mechanisms for an effect of cigarette smoking on estrogen-related phenomena Mechanism

1. Decreased production of estrogens Disturbed gonadotropin release Ovarian atresia Aromatase or other enzyme inhibition 2. Altered metabolism of estrogens Shift to catechol estrogens Other disturbances of metabolism 3. Increased circulating androgens Adrenal cortical stimulation Adrenal enzyme inhibition

Cigarette constituent Involved

References

Nicotine Polycyclic aromatic hydrocarbons Nicotine, carbon monoxide, others?

217-220 95,201-203 188-192

Polycyclic aromatic hydrocarbons

153, 193, 194,247 195-200

Nicotine Nicotine

5,6,10-12,157-159,171-180 182

Clatton with cigarette smoking is consistent with an acute increase in cortisol levels that may be seen with smoking after several hours of abstinence. 5. 6.10·12.171-174 This is presumably due to nicotine-induced adrenocorticotropic hormone release,175 though some investigators have disputed this.I72· 171. 176. 177 There may be habituation to this effect, whatever its mechanism; the total secretion of cortisol or 17 -hydroxysteroids appears not to be increased over longer periods of continued smoking.178.ls1 In vitro, nicotine can partially inhibit adrenal 11 (3hydroxylase and 21-hydroxylase. 182 This could explain the increased levels of the cortisol precursors DHEA and androstenedione in smokers. In fact, an androgenic or progestational effect might explain many of the epidemiologic findings summarized here. 183 An exception is osteoporosis, where androgenic or progestational influences would, if anything, increase bone density and decrease fracture risk. 184.185 Cigarette smoking could also affect sex hormone metabolism through induction or inhibition of other enzyme systems. For example, in postmenopausal women, most circulating estrogens are derived from aromatization of adrenal androgens, a conversion catalyzed by aromatase. 186. 187 Smoking women may have a lower metabolic clearance of androstenedione, consistent with an inhibition of this conversion,158 and in vitro nicotine does inhibit aromatase. 188 . 189 A study of placental aromatase activity in smokers and nonsmokers disclosed no differences, 190 consistent with an effect that is reversible if the inhibiting substance is removed. Aromatase inhibition, of course, would limit estrone and estradiol synthesis and might well be necessary to prevent smoking from increasing estrogen production through aromatization of the increased levels of androstenedione in smokers. Another enzyme-related mechanism by which smoking could limit the formation of estradiol is inhibition of C-20:22 desmolase, which would impair synthesis of both progestational and estrogenic hormones. 191. 192 Michnovicz et al. 153. IQ3 demonstrated an enhancement of 2-hydroxylation of estradiol in smokers, leading to

the formation of 2-hydroxyestradiol, which has virtually no agonist activity. Nonsmokers form relatively more estriol (with weak agonist properties), leaving them with more estrogenic activity. These results are consistent with the increased activity of 2-hydroxylation and 4-hydroxylation in placental microsomes of smokers,194 as well as with the reduced urinary excretion of estriol in premenopausal smokers. 152.153 Polycyclic aromatic hydrocarbons in tobacco smoke also may induce microsomal mixed function oxidase systems that metabolize sex hormones. 195 In vitro, these compounds can affect the metabolism of testosterone and androstenedione and can enhance the formation of catechol metabolites of estradiol. 195-198 On the other hand, carbon monoxide can inhibit some of these enzymes. 199.200 The clinical relevance of these in vitro results is not clear, but plausible mechanisms are suggested by which smoking might affect sex hormone metabolism. The fact that smoking alters hormone levels in postmenopausal women receiving oral estrogens, but not percutaneous ones, is consistent with such effects occurring in the liver. 138 There are other possible pathways for the antiestrogenic effect of smoking. Mattison 95 has noted that cigarette smoke extracts cause ovarian atresia in rodents, confirming earlier uncontrolled studies of cigarette smoke itself.2 10 (Parenteral nicotine seems to have no effect on the ovaries. 202 ) Mattison95 postulates that this could explain the early menopause seen in women who smoke; disturbances in estrogen-dependent processes before menopause could presumably be due to a similar toxic impact on the developing graafian follicle?O' While this could explain both the early menopause seen in smokers and other effects among premenopausal women, it could not explain how cessation of smoking would leave women at a virtually normal risk of early menopause, nor would it explain an antiestrogenic effect among post-menopausal women beyond that dependent on age at menopause. Cigarette smoking also might disturb hypothalamic regulation of ovarian secretion. Nicotine crosses the

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blood-brain barrier and is readily taken up by brain tissue,"04-206 where nicotinic cholinergic receptors are widespread.207-209 Both cigarette smoking and parenteral nicotine administration have been shown to affect neurotransmitter turnover, especially in adrenergic systems!lO. 211 An enhancement of dopamine turnover may explain the low prolactin levels and lowered risk of Parkinson's disease among smokers.i6; 2i2-216 In female rodents, cigarette smoke or parenteral nicotine (but apparently not carbon monoxide) inhibits luteinizing hormone release, presumably from hypothalamic dopaminergic stimulation. m -22o Thus a central disturbance could explain both menstrual irregularity in premenopausal smokers and the early cessation of menses but would not explain postmenopausal antiestrogenic effects. Men

Men who smoke cigarettes have a lower risk of benign prostatic hypertrophy than nonsmokers,22l·222 and dogs chronically exposed to cigarette smoke have smaller prostate glands as well!"' It is tempting to ascribe these effects to hormonal changes, and testosterone levels were, in fact, decreased in the dogs. In humans, however, men who smoke cigarettes generally have been found to have higher levels of testosterone and adrenal androgens and possibly higher levels of estradioJ.221-212 The mechanisms underlying these effects are not established but may include increased adrenal secretion and alterations in the production and metabolism of testosterone.223.242-246 The direct relevance of these results to women is unclear. However, these data do reinforce the fact that constituents of cigarette smoke can affect the production and metabolism of steroid hormones. Also, it is noteworthy that both male and female smokers have higher levels of adrenal androgens and increased 2hydroxylation of estrogens!27. 229. 230. 217 Comment

In conclusion, there is epidemiologic evidence that cigarette smoking affects several estrogen-related conditions in women. Smoking increases the risk of early menopause, reduces the risk of endometrial cancer, and probably increases the risk of osteoporotic fractures. Although available data are scanty, it appears that uterine fibroids, vomiting of pregnancy, and endometriosis are less common in smokers and menstrual irregularity and menopausal symptoms are aggravated. Epidemiologic evidence, on the other hand, is inconsistent in relation to benign breast disease. The mechanisms involved are not precisely understood and probably are complex and heterogeneous (Table III). To correspond with the epidemiology, the

February 1990 Am J Obstet Gyneco1

mechanisms must include reversible processes relevant to both premenopausal and postmenopausal women and possibly be more potent among the latter. Stimulation of adrenal androgen production with simultaneous aromatase inhibition could do this, although this would not explain the association of cigarette smoking with osteoporosis. It is also conceivable that different effects are relevant at different ages. For example, disturbance of gonadotropin release and follicular survival might playa role in premenopausal women, and alterations in peripheral metabolism in postmenopausal women. It is not clear what constituents of cigarette smoke are responsible for these effects. Nicotine has been directly implicated in decreased luteinizing hormone release, increased circulating cortisol levels, and inhibition of adrenal enzymes. Carbon monoxide or polycyclic aromatic hydrocarbons also may modulate the activity of enzymes involved in sex hormone metabolism or be directly toxic to ovarian follicles. The relationships summarized here help elucidate the pathophysiologic effects of smoking and illustrate how sex hormone systems in women are open to environmental influences. Some of the consequences of the hormonal disturbances caused by smoking are beneficial, such as the inverse association with endometrial cancer. However, the overall effect of smoking is clearly harmful, and cessation should continue to be a health priority for cigarette smokers. REFERENCES 1. Fielding ]E. Smoking: health effects and control. Part 1. N Engl] Med 1985;313:491-8. 2. International Agency for Research on Cancer. Tobacco smoking. IARC Monogr Eval Carcinog Risk Chern Hum 1985;38. 3. Schottenfeld D, Fraumeni]F Jr. Cancer epidemiology and prevention. Philadelphia: WB Saunders, 1982. 4. Silvette H, Larson PS, Haag HB. Action of nicotine and tobacco-smoking on the adrenal medulla. Arch Intern Med 1961;107:915-31. 5. Cryer PE, Haymond MW, Santiago lV, Shah SD. Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events. N Engl] Med 1976;295:573-7. 6. Quigley ME, Sheehan KL, Wilkes MM, Yen SSe. Effects of maternal smoking on circulating catecholamine levels and fetal heart rates. A~ ] OBSTET GY:-;ECOL 1979; 133:685-9. 7. Hokfelt B. The effect of smoking on the production of ad reno-cortical hormones. Acta Med Scand 1961; 170(suppl 369): 123-4. 8. Kershbaum A, Pappajohn D], Bellet S, et al. Effect of smoking and nicotine on adrenocortical secretion.] AMA 1968;203:275-8. 9. Suzuki T, Ikeda H, Narita S, et al. Adrenal cortical secretion in response to nicotine in conscious and anaesthetized dogs. Q] Exp Physiol 1973;58: 139-42. 10. Winternitz WW, Quillen D. Acute hormonal response to cigarette smoking.] Clin Pharmacol 1977; 17:389-97. 11. Gossain VV, Sherma NK, Srivastava L, et al. Hormonal

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13. 14. 15. 16. 17. 18.

19. 20. 21.

22.

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172. Seyler LE, Fertig J, Pomerleau 0, et al. The effects of smoking on ACTH and cortisol secretion. Life Sci 1984;34:57-65. 173. Baer L, Radichevich I. Cigarette smoking in hypertensive patients. Am J Med 1985;78:564-8. 174. Seyler LE Jr, Pomerleau OF, Fertig JB, et al. Pituitary hormone response to cigarette smoking. Pharmacol Biochern Behav 1986;24: 159-62. 175. Cam GR, Bassett JR, Cairncross KD. The action of nicotine on the pituitary-adrenal cortical axis. Arch Int Pharmacodyn 1979;247:49-66. 176. Rubin RP, Warner W. Nicotine-induced stimulation of steroidogenesis in adrenocortical cells of the cat. Br J Pharmacol 1975;53:357-62. 177. Turner DM. The role of adrenal catecholamines in the release of corticosterone and fatty acids by nicotine in the rat. Res Commun Chern Pathol Pharmacol 1975; 12:645-55. 178. Hokfelt B. The effect of smoking on the production of ad reno-cortical hormones. Acta Med Scand 1961; 170(suppI369):123-4. 179. Sode J, Tucci JR, Foreman DR, Sabol JJ. Adrenocortical activity in habitual smokers and non-smokers. Clin Res 1968;16:526. 180. Tucci JR, Sode J. Chronic cigarette smoking: effect on adrenocortical and sympathoadrenomedullary activity in man. JAMA 1972;221:282-5. 181. Benowitz NL, Kuyt F,Jacob P III. Influence of nicotine on cardiovascular and hormonal effects of cigarette smoking. Clin Pharmacol Ther 1984;36:74-81. 182. Barbieri RL, York CM, Cherry ML, Ryan KJ. The effects of nicotine, cotinine and anabasine on rat adrenal 1113hydroxylase and 21-hydroxylase. J Steroid Biochem 1987;24:1-4. 183. Greenblatt RB. The use of androgens in the menopause and other gynecologic disorders. Obstet Gynecol Clin North Am 1987;14:251-68. 184. Longcope C, Baker RS, Hui SL, Johnston CC Jr. Androgen and estrogen dynamics in women with vertebral crush fractures. Maturitas 1984;6:309-18. 185. Devogelaer JP, Crabbe J, de Deuxchaisnes CN. Bone mineral density in Addison's disease: evidence for an effect of adrenal androgens on bone mass. Br Med J 1987;294:798-800. 186. Grodin JM, Siiteri PK, MacDonald PC. Source of estrogen production in post-menopausal women. J Clin Endocrinol Metab 1973;36:207-14. 187. Siiteri PK. Extraglandular oestrogen formation and serum binding of oestradiol: relationship to cancer. J Endocrinol 1981 ;89: 119P-29P. 188. Barbieri RL, Gochberg J, Ryan KJ. Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro. J Clin Invest 1986;77: 1727-33. 189. Barbieri RL, McShane PM, Ryan KJ. Constituents of cigarette smoke inhibit human granulosa cell aromatase. Fertil Steril 1986;46:232-6. 190. Pasanen M. Human placental aromatase activity: use of a CIS reversed-phase cartridge for separation of tritiated water or steroid metabolites in placentas from both smoking and non-smoking mothers in vitro. Bioi Res Pregn 1985;6:94-9. 191. Gunasegaram R, Loganath A, Peh KL, et al. Cigarette smoke-induced cholesterol C-20, 22-desmolase inhibition in pregnancy. Ann Acad Med 1982;11:580-6. 192. Gunasegaram R, Peh KL, Loganath A, et al. Inhibition of second trimester human placental cholesterol C-20, 22-desmolase activity by soluble constituents of cigarette smoke. IRCS J Med Sci Pharmacol 1982; 10:322-3. 193. Michnovicz JJ, Naganuma H, Hershcopf RJ, et al. Increased urinary catechol estrogen excretion in female smokers. Steroids July-August 1988:69-83. 194. Juchau MR, Namkung MJ, Chao ST. Mono-oxygenase induction in the human placenta: interrelationships among position-specific hydroxylations of 1713-estradiol

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and benzo(a)pyrene. Drug Metab Dispos 1982;10: 220-4. 195. Lu AYH, Kuntzman R, West S, et al. Reconstituted liver microsomal enzyme system that hydroxylates drugs, other foreign compounds, and endogenous substrates. J Bioi Chern 1972;247:1727-34. 196. Meijer J, DePierre JW. Comparison of trans-stilbene oxide, phenobarbital and 3-methylcholanthrene as inducers of steroid metabolism by the rat liver microsomal cytochrome P-450 system. J Steroid Biochem 1983; 18:425-35. 197. Chao ST, Omiecinski CJ, Namkung MJ, et al. Catechol estrogen formation in placental and fetal tissue of humans, macaques, rats and rabbits. Dev Pharmacol Ther 1981;2:1-16. 198. Schneider J, Sass a S, Kappas A. Metabolism of estradiol in liver cell culture: differential responses of C-2 and C16 oxidations to drugs and other chemicals that induce selective species of cytochrome P-450. J Clin Invest 1983;72: 1420-6. 199. McMurtry RJ, Hagerman DD. Carbon monoxide inhibition of progesterone hydroxylation and side-chain cleavage catalyzed by rat testis micro somes. Steroids Lipids Res 1972;3:8-13. 200. Numazawa M, Soeda N, Kiyono Y, Nambara T. Properties of estradiol 2-hydroxylase and 2-hydroxy-3deoxyestradiol 3-hydroxylase in rat liver. Steroid Biochern 1979;10:227-33. 201. EssenbergJM, Fagan L, Malerstein AJ. Chronic poisoning of the ovaries and testes of albino rats and mice by nicotine and cigarette smoke. West J Surg Obstet GynecoI1951;59:27-32. 202. Thienes CH. Chronic nicotine poisoning. Ann NY Acad Sci 1960;90:239-48. 203. Mattison DR. Morphology of oocyte and follicle destruction by polycyclic aromatic hydrocarbons in mice. Toxicol Appl Pharmacol 1980;53:249-59. 204. Schmiterlow CG, Hansson E, Andersson G, et al. Distribution of nicotine in the central nervous system. Ann NY Acad Sci 1967;142 :2-14 . 205. Sershen H, Lajtha A. Cerebral uptake of nicotine and of amino acids. J Neurosci Res 1979;4:85-91. 206. Benowitz NL, Jacob III P. Metabolism, pharmacokinetics, and pharmacodynamics of nicotine in man. In: Martin WR, Van Loon GR, Iwamoto ET, Davis L, eds. Tobacco and smoking and nicotine: a neurobiological approach. New York: Plenum Press, 1987. 207. Schwartz RD, McGee R Jr, Kellar KJ. Nicotinic cholinergic receptors labeled by [3H]acetylcholine in rat brain. Mol Pharmacol 1982;22:56-62. 208. Morley BJ. The properties of brain nicotine receptors. In: Balfour DJK, ed. Nicotine and the tobacco smoking habit. Oxford: Pergamon Press, 1984. 209. Kellar KJ, Schwartz RD, Martino AM. Nicotinic cholinergic receptor recognition sites in brain. In: Martin WR, Van Loon GR, Iwamoto ET, Davis L, eds. Tobacco smoking and nicotine: a neurobiological approach. New York: Plenum Press, 1987:467-79. 210. Balfour DJK. The effects of nicotine on brain neurotransmitter systems. Pharmacol Ther 1982; 16:269-82. 211. Rowell PP. Current concepts on the effects of nicotine on neurotransmitter release in the central nervous system. In: Martin WR, Van Loon GR, Iwamoto ET, Davis L, eds. Tobacco smoking and nicotine: neurobiological approach. New York: Plenum Press, 1987:191-208. 212 . Andersen AN, Lund-Andersen C, Larsen JF, et al. Suppressed prolactin but normal neurophysin levels in cigarette smoking breast-feeding women. Clin Endocrinol 1982; 17:363-8. 213 . Andersen AN, Schioler V. Influence of breast-feeding pattern on pituitary-ovarian axis of women in an industrialized community. AM J OBSTET GYNECOL 1982;143: 673-7.

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