Endometriosis
A significant number of infertile women show ovarian dysfunction with endometriosis. Higher progesterone levels in late follicular and luteal phases have been associated with endometriosis.50 A recent study of women with similar etiology found that 50% had normal progesterone cycles, while 45% showed higher progesterone levels. Among the latter, 18% of the subjects exhibited elevated levels in the follicular phase, 20% in the luteal phase, and 7.5% in both phases.51 It has also been observed that maintaining adequate estrogen levels in post-menopausal women may be a risk factor for developing endometrial cancer.52
Breast Disease
Elevated estrogen levels are generally considered an increased risk factor for breast cancer, especially in women after menopause. A study of 276 British and Thai women with different levels of progesterone indicated that higher levels of progesterone might also be a risk factor for breast cancer. This hypothesis was further strengthened by another study of 362 young women.53
There is good evidence for photoperiod dependence and/or melatonin responsiveness in the initiation and evolution of certain cancers, particularly hormone-dependent cancers. Because of its powerful oncostatic effects and its estrogen-blocking ability, melatonin demonstrates particular promise in the treatment of breast cancer. Numerous studies have reported an inverse correlation between melatonin levels and the growth of estrogen-receptive positive tumors. Used in conjunction with tamoxifen to modulate cancer endocrine therapy, melatonin shows marked ability to influence estrogen receptor expression and inhibit breast cancer cell growth. Moreover, researchers surmised that melatonin might induce objective tumor regressions in metastatic breast cancer patients refractory to tamoxifen alone. 54
Clinical Studies
Estrogen and Cancer Risk
Dr Henry Lemon (MD) observed that women with higher levels of estriol as opposed to estrone or estradiol were more likely to be long-term survivors after breast cancer surgery. This corresponds to a great deal of laboratory research showing estriol to be anti-carcinogenic.
Epidemiological studies have also shown an inverse relationship between estriol and breast cancer. Lemon introduced the “Estrogen Quotient” (EQ), which is equal to the estriol level (urine or serum) divided by the sum of the values for estrone and estradiol. This was later refined to look at the ratio of 2-OH estrogens to 16-a-hydroxyestrone. This ratio, known as the “2/16” test, is a well-established risk factor for estrogen related reproductive cancers. The mean value is considered to be 2.0-2.3, with high values indicating protection.
Dietary factors, such as the consumption of brassicas (cabbage, kale, broccoli, cauliflower, brussel sprouts, bok choy, mustard greens), flax, and soy, have all been shown to positively influence the “2/16” ratio, as have supplements of DIM (di-indolymethane) and I3C (indole-3-carbinole). These foods and supplements appear to offer some protection to women who wish to reduce their breast cancer risk.
Some research has shown that men who consume these vegetables have close to a 50% reduction in prostate cancer risk. Future research is needed to investigate the adverse effects of estrogen ratios on male reproductive cancers.55
Hypertension and Heart Disease
Estrogen replacement has been shown to improve endothelium-dependent vasodilation of coronary arteries in women with risk factors for atherosclerosis, perhaps due to its antioxidant properties. High levels of cortisol are associated with hypertension, and, interestingly, it has been found that simply having a family history of hypertension predisposes an individual to exaggerated cortisol excretion in response to stress.
One important study in Scotland explored the connection between cardiovascular risk factors and abnormal glucocorticoid activity. Researchers demonstrated a relationship between tissue sensitivity to cortisol and high blood pressure, insulin resistance, glucose intolerance, and hypertriglyceridemia.
Patients with heart diseases exhibit higher cortisol levels than do controls. Recently, Japanese scientists discovered a direct correlation between electrocardiographic abnormalities, such as myocardial hypertrophy, and elevated cortisol levels. A significant surge in cortisol levels accompanies the actual onset of myocardial infarction, with levels substantially decreasing within three days following the stress.
A decrease in melatonin causes increased nighttime sympathetic activity, which in turn appears to increase the risk for coronary disease. One study found that patients with coronary heart disease had nocturnal melatonin levels five times lower than in healthy controls. Investigators surmised that lower levels of melatonin might act to increase circulating epinephrine and norepinephrine, which have been implicated in damage to blood vessel walls. Atherogenic uptake of LDL cholesterol is accelerated by these amines at pathophysiological concentrations.
Research conducted on laboratory rodents has shown that melatonin treatment exerts the beneficial effect of increasing the HDL/LDL cholesterol ratio, perhaps by enhancing endogenous cholesterol clearance mechanisms. Specific binding sites for the melatonin agonist 2-[125I] iodomelatonin have been discovered in the heart (and lungs) of various animals. In addition, melatonin seems to inhibit platelet aggregation. Platelet aggregation plays a significant role in the progression of cardiovascular disease.
Hormone Disruption Factors
Stress: Stress has been shown to decrease the production of sex steroids, which could lead to reduced libido and menstrual irregularities. Maladaption of the adrenal cortex in producing high cortisol levels is, at least in part, responsible for the reduction of sex steroid levels.
Diet: There is strong evidence that the foods consumed by women have an effect on hormone levels. Investigation into dietary habits and, in particular, vegetarian diets, has established that certain foods can modify gonadal estrogen metabolism.56 Researchers have also speculated that early menarche recorded in girls of developed countries could be due to consumption of steroid hormones in meats.
Exercise: Menstrual irregularities (oligomenorrhea, amenorrhea, anovulation) in athletic women have been attributed to strenuous physical exercise. These patients showed increased estrogen and decreased progesterone levels in the luteal phase. This pattern could be due to an impaired metabolic clearance rate (MCR) of estradiol during physical exercise and decreased sex steroid production under stress.57
Cigarette Smoking: Although there is evidence of reduced fertility caused by cigarette smoking, the relationship between cigarette smoking and the anti-estrogenic effect related to infertility remains unclear. Several studies show a positive correlation. However, a recent publication suggests no significant correlation between hormone levels and smoking.58
