Association between hormone replacement therapy and subsequent stroke: a meta-analysis

John Howard, who advocates use of androgenic DHEA, writes I am wrong to know that exogenous steroid use can cause zinc deficiency. He cites a Turkish study of 38 women which claimed a beneficial effect of progesterone-dominant HRT on serum levels of trace minerals and also “well known other benefits”.1 The benefits of HRT are so well established that the world’s major HRT studies have been terminated early because of increases in vascular diseases and breast and endometrial cancers.

The HABITS study found (hormonal replacement therapy after breast cancer-is it safe?) trial was terminated after 2 years because 28 patients, mostly current HRT users, had new breast-cancer events, compared with 5 non users.2 The MWS found a significant 45% increased relative risk of incident invasive breast cancer in current users of the synthetic steroid tibolone which has progestogenic, androgenic and oestrogenic activities.3

The most important mineral abnormalities caused by exogenous progesterone and oestrogen hormone use are lowering zinc and elevating copper levels, as first reported in 1968.4 I have confirmed this fundamental finding in numerous patients since the 1970s. Abnormally high copper levels in my patients are invariably due to exogenous hormone use, except for occasional acute infections. Since the start of the London oral contraceptive trials in the1960s, very few women consulting me have never used hormones. Often past users have residual zinc deficiency or copper store deficiencies after stopping OCs or HRT because of side- effects.

In 1998 I reported the results of 3 groups of patients tested at Biolab Medical Unit in London.5 Current hormone takers had significantly higher copper levels in sweat, serum and hair compared with either men or past hormone takers (all significant at p < 0.0001). Among hormone takers abnormally high copper values were found in 90% of sweat samples, 80% of serum samples and 60% of hair samples. Hormone takers and past hormone takers had lower serum zinc levels than men (p< 0.001). The mean sweat zinc value for men was at the lower end of the male reference range among men who seemed healthy but were accompanying their partners for preconception care. The mean sweat zinc for the women was below the female reference range and all were or had been exposed to exogenous hormones. There was little or no overlap in sweat, serum or hair in copper/zinc ratios in the three groups, with current hormone takers having the highest copper/zinc ratios. We had previously found that an abnormally high copper/zinc ratio related to abnormal liver clearance of carcinogens, like benzpyrenes, which helps to explain the adverse synergistic effects of OCs, HRT and smoking.6

Furthermore, John McLaren-Howard’s nutritional osteoporosis profile results found that among women with osteoporosis, all those taking HRT had abnormally high serum copper levels.7 HRT users also had significantly lower white cell zinc, red cell magnesium, lower serum bone specific alkaline phosphatase (ALP) concentrations and higher mean serum phosphate levels, than other women with osteoporosis. HRT users also had lower serum manganese, tartrate-resistant acid phosphatase (a measure of bone resorption) and vitamin C levels, and higher urinary zinc and hydroxyproline excretion. These results suggested that exogenous steroid sex hormones are associated with a reduction in bone essential nutrients, especially zinc and magnesium, and reduced bone formation.

A repletion study found the lowest serum bone ALP values in women on HRT with osteoporosis and a slower improvement with nutritional supplements. Since then, I have followed up individual women who have maintained excellent nutritional and bone formation profiles without HRT but with monitored nutritional supplementation. The international incidence of fractures has increased dramatically in women age 35-95 years in hormone prescribing countries.8 HRT beneficial claims have been mistaken, due to underestimations of risks caused by lack of never-ever takers of hormones for valid comparisons, which is also likely to apply to the WHI study results.

Taking exogenous steroids lowers endogenous steroid production because of feed-back mechanisms but zinc deficiency also further impairs steroid production.

1 Meram I, Balat O, Tamer L, Ugur MG. Trace elements and vitamin levels in menopausal women receiving hormone replacement therapy. Clin Exp Obstet Gynecol. 2003; 30: 2-4.

2 Holmberg L, Anderson H; et al. HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet 2004; 363: 453- 5.

3 Beral V, Banks E, Reeves G, Bull D, on behalf of the Million Women Study Collaborators. Breast cancer and hormone-replacement therapy: the Million Women Study. Lancet 2003; 362: 1331.

4 Halsted HJ, Hackly BM, Smith JC. Plasma zinc and copper in pregnancy and after oral contraceptives. Lancet 1968; 2: 278-83.

5 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity, and mineral imbalance .J Nutr Environ Med 1998; 8: 105- 116.

6 Capel ID, Grant ECG, Dorrell HM, et al. Disturbed liver function in migraine patients. Headache 1979; 19: 270-272.

7 McLaren-Howard Grant ECG, Davies S. Hormone replacement therapy and osteoporosis: bone enzymes and nutrient imbalances. J Nutr Environ Med 1998; 8: 129-138.

8 Little K. Progestogens: thrombosis and osteoporosis. J Nutr Environ Med 1998; 8: 139- 152.

Competing interests: None declared