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Scientific Activities - Actividades Científicas

Honorary Committee Lecture

Tobacco: The assault on women - VIa
Published in ProCOR

Bernard Lown, MD
Awarded with Nobel Prize

1. Cancer and other derangements

4. Cervical Cancer

2. Lung cancer 5. Infertility and pregnancy
3. Hip fracture 6. Macular degeneration

7. Bibliography


Tobacco VIa:The assault on women - Cancer and other derangements

Throughout my practice of medicine I witnessed many sordid events, but few compare to the seduction of women to smoke. This would not have happened without the prodigious investment in advertising by the tobacco companies, more than  $5 billion annually. Only the American automobile industry is more lavish in product promotion.  At present, of the nearly 50 million Americans who smoke, 32% are male and 27% are female. The gender gap has been closing rapidly. It is anticipated that women will exceed men during the first decade of the next century. The explanation is that more girls than boys are taking up the habit and fewer of them quit.

A majority of Americans currently regard smoking as offensive social behavior and a habit, if not sinful, certainly the result of defective character or dim wittiness. As smoking is prohibited in most public buildings, in order to indulge the sick fixation to inhale noxious fumes, one has to huddle, as an outcast on the street, rain or shine, hot or cold.  How does one account for the power of cigarettes to cast such a binding spell?  The reasons are several and complex.  First though, it is appropriate to examine the various health consequences of women's smoking.

Smoking is estimated to kill each year over half a million women globally and the numbers are increasing.(1) In several developed countries, such as US and UK, cigarette smoking is the single leading preventable cause of premature death among women and accounts for at least a third of the deaths of those aged 35 to 69.(1) 

Lung  cancer

This mounting problem is tragically illustrated by the growing incidence of lung cancer. When I went to medical school fifty years ago, such cancers among women were a rarity. In the past half century their incidence has increased by 550%.(2) Whereas in 1950, lung cancer accounted for 3% of all female cancer deaths, by 1995 it rose to an estimated 24%.(3) While women are far more aware and fearful of  breast cancer, lung cancer now has far surpassed it as the leading cause of cancer fatality in the USA. In fact, by 1995, there were 19,000 more lung than breast cancer deaths annually.(3)   About 80% of female lung cancers are presently attributable to cigarette smoking.(4) The problem is further amplified by the fact that survival rates for pulmonary malignancies are worst compared to any other cancer sites. The shame of it is that these are largely preventable deaths.

Rates of smoking are higher among less educated, lower income, and minority groups, already disproportionately afflicted with illness. These groups are likely to smoke more heavily. The risk of lung cancer increases with the number of cigarettes smoked daily and particularly with the accumulated years of smoking. Data from the American Cancer Society's Cancer Prevention II prospective study report a significant cigarette dose response relation in women for lung cancer. Those who have smoked anywhere from 1-10 cigarettes daily have an overall risk of 5.5 as contrasted to 22.0 for those who smoked 31 or more cigarettes daily.(2)  Girls who start smoking before age 15 have twice as many mutations that predispose to lung cancer than those who start after the age of 20. With the same degree of smoking women appear to have a higher risk than men for developing lung cancer. In a large case control study of 442 females and 403 males wit verified lung cancer, the incidence of malignancy increased sharply in a dose depended fashion. At each increasing level of smoking, the odds ratio (OR) for females rose faster than for males, nearly threefold in each category step up. Thus for 40 pack years of cigarette consumption the OR for females was 27.9 and for men 9.60.(5)

Unfortunately cigarettes exact a toll in nonsmoking women as well. A multicenter population based case-control study consisting of 653 nonsmoking females with lung cancer compared to 1253 matched controls has confirmed that passive smoking of a spouse enhances risk. The adjusted OR for lung cancer in women whose husbands smoked was 1.29 (95%CI:1.04-1.6).(6) The OR increased with greater exposure.  Among those exposed to greater than 80 pack years of tobacco smoke the odds ratio rose to 1.79 (95% CI: 0.99-3.25). The US Environmental Protection Agency (EPA) estimated that 3.9% of lung cancer deaths among female nonsmokers in the USA in 1985 was attributable to environmental tobacco smoke.(7)

All histological types of lung cancer show a strong dose-response relationship to smoking, but relative risks appear to be much greater for small-cell and squamous cell carcinoma than for adenocarcinoma.(8) Women appear to be more susceptible than male smokers to small cell carcinoma for the same degree of smoking.(9) In a recent large study in the UK, involving 1000 patients with lung cancer, women under the age of 65 were particularly at risk of small cell lung cancer, with 34% having this type compared to 18% for males. Seven out of ten cases with this aggressive form of the disease were inoperable.(10)

Most studies also demonstrate that risk is reduced in females who smoke lower tar compared to higher tar cigarettes and in  those who smoke filtered compared to unfiltered cigarettes.(11,12) Far better though is to stop the noxious habit. With smoking cessation the risk of lung cancer abates with the passage of time. The excess risk declines by about 45% within 6 to 10 years after quitting and by about 85% after 16 years.(13) As many women are now beginning to quit, the current rising lung cancer mortality in the USA is   expected to plateau around the year 2000 to 2010.(8)

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Other Pathologic Conditions

Cervical cancer  

Predisposition to nearly every type of cancer in the human body is enhanced by tobacco smoke.  Curious is the special predilection for cervical cancer in smokers. Winkelstein first suspected this in 1977 based on squamous cell characteristics of cervical cancer.(14) Since then a number of studies have reported larger risk for cervical dysplasia, carcinoma in situ and invasive cancer among cigarette smokers as compared to nonsmokers.  Tobacco use predisposes to squamous cell carcinoma in the lung and larynx, the very type of malignancy predominant in the cervix.  The adjusted risk for cervical cancer among current smokers is 3.42. (15)  

As with the case of lung cancer, exposure to passive smoking is an independent risk factor for cervical malignancy. In a population-based case-control study in Utah, the risk estimate for exposure to environmental smoke for more than 3 hours a day was 2.96 (95% CI: 1.25 to 7.03, P=0.0028 for linear trend). This relation held after adjusting for age, years of education, church attendance, number of sexual partners, and pack years of smoking.(15) Exposure to environmental smoke at home was a far greater risk factor as compared to passive smoking away from home. The problem with cervical cancer is confounded by the inability of epidemiologists to exclude behavioral differences between smokers and nonsmokers with respect to the operation of other risk factors. A relevant example is the accuracy of reported sexual activity. Cervical cancer is believed to be due to an infectious agent transmitted sexually. Women who smoke are sexually more active.

The extraordinary sensitivity of the cervix to tobacco may relate to the finding of high levels of nicotine and conitine in the cervical mucus of smokers.(16) Perhaps carcinogenic constituents of cigarette smoke also concentrate in the cervix and play a direct mutagenic role in the etiology of the malignancy. The risk is increased when smoking is started early in life when the uterine cervix is undergoing metaplastic changes of puberty and may be particularly sensitive to carcinogenic insults.

 

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Infertility and pregnancy

In addition to the higher incidence of cervical cancer, women who smoke experience detrimental effects on their reproductive health including dysmenorrhea, reduced fertility and earlier menopause. A wealth of literature supports the robust association between female smoking of more than half a pack a day and reduced fecundity. (17) Smokers, compared with nonsmokers, have substantially and significantly lower levels of all three major estrogens during the luteal phase of their menstrual cycle.(18) The reduction of estrogen stimulus by cigarettes may account for the fact that smokers experience premature  menopause. Components of tobacco smoke probably act on the hypothalamus-pituitary-ovarian axis, thereby affecting every stage of fertilization and conception.(19)      

A Finnish study points to late deleterious consequences from smoking during pregnancy.(20) Tobacco consumption was monitored  during pregnancy among almost 12,000 women in northern Finland who gave birth in 1966.  Mortality over a 28-year follow-up period, adjusted for age, place of residence, years of education and marital status, was 2.3 times greater among smokers than non-smokers; a rate higher than among non-pregnant women who smoke. Deaths were the result of tobacco-related diseases, but also accidents and suicides.(20)   

Smoking during pregnancy increases the risk of miscarriage by one quarter,  the risk of perinatal death by a third, doubles the risk of premature labor and trebles the likelihood of a low birth weight baby.(21) Smoking is also related to  failure of the newborn to thrive and glue in the ears.  Birth weight is also compromised when mothers are exposed to environmental smoke. In a prospective study, Martin and Bracken (22) have shown that the adjusted relative risk of delivering a low birth-weight baby (less than 2500 gm) among passive smoking women was 2.2 as compared to unexposed women. There is evidence that infants of passive smokers are exposed to measurable levels of nicotine.(23) One of the strongest carcinogens in tobacco, NNK (4-(methylnitrosamine)-1)3--(-pyridil)-1-butanone) is transmitted to the developing fetus when the mother smokes. Disconcerting therefore is that between the late seventies and the early nineties, the concentration of NNK has increased in cigarettes by about 50%. (24)       It is astonishing that with such an encyclopedic roster of pathology, women  resist quitting.  Even more dismaying is that the addiction is more dominating than the powerful biological maternal instinct to protect their newborn.  In the United States, smoking by pregnant women causes 5,600 deaths of babies and 115,000 miscarriages annually.  To this perverse toll one must add the 55,000 low birth weight babies and the 22,000 who require intensive care.  The basis for these adverse effects, no doubt, relates to the finding that newborns whose mothers smoked during pregnancy have the same nicotine levels in their bodies as the adult smokers.  During the first most trying days of life these infants therefore experience the additional stress of tobacco withdrawal.

Cessation of smoking during pregnancy would reduce low birth weight by 20%,  preterm deliveries by 8% and fatal or early infant deaths by 5%. Yet despite evidence linking smoking prevalence to poor outcomes, the majority do not give up the habit. Indeed nearly 25% of American pregnant women continue to smoke during pregnancy.  This preventable toll is likely to be far greater in developing countries where the health of mother and baby are already compromised by poverty and malnutrition. In Chile, for example, about 10% of non-accidental perinatal deaths are attributable to smoking. (21) 

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Hip fracture   

The adverse consequences are hardly exhausted with the sad litany so far reported. Low bone mineral density, as a complication of smoking, was already recognized nearly a quarter of a century ago.(25) Smoking is now appreciated as a major cause of hip fracture. In a meta-analysis, data from 29 cross-sectional studies on 2,156 smokers and 9,705 nonsmokers, and 19 cohort and case-control studies re-ported on 3,889 hip fractures.(26)  Among premenopausal women, smokers and nonsmokers had similar bone density.   However, postmeno-pausal women who smoked had greater bone loss than those who did not, with a 2% decrease in bone density for every 10-year increase in age. 

Smoking and age are interactive in predisposing to hip fractures. Thus, while smoking had no effect on risk for hip fracture at age 50, the risk progressively mounted with age. The risk was 17% greater in smokers than nonsmokers by age 60, increased to 41% at 70, 71% at 80, and constituted a remarkable 108% greater risk at age 90. These dif-ferences remained after adjustment for weight, age at menopause, and fre-quency of exercise.(26) Smoking increases the lifetime risk of hip fracture by half. It is estimated that one in eight fracture is attributable to cigarettes. The fact that former smokers have a risk in between those who never smoked and current smoker, suggests that the effects of tobacco on bone density may be partly reversible.  

These findings on bone density are not incongruent with an inter-action of some hormonal factors with components of the inhaled smoke.  Already commented is the evidence that women who smoke are relatively deficient in estrogens. In addition to an earlier menopause, they have a decreased risk of cancer of the endometrium, and reduced incidence of uterine fibroids. The same biologic mechanism may account for the greater incidence of osteoporosis and of osteoporotic fractures.     

Macular degeneration

The litany of adverse health effects of smoking appears without end. Persuasive data now implicates tobacco in a predisposition to macular degeneration. Age-related macular degeneration (AMD) is the leading cause of severe visual impairment among the elderly in the US and occurs in 7% of persons over the age of 75.  Treatment is unavailable and is ineffective.

This issue was recently investigated in The Nurses' Health Study.(27) From among the 121,700 female registered nurses, a prospective cohort of 31,843 aged 50-59 was followed up for 12 years with exams every 2 years.  Women who currently smoked more than 25 cigarettes  daily, as compared with women who never smoked, had a relative risk of AMD of 2.4 (95% CI:1.4-4.0). A dose response relationship was noted after adjusting for other risk factors. Compared with women who never smoked, those in the lowest category of smoking  (1-9 pack years) had a 40% higher risk, while women in the highest category (65 or more pack years) had a 140% greater risk of AMD. Risk increased with the number of pack years smoked.  The relationship held for exudative as well as dry subtypes of AMD.  Little reduction of risk was observed even 15 years or more after quitting smoking.

Several potential mechanisms of cigarette smoking are implicated in the pathogenesis of age related macular degeneration. These include increasing  oxidative stress, reducing the plasma level of anti-oxidants, and augmenting predisposition to vascular disease.

 

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Bibliography

1. Peto R. et al: Mortality from smoking in developed countries 1950-2000. Oxford, Oxford University Press, 1994.
2. Ernster L V: Female lung cancer. Annu Rev of Public Health 1996;17:77-114.
3. Wing PA et al, 1995 Cancer Statistics. CA Cancer J. Clin. 1995;45:8.
4. U.S. Department of Health and Human Services 1987. Data from the Natl. Health Survey, Ser. No 92. DHHS Publ. No. (PHS) 88-1753. Washington DC: GPO.
5. Risch et al: Are female smokers at higher risk of lung cancer than male smokers? Am J Epidemiol.  1993:138:281.   
6. Fontham ET, et al: Environmental tobacco smoke and lung cancer in non-smoking women. A multicenter study. JAMA 1994; 271:1752.
7. Office Health Environment. Asses Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders. Washington, DC US EPA 1992.
8. Ernster LV: The epidemiology of lung cancer in women. Ann. Epidemiol. 1994; 4:102.
9. Osman KE et al: Sex differences in lung cancer risk associated with cigarette smoking. Int J Cancer 1993; 54:44.
10. Kmietowicz Z: Women at double risk of small cell lung cancer. News Report  BMJ 1998;317:1614.
11. Garfinkel L, Stellman SD: Smoking and lung cancer in women; findings in a prospective study. Cancer Res 1988;48:6951.  
12. Lubin JH et al: Modifying risk of developing smoking by changing habits of cigarette smoking. Br. Med J. 1984; 288:1953. 12. Zang EA, Wynder EL: Cummulative tar exposure: A new index for estimating lung cancer risk among cigarette smokers. Cancer 1992;70:69.
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14. Winkelstein W: smoking and cancer of the uterine cervix: hypothesis. Am J Epidemiol. 1977;106:257.
15. Slattery ML et al: Cigarette smoking and exposure to passive smoke are risk factors for cervical cancer. JAMA 1989;261:1593.
16. Sassoon IM et al: Cigarette smoking and neoplasia of the uterine cervix: smoke constituents in cervical mucosa.  N Eng J Med. 1985;312:315. 17. Bolumar F et al: Smoking reduces fecundity: a European multicenter study on fertility and subfecundity. Am J Epidemiol 1996;143:578.
18. McMahon B et al: Cigarette smoking and urinary estrogens. N Eng J Med 1982;307:1062.
19. Jick H et al: Relation between smoking and age of natural menopause: report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. Lancet 1977;1:1354.
20. Rantakallo P et al: A 28 year follow up of mortality among women who smoked during pre gnancy. BMJ 1995; 311:477.
21. Amos A. Women and smoking: a global issue. World Health Statistics Quarterly 1996;49:127.   
22. Martin and Bracken: Am J Epidemiology 1986 124:633-42.
23. Eliopoulos C et al Hair concentration of nicotine and conitine in women and their newborn infants. JAMA 1994;271:621.
24. Hoffman D, Hoffman I: Tobacco Consumption and Lung Cancer In: Hansen HH, ed.  Lung Cancer. Boston: Kluwer Academic Publications, 1994: 1-42.
25. Daniel HW: Osteoporosis in the slender smokerArchives Int Med 1976;136:298.
26. Law MR, Hackshawi AK: A meta-analy-sis of smoking, bone mineral density and risk of hip fracture. Recognition of a major effect. BMJ 1997;315: 841.
27. Seddon JM et al: A prospective study of cigarette smoking and age-related macular degeneration in women JAMA 1996;276:1141.

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Update
Dic/08/1999