Gonadal Replacement

FCW Wu

Department of Endocrinology, Manchester Royal Infirmary, University of Manchester

Summer School 15-18 July 2003
University of Manchester, Hulme Hall, Manchester, UK

Female Hormone Replacement – What now?

Observational studies over the last 2 decades have consistently demonstrated a striking protective effect of oestrogens against heart disease and osteoporotic fractures in menopausal women. This has fostered the trend towards the long-term use of oestrogen as preventative treatment against diseases of ageing such as coronary artery disease, strokes and osteoporosis. However, the observation data, on which the evidence to support oestrogen prophylaxis was entirely based, were subject to serious biases caused by women with higher socio-economic status and lower risk profiles self selecting as hormone users. Several randomised prospective controlled trials (the largest and most important being the Women’s Health Initiative) in the last 5 years have now confirmed that conjugated oestrogen continuously combined with medroxyprogesterone acetate do not protect against (primary and secondary prevention) heart disease but actually increase the risk of cardiovascular events (myocardial infracts and strokes, thromboebolism) and breast cancer. There was also no protection against cognitive impairment or any improvement in quality of life in asymptomatic postmenopausal women. Against the reduction in hip fractures and colon cancer, the overall harm of hormone replacement outweighed the benefits. Whether oestrogens alone or if hormone replacement is started earlier in the perimenopausal years will provide greater benefits remains to be seen. In the meantime, the new recommendations are 1) oestrogens should be used for short-term (< 5 yr) relief of menopausal symptoms 2) oestrogens should not be used for prevention against diseases of ageing 3) alternatives such as biphosphonates and raloxifene should be preferred treatment for postmenopausal osteoporosis.

Male Hormone Replacement – Where are we now?

Testosterone replacement therapy has been used for over 60 years to treat a relatively small number of patients with hypogonadism or failure of sexual development. In the last 10 years, there has been increasing interest in, and some evidence to support, the extended therapeutic applications of androgens for non-classical indications such as male contraception, ageing, HIV infection etc. In particular, a great deal of interest has been shown in the so-called ‘male menopause’.
In men, one aspect amongst many of these ageing-related changes is the gradual and variable decline of circulating testosterone into the low normal (rather than the truly hypogonadal) range. Causal relationships between the various well recognised ageing-associated functional decline and decreased testosterone, and thus a rational basis for a ‘clinical syndrome of androgen insufficiency’ in elderly men, has not been established. Short-term interventional trials (in highly selected clinic populations) with testosterone have shown that hormone supplementation can increase sexual interest, lean body mass and possibly bone density and decrease fat mass (mostly surrogate endpoints). But, as yet, significant improvements in function (including fracture incidence), muscle strength and performance, activities of daily living and quality of life have not been demonstrated. So far, the limited studies are not powered to assess longer-term risks of testosterone treatment. They include exacerbation of occult prostate cancer, polycythaemia, sleep apnoea, fluid retention. Accurate risk-benefit assessment of hormone replacement in ageing men is currently not possible. Large-scale prospective randomised placebo-controlled trials, along the lines of those conducted for female hormone replacement, are required. Thus ageing per se is not an acceptable cause of hypogonadism. In the meantime, best practice guidelines for the increasing number of older men presenting for evaluation and management of possible androgen deficiency are required. These should be based on the same physiological principles established in the management of younger men with proven pathological hypogonadism.

The opinions expressed in this paper are those of the speaker and do not necessarily reflect the views of the Society

Revised: 04-Sep-2003