J. S. W. Li Voon Chong*, J. Sent, Z. Johnsont, G. Kylet and I. A. MacFarlane*
* Department of Endocrinology and Ophthalmology, University Hospital Aintree, Liverpool, UK
(Received 12 April 2000; returned for revision 26 June 2000; finally revised 28 September 2000; accepted 18 October 2000)
Correspondence: Dr J.S.W. Li Voon Chong, Royal Hampshire Hospital, Romsey Road, Winchester, Hampshire, S022 5DG, UK.
Fax: + 44 (0) 1962 824378.
Summary
BACKGROUND: It has been suggested that the variation of intraocular pressure (IOP) during the day follows the diurnal variation of serum cortisol. There is also a higher risk of ocular hypertension and glaucoma in patients taking excessive oral steroid treatment. We assessed whether different replacement doses of hydrocortisone (HC) influenced IOP. METHODS: Seventeen patients (six Addison’s disease, 11 hypopituitarism; seven males) aged 24-58 years mean 42-7 years and 20 control subjects (nine males) aged 20-59 years mean 38-7 years were studied. On the first visit, the 17 patients had been taking HC replacement doses, 20 mg morning and 10 mg afternoon. Serum cortisol and IOP in both eyes (Goldmann applanation tonometer) were measured at 0900, 1100, 1300, 1500, 1700 hours with HC 20 mg taken after the 0900 h assessment. The dose of HC was then reduced to 10 mg morning and 10 mg afternoon for 1 week and the measurements were repeated in 16 patients, with HC 10 mg taken at 0900 h. RESULTS: In the patients the peak serum cortisol occurred at 1100 h after the 0900 h HC dose. Cortisol levels were significantly higher at 1100, 1300, 1500 and 1700 h after taking 20 mg compared to 10 mg HC. The mean (SEM) IOP (mmHg) was significantly higher after 20 mg HC compared with 10 mg HC at 1300 h: 14-7(0-6) v 13-1(0-6) (P = 0-004) and at 1500 h: 14-4(0-6) v 13-1(0-5) ( P = 0-04). The total mean (SEM) daily IOP score was significantly higher after 20 mg HC compared with 10 mg HC: 14-5(0-3) v 13-5(0-3) (P = 0-0002). The total mean (SEM) daily IOP score after the 20 mg HC dose compared with the control subjects was: 14-5(0-3) v 13-7(0-3) ( P = 0-08). CONCLUSION: Intraocular pressures during the day are influenced by the morning hydrocortisone replacement dosage with significantly higher intraocular pressure levels in the early afternoon following 20 mg compared with 10 mg. A morning hydrocortisone dose of 10 mg leads to a more physiological intraocular pressure profile during the day. These data support the view that a daily replacement dose of 30 mg hydrocortisone may be excessive.
Patients with cortisol deficiency (either primary or secondary) have traditionally been replaced with 30 mg daily of hydrocortisone (usually 20 mg morning, 10 mg afternoon) (Besser & Jeffcoate, 1976). This replacement dosage of hydrocortisone is empirical and produces very different serum cortisol profiles from normal physiology. More recently the daily production of cortisol has been shown to be lower (5-7 mg/m2/day) than previously thought (12-15 mg/m2/day) (Esteban et al., 1991). This has led to debate about the optimum replacement daily dose of hydrocortisone and it has been suggested that most patients only require 20 mg of hydrocortisone per day (Howlett, 1997; Peacey et al, 1997).
One suggestion is to start the initial dose at 25 mg of hydrocortisone (15 mg early morning and 10 mg afternoon) and to decrease the daily dose to 20 or 15 mg of hydrocortisone as long as the patient feels well (Oelkers, 1996). This issue is of clinical importance because studies have suggested that chronic excessive replacement with glucocorticoids may lead to osteoporosis (Zelissen et al., 1994) and glucose intolerance (Al-Shoumer et al., 1995). Furthermore it has been argued that an increased mortality in patients with hypopituitarism may be related to excessive glucocorticoid replacement (Stewart & Sheppard, 1999).
The intraocular pressure (IOP) in normal individuals varies during the day with the peak IOP in late morning and lower values from mid-afternoon (Kitazawa & Horie, 1975; David et al., 1992; Wilensky et al., 1993; Pointer, 1997). When measured over a 24-h period, the lowest IOP values have been found to be between 2 and 4 am (Henkind et al., 1973). It is possible that this pattern may be related to other diurnal endogenous variations in the body, such as the production of cortisol (Becker & Mills, 1963; Boyd & Mcleod, 1964; Weitzman et al., 1975; Kimura & Maekawa, 1976; Schwartz & Seddon, 1981; Weinreb et al, 1985; Wilensky, 1991). The diurnal fluctuation in IOP is increased in patients with chronic simple glaucoma, and it has been suggested that this may reflect increased sensitivity to plasma cortisol (Schwartz & Levene, 1972).
It is recognized that oral steroid treatment may be associated with ocular hypertension or open angle glaucoma (Long, 1977; Garbe et al., 1997a). There have also been reports of an increased risk of ocular hypertension or open-angle glaucoma in patients taking inhaled or nasal steroid treatment (Opatowsky et al., 1995; Dreyer, 1993; Garbe et al., 1997b). The rise in ocular pressure from corticosteroid therapy is thought to be due to an increase in the resistance to aqueous humour outflow (Becker & Mills, 1963; Skuta et al., 1996).
There is no information on whether different replacement doses of hydrocortisone influence IOP in patients with Addison’s disease and hypopituitarism. Therefore we studied the daytime variation of IOP following two different replacement regimens of hydrocortisone and compared the data with a group of healthy control subjects.
Patients and methods
Patients and controls
Seventeen patients (seven males) aged 24-58 years (mean 42-7 years) who were attending the endocrine clinic were recruited. Eleven patients had hypopituitarism (seven nonfunctioning pituitary macroadenomas, four macroprolactinomas) and six had Addison’s disease. The patients with Addison’s disease had been taking hydrocortisone 20 mg morning, 10 mg afternoon and fludrocortisone 0-05 mg daily for at least 5 years. All patients with hypopituitarism were diagnosed in adult life and also had been taking hydrocortisone 20 mg morning, 10 mg afternoon for at least 5 years. Nine were also receiving stable replacement with thyroxine (T4), five growth hormone, five males testosterone (sustanon-250) and four females oestrogens. The four patients with prolactinomas were all taking bromocriptine. All patients had a normal serum free T4 at the time of study. Twenty control subjects (nine males) aged 20-59 years (mean 38-7 years) were also studied.
They were healthy volunteers including hospital staff and relatives of patients. None of the patients or controls had a known history of ocular hypertension or glaucoma.
Methods
The patients attended on 2 days 1 week apart. At the first visit, the serum cortisol and IOP in both eyes were measured at 0900 h, 1100 h, 1300 h, 1500 h and 1700 h and 20 mg of HC was taken after the 0900 h samples. The daily dose of HC was then reduced to 10 mg bd and the patients took this until the second visit, 1 week later. The serum cortisol and IOP were again measured at 0900 h, 1100 h, 1300 h, 1500 h and 1700 h and hydrocortisone 10 mg was taken after the 0900 h samples. Patients with Addison’s disease did not take their usual morning doses of fludrocortisone at the two visits. The patients were not fasted and not fluid restricted.
The IOP was measured by an ophthalmologist using a Goldmann applanation tonometer attached to a slit lamp. Serum cortisol was measured using the direct chemiluminescent technique (Chiron Diagnostics ACS:180).
Ethical approval was granted by the South Sefton Research Ethics Committee and all patients gave informed consent.
Statistical analysis
Data are expressed as mean ± SEM. Statistical analysis was performed using paired and unpaired t-test as appropriate. P-values < 0-05 were considered significant.
Results
Seventeen patients had their IOP and hydrocortisone day curve measured before and after taking hydrocortisone 20 mg at 0900 h. Sixteen patients had their IOP and hydrocortisone day curves repeated 1 week after dose reduction in hydrocortisone to 10 mg bd. One patient did not volunteer for the second occasion as she felt unwell on the lower steroid dosage.
The peak serum cortisol was at 11 am and was significantly higher at 11 am, 1300 h, 1500 h and 1700 h after taking hydrocortisone 20 mg compared to 10 mg after the 0900 h sample (Fig. 1). The mean(SEM) IOP values on the five different occasions were lower on the reduced dose of hydrocortisone. This was statistically significant at 1300 h, 14-7 (0-6) v 13-1 (0-6) mmHg (P = 0-004) and at 1500 h, 14-4 (0-6) v 13-1 (0-5) mmHg (P = 0-04) (Fig. 2). The total mean (SEM) IOP score combining the five occasions was significantly lower on the reduced dose profile: 14-5(0-3) v 13-5(0-3) (P = 0-0002). The total mean (SEM) IOP score was higher but not significantly different comparing the patients taking the 20 mg dose of hydrocortisone at 0900 h and the controls, 14-5 (0-3) v 13-7 (0-3) (P = 0-08).
There was no difference in the IOP values after taking the 10 mg HC dose compared to controls.
Fig. 1 Variation of serum cortisol during the day in patients with hypoadrenalism: 17 treated with hydrocortisone (HC) 20 mg at 0900 h (•); 16 with HC 10 mg at 0900 h (O); and 20 controls (■).
Fig. 2 Variation of intraocular pressure (IOP) during the day in patients with hypoadrenalism: 17 treated with hydrocortisone (HC) 20 mg at 0900 h (•); 16 with HC 10 mg at 0900 h (O); and 20 controls (■). *P — 0.04; +P — 0.004 20 mg vs.10 mg HC.
Analysing the patients with Addison’s disease and hypopituitarism separately, the total mean IOP scores, combining the five occasions were: Addison’s disease, 20 mg vs. 10 mg HC dose: 13-4 (0-4) vs. 12-6(04) (P — 0-02) and those with hypopituitarism, 20 mg vs. 10 mg HC dose: 15-1(0-3) v 14-0(0-4) (P — 0-02).
Discussion
For an individual the assessment of the optimal replacement dose or regimen of hydrocortisone is difficult and no simple tests exist. Current methods include performing a cortisol day curve, which consists of measuring serum cortisol concentrations at various times during the day (Besser & Jeffcoate, 1976; Feek et al., 1981). However this is time consuming and there are no accepted criteria to interpret the results and make meaningful recommendation on replacement dosages or regimens. Urinary collections for free cortisol levels have been used and it has been suggested that results correlate with plasma cortisol profiles in patients (Burch, 1982; Contreras et al., 1986, Trainer et al., 1993). Others however, have argued that although free urinary cortisol is a useful marker of endogenous secretion, it is unreliable in people taking replacement therapy (Jeffcoate, 1999). There is a disproportionate rise in the urine free cortisol after a dose of HC from temporary saturation of cortisol-binding globulin (Howlett, 1997).
Recently many authors have suggested that 30 mg per day of hydrocortisone can have long-term side-effects. Long-term use of hydrocortisone replacement at this dosage may increase the risk of osteoporosis (Zelissen et al., 1994), hyperinsuli-naemia and glucose intolerance (Al-Ashoumer et al., 1995). Also over-replacement with glucocorticoids may be a contributor to cardiovascular disease (Monson, 1997; Beshyah & Johnston, 1999; Stewart & Sheppard, 1999). There are, however, no long-term studies on the biological effects of lower HC replacement doses. One study has examined quality of life and well being on various daily dosages of hydrocortisone and showed no differences in these measures after taking 15, 20 or 30 mg of hydrocortisone per day (Wichers et al., 1999). Other studies of patients taking twice daily hydrocortisone found that some individuals have low cortisol levels and tiredness in the afternoon and felt better when they take hydrocortisone three times daily (Groves et al., 1988; Howlett, 1997).
In the present study the serum cortisol of the control subjects was highest in the morning at 0900 h and gradually declined thereafter (Fig. 1). In contrast, the patients taking twice daily HC replacement had completely unphysiological cortisol profiles. The serum cortisol was markedly low before the 0900 h dose of HC and peaked 2 h afterwards with significantly higher levels following 20 mg of HC compared to 10 mg HC. Other authors have showed similar cortisol profiles on twice daily HC replacement regimens (Kehlet et al., 1976; Scott et al., 1978; Feek et al., 1981; Al-Shoumer et al., 1996).
The IOP of the control subjects was highest in the morning followed by a dip at 1300 h and remained lower for the rest of the afternoon. This is similar to previous studies of IOP during the day in normal subjects (Kitazawa & Horie, 1975; David et al., 1992; Wilensky et al., 1993; Pointer, 1997). The IOP profile of the patients taking 20 mg HC showed an initial fall at 1100 h followed by a pronounced rise in the afternoon. When these patients reduced the daily dose of HC, the IOP profile after HC 10 mg at 0900 h was very similar to the control subjects (Fig. 2) with significantly lower IOP levels at 1300 and 1500 h, compared with the higher HC dose. In addition these patients had a lower total mean IOP score on the lower HC dose. These observations support the view that a marked rise in circulating cortisol may lead to an increase in IOP some 4 h later. There cannot, however, be a simple relationship between serum cortisol and IOP. The 0900 h IOP levels in the patients were similar to the controls despite considerably lower 0900 h cortisol levels. It is possible that the 0900 h IOP levels reflect the daily glucocorticoid replacement dosage over several days in these patients.
It is important to consider the biological significance of higher IOP levels after a 0900 h dose of 20 mg HC. A study of patients with primary open-angle glaucoma who were given 20 mg of hydrocortisone at 1700 h showed a significant rise in their intraocular pressure from baseline during the night (Kimura & Maekawa, 1976). None of the patients in the present study, however, had a known history of ocular hypertension or glaucoma and we did not find a rise in the IOP above 20 mmHg (the lower limit for ocular hypertension) during the day after taking 20 mg HC. Nevertheless many patients with primary and secondary hypocortisolism are replaced with 30 mg of HC daily and it is possible that relatively high IOP levels during the afternoon may predispose to an increased risk of ocular hypertension in future years. Elderly patients taking oral glucocorticoids have a higher risk of ocular hypertension or open-angle glaucoma (Garbe et al., 1997a). It will therefore be of interest to study the influence of different HC replacement doses on IOP levels in elderly patients.
In conclusion, intraocular pressures during the day are influenced by the morning hydrocortisone replacement dosage with significantly higher IOP levels in the early afternoon after taking 20 mg of HC at 0900 h. A morning HC dose of 10 mg leads to a more physiological IOP profile during the day and these data support the view that 30 mg/day HC may be excessive corticosteroid replacement.
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