Monitoring hormone replacement therapies
The administration of therapeutic hormones to replace natural deficits is complicated by the normal rise and fall in concentrations following oral or parenteral dosing. Indeed, in most cases the most important guide to the adequacy of replacement is the patient’s symptomatic response. The following discusses the problems of laboratory monitoring.
Thyroid hormone replacement therapy is almost always given in the form of thyroxine (T4). In health, 20% of tri-iodothyronine (T3) is produce by the thyroid gland rather than by conversion of T4 in the periphery, but in patients on T4 replacement all T3 is produced by peripheral conversion, and so circulating T4 levels may need to be maintained slightly above the "normal" reference range to generate adequate tissue T3 concentrations.
In primary hypothyroidism TSH is generally considered to be the most important guide as it reflects a biological response by the pituitary gland to the administered hormone. a useful guide to the adequacy of thyroxine replacement. Our practise is to aim to maintain the TSH concentration within the bottom half of the reference range ie 0.5-3.5 mIU/L. However, some patients do not respond symptomatically until the TSH is suppressed and in this case thyroid hormones levels should be kept within the upper half of the reference range. The British Thyroid Association guidelines recommend that TSH should be monitored at least annually.
In those with secondary hypothyroidism, TSH is of no value. Replacement should be based on symptoms with an aim of keeping thyroid hormone levels within the upper half of the reference range.
The British Thyroid Association guidelines (July 2006) can be downloaded here.
There is no single test to ensure adequate cortisol replacement. If it is thought that the replacement dose is incorrect a cortisol day curve can help to demonstrate proximity to a physiological profile.
In patients with primary adrenal insufficiency mineralocorticoid replacement should be monitored to maintain normal concentrations of plasma renin activity.
When oestrogen replacement therapy is used for relief of menopausal symptoms response should be judged by the symptomatic response. FSH is useful for diagnosing menopause but is not lowered by HRT.
Longer term oestrogen replacement therapy has been advocated for the prevention of osteoporosis and ischaemic heart disease in post-menopausal women on the basis of large cohort and case-control studies, despite probable increased risk of breast cancer and venous thromboembolism. Recently the HERS study, a randomised, placebo controlled study of oestrogen replacement in post-menopausal women with ischaemic heart disease failed to show any beneficial effect in reducing cardiovascular events. Even in studies where benefit has been demonstrated the effects attenuate once oestrogen replacement is stopped, the risk of ischaemic heart disease and osteoporotic fracture increasing to control levels after 5 to 10 years.
When women use oestrogen replacement therapy for osteoporosis prevention the response can be monitored using bone densitometry.
Testosterone replacement therapy should be judged according to symptomatic response. Ideally the dosage and frequency of intramuscular administration should be adjusted to ensure that plasma testosterone concentrations remain in the midnormal range 1 week after injection and within the normal range until the next dose. For patches plasma testosterone should be measured 24-48 hours after patch application. Once physiological steady states have been achieved patients should be reassessed every 6 months. Screening for lipids and prostate specific antigen should probably be performed annually.
Low-dose testosterone replacement (100 mg implant 4 to 6 monthly) may be indicated in post-menopausal women with diminished libido despite oestrogen replacement therapy.
Vitamin D derivatives are used for the treatment of chronic hypocalcaemia, in combination with 1.5-2 g supplemental calcium. Alfacalcidol (1a-hydroxycholecalciferol) and calcitriol (1,25 dihydroxycholecalciferol) are most commonly used. These agents have a short half-life (about 6 hours) and produce an optimal effect within 3 days.
Initially plasma calcium levels should be checked twice weekly and the dose of vitamin D adjusted accordingly until a steady state is achieved. Thereafter calcium levels should be checked frequently, at most 3 monthly, and renal function and urinary calcium excretion should be assessed 6 to 12 monthly. The aim is to maintain plasma calcium levels towards the lower half of the normal range, and to ensure normal urinary calcium excretion. Patients should be warned of the symptoms of hypercalcaemia. If hypercalcaemia occurs the drug should be stopped and intravenous rehydration commenced. Plasma calcium will rapidly normalize due to the short half-life of these agents.
Monitoring should be performed more frequently during pregnancy, since the requirements for vitamin D therapy may double or triple towards the end of pregnancy. Post-partum the dose should be reduced to the pre-pregnancy level if not breastfeeding, or to half the pre-pregnancy dose if breast feeding, increasing to the equivalent dose on cessation of breast-feeding. This is because of the increase in endogenous vitamin D production during lactation.
- UK guidelines for the use of Thyroid Function Tests. July 2006.
- Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13.
- Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PWF, Benjamin EJ, D'Agostino RB. Low serum thyrotropin concentrations as a risk factor or atrial fibrillation in older persons. NEJM 1994;331:1249-1252.