Exogenous Glucocorticoids: Much to Consider

Steroid Terminology

Corticosteroids, a class of steroid hormones, include both glucocorticoids and mineralocorticoids.

  • The adrenal cortex produces endogenous corticosteroids. Specifically, the zona fasciculata produces glucocorticoids (e.g., cortisol) and the zona glomerulosa produces mineralocorticoids (e.g., aldosterone)

The remainder of this post will focus on exogenous glucocorticoids (GC), of which there are MANY approved by the FDA and available in a wide range of formulations (e.g., oral, topical, inhaled, ophthalmic, and parenteral).

Adverse Drug Effects

Exogenous GC have MANY potential adverse drug effects (ADEs), which are generally dose- and duration-dependent.

  • Some ADEs follow a linear dose-response pattern, including ecchymosis, cushingoid features, parchment-like skin, leg edema, and sleep disturbance
  • Other ADEs tend to follow a threshold dose-response pattern with an elevated frequency of events beyond a specific threshold value (e.g., weight gain at prednisone doses >5 mg daily; glaucoma, depression, and elevated BP at prednisone doses >7.5 mg daily)
  • Other factors that may influence the occurrence and magnitude of ADEs include older age, comorbid conditions (e.g., DM), concomitant use of other immunosuppressive agents, the severity and nature of underlying disease, and poor nutritional status

ADEs of GC include but are not limited to

  • MSK: myopathy, osteoporosis, osteonecrosis
  • Metabolic: hyperglycemia, Cushing syndrome, suppression of the hypothalamic-pituitary-adrenal (HPA) axis, adrenal suppression/insufficiency, poor growth
  • Infections (increased risk of essentially any type)
  • Cardiovascular: fluid retention, edema, weight gain, hypertension, arrhythmias, premature atherosclerosis
  • Skin: ecchymosis, skin thinning and atrophy, acne, mild hirsutism, facial erythema, stria, impaired wound healing, thinning of hair, perioral dermatitis
  • Ophthalmologic: cataracts, increased intraocular pressure, glaucoma, central serous chorioretinopathy
  • GI: gastritis, gastric ulcer formation, GI bleeding, pancreatitis, visceral perforation, hepatic steatosis
  • Neuropsychiatric: emotional lability, depressed/anxious mood, psychosis, sleep disturbance, akathisia, pseudotumor cerebri

Distinguishing Cushing’s disease vs Cushing’s syndrome:

  • Cushing’s disease is increased cortisol from an ACTH-secreting pituitary tumor
  • Cushing’s syndrome (CS) is the symptoms and signs that result from increased cortisol due to any cause (either ACTH-dependent or independent)
    • Most common cause (by far) is exogenous GC

The clinical presentation of CS varies, and not all symptoms and signs are seen in every patient:

More common signs/symptomsLess common signs/symptoms
Decreased libido
Obesity/weight gain
Plethora
Round face
Menstrual changes
Hirsutism
Hypertension
Ecchymoses
Lethargy, depression
Dorsal fat pad
Abnormal glucose tolerance
ECG abnormalities or atherosclerosis
Striae
Edema
Proximal muscle weakness
Osteopenia or fracture
Headache
Backache
Recurrent infections
Abdominal pain
Acne
Female balding
Source: Nieman LK. Eur J Endocrinol. 2015

“Because of the variety in presentation [of Cushing’s syndrome], patients are often referred to subspecialists for complaints that are gynecologic (oligomenorrhea, hirsutism, infertility), dermatologic (red facial skin, poor wound healing, striae, acne), orthopedic/rheumatologic (fractures, low bone mineral density), metabolic (hypertension, diabetes, dyslipidemia), infectious (community acquired and infections seen with immunosuppression), cardiovascular (stroke, myocardial infarction, pulmonary embolism), neurologic (decreased strength, headaches, decreased memory and cognition), psychiatric (depression, anxiety, mood change), and nonspecific (fatigue, backache, and weight gain).”

Nieman LK. Cushing’s syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol. 2015

Discontinuing Glucocorticoids

Administration of exogenous GC can suppress the HPA axis. Abrupt cessation, or too rapid withdrawal, of GC in such patients may cause secondary adrenal insufficiency.

A 2016 systematic review of 73 studies found evidence for adrenal insufficiency across all average and cumulative doses of exogenous GC.

There was no obvious pattern when stratifying by the dose, duration or cumulative dose. Across all strata, the median percentage of patients with adrenal insufficiency ranged from 14% (IQR: 0–40%) for a medium cumulative dose (0.5–5 g) to 50% (IQR: 35–66%) for a high cumulative dose (greater than 5 g).
Source: Joseph et al. Semin Arthritis Rheum. 2016
A total of 13 studies tested adrenal function after a GC taper. The median percentage of patients with AI after a GC taper was 38% and ranged from 0% to 84%. The studies varied in the initial GC doses, duration of tapering and prior exposure pattern.
Source: Joseph et al. Semin Arthritis Rheum. 2016

Similarly, a 2015 systematic review and meta-analysis of 74 studies found that, for patients who have discontinued exogenous GC, there is no administration form, dosing, treatment duration, or underlying disease for which adrenal insufficiency can be excluded with certainty, although higher dose and longer use give the highest risk.

Source: Broersen et al. J Clin Endocrinol Metab. 2015
Term: Short = <1mo Medium = 1mo-1yr Long = >1yr; Dose: Low = below lower bound of usual dose; High = above upper bound of usual dose.
Source: Broersen et al. J Clin Endocrinol Metab. 2015

A lesser known entity associated with GC discontinuation is glucocorticoid withdrawal syndrome (GWS), which can occur following withdrawal of supraphysiologic exposure to either exogenous or endogenous GC of at least several months duration.

“The first symptoms of GWS vary but usually consist of myalgias, muscle weakness, fatigue, and hypersomnolence. Anorexia, nausea, and abdominal discomfort are common… Mood changes develop more gradually and range from mood swings to depression, and the fatigue with myalgias can exacerbate mood changes.”

Source: He et al. Pituitary. 2022

Differentiating GWS from CS and AI can be challenging because of overlapping symptoms. All three conditions are associated with symptoms of myalgias, weakness, and fatigue; however, rapid weight loss, hypoglycemia, and hypotension are suggestive of AI.

Source: He et al. Pituitary. 2022

Tapering Glucocorticoids

There is a lack of evidence supporting any particular approach to tapering GC. In general, short-term GC therapy <2 weeks can simply be stopped and need not be tapered because HPA suppression is unlikely (but possible, as described above).

The goal of tapering GC is to use a rate of change that will prevent both recurrent activity of the underlying disease and symptoms of cortisol deficiency from persistent HPA suppression. Consider the following approach to tapering:

  • 5 to 10 mg/day every 1-2 weeks from an initial dose above 40 mg of prednisone or equivalent per day;
  • 5 mg/day every 1-2 weeks at prednisone doses between 40 and 20 mg/day;
  • 2.5 mg/day every 2-3 weeks at prednisone doses between 20 and 10 mg/day;
  • 1 mg/day every 2-4 weeks at prednisone doses between 10 and 5 mg/day;
  • 0.5 mg/day every 2-4 weeks at prednisone doses from 5 mg/day down.

Blog post based on Med-Peds Forum talk by Matt Lorenz, MP Core Faculty

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