Hormonal profiles in women with breast cancer

Also see:
PUFA Increases Estrogen
Radiation Increases Breast Cancer Incidence
PUFA Inhibit Glucuronidation
PUFA Promote Cancer
Maternal PUFA Intake Increases Breast Cancer Risk in Female Offspring
Estrogen and Bowel Transit Time
Progestin and Cancer
Study: Acquired Breast Cancer Risk Spans Multiple Generations
Ray Peat, PhD on Thyroid, Temperature, Pulse, and TSH
Pre and Postmenopausal Women: Progesterone Decreases Aromatase Activity
Endometriosis and Estrogen
Progestin and Cancer
Ray Peat, PhD on the Menstrual Cycle
Lab study: Daily aspirin could block growth of breast, other cancers
Breast Cancers Can Produce Their Own Estrogen to Resist Aromatase Inhibitors

Quotes by Ray Peat, PhD:
“When the estrogen dominance persists for a long time without interruption, there are progressive distortions in the structure of the responsive organs–the uterus, breast, pituitary, lung, liver, kidney, brain, and other organs–and those structural distortions tend to progress gradually from fibroses to cancer.

As a result of the early studies in both humans and animals, progesterone was used by many physicians to treat the types of cancer that were clearly caused by estrogen, especially uterine, breast, and kidney cancers.”

“If the cancer-productive field is taken into account, all of the factors that promote and sustain that field should be considered during therapy.

Eliminating polyunsaturated fats from the diet is essential if the bystander effect is eventually to be restrained. Aspirin and salicylic acid can block many of the carcinogenic effects of the PUFA. Saturated fats have a variety of antiinflammatory and anticancer actions. Some of those effects are direct, others are the result of blocking the toxic effects of the PUFA. Keeping the stored unsaturated fats from circulating in the blood is helpful, since it takes years to eliminate them from the tissues after the diet has changed. Niacinamide inhibits lipolysis. Avoiding over-production of lipolytic adrenaline requires adequate thyroid hormone, and the adjustment of the diet to minimize fluctuations of blood sugar.”

“The radical mastectomy, which removed massive amounts of apparently normal tissue as well as the breast tumor, was practiced for hundreds of years, and was the standard treatment for breast cancer until the 1980s, after G.W. Crile, Jr., had publicized the evidence showing that simply removing the tumor lump itself didn’t cause a higher mortality rate, and that the surgery produced much less disability.

Although the lumpectomy was eventually accepted by the profession, the evidence that the long term survival rate was higher when the surgery was done during the luteal phase in premenopausal women has been generally ignored, because the cancer ideology maintains that the fate of the cancer is in the cells, rather than in the patient’s hormone balance.”

“In the 1960s I read some articles in a small town newspaper about Leonell Strong’s cancer research, and his treatment by the American Cancer Society and the Salk Institute. Leonell Strong had developed strains of mice for use in cancer research. In some of the strains, 100% of the females developed mammary cancer. Strong had demonstrated that these strains had very high levels of estrogen.”

“Over the decades, many studies have confirmed that prolonged, continuous exposure to estrogen is carcinogenic, and that progesterone offsets those effects.

Following the animal studies that showed that carcinogenesis by estrogen could be prevented or reversed by progesterone, studies of the endogenous hormones in women showed that those with a natural excess of estrogen, and/or deficiency of progesterone, were the most likely to develop uterine or breast cancers.”

“A 1994 publication (B. Zumoff, “Hormonal profiles in women with breast cancer,” Obstet. Gynecol. Clin. North. Am. (U.S.) 21(4), 751-772) reported that there are four hormonal features in women with breast cancer: diminished androgen production, luteal inadequacy, increased 16-hydroxylation of estradiol, and increased prolactin. The 16-hydroxylation converts estradiol into estriol.”

“Two background facts are needed to interpret the JAMA article. The first is that hypothyroidism is a major cause of breast cancer, because of the chronic excess of estrogen and deficiency of progesterone. The second is that US doctors don’t correct hypothyroidism, because they don’t prescribe the active hormone T3, only the precursor T4, which fails to be converted because hypothyroid women’s livers aren’t efficient. T3 is needed for the storage of glycogen and the efficient use of glucose, and glucose is needed to form T3. Therefore, women in the US who “are treated for hypothyroidism” are still hypothyroid, and hypothyroid women are much more likely to get cancer.”

Obstet Gynecol Clin North Am. 1994 Dec;21(4):751-72.
Hormonal profiles in women with breast cancer.
Zumoff B.
The literature findings on endogenous hormonal profiles in women with breast cancer are reviewed in detail. It is concluded that four sets of findings are valid: (1) diminished adrenal androgen production, probably genetic, in women with premenopausal breast cancer; (2) ovarian dysfunction (luteal inadequacy plus increased testosterone production) in breast cancer at all ages; (3) increased 16 alpha-hydroxylation of estradiol in breast cancer at all ages; and (4) evidence that prolactin is a permissive risk factor for breast cancer, and that the pregnancy-induced decrease in prolactin levels may account for the protective effect of early pregnancy against breast cancer.

J Natl Cancer Inst. 1986 Sep;77(3):613-6.
Endogenous sex hormones, prolactin, and breast cancer in premenopausal women.
Meyer F, Brown JB, Morrison AS, MacMahon B.
Forty-one women with breast cancer and 119 controls participated in a case-control study of the relation of endogenous sex hormones to breast carcinoma in premenopausal women. During the follicular phase of the menstrual cycle, one overnight urine specimen was collected. During the luteal phase, urine and blood specimens were obtained. 17 beta-Estradiol, sex hormone-binding globulin, progesterone, and prolactin were measured in plasma, whereas estrogen metabolites (estrone, estradiol, and estriol) and pregnanediol were assessed in the urine. Breast cancer was associated with high-plasma estradiol and prolactin and with low progesterone. Similar but weaker associations were observed for urinary estrogens and pregnanediol in the luteal phase.

J Mammary Gland Biol Neoplasia. 1998 Jan;3(1):49-61.
Role of hormones in mammary cancer initiation and progression.
Russo IH, Russo J.
Breast cancer, the most frequent spontaneous malignancy diagnosed in women in the Western world, is a classical model of hormone dependent malignancy. There is substantial evidence that breast cancer risk is associated with prolonged exposure to female hormones, since early onset of menarche, late menopause, hormone replacement therapy and postmenopausal obesity are associated with greater cancer incidence. Among these hormonal influences a leading role is attributed to estrogens, either of ovarian or extra-ovarian origin, as supported by the observations that breast cancer does not develop in the absence of ovaries, ovariectomy causes regression of established malignancies, and in experimental animal models estrogens can induce mammary cancer. Estrogens induce in rodents a low incidence of mammary tumors after a long latency period, and only in the presence of an intact pituitary axis, with induction of pituitary hyperplasia or adenomas and hyperprolactinemia. Chemicals, radiation, viruses and genomic alterations have all been demonstrated to have a greater tumorigenic potential in rodents. Chemical carcinogens are used to generate the most widely studied rat models; in these models hormones act as promoters or inhibitors of the neoplastic process. The incidence and type of tumors elicited, however, are strongly influenced by host factors. The tumorigenic response is maximal when the carcinogen is administered to young and virgin intact animals in which the mammary gland is undifferentiated and highly proliferating. The atrophic mammary gland of hormonally-deprived ovariectomized or hypophysectomized animals does not respond to the carcinogenic stimulus. Administration of carcinogen to pregnant, parous or hormonally treated virgin rats, on the other hand, fails to elicit a tumorigenic response, a phenomenon attributed to the higher degree of differentiation of the mammary gland induced by the hormonal stimulation of pregnancy. In women a majority of breast cancers that are initially hormone dependent are manifested during the postmenopausal period. Estradiol plays a crucial role in their development and evolution. However, it is still unclear whether estrogens are carcinogenic to the human breast. The apparent carcinogenicity of estrogens is attributed to receptor-mediated stimulation of cellular proliferation. Increased proliferation could result in turn in accumulation of genetic damage and stimulation of the synthesis of growth factors that act on the mammary epithelial cells via an autocrine or paracrine loop. Alternatively estrogens may induce cell proliferation through negative feedback by removing the effect of one or several inhibitory factors present in the serum. Multidisciplinary studies are required for the elucidation of the mechanisms responsible for the initiation of breast cancer. Understanding of such mechanisms is indispensable for developing a rational basis for its prevention and control.

Tumori. 2000 Jan-Feb;86(1):12-6.
Factors of risk for breast cancer influencing post-menopausal long-term hormone replacement therapy.
Chiechi LM, Secreto G.
The advantages of hormone replacement therapy (HRT) are well documented in contrasting the symptomatology of climacterium and in reducing morbidity and mortality associated with coronary heart disease and osteoporotic fractures of postmenopausal age. However, growing evidence points to increased breast cancer risk in HRT long-term users, and the adverse effect would, obviously, overwhelm any other benefit. At present, the risk/benefit ratio of HRT is an object of hot debate, and we feel it necessary and urgent to select women who can safely benefit from HRT and women whose risk of breast cancer can be perilously increased by the raised hormonal levels related to HRT. We have reviewed studies on the breast cancer risk in HRT users and data on the interaction between steroid hormones and breast cancer. Reasoning that the outcome of mammary cancer can be increased by hormonal overstimulation of the breast, we have focused on those factors of risk that could be further enhanced by the exogenous hormonal stimulus of HRT, so as to cause a further significant increase in the risk of breast cancer. We conclude that some biologic and clinical markers, namely android obesity, bone density, mammographic density, androgen and estrogen circulating levels, alcohol consumption, benign breast disease, and familiarity, should be carefully considered before prescribing long-term HRT. Our analysis suggests that HRT could increase the risk of breast cancer and useless in preventing coronary heart disease and osteoporotic fractures when administered in women with positivity for one or more of these markers.

Endocrinol Metab Clin North Am. 2011 Sep;40(3):473-84, vii. Epub 2011 Jun 29.
Estrogen carcinogenesis in breast cancer.
Germain D.
Many studies have reported a correlation between elevated estrogen blood levels and breast cancer and this observation has raised controversy concerning the long-term use of hormonal replacement therapy. This review will not address further this controversial topic; but rather, this review focuses on the role of estrogen signaling in first, the normal development of the breast and second, how alterations of this signaling pathway contribute to breast cancer.

Ann N Y Acad Sci. 1988;538:257-64.
Possible relevance of steroid availability and breast cancer.
Bruning PF, Bonfrer JM.
The as yet circumstantial evidence for a central role of estrogens in the promotion of human breast cancer is supported by many data. However, it has not been possible to identify breast cancer patients or women at risk by abnormally elevated estrogen levels in plasma. The concept of available, i.e., non-SHBG bound sex steroid seems to offer a better understanding than total serum steroid levels do. We demonstrated that sex steroid protein binding is decreased by free fatty acids. This finding may help to explain how the affluent Western diet and sedentary life style is related to high incidence rates of breast cancer. We have postulated that it is especially the central (abdominal) type of obesity which may increase sex steroid availability. This mechanism could be important already at the age of breast development when the sensitivity to promotion seems relatively great. It may also explain the increased incidence rates which are observed in Western industrialized countries after menopause. It seems likely that other endocrine-related cancer, such as endometrial or prostatic carcinomas are influenced in an analogous way.

Am J Epidemiol. 1981 Aug;114(2):209-17.
Breast cancer incidence in women with a history of progesterone deficiency.
Cowan LD, Gordis L, Tonascia JA, Jones GS.
In order to investigate the nature of the association of involuntarily delayed 1st birth and breast cancer risk, 1083 white women who had been evaluated and treated for in fertility from 1945-65 were followed prospectively through April 1978 to ascertain their breast cancer incidence. These women were categorized as to the cause of infertility into 2 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 as compared to women in the NH group. This excess risk could not be explained by differences between the 2 groups in age at menarche or age at menopause, history of oral contraceptive use, history of benign breast dieases, or age at 1st birth. Women in the PD group also experienced a 10-fold increase in deaths from all malignant neoplasm compared to the NH group. The incidence of postmenopausal breast cancer did not differ significantly between the 2 groups.

Cancer Res August 1, 2014 74; 4078
Recent Oral Contraceptive Use by Formulation and Breast Cancer Risk among Women 20 to 49 Years of Age
Elisabeth F. Beaber, Diana S.M. Buist, William E. Barlow, Kathleen E. Malone, Susan D. Reed, and Christopher I. Li
Previous studies of oral contraceptives and breast cancer indicate that recent use slightly increases risk, but most studies relied on self-reported use and did not examine contemporary oral contraceptive formulations. This nested case–control study was among female enrollees in a large U.S. integrated health care delivery system. Cases were 1,102 women ages 20 to 49 years diagnosed with invasive breast cancer from 1990 to 2009. Controls were randomly sampled from enrollment records (n = 21,952) and matched to cases on age, year, enrollment length, and medical chart availability. Detailed oral contraceptive use information was ascertained from electronic pharmacy records and analyzed using conditional logistic regression, ORs, and 95% confidence intervals (CI). Recent oral contraceptive use (within the prior year) was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.3–1.9) relative to never or former OC use. The association was stronger for estrogen receptor–positive (ER+; OR, 1.7; 95% CI, 1.3–2.1) than estrogen receptor–negative (ER−) disease (OR, 1.2, 95% CI, 0.8–1.8), although not statistically significantly different (P = 0.15). Recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1–6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4–4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9–5.1; Pheterogeneity compared with using other oral contraceptives = 0.004) was associated with particularly elevated risks, whereas other types, including low-dose estrogen oral contraceptives, were not (OR, 1.0; 95% CI, 0.6–1.7). Our results suggest that recent use of contemporary oral contraceptives is associated with an increased breast cancer risk, which may vary by formulation. If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks. Cancer Res; 74(15); 4078–89. ©2014 AACR.

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Environment and breast cancer risk:

Environmental Health 2012, 11:87
Breast cancer risk in relation to occupations with exposure to carcinogens and endocrine disruptors: a Canadian case–control study
James T Brophy, Margaret M Keith, Andrew Watterson, Robert Park, Michael Gilbertson, Eleanor Maticka-Tyndale, Matthias Beck, Hakam Abu-Zahra, Kenneth Schneider, Abraham Reinhartz, Robert DeMatteo and Isaac Luginaah
Background
Endocrine disrupting chemicals and carcinogens, some of which may not yet have been classified as such, are present in many occupational environments and could increase breast cancer risk. Prior research has identified associations with breast cancer and work in agricultural and industrial settings. The purpose of this study was to further characterize possible links between breast cancer risk and occupation, particularly in farming and manufacturing, as well as to examine the impacts of early agricultural exposures, and exposure effects that are specific to the endocrine receptor status of tumours.
Methods
1006 breast cancer cases referred by a regional cancer center and 1146 randomly-selected community controls provided detailed data including occupational and reproductive histories. All reported jobs were industry- and occupation-coded for the construction of cumulative exposure metrics representing likely exposure to carcinogens and endocrine disruptors. In a frequency-matched case–control design, exposure effects were estimated using conditional logistic regression.
Results
Across all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk (OR = 1.42; 95% CI, 1.18-1.73, for 10 years exposure duration). Specific sectors with elevated risk included: agriculture (OR = 1.36; 95% CI, 1.01-1.82); bars-gambling (OR = 2.28; 95% CI, 0.94-5.53); automotive plastics manufacturing (OR = 2.68; 95% CI, 1.47-4.88), food canning (OR = 2.35; 95% CI, 1.00-5.53), and metalworking (OR = 1.73; 95% CI, 1.02-2.92). Estrogen receptor status of tumors with elevated risk differed by occupational grouping. Premenopausal breast cancer risk was highest for automotive plastics (OR = 4.76; 95% CI, 1.58-14.4) and food canning (OR = 5.70; 95% CI, 1.03-31.5).
Conclusions
These observations support hypotheses linking breast cancer risk and exposures likely to include carcinogens and endocrine disruptors, and demonstrate the value of detailed work histories in environmental and occupational epidemiology.

Intestinal flora, diet, and estrogen:
Rev Infect Dis. 1984 Mar-Apr;6 Suppl 1:S85-90.
Estrogens, breast cancer, and intestinal flora.
Gorbach SL.
Epidemiologic evidence has linked diet to breast cancer, with the highest cancer rates observed in women who eat a high fat-low fiber diet. There is also substantial information, both clinical and experimental, that implicates estrogens in the etiology of breast cancer. A recent study from our laboratory has shown that diet influences levels of estrogens, and the main mechanism is metabolism of estrogens in the intestine. The intestinal microflora plays a key role in the enterohepatic circulation of estrogens by deconjugating bound estrogens that appear in the bile, thereby permitting the free hormones to be reabsorbed. By suppressing the microflora with antibiotic therapy, fecal estrogens increase and urinary estrogens decrease, changes indicating diminished intestinal reabsorption. A low fat-high fiber diet is associated with similar findings-high fecal estrogens and low urinary estrogens. It appears that the microflora plays a key role in the metabolism of female sex hormones.

Phase of menstrual cycle and breast cancer surgery:
“Long range survival after breast cancer surgery is affected by the time in the menstrual cycle when the surgery is done (Lemon, et al., 1996).” -Ray Peat, PhD

Nebr Med J. 1996 Apr;81(4):110-5.
Timing of breast cancer surgery during the luteal menstrual phase may improve prognosis.
Lemon HM1, Rodriguez-Sierra JF.
A meta-analysis has been performed of available retrospective reports concerning the 5-15 year disease-free survival of 5,353 premenopausal breast cancer patients operated on either during the follicular or luteal phases of the menstrual cycle. Patients with surgery performed during the luteal phase (d 14-23+) had an overall mean 5% benefit compared to those operated on the follicular phase determined by date of onset of their last menstrual period p = 0.02 by Wilcoxon 2-tailed test. When nodal invasion was reported, node-negative patients had a 5 +/- 2% SEM benefit. Patients with positive nodes had a 34 +/- 3% SEM increase in survival (p = .05), including both estrogen and progesterone-receptor negative as well as positive neoplasms. In 3 of 4 reports from major cancer treatment centers, each containing 249-1175 cases, risk of recurrent cancer and/or death increased 5 to 6-fold after 10 years for women receiving surgery during d 7-14 of their cycle, compared to those resected during d 21-36. Improvement in prognosis was greatest for patients with the highest risk of recurrence due to node-invasive disease and receptor dysfunction. Several cell-mediated immunologic factors inimical to metastasis are maximal in the luteal phase of the menstrual cycle, including natural killer cell activity. A new drug which augments natural killer cell activity may extend any beneficial survival results to post-menopausal breast cancer patients in the future. We conclude that accurate menstrual histories should be included in the medical record from now on for all premenopausal women receiving any surgical procedure upon the breast, preferably using an objective method of determining the date of last ovulation. Prospective randomized clinical trials are necessary to determine the full extent of survival benefits of late luteal surgical timing.