Choice and timing of Glucocorticoid Replacement

Hydrocortisone, the generic pharmaceutical name for cortisol, is the standard form of glucocorticoid replacement for ACTH deficiency, and directly replaces the missing active hormone. Cortisone acetate was previously widely used, but is metabolized to cortisol to achieve its glucocorticoid activity, so that its onset of action is slower than hydrocortisone (a slight disadvantage) and biological half- life slightly longer (potentially a slight advantage).

The normal pattern of diurnal cortisol secretion is difficult to mimic precisely with oral therapy and there is no universal agreement regarding the appropriate dose, timing, and monitoring of hydrocortisone replacement, although the need for close attention has been highlighted. Cortisol diurnal rhythm in normal individuals is regulated by the suprachiasmatic nucleus in hypothalamus (the body clock). Cortisol rises between 03.00 hrs and 04.00 hrs, peaks within an hour of waking, falls over the day with a quiet period from 19.00 hrs, and nadirs at 00.00 hrs. In addition to this diurnal variation, variable peaks of cortisol secretion (ultradian rhythm) may occur due to other factors such as in response to stress, meal, and exercise. There is currently no ideal glucocorticoid regime available to mimic this rhythm. The best approximation to this pat tern is with hydrocortisone in three divided doses per day: 10 mg of hydrocortisone on awakening, 5 mg at lunch and 5 mg in the early evening. This is widely believed to achieve ‘physiological’ plasma cortisol levels compared to a traditional twice daily regime, which usually results in very low cortisol levels in late afternoon before the evening dose.

Patients with ACTH deficiency may still experience symptoms of hypoadrenalism on hydrocortisone leading to development of two compounds namely, Duocort® or Plenadren® [3] and Chronocort® [4], purported to mimic normal circadian rhythm more closely. Plenadren® is a dual- release once daily hydrocortisone formulation (available in 20 mg and 5 mg tablets), currently available for prescription in the United Kingdom and rest of Europe. It has an immediate release coating with an extended release core obviating the need for midday dosing when taken first thing in the morning. It has been shown to reduce cardiovascular risk factors (weight, HbA1c, and blood pressure) and fatigue. Its prime advantage, due to 20% lower bioavailability than conventional hydrocortisone, may include reduction in cardiovascular risk factors, although dose adjustment may be required. The main limitation however is same as that for hydrocortisone as it too can only be taken after waking. Chronocort®, on the other hand, with its pH- sensitive enteric coated modified- release multiparticulate hydrocortisone capsule formulation, is reported to have an edge in this regard, it provides an overnight cortisol rise and peak around awakening. It is taken twice daily, 20 mg at 23.00 hrs and 10 mg 07.00 hrs. The potential clinical advantage of this compound may be alleviation of early morning fatigue experienced by some of these patients.

Another potentially useful route of hydrocortisone administration, currently under evaluation, is continuous subcutaneous hydrocortisone infusion (CSHI) via a programmable pump. This has been used with variable success, and needs more evidence and safety data prior to routine clinical use.

Some groups have advocated the use of low- dose prednisolone (3– 4 mg daily) instead of hydrocortisone in patients with hypoadrenalism. Prednisolone has a longer half- life, given as a once daily preparation, and may have a comparable cardiovascular risk profile to hydrocortisone and provide better patient satisfaction. The lack of widely available prednisolone assays for monitoring purposes along with reported adverse cardiovascular and bone health outcomes, has led to some concerns about the use of prednisolone, although this may simply be due to higher doses of prednisolone being used in these studies. Currently, it may be reasonable to use prednisolone 3– 5 mg/ day in patients who have difficulty in adhering to multiple- dose regimen, non- availability of hydrocortisone, or in patients who have a poor quality of life despite optimization of their hydrocortisone regime. Dexamethasone should be avoided as a replacement glucocorticoid due to the high incidence of adverse glucocorticoid effects.

Assessment of Hydrocortisone Replacement

Conventionally, glucocorticoid replacement with hydrocortisone is monitored using plasma cortisol measurements at multiple times throughout the day— a hydrocortisone day curve (HCDC). Studies using frequent sampling for plasma cortisol have identified wide interindividual variations in plasma cortisol levels obtained after the same dose of hydrocortisone and highlighted the need for individual adjustment of hydrocortisone dose, but such frequent sampling is rarely possible or necessary in routine practice.

One such conventional practice is to monitor hydrocortisone re placement with a simple HCDC involving collection of a 24 h urine for free cortisol (UFC) on the day prior to the test, and three plasma cortisols during a day- case attendance. However, this strategy is now not recommended as the practice was based on underpowered short term- studies; given lack of objective evidence, guidelines currently advocate basing hydrocortisone dose adjustments on clinical criteria alone.

The criteria for deciding optimum hydrocortisone regimes are inevitably a compromise between theory, practicality, and patient convenience. A thorough history of patients’ daily habits should be accounted for dose adjustments, including sleep timings, shift- working nature, dips in energy, daytime somnolence, and general well- being. Clinical markers of over- replacement are weight gain, insomnia, and peripheral oedema. Markers of insufficient replacement include nausea, lethargy, postural dizziness, weight loss, and lack of appetite.

Even thrice daily regimes fail to accurately mimic the normal physiological circadian rhythm of cortisol and attention has been focused on the differences in circulating cortisol levels overnight in patients on hydrocortisone replacement (where levels are low or un detectable throughout the night) compared to normal individuals (where levels rise substantially during the last hours of sleep). These differences would be hard to avoid using standard preparations of hydrocortisone, since few patients would be prepared to wake to take a tablet during the night, but certainly represent an unphysiological feature of current replacement regimes, may contribute to an overnight deficiency of a variety of metabolic fuels and is potentially an area where the newer delayed preparations described earlier, particularly Chronocort®, may have a role. For now, in practical terms, patients should be advised to take hydrocortisone as soon as possible after wakening to avoid prolonged activity with low circulating cortisol levels, and those who habitually wake in the early hours some time before rising might benefit from taking their hydrocortisone dose at that time. Patients with ACTH deficiency should not require mineralocorticoid replacement, since the renin- angiotensin- aldosterone axis is not disrupted by pituitary disease.

Replacement During Intercurrent Illness

During intercurrent illness, glucocorticoid replacement is mandatory, and doses need to be increased for all but the most minor illness in order to mimic the normal increase in ACTH and cortisol secretion, which occurs during stress and illness. Appropriate patient education on this aspect of replacement is a vital part of management of hypoadrenalism. Patients must be advised to double their normal oral dose of hydrocortisone during common pyrexial illnesses, and understand the need for parenteral glucocorticoid replacement if illness, operation, vomiting, or diarrhoea prevents the effective administration or absorption of oral glucocorticoid. Patients should seek medical advice if symptoms worsen in spite of increased oral hydrocortisone, should keep an ‘emergency’ ampoule of hydrocortisone at home, and if possible they or their family should be taught to give the injection if medical help is unavailable. Some patients also find a symptomatic need for increased glucocorticoid replacement during psychological stress, but this is much more difficult to define or regulate. During severe intercurrent illness or major surgery, immediate parenteral injection of hydrocortisone 100 mg (50 mg/ m2 for children) should be administered, followed by parenteral hydrocortisone 200 mg/ day in divided doses every 6 hourly. This regime is noted to provide consistent, high levels of circulating cortisol comparable with those found in normal individuals during such stress in cases of primary adrenal insufficiency. Some studies indicate lower hydrocortisone dose requirements (25– 75 mg/ 24 hrs) in the first 24 hours after non- pituitary surgery, in secondary adrenal insufficiency. However, the former regime is recommended based on common practice, as it is the safer approach. Intravenous boluses of hydrocortisone produce wide swings in cortisol levels and are therefore less desirable, but stable, high plasma cortisol levels can be achieved by an intravenous infusion of hydrocortisone 5 mg/ hr (preceded by a 25 mg intravenous bolus), although this is only appropriate in circumstances where an intravenous infusion can be reliably maintained and monitored.

Patient support groups have developed clear formatted guidance on replacement for intercurrent illness and during surgery and other procedures, which are readily available on the internet and useful for providing advice to patients and surgical colleagues.

In summary, following should be made mandatory for care providers in all healthcare settings dealing with steroid dependent patients:

1. Verbal and written patient education information should be provided about drug compliance, risk of hypoadrenal crisis, steroid sick- day rules, and emergency hydrocortisone injection technique at each clinical encounter.

2. Patients should be encouraged to carry an emergency card, wear a medical alert bracelet, or pendant, and carry a rescue- pack of hydrocortisone at all times.

3. Patients should be issued an emergency intramuscular hydro cortisone kit designed for self- injection; enquired if there is a need for reissue in case of expired ampoules; patient confidence and satisfaction with their injection technique should be ascertained at each consultation.

Adverse Effects of Hydrocortisone Replacement

 It is challenging to balance adverse effects of chronic supra physiological glucocorticoid exposure, which are serious and well known, against those of deficiency. In theory perfect physio logical replacement should lead to no adverse effects, since circulating cortisol levels would be no different from normal subjects, but close attention to replacement doses is essential in order to achieve this.

Gross Cushingoid side effects and symptoms of severe hypoadrenalism are usually clinically obvious and most endocrinologists can avoid such extremes of inappropriate replacement. Minor degrees of over- or under- replacement may be clinically undetectable, resulting in morbidity (poor quality of life, cardiovascular risks, osteoporosis) or even mortality. Several studies support this view: glucose tolerance and insulin secretion alter with hydrocortisone replacement, and blood pressure rises with replacement therapy. The European Adrenal Insufficiency Registry data suggest that the type of glucocorticoid, dose, and regimen are very variable. One in eight patients are noted to be on hydrocortisone ≥30 mg/ day, a cut- off level that increases the risk of endothelial dysfunction, higher arterial stiffness, poor quality of life, and dose- related high cardiovascular and metabolic consequences.

Therefore, if minor over- replacement caused slight worsening cardiovascular risk factors such as glucose intolerance, central obesity, or blood pressure, then this might be undetectable in an in dividual yet have a significant influence on overall cardiovascular morbidity. Studies of cortisol production rates using stable nucleotides show daily secretion of 5– 7 mg/ m2, equivalent of 9– 11 mg/ day of hydrocortisone. Unlike Addison’s disease, where severe cortisol deficiency is noted, hypopituitary individuals often have some residual cortisol secretion. Hydrocortisone 10 mg am/ 5 mg pm regimen showed improved quality of life, beneficial cardiovascular profile secondary to weight loss (average 7 kg weight loss when reduced from higher doses), reduced arterial stiffness, and a more physiological nocturnal blood pressure dip. In summary, it appears the lower the hydrocortisone dose the better in terms of metabolic and cardiovascular risk. It may be appropriate to use doses of hydro cortisone as low as 10 mg/ day in patients with partial adrenal in sufficiency while monitoring for hypothalamic– pituitary– adrenal (HPA) axis recovery.

It is well recognized that bone health is adversely affected with overexposure of glucocorticoids. Increased incidence of vertebral fractures was noted in hypopituitarism individuals on hydrocortisone 30 mg/ day dose, despite correction of gonadotrophin deficiency. Reduction of hydrocortisone to 15 mg/ day showed increased bone formation and better bone remodelling ability.

In summary, there is a need to avoid even subclinical glucocorticoid over- replacement and aim for the lowest total dose of hydrocortisone replacement compatible with good health. Conversely avoidance of very low cortisol levels before the next dose seems advisable to minimize the risk of hypoadrenalism if intercurrent illness or stress occurs at that time.

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