- Email: [email protected]
Pituitary hormone replacement
PITUITARY
Pituitary hormone replacement
in the same manner as hydrocortisone. Cortisone acetate’s onset of action is slower than that of cortisol, but its duration of activity is longer. Cortisol is predominantly a glucocorticoid but has some mineralocorticoid action, as opposed to various synthetic glucocorticoids, such as prednisolone and dexamethasone, which are potent, pure glucocorticoids that are more difficult to dose titrate or monitor. The aims of hydrocortisone replacement are to replicate normal circadian rhythm and to avoid over-dosing, which can lead to features of Cushing’s syndrome, including increased bone turnover and reduced insulin sensitivity. However, it is impossible to completely mimic normal physiology with the preparations of hydrocortisone currently available.1 The plasma half-life of cortisol is less than 2 hours and twice-daily regimens are associated with non-physiological high levels post-dose and very low cortisol levels in the late afternoon; studies have shown that quality-of-life scores are lower at this time in patients on such regimens. Three-times-daily regimens (on rising, at noon and in the early evening (before 6 pm)) are therefore recommended, although it is best to avoid large doses of glucocorticoid in the evening. Newer preparations of modified-release hydrocortisone may allow more close mimicking of physiological levels in plasma but are not yet available. The total dose of hydrocortisone used in traditional regimens is supra-physiological for most patients. Recent evidence shows that cortisol production rates in normal individuals are significantly lower than previously believed. A total daily dose of 15e20 mg (10 mg in the morning, 5 mg at noon and 5 mg in the evening) is likely to be the ‘best-guess’ starting dose. Monitoring of therapy is mainly based on clinical assessment of symptoms of over- or under- replacement, as there is no biochemical gold standard. However, most patients will undergo an 8-hour hydrocortisone day-curve or a modified three-point day-curve, aiming to place serum cortisol levels within the physiological range. Such monitoring may allow detection of minor degrees of over-replacement or under-replacement that are unlikely to be clinically obvious. It is crucial that patients understand the need to increase their hydrocortisone dose whenever they suffer an intercurrent illness or undergo a minor procedure; under these circumstances, the dose must be increased two- to three-fold. The possibility of vomiting means that all patients should be advised to carry an emergency hydrocortisone pack containing hydrocortisone for intramuscular administration. In addition, patients should carry a steroid card or MedicAlert bracelet.
Claire Higham Stephen Shalet Peter J Trainer
Abstract Hypopituitarism is associated with increased morbidity and mortality. Hormone replacement therapies are available for effective treatment of anterior pituitary deficiencies of growth hormone: adrenocorticotropic hormone, thyroid-stimulating hormone, luteinizing hormone and folliclestimulating hormone. The posterior pituitary antidiuretic hormone can also be replaced. The aim of replacement therapy is to mimic as far as possible the normal physiology of the hormone and to avoid overtreatment. Currently available hormone preparations and their advantages and disadvantages are discussed.
Keywords adrenocorticotropic hormone; dehydroepiandrosterone; growth hormone; hydrocortisone; hypopituitary; oestrogen; testosterone; thyroxine
Hypopituitarism is associated with increased morbidity and mortality, and endocrine replacement therapy should aim to mimic the normal hormonal milieu as far as possible, thereby improving symptoms while avoiding over-treatment. Replacement therapy is available for corticotropin, thyrotropin, gonadotropin, growth hormone (GH) and antidiuretic hormone (ADH) deficiencies.
Adrenocorticotropic hormone deficiency Hydrocortisone is pharmaceutically manufactured cortisol and is the logical choice for glucocorticoid replacement therapy because it directly replaces the missing hormone, cortisol, and serum levels can be monitored. Alternatives include cortisone acetate, which is metabolized to cortisol and can therefore be monitored
Claire Higham BA DPhil MRCP is a Specialist Registrar in Diabetes and Endocrinology in Manchester, UK. Her research interests include pituitary disorders, particularly acromegaly and the metabolic consequences of endocrine conditions. Competing interests: none declared. Stephen Shalet MD FRCP is a Professor and Consultant Endocrinologist at The Christie Hospital, Manchester, UK. His research interests include pituitary disorders, abnormalities of growth hormone secretion and the endocrine complications of cancer treatment. Competing interests: has received research support from Pfizer, Novartis and Novo Nordisk.
Thyroid-stimulating hormone deficiency Diagnosing thyroid-stimulating hormone (TSH) deficiency and knowing when to start replacement therapy is a challenge; as in pituitary disease, TSH is of little diagnostic value and to wait until T4 is below the lower limit of a reference range is to wait too long. Secondary hypothyroidism is treated in the same manner as primary hypothyroidism: with thyroxine (T4) replacement therapy (see hypothyroidism article on pp. 426e 429). The normal starting dose in young patients without evidence of cardiac disease is 100 mg daily. In the elderly and
Peter J Trainer MD FRCP is a Professor and Consultant Endocrinologist at The Christie Hospital, Manchester, UK. His research interests are pituitary and adrenal disease, particularly Cushing’s syndrome, acromegaly and glucocorticoid receptors. Competing interests: has received research support from Pfizer, Ipsen, Novartis and Novo Nordisk.
MEDICINE 37:8
399
Ó 2009 Elsevier Ltd. All rights reserved.
PITUITARY
Hormone replacement therapy Hormone deficiency
Replacement
Usual daily dose
Growth hormone Gonadotropins C Women
Growth hormone
0.3e1 mg s.c. in the evening
(Oestradiol valerate or Conjugated equine oestrogens) plus Progesterone
1e2 mg daily p.o.
C
Men
0.625e1.25 mg daily p.o. Dose depends on preparation used Sex steroids may be administered transdermally (estradiol, 25e100 mg/24 hours)
Intramuscular Testosterone ester (Sustanon) (testosterone propionate, phenylpropionate and isocaproate) C Testosterone undecanoate (Nebido) Transdermal C Patch C Gel sachet C Gel dispenser Buccal C
Thyroid-stimulating hormone Adrenocorticotropic hormone Prolactin Antidiuretic hormone
Thyroxine Hydrocortisone Nil Desmopressin
250 mg i.m. every 2 or 3 weeks
1000 mg/12 weeks 5e7.5 mg/24 hours 50 mg/5 g sachet/24 hours 10 mg/0.5 g dispensed 30 mg/12 hours 75e150 mg daily 10 mg morning, 5 mg noon, 5 mg evening e 10e40 mg daily intranasally in two or three divided doses 300e600 mg daily p.o. in two or three divided doses
Table 1
those with evidence of ischaemic heart disease, therapy should start at lower doses (25e50 mg daily). Measurement of serum thyroid-stimulating hormone is unhelpful in the monitoring of T4 replacement therapy and there is a lack of evidence base about the biochemical target of therapy. It is generally accepted that the aim should be to restore the serum-free T4 concentration to the upper end of the normal range by titrating the thyroxine in 25 mg increments. Overreplacement with T4 over long periods of time may be associated with reduced bone mineral density (BMD), increased risk of osteoporotic fracture and an increase in the rate of development of atrial fibrillation; excessive doses of T4 should therefore be avoided. In patients with suspected hypopituitarism, T4 therapy should be delayed until adrenocorticotropic hormone (ACTH) deficiency has been excluded or treated because there is a risk of worsening the features of cortisol deficiency. Although it is much discussed in the literature and sometimes used in clinical practice, there is currently no good evidence for the addition of liothyronine (T3) to the thyroid replacement regimen.2
Women: sex steroids can be provided by many standard hormone replacement therapy preparations. Progesterone must be given cyclically or continuously in all women with a uterus in order to prevent the possible effects of unopposed oestrogen on the endometrium (dysfunctional bleeding, endometrial cancer). Oestrogen can be delivered as a tablet, a patch, a gel or an implant. Oestrogen replacement therapy can minimize the risk of osteoporosis when started early, but its long-term effects on the cardiovascular system and breast cancer risk in women below the age of 50 remain understudied. Treatment should be continued until the typical age of the menopause (about 51 years of age) and the decision to treat for longer should be based on the principles guiding hormone replacement therapy in all postmenopausal women (Table 1). Men: androgen replacement therapy for men with gonadotropin deficiency is available in many modalities. The choice of preparation depends on local availability and the wishes of the patient. Intramuscular injection of testosterone esters every 2e3 weeks has traditionally been the most commonly used method, but this leads to significant variations in the peak and trough plasma testosterone levels and has been largely abandoned in favour of trans-dermal or longer-acting intramuscular preparations, which generate more stable plasma concentrations. Trans-dermal preparations, gels and patches are now the most popular forms of testosterone replacement. They have the
Gonadotropin deficiency Patients who do not desire fertility In both sexes, sex steroid replacement therapy is important for the maintenance of well-being, normal body composition, BMD and sexual function.
MEDICINE 37:8
400
Ó 2009 Elsevier Ltd. All rights reserved.
PITUITARY
advantage of maintaining stable physiological testosterone profiles and are easy to administer but they have to be applied daily, can cause local irritation (patch) and care must be taken to avoid testosterone transfer to other people, particularly pregnant women and children. Most gels are available in 50 mg sachets, but a newly available gel dispenser system allows more careful titration of testosterone, with 10 mg testosterone in every 0.5 g dispensed. Oral androgen replacement therapy is available using testosterone undecanoate, a 17-hydroxyl ester of testosterone. This method requires frequent dosing (two to four times daily), and the testosterone levels achieved are often subnormal as a result of variable absorption. In most men, this is not the preparation of choice. A 3-monthly intramuscular injection of testosterone undecanoate is a convenient and effective testosterone replacement in many men. In contrast to the other preparations, the long half-life of this drug means caution must be used in those with prostate abnormalities. Judgement on the effectiveness of treatment should be primarily based on symptoms, such as libido, erectile function and energy levels. Serum testosterone, annual prostate-specific antigen and haematocrit (to assess for polycythaemia) levels must be monitored in patients using testosterone replacement. In some patients, adequate testosterone levels are not achieved and alternative preparations should be considered. There is no upper age limit at which testosterone therapy should be discontinued.
ovulation induction for other causes of infertility. Pulsatile GnRH therapy is more likely than HMG to result in development and ovulation of a single follicle, thereby reducing the risks of ovarian hyperstimulation and multiple gestation. However, residual gonadotropin function is insufficient to support this method in more than 50% of women with organic pituitary disease.
Growth hormone deficiency GH replacement therapy in adults with GH deficiency remains a controversial area. In the UK, current practice is to consider GH replacement therapy only in severely GH-deficient patients with markedly impaired quality of life. Elsewhere (particularly Scandinavia), GH replacement therapy is offered to all severely GHdeficient adults. There is now a large body of evidence demonstrating that GH replacement in adults with severe GH deficiency can significantly improve quality of life, body composition (reduction in fat mass and increase in lean mass) and lipid profile. However, there is still limited evidence that GH replacement normalizes the increased mortality rate observed in the untreated state.4 Most modern GH replacement regimens involve a low starting dose (0.3 mg/day in those aged less than 60) as a daily subcutaneous injection; this should be increased every 4e6 weeks, based on clinical response and the insulin-like growth factor I (IGF-I) standard deviation score, until a steady replacement dose is reached (up to 1 mg/day). Preparations of GH that can be administered less frequently have been successfully used in the trial setting (depot monthly injections or sustained-release weekly formulations) and the hope is that these will soon be licensed, improving convenience and compliance. As with T4 therapy, GH therapy should be delayed until ACTH deficiency has been excluded or treated because there is a risk of worsening the features of cortisol deficiency. Improvements in physiological well-being and quality of life do not occur in all GH-deficient patients. The UK National Institute for Clinical Excellence guidance on GH replacement in GH-deficient adults indicates that for a patient to be eligible for GH replacement therapy, it must be shown that he or she suffers severe impairment of quality of life, reflected by a reported score of at least 11 in the Quality of Life Assessment of GH Deficiency in Adults (QoLeAGHDA) questionnaire, which has a range of zero to 25; higher scores indicate poorer quality of life. The guidance further stipulates that patients who have been started on GH replacement should be reassessed 9 months after the initiation of therapy (allowing for a dose titration period of 3 months followed by a 6-month therapeutic trial period), and that GH therapy should be discontinued in patients in whom the QoLeAGHDA score improves by less than 7 points.5 Monitoring of GH replacement therapy should include regular measurement of weight, blood pressure, HbAlc, lipid profile and IGF-I, determination of fat distribution (waist:hip ratio), and assessment of quality of life using a disease-specific questionnaire and patient interviews.
Therapeutic testosterone in women: women who are both ACTH- and gonadotropin-deficient are also likely to be androgendeficient. There are limited data with regards to testosterone or dehydroepiandrosterone replacement in women with hypogonadotropic hypogonadism and these trials are limited by difficulties with defining normal free testosterone levels in women. However, there is a suggestion that replacement with low-dose testosterone leads to improvements in bone indices, quality of life and sexual satisfaction.3 More data are required before this becomes standard practice. Patients who desire fertility Men: in hypogonadotropic hypogonadal men, fertility can be achieved using gonadotropin replacement or gonadotropinreleasing hormone (GnRH). The former is the traditional approach. Initially, luteinizing hormone activity is provided as human chorionic gonadotropins (HCG), 1000e2000 IU s.c. or i.m. two or three times weekly. If adequate spermatogenesis is not achieved, follicle-stimulating hormone (FSH) in the form of human menopausal gonadotropin (HMG) or a more purified preparation of FSH is added. In the alternative regimen, pulsatile GnRH is administered subcutaneously via a catheter attached to a mini-pump. This method is suitable in men with a hypothalamic defect with normal pituitary gonadotropin secretion. Both regimens may take up to 2 years to achieve adequate spermatogenesis. Once they are effective, storing several samples of frozen sperm for any future attempts at pregnancy should be considered.
Antidiuretic hormone deficiency
Women: in hypogonadotropic hypogonadism, pregnancy rates of 83% are reported following pulsatile GnRH or gonadotropin therapy. These rates are better than those achieved with
MEDICINE 37:8
Desmopressin is the drug of choice for the treatment of ADH deficiency of the posterior pituitary. It is a synthetic analogue of
401
Ó 2009 Elsevier Ltd. All rights reserved.
PITUITARY
5 National Institute for Clincal Excellence. Human growth hormone in adults with growth hormone deficiency. Available at: http://www.nice. org.uk/nicemedia/pdf/TA64_HGHadults_fullguidance.pdf (accessed 25 May 2009).
arginine vasopressin, with two minor alterations in its molecular structure e a switch from L-arginine to D-arginine at position eight, and de-amination of cysteine in position one. These changes increase the antidiuretic activity by 2e4-fold, prolong the biological half-life to 6e8 hours and eliminate pressor activity. Desmopressin is available as oral, intranasal and parenteral preparations The dose required varies widely (up to tenfold between individuals) with no apparent relationship to age, sex, weight or degree of polyuria. The drug should be started at a low dose and increased gradually until urine output is controlled. Overdose carries a risk of hyponatraemia, and sodium levels should be checked after starting therapy and when the dose is changed. A
FURTHER READING Carroll PV, Christ ER, Bengtsson BA, et al. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. J Clin Endocrinol Metab 1998; 83: 382e95. (A detailed review of the effects of GH.) Lamberts SWJ, ed. The diagnosis and treatment of pituitary insufficiency. Bristol: Bioscientifica, 1997. (Excellent reviews of replacement requirements for ACTH, thyroidstimulating hormone, gonadotrophin and ADH deficiencies.) Peacey SR, Guo CY, Robinson AM, et al. Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin Endocrinol (Oxf) 1997; 46: 255e61. (Highlights the adverse effects of a subtle degree of hydrocortisone over-replacement.)
REFERENCES 1 Crown A, Lightman S. Why is the management of glucocorticoid deficiency still controversial: a review of the literature. Clin Endocrinol (Oxf) 2005; 63: 483e92. 2 Slawik M, Klawitter B, Meiser E, et al. Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine. J Clin Endocrinol Metab 2007; 92: 4115e22. 3 Miller KK, Biller BM, Beauregard C, et al. Effects of testosterone replacement in androgen-deficient women with hypopituitarism: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2006; 91: 1683e90. ¨therstro ¨m G, Bengtsson BA, Bosaeus I, Johannsson G, 4 Go Svensson JA. 10-year, prospective study of the metabolic effects of growth hormone replacement in adults. J Clin Endocrinol Metab 2007; 92: 1442e5.
MEDICINE 37:8
Practice points C
C
C
C C
402
The optimal dose of hydrocortisone replacement for everyday needs has been shown to be less than that previously used Initiating T4 and GH replacement in unreplaced ACTH-deficient patients may be dangerous An intercurrent illness in a patient with hypopituitarism may be fatal if the hydrocortisone dose is not increased appropriately There are multiple preparations of testosterone available GH replacement is beneficial to quality of life and metabolic profiles in both adults and children
Ó 2009 Elsevier Ltd. All rights reserved.
Pituitary hormone replacement
in the same manner as hydrocortisone. Cortisone acetate’s onset of action is slower than that of cortisol, but its duration of activity is longer. Cortisol is predominantly a glucocorticoid but has some mineralocorticoid action, as opposed to various synthetic glucocorticoids, such as prednisolone and dexamethasone, which are potent, pure glucocorticoids that are more difficult to dose titrate or monitor. The aims of hydrocortisone replacement are to replicate normal circadian rhythm and to avoid over-dosing, which can lead to features of Cushing’s syndrome, including increased bone turnover and reduced insulin sensitivity. However, it is impossible to completely mimic normal physiology with the preparations of hydrocortisone currently available.1 The plasma half-life of cortisol is less than 2 hours and twice-daily regimens are associated with non-physiological high levels post-dose and very low cortisol levels in the late afternoon; studies have shown that quality-of-life scores are lower at this time in patients on such regimens. Three-times-daily regimens (on rising, at noon and in the early evening (before 6 pm)) are therefore recommended, although it is best to avoid large doses of glucocorticoid in the evening. Newer preparations of modified-release hydrocortisone may allow more close mimicking of physiological levels in plasma but are not yet available. The total dose of hydrocortisone used in traditional regimens is supra-physiological for most patients. Recent evidence shows that cortisol production rates in normal individuals are significantly lower than previously believed. A total daily dose of 15e20 mg (10 mg in the morning, 5 mg at noon and 5 mg in the evening) is likely to be the ‘best-guess’ starting dose. Monitoring of therapy is mainly based on clinical assessment of symptoms of over- or under- replacement, as there is no biochemical gold standard. However, most patients will undergo an 8-hour hydrocortisone day-curve or a modified three-point day-curve, aiming to place serum cortisol levels within the physiological range. Such monitoring may allow detection of minor degrees of over-replacement or under-replacement that are unlikely to be clinically obvious. It is crucial that patients understand the need to increase their hydrocortisone dose whenever they suffer an intercurrent illness or undergo a minor procedure; under these circumstances, the dose must be increased two- to three-fold. The possibility of vomiting means that all patients should be advised to carry an emergency hydrocortisone pack containing hydrocortisone for intramuscular administration. In addition, patients should carry a steroid card or MedicAlert bracelet.
Claire Higham Stephen Shalet Peter J Trainer
Abstract Hypopituitarism is associated with increased morbidity and mortality. Hormone replacement therapies are available for effective treatment of anterior pituitary deficiencies of growth hormone: adrenocorticotropic hormone, thyroid-stimulating hormone, luteinizing hormone and folliclestimulating hormone. The posterior pituitary antidiuretic hormone can also be replaced. The aim of replacement therapy is to mimic as far as possible the normal physiology of the hormone and to avoid overtreatment. Currently available hormone preparations and their advantages and disadvantages are discussed.
Keywords adrenocorticotropic hormone; dehydroepiandrosterone; growth hormone; hydrocortisone; hypopituitary; oestrogen; testosterone; thyroxine
Hypopituitarism is associated with increased morbidity and mortality, and endocrine replacement therapy should aim to mimic the normal hormonal milieu as far as possible, thereby improving symptoms while avoiding over-treatment. Replacement therapy is available for corticotropin, thyrotropin, gonadotropin, growth hormone (GH) and antidiuretic hormone (ADH) deficiencies.
Adrenocorticotropic hormone deficiency Hydrocortisone is pharmaceutically manufactured cortisol and is the logical choice for glucocorticoid replacement therapy because it directly replaces the missing hormone, cortisol, and serum levels can be monitored. Alternatives include cortisone acetate, which is metabolized to cortisol and can therefore be monitored
Claire Higham BA DPhil MRCP is a Specialist Registrar in Diabetes and Endocrinology in Manchester, UK. Her research interests include pituitary disorders, particularly acromegaly and the metabolic consequences of endocrine conditions. Competing interests: none declared. Stephen Shalet MD FRCP is a Professor and Consultant Endocrinologist at The Christie Hospital, Manchester, UK. His research interests include pituitary disorders, abnormalities of growth hormone secretion and the endocrine complications of cancer treatment. Competing interests: has received research support from Pfizer, Novartis and Novo Nordisk.
Thyroid-stimulating hormone deficiency Diagnosing thyroid-stimulating hormone (TSH) deficiency and knowing when to start replacement therapy is a challenge; as in pituitary disease, TSH is of little diagnostic value and to wait until T4 is below the lower limit of a reference range is to wait too long. Secondary hypothyroidism is treated in the same manner as primary hypothyroidism: with thyroxine (T4) replacement therapy (see hypothyroidism article on pp. 426e 429). The normal starting dose in young patients without evidence of cardiac disease is 100 mg daily. In the elderly and
Peter J Trainer MD FRCP is a Professor and Consultant Endocrinologist at The Christie Hospital, Manchester, UK. His research interests are pituitary and adrenal disease, particularly Cushing’s syndrome, acromegaly and glucocorticoid receptors. Competing interests: has received research support from Pfizer, Ipsen, Novartis and Novo Nordisk.
MEDICINE 37:8
399
Ó 2009 Elsevier Ltd. All rights reserved.
PITUITARY
Hormone replacement therapy Hormone deficiency
Replacement
Usual daily dose
Growth hormone Gonadotropins C Women
Growth hormone
0.3e1 mg s.c. in the evening
(Oestradiol valerate or Conjugated equine oestrogens) plus Progesterone
1e2 mg daily p.o.
C
Men
0.625e1.25 mg daily p.o. Dose depends on preparation used Sex steroids may be administered transdermally (estradiol, 25e100 mg/24 hours)
Intramuscular Testosterone ester (Sustanon) (testosterone propionate, phenylpropionate and isocaproate) C Testosterone undecanoate (Nebido) Transdermal C Patch C Gel sachet C Gel dispenser Buccal C
Thyroid-stimulating hormone Adrenocorticotropic hormone Prolactin Antidiuretic hormone
Thyroxine Hydrocortisone Nil Desmopressin
250 mg i.m. every 2 or 3 weeks
1000 mg/12 weeks 5e7.5 mg/24 hours 50 mg/5 g sachet/24 hours 10 mg/0.5 g dispensed 30 mg/12 hours 75e150 mg daily 10 mg morning, 5 mg noon, 5 mg evening e 10e40 mg daily intranasally in two or three divided doses 300e600 mg daily p.o. in two or three divided doses
Table 1
those with evidence of ischaemic heart disease, therapy should start at lower doses (25e50 mg daily). Measurement of serum thyroid-stimulating hormone is unhelpful in the monitoring of T4 replacement therapy and there is a lack of evidence base about the biochemical target of therapy. It is generally accepted that the aim should be to restore the serum-free T4 concentration to the upper end of the normal range by titrating the thyroxine in 25 mg increments. Overreplacement with T4 over long periods of time may be associated with reduced bone mineral density (BMD), increased risk of osteoporotic fracture and an increase in the rate of development of atrial fibrillation; excessive doses of T4 should therefore be avoided. In patients with suspected hypopituitarism, T4 therapy should be delayed until adrenocorticotropic hormone (ACTH) deficiency has been excluded or treated because there is a risk of worsening the features of cortisol deficiency. Although it is much discussed in the literature and sometimes used in clinical practice, there is currently no good evidence for the addition of liothyronine (T3) to the thyroid replacement regimen.2
Women: sex steroids can be provided by many standard hormone replacement therapy preparations. Progesterone must be given cyclically or continuously in all women with a uterus in order to prevent the possible effects of unopposed oestrogen on the endometrium (dysfunctional bleeding, endometrial cancer). Oestrogen can be delivered as a tablet, a patch, a gel or an implant. Oestrogen replacement therapy can minimize the risk of osteoporosis when started early, but its long-term effects on the cardiovascular system and breast cancer risk in women below the age of 50 remain understudied. Treatment should be continued until the typical age of the menopause (about 51 years of age) and the decision to treat for longer should be based on the principles guiding hormone replacement therapy in all postmenopausal women (Table 1). Men: androgen replacement therapy for men with gonadotropin deficiency is available in many modalities. The choice of preparation depends on local availability and the wishes of the patient. Intramuscular injection of testosterone esters every 2e3 weeks has traditionally been the most commonly used method, but this leads to significant variations in the peak and trough plasma testosterone levels and has been largely abandoned in favour of trans-dermal or longer-acting intramuscular preparations, which generate more stable plasma concentrations. Trans-dermal preparations, gels and patches are now the most popular forms of testosterone replacement. They have the
Gonadotropin deficiency Patients who do not desire fertility In both sexes, sex steroid replacement therapy is important for the maintenance of well-being, normal body composition, BMD and sexual function.
MEDICINE 37:8
400
Ó 2009 Elsevier Ltd. All rights reserved.
PITUITARY
advantage of maintaining stable physiological testosterone profiles and are easy to administer but they have to be applied daily, can cause local irritation (patch) and care must be taken to avoid testosterone transfer to other people, particularly pregnant women and children. Most gels are available in 50 mg sachets, but a newly available gel dispenser system allows more careful titration of testosterone, with 10 mg testosterone in every 0.5 g dispensed. Oral androgen replacement therapy is available using testosterone undecanoate, a 17-hydroxyl ester of testosterone. This method requires frequent dosing (two to four times daily), and the testosterone levels achieved are often subnormal as a result of variable absorption. In most men, this is not the preparation of choice. A 3-monthly intramuscular injection of testosterone undecanoate is a convenient and effective testosterone replacement in many men. In contrast to the other preparations, the long half-life of this drug means caution must be used in those with prostate abnormalities. Judgement on the effectiveness of treatment should be primarily based on symptoms, such as libido, erectile function and energy levels. Serum testosterone, annual prostate-specific antigen and haematocrit (to assess for polycythaemia) levels must be monitored in patients using testosterone replacement. In some patients, adequate testosterone levels are not achieved and alternative preparations should be considered. There is no upper age limit at which testosterone therapy should be discontinued.
ovulation induction for other causes of infertility. Pulsatile GnRH therapy is more likely than HMG to result in development and ovulation of a single follicle, thereby reducing the risks of ovarian hyperstimulation and multiple gestation. However, residual gonadotropin function is insufficient to support this method in more than 50% of women with organic pituitary disease.
Growth hormone deficiency GH replacement therapy in adults with GH deficiency remains a controversial area. In the UK, current practice is to consider GH replacement therapy only in severely GH-deficient patients with markedly impaired quality of life. Elsewhere (particularly Scandinavia), GH replacement therapy is offered to all severely GHdeficient adults. There is now a large body of evidence demonstrating that GH replacement in adults with severe GH deficiency can significantly improve quality of life, body composition (reduction in fat mass and increase in lean mass) and lipid profile. However, there is still limited evidence that GH replacement normalizes the increased mortality rate observed in the untreated state.4 Most modern GH replacement regimens involve a low starting dose (0.3 mg/day in those aged less than 60) as a daily subcutaneous injection; this should be increased every 4e6 weeks, based on clinical response and the insulin-like growth factor I (IGF-I) standard deviation score, until a steady replacement dose is reached (up to 1 mg/day). Preparations of GH that can be administered less frequently have been successfully used in the trial setting (depot monthly injections or sustained-release weekly formulations) and the hope is that these will soon be licensed, improving convenience and compliance. As with T4 therapy, GH therapy should be delayed until ACTH deficiency has been excluded or treated because there is a risk of worsening the features of cortisol deficiency. Improvements in physiological well-being and quality of life do not occur in all GH-deficient patients. The UK National Institute for Clinical Excellence guidance on GH replacement in GH-deficient adults indicates that for a patient to be eligible for GH replacement therapy, it must be shown that he or she suffers severe impairment of quality of life, reflected by a reported score of at least 11 in the Quality of Life Assessment of GH Deficiency in Adults (QoLeAGHDA) questionnaire, which has a range of zero to 25; higher scores indicate poorer quality of life. The guidance further stipulates that patients who have been started on GH replacement should be reassessed 9 months after the initiation of therapy (allowing for a dose titration period of 3 months followed by a 6-month therapeutic trial period), and that GH therapy should be discontinued in patients in whom the QoLeAGHDA score improves by less than 7 points.5 Monitoring of GH replacement therapy should include regular measurement of weight, blood pressure, HbAlc, lipid profile and IGF-I, determination of fat distribution (waist:hip ratio), and assessment of quality of life using a disease-specific questionnaire and patient interviews.
Therapeutic testosterone in women: women who are both ACTH- and gonadotropin-deficient are also likely to be androgendeficient. There are limited data with regards to testosterone or dehydroepiandrosterone replacement in women with hypogonadotropic hypogonadism and these trials are limited by difficulties with defining normal free testosterone levels in women. However, there is a suggestion that replacement with low-dose testosterone leads to improvements in bone indices, quality of life and sexual satisfaction.3 More data are required before this becomes standard practice. Patients who desire fertility Men: in hypogonadotropic hypogonadal men, fertility can be achieved using gonadotropin replacement or gonadotropinreleasing hormone (GnRH). The former is the traditional approach. Initially, luteinizing hormone activity is provided as human chorionic gonadotropins (HCG), 1000e2000 IU s.c. or i.m. two or three times weekly. If adequate spermatogenesis is not achieved, follicle-stimulating hormone (FSH) in the form of human menopausal gonadotropin (HMG) or a more purified preparation of FSH is added. In the alternative regimen, pulsatile GnRH is administered subcutaneously via a catheter attached to a mini-pump. This method is suitable in men with a hypothalamic defect with normal pituitary gonadotropin secretion. Both regimens may take up to 2 years to achieve adequate spermatogenesis. Once they are effective, storing several samples of frozen sperm for any future attempts at pregnancy should be considered.
Antidiuretic hormone deficiency
Women: in hypogonadotropic hypogonadism, pregnancy rates of 83% are reported following pulsatile GnRH or gonadotropin therapy. These rates are better than those achieved with
MEDICINE 37:8
Desmopressin is the drug of choice for the treatment of ADH deficiency of the posterior pituitary. It is a synthetic analogue of
401
Ó 2009 Elsevier Ltd. All rights reserved.
PITUITARY
5 National Institute for Clincal Excellence. Human growth hormone in adults with growth hormone deficiency. Available at: http://www.nice. org.uk/nicemedia/pdf/TA64_HGHadults_fullguidance.pdf (accessed 25 May 2009).
arginine vasopressin, with two minor alterations in its molecular structure e a switch from L-arginine to D-arginine at position eight, and de-amination of cysteine in position one. These changes increase the antidiuretic activity by 2e4-fold, prolong the biological half-life to 6e8 hours and eliminate pressor activity. Desmopressin is available as oral, intranasal and parenteral preparations The dose required varies widely (up to tenfold between individuals) with no apparent relationship to age, sex, weight or degree of polyuria. The drug should be started at a low dose and increased gradually until urine output is controlled. Overdose carries a risk of hyponatraemia, and sodium levels should be checked after starting therapy and when the dose is changed. A
FURTHER READING Carroll PV, Christ ER, Bengtsson BA, et al. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. J Clin Endocrinol Metab 1998; 83: 382e95. (A detailed review of the effects of GH.) Lamberts SWJ, ed. The diagnosis and treatment of pituitary insufficiency. Bristol: Bioscientifica, 1997. (Excellent reviews of replacement requirements for ACTH, thyroidstimulating hormone, gonadotrophin and ADH deficiencies.) Peacey SR, Guo CY, Robinson AM, et al. Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin Endocrinol (Oxf) 1997; 46: 255e61. (Highlights the adverse effects of a subtle degree of hydrocortisone over-replacement.)
REFERENCES 1 Crown A, Lightman S. Why is the management of glucocorticoid deficiency still controversial: a review of the literature. Clin Endocrinol (Oxf) 2005; 63: 483e92. 2 Slawik M, Klawitter B, Meiser E, et al. Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine. J Clin Endocrinol Metab 2007; 92: 4115e22. 3 Miller KK, Biller BM, Beauregard C, et al. Effects of testosterone replacement in androgen-deficient women with hypopituitarism: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2006; 91: 1683e90. ¨therstro ¨m G, Bengtsson BA, Bosaeus I, Johannsson G, 4 Go Svensson JA. 10-year, prospective study of the metabolic effects of growth hormone replacement in adults. J Clin Endocrinol Metab 2007; 92: 1442e5.
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The optimal dose of hydrocortisone replacement for everyday needs has been shown to be less than that previously used Initiating T4 and GH replacement in unreplaced ACTH-deficient patients may be dangerous An intercurrent illness in a patient with hypopituitarism may be fatal if the hydrocortisone dose is not increased appropriately There are multiple preparations of testosterone available GH replacement is beneficial to quality of life and metabolic profiles in both adults and children
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