[CANCER RESEARCH 41, 371 1-371 7, September1981]0008-5472/81/0041-0000502.00
Obesity, Hormones, and Cancer1
MarvinA. Kirechner,2NormanErtel,andGeorgeSchneiderNewark Beth Israel Medical Center, Newark, New Jersey 071 12, New Jersey Medical School, Newark, New Jersey 07103, and the Veteran‘sAdministrationHospital, East Orange, New Jersey 07019
Abstract
Obesity is a physiological state associated with alterations inhormone production and metabolism. These hormonal changesmay bear on the increased risk for selected neoplastic disorders.
Obesity is associatedwith increasedestrone production inyoung and older women as well as in men. The source of thisincreased estrogen appears to be extragonadal metabolism ofthe prehormone androstenedione, which increases 3- to 4-foldin proportion to the obesity. In severe obesity, androstenedioneproductionitself may be increased, providing extra prehormonefor conversion to estrogens. In addition, obesity appears toshift peripheral metabolism of estradiol, resulting in decreasedexcretion of catechol estrogens which in turn may influencetarget organ stimulation.
Testosterone production is unchanged in obesity; however,there are decreased levels of sex hormone-binding /3-globulinleading to increased clearance rates and spuriously low levelsof circulating testosterone in both obese men and obesewomen. Alterations in sex hormone-binding /3-globulin mayfurther lead to changes in ‘‘free'‘estradiol, which may play arole in target organ stimulation.
Other changes noted in obesity include: (a) increased excretion of corticoid metabolites; (b) increased secretion of insulinbut decreased insulin effectiveness; (c) blunted growth hormone responsesto various challenges; and (d) possibly bluntedprolactin responsiveness. There are no reasons at present tosuspect that these changes influence cancer risk.
With weight loss, sex hormone-binding /3-globulin changes
are restored toward normal as are the elevated plasma estrogens and decreased testosterone levels. Because weight lossand dieting per se are associated with many physiologicalchanges, hormonal measurements during these times are difficult to interpret. Few studies to date have been performed informerlyobesepatientsstabilizedat their newweight.
At the Senate Select Committee on Nutrition and HumanNeeds,the current Americandiet was characterizedas beinghigh in fats, sugars, and total calories (68). Obesity is commonin our society; in the United States, it is estimated to exist in 30to 60% of the adult population (7, 8, 36). Several types ofneoplastic disorders, such as carcinomas of the breast, endometrium, and colon, appear to occur more commonly in populations consuming this type of overabundant, obesity-generating diet (6, 46, 79, 82). It thus becomes relevant to questionwhethera particulardiet,obesity,or bothfactorsmaybeinvolved as tumor promoters.
At the present time, there are but fragmentary data indicating
I Presented at the Workshop on Fat and Cancer, December 1 0 to 1 2, 1979,
Bethesda, Md.2 To whom requests for reprints should be addressed, at Newark Beth Israel
MedicalCenter, 201 Lyons Ave., Newark, N. J. 07112.
that a specific eucaloric dietary pattern alters hormone production and metabolism in a given individual (33, 74). There is,however, a growing body of data indicating that obesity per seis associated with alterations in hormone production and metabolism. Some of these changes may provide a link betweennutrition and cancer. In the subsequent review, we will considerthe hormonal changes associated with obesity and relate theirpotential significance to the cancer problem.
Estrogen Production and Metabolism
PostmenopausalWomen.StudiesbySiiteriandMacDonald(71 ), Longcope (47), and others (30, 63) helped to establishthat urinary estrone production rates are elevated in obesepostmenopausal women (Table 1). MacDonald et a!. (51 , 52)showed that, if estrogen production were of sufficient magnitude, endometrial hyperplasia and uterine bleeding could resuIt. Since the postmenopausal ovary no longer secretes estrogens (35, 77), extraovarian sources of production were investigated to explain the hyperestrogenemia observed in thesewomen. Several groups have demonstrated increased peripheral metabolism of the prehormone androstenedione to estronein obese women (30, 47, 50, 63, 71). This pathway of metabolism which normally accounts for all estrogens produced inpostmenopausal women becomes even more important in theobese woman (Chart 1). MacDonald et a!. (50) have shown aclose relationship between excessive body weight and metabolic transformation of androstenedione to estrone. In thepostmenopausal woman, androstenedione continues to be secreted by the ovaries, although the adrenal gland is likely to bethe major source in this age group. As noted in Table 1,increased peripheral transformation of normal amounts of androstenedione could account for all the estrone produced inobese women; however, recent studies in men suggest thatmarked obesity is also associated with increased androstenedione production,3 providing an additional source of prehormones for conversion to estrone.
The above data linking obesity with excessive estrogen production have led to much speculation on the relationship ofobesity to increased frequency of selective neoplasms. Endometrial cancer has been shown to be 2 to 3 times more commonin obese women (53), and a similar increased risk for breastcancer has been noted in obese women (19, 57). Since bothneoplasms arise in tissues which normally respond to estrogenic stimulation, a sequence of events shown in Chart 2 canbe constructed leading from obesity to excess estrogens totarget organ neoplasia. At present, these considerations cannot be applied to link obesity with carcinoma of the colon.
The possibility that carcinoma of the endometrium per se ina given patient alters peripheral steroid metabolism was raisedby Hausknecht and Gusberg (30) and Calaong et a!. (14), who
production rates. The data presented in Table 2 thus representa compilation of estrone production rates and androstenedioneconversion to estrone obtained from the combined laboratoriesof Edman,4 Longcope,5 and Kirschner.3 In each case, estroneproduction was determined on Days 5 to 8 of the menstrualcycle. These data indicate that estrone production rates inyoung women increase progressively with body weight. Similarly, peripheral conversion of androstenedione to estroneshows increasing values as a function of obesity. These datastrongly suggest that obese women in their reproductive yearsproduce increased (basal) amounts of estrone. Superimposedon this high level are the cyclical estrogens, chiefly estradiol,produced from the ovary during the course of the menstrualcycle. To date, there is no evidence thatthe developing ovarianfollicle of the obese woman hypersecretes estrogens, althoughZumoff@has found markedly elevated plasma estradiol versusestrone levels in young obese women. The current data indicatethat normally menstruating obese women probably producemore estrogens chronically than do their lean counterparts.
Obesity has been associated with other endocrine phenomena which may bear on the hormonal milieu. For example,menarche has been reported to occur earlier in obese girls,possibly triggered by a critical body mass (25, 26). Similarly,menopause is thought to occur later in the obese woman (70).Thus, the obese woman has a prolonged ‘‘menstruallife,―withlonger years of exposure to higher estrogen levels. Furthermore, obesity has been associated with an increased incidenceof abnormal menstrual cycles, functional uterine bleeding, andanovulation (43, 64). The relationship of abnormal menstrualcycles in women to the increased incidence of breast cancerhas been speculated upon by Sherman and Korenman. (69).
demonstrated increased conversion of androstenedione to estrone in such women. These conclusions could not be substantiated by MacDonald et a!. (50), who found no differences inandrostenedione conversion to estrone between women withendometrial cancer versus normal women when the transferconstants were related to the degree of obesity. Similarly, wefound no evidence for increased conversion of androstenedione to estrone in postmenopausal women with establishedbreast cancer (37). It thus appears that obesity and not thepresence of cancer influences transformation of androstenedione to estrone.
Finally, if endometrial carcinoma occurs more frequently inobese women through the mechanism of increased estrogenproduction, MacMahon (53) reminds us that endometrial cancer occurs most frequently at menopausal age, a time whenendogenous estrogen production is falling. Similarly, de Waard(19) has shown that obesity is associated with a higher mcidence of postmenopausal breast cancer, again at a time ofdecreased estrogen production. Since estrogenic stimulationis thought to induce hyperplastic (and possibly neoplastic)changes over a prolonged period of time, interest has focusedon whether obese women produce excessive estrogens duringtheir younger, reproductive years which then are manifestedas neopiasms at target organ sites in later life.
Women in Reproductive Years. The determination of estrogen production rates and prehormone conversion to estrogensin younger women is considerably more difficult to determine,because the menstrual cycle is associated with rapid changesin ovarian estrogen secretion. Estrone production rates innormal young women range from a low point of 60 to 100 @g/day to elevations of 2- to 4-fold at peak times prior to ovulationand midluteal phases (4). Edman et a!. (21) have shown that aminimum of 4 days is necessary to ensure complete tracerequilibrium in order to accurately assess the urinary estrone
Table 1Estrone production in postmenopausal women (4 7, 71)
HYPERPLASIA HYPERPLASIA
NEOPLASIA NEOPLASIA
Chart 2. Schematic diagram showing potential relationships between obesity,increased estrogen production, and target organ stimulation leading to neoplasia.See text for details.@ androstenedione; E, , estrone.
Table 2Estrone production rates in obese women (4, 5)3
ETIOCHOLANOLONE ANDROSTERONE
Chart 1. Peripheral metabolism of androstenedione in normal and obesesubjects. Peripheral aromatization of this C,9 prehormone to estrone is significantly elevated in obese subjects, accounting for most or all of the elevatedestrogens noted in obese subjects.
Men.Studiesinourlaboratorydemonstratedincreasedproduction of both estrone and estradiol in obese men (66), asnoted in Chart 3. Schneider eta!. (66)further showed increasedperipheral metabolism of androstenedione to estrone as wellas increased conversion of testosterone to estradiol in obesemen. Elevated plasma estrone and estradiol levels have beendescribed in obese men by Stanik et a!. (75), Schneider et a!.(66), Kley et a!. (40), and Zumoff.6 It is of interest that theincreased estrogens produced by obese men appear to havelittle or no biological effect, evidenced by: (a) lack of gynecomastia or other signs of hyperestrogenism; (b) normal (unsuppressed) plasma concentrations of follicle-stimulating and luteinizing hormones; and (c) decreased rather than increasedlevels of the sex hormone-binding globulin (see below). Therelationship of hyperestrogenemia to neoplastic disorders affecting men is unknown.
Effects of Obesity on Peripheral Estrogen Metabolism.Earlier studies of Lemon et a!. (44, 45) showed differences inestriol excretion in woman with breast cancer and women withvarying risks for human breast cancer. Dickinson (20) showedthat estriol ratios were different in subpopulations of Hawaiianwomen at varying risks for breast cancer. Estriol quotientscomparing estriol with other estrogen metabolites were lowestin women at greatest risk for breast cancer and vice versa. Aninteresting hypothesis was devised suggesting that estriol represented an ‘‘impeded'‘or protective estrogen which blockedexcessive stimulatory effects of more potent estrogens, suchas estrone and estradiol, on the target organ (breast cell) (15,54). Subsequent studies of Longcope et a!. showed, however,that plasma estriol levels and estriol production rates were nodifferent in women with breast cancer versus normal women(24, 60) and in women with high urinary estriol ratios versusthose with low estriol ratios (48). Thus, it seems likely thatdifferences in excretory patterns of estrogen metabolites seenby Lemon, Dickinson, and others may well be related to diet,obesity, or other influences. These influences probably shiftdistal estrogen metabolism rather than influence circulating ortissue levels of estriol.
Of considerable interest have been the observations ofFishman et a!. (23) that peripheral metabolism of estradiol toform catechol estrogens (2-hydroxy metabolites) is decreasedin obese women. (Chart 4). The 2-hydroxy metabolites areinteresting in view of the data showing that these substances
Chart 4. Alterations in peripheral metabolism of estradiol noted in obesesubjects (23). In obesity, there is increased 16-hydroxylation of estradiol withdecreased excretion of 2-hydroxyestrone (catechol estrogens). The catecholestrogens appear to be devoid of biological activity but bind to estrogen receptor,perhaps playing a significant role as an impeded estrogen.
bind to estrogen cytosol receptors (55) but have no inherentuterotrophic action (32). Although much early emphasis hadbeen placed on estriol as being an impeding estrogen, it maywell be that catechol estrogens are the ‘‘trulyimpeding estrogens. ‘‘In this regard, Fishman et a!. (23) have demonstratedthat obesity is associated with increased peripheral metabolismof estradiol to the 16-hydroxy metabolite (estriol) and de-@creased transformation to the 2-hydroxy metabolite (Chart 4).Additional developments in this area are anxiously awaited.
Androgen Production and Metabolism
Testosterone.Testosteroneproductionrateswerefoundtobe normal in obese men (66) as well as in normally menstruatingobese women.3 However, many laboratories, including ourown, reported decreased circulating testosterone levels inobese men (1, 29, 39, 40, 66),6 and we now have dataindicating decreased testosterone levels in obese women. Itbecame apparent that obesity was associated with increasedmetabolic clearance rates of testosterone caused at least inpart by alterationsin the sex hormone-bindingplasmaprotein(66). Several groups using different techniques to assess sexhormone-binding protein binding have confirmed the association of obesity with decreased concentrations of this /3-globulin(1, 29, 40, 66). As a result, testosterone which is produced innormal amounts is cleared at an excessive rate in the obeseperson. Although decreased sex hormone-binding /3-globulinlevels seen in obese men and women may account entirely forthe phenomenon of increased clearance rates, the possibilityof increased tissue extraction (presumably at adipose tissuesites) cannot be excluded and will be considered below. In anyevent, determination of the@@ free testosterone, ‘‘calculated asa product of the testosterone and the dialyzable testosteronefraction, shows normal rates in both obese men and obesewomen.
The significance of decreased sex hormone-binding globulinlevels in obesity and the resultant alterations in testosteronemetabolism remain obscure at the present time. In this regard,a recent study by KIey et a!. (39) suggests that ‘‘freeestradiol―is elevated in obese men. Since estradiol is also bound with
E2
.
100F
5°1
50 100 50 200
PERCENT ABOVE IDEAL BODY WEIGHT
Chart 3. UrInary estradiol (E2)and estrone (E) production rates as a functionof obesity in I 0 men. (Reproduced by permission of the Journal of ClinicalEndocrinologyend Metabolism.)
high affinity to the sex hormone-binding globulin, decreasedlevels of this binding protein along with increased extragonadalproduction of estradiol from testosterone resulted in the findingof elevated free estradiol levels. Thus, alterations in sex hormone-binding globulins may become more relevant with regardto circulating biologically active estrogens than to androgens.
Androstenedione. This C19steroid has no androgenic activity of its own but, as discussed earlier, is a key prehormone inthe extragonadal production of estrogens noted in obesity.Recent data from our laboratory indicate that androstenedioneproduction rates are elevated in markedly obese men as notedin Chart 5. Our data on androstenedione production in obesewomen are too limited to draw a similar conclusion at this point.It is of interest that clearance rates of androstenedione areconsiderably elevated from 2500 to 8000 liters/day in markedly obese men. Since androstenedione is not appreciablybound to the sex hormone-binding globulin, these data suggestincreased tissue extraction and/or other factors as playing arole in excessive clearance of androgenic steroids. Furthermore, if androstenedione production rates are increased inobesity, then more prehormones are available for extragonadalmetabolism to estrone. Thus, excessive production of thissteroid in obesity may bear greatly on hyperestrogenism notedin obese individuals.
DHEA.7 This C19 androgen has been of interest in defining
the hormonal milieu of women with breast cancer. Poortman eta!. (61) reported decreased DHEA production in women withbreast cancer. DHEA is transformed in its peripheral metabolism to @5-androstenediol,and this metabolite was observed tocompetitively bind with estrogen cytosol receptor in targettissues (61 , 76). These data raise the possibility that the DHEAmetabolite could, under physiological conditions, be active asan impeding estrogen, modulating the stimulatory effect ofmore potent estrogens. In this regard, an earlier report byLopez and Kiehi (49) indicated decreased excretion of DHEAin the urine of very obese subjects. Confirmatory data areneeded here.
Other Androgens. Bulbrook et a!. (9, 11, 12) observed acorrelation between excretion of urinary 17-ketosteroid metabolites and response of patients with metastatic breast cancerto endocrine manipulation. From these data, a discriminantfunction was constructed relating the excretion of the 17-ketosteroids to that of 17-hydroxysteroids. A positive discriminant in urine of a given patient with breast cancer suggestedthe presence of a hormone-responsive tumor; similarly, a negative value suggested hormone unresponsiveness of the patient. Subsequent studies from this group showed that lowerlevels of urinary etiocholanolone were present in the urine ofasymptomaticwomen who subsequently developed breast cancer (10). Decreased 17-ketosteroid excretion was thus associated with a higher incidence of breast cancer in women anda poor response of patients with breast cancer to endocrinetherapy. These workers subsequently demonstrated decreasedexcretion of 17-ketosteroid metabolites in Japanese (low-risk)versus British (high-risk) women, a trend opposite to thatexpected (13). Furthermore, Zumoff et a!. (81) found thatchronic illness, undernutrition, or even dieting could decreasethe conversion of circulating androgens to their usual urinary17-ketosteroid metabolites, thereby decreasing the quantity of
7 The abbreviations used are: DHEA, dehydroepiandrosterone; TRH, thyrotro
phin-releasing hormone.
0@b.
3-
2
.
I I I I I50 100 150 200 250
% ABOVE IDEAL BODYWEIGHT
Chart 5. Androstenedione production rates in men with progressive obesity.
17-ketosteroids excreted. Again, the role of under- or overnutrition comes to the foreground in our understanding of hormonal changes noted in patients with hormone-responsivecancers.
Cortisol Metabolism in Obesity
In earlier studies, Schteingart et a!. (67) suggested increasedadrenal cortical activity in obese subjects, as reflected byincreased urinary 17-hydroxysteroids and increased cortisolsecretion rates. By contrast, plasma cortisol and urinary freecortisol concentrations are not elevated in obese subjects.Furthermore, the normal diurnal pattern of cortisol secretion isgenerally maintained (7), and obese subjects usually exhibitsuppressibilitywith exogenous glucocorticoids(67). Migeon eta!. (56) demonstrated that obese subjects exhibit enhancedturnover rates of cortisol, possibly accounting for lower-thanexpected plasma cortisol concentrations. The explanation forapparent increased cortisol secretion rates and excretion ratesin obese subjects is not apparent. Adrenocorticotropic hormone levels are normal in obese men.3
Normalization of adrenocortical functions by relating theexcretion and secretion rates on a weight basis has beenattempted (16, 41 , 56). The significance of these minor abnormalities of cortisol production and hydroxysteroid excretion inobese subjects in relation to oncogenic potential is not understood at present.
Insulin Secretion and Action
Obesity is associated with insulin hypersecretion. Perley andKipnis (59) found fasting levels of plasma insulin to be elevated3-fold in obese subjects. Furthermore, insulin responses toglucose, proteins, or other insulin secretogogues administeredP.O.or i.v. were approximately double those observed in leancontrols. With progressive obesity, there is an increased mci
showing that prolactin secretion is lowered in women afterhigh-carbohydrate, high-fiber diets provide grounds for furtherinvestigation on the roles of nutrition and obesity in the secretory responses of this hormone.
Effect of Weight Reduction
If obesity is a physiological state characterized by alterationsin hormone production and metabolism as well as by increasedpredilection for certain cancers, what are the prospects ofreversing these abnormalities? In this regard, Siiteri et a!. (72)reported no change in urinary estrone production rates or inandrostenedione conversion to estrone in 6 obese subjectsstudied before and after significant weight loss. The validity ofthese studies, however, has been questioned by the authors,who point out that ‘‘after'‘studies may have been performedduring an unphysiological state. More recent data by Stanik eta!. (75) demonstrated that 10 weeks of weight loss in mencorrected the increased plasma estrone and estradiol and thedecreased levels of plasma testosterone toward normal. Ongoing studies in our laboratory have shown that starvation andweight loss are associated with restoration of the sex hormonebinding /3-globulin toward normal in both obese men and obesewomen. It is important to emphasize that dieting may be associated with significant changes in hormone metabolism per se.It thus seems quite risky to extrapolate hormonal values obtamed during the process of weight loss as being indicative ofchanges that might be expected after the period of weight lossis ended and the subject is stabilized at a new, lower weightlevel. At the present time, only a few studies are available thatexamine hormone parameters in the stabilized, formerly obesesubjects. Until such data are more abundant, we can onlyspeculate that some or most of the hormonal abnormalitiesreported in obese subjects are reversed with weight loss.
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dence of impaired glucose tolerance despite elevated basalinsulin levels and excessive insulin responses, implying animpaired peripheral action of insulin or ‘‘peripheralinsulinresistance.―The mechanism and sites of insulin resistance inobesity have been areas of great interest. Roth et a!. (3, 73)demonstrated a decreased number of available insulin-bindingsites in tissues obtained from experimentally obese animalsand from circulating lymphocytes of obese patients. Othergroups have found impaired insulin action at the level of adipose tissue (35, 58), liver (22), and other sites (62). Studiesfrom other laboratories, however (2, 58), suggest impairedinsulin action at cellular sites distal to the binding of insulin.Mostgroupsagreethatmarkedimprovementofinsulineffectiveness is observed in obese patients shortly after institutionof weight loss and/or starvation programs (3). Most cases ofmaturity onset diabetes mellitus are remarkably ameliorated byweight loss and/or starvation (27, 38).
Although the phenomena of hypermnsulmnism,blunted insulinaction, and increased incidence of impaired glucose toleranceobserved in obese subjects provide an explanation for thegenesis of maturity onset diabetes mellitus, there is as yet noready association between hyperinsulinism and neoplastic induction. It should be remembered, however, that under normalcircumstances insulin is a potent anabolic hormone, and itspotential role in tumor stimulation should not be overlooked.
HumanGrowthHormoneMetabolism
Several lines of data indicate that obesity is associated withblunted growth hormone responses to a variety of challenges.Although basal levels of growth hormone are normal in obesesubjects, both Roth et a!. (65) and Yalow et a!. (80) observedthat late growth hormone responses which occur 4 to 6 hr aftera glucoseload were decreased in obese subjects. Furthermore,the growth hormone responses to hypoglycemia, 2-deoxyglucose,andarginine(5, 80) allwereimpairedin obesecomparedwith normal subjects. The significance of blunted growth hormone responses noted in obesity with hormone-related neoplasms Is presently obscure.
Prolactin
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