H. Lester Reed
The environment in which humans live and work can be defined as a complex of climatic, terrestrial, and biotic factors that act upon an organism to determine its form and survival. Accumulating evidence over the past three decades now supports the concept that human physiology acclimates to changing environmental factors, such as temperature (1,2), photoperiod (3), altitude (4), gravity (5,6), season (7,8,9,10), and time zone (11). Understanding the influences of these changes upon thyroid hormone economy may help with our insight into a seasonal presentation of thyroid cancer (12,13), interpreting repeated measures of thyroid function, planning clinical studies, and predicting the hormone changes for pregnancy and nonthyroidal illness (see Chapter 80). These extrinsic influences on iodothyronine homeostasis may be characterized as direct, which include cold (14,15,16) and warm (17) temperature, photoperiod (3), altitude (18), and microgravity (6); or more interactive, which include exercise (19), sleep (20,21), nutrition (22), age (see preceding section), pregnancy (see Chapter 80), illness, depression, and toxic or geographic radiation exposure (see Chapter 70). Under usual circumstances, humans cannot completely isolate themselves from many direct factors, such as temperature (22,23), photoperiod (3,9,10,11), and altitude (18,24,25,26).
Although detailed studies are possible using small rodents, these models often lack similarity to humans with respect to such basic homeostatic mechanisms as thermal regulation (27,28). Therefore, this review will include human studies and will only reference alternate animal studies when no other data are available. The present review will not address whether the human thyroidal responses to the described environmental changes are adaptive or maladaptive.
EFFECTS OF ENVIRONMENTAL TEMPERATURE
Cold
Physiologic Cold Adaptation
When tested during a cold air tolerance test (1,15,29), humans show physiologic cold adaptation after repeated exposure to either cold water (15) or air (29,30). These characteristics include a decrease in skin and rectal temperature (15), as well as in the threshold for shivering and the blood pressure response with cold air (29). Human adaptation to cold may be observed when only the face, hands, or feet are repeatedly exposed to cold temperatures (15,31).
Thyroid Hormone Responses to Brief Cold Climate Chamber Exposures
Serum iodothyronines and thyrotropin (thyroid-stimulating hormone, TSH) do not change dramatically in adults (32) exposed up to 120 minutes of cold air to when they have not been previously exposed to cold (cold naive) (7,16,30). If the subjects walk at 3 miles per hour in 5°C air for 6 hours, serum total triiodothyronine (T3) and total thyroxine (T4) increase only during the cold air exercise period without a change in TSH (33). These increases are not common with the same amount of or even more severe exercise at 20° to 24°C (see Table 11B.1). After correcting for changes in plasma volume, free T3 and free T4decline following 115 minutes of resting while exposed to cold air without changes in T3, T4, or TSH (15,30). Neonates, however, unlike adults, have substantial thermogenic brown adipose tissue (see Chapter 74) and, in contrast to adults, have an increase in serum TSH during cold air exposure (16,32).
TABLE 11B.1. EFFECTS OF COLD ON THYROID FUNCTION
Cold Exposure Testing
During initialaExposure (0°–5°C)
Following MultiplebExposures (20°–24°C)
During fieldcExprosures (20°–24°C)
Field Time Coursed (Approx. No. Days)
Seasonal Peak Change (Month)
Conditions:
Chambere
Ambientf
Ambiend
T3
≈(↑g)
≈
≈/↓(4%h)
5–30
↑(5%)[IIIi] (Jan.)
free T3
↓
≈/↓
≈/↑(7%)k
35–60k
↑(6%)[IV] (Mar.)
UT3
N/A
N/A
N/A
N/A
↑(23%) (Feb.)
T4
≈(↑g)
≈
≈(4%)
60–140
↑(Nov.–Jan.)
free T4
≈/↓
≈
≈/↓
60–140
↑(Mar.)
TBG
≈
≈
≈/↑
60–120
N/A
TSH
≈
≈
↑(15%–30%)
70–140
↑(14%)[III] (Dec.)
Tg
N/A
N/A
↑(17%–30%)
70–140
N/A
T3 PAR
N/A
↑
↑↑
14–30
N/A
T3 PCR
N/A
↑
↑↑(15%–180%)
14–30
N/A
T3 Vd
N/A
≈
↑↑(100%–300%)
70–140
NA
T4 PAR
N/A
↑
≈
12–14
NA
Adaptedj
No
Yes
Yes
10–14
Sep.
Reference no.
14,29,33,34,82
14,15,16,29,30,32,34
16,34,37,38,39,40,46
15,16,23,31,38,39,40,41,42,99,101
23,48,98
↑, increased; ↓, decreased;, no change; FT3, free triiodothyronine; FT4, free thyroxine; N/A, not available; PAR, plasma appearance rate; PCR, plasma clearance rate; TBG, thyroxine-binding globulin; Tg, thyroglobulin; TSH, thyrotropin; TT3, total T3; TT4, total T4; UT3, urinary T3; Vd, distribution volume.
aSubjects never exposed to experimental cold-air testing.
bSubjects with repeated exposures to cold air in an environmental chamber.
cSubjects tested after cold exposure from their occupation or geographic relocation.
dPer changes in the “During field” category.
eStudies during a cold-air challenge test.
fStudies conducted after cold-air challenge.
gChange summarized as increased (↑), decreased (↓), or no changes.
hPercentages indicate change from the annual mean.
iRoman numerals indicate the northern hemisphere seasonal time sequence.
jThe presence or absence of hypothermic cold adaptation.
kStudies in references 34 and 38. The comparisons of changes are between conditions of either before and after the chamber studies, before and after the geographic relocation, between cold-exposed and non-cold-exposed occupations, and percentage change from the annual mean. Intrinsic and Extrinsic Variables
Thyroid Hormone Responses to Repeated Cold Chamber Exposures
Subjects undergoing multiple (14,15,30,34) (-20° to 10°C) or extended (10° to 12°C) air exposure for 4 hours to 14 days have changes in both thyroid hormone kinetic and static values. Ingbar and Bass originally reported that in seminude men exposed to cold (11° to 16°C) for 12 to 14 days, organic iodide production more than doubled and radiolabeled T4 degradation increased (16,32). Men exposed briefly to cold air (4°C) twice a day (14) increase their T3plasma clearance rate (PCR) and T3 plasma appearance rate (PAR) by approximately 18% after the first 14 days. All of these men had similar increases in T3PCR and PAR, and all developed cold adaptation, even though half received oral T3 to suppress TSH and free T4 by approximately 50% (14), suggesting that cold-induced T3 PCR and PAR have little dependence on serum TSH and free T4 (14). Following 40 exposures of the legs to cold (4°C) water for 5 to 60 minutes, each over for 30 days, a 115-minute cold air test showed both cold adaptation physiology and decreases in serum T3 (15). This decrease is in general agreement with longer cold air tests (30,34,35) but not shorter ones (29) (Table 11B.1). Factory workers with occupational exposure for approximately 3.5 hours to severe cold (-40° to -20°C) or continuous moderate exposure (-10° to 8°C) for 8 hr/day show a decline in serum T3 by 10% with cold exposure, whereas only with the most severe temperature did T4 decrease (34). Serum T4 was decreased before their daily duties only in the severely cold-exposed group while the free T4 and free T3 values were generally elevated and did not change much with cold exposure in this severely cold exposed group (34). Specific occupational controls and study protocol, subject sex, lack of plasma volume status correction, and free hormone analogue assay differences may account for the discrepancy in free T4 and free T3 values when compared with other studies (15,29,35). The study also reported reverse T3 (rT3) to follow the same pattern as the T3 and T4 decline, thus arguing against the notion that the decline in T3 (15,16,29,34) is from a decrease in PAR or inhibition of iodothyronine 5′-deiodinase type 1 (5′-D1) activity as seen with fasting (22,36) or illness.
Thyroid Hormone Responses to Cold Climate Environmental Field Studies
Results from early field studies are in contrast to more recent publications describing polar residents (35,37,38,39,40) or occupational exposure (34) (Table 11B.2). These prior studies may have been confounded by sleep deprivation (20), dietary changes (22), and plasma volume shifts (15). Extended residence in Antarctica and other high latitude environments is associated with exposures to extremes of photoperiod, low relative humidity, social isolation, and low temperatures, along with seasonal variability (7,31,41,42,43). Humans living in these conditions for approximately 5 months develop cold adaptation (16,35), even though only the hands and face may be directly exposed to outdoor temperatures (15). Furthermore, energy requirements increase by approximately 40%, and appear to be divided between a decrease in exercise efficiency by 22% to 25% and an increase in resting metabolic rate by 11% to 19% (44). Body temperature declines within the first month when compared with measurements taken before deployment to Antarctica (16,31,35,37,40,44). Indigenous populations at high latitudes have basal metabolic rates (BMR) that are approximately 12% higher (42) and energy requirements approximately 35% higher (43) than mid latitude standards. The BMR variances are correlated to serum thyroid hormones in some of these populations (42).
TABLE 11B.2. EFFECTS OF ALTITUDE ON THYROID FUNCTIONa
Altitude
2,315–3,048 m
3,500 m
3,750–3,810 m
4,300 m
5,080–5,400 m
6,300 m
T3
≈
↑(17%–80%)
≈
N/A
↑(16%)
↑(12%)
free T3
↑
N/A
↑
N/A
≈
↑(b)
T4
≈/↓
↑(70%–128%)
↑
↑(PAR)
↑(27%)
↑(44%)
free T4
↑
N/A
↑
N/A
↑(28%)
↑(28%)
T4:T3
≈
↑
N/A
N/A
↑
↑
TSH
≈
≈
N/A
N/A
↑(69%)(c↓)
↑(50%)
TSHTRH
↑
N/A
N/A
N/A
↑(~60%)
TBG
N/A
≈
N/A
N/A
↑(23%)
↑(19%)
RAIU24h
N/A
N/A
↑(80%-100%)
↑(50%)
N/A
N/A
TER
N/A
N/A
N/A
↑(6%)
NA
N/A
Reference no.
24, 25, 59
18
26, 60
61, 62, 69
26, 63
26, 63
↑, increased; ↓, decreased;, no change; free T3, free triiodothyronine; free T4, free thyroxine; N/A, not available; RAIU24h, 24-hour thyroidal radioactive iodine uptake; TBG, thyroxine-binding globulin; Tg, thyroglobulin; TER, total energy requirements; TRH, thyrotropin-releasing hormone; TSH, thyrotropin; TSHTRH, TSH response to a TRH stimulus; T3, total T3; T4, total T4.
aThyroid hormone responses to altitude derived from hypobaric chamber studies and field conditions.
bAltitude adapted at 6, 300 m.
cAcute change within 17 days.
T3 is a likely candidate to mediate some of these effects (14,16). Much of the 24-hour energy expenditure is dependent on skeletal muscle (36), the thermogenic effects of thyroid hormones are becoming more clear (27,28,42,45). T3 is concentrated in muscle, along with theoretical mechanisms of uncoupling energy use (27,28,45). Serum TSH and thyroglobulin (46) increase by about 30% above baseline after 2 to 4 months in Antarctica (16,31,39,40,47), although they retain sensitivity to T3 (40) and T4 (44,46). These hormonal changes are associated with a more than doubling in the T3distribution volume (Vd), PAR, and PCR (37). Small changes in T4 kinetics suggest an approximate 17% decline in the T4 Vd without an increase in the T4 PAR (37). A small decline in free T4 (~6) and can be detected using serial measurements after arrival in Antarctica (39,44,47). These observations suggest a change in T3 kinetics and distribution, initiating a chain of effects that are time dependent (Table 11B.1) (16) and eventually replacing in an equimolar fashion approximately 17% of the T4 pool with T3, thus more than doubling the T3 pool (7,16,37); hence, the term “polar T3 syndrome” (15,35,37). Both the increased T3 PCR and cold adaptation seem independent (14,29) of low serum free T4 and TSH, and the TSH response (34) that subsequently occurs (39). The TSH change may be insufficient in some settings to return free T4 to basal concentrations (16,39,41,44,48). Within the first 4 months of Antarctic residence, memory declines by approximately 13%, a decrement that returns to baseline with the administration of T4 (44). A placebo group continues to display this same decrease in cognition over the next 7 months of Antarctic residence, and the cognitive decline was correlated with a decrease in serum free T4 (44). Elevations in serum TSH, in both U.S. (49) and Chinese Antarctic expeditioners (47), are associated with increases in anxiety and derepression.
Military troops operating in circumpolar locations who are involved in physical exercise with marginal nutritional intake and partial sleep deprivation have declines in serum T3 and T4 regardless of their housing conditions (38,50). free T3 and free T4 are increased after 5 to 10 days (38) and decreased after 60 days (50). T3 PCR and Vd are increased, and TSH is insufficient after 60 days to return free T4 to predeployment concentrations (50). In contrast, soldiers stationed at high latitudes who are relatively sedentary and living in heated quarters show a seasonal change in both total and free T3 and T4 that extends the seasonal change in T3 observed at temperate climates (23,41) (Table 11B.1, Fig. 11B.1). Multifactorial influences such as undernutrition (51), sleep deprivation, and exercise (33) possibly interact to influence the effects of photoperiod and temperature inherent to these high-latitude residents. An element of mild tissue-specific or thyroid receptor isoform-specific (45) hypothyroxinemia (16) may develop in the brain (44) along with a decrease in nuclear T3binding (52) during cold exposure. In addition, possibly similar hepatic changes may occur (39) and neither inhibit the T3 kinetic changes of cold exposure (14) or the development of cold adaptation (15,29).
FIGURE 11B.1. Upper panel: The seasonal periodicity for the northern hemisphere of human serum thyrotropin (TSH) (filled square) and triiodothyronine (T3) (filled circle) as cosinor functions repeated at 366 (p < 0.00004) days for T3 and 169 (p < 0.007) days for TSH are shown. The TSH annual maximum (acrophase) precedes the T3 acrophase by 30 days (p < 0.0002). Lower panel: The season incidence of the presentation for thyroid cancer in Sweden and Norway for over 6,060 patients (open diamond) (p < 0.001); and the seasonal presentation for Graves' disease in Arizona, USA (open square), where 47% of the variability is due to seasonal temperature. (From Maes M, Mommen K, Hendrickx D, et al. Components of biological variation, including seasonality, in blood concentrations of TSH, TT3, FT4, PRL, cortisol and testosterone in healthy volunteers. Clin Endocrinol (Oxf) 1997; 46:587; Lambe M, Blomqvist P, Bellocco R. Seasonal variation in the diagnosis of cancer: a study based on national cancer registration in Sweden. Br J Cancer 2003;88: 1358–1360; Akslen LA, Sothern RB. Seasonal variation in the presentation and growth of thyroid cancer. Br J Cancer 1998;77:1174–1179; and Westphal SA. Seasonal variation in the diagnosis of Graves' disease. Clin Endocrinol (Oxf) 1994; 41:27, with permission.)
Possible Cellular Mechanisms
Human leukocyte nuclear T3 receptor binding increases three- to fivefold when serum free T4 concentrations are decreased during multiple cold exposures (53). Human cytosolic T3-binding proteins retain binding with cold (54). These observations support an interrelationship between cold exposure and the possible expansion of T3 Vd (15,37,39). Muscle isoforms of calcium adenosine triphosphatase(ATPase) (SERCA2a) changes with T3 (55), the uncoupling of ATP synthesis in human muscle by T3 (27), and the role of adaptive thermogenesis by thyroid hormone receptor isoforms (28,45) all support a molecular mechanism in humans for augmenting thermogenesis from muscle with exposure to cold. Uncoupling protein isoforms may be responsive to T3, adding possible controls (28). Hormone delivery and tissue uptake in responseto cold were studied by Margarity et al, who reported that local T3 production and receptor binding decrease in the brain of cold exposed rats (52), while from other reports, peripheral tissues have increased T3 availability and binding (28).
Heat
Physiologic and Thyroid Hormone Responses to Heat Exposure
Human physiologic adaptation to heat involves an expansion of the plasma compartment, increased rate of sweat loss, and an increase in aldosterone, which have been well described (2). In contrast to cold exposure, the human thyroid axis during exposure to heat has been studied much less. Thyroidal uptake of iodine-131 (131I) is decreased in warm environments (56), although some of this decrement may be accounted for by an expanded extracellular volume. Heat-naive subjects exposed to 60 minutes of 35°C air have an elevation in rectal temperature, a decrease in serum T3, and an increase in rT3 without changes in T4, suggesting a decrease in 5′-deiodinase type 1 activity (17). Saini et al reported that although the nocturnal surge of TSH was attenuated at 35°C, it was not statistically different, whereas 24-hour elevations in plasma renin activity (PRA) occurred during 6 days of heat exposure (2). Chronic residence at equatorial latitudes may affect the sleep-associated inhibition of nocturnal TSH secretion. In a warm climate study, 17% of the annual cases of thyrotoxicosis were identified in the northern hemisphere in the month of May (57), highlighting a possible interaction with circannual patterns of changing thyroid status and heat intolerance (Fig. 11B.1). A 72-kDa protein called heat shock protein (HSP) has been implicated in enhanced cytoprotective mechanisms following acclimation. The full expression of HSP seems to occur when a fall in T3 and T4 exceed 30% to 40% (58).
EFFECTS OF ALTITUDE AND HYPOXIA
Humans residing at or being transported to high altitudes of 2,315 (24), 3,000 (59), 3,500 (18), 3,810 (60), 4,300 (61,62), 5,400 (63), and 6,300 (63) meters are exposed to graded changes in low partial pressures of oxygen, hypobaric conditions, cold temperatures, low relative humidity, increased ultraviolet radiation, high winds, and often extreme physical exertion during altitude acclimation (4). Some studies have tried to isolate these factors by using hypobaric chamber experiments (18,59,60), whereas others have evaluated field conditions (62,63,64) or studied subjects who reside for extended periods at high altitudes (25,26).
Simulated Altitude in Environmental Chambers
Intermittent (4 to 8 hr/day) exposure to simulated altitude in thermoneutral hypobaric environmental chambers (18, 59,60,65) mostly supports the notion that elevations of up to 3,500 m increase serum T4 and T3 concentrations (18) and thyroidal 131I uptake (60) without changes in thyroxine-binding globulin (TBG) (18). Additionally, in these chamber studies, T4 administration and subsequent TSH suppression does not appear to negate increases in T4 and T3 observed below 4,500 m (Table 11B.2) (18).
Altitude Field Studies
In a 5-day study in which humans were transported rapidly to 2,315 m, the subjects had a mild hypoxic response of increased serum erythropoietin concentration, whereas serum free T4, free T3, and TSH remained unchanged. In contrast, individuals residing at 2,600 m (25) and 3,750 m (26) have increased free T3 and free T4 compared with sea-level residents, but without changes in TSH (25). Athletes training at 1,100 to 2,700 m have only increased free T3 (66), suggesting the interaction of exercise and altitude exposure and perhaps temperature (19,33,67). Field studies conducted at higher elevations of 4,300 m (61,62) and 5,400 to 6,300 m (63) showed increases in serum T4, free T4, and T3 without changes in free T3 unless the subjects were chronically exposed to the high altitudes (26), findings that are in general agreement with chamber studies (18,60). A decreased peripheral T4 conversion from undernutrition associated with exercise (51,68) and an increased BMR of 6% at 4,300 m (69) may modify the augmented free T3 response (51,63,69,70). This blunted response recovers with free T3 increased over low-altitude controls if climbers remain at 6,300 m for an extended period without further exertion (51). Changes in TBG are found in some (63) but not all (18) reports. Thyroidal 131I uptake (61) and T4 degradation (62) are increased at 4,300 m. At 5,000 and 6,300 m, serum TSH and the results of a thyrotropin-releasing hormone (TRH) challenge test, respectively, were elevated over preascent responses (63), in contrast to observations at lower elevations (18,25). Changes in plasma volume and binding proteins cannot account for all the reported hormone elevation (18), and some researchers speculate that a decrease in extravascular binding may occur (64). The discordant responses of serum free T4 and TSH at high altitudes support the concept that the hypothalamic–pituitary feedback of T4 may be altered near 5,400 m (63,65) (Table 11B.3). Possibilities to explain these findings would include an inhibition of pituitary 5′-deiodinase type 2 activity, a decrease in nuclear binding and local production of central nervous system T3, as happens with cold exposure in some species, or suppression of TSH by cortisol at lower altitudes (25,52,70,71).
TABLE 11B.3. EFFECTS OF EXERCISE AND NUTRITION ON THYROID FUNCTION
↑Energy Intakea
↓Energy Intakeb
Exercise and Low Energy Intake
Exercise and
Balanced Engery Intakec
T3
↑(≈)
↓↓
↓
≈(↓), (d, ↑)
free T3
↑
↓↓
↓
≈(↓)
rT3
↓(↓)
↑(↑)
↑
≈(↓)
T4
≈(≈)
≈(≈/↓)
↑
≈(↓),(d, ↑)
free T4
N/A (≈)
↑(↑)
↑
≈(↓)
TSH
≈(≈)
≈(↓)
≈
≈(↓),(d, ↑)
T3 PAR
↑
↓↓
N/A
↑
T3 PCR
↑
↓
N/A
↑
T3 Vd
↑
N/A
N/A
↑
T4 PAR
≈
≈/↓
N/A
↓
T4 PCR
≈
≈/↓
N/A
≈
rT3 PCR
↑↑
↓↓
N/A
N/A
RAIU
N/A
N/A
N/A
↑
TV
N/A
N/A
↓
N/A
Weight
↑
↓
↓
≈
Reference no:
22
22, 36, 71, 83
68, 85
19, 33, 67, 80, 84, 87
↑, increased; ↓, decreased; ≈, no change; free T3, free triiodothyronine; free T4, free thyroxine; N/A, not available; PAR, plasma appearance rate; PCR, plasma clearance rate; RAIU, thyroidal radioactive iodine uptake; TSH, thyrotropin; T3, total T3; T4, total T4.
aExtended overnutrition for 3 to 7 months.
bExtended fasting for 2.3 to 14 days or energy restriction for up to 2 years.
cAmenorrheic athletic women.
dSpecial combined conditions of walking 3 mph for 6 hr in 5°C air while wet (33).
EFFECTS OF MICROGRAVITY AND EXAGGERATED GRAVITY
Acceleration results from impaired cerebral blood flow when the inertial vector is in a head-to-foot direction [positive z-axis orientation of the gravitational vector (+Gz)] (72). A human centrifuge can isolate this stimulus from other aviation-related conditions such as hypoxia and microgravity (5,72). Serum TSH does not change with about 1 minute of 1- to 6-Gz stress (72). This degree of Gz stimulus decreases plasma volume (72) and is accompanied by an increase in PRA and serum T4 without changes in T3 (5). Working at 4 to 11 atmospheres pressure during simulated saturation diving decreases T4 by 10% and T3 by 20%, while increasing plasma volume by only 5% (73).
Microgravity is encountered routinely on space shuttle flights (6), and a G stress of 1 to 3 has been documented on Apollo flights during reentry into the earth's atmosphere (74). Early flights lasting 8 to 13 days are associated with elevated serum T4 values. These elevated values, obtained 2 hours after an ocean landing, do not appear to result from a decreased plasma volume, and they returned to preflight concentrations over 14 days (74). Later reports suggest serum TSH is elevated and T4 and T3 decreased during spaceflight (75,76). However, in a recent survey of all US spaceflights, McMonigal et al report that iodinated water sources on early missions were associated with elevations in TSH (77). During flights since 1998, where total iodine exposure has been reduced to 8 mg over 17 days, serum TSH values were no longer elevated (77). T3 administration appears to allow the “bed rest” model to more closely approximate weightlessness (78), supporting a possible role of thyroid hormones during spaceflight, but more work is needed in this area.
EFFECTS OF EXERCISE
A negative energy balance, which may have genetic and geographic contributions (42,43), results if nutrient intake is not increased during physical training (69,79). Four-day fixed energy expenditures with small deficits in energy availability will lower serum free T3 by approximately 9% and, with further negative energy balance, will increase free T4 by 11% and rT3 by 22% (68). Female competitive rowers who intensively train over a 20-week period while consuming adequate nutrition can show a decrease in TSH and free T3 temporarily during the first 5 weeks of resistance training (80). During further endurance training, these values return to normal gradually; the fall in TSH strongly correlates with a fall in leptin (80). Strenuous training protocols in men are associated with declines in T4, T3, and TSH, as well as a declining trend in free T4 (81,82). These situations are very similar to periods of energy restriction without exercise during which small decreases in energy intake will reduce serum T3 (22) and more severe restriction will lower serum TSH (71). An exercise-mediated negative energy balance does not appear to change declines in free T4 and free T3 with acute cold exposure (82). With continued energy restriction for up to 2 years, T3 remains reduced by 19% and body weight by 17% (82). However, by replacing calories either during short 3.5-hour bicycle exercise (79), extensive aerobic exercise (51), or following 2 years of restriction (83), serum T3 can return to baseline quickly. Castellani et al report that a eucaloric 7-day exercise protocol with cold and wet exposure increases T3 and T4 during the cold exposure exercise period only (33). These values return to baseline after the exercise period (33), suggesting that the combination of temperature and exercise can interact to affect thyroid economy differently than either one individually.
During 4 to 6 weeks of aerobic training, T3 PAR increases by approximately 10%, PCR increases by approximately 9% (19), thyroidal iodide uptake increases (84), and body weight does not change (19). With extensive exercise over 6 months, a fall in body weight is highly correlated with a decrease in thyroid volume measured by ultrasound (85). In contrast, the T4 degradation rate decreases by approximately 9% during this type of aerobic training, and serum free T4 tends to decline by 7% but does not reach a level of significance (19). Male athletes have an approximate 30% increase in T3 PAR, PCR, and Vd, with no difference in serum T3, T4, or TSH when compared with sedentary controls (67) (Table 13.3).
Athletic men do not have dramatic changes in serum T4, T3, or TSH (67,85), whereas women, depending on their menstrual and gonadal status, have decreases in serum T4, free T4, T3, and free T3 when compared with sex-matched sedentary controls. TSH stimulation by TRH is not different in trained men (86), but may be blunted in athletic women with hypothalamic–pituitary ovarian dysfunction (87).
When the increased energy requirements with exercise are corrected, T3 PAR, PCR, and radioiodine uptake (RAIU) increase and are similar, but not identical, to results of overfeeding studies (22). Furthermore, hypothalamic–pituitary–thyroid axis changes with extreme exercise may occur in amenorrheic women (87) and in men who have low testosterone production (51).
EFFECTS OF PHOTOPERIOD, SLEEP, AND CIRCADIAN RHYTHMS
The circadian pattern of TSH appears as a combination of the ultradian rhythm and factors such as photoperiod (3), serum T4 and T3 (71), sleep (20,21), and energy restriction (71, see Chapter 13). This circadian TSH oscillation is linked closely with body temperature (3) and is regulated in part by TRH (see Chapter 13). The TSH and body temperature rhythm can be reset by a pulse of light (5,000 lux) or sleep deprivation (3), and natural sleep can suppress the circadian TSH peak (20). By the second day of a shift-work change, the circadian pattern of TSH can be reset (88). The typical nocturnal surge in TSH rises 70% (3) (see Chapter 13) over the 24-hour mean, whereas the ratio of T3:T4 has a nocturnal increase of only 8% (89). Furthermore, the changing T3:T4 ratio is eliminated by fasting and unaltered by T4 suppression of TSH, suggesting a peripheral mechanism for this rhythm (89). Thyroid receptor TRβ1 undergoes a diurnal variation with a 25% increase in binding capacity when studied in rat hepatic tissue, possibly related to a nocturnal feeding pattern (90). Pharmacologic sleep facilitation has limited effectiveness after 24 hours in normalizing nocturnal elevations in serum TSH following an intentional phase shift (90). Acutely, both total and partial sleep deprivation will raise serum TSH, T4, free T4, and T3, although the patterns are slightly different with the degree of deprivation (20,21). Chronically, a partial sleep debt of 4 hours per night for 6 nights decreases the 24-hour profile of TSH by 33% and increases salivary cortisol by 20% compared with sleep restoration (91).
EFFECTS OF CIRCANNUAL RHYTHMS
Mid-latitude residents who are exposed to changing patterns of light and temperature demonstrate physiologic and endocrine seasonal rhythms for thyroid cancer presentation (12,13), cerebral and myocardial infarction (7,8), blood pressure (7), serum cholesterol (7), calcium metabolism (9), glucocorticoid activity (92), female (7) and male (93) gonadal hormones, sperm number (94), and mood disorders (10).
Seasonal Rhythm of Thyrotropin in Hypothyroid and Euthyroid Subjects
The serum TSH response to TRH increases during the winter in hypothyroid patients taking a fixed dose of T4 (7,95). In early studies, euthyroid subjects were not reported to have increased serum TSH or TRH-stimulated TSH, or altered 24-hour circadian TSH profiles (7), during the winter season (16). Also, when the intersubject variation was large, no seasonal difference in TSH was found (96). However, when 24-hour circadian patterns were studied in the same elderly euthyroid women, serum TSH had a clear circannual pattern, but this was not seen in men near the same age (97). With the improved TSH assay and better control of study populations to eliminate subclinical thyroid disease, this issue has been clarified with a study of 8,310 euthyroid subjects in Italy, stratified by age and sex (98). Men and women over 41 years of age had a serum TSH peak in December, which represents an increase of approximately 30% over the trough summer value (98). Using monthly samplings and a cosinor analysis, a serum TSH change of 29% was also described between a spring minimum and winter maximum in Belgium subjects with a mean age of 39 years (23). In this study, there was a circannual rhythm (peak or acrophase, December 11; p < 0.004), as well as two underlying harmonic rhythms of 104 and 169 days for TSH (Fig. 11B.1). The December peak was confirmed by Hassi et al, who reported on approximately 28% elevation in serum TSH over the seasonal mesor for men 26 to 40 years old who live in Finland (48). The changes in TSH are linked to luminosity 7 days before the blood sample (p < 0.001). The circadian and ultradian TSH rhythms may obscure a smaller amplitude seasonal rhythm unless attention is directed to intrasubject variability (23) and sampling time.
Seasonal Rhythm of Thyroxine and Triiodothyronine in Euthyroid and Hypothyroid Subjects
It is unknown whether these circannual patterns of TSH secretion are a primary response of the hypothalamic–pituitary axis to changing light and ambient temperature (7) or whether they reflect small declines in either the Vd or serum T4 (7,95). Investigations of T3 and T4 report serum T3 elevation (23,35), urinary T3 elevation (7,48), or no change in serum T3 during the autumn and winter months. Little change in T4 and no clear or consistent circannual pattern of free T4 was found with most mid-latitude winter studies (23,98). The reported 8.2% winter elevation for Belgian residents in total T3 (acrophase, January 10) was preceded by an elevation of TSH by 30 days (p < 0.0001) and inversely related to temperature but not luminosity (Fig. 11B.1) (23). Hassi et al have extended this observation in Finland by showing a small decline in serum free T3 and increase in urinary T3 in winter (February) by 32% over the annual mean (48). They correlated these seasonal increases to preceding declines in temperature but not luminosity (48). The PCR of T3 increases within 14 days after repeated cold air exposure (14). Kinetic studies in euthyroid subjects at mid-latitudes (Bethesda, MD; USA) suggest that T3 PCR increases by approximately 30% between spring–summer trough values and autumn–winter peaks (99) (Table 11B.2). This increase in T3 PCR precedes and possibly initiates a small and nearly undetectable decline in free T4 (14). Indigenous populations (42) and other residents (44) living at high latitudes have increased energy requirements. The BMR of these indigenous peoples are about 12% higher than expected, and these variations in BMR are positively correlated with serum free T4 (1). Small changes in serum TSH have been linked to corresponding changes in BMR during clinical studies (28), which could support the broader environmental observation by Leonard et al (42).
Circannual Changes of Thyroid Size, Iodine Content, Thyroid Cancer Presentation, and Growth
The intrathyroidal iodine content studied in Belgian subjects using X-ray fluorescence had a peak in April and a trough in September (100). The approximate 40% increase in these subjects' thyroidal iodine during April was not thought to be from differences in dietary iodine between winter and summer (100). The seasonal TSH profile reported in Belgium and Finland shows a peak in December (23,48) (Fig. 11B.1). Thyroidal size measured by serial ultrasonography increases by approximately 23% from summer to winter without a change in serum T4, T3, or TSH in Denmark (101), however with a reduced serum thyroglobulin in winter, when gland size is greater (96). Thyroid cancer presents more frequently, with a larger size and higher indicators of proliferation in late autumn and winter compared with summer in Norway and Sweden (12,13) (Fig. 11B.1). This difference of more than a 60% increase of winter suggests an environmental trigger such as TSH (13).
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