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Original Studies |
Institute of Endocrine Sciences (L.P., S.G., P.B.-P.), University of Milan, Ospedale Maggiore IRCCS, Istituto Auxologico Italiano IRCCS, and Istituto Clinico Humanitas, Milan; the Department of Endocrinology (E.F., G.T.), University La Sapienza, Rome; and the Department of Experimental Medicine (E. F., M.-L.J.-R.), University of L’Aquila, L’Aquila, Italy
Address all correspondence and requests for reprints to: Paolo Beck-Peccoz, M.D., Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano-Milan, Italy. E-mail: paolo.beck-peccoz{at}humanitas.it
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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In conclusion, our results indicate that the diagnosis of CH is reached at best by measuring TSH and FT4 concentrations. In the evaluation of the adequacy of L-T4 replacement therapy, both FT4 and FT3 serum levels together with some biochemical indexes of thyroid hormone action are all necessary to a more accurate disclosure of over- or undertreated patients.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Restoration and maintenance of euthyroidism represent the therapeutic goals in CH. Specific therapies, such as oral TRH administration have been abandoned because of their cost and their restricted applicability to few patients with hypothalamic hypothyroidism (9, 10). Thus, patients with CH are treated with levothyroxine (L-T4), but no consensus has been found yet concerning the evaluation of the adequacy of L-T4 replacement dose, as, unlike for primary hypothyroidism, serum TSH levels cannot be used in either the diagnosis or the monitoring of L-T4 therapy (11, 12, 13, 14, 15, 16, 17).
Measurements of several clinical and biochemical peripheral parameters both in vivo (heart rate) and in vitro [cholesterol, sex hormone-binding protein (SHBG), angiotensin-converting enzyme (ACE), carboxyl-terminal telopeptide of type I collagen (ICTP), and osteocalcin or bone GLA protein (BG-P), etc.] have been proposed as indexes of thyroid hormone action in patients with thyroid disorders (18). These peripheral parameters have been proven to be useful in 1) the diagnosis of subclinical thyroid disorders, 2) the evaluation of thyroid dysfunction in nonthyroidal illnesses, 3) monitoring L-T4 treatment at TSH-suppressing doses in patients with goiter or with differentiated thyroid cancer after thyroidectomy, and 4) the differential diagnosis of inappropriate TSH secretion (18). Serum soluble interleukin-2 receptors (sIL-2R) have been shown to be a sensitive marker of the biological effects of thyroid hormones on lymphocytes in various thyroid diseases (19, 20) and in thyroid hormone resistance syndromes (21); in addition, SHBG determination has been demonstrated to be of help in various forms of inappropriate TSH secretion (22) and in nonthyroidal illness (23), whereas ICTP, a reliable marker of bone resorption, is useful in the differential diagnosis of syndromes of inappropriate TSH secretion and in the disclosure of L-T4 overtreatment (24). To our knowledge, these parameters have not been analyzed in patients with CH.
The aim of this study was to identify the most reliable markers, including hormonal parameters and a series of peripheral indexes of thyroid hormone action, for monitoring the adequacy of L-T4 replacement therapy in patients with CH. To this end, a series of 37 patients with CH of various etiologies, already receiving long term replacement therapy with L-T4, were prospectively studied both off and on therapy.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Thirty-seven patients (24 males and 13 females, aged 48 ± 13.5 yr; range, 20–70 yr) affected with CH were enrolled. Twenty-one patients had functioning or nonfunctioning pituitary adenomas, 8 had suprasellar tumors, 6 had idiopathic pituitary insufficiency, 1 had primary empty sella, and 1 had hypophysitis. Thirty subjects underwent pituitary surgery, and 14 had radiotherapy. Disease duration ranged from 1–25 yr, so that the initial diagnostic criteria were heterogeneous, consisting of serum thyroid hormone levels [total T4 (TT4) and T3 (TT3) or free T4 (FT4) and T3 (FT3)] below the normal range. Informed consent was obtained from all subjects before they entered the study. All patients were studied during appropriate replacement therapy for concomitant pituitary deficiencies, with the exception of GH, and were negative for the presence of circulating antithyroglobulin and antithyroperoxidase autoantibodies. Patients were subdivided into 1) eugonadal females [n = 8; women with spontaneous menses or receiving estrogen replacement therapy with transdermal estrogen patches (estradiol 50 mg)], 2) hypogonadal females (women with untreated secondary amenorrhea or menopause; n = 5), 3) eugonadal males (n = 21; men with normal testosterone values or hypogonadal treated with im testosterone enanthate injections every 15–28 days), and 4) hypogonadal males with untreated hypogonadism (n = 3). Moreover, patients were divided into group C+ (n = 28) for those receiving replacement therapy with cortisone acetate (37.5 mg/day) and group C- (n = 9) for those without adrenal insufficiency.
Experimental design and follow-up
All patients were analyzed at five different time points according to the following protocol.
Visit I. Thirty-four patients receiving long term L-T4 therapy were evaluated. Each patient had started L-T4 treatment at the time of diagnosis, and the dose was individually adjusted to restore clinical euthyroidism and to maintain TT4, TT3, FT4, and FT3 within the normal range. At this point L-T4 therapy was discontinued.
Visit II. Thirty-seven (the previous 34 plus 3 who were newly diagnosed) patients were evaluated off therapy, after a mean 60-day period of L-T4 therapy discontinuation. At this point, L-T4 treatment was gradually restored.
Visit III. A subgroup of 15 patients was evaluated at the end of a 15-day period of L-T4 therapy at a daily dose of 50 µg. The full L-T4 dose was subsequently restored.
Visit IV. All 37 patients were evaluated 3 months after L-T4 therapy restoration at the prestudy daily dose. At this point, the dose of L-T4 was modified in 5 patients according to the values of the analyzed parameters.
Visit V. Thirty-five patients were evaluated 6 months after therapy restoration. At each time point, patients have been evaluated for: 1) a clinical examination by two clinicians based on a standard interview about symptoms of hypo- or hyperthyroidism and a physical evaluation with particular reference to skin aspects, facial and limb edema, heart rate, blood pressure (BP), and body mass index; 2) a biochemical evaluation, including serum TSH, thyroid hormones (TT4, TT3, FT4, and FT3), thyroglobulin (Tg), cholesterol [total, low density lipoprotein (LDL), and high density lipoprotein (HDL)], triglycerides, creatine kinase (CK), ferritin, total alkaline phosphatase, aspartate transaminase (AST), alanin transaminase (ALT), SHBG, ACE, ICTP, BG-P, and sIL-2R. All serum samples were taken before administration of the daily L-T4 dose. Patients were considered in the euthyroid state in the presence of normal FT4 and FT3 values associated with the disappearance of clinical symptoms and signs of hypothyroidism together with values of peripheral parameters of thyroid hormone action in the normal range.
A TRH stimulation test was performed off therapy (visit II) to
determine the hypothalamic or pituitary origin of CH. A prevalent
hypothalamic lesion was attributed to the patients with a
normal/exaggerated TSH response (net TSH increment, 
4 mU/L); patients
with blunted TSH responses (<4 mU/L) were classified as having
prevalent pituitary involvement.
Laboratory assays
Serum TSH was measured by a third generation immunofluorometric assay (Delfia, Upjohn-Pharmacia, Milan, Italy), using the WHO reference preparation TSH 80/558 as standard. FT4 was measured by a direct back-titration technique using Delfia technology (Upjohn-Pharmacia), and FT3 was determined using a competitive immunoperoxidase technique (Johnson & Johnson Clinical Diagnostic, Cinisello B., Milan, Italy), respectively. TT4 and TT3 levels were determined using conventional RIAs (CIS-Bio International, Tronzano Vercellese, Italy). Tg was measured by means of a sensitive and specific FIA (Delfia, Upjohn-Pharmacia), evaluating the recovery of added Tg in each sample. Circulating sIL-2R levels were evaluated by an immunoenzymatic technique (CellFree, T Cell Diagnostic, Inc., Woburn, MA) with a detection limit of 24 U/mL; the intra- and interassay coefficients of variation were 6.3% and 8.0%, respectively. Circulating SHBG levels were measured by an immunofluorometric assay (Delfia, Upjohn-Pharmacia) with a detection limit of 0.5 nmol/L; the intra- and interassay coefficients of variation were 1.5% and 7.8%, respectively. Circulating ACE levels were determined by spectrophotometry (Buhlmann Laboratories, Geneva, Switzerland) with a detection limit of 3 ACE units; the intra- and interassay coefficients of variation were 2.8% and 5.1%, respectively. Serum ICTP levels were measured with a specific commercial RIA kit (Orion, Turku, Finland). The ICTP assay showed a sensitivity of 0.5 ± 0.1 µg/L, and both the intra- and interassay coefficients of variation were lower than 6%. An immunoradiometric assay (ELSA-OSTEO, CIS-Bio International, Tronzano Vercellese, Italy) was employed for BG-P determination. The detection limit of this assay was 0.4 ng/mL, and the intra- and interassay coefficients of variation were 3.8% and 5.2%, respectively. All other biochemical parameters were analyzed according to standard laboratory methods.
Statistical analysis
All results are presented as the mean ± SD. Multifactorial ANOVA was used for comparing the differences observed among the five time points for each parameter. Correlations between FT3 or FT4 and other parameters were calculated by simple regression analysis. P < 0.05 was considered the limit for statistical significance. All statistical evaluations were carried out using a StatView 4.02 software for McIntosh (Abacus Concepts, Inc., Berkeley, CA).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The clinical examination showed that the most frequent symptoms and signs observed in patients off therapy were asthenia and edema, occurring in more than 50% of the patients, followed by drowsiness, adynamia, and skin dryness. Among the other clinical parameters, only the heart rate values were significantly changed after L-T4 withdrawal (off therapy, 64 ± 8 beats/min; on therapy, 69 ± 7 beats/min; P < 0.05). No significant change was observed for BP (systolic BP, 128 ± 15 vs. 132 ± 16 mm Hg; diastolic BP, 83 ± 9 vs. 86 ± 10 mm Hg, off and on therapy, respectively) and body mass index (28.8 ± 4 vs. 27.4 ± 4 kg/m2, off and on therapy, respectively).
The biochemical evaluation showed that after
L-T4 withdrawal,
FT4 levels were below the normal range in all
patients, whereas values of FT3,
TT4, and TT3 were below the
normal range in 73%, 57%, and 19% of the cases, respectively. Among
the patients with normal TT4 levels, 2 of 6 were
females receiving sex steroid replacement therapy. TSH levels were
below 0.2 mU/L in 19%, normal in 70%, and slightly increased in 11%
of the patients, respectively. According to the TSH response to the TRH
stimulation test, the origin of CH was judged to be prevalently
hypothalamic in 14 cases (38%), whereas a prevalent pituitary origin
was present in the remaining 23 patients (62%). As far as the routine
biochemical parameters were concerned, a significant variation was
observed in circulating levels of total cholesterol, LDL cholesterol,
CK, and AST (with values above the upper normal limits in 95%, 89%,
54%, and 33% of the cases, respectively); the most significant
alteration was the increase in CK levels (P < 0.0001
vs. values during replacement therapy; Table 1
). Significant modification of all other
indexes of peripheral thyroid hormone action, except ferritin, was also
recorded (Table 2); the most significant
difference was observed with sIL-2R (P < 0.0001
vs. long term replacement therapy). Nevertheless, most
sIL-2R values (35 of 37) recorded in patients at visit II overlapped
the normal range matched for age and sex.
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During low dose L-T4 treatment
(visit III), TSH levels were suppressed in 80% of patients and
symptoms of hypothyroidism were still present, although total and free
T4 and T3 were
significantly increased compared to the values off therapy (Table 3). Specifically,
FT4 remained in the hypothyroid range in most
patients (73%), whereas TT4,
FT3, and TT3 were already
normalized in about 75% of the cases. Among female patients with
normal TT4 levels, no one was receiving sex
steroid replacement therapy.
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All of the other biochemical indexes of peripheral thyroid hormone
action (SHBG, sIL-2R, ACE, ICTP, and BG-P) were significantly affected
by the restoration of L-T4 therapy at
full replacement doses (Table 2). SHBG and the bone markers were
significantly influenced by the sex and gonadal status of the patients
throughout the study period. In fact, SHBG, ICTP, and BG-P were
sensitive indexes of peripheral thyroid hormone action only in
eugonadal males, whereas sIL-2R and ACE were not influenced by the
gonadal status of the patient (data not shown). Furthermore, both BG-P
and ICTP were significantly lower in patients treated with cortisone
acetate than in untreated patients [P < 0.05 for both
markers; BG-P 16.5 ± 6.0 and 23.5 ± 3.8 ng/mL for treated
(C+) and untreated (C-) patients, respectively; ICTP, 2.7 ± 2.2
and 4.6 ± 3.0 µg/L, respectively]. Of note, highly significant
correlations were observed between most of these indexes
(i.e. CK, sIL-2R, SHBG, ACE, BG-P, and ICTP) and
FT4 or FT3 [values
recorded at visit II (off L-T4) and
visit V (on L-T4)]. The highest
correlation was observed in all cases with FT3,
in particular between FT3 and either sIL-2R
(P < 0.0001; r = 0.62) or the bone markers ICTP
(P < 0.005; r = 0.36) and BG-P (P
< 0.0001; r = 0.56; Fig. 1).
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When examined individually, two patients had borderline low FT4 and FT3 levels at visit I. At visit IV, when treatment was restored at previous doses, FT4 and FT3 levels were still in the hypothyroid range. Then, the L-T4 daily dose was increased by 25 µg, and FT3/FT4 levels were clearly into the normal range at visit V. In these two patients, the levels of the indexes of thyroid hormone action (including sIL-2R and CK) were within the normal range both at baseline and after adjustment of the L-T4 daily dose. Both undertreated subjects suffered from asthenia that partially improved by increasing L-T4 dose.
Conversely, five patients showed circulating levels of FT3 above the upper limit of the normal range at visit I despite the lack of signs or symptoms of overtreatment. At visit IV, when treatment was restored at previous doses, FT3 levels in the upper limit of normal range were confirmed in only three cases (FT3 range, 8.3–8.6 pmol/L), who showed normal FT4 and high sIL-2R levels (sIL-2R range, 1234–1513 U/mL). The L-T4 daily dose was then reduced in these three patients by 25 µg, and 3 months later (visit V), normalization of FT4, FT3, and sIL-2R was observed.
The mean daily dose of L-T4
replacement therapy in patients defined as euthyroid on the basis of
free thyroid hormones and peripheral indexes of thyroid hormone action
at the end of the study was 1.5 ± 0.3 µg/kg (visit V). Figure 2 indicates the mean daily dose observed
in patients less than 60 yr of age (1.6 ± 0.3 µg/kg BW; range,
1.1–2.3 µg/kg BW) and in patients more than 60 yr of age (1.3
± 0.2 µg/kg BW; range, 1.1–1.8 µg/kg BW). Moreover, no difference
was found according to sex or the origin (pituitary or
hypothalamic) of the disease.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Data obtained during L-T4 withdrawal clearly indicate that the classic features of hypothyroidism assessed in the clinical examination of CH patients are similar to those of primary hypothyroidism, but are less specific because associated hormonal deficiencies may contribute to the clinical picture. The most reliable marker of hypothyroid state in patients with hypothalamic-pituitary diseases is serum FT4, which is below the normal range even in asymptomatic patients. Serum FT3 remained within the normal range in about 25% of the patients with low FT4. This situation is similar to that found in primary hypothyroidism, where a higher production of FT3 takes place. Serum total T4 and T3 levels were in the normal range in an even higher percentage of patients, showing the unreliability of total thyroid hormone measurement in the diagnosis of central hypothyroidism. Provided that free thyroid hormones are assessed by direct methods and avoiding analog techniques (25), the concomitant measurements of TSH and FT4 appear to be able to reveal the presence of CH in all cases.
The increase in CK and total and LDL cholesterol as well as the decrease in heart rate values recorded during L-T4 withdrawal are similar to the alterations reported in primary hypothyroidism (17, 26, 27). However, the use of these or other parameters of peripheral thyroid hormone action is not suitable for the diagnosis of hypothyroid state in patients with CH.
The optimization of L-T4 therapy monitoring is important for the long term quality of life of CH patients, because both over- and undertreatment may increase the risk of developing complications of pituitary failure. L-T4 overtreatment may contribute to a premature osteoporosis already due to associated gonadotroph and GH deficiencies (15, 28, 29, 30, 31, 32), whereas L-T4 undertreatment might increase the higher cardiovascular risk due to GH deficiency.
Our study indicates that in CH patients, the monitoring of L-T4 therapy should be a combination of free thyroid hormones (FT4 and FT3) and some biochemical indexes of thyroid action. The clinical evaluation did not provide any specific parameter to be used for the follow-up of such patients. In fact, values of FT3 above the normal range could be observed despite normal FT4 values; thus, FT3 appears more sensitive than FT4 to disclose L-T4 overtreatment in these patients. This suggests that the use of daily doses of L-T4 able to restore FT4 values in the upper normal range, as previously recommended (28), may lead to L-T4 overtreatment. The serum FT4 level is the more appropriate marker for the disclosure of L-T4-undertreated CH patients.
The strong correlation observed between sIL-2R levels, which are independent from gonadal status and glucocorticoid replacement, and free thyroid hormone levels makes this measurement the most suitable additional index of thyroid status in CH patients. Although its measurement in the disclosure of L-T4 undertreatment is deceiving, its longitudinal evaluation appears more useful for the identification of L-T4-overtreated patients. In fact, the longitudinal evaluation of sIL-2R has shown abnormally high values in three overtreated patients, returning within the normal range after the reduction of the L-T4 daily dose. In contrast, SHBG measurement is not indicated because its secretion is greatly influenced by gonadal status (low levels in hypogonadal females and high values in women taking estrogen replacement therapy and in hypogonadal males) and somatotroph function. In this series, it was accurate only in eugonadal males. Bone metabolism is also known to be regulated by multiple factors, including GH, sex steroids, and glucocorticoids (32). Data from the present study show that bone turnover is significantly decreased by standard glucocorticoid replacement therapy, i.e. cortisone acetate. Similar findings have been reported in Addisonian patients (33), thus indicating that BG-P and ICTP should be interpreted with caution in patients treated with glucocorticoids, even at physiological replacing doses. Serum ACE levels did not appear to be influenced by other hormone deficiencies; however, they are affected by a variety of other nonendocrine pathological conditions (18, 34) and lack sufficient specificity in the evaluation of the thyroid status. As far as the routine biochemical parameters are concerned, the use of hypercholesterolemia as an index of L-T4 undertreatment is hampered by the fact that about 50% of patients receiving adequate L-T4 replacement therapy showed high cholesterol levels due to either unreplaced GH deficiency or other alterations of lipid metabolism. On the contrary, the measurement of serum levels of CK along with FT4 and FT3 may be useful in the disclosure of L-T4 undertreatment.
With regard to L-T4 dose, in patients with primary thyroid disorders, replacement or suppressive effects are usually achieved with daily L-T4 doses of about 1.2–1.8 and 1.5–2.5 µg/kg BW, respectively; the effective dose is lower in older subjects (11). In our series of patients affected by CH, the adequate L-T4 replacement dose had been individually attained before patients entered the study (see visit I), and very few changes in the treatment schedule were made during the follow-up. When indexed for body weight, the L-T4 daily dose was unexpectedly variable (from 1.1–2.3 µg/kg BW), although the mean daily dose was lower in patients over 60 yr of age (1.3 µg) compared to younger patients (1.6 µg), as reported in subjects with primary hypothyroidism (11). Consequently, according to our data, the starting L-T4 daily dose should be established taking into account the age, but not the sex, of the patients, considering the presence of other pituitary hormone deficiencies and pharmacological treatments (such as antiseizure drugs) (15, 28). Thus, the starting L-T4 daily dose in all patients should be 25 µg/day·2–3 weeks and then increased up to about 1.1 µg/kg BW in patients more than 60 yr of age and 1.3 µg/kg BW in those less than 60 yr of age and subsequently adjusted according to the biochemical parameters described above. It should be noted that before L-T4 therapy is initiated, the need for glucocorticoid replacement therapy should be assessed, and adequate treatment with cortisone acetate started if necessary.
In conclusion, our results indicate that the diagnosis of CH is reached at best by measuring serum TSH and FT4 concentrations. As far as the most reliable parameters for monitoring the adequacy of L-T4 replacement therapy in patients with CH are concerned, measurements of serum FT4 and FT3 are both necessary. In addition, serial evaluation of some indexes of peripheral thyroid hormone action can contribute to a more accurate disclosure of over- or undertreated patients, helping to avoid therapeutic adverse effects. This is of particular importance when taking into account the wide range of L-T4 replacement dose observed in our CH patients due to the influence of age, weight, concomitant hormone(s) deficiency, or other treatment(s). The present findings represent a new contribution that may be useful for the clinical management of CH patients, as only few, and somehow discordant, guidelines for the treatment of this condition are available.
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Acknowledgments |
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Footnotes |
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Received July 7, 1998.
Revised November 9, 1998.
Accepted December 8, 1998.
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