Cancer and Hormones

Arch Intern Med. 1991; 151(1):75-8 (ISSN: 0003-9926)

Henderson BE; Paganini-Hill A; Ross RK
Department of Preventive Medicine, Kenneth Norris Jr Comprehensive Cancer Center, University of Southern California, Los Angeles 90033.

In a prospective study of 8881 postmenopausal female residents of a retirement community in southern California, we evaluated in detail the relationship between estrogen use and overall mortality. After 7 1/2 years of follow-up, there had been 1447 deaths. Women with a history of estrogen use had 20% lower age-adjusted, all-cause mortality than lifetime nonusers (95% confidence interval, 0.70 to 0.87). Mortality decreased with increasing duration of use and was lower among current users than among women who used estrogens only in the distant past. Current users with more than 15 years of estrogen use had a 40% reduction in their overall mortality. Among oral estrogen users, relative risks of death could not be distinguished by specific dosages of the oral estrogen taken for the longest time. Women who had used estrogen replacement therapy had a reduced mortality from all categories of acute and chronic arteriosclerotic disease and cerebrovascular disease. This group of women had a reduced mortality from cancer, although this reduction was not statistically significant. The mortality from all remaining causes combined was the same in estrogen users and lifetime nonusers

Am J Obstet Gynecol. 1999; 181(2):288-95 (ISSN: 0002-9378)

Natrajan PK; Soumakis K; Gambrell RD
Department of Physiology, Medical College of Georgia, Augusta, Georgia, USA.

OBJECTIVE: We sought to review the status of patients with breast cancer who were treated with estrogen replacement therapy and compare the results with those of nonestrogenic hormone users and women not treated with hormone replacement.

STUDY DESIGN: The study group consisted of 76 patients with breast cancer, including 50 using estrogen replacement for up to 32 years, 8 using nonestrogenic hormone replacement for up to 6 years and followed for up to 11 years, and 18 using no hormones for up to 10 years. In addition to estrogen use, 40 of the 50 hormone users were treated with androgens, usually in the form of implantation of testosterone pellets. Forty-five subjects were also given progestogens, usually megestrol acetate 20 to 40 mg for 10 to 25 days each month. The 8 nonestrogen hormone users were treated with various combinations of testosterone pellets, tamoxifen, and progestogens. Forty-two of the 50 estrogen users are still being treated in our clinic, as are 2 of the 8 subjects using nonestrogen hormone. Follow-up was done through the tumor registry at University Hospital, and those whose tumor records were not current were telephoned.

RESULTS: Of the 50 estrogen users, 3 have died (a mortality rate of 6%), and the rest have been followed for 6 months to 32 years, with a mean duration of follow-up of 83.3 +/- 8.81 months. One of the 8 nonestrogen hormone users has died (a mortality rate of 12.5%), and the rest have been followed for 2 to 11 years, with a mean duration of follow-up of 72.0 +/- 5. 93 months. Six of the 18 women not using hormone replacement have died (a mortality rate of 33.3%), and the rest have been followed for 6 months to 10 years, with a mean duration of follow-up of 50.5 +/- 6.01 months.

CONCLUSION: Estrogen replacement therapy apparently does not increase either recurrences or mortality rates. Adding progestogens may even decrease recurrences. Women with early breast cancer should be offered hormone replacement therapy after a full explanation of the benefits, risks, and controversies.

Schweiz Med Wochenschr. 1998; 128(43):1675-89 (ISSN: 0036-7672)

Birkhäuser M
Abteilung für Endokrinologie, Universitäts-Frauenklinik, Inselspital Bern.

A correct Hormone Replacement Therapy (HRT) guarantees a successful treatment of subjective symptoms of oestrogen deficiency and an efficient prevention of postmenopausal osteoporosis, of cardiovascular diseases and of M. Alzheimer. In non-substituted postmenopausal women, the risk to die from a myocardial infarction is ten times higher than the risk to die from a carcinoma of the breast or the consequences of a fracture of the femoral neck. In spite of this observation, the acceptance is still insufficient because of an unjustified fear of hormone-induced carcinomas. The incidence of a carcinoma of the breast is not higher in women profiting of a HRT by a correct combination of an oestrogen and a progestogen administered up to 5 years than in untreated controls. Although some but not all authors suspect a slight increase of the relative risk of a carcinoma of the breast to approximately 1.5 after > or = 10 years of HRT, the overall mortality of substituted women is clearly inferior to the one of a non-substituted population. However, the final goal of HRT is not prolongation of life, but a better quality of life. Quality of life is often miserable in women treated for breast cancer. The final answer to the question if women after treatment of breast cancer should be allowed to profit of HRT is still open because formal evidence is missing. However, a woman should not be denied HRT if she lived two years without relapse since her primary cancer and if she does not belong to the subgroup where adjuvant treatment by tamoxifen is appropriate. In the future, selective oestrogen receptor modulators may be used in women after breast cancer.

Am J Clin Oncol. 2000; 23(6):541-5 (ISSN: 0277-3732)

DiSaia PJ; Brewster WR; Ziogas A; Anton-Culver H
Department of Obstetrics and Gynecology, University of California Irvine Medical Center, The Chao Family Comprehensive Cancer Center, 92868, USA.

Controversy exists regarding the safety of hormone replacement therapy (HRT) after a diagnosis of breast cancer. The objective of this study is to perform a matched cohort analysis to evaluate the impact of HRT on mortality in breast cancer survivors. Patients with breast cancer who received HRT after diagnosis of breast cancer were identified. Control subjects were identified from the regional cancer registry. Matching criteria included age at diagnosis, stage of breast cancer, and year of diagnosis. Controls were selected only if they were alive at the time of initiation of HRT of the matched case. Only subjects not included in a previously reported matched analysis were selected. One hundred twenty-five cases were matched with 362 controls. Ninety-eight percent (123/125) of the cases received systemic estrogen; 90/125 (72%) also received a progestational agent. The median interval between diagnosis of breast cancer and initiation of HRT was 46 months (range 0-401 months). The median duration of HRT was 22 months (range 1-357 months). The risk of death was lower among the HRT survivors; odds ratio 0.28 (95% confidence interval 0.11-0.71). This analysis does not suggest that HRT after the treatment of breast cancer is associated with an adverse outcome.

Med J Aust. 2002; 177(7):347-51 (ISSN: 0025-729X)

Durna EM; Wren BG; Heller GZ; Leader LR; Sjoblom P; Eden JA School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.

OBJECTIVE: To determine whether hormone replacement therapy (HRT) after treatment for breast cancer is associated with increased risk of recurrence and mortality.

DESIGN: Retrospective observational study.

PARTICIPANTS AND SETTING: Postmenopausal women diagnosed with breast cancer and treated by five Sydney doctors between 1964 and 1999.

OUTCOME MEASURES: Times from diagnosis to cancer recurrence or new breast cancer, to death from all causes and to death from primary tumour were compared between women who used HRT for menopausal symptoms after diagnosis and those who did not. Relative risks (RRs) were determined from Cox regression analyses, adjusted for patient and tumour characteristics.

RESULTS: 1122 women were followed up for 0-36 years (median, 6.08 years); 154 were lost to follow-up. 286 women used HRT for menopausal symptoms for up to 26 years (median, 1.75 years). Compared with non-users, HRT users had reduced risk of cancer recurrence (adjusted relative risk [RR], 0.62; 95% CI, 0.43-0.87), all-cause mortality (RR, 0.34; 95% CI, 0.19-0.59) and death from primary tumour (RR, 0.40; 95% CI, 0.22-0.72). Continuous combined HRT was associated with a reduced risk of death from primary tumour (RR, 0.32; 95% CI, 0.12-0.88) and all-cause mortality (RR, 0.27; 95% CI, 0.10-0.73).

CONCLUSION: HRT use for menopausal symptoms by women treated for primary invasive breast cancer is not associated with an increased risk of breast cancer recurrence or shortened life expectancy.

J Clin Epidemiol. 2000; 53(4):367-75 (ISSN: 0895-4356)

Coughlin SS; Giustozzi A; Smith SJ; Lee NC
Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 4770 Buford Highway, NE (K-55), Atlanta, GA 30341, USA. SIC9@CDC.Gov

Estrogen replacement therapy (ERT) has not been associated with epithelial ovarian cancer in most reported epidemiologic studies that have looked for an association. Some studies may have found weak statistically nonsignificant associations because the number of cases or number of women who reported estrogen use was small. We performed a meta-analysis of data from 15 case-control studies that provided data on ERT and risk of epithelial ovarian cancer. The 15 combined studies were statistically heterogeneous (chi(2) (14) = 26. 3, P < 0.05) in terms of the effect they found. When we combined these studies using a random effects model, we did not find a significant association of ERT with ovarian cancer (odds ratio = 1.1, 95% confidence interval = 0.9-1.3). There was no clear evidence of a dose-response relation with increasing duration of estrogen use in a subset of five studies that reported estrogen use by duration (overall slope = 0.0012, 95% confidence interval = -0.0055 to 0. 0080). The influences of statistical outliers, study design (hospital or clinic controls vs. community controls), and location (U.S. and Canada vs. Europe and Australia) were examined. The odds ratio was 1.3 (95% confidence interval = 1.0-1.6) in the relatively homogeneous subset of four U.S. case-control studies with community controls, but we cannot rule out the possibility of uncontrolled confounding. The odds ratios for estrogen use for other subgroups defined by geographic location and type of control group were not significantly different from one.

Cancer Epidemiol Biomarkers Prev. 1998; 7(8):653-9 (ISSN: 1055-9965)

Hébert-Croteau N
Direction de la santé publique, Régie régionale de la santé et des services sociaux de Montréal-Centre, Québec, Canada. ncroteau@santepub-mtl.qc.ca

The influence of endocrine factors on colorectal tumor development remains unclear. We performed a meta-analysis of studies of the association between the use of menopausal hormones and colon cancer in women, published up to December 1996. We derived summary measures of relative risk (RR) by fitting both fixed and random effects models. We also performed analyses by tumor location to the right or left colon, as well as by recency and duration of use. Heterogeneity was assessed according to study design, chronology, or other criteria. Overall, the 20 independent estimates of the association between ever use of menopausal hormones and colon cancer led to a summary RR of 0.85, (0.73, 0.99), using a random effects model. There was substantial heterogeneity among studies. The suggested protective effect of hormones was estimated to be stronger in studies published since 1990 [RR: 0.83, (0.66, 1.04), versus 0.93, (0.78, 1.10), for those published previously]. The estimated RRs were lower among current or recent users [RR: 0.69, (0.52, 0.91)] and among users of more than 5 years [RR: 0.73, (0.53, 1.02)] as compared with short-term users [RR: 0.88, (0.64, 1.21)]. The current state of knowledge suggests a 0-25% risk reduction among ever users of hormone replacement therapy. Inadequate assessment of exposure, poor control of confounding factors, and changing patterns of use over time might have contributed to the slow emergence of this association postulated almost two decades ago. Additional large studies are needed to replicate this finding and explain the exact mechanism of this putative protective effect.

J Clin Oncol. 2002; 20(3):699-706 (ISSN: 0732-183X)

Ursin G; Tseng CC; Paganini-Hill A; Enger S; Wan PC; Formenti S; Pike MC; Ross RK
Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA. gursin@hsc.usc.edu

PURPOSE: We and other investigators have previously shown that postmenopausal combined estrogen and progestin replacement therapy (EPRT) increases the risk of breast cancer and that the risk associated with EPRT is substantially higher than for estrogen replacement therapy (ERT) alone. The present study was conducted to determine whether any particular subgroup of women are at particularly high risk of breast cancer if they use EPRT and whether tumor characteristics in women who develop cancer while on ERT or EPRT are different from those in women not using ERT or EPRT.

PATIENTS AND METHODS: We conducted a population-based case-control study in Los Angeles, CA, with patients diagnosed with breast cancer in the late 1980s and early 1990s. Control subjects were matched to patients on age, ethnicity, and neighborhood of residence. We present data on 1,897 postmenopausal patients and 1,637 controls aged 55 to 72 years who had not undergone a simple hysterectomy.

RESULTS: Relative risk of breast cancer associated with EPRT use did not vary with body mass index (body mass index at or below v above median [24.6 kg/m(2)]; P =.98), alcohol intake (> or + one v < one drink per week; P =.16), parity (nulliparous v parous; P =.45), history of benign breast disease (yes v no; P =.99), or family history of breast cancer (first degree v none; P =.57). All of these results were compatible with our previously reported estimate of an increased risk of breast cancer of 5% per year of use of EPRT. Hormone users, principally EPRT users, were more likely to have hormone receptor--positive, especially progesterone-positive, tumors.

CONCLUSION: We found no evidence that the risk of breast cancer associated with EPRT is limited to subgroups of women with specific cofactors. Tumors in EPRT users are more often hormone receptor--positive, indicating that they may have a better prognosis than breast cancer overall.

Am J Obstet Gynecol. 2007; 196(4):342.e1-9 (ISSN: 1097-6868)

Schuetz F; Diel IJ; Pueschel M; von Holst T; Solomayer EF; Lange S; Sinn P; Bastert G; Sohn C
Breast Unit, University Hospital Heidelberg, Heidelberg, Germany. florian_schuetz@med.uni-heidelberg.de

OBJECTIVE: Substitution of estrogens (hormone replacement therapy [HRT]) is the most common therapy and prophylaxis of postmenopausal complaints. However, in most studies, long-term HRT has been associated with an increased risk for breast cancer, but the influence on a prognosis of breast cancer has been examined rarely.

STUDY DESIGN: For further investigation, we analyzed 1072 patients aged 45-70 years at the time of first diagnosis of breast cancer with and without preoperative HRT with regard to the incidence of distant metastases and overall survival. Of these, 279 women were premenopausal (mean, 47.8 +/- 3.2 years); 793 women were postmenopausal (mean, 54.5 +/- 3.5 years); 320 women had received HRT over a minimum of 1 year (mean, 5.5 +/- 4.0 years; group HRT+); and 473 women had not received HRT (group HRT-). The median follow-up time was 73.2 months.

RESULTS: Although body mass index, tumor size, and grading of group HRT- were significantly higher than in group HRT+, nodal status, S-phase fraction, hormone-receptor status, and local recurrence showed no significant differences. In regard to the incidence of distant metastases, women without HRT have significantly (P < .001) more metastases to bone (68 vs 20 women), lung (47:13 women), and liver (47:13 women). Overall survival was significantly lower in the HRT- group.

CONCLUSION: We were able to show that the use of HRT before the diagnosis of breast cancer results in more favorable primary tumors, with a lower incidence of recurrences and a better overall survival rate. This might be due to normalized bone metabolism by the use of HRT, which may lower the conditions of tumor cell seeding.

Obstet Gynecol. 1996; 87(1):6-12 (ISSN: 0029-7844)

Ettinger B; Friedman GD; Bush T; Quesenberry CP
Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA.

OBJECTIVE: To compare all-cause and specific-cause mortality rates in women who had or had not used long-term postmenopausal estrogen replacement therapy (ERT).

METHODS: We identified women who used long-term postmenopausal ERT and compared them with a sample of age-matched postmenopausal nonusers. Through linking of these subjects' medical record numbers to various data bases, we examined survivorship and cause of death among estrogen users and nonusers. The risk of death in 232 postmenopausal women who began ERT within 3 years of menopause and used it for at least 5 years was compared with that of 222 age-matched postmenopausal nonusers. In the users, the mean length of estrogen use was 17.1 years.

RESULTS: Statistically significant reductions in all-cause mortality were found in users compared with nonusers. For death from any cause, the age-adjusted relative risk (RR) and associated 95% confidence interval (CI) in estrogen users was 0.54 (0.38-0.76). The reduction in all-cause mortality was largely due to reductions in coronary heart disease (RR 0.40, CI 0.16-1.02) and other cardiovascular disease (RR 0.27, CI 0.10-0.71). Overall cancer mortality was similar in the two groups (RR 0.85, CI 0.46-1.58), although estrogen users had a higher risk of death from breast cancer (RR 1.89, CI 0.43-8.36) and lower risk of death from lung cancer (RR 0.22, CI 0.04-1.15).

CONCLUSION: Long-term ERT use is associated with lower all-cause mortality and confers this apparent protection primarily through reduction in cardiovascular disease.

Ann Surg Oncol. 2001; 8(10):828-32 (ISSN: 1068-9265)

Peters GN; Fodera T; Sabol J; Jones S; Euhus D
The Center for Breast Care, The University of Texas Southwestern Medical Center at Dallas, 75390-9161, USA. george.peters@utsouthwestern.edu

BACKGROUND: In the United States, estrogen replacement therapy (ERT) is discouraged in breast cancer survivors because of concerns that hormones may reactivate the disease. Because ERT can improve quality of life and decrease morbidity from osteoporosis and cardiovascular disease, however, this policy is increasingly being challenged.

METHODS: From February to August 1995, 607 breast cancer survivors were interviewed concerning ERT usage. Sixty-four patients indicated they received some form of ERT after their breast cancer diagnosis. Medical records for these patients were analyzed for disease stage, surgical treatment, adjuvant treatment, estrogen and progesterone receptor status, date of initiation of ERT, type of ERT, recurrence, and final outcome. Patients receiving ERT were followed prospectively.

RESULTS: Eight patients were excluded because they had used only vaginal cream ERT. The remaining 56 received ERT as conjugated estrogens, an estradiol patch, estropipate, or birth control pills. The median follow-up from diagnosis was 12.8 years (range, 4.7-38.9 years). The median time on ERT since diagnosis was 6.4 years (range, 1.0-20.9 years); 38% of the patients initiated ERT within 2 years of diagnosis. Estrogen receptors were positive in 28 (74%) of the 38 cases with available information. Pathological disease stage at time of diagnosis and treatment was 0 in 15 cases (27%), I in 27 (48%), and II in 14 (25%). Twenty-six patients (47%) received adjuvant chemotherapy or hormonal therapy. One local recurrence and one contralateral breast cancer occurred during the follow-up period (13.5 and 9.6 years, respectively), with no regional or distant recurrences, for a 15-year actuarial disease-free survival rate of 92.5%. There were no breast cancer deaths.

CONCLUSIONS: Use of ERT in a cohort of breast cancer survivors with tumors of generally good prognosis was not associated with increased breast cancer events compared with non-ERT users, even over a long follow-up period.

Br J Cancer. 1996; 73(12):1552-5 (ISSN: 0007-0920)

Mohr PE; Wang DY; Gregory WM; Richards MA; Fentiman IS
Imperial Cancer Research Fund, Clinical Oncology Unit, Guy's Hospital, London, UK.

Several studies have now shown that women with operable breast cancer undergoing tumour excision during the luteal phase of the menstrual cycle have a better prognosis than those having surgery during the follicular phase. As part of a prospective study of prognostic factors in breast cancer, blood was taken at the time of surgery. Between 1975 and 1992 this was available from 289 premenopausal women within 3 days of tumour excision. All were treated by either modified radical mastectomy or breast conservation including axillary clearance and the date of last menstrual period (LMP) was known in 239 (80%) cases. Blood samples were assayed for both oestradiol (E2) and progesterone (P). Because of the wide inter-individual variation in E2 levels there was no clear relationship between E2 and LMP. However, using a running mean smoothing technique the expected cyclical variation could be discerned. There was no significant association between E2 and survival. Smoothing of the P data yielded a pattern similar to the normal hormone profile. Those cases with a progesterone level of 4 ng ml-1 or more had a significantly better survival than those with a level < 4 ng ml-1. This was especially clear in node-positive patients (P < 0.01). The possibility of misclassification of menstrual cycle status, because of misreported LMP, has been minimised by applying an independent hormonal measurement (P) of cycle activity. This parameter will also identify women who may be undergoing anovular cycles. Thus this study has confirmed that a raised level of progesterone at the time of tumour excision is associated with an improvement in prognosis for women with operable breast cancer.

Am J Epidemiol. 1981; 114(2):209-17 (ISSN: 0002-9262)

Cowan LD; Gordis L; Tonascia JA; Jones GS

In order to investigate the nature of the association of involuntarily delayed first birth and risk of breast cancer, 1083 white women who had been evaluated and treated for infertility from 1945-1965 were followed prospectively through April 1978 to ascertain their breast cancer incidence. These women were categorized as to the cause of infertility into two groups, those with endogenous progesterone deficiency (PD) and those with nonhormonal causes (NH). Women in the PD group had 5.4 times the risk of premenopausal breast cancer compared to women in the NH group. This excess risk could not be explained by differences between the two groups in ages at menarche or menopause, history of oral contraceptive use, history of benign breast disease or age at first birth. Women in the PD group also experienced a 10-fold increase in deaths from all malignant neoplasms compared to the NH group. The incidence of postmenopausal breast cancer did not differ significantly between the two groups.

Cancer Detect Prev. 1999; 23(4):290-6 (ISSN: 0361-090X)

Plu-Bureau G; Lê MG; Thalabard JC; Sitruk-Ware R; Mauvais-Jarvis P
INSERM, Gustave-Roussy Institute, Villejuif, France; Department of Reproductive Endocrinology, Necker Hospital, Paris, France.

Percutaneous progesterone topically applied on the breast has been proposed and widely used in the relief of mastalgia and benign breast disease by numerous gynecologists and general practitioners. However, its chronic use has never been evaluated in relation to breast cancer risk. The association between percutaneous progesterone use and the risk of breast cancer was evaluated in a cohort study of 1150 premenopausal French women with benign breast disease diagnosed in two breast clinics between 1976 and 1979. The follow-up accumulated 12,462 person-years. Percutaneous progesterone had been prescribed to 58% of the women. There was no association between breast cancer risk and the use of percutaneous progesterone (RR = 0.8; 95% confidence interval 0.4-1.6). Although the combined treatment of oral progestogens with percutaneous progesterone significantly decreased the risk of breast cancer (RR = 0.5; 95% confidence interval 0.2-0.9) as compared with nonusers, there was no significant difference in the risk of breast cancer in percutaneous progesterone users versus nonusers among oral progestogen users. Taken together, these results suggest at least an absence of deleterious effects caused by percutaneous progesterone use in women with benign breast disease.

Obstet Gynecol. 1983; 62(4):435-43 (ISSN: 0029-7844)

Gambrell RD; Maier RC; Sanders BI

In a prospective study at Wilford Hall USAF Medical Center from 1975 to 1981, 5563 postmenopausal women were followed for a total of 37,236 patient-years of observation. During these seven years, 53 patients were found to have breast cancer, for an incidence of 142.3:100,000 women per year. The mean age (+/- SD) of the patients with cancer was 56.9 +/- 8.24 years, and the mean age of the entire patient population was 56.8 +/- 6.75 years. The expected incidence of breast cancer in this age group, according to the Third National Cancer Survey (1975), is 188.3:100,000 women, and for ages 55 to 59, according to the National Cancer Institute Surveillance, Epidemiology, and End-Result Reporting (NCI SEER) data (1980), is 229.2:100,000. The lowest incidence of breast cancer (67.3:100,000) was observed in the estrogen-progestogen users and was significantly lower than that of the untreated group (342.3:100,000), with P less than or equal to .01. The incidence of the estrogen-progestogen users was also significantly lower than that expected from the NCI SEER data, with a relative risk of 0.3 (95% confidence interval, 0.1 to 0.8). The incidence of mammary malignancy in the estrogen users (141.0:100,000) was significantly lower than in the untreated group (342.3:100,000), with P less than or equal to .01. Although the incidence in the estrogen users was not significantly lower than that expected according to the NCI SEER data (relative risk = 0.7, 0.5 to 1.1), there was a trend in that direction. These data indicate that estrogen therapy for postmenopausal women does not increase the risk of breast cancer and may afford some protection. Added progestogen to postmenopausal estrogen therapy significantly decreases the risk for this malignancy.

J Clin Endocrinol Metab. 1982; 54(6):1104-8 (ISSN: 0021-972X)

Meikle AW; Stanish WM

We investigated whether familial factors influence 1) the incidence of prostatic cancer and 2) the plasma content of sex steroids. A 4-fold higher relative risk for the development of prostatic cancer was observed for brothers (n = 257) of prostatic cancer cases (n = 150) compared to their brothers-in-law (n = 202) and males in the general population of the state Utah. The intraclass correlation for plasma testosterone content [intraclass correlation coefficient (r1) = 0.51; P less than 0.01] and the apparent free testosterone concentration (r1 = 0.54; P less than 0.01) were highly significant in nonendocrinologically treated cases and their brothers. Further, sons and their fathers had significant intraclass correlations for both plasma dihydrotesterone (r1 = 0.83; P less than 0.01) and the ratio of testosterone to dihydrotestosterone (r1 = 0.46; P less than 0.05). Probands and their brothers, and sons of the patients with the disease had significantly lower plasma testosterone levels than controls of comparable age. This is the first documentation indicating that familial (possibly genetic) factors are potent risk factors for predisposing men to the development of prostatic cancer and in regulating the plasma content of androgens. Our results indicate that plasma androgen levels in families with prostatic cancer are clustered in the lower range of the normal population. They also suggest that plasma androgen content is more similar within each family with the cancer than among the families without cancer.

J Surg Oncol. 1990; 44(2):122-8 (ISSN: 0022-4790)

Kumar VL; Wadhwa SN; Kumar V; Farooq A
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi.

Cytosolic and nuclear androgen, estrogen and progesterone receptor content was measured in the groups of 11 prostatic carcinoma (PCA) and 32 benign prostatic hypertrophy (BPH) samples. All BPH cases were positive for the cytosolic progesterone (PRc) and estrogen receptor (ERc), whereas only 85% of cases (23/27) contained the androgen receptor (ARc). Only those five patients who received estrogen treatment in the PCA group had detectable ARc. PRc was present in all of the PCA cases, whereas ERc could be detected in only 82% (9/11) of cases. Cytosolic contents of all three steroid receptors, however, were higher in the PCA group. The level of nuclear steroid receptors, although present in fewer cases in both groups, was higher than the cytoplasmic receptors. The serum profile of estradiol, cortisol, and prolactin was normal in both groups, whereas LH, FSH, and progesterone levels were higher than in normal adults. Serum testosterone level was within normal range in the BPH group, but it was significantly below normal (P less than 0.005) in PCA patients.

Prostate. 1982; 3(6):579-88 (ISSN: 0270-4137)

Zumoff B; Levin J; Strain GW; Rosenfeld RS; O'Connor J; Freed SZ; Kream J; Whitmore WS; Fukushima DK; Hellman L

The 24-hr mean plasma concentrations of 13 hormones or hormone metabolites (cortisol, testosterone, dihydrotestosterone, dehydroisoandrosterone, dehydroisoandrosterone sulfate, androsterone, androsterone sulfate, estrone, thyroxine, triiodothyronine, LH, FSH, and prolactin) were measured in 16 rigorously screened patients (aged 55-80) with stage C or D prostate cancer and 36 normal men. Nine of the hormones showed no abnormalities in the patients but four (testosterone, dihydrotestosterone, cortisol, and estrone) showed abnormalities. Testosterone and dihydrotestosterone, which, respectively, decreased with age and showed no change with age in the normal men, rose sharply with age in the patients. The patients' curves crossed the normal curves at about age 65; patients 65 or above showed normal values while patients under age 65 showed significantly subnormal levels of both hormones: testosterone averaged 282 ng/dl in patients vs 434 ng/dl in controls (P less than 0.0001) and dihydrotestosterone averaged 70 ng/dl in patients vs 99 ng/dl in controls (P less than 0.01). Cortisol, which was age invariant in the normal men, fell sharply with age in the patients; patients under 65 had significantly elevated levels (10.1 vs 6.9 micrograms/dl; P less than 0.0001), while patients 65 or older had normal levels. Estrone levels were age invariant in both patients and controls, but the mean level in patients was markedly elevated (81 vs 47 pg/ml in controls; P less than 0.001). The cortisol/testosterone ratio almost completely separated prostate cancer patients under 65 from normal men, but did not discriminate patients 65 or older from normal. The findings indicate that prostate cancer patients under 65 differ markedly in their endogenous hormonal pattern from patients 65 or older. This leads us to propose a "two-disease" theory of prostate cancer, with possible differences in genetic factors and prognosis.

Cancer Res. 1988; 48(12):3515-7 (ISSN: 0008-5472)

Nomura A; Heilbrun LK; Stemmermann GN; Judd HL
Japan-Hawaii Cancer Study, Kuakini Medical Center, Honolulu 96817.

J Urol. 2005; 174(6):2178-80 (ISSN: 0022-5347)

Teloken C; Da Ros CT; Caraver F; Weber FA; Cavalheiro AP; Graziottin TM
Urology Department, Santa Casa Hospital, Porto Alegre, RS, Brazil 90450180.

PURPOSE: It has been reported that more aggressive prostate cancer (PC) can be associated with low serum testosterone levels. The relationship between serum androgens and PC is still not completely understood. In this study we examined the association of prognostic factors in men who underwent radical retropubic (RRP) prostatectomy with low or normal total testosterone.

MATERIALS AND METHODS: We retrospectively evaluated 64 consecutive patients with localized PC treated with RRP between July 2002 and November 2003. PC was diagnosed by transrectal ultrasonography guided biopsy performed for either a suspicious digital rectal examination or serum prostate specific antigen greater than 4.0 ng/ml. Gleason score was determined in prostatic biopsies. Pathological TNM staging (1997), capsular perforation, seminal vesicle involvement and surgical margin status were determined in all surgical specimens. The threshold for serum total testosterone was 270 ng/dl. In all analyses p <0.05 was considered statistically significant.

RESULTS: There were no statistically significant differences among prostate specific antigen, Gleason score (biopsy or specimen), pathological stage, capsular perforation and seminal vesicle involvement. However, patients with low total testosterone had increased positive surgical margins (p = 0.026).

CONCLUSIONS: Patients with low total testosterone more frequently present with positive surgical margins in RRP specimens. The true association between low testosterone and poor clinical outcome in the long term needs validation in large prospective studies.