David H. Ingbar
Respiratory manifestations are seldom the major complaint of patients with hypothyroidism; nonetheless, the pulmonary system may be affected in many ways. Fatigue and dyspnea on exertion are frequent symptoms (1). Occasionally, pulmonary involvement is major and life threatening, as in the patient with myxedema coma and CO2 retention.
The roles of thyroid hormone in lung development, respiratory muscle function, and regulation of ventilation during sleep and wakefulness are of interest to multiple specialties. All these subjects are brought together in the patient with hypothyroidism. This chapter examines the ways that the respiratory system can be affected in hypothyroid patients. The pulmonary consequences of hypothyroidism can be categorized as those that directly affect the lung and those that result from changes in the function of other organ systems. Table 54.1 classifies these consequences.
TABLE 54.1. PULMONARY CONSEQUENCES OF HYPOTHYROIDISM
Altered pulmonary function tests
Increased (A-a) O2 gradient
Decreased DLCO (?)
Decreased maximal exercise capacity
Depressed ventilatory drives
Decreased surfactant production in the neonate
Upper airway obstruction (goiter, enlarged tongue, or pharyngeal muscle dysfunction)
Sleep apnea syndrome, obstructive > central type
Phrenic nerve paralysis
Neuromuscular weakness or dyscoordination (?)
Obesity causing atelectasis
Congestive heart failure causing pulmonary edema
Difficulty in weaning from mechanical ventilation
Tendency toward theophylline intoxication
A-a, alveolar-arterial; DLCO, diffusing capacity of the lung for carbon monoxide.
ALTERATIONS IN PULMONARY FUNCTION IN ADULTS
Pulmonary Function Tests and Gas Exchange
Analysis of changes in pulmonary function is complicated by an increased frequency of obesity in hypothyroid patients. Abnormalities attributed in the literature to hypothyroidism actually may have been due to obesity. Obesity alone frequently may decrease one of more of the following: diffusing capacity of the lung for carbon monoxide (DLCO), vital capacity (VC), total lung capacity (TLC), functional residual capacity (FRC), and especially expiratory reserve volume. All these abnormalities do not necessarily occur together in the individual patient.
In an old study contrasting patients with either hypothyroidism alone or hypothyroidism accompanied by obesity, the 16 patients with hypothyroidism alone had normal lung volumes and arterial blood gases (ABG), but decreased DLCO (2). After replacement with thyroid hormone, the patients lost a mean of 6 kg from their initial mean weight of 71 kg, and the DLCO returned to normal. Pretherapy, patients with hypothyroidism and obesity had hypercapnia (arterial PCO2 55 mm Hg), hypoxemia (83% oxygen saturation), and diminished lung volumes, DLCO, peak expiratory flow rate, and maximal voluntary ventilation. After hormone replacement and weight loss, the DLCO, Paco2, and lung volumes returned to normal.
The few studies of resting pulmonary function in nonobese patients with hypothyroidism have found minor abnormalities; they included a decrease in VC, slightly decreased Pao2, a decreased DLCO corrected for hemoglobin, and a widened alveolar-arterial (A-a) DO2 (oxygen partial pressure) gradient. Some researchers propose that microatelectasis that is not radiographically visualized exists and that this results from either respiratory muscle weakness or a deficiency of surfactant; altered muscle function, abnormal surfactant production, or an opening of anatomic shunts in the lung has not been documented.
Many patients with hypothyroidism complain of fatigue and exercise intolerance. These subjective sensations could arise from limited pulmonary reserve, limited cardiac reserve, decreased muscle strength, or increased muscle fatigue. Although there are few clinical studies of exercise in hypothyroid patients, the most detailed study suggested that the primary problem is cardiac limitation resulting from an inability to increase stroke volume (3). Maximal oxygen consumption and workload were diminished significantly, and arterial lactate levels rose more than normal. Abnormalities of blood flow distribution, especially to muscles, also may be present. On return to euthyroid status, some, but not all, exercise parameters returned to normal. For example, the A-a O2 gradient worsened, and the lactate levels remained high (3).
Hypothyroid rats have decreased endurance. Biochemical changes observed have included decreases in muscle oxidation of pyruvate and palmitate, with more rapid use of glycogen stores and diminished fatty acid mobilization (4), and increased activity of enzymes of glycolysis, the tricarboxylic acid cycle, and fatty acid oxidation in resting diaphragm muscle (5).
Hypothyroidism may reduce the severity of dyspnea in patients with severe chronic obstructive pulmonary disease (COPD) (6,7). However, these reports provide little information on changes in pulmonary functions, ABG, responses to exercise, or ventilatory drives. One study of 10 euthyroid COPD patients treated with carbimazole in a double-blind crossover trial found no effect on ABG, dyspnea, 12-minute walking distance, or resting minute ventilation (8). It is unknown whether the increased dyspnea with an increase in thyroid hormone results either from greater work of breathing with higher minute ventilation or from a mismatch of increased ventilatory drive to breath more than the augmented ventilatory capacity.
In summary, limited data suggest that decreased stroke volume and cardiac output play greater roles than pulmonary dysfunction in limiting the exercise capacity of hypothyroid patients. The roles of abnormal muscle function, blood flow distribution, and energy metabolism are not yet well defined. Some patients with severe lung disease may have increased dyspnea upon correction of hypothyroidism as a result of increases in either oxygen consumption or ventilatory drive.
Patients with myxedema coma first were noted to retain CO2 in the late 1950s (9), and in the mid-1960s diminished ventilatory responses to hypercapnia in hypothyroidism were reported, which improved after thyroid hormone replacement therapy (10,11). This finding led to interest in ventilatory control in hypothyroid patients without myxedema coma.
Ventilatory drive is the net output of the respiratory centers in response to a given physiologic stimulus, as measured indirectly by examining the change in function of the pulmonary system when the respiratory center input is changed. Ventilatory drive output measured as ventilatory response to either progressive hypercapnia (HCVR) or isocapneic hypoxia (HVR) includes minute ventilation (liters per minute), transdiaphragmatic pressure (Pdi), percentage of inspiratory time per respiratory cycle, diaphragmatic electromyogram (EMG), and inspiratory mouth occlusion pressure in the first 0.1 second (Po.1).
Patients with hypothyroidism have depressed HVR and HCVR (12). In one study, the HVR was more severely depressed in the patients with idiopathic primary hypothyroidism, but both the HVR and HCVR rapidly returned to normal with therapy. In patients with iatrogenic hypothyroidism, the HVR, but not the HCVR, increased significantly after 3 to 9 months of therapy but did not return to normal. Lung volumes and ABGs did not improve with therapy in either group, and muscle weakness was not assessed.
In the largest study, ventilatory drive was decreased in 34% of 38 hypothyroid patients (13). Depressed responses to hypercapnia or hypoxia often did not occur in the same patients. In almost all these patients, ventilatory drive normalized after 1 week of replacement therapy, and HVR often returned more rapidly than HCVR.
A detailed study (14) of 13 patients with severe hypothyroidism identified two abnormal patient subsets with slight overlap: muscle weakness and depressed ventilatory drive. Seven patients had a normal ventilatory drive, but four of them had decreased maximal inspiratory pressures (Pimax). The other six patients had decreased HCVR, as assessed by minute ventilation and diaphragmatic EMG, but only two Pimax. The HCVR increased after thyroid hormone replacement, but Pimax did not increase in patients with low pretreatment values. These results suggest that the low HCVR in some patients is not due to impaired respiratory muscle function, but is more likely a central nervous system effect. The lack of correlation between respiratory muscle strength and ventilatory drive indicates that these abnormalities occur independently and are not directly related.
In summary, patients with hypothyroidism often have depressed HVR or HCVR. Usually, there is rapid reversibility of at least the hypercapneic component with hormone replacement. The mechanism by which thyroid hormone influences ventilatory drive is unknown. It also is unclear why these changes occur only in some patients.
PULMONARY FUNCTION IN MYXEDEMA COMA
The role of pulmonary dysfunction resulting from hypothyroidism in causing myxedema coma is not clearly defined and remains controversial. Not only is coma a rare complication of hypothyroidism, but the analysis of cause and effect is difficult. Depressed ventilatory drive also may result from the central nervous system damage causing coma, obesity–hypoventilation syndrome, chronic CO2 retention, or sleep apnea. The many other potential precipitants of coma in hypothyroidism include decreased cerebral oxygen delivery, sedative and respiratory depressant drug treatment, hyponatremia, adrenal insufficiency, infection, heart failure, hypoglycemia, and hypothermia (15,16,17). Because many of these factors occur together in the seriously ill patient, it is difficult to ascribe causality to a single factor. Hypercapnic patients with myxedema coma almost always have at least one other factor causing hypoventilation, such as lung disease, central nervous system disease, neuromuscular weakness, obesity, kyphoscoliosis, or pleural restrictive disease (11,18).
In summary, all reported cases of myxedema coma with severe CO2 retention have had at least one additional potential cause for hypoventilation. Although some causes of hypoventilation, such as respiratory depressant drug treatment, are avoidable, most are not. It seems likely that hypothyroidism contributes to coma in some patients by decreasing the HVR and HCVR. Alone, however, it probably is not sufficient to cause CO2 retention and thereby precipitate myxedema coma. Thus, a careful review of all potential contributing causes of an elevated Paco2 is worthwhile in the patient with respiratory failure and myxedema coma.
Effusions may occur at many sites in patients with hypothyroidism. Most common among them is the pericardial space, but peritoneal, pleural, middle ear, and uveal effusions also occur (19,20,21). Whereas pericardial exudative effusions are typical, in the few well-characterized cases with hypothyroidism as the sole cause of pleural effusion, both transudates and exudative pleural effusions are well reported (22). In most patients, congestive heart failure, pericardial effusion, or transdiaphragmatic passage of ascitic fluid contributes to the pleural effusions (22). The pleural effusion in patients with hypothyroidism may be either bilateral or unilateral, it is usually small, and it usually does not cause symptoms (22,23). Chylous effusions occur rarely in hypothyroidism.
The reason effusions occur in patients with hypothyroidism is not well established, but changes in the capillaries may be involved. Extrapulmonary capillary structure is altered in patients with hypothyroidism, with a probable decrease in number, a narrowed diameter (24), and an increase in permeability (25). No histopathologic studies of the pulmonary capillary bed in patients with hypothyroidism have been done.
SLEEP APNEA AND OBESITY–HYPOVENTILATION SYNDROMES
Sleep apnea syndrome (SAS) is prevalent in the population, and obesity is a major predisposition. The three forms of SAS are obstructive, central, and mixed sleep apnea. In obstructive apnea, decreased ventilatory drive is a secondary consequence of the effect of recurrent hypoxia on brain neurochemistry.
Obesity–hypoventilation syndrome (or pickwickian syndrome) is defined as daytime resting hypercapnia while awake and upright in obese individuals with normal pulmonary function and no underlying lung disease. Their diminished ventilatory drive may be a primary pathogenic factor or acquired from a chronic increase in PaCO2, neurologic dysfunction, hypoxemia, or increased work of breathing with an increased ventilatory load.
How are these two disorders related to hypothyroidism? Many patients with myxedema coma described in the 1960s were obese and probably had the obesity–hypoventilation syndrome. It is not surprising that the increased work of breathing and increased CO2 production rate found in obese patients combine with the diminished HCVR in patients with myxedema to cause CO2 retention.
Hypothyroidism is a well-recognized cause of obstructive sleep apnea (OSA) (26,27,28). In all reported cases, the patient's sleep apnea responded to thyroid therapy or weight loss. Sleep apnea may improve with treatment of hypothyroidism without weight change (29). The moderate degree of weight loss with thyroid replacement probably is not sufficient to account for significant improvement in sleep apnea (26). The prevalence of sleep apnea in hypothyroidism is not well defined. Recent studies of 1,000 and 290 sleep clinic found that 1.2% to 2.4% of patients diagnosed with OSA had undiagnosed hypothyroidism (30,31,32). Conversely, 9 of 11 consecutive patients newly diagnosed with hypothyroidism had sleep apnea, with much worse severity of apnea in the six patients who also were obese (28). All patients improved significantly, with a sixfold reduction in sleep apnea after thyroxine (T4) replacement, even without weight loss. Ventilatory drive also increased after therapy. Of 26 consecutive Finnish patients with hypothyroidism screened with polysomnography, nocturnal breathing abnormalities were seen in 50% and severe obstructive apnea in 7.7% (29). However, male sex and obesity were stronger independent predictors of nocturnal breathing abnormalities than hypothyroidism.
Hypothyroidism may predispose to upper airway obstruction by several mechanisms: increased size of the tongue and other pharyngeal skeletal muscles, a slow and sustained pharyngeal muscle contraction pattern, or diminished neural output of the respiratory center. Most patients have had an enlarged tongue. Decreased neural output likely plays a role in some patients, because there may be a favorable response to the respiratory stimulant medroxyprogesterone alone (26). One hypothyroid patient with purely central sleep apnea has been reported (33).
UPPER AIRWAY EFFECTS
Minor complaints referable to the upper airway, ear, nose, and throat are common in hypothyroidism. Patients frequently have nasal stuffiness, recurrent colds, voice change, foreign body sensation, and discomfort or dryness of the throat (34). However, it is not proven that these complaints truly are more prevalent in hypothyroidism, and their cause is uncertain. Secretion of nasal mucus may be increased, and 20% of patients have tonsillar enlargement. Although myxedematous thickening of the vocal cords or larynx or stretching of the recurrent laryngeal nerves by an enlarging thyroid gland have been proposed, little evidence supports either theory.
Hypothyroid myopathy may involve the respiratory muscles and the diaphragm, slowing contraction and relaxation and decreasing maximal power. It can occur in either children or adults. In adults, it may be accompanied by an increased muscle volume, in which case it is known as Hoffman's syndrome.
Respiratory muscle dysfunction clinically manifests as hypoventilation, atelectasis, or easy fatigability. Values for many classic pulmonary function tests usually decrease: peak expiratory flow, compliance, DLCO, Pimax, and all lung volumes except residual volume (RV). The RV/TLC ratio increases, and the PaCO2may be elevated. The most sensitive readily available test of diaphragmatic function is measurement of Pimax and maximal expiratory pressure (Pemax). The Pdi and diaphragmatic EMG are noninvasive methods for early detection of myopathy.
Diaphragm dysfunction resulting from hypothyroidism was reported in the 1980s (35,36). The abnormalities returned toward or to normal with thyroid replacement therapy, although there also was an average 7 kg weight loss. In 43 hypothyroid patients, the mean pretreatment values for VC, forced vital capacity, and forced expiratory volume in 1 second were within the normal range, but each variable increased significantly after thyroid therapy (37). Before treatment, both the Pimax and Pemax were reduced. After 3 months of treatment, there was almost a 50% increase in both pressures, even though only half the patients had normal serum thyrotropin (TSH) concentrations and there was almost no mean weight change. It is difficult to estimate the prevalence of respiratory muscle dysfunction in hypothyroidism, but this study suggests it may be common. Other respiratory system abnormalities (e.g., obesity, ventilatory drive) need to be looked for carefully in these patients, because they also generate a restrictive physiologic pattern and predispose to hypoventilation and a shallow, rapid respiratory pattern.
The mechanism of thyroid myopathy remains undefined. The activity of muscle 1,4-glucosidase (acid maltase) may be decreased. This enzyme also is deficient in Pompe's disease, the rare, recessive disease of generalized glycogenolysis; these patients may present with acute hypercapneic respiratory failure without glycogen accumulation in the heart, liver, or brain (38). Hamsters have a recessive genetic dystrophy accompanied by abnormal thyroid metabolism, decreased ventilatory drive, and abnormal diaphragm morphology and function (39). Hypothyroidism also may alter the balance of fast and slow muscle fibers in the diaphragm, favoring slow fibers; type I heavy-chain myosin (40,41) shifting the myosin heavy chain isoforms (42), or the expression of peroxisome proliferator–activated receptor gamma coactivator 1-alpha (43). Hypothyroid rats also have significantly reduced maximal shortening velocity, tension, and specific force of the diaphragm.
Two patients with orthopnea and dyspnea on exertion had bilateral phrenic nerve paralysis resulting from hypothyroidism (44). One patient had return of normal phrenic nerve function after 4 months of thyroid hormone therapy. The other patient died in an accident; autopsy revealed demyelination and fibrosis of the phrenic nerves.
In summary, weakness of the diaphragm is likely one of the most common respiratory system abnormalities of hypothyroidism.
MISCELLANEOUS PULMONARY CONSEQUENCES OF HYPOTHYROIDISM
Hypothyroidism slows theophylline metabolism and therefore predisposes patients to theophylline intoxication if they are given usual daily doses (45). Hypothyroidism may limit weaning patients from mechanical ventilation by a combination of the mechanisms discussed previously: decreased VC, respiratory muscle weakness, decreased ventilatory drive, and pleural effusions. Screening of 121 ventilator-dependent patients in a long-term ventilator care unit found four hypothyroid patients (46). The weaning of three of these patients was facilitated by treatment of their hypothyroidism. Finally, the response to sepsis may be altered by hypothyroidism. Rats with hypothyroidism and sepsis had decreased survival, as compared with euthyroid septic rats (30% vs. 65% survival), possibly related to decreases in oxygen consumption (47) or more severe pulmonary edema (48).
LUNG MATURATION AND SURFACTANT PRODUCTION
After the pioneering discovery that glucocorticoids accelerated surfactant production by type II pneumocytes, studies in the early 1970s demonstrated that thyroid hormone accelerates surfactant production and fetal lung maturation (49,50). The role of the thyroid hormones in lung development and their effects of thyroid hormones on type II alveolar epithelial cells are discussed in Chapter 32, but studies important for understanding the consequences of hypothyroidism on developmental lung problems are summarized herein.
Injection of T4 into rabbit fetuses in utero led to earlier appearance of both surface-active material in lung washes and lamellar bodies in type II alveolar epithelial cells (50). Exogenous T4 given subcutaneously to adult rats for 14 days increased type II cell size, lamellar body size and number, and surfactant per unit wet weight of lung; hypothyroidism led to the converse changes (49). Acceleration of fetal lung maturation and surfactant production occurs in many in vitro model systems, including fetal rat lung explants and cultures of mixed fetal rabbit lung cells or fetal type II cells (51,52). The ability of triiodothyronine (T3) or T4 to cross the placenta in different species remains controversial, although small quantities of T4 do so (53). It is not clear whether it is fetal or maternal hormone that may be physiologically important in normal development or whether T3 or T4 is involved. A T4 analogue that readily crosses the placenta, 3,5-dimethyl-3′-isopropyl-l-thyronine, increases fetal rabbit phosphatidylcholine synthesis (54). Exogenous thyrotropin-releasing hormone (TRH) also crosses the placenta. Lung lavage from the fetuses of mothers given TRH displayed increases in phosphatidylcholine, total phospholipids, and the phosphatidylcholine:sphingomyelin ratio (55). The lung tissue itself did not reveal a change in any of these variables, suggesting an effect on surfactant release but not synthesis. Whether or not thyroid hormones affect the production of any of the surfactant apoproteins is uncertain.
Beyond promoting early alveolar development before birth, thyroid hormones modulate postnatal alveolar development. Rat pups given exogenous T3postnatally have a greater than normal increase in their alveolar gas exchange surface area and the surface:volume ratio, whereas postnatal propylthiouracil (PTU) has the opposite effect (56).
Other hormones interact with thyroid hormones to influence lung development. Thyroid hormones may potentiate glucocorticoid promotion of surfactant and lung maturation (57,58,59,60). In fetal sheep, the β-adrenergic-induced increase in lung liquid resorption that normally occurs before birth is inhibited by fetal thyroidectomy (61). In vitro, dexamethasone, T3, and theophylline synergistically promote phospholipid release in organ cultures of fetal rat lung explants (60,62), human lung explants (62,63), and fetal rat cells in vitro (57). This combined effect is faster and greater than the impact of glucocorticoids alone (59).
Although thyroid hormones can affect lung lipid biosynthesis, their physiologic roles in normal lung maturation and surfactant synthesis are not clear and may differ at different ages. The responsible form of the hormone also is uncertain. In the adult, this is likely to be T3 rather than T4, because high-affinity nuclear receptors for T3 exist in lung cells (55,64). T3 stimulates transcription and activity of the key surfactant phospholipid synthesis enzyme cholinephosphotransferase (65) and may act at other biochemical loci. Finally, the effects of thyroid hormones could be exerted indirectly, such as serving as a permissive factor in the regulation of lung β-adrenergic receptors (66), or potentiating the action of glucocorticoids or fibroblast-pneumocyte factor. Multiple steps in type II pneumocyte development and surfactant synthesis likely are regulated in a complex and interactive fashion by different hormones, including thyroid hormones.
In summary, there is good in vitro evidence for thyroid hormone stimulation of type II pneumocyte differentiation and function in the fetus and adult. The in vivo physiologic significance of thyroid hormones in this role, however, apart from interactions with glucocorticoids, is not yet clear for any age group. Their significance may depend on the stage of lung development.
RESPIRATORY DISTRESS SYNDROME OF THE NEWBORN
The stimulation of surfactant production by type II pneumocytes by thyroid hormones raises the question of whether hypothyroidism in utero or in the early postnatal period contributes to the pathogenesis of respiratory distress syndrome (RDS) in preterm infants. Preterm infants at less than 30 weeks have lower initial and postnatal surge thyroid hormone levels than full-term infants (67). Early studies supported an association of hypothyroidism with an increased frequency of RDS. Cord serum values for total T4 and free T4 index were lower in premature infants with RDS than in premature infants without RDS (68). In premature infants born at 33 to 37 weeks with and without RDS, those with RDS had lower values for serum T3, and free T3 index; serum TSH levels and the T4:T3 ratio were increased, but the free T4 index was unchanged (69). The same investigators later reconfirmed these results, except that the postnatal TSH surge in infants with RDS was less than that in control infants of the same gestational age (70).
Other data raised uncertainty about the physiologic significance of these associations. Klein and colleagues found that the initial cord serum TSH levels and the increases after birth were the same in RDS and normal premature infants, although the increase was less than that seen in mature-term infants (71,72). The reverse T3 level gradually increased after birth only in the infants with RDS. A later case control study (73) showed a lower cord serum T3level at birth in the infants with RDS but no difference in serum total, reverse T3, or TSH levels. Lower fetal and neonatal T3 levels may have been due to altered peripheral thyroid hormone metabolism associated with nonthyroidal illness, rather than hypothyroidism, given the lack of an elevated serum TSH level. The incidence of RDS has not been explained as a function of maternal thyroid status. Thus, the role of fetal hypothyroidism predisposing to RDS is uncertain.
Treatment with thyroid hormone for prevention of RDS in high-risk premature infants has been studied. In a small number of infants, intra-amniotic injection of 200 µg of T4 was performed in eight mothers with nine fetuses at high-risk for RDS who required early delivery (73). In seven of eight cases, repeat amniocentesis yielded fluid with improved parameters of fetal lung maturity. None of the nine fetuses developed RDS, but no control group was included in this study. Eighteen mothers with severe toxemia of pregnancy received intra-amniotic injections of T4 for immature amniotic lipid profiles (74). Within 24 hours, the lecithin:sphingomyelin ratios of the amniotic fluid increased at least twofold in all cases. Only one child died, and none of the others had RDS. In a recent randomized trial of postnatal oral or intravenous T4 treatment of 49 newborns less than 32 weeks' gestation, there was no benefit of T4 on chronic lung disease or other complications of prematurity (75).
Another important question is whether there is an additive or synergistic effect on lung maturation when thyroid hormone and glucocorticoids are given in combination. In vitro studies suggest that there may be little additive benefit in midgestation. Thyroid hormone also may have adverse effects, slowing increases in lung glycogen stores (76) and antioxidant enzymes (77). Inhibition of thyroid hormone synthesis with PTU in premature rats increased their antioxidant enzymes and promoted survival in hyperoxia (78). In contrast, considerable experimental data suggest that combined use of thyroid hormone and glucocorticoids accelerates lung epithelial maturation, surfactant production, and surfactant release (79). Two early randomized clinical trials used maternal antenatal treatment with TRH combined with glucocorticoids. Combined therapy reduced adverse outcomes, including ventilator days and bronchopulmonary dysplasia (80,81). However, despite these encouraging results, large trials of combining either TRH or T3 with glucocorticoids have not shown large clinical benefits thus far. The North American TRH Study Group found that antenatal maternal administration of TRH and glucocorticoids was not more beneficial in reducing infant RDS, death, or chronic lung disease than treatment with glucocorticoids alone (82). Infants of TRH-treated mothers had reduced postnatal surge in serum TSH and T3 concentrations, but recovered within 28 days. The THORN trial of T3 and hydrocortisone treatment of preterm infants of less than 30 weeks' gestation did not demonstrate outcome benefits of T3 treatment, but higher serum free T3 or T4 levels were statistically associated with better outcome (83). Despite these discouraging results, intra-amniotic combined therapy enhances lung maturation in the preterm rhesus fetal monkey compared with maternal injection (84). Thus, studies of combined treatment should not yet be abandoned.
The complex interactions of thyroid hormones with multiple other hormone systems during fetal lung development are not yet well defined. Clearly, thyroid hormones can influence development of the lung and the response to prematurity, but to affect development favorably, the degree of benefit, optimal timing, and best agent for exogenous stimulation of the fetal thyroid axis need to be determined. Clinical studies thus far do not support an additive or synergistic effect of combined thyroid axis and glucocorticoid treatment. Because complications of perinatal glucocorticoid therapy are being appreciated, there still is a potential role for thyroid hormone prevention or treatment of the lung disease of prematurity.
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