The new books, "Infections and Human Cancer," Plainview, N.Y., Cold Spring Harbor Laboratory Press, 1999, ISBN 0-87969-549-8 and "Microbes and Malignancy: Infection as a Cause of Human Cancers," New York, Oxford University Press, 1999, ISBN 0-19-510401-3, suggest infections cause some cancers. I suggest a common mechanism causes this connection, that is, low dehydroepiandrosterone, DHEA. Cancer and infections are both increasing. My explanation, of these increases, involves testosterone, which I think is increasing, and may reduce the availability of DHEA. This combination is demonstrable in breast cancer, infections, and their current increases. These are coincident with the "secular trend," which I think may represent an increase in individuals of higher testosterone.

My principal hypothesis is that DHEA is involved in optimal transcription and replication of DNA. I suggest activation of genes of cell division require larger amounts of DHEA than genes of differentiation. As growth occurs, DHEA availability decreases because of increased competition. As tissues form, cell surface areas decrease and the increased numbers of transcriptions of genes of differentiation begin to use DHEA and further reduce the probability of cell division. (Transcription of smaller groups of genes can occur during times of reduced DHEA.) This is how differentiation competes with, and inhibits, cell division. DHEA begins to decline around age twenty. As aging begins, I suggest loss of DHEA sometimes begins the opposite process. That is, genes of differentiation are closed down in reverse order, as a result of declining DHEA. For oncogenes (genes of the undifferentiated, rapidly replicating state) to be activated, they must be exposed to increased availability of DHEA. I suggest the beginnings of "differentiation reversal" includes loss of transcription of genes controlling cell adhesion. (Loss of cell adhesion is characteristic of oncogene activation.) I suggest loss of cell adhesion triggers oncogene, or mutated gene, activity, because the cell surface area is increased and increased DHEA is absorbed. That is, genes of cell division, which require large amounts of DHEA, would than have an increased supply.

This is why more cancer occurs in old age, but grows less rapidly. That is, old age increases the probability of regression of the differentiated state (loss of DHEA of old age). This increases the likelihood of loss of cell adhesion. Once the increased surface area of these cells has increased DHEA absorption, cell division is triggered. However, cancer grows less rapidly because old age is a time of reduced DHEA. Since DHEA is used for all growth and maintenance, even in old age, cachexia of cancer may result from increased absorption of DHEA for cancer growth, at the expense of the rest of the body. This may be why some cancers exaggerate the aging process. Absorption of DHEA and, therefore, further reduction in the availability of DHEA by cancer, may trigger further oncogene activation in other tissues. This could explain metastasis.

My explanation of breast cancer is based on low DHEA and high testosterone. It has been known for a long time that DHEA is low, and testosterone is high, in breast cancer. (I was unaware of this when I developed my ideas regarding cancer and was delighted to discover this.) However, no hypothesis, other than mine, proposes a mechanism to account for these phenomena as causes of breast cancer and cancer, generally. "Two long and broad streams of medical literature, from the 1950's to date, have established the existence of two unrelated abnormalities of androgen production in women with breast cancer. One is the genetically determined presence of subnormal production of adrenal androgens (i.e. DHEA and DHEAS) in women with premenopausal breast cancer and their sisters, who are at increased risk for breast cancer. The other is excessive production of testosterone, of ovarian origin, in subsets of women with either premenopausal or post menopausal breast cancer and women with atypical breast-duct hyperplasia, who are at increased risk for breast cancer; along with the hypertestosteronism, there is frequently chronic anovulation in the premenopausal patients. The combination of ovarian hypertestosteronism and chronic anovulation is characteristic of the polycystic ovary syndrome and is also frequently seen in women with abdominal ('android') obesity." (Anticancer Res. 1994; 14 (5B): 2113). It is known that breast tumors, but not normal breast tissue, concentrate DHEA (J. Ster. Biochem. 1987; 26: 151). Measurable levels of DHEA are reduced in women with breast cancer, and this reduction in DHEA occurs as early as nine years prior to diagnosis (Geriatrics 1992; 37: 157). I suggest that the low levels of DHEA prior to diagnosis may participate in subsequent cancer formation.

There should be two basic kinds of breast cancer formation. One should involve oncogene activation due to reductions in DHEA, as just described, and the other should involve gene mutations. This quotation, part of an abstract, supports this. "Results: DHEA is reported to inhibit the growth of human mammary cancer cells in vitro and also the growth of chemically-induced mammary cancer in rats. However, growth inhibition occurs only in the presence of high oestrogen concentrations, and growth stimulation occurs in both models in the presence of a low-oestrogen milieu. Epidemiological studies report a positive correlation between higher serum concentrations of DHEA and increased breast cancer risk in the case of postmenopausal but not premenopausal women." (Eur. J. Clin. Nutr. 1999; 53: 771) In these cases, the estrogen would direct the differentiated state and additional DHEA would maintain this state. The DHEA would be used for maintenance of differentiation instead of growth. If estrogen is not added, then the increased surface area of cells in vitro increases absorption of DHEA and stimulates growth of cancer cells. In premenopausal women, who produce sufficient estrogen, extra DHEA would be used to maintain the differentiated state. The opposite would occur in postmenopausal women. If estrogen stimulates mutated genes, then extra DHEA would increase growth of cancer cells. Therefore, in younger women, who are producing larger amounts of DHEA, estrogen-directed, mutated genes would grow rapidly. In postmenopausal women who have estrogen-directed, mutated genes, cancer may form, but would grow less rapidly, unless she takes estrogen. In that case, taking extra DHEA would also increase growth. Once started, DHEA will positively affect breast cancer growth.

The authors of the study, paragraph above, point out that "Late promotion of breast cancer in postmenopausal women may be stimulated by prolonged intake of DHEA, and the risk may be increased by the endocrine abnormality associated with pre-existing abdominal obesity." "Pre-existing abdominal obesity" brings the influence of testosterone to my explanation of why breast cancer is increasing. I suggest testosterone interferes with the availability of DHEA; reduces DHEA. In women, testosterone increases abdominal fat (Eur. J. Endocrinol. 1995; 133: 200 and J. Endocrinol. 1996; 150 Suppl: S155). Increased testosterone in premenopausal women should reduce the availability of DHEA and increase the probability of breast cancer. Therefore, estrogen and testosterone should, both, increase the risk of breast cancer. This is supported: "Compared to women in the lowest quartile [of breast cancer risk], those in the highest quartile for non-sex hormone-binding globulin bound estradiol had a relative risk of 5.2 (95% confidence interval [CI] = 1.5-18.50 and those in the highest quartile for testosterone had a relative risk of 6.2 (95% CI = 2.0-19.0)." (Environ. Health Perspect. 1997; 105 Suppl 3: 583) The background reserve form of DHEA in blood plasma is DHEAS (DHEA sulfate). If a woman is not converting DHEAS to DHEA, then she might be "low DHEA." This is also supported: "The relationship of DHEAS to breast cancer was less consistent, but women whose serum DHEAS concentration was in the highest quartile also exhibited a significantly elevated risk ratio of 2.8 (95% CI, 1.1-7.4)." (Cancer Epidemiol. Biomarkers Prev. 1997; 6: 177). Furthermore, "Data are consistent with the hypothesis that the plasma source contributes remarkably to DHEA found within breast cancer tissue." (Breast Cancer Res. Treat. 1995; 33: 171).

Breast cancer is increasing and studies suggest this is not merely a reflection of better surveillance. I think the secular trend, the increase in size and earlier puberty occurring in our children, is due to increasing numbers of individuals who produce more testosterone. That is, they reproduce faster than individuals who produce less testosterone. One high risk factor for developing breast cancer is early puberty. If I am correct, that testosterone negatively affects the availability of DHEA, and the secular trend represents increasing testosterone, then we should see an increase in breast, and other, cancers. This also may explain the increase in infections and the connection of infections and cancers.

It is my hypothesis that DHEA is directly involved in optimal activity of every tissue. Therefore, DHEA should strengthen the immune response. It has recently been found that DHEA, and its conversion products, protect against bacterial infections. "The data suggest that both DHEA and AED may have a role in the neuro-endocrine regulation of antibacterial immune resistance." (J. Med. Microbiol. 1999; 48: 425) In studies on mice, DHEA protects against numerous viruses. "Dehydroepiandrosterone (DHEA) has a significant protective effect in mice infected with West Nile virus (WNV), Sindbis virus neurovirulent (SVNI) and Semliki Forest virus (SFV)." (Arch. Virol. 1991; 120: 263)

There are a number of investigations that support my contention that testosterone adversely affects the immune system. One contains this generality: "…sexually mature male vertebrates are often more susceptible to infection and carry higher parasite burdens in the field." (Int. J. Parasitol. 1996; 26: 1009). Another investigation determined the following: "Conclusions: Castration before soft-tissue trauma and hemorrhagic shock maintains normal immune function in male mice, but sham-castrated male mice show significant immunodepression. …Thus, the use of testosterone-blocking agents following trauma-hemorrhage should prevent the depression of immune functions and decrease the susceptibility to sepsis under those conditions." (Arch. Surg. 1996; 131: 1186) In a study of mice exposed to Mycobacterium marinum, testosterone was found to increase susceptibility in males and females. This study carefully controlled for the presence of testosterone. "Although this ordering corresponded to the susceptibilities of both male and female mice to the organisms, much greater strain dependency was seen in males than females. Castration caused an increase in the host resistance of males, but this effect was substantially reversed by continuous testosterone treatment. Testosterone also increased the susceptibility of female mice to this infection. These findings imply that the male sex hormone is involved in the lowered anti-M. marinum resistance of males." (Infect. Immun. 1991; 59: 4089).

The same pattern is discernible in humans. "The rate of invasive group B streptococcal infection was twice as high in black adults; the incidence increased with age and was particularly high in older blacks, although there was a relatively small black population over 70 years." (New Eng. J. Med. 1993; 328: 1807) Healthy, black males produce significantly more testosterone than healthy, white males (J. National Cancer Institute 1986; 76: 45). Testosterone is higher in black women than white women (J. Clin. Endocrin. Metabolism 1996; 81: 1108). This explains Farley's findings and, I suggest, the "unexplained finding that under the same social conditions, blacks are apparently infected more readily by Mycobacterium tuberculosis than whites" (New Eng. J. Med. 1990; 322: 422). Testosterone interferes with the availability of DHEA and DHEA declines during old age.

Infections should increase because of the same mechanism that may be increasing cancer, that is, increasing testosterone. It is possible that cancer and infections further reduce DHEA in some individuals. This would increase the probability of one increasing the other. I suggest that the connection of infections and cancer is low DHEA.