Glucocorticoids

P2-579

Maternal Consumption of a High Meat, Low Carbohydrate Diet in Late Pregnancy: Relation to Adult Cortisol Concentrations in the Offspring.

Kirsten Herrick1, David IW Phillips*1, Soraya Haselden1, Mary Campbell-Brown2, Keith M Godfrey1. 1MRC Envir Epidemiology Unit, Southampton Gen Hosp, Southampton, United Kingdom; 2Dept of Ob and Gyn, Univ of Glasgow, Glasgow, United Kingdom.

Recent studies have linked an unbalanced high protein maternal diet in late pregnancy with impaired prenatal growth and raised adult blood pressure in the offspring. A group of women in Motherwell, Scotland, UK had been advised to eat 1lb. (0.45 kg) of red meat daily during pregnancy and avoid carbohydrate-rich foods; we previously found raised blood pressure in the adult offspring of those whose mothers’ had reported high meat/fish and low green vegetable intakes in late pregnancy. Because high protein diets stimulate the hypothalamic-pituitary-adrenal axis, these findings could be explained if a high protein maternal diet increased maternal cortisol levels and exposed the fetus to excess cortisol, programming its developing hypothalamic-pituitary-adrenal axis and leading to lifelong hypersecretion of cortisol. We tested this hypothesis by measuring fasting plasma cortisol concentrations in 251 of the men and women aged 28-30 years born in Motherwell. Fasting plasma cortisol concentrations were higher in men and women with a lower body mass index (P<0.0001) and in those who reported vigorous activity in the previous four weeks (P=0.03) and greater alcohol consumption (P=0.004). Allowing for the effects of gender, current body mass index, activity and alcohol consumption, cortisol concentrations increased 5.4% per portion of maternal meat/fish consumption per day (P=0.03), decreased 3.3% per portion of maternal green vegetables consumption per week (P=0.14) and were 12.2% higher in those born into manual social class families (P=0.03). This is the first human evidence that an unbalanced diet during pregnancy may program lifelong hypercortisolaemia in the offspring.

Supported by Dunhill Medical Trust and the National Institute of Child Development (1 R01 HD41107-01).

CLINICAL POSTER: Glucocorticoids (11:00 AM - 12:00 PM and 2:30 PM - 3:30 PM)

Presentation Date: Friday, June 20, 2003

Glucocorticoids

P2-579 News Summary

Unbalanced diets in pregnant women may affect lifelong health of their children

Pregnant women who eat unbalanced high protein diets can affect the lifelong health of their children by altering the intensity of their stress response, according to first-of-a-kind findings being presented on Friday, June 20, at The Endocrine Society’s 85th Annual Meeting in Philadelphia.

Mothers of children born at Motherwell Maternity Hospital in Scotland, United Kingdom, around 30 years ago were advised to eat one pound of red meat per day and avoid carbohydrate-rich foods during pregnancy.

Previous Motherwell studies show that the offspring of mothers who reported greater meat and fish and lower green vegetable consumption have evidence of raised blood pressure and glucose intolerance in adult life. Because high protein diets stimulate the hypothalamic-pituitary-adrenal axis, researchers believed these findings could be explained if a high-protein maternal diet increased maternal cortisol levels and exposed the fetus to excess cortisol, programming its developing hypothalamic-pituitary-adrenal axis and leading to lifelong hypersecretion of cortisol.

Dr. David Phillips and colleagues in Glasgow and Southampton, United Kingdom, tested this hypothesis by measuring fasting plasma cortisol concentrations in 251 men and women between the ages of 28–30 years old who were born in Motherwell. They found that they have higher levels of the stress hormone cortisol. They report that is the first human evidence that an unbalanced diet during pregnancy may program lifelong hypersecretion of cortisol in offspring. Further studies are needed to confirm these findings, say the researchers, and to understand their relevance to pregnant women today. They suggest that an unbalanced maternal diet can increase the mother’s stress hormone levels, exposing the fetus to excess amounts of these hormones and leading to persisting changes in stress responses.

This study was supported in part by the Dunhill Medical Trust and the National Institute of Child Development.

Glucocorticoids & Cushing’s Syndrome

OR30-2

Glucocorticoid Therapy Increases Event Rates from Cardiovascular Disease; Results from Two Pharmacoepidemiological Studies of 265,445 Participants.

Brian R Walker*1, Patrick C Souverein2, Li Wei3, Anick Berard4, Toine CG Egberts2, Hubert GM Leufkens2, Cyrus Cooper5, Tjeerd van Staa2, Thomas M MacDonald3. 1Endocrinology Unit, Sch of Molec and Clin Med, Univ of Edinburgh, Edinburgh, United Kingdom; 2Dept of Pharmacoepidemiology and Pharmacotherapy, Utrecht Inst for Pharmaceutical Scis, Utrecht, Netherlands; 3Meds Monitoring Unit, Dept of Clin Pharmacol and Therapeutics, Univ of Dundee, Dundee, United Kingdom; 4Fac of Pharmacy, Univ of Montreal, Montreal, Canada; 5MRC Envir Epidemiology Unit, Univ of Southampton, Southampton, United Kingdom.

Glucocorticoids (GCs) induce systemic cardiovascular risk factors (eg hypertension, hyperglycaemia) but may also have beneficial anti-inflammatory effects in the vessel wall. The net effect of GC therapy on cardiovascular events, and its contribution to increased cardiovascular risk in inflammatory conditions such as rheumatoid arthritis, has yet to be examined in studies with sufficient statistical power to compare event rates.

We performed two studies: (i) a population based cohort study in the Tayside region of Scotland to compare hospitalisation or death from ischemic heart disease, stroke, or heart failure (n=14,519 events) in subjects with different levels of GC exposure (total n=164,133, age > 40y, surveyed 1993-96); and (ii) a nested case-control study in the UK General Practice Research Database (GPRD) to compare GC exposure in subjects with (n=50,656) and without (n=50,656) these cardiovascular events (age >50y, surveyed 1988-97). GC exposure was classified as ‘none’ (Tayside 54%, GPRD 0%), ‘low’ (topical or inhaled GC only; Tayside 35%, GPRD 73%), ‘medium’ (systemic equivalent to <7.5 mg prednisolone daily; Tayside 10%, GPRD 9%), or ‘high’ (systemic equivalent to > 7.5 mg prednisolone daily; Tayside 1%, GPRD 18%). Data are adjusted relative risks or odds ratios with 95% confidence intervals.

In both studies, there was a dose-dependent association of GC exposure with events: ‘low’ GC exposure had no effect; ‘medium’ GC exposure was associated with increased rate of heart failure alone in Tayside (RR 1.56, 95% CI 1.33-1.82) and all cardiovascular events in GPRD (OR 1.44, 1.34-1.55); and ‘high’ GC exposure was associated with increased rate of all cardiovascular events in both studies (Tayside 2.70, 2.33-3.13; GPRD 1.30, 1.21-1.40). In the ‘high’ dose group, risks were greatest for heart failure, intermediate for ischemic heart disease, and detected for stroke only in Tayside. The risks of GC exposure were similar in patients with different underlying diseases and not attenuated by adjustment for use of anti-rheumatic drugs or bronchodilators.

We conclude that supraphysiological doses (>7.5 mg prednisolone equivalent) of GCs are associated with an increased risk of cardiovascular events which is both statistically and, given the high prevalence of GC prescriptions, clinically significant. Moreover, conventionally ‘physiological’ doses of GC are associated with a small increase in cardiovascular risk which may be relevant, eg in hypopituitarism.

CLINICAL ORAL: Glucocorticoids & Cushing’s Syndrome (1:00 PM - 2:30 PM)

Presentation Date: 6/21/2003, Time: 1:15 PM; Location: 204 A

Glucocorticoids & Cushing’s Syndrome

OR30-2 News Summary

Anti-inflammatory glucocoritcoids increase a person’s risk for heart disease

People taking high doeses of anti-inflammatory glucocorticoids appear to be at an increased risk for developing heart problems like heart attacks, strokes and heart failure, according to a new study being presented on Saturday, June 21, at The Endocrine Society’s 85th Annual Meeting in Philadelphia.

Glucocorticoid steroids are among the most commonly prescribed drugs and are used in the treatment of inflammatory diseases, including asthma, rheumatoid arthritis and inflammatory bowel disease. They are highly effective but also have well-known side effects, such as aggravating obesity, high blood pressure and diabetes, also risk factors for heart disease. It has long been suspected that glucocorticoids may increase the risk of heart disease, but the magnitude of the risk and whether there is a threshold dose below which these steroids are safe for the heart have not been previously examined.

To investigate these issues, researchers from the United Kingdom, the Netherlands, and Canada, led by Dr. Brian R. Walker, carried out two studies on the topic. In the first study, conducted in the Tayside region of Scotland, they collected information over a four-year period on drug prescriptions, hospitalizations and causes of death in more than 164,000 randomly selected adults, aged 40 years and older. Nearly half received a prescription for a glucocorticoid, such as a cream or inhaler, and approximately 2 percent received high doses of oral steroids. Cardiovascular events – such as heart attacks, strokes and, in particular, heart failure – were more common in the steroid-treated group. The results suggest that in following 100 patients for 10 years 19 would have a cardiovascular event in the non-steroid treated group, but 32 would have a heart-related event in the steroid-treated group. The risk was highest in those receiving high oral doses and negligible in the lowest dose group. The risk could not be accounted for by the underlying disease for which the steroids were being prescribed.

In the second study, similar information was collected over nine years from the U.K.’s General Practice Research Database. This analysis included more than 50,000 patients – aged 50 years and older – who had sustained a cardiovascular event and the same number of healthy controls. The researchers found that patients with heart disease were 30 percent more likely than controls to have been taking oral doses of glucocorticoids. Again, the risk was greatest for heart failure and for the highest steroid doses, and the risk was not explained by the underlying disease.

These results suggest that physicians should aggressively treat cardiovascular risk factors in patients receiving high doses of glucocorticoids and be vigilant for signs of heart failure. The researchers emphasize the need to devise drugs with the benefits of steroids but without the adverse side effects.

The research was supported by the Scottish Executive and the British Heart Foundation.