Excess Vascular Mortality in Hypopituitarism: Is it the Result of Estrogen or GH Deficiency?

Tarik A. Elhadd, Tarig A.M. Abdu and Richard N. Clayton

Department of Medicine, Keele University Hartshill, Stoke-on-Trent, United Kingdom ST4 7QB

Address correspondence to: Dr. T. A. Elhadd, Department of Endocrinology, Wordsley Hospital, Stream Road, Stourbridge, West Midlands DY8 5QX, United Kingdom. E-mail: . tarikelhadd{at}aol.com

To the editor:

Patients with hypopituitarism are well documented to have excess vascular morbidity and mortality (1), but the mechanisms underlying such propensity remain uncertain (2). We read with interest the recent article by Sesmilo et al. (3) who demonstrated excess inflammatory markers, including C-reactive protein (CRP) and IL-6, in a group of 51 women with hypopituitarism. Earlier in the journal, Bulow et al. (4) also demonstrated excess cardiovascular morbidity and clustering of cardiovascular risk factors in a group of 33 Swedish women with hypopituitarism. Similar findings were demonstrated by our own group (5). Both authors concluded that growth hormone deficiency is the main culprit behind their observation and that estrogen deficiency doesn’t contribute to the propensity for excess vascular morbidity in these patients.

In the paper by Bulow et al. (4), the patients and their controls were well matched at the time of the study for the estrogen/hormone replacement therapy. However, it is important to point out that nearly 50% (8 of 17) of the patient cohort who started such therapy before 50 yr of age had been without such treatment for 10–20 yr. This fact probably has affected their final analysis in terms of the contribution of sex hormone deficiency to the abnormalities observed in their study. On the other hand, Sesmilo et al. showed that hypopituitary women (87% of whom had sex hormone deficiency, but only 57% of whom were on sex hormone replacement therapy) have a worse profile of CRP and IL-6. The level of CRP, but not that of IL-6, was modulated by estrogen use. The authors concluded that GH deficiency per se is a major mechanism behind the abnormalities demonstrated in their study, but understandably the paradox of the effect of estrogen use on CRP could not be explained.

The results of these two papers were at variance with our own observations as well as with that from a major epidemiological study published last year (6). Tomlinson et al. (6) studied a large number of hypopituitary adults (including patients of our own) and found significant excess cardiovascular and cerebrovascualr mortality, and that was more prevalent in estrogen-deficient females. In contrast, GH deficiency has not been found to be a major contributor to the observed excess vascular mortality. We have demonstrated that the absolute 5-yr risk of fatal and nonfatal coronary event in patients with hypopituitarism is in excess of that for similar controls. Interestingly, in this study when the patients were split by gender it was the female cohort who demonstrated the highest risk observed. Our female patients, similar to those of Sesmilo et al. and Bulow et al. (3, 4), displayed significant abnormalities of lipid profile and visceral adiposity. Furthermore, and in line with the above findings, our female hypopituitary patients displayed significant abnormalities of both biochemical and biophysical markers of endothelial dysfunction, which was more evident in the estrogen-deplete group but less so in the estrogen-replete group (7). Recent observations suggested that the neuroendocrine response to cytokine stimulation is augmented by gonadectomy and attenuated by estrogen replacement (8).

Therefore, we feel that putting much weight on the GH hypothesis to explain the excess clustering of cardiovascular risk factors and excess vascular morbidity and mortality is probably not entirely correct. Most likely, growth hormone deficiency is an important factor along with others amplifying the susceptibility of hypopituitary patients to vascular events, with the sex hormone deficiency as a strong factor behind such suscepitibilty. Trials looking at long-term and early replacement with sex steroids in hypopitutary females are badly needed.

Received March 11, 2002.

References

  1. Rosen T, Bengtsson B-A 1990 Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336:285–288[Medline]
  2. Elhadd TA, Abdu TAM, Clayton RN 2001 Hypopituitarism and atherosclerosis: a review. Ann Med 33:477–485[Medline]
  3. Sesmilo G, Miller K, Hayden D, Klibanski A 2001 Inflammatory cardiovascular risk markers in women with hypopituitarism. J Clin Endocrinol Metab 86:5774–5781[Abstract/Free Full Text]
  4. Bulow B, Hagmar L, Eskilsson J, Erfurth EM 2000 Hypopituitary females have high incidence of cardiovascular morbidity and an increased prevalence of cardiovascular risk factors. J Clin Endocrinol Metab 85:574–584[Abstract/Free Full Text]
  5. Abdu TAM, Neary R, Elhadd TA, Clayton RN 2001 Coronary risk in growth hormone deficient adults: increased predicted risk is due largely to lipid profile abnormalities. Clin Endocrinol (Oxf) 55:209–216[CrossRef][Medline]
  6. Tomlinson JW, Holden N, Hills R, Wheatley K, Clayton RN, Bates AS, Sheppard MC, Stewart PM 2001 Premature mortality in 1014 patients with hypopituitarism. Lancet 357:425–431[CrossRef][Medline]
  7. Elhadd TA, Abdu TAM, Kennedy G, McLaren M, Oxtoby J, Neary R, Belch JJF. Clayton RN 2001 Relationship between biochemical and biophysical markers of endothelial dysfunction in adults with growth hormone deficiency: the missing link between hypopituitarism and reduced life expectancy? J Clin Endocrinol Metab 86:4223–4232[Abstract/Free Full Text]
  8. Puder JJ, Freda PU, Goland R, Wardlaw SL 2001 Oestrogen modulates the hypothalamic-pituitary-adrenal and inflammatory cytokine responses to endotoxin in women. J Clin Endocrinol Metab 86:2403–2408[Abstract/Free Full Text]




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