Sammenhæng mellem medicindose og årstider

Hvem er jeg? Jeg er et menneske, der måtte leve med sygdommen lavt stofskifte de sidste 38 år, hvoraf de 29 år i behandling med syntetisk T4-analog - Eltroxin. Det gik nogenlunde de første 5-6 år, mens de næste 23 år blev en gradvis omend accelererende deroute. Behandlingen fungerede dårligere og dårligere. Helbredet var ved at falde fra hinanden, ignoreret af lægerne, indtil - nærmest i sidste øjeblik - fandt jeg selv en løsning. Et gammelt, effektivt lægemiddel - NDT (Natural Desiccated Thyroid) siden 1890-erne over hele verden anvendt til behandling af lavt stofskifte, men af uransagelige årsager, efter 70 år udfaset i 1960-erne til fordel for det syntetiske stads, der var ved at tage livet af mig gennem de 29 år jeg var i den behandling.

Efter at have udskiftet Eltroxin med det ellers gammelkendte Armour Thyroid i 2007, har jeg tilbragt det meste af min fritid på det norske Forum for Stoffskiftesykdommer - for at lære mere af andres erfaringer, og for at dele ud af det, jeg undervejs har lært andre steder på Internettet. Og det er også på forummet i Norge, at vi begyndte lægge mærke til at mange af os, ellers såkaldt "velbehandlede" stofskiftepatienter kommer ud for "uforklarlige", regelmæssigt tilbagevendende forværringer, og bedringer - uanset samme medicindose og blodprøveresultater indenfor normalområder.

Allerede i 2006 flere af os begyndte føre dagbogsoptegnelser med blodprøveresultater, symptomer, ændringer i medicindoser, notater om trivsel eller mangel på samme (meget ofte det sidste) og efterhånden i løbet af 2-3 år har vi lagt mærke til regelmæssigt skiftende "afvigelser" i forhold til årstiderne: fra maj/juni til september/oktober havde vi det bedre; fra oktober/november til april/maj havde vi det værre. Løsningen blev en sæsonbestemt regulering af medicindose, flere norske læger heldigvis efterhånden lader komme an på en prøve.

I perioden oktober/november til april/maj mange stofskiftepatienter har gavn af at øge medicindosen - ofte med op til mellem 25 og 50% af den hidtidige dosering, hvorimod i perioden maj/juni til september/oktober bliver medicindosen tilsvarende reduceret. I løbet af første uge efter op- eller ned-dosering har denne metode vist sig at stabilisere stofskiftet over hele året med den effekt at udsving i formen og trivsel samt symptomer blev enten færre, sjældnere, eller ophørte helt. Reguleringen af medicindose i overensstemmelse med årstider har vist sig at fungere perfekt for mange stofskiftepatienter, men det er en myte, ifølge dr. Birte Nygaard, overlæge ph.d., speciallæge i Intern Medicin og Endokrinologi.

Den 12. maj læste jeg i dagbladet Information et debatindlæg "En god læge giver ikke altid patienterne, hvad de beder om", hvor dr. Nygaard skrev bl.a.:

"Som læge bliver jeg altid bekymret, når en patient indimellem viser mig, hvad der foregår af anvisninger på disse chatfora. Patienterne forsøger at hjælpe hinanden ved blandt andet at beskrive deres symptomer og lægge blodprøver ud for derefter at få respons fra andre patienter, som har erfaring fra deres egen sygdomsoplevelse.

Men det er ikke altid til patientens bedste. Inden for mit felt findes der eksempelvis myten om, at man skal have mere stofskifte-medicin, når det bliver efterår:

»Nu er det november og koldt – du har brug for mere stofskiftehormon,« lyder det fejlagtigt. Vi har at gøre med anbefalinger, som er helt parallelle med dem, som findes på dopingsider for cykelryttere og bodybuildere mv.
"


Mig bekendt er der intet "parallelt" mellem chronobiologi og chronomedicin og "dopingsider for cykelryttere og bodybuildere mv." ?

Jeg kan anbefale alle læger der har patienter ramt af lavt stofskifte, i medicinske databaser og tidsskrifter at søge med fraser som "seasonal variation of serum TSH and thyroid hormones" eller "seasonal variations of total and free thyroid hormones", eller "circannual rhythms of thyroid hormone and TSH".

Overlæge Nygaard afslutter sit debatindlæg i Information med bl.a. disse ord: "Derfor vil jeg appellere til, at patienter bruger deres kritiske sans i læsningen af information fra nettet og ikke lader sig forføre at beskrivelser af hurtige mirakelløsninger, som sjældent holder i længden og har mulige senfølger".

Senfølger af hvad?

Af "myten" om sæsonregulering af medicindose?

Lad os sammen undersøge denne "myte". Vi kan starte med sæsonbestemt variation i størrelsen af en ganske sund og rask skjoldbruskkirtel hos normale, sunde og raske mennesker:



Kilde: http://ekstern.infonet.regionsyddanm...=1463658748339 (Infonet Region Syddanmark Endokrinologisk Instruks)

Hvorfor bliver skjoldbruskkirtlen hos sunde ikke-gravide, lidt større om vinteren end om sommeren?

Det bliver den fordi om vinteren skal den yde mere ("fange" mere jod) og producere lidt mere hormon, end den skal om sommeren. Derfor.

Idet der ikke forskes i "myter" i Danmark, se eksempler på udenlandsk, medicinsk forskning i årstidernes indflydelse på levende organismers thyreoideafunktion, og behandling af thyreoideasygdomme - i tilfældig rækkefølge:


Tissue-Specific Posttranslational Modification Allows Functional Targeting of Thyrotropin
Cell Reports ISSN: 2211-1247 DOI: http://dx.doi.org/10.1016/j.celrep.2014.10.006

Citat: An international collaborative study between Japanese and American scientists has revealed how a single hormone multi-tasks without muddling up its functions. The hormone in question is thyrotropin, the thyroid-stimulating hormone (TSH) that manages to activate seasonal sensing and regulate metabolism without any confusion.

How Does TSH Act As A Spring-Calling Hormone?

Many activities of animals change with the onset of spring or change in the duration of night and day, such as seasonal breeding, bird migration, wool shedding, and hibernation. How the internal clocks of these animals were so attuned to the changing season was quite a mystery to researchers. Then, in 2008, the Japanese team identified the spring-calling hormone or the TSH secreted from the pars tuberalis (PT-TSH) in the pituitary gland that on arrival of spring or longer days sends information on seasonal changes to the hypothalamus in the brain.

Once this was discovered, the next question that baffled researchers was how the hormone performed these diverse biological functions of acting as a spring-calling hormone and a growth regulator without the two processes interfering in the blood stream.


Effect of Age, Sex and Seasons on the Concentration of Thyroid and Thyroid Stimulating Hormones
Journal of Medical Sciences (Faisalabad) · April 2001 DOI: 10.3923/jms.2001.224.227

Abstract: Effect of age, sex and seasons on the concentration of thyroid hormones (T3 and T4) and thyroid stimulating hormone (TSH) was studied in 25237 thyroid patients who were referred to the radioimmunoassay (RIA) laboratory of the Institute of Radiotherapy and Nuclear Medicine (IRNUM), Peshawar during 1984-1990 (except 1987) and 1995-1996. T3 and T4 of all of these patients were determined by RIA and TSH was determined by immuno-radiometric assay (IRMA). The difference in mean concentration of T3, T4 and TSH in infants and children was non-significant at p<0.05. Comparing all age groups together, higher mean concentration of T3 was found in old age group followed by infants, adults and children. Similarly, the mean concentration of T4 was higher in old age group followed by adults, infants and children. While higher mean values for TSH were observed in infants followed by children, adult and old age group. The infants and children were having significantly higher values of TSH than the old age group and adults at p< 0.05. Concentration of T3 and T4 was significantly higher (p<0.05) in females than males, while TSH concentration was not significantly different (P>0.05) in both sexes.

Mean concentration of T3 in summer and autumn was significantly higher than the other seasons and mean concentration of T4 in winter and summer was higher. The mean concentration of TSH in spring and autumn was significantly higher than the mean concentration of TSH in winter and summer at p<0.05.


Influence Factors on Serum Thyroid Hormone Level in Healthy People
Journal of Sichuan University. Medical Science Edition [2015, 46(4):611-614]

Abstract: To explore the influences of age, gender and season on serum thyroid stimulating hormone level and thyroid hormone level in healthy people.There were 2 564 healthy volunteers enrolled in this study, whom were divided into different groups according to gender, age and the season. The levels of serum TSH, T3, T4, FT3, FT4 were measured and the data were statistically analyzed.The level of serum TSH in both young and middle-age groups of female was higher than that in the same age groups of male. The serum levels of T3, FT3, FT4 in both young and middle-age groups of female were lower than those in the same age groups of male (P < 0.05). In female, the serum level of TSH was increasing with age. However, the serum levels of FT3, FT4 had the opposite tendency. The level of serum FT3 in young group was higher than that in elderly group of, but T4 were lower. Lower levels of TSH, T3, FT4 were found in summer than in winter (P < 0.05) and there was no significant difference of FT3 between that two seasons. The levels of serum TSH, T3, T4 and FT4 were correlated with seasons (r = 0.079, 0.092,-0.137, 0.140). The levels of serum TSH and thyroid hormones are influenced by age, gender and seasons, which needs to be considered for the diagnosis of thyroid diseases and evaluation of thyroid function.


Seasonal variation of serum thyrotropin concentration and thyrotropin response to thyrotropin-releasing hormone in patients with primary hypothyroidism on constant replacement dosage of thyroxine.
J Clin Endocrinol Metab. 1982 Jun;54(6):1118-24.

Abstract: Ten patients with primary hypothyroidism (aged 32--66 yr), replaced on constant daily doses of L-T4 (mean +/- SD, 1.90 +/- 0.22 micrograms/kg BW), were used to examine seasonal variations in serum levels of thyroid-related hormones for a period of 14 months. Basal and peak TSH concentrations after TRH (500 micrograms) were higher in winter than in summer. Summer values for basal TSH were all normal (normal range, less than 4.8 microU/ml), while winter values were supranormal in 5 of 10 patients. Summer values for peak TSH were subnormal or normal (normal range, 5.0--40.0 microU/ml), while winter values were supranormal in 3 patients, with the remaining values being normal [log basal TSH, 0.511 +/- 0.438 vs. 0.084 +/- 0.244 (P less than 0.05); log peak TSH, 1.394 +/- 0.410 vs. 1.017 +/- 0.423 (P less than 0.05)]. Serum resin T3 uptake, T4, free T4 index(FT4I), T3, free T3 index, and rT3 levels did not vary seasonally, although T4 and FT4I tended to fall in the winter. The summer and winter QKd interval (the interval from the onset of a QRS complex in the electrocardiogram to the appearance of the Korotkoff sound at diastolic pressure), basal metabolic rate, and serum cholesterol concentrations were all within the normal range. Basal and peak TSH after TRH were inversely correlated with serum T4 and FT4I levels. The basal TSH concentration was further inversely correlated with the seasonally altering ambient temperature.

These results indicate that during the treatment of primary hypothyroidism with constant doses of T4, 1) serum TSH and its response to TRH show seasonal variation, 2) the hypersecretion TSH in the winter is related to small changes in serum T4 and FT4I levels, and 3) the seasonal variation in the serum TSH concentration may need to be taken into consideration when evaluating the adequacy of a T4 replacement dose.


Effect of seasonal changes on the transition between subclinical hypothyroid and euthyroid status.
J Clin Endocrinol Metab. 2013 Aug;98( 8 ):3420-9. doi: 10.1210/jc.2013-1607. Epub 2013 Jun 14.

Abstract

CONTEXT: The widespread use of thyroid tests in asymptomatic individuals identifies many patients with transient subclinical hypothyroidism.

OBJECTIVE: Our objective was to determine the effect of seasonal change on serum TSH levels and the transition between subclinical hypothyroid and euthyroid status.

DESIGN, SETTING, AND SUBJECTS: This was a retrospective longitudinal study of 1751 subclinical hypothyroid and 28096 euthyroid subjects aged over 18 years who underwent serial thyroid function tests at a health screening center between October 2003 and May 2011.

MAIN OUTCOME MEASURES: Age-adjusted geometric mean values of the TSH level by month were calculated using linear mixed models. Adjusted odds ratios of test season and multiple baseline clinical factors were determined using generalized estimating equations.

RESULTS: During a median 36 months of follow-up, 57.9% of subclinical hypothyroid subjects reverted to euthyroidism, and 4.3% of euthyroid subjects developed subclinical hypothyroidism. The monthly distribution of follow-up TSH levels indicated a biphasic pattern, ie, an increase during the winter-spring season and a decrease during the summer-fall season, with a maximal TSH difference of 0.69 mIU/L in subclinical hypothyroid and 0.30 mIU/L in euthyroid subjects. Normalization of subclinical hypothyroidism was increased 1.4-fold in follow-up tests during the summer-fall follow-up, whereas subclinical hypothyroidism increased 1.4-fold in euthyroid subjects during the winter-spring follow-up.

CONCLUSIONS: The season in which thyroid testing was performed was independently related to the transition between subclinical hypothyroid and euthyroid status. Seasonal variations in TSH concentration should be considered before deciding on treatment of subclinical hypothyroidism, particularly in the areas with a wide annual temperature range.

Min bemærkning: Studiet påviser at mens en person er "subklinisk" hypothyroid om vinteren, om sommeren kan samme person være sund som en havørn (euthyroid), ifølge blodprøveresultater. Altså: "hypo" om vinteren, og "normal" om sommeren. Det har man fundet ud af på baggrund af statistikker omfattende næsten 30.000 personer, fulgt gennem 18 år.

Der burde dog ikke være selv den mindste forskel hvis årstidsbestemte forskelle i behov for thyreoideahormoner er en myte, medmindre endokrinologer går med til opfindelsen af en helt ny diagnose: "vinter-hypothyreose", men mon det alligevel ikke ville være at gå for langt, for at redde dr. Nygaards myte-teori?

Ellers (off topic) kan man anbefale at personer plaget af symptomer på lavt stofskifte, men med "fine" blodprøveresultater - bør konsultere lægen til vinter, ikke om sommeren.


Is it necessary to adjust the replacement dose of thyroid hormone to the season in patients with hypothyroidism?
Metabolism. 1984 Mar;33(3):215-8. DOI: http://dx.doi.org/10.1016/0026-0495(84)90039-8

Abstract: Hypothalamo-pituitary-thyroid activity varies with the temperature of the environment; we therefore measured variables involved with thyroid function in summer and winter in normal controls and in patients with primary hypothyroidism. All seven patients had impalpable thyroid glands and had received a set replacement dose of thyroxine for over a year. In the patients, serum T3 and FT4 levels were slightly but significantly lower in winter, and TSH levels and ΔTSH at 30 minutes in the TRH tests were significantly higher. In the controls, there were no significant differences between summer and winter in these values. These findings suggest that the dose required for replacement of thyroid hormone in patients with hypothyroidism may be higher in winter than in summer.


Thyroid hormone and seasonal rhythmicity
Front Endocrinol (Lausanne). 2014; 5: 19.
Published online 2014 Feb 26. Prepublished online 2014 Feb 3. doi: 10.3389/fendo.2014.00019

From Abstract: Living organisms show seasonality in a wide array of functions such as reproduction, fattening, hibernation, and migration. At temperate latitudes, changes in photoperiod maintain the alignment of annual rhythms with predictable changes in the environment.

From Conclusion:Therefore, even though a theoretical possibility exists that another TSH-dependent – but T3-independent pathway – leads to seasonal changes of the reproductive axis, the most parsimonious model is one in which T3 action on RF-amide neurons link the photoperiodic production of TSH within the PT to the seasonal control of GnRH secretion.


Components of biological variation, including seasonality, in blood concentrations of TSH, TT3, FT4, PRL, cortisol and testosterone in healthy volunteers

Abstract

OBJECTIVE: There are few detailed studies of annual or seasonal variations in hormone concentrations in man. This study examines the components of biological variation, including seasonality, in plasma TSH, total T3 (TT3), free T4 (FT4), PRL, cortisol and testosterone in healthy volunteers.

DESIGN: Monthly blood samplings for the assay of the above hormones were collected during one calendar year.

SUBJECTS: Thirteen normal men and 13 normal women participated in the present study (mean age 38.7 ± 13.4 years).

MEASUREMENTS: Assays of TSH, TT3 and FT4 were carried out by means of Immunoradiometric assays (IRMA), PRL by ELISA, cortisol by a fluorescence immunoassay, and testosterone with RIA. The time series were analysed by means of (bivariate or multivariate) spectral and cosinor analyses.

RESULTS: Significant annual, four-monthly and biannual rhythms were detected in serum TSH; the lowest TSH values were observed in spring. A significant annual rhythm was detected in TT3, with lower values in spring and summer than in the other seasons. The peak–trough differences in the yearly variation expressed as a percentage of the mean were 29.1% and 8.2% for TSH and TT3, respectively. The yearly variation in plasma cortisol was significantly different between men and women: in men, 5.9% of the variation was explained by an annual rhythm, while in women 14.7% was explained by the fourth and seventh harmonical wave. The peak–trough differences in the yearly variation in plasma cortisol were 17.6% and 31.8% in men and women, respectively. There were no significant seasonal rhythms in PRL, FT4 or testosterone. The intraindividual/interindividual CV values were: TSH 29.3/48.4%, TT3 9.4/18.5%, FT4 7.1/9.1%, PRL 39.2/65.0%, cortisol 21.7/46.2%, and testosterone 12.6/40.8%.

CONCLUSIONS: The degree of individuality measured in the plasma hormones is such that conventional population-based reference ranges may not correctly identify major alterations in these hormones in individual subjects.


The evidence of TSH variation according to the temperature and geographic region in patients with thyroid pathology
12th European Congress of Endocrinology. Endocrine Abstracts (2010) 22 P774

Abstract: Because of the increased prevalence of thyroid disorders in Romania we realized a retrospective study in which we followed the variance of TSH, function of temperature, in different seasons. In this context, based on TSH value we appreciated the need of thyroid hormones and antithyroid drugs to maintain an euthyroid state.

Material and methods: The group of study consist of 634 patients, men and women over 18-years-old with thyroid disorders: hypo, hyper, euthyroidism per novo or under treatment which presented in summer and winter months in C. I. Parhon Institute. The patients were followed in the summer months versus winter months being distributed on geographical regions.

Results: In the case of hypothyroid patients, the mean TSH value in summer month was 9.37±5.53 μUI/ml and in winter month was 18.68±2.31 μUI/ml. Based on the TSH value we appreciated that the need of thyroid hormones is lesser in summer months than in winter months with a P=0.12 and actually lesser in the geographical regions with high temperature.

In the case of hyperthyroid patients we remarked that the need of antithyroid drugs, appreciated by the TSH value, is bigger in summer months (mean TSH value: 0.148±0.76 μUI/ml) than in winter months (mean TSH value: 0.23±0.021 μUI/ml) with a P=0.46 and even bigger in the geographical regions with high temperature.

For the patients with multinodular goiter but with euthyroidism we remarked mean TSH values lesser in summer months (mean TSH value: 1.57±0.496 μUI/ml) than in winter months (mean TSH value: 2.39±0.78 μUI/ml) with a P=0.08.

Conclusions: TSH value has circanual variations being lesser in spring–summer and bigger in winter. Based on TSH value we appreciate that the need of thyroid hormones is bigger in winter than in summer and the need of antithyroid drugs in bigger in summer than in winter.


Circannual changes in thyroid hormone physiology: the role of cold environmental temperatures
Arctic Med Res. 1995;54 Suppl 2:9-15.

Abstrac:t Hypothyroid subjects given a constant dose of thyroxine (T4) show both an increase in serum thyrotrophin (TSH) of approximately 50% and a decline of serum T4 by approximately 15% during the winter months.

Euthyroid subjects who are older than 41 years of age show an increase of approximately 30% in serum TSH during the winter months without a change in T4. Young euthyroid subjects, between the ages of 19 and 41 years, show neither a circannual pattern of TSH nor T4 but have an increase in triiodothyronine (T3) plasma clearance rate and production rate of approximately 30% during the winter seasons. Additionally, young subjects living for greater than 5 months in Antarctica show a doubling in T3 plasma clearance rate and production rate, as well as elevations of approximately 30-50% in TSH and small declines in T4. Repeated exposure to cold air has recently been reported to induce declines in serum T3, and T4 and increases in T3 clearance and production rate, thus linking a possible physiological stimulus to these seasonal observations.

This collection of studies from several laboratories supports the concept that T3 kinetic changes have a seasonal dependence and that cold exposure provides one possible mechanism. As the subjects age, have a fixed thyroid hormone dosage for hypothyroxinemia, or spend an extended number of months in polar conditions, a reflex TSH rise occurs. This rise in TSH signals a hypothalamic-pituitary hypothyroxinemia whose clinical significance is unknown.

And it's going on, and on, and on... Der er SÅ meget forskning i sæsonale forskelle i behovet for thyreoideahormoner (og alle andre hormoner). Det overgår min forstand (der skal ellers meget til) at der findes endokrinologer i høje ekspertstillinger, der endnu ikke ikke har opdaget at behandlingen fungerer bedst når behandlingsdoser justeres efter årstider.

Det er "eksperternes" tyrkertro på "reference intervaller" ("normalområder") som lokker dem på afveje, idet disse "reference intervaller" er SÅ brede (rummelige) at de årstidsbestemte forskelle i TSH, T3 og T4 er simpelthen ikke store nok til at overskride "reference intervaller", og derfor bliver de ikke bemærket af "eksperterne", som fokuserer blindt på "rammen", i stedet for på "billedet".

Mon nogen her eller udenfor, fortsat tror på at varierende med årstider, sæsonbestemt behov for thyreoideahormoner er en... myte?

I hope not.