1. No category

Melatonin treatment of aging
women: doses, side effects,
how to manage them
4rth European Congress in Anti-aging
medicine –
Paris, France; October, 17-19, 2008
Palais des Congrès de Paris (Porte Maillot)
The amount of melatonin secretion
from human pineal gland during
various time of day
Long-Day Suppressed Expression of Type 2 Deiodinase Gene in the Mediobasal Hypothalamus of the
Saanen Goat, a Short-Day Breeder: Implication for Seasonal Window of Thyroid Hormone Action on
Reproductive Neuroendocrine Axis. Shinobu Yasuo1, Nobuhiro Nakao1, Satoshi Ohkura,and Coll.
Endocrinology 2005 : Vol. 147, No. 1 432-440
Melatonin deficiency :
plasma levels at night
50
30
http://www.fit-zone.com/library/M/melatonin/melaton.html
www.benbest.com/nutrceut/mela_age.jpg
40 years : ↓50%
50 years : ↓75%
60 years : ↓91%
3.6
Melatonin deficiency :
plasma levels at night
Optimal
130 pg/ml
Mild
< 80
Moderate
< 55
Severe
< 30
Melatonin deficiency :
24 h urine 6-sulfatoxy-melatonin
Optimal
50 mcg / 24h
Mild
< 35 mcg / 24h
Moderate
< 25 mcg / 24h
Severe
< 15 mcg / 24h
Melatonin treatment :
doses & timing
Dose
Physiological secretion
Absorption
Time
Sublingual M. supplements
Oral M. supplements
0.1 to 3 mg daily
0.05 to 0.2 mg daily
10 - 50% of melatonin
dose, depending on the
individual
Before bedtime
10 - 15 minutes
30 - 60 minutes
Average concentrations of melatonin in plasma (black,
average N=133), saliva (blue, average N=28) and
6-sulphatoxymelatonin (aMT6s) in urine (red, average
N=88), all measurements by radioimmunoassay.
Diagrammatic representation of mean normal values
(healthy men and women over 18 years old) from the
author's laboratory.
HUMAN PINEAL PHYSIOLOGY AND PATHOLOGY
Melatonin by Ben Best
http://www.endotext.org/neuroendo/neuroendo15/ch01s05.html
http://www.benbest.com/nutrceut/melatonin.html
Very deep sleep durinfg 3 to 5 hours
with precocious waking up.
Cause
• Melatonin overdosage
• Melatonin stimulates
too much and too fast
after 3 to 5 hours the
conversion of T4 to T3
while normaly it takes 6
to 8 hours.
Peripheral conversion of T4 to T3
At present we assert that the six-month
treatment with 3mg Melatonin daily
produced a remarkable and highly
significant improvement of
thyroid function.
Effects of melatonin in perimenopausal and menopausal women: our personal experience.
Bellipanni G, DI Marzo F, Blasi F, Di Marzo A.
Ann N Y Acad Sci. 2005 Dec;1057:393-402
• Oral melatonin administration tended to exert a more marked
effect on enzyme activity than s.c. injection of the hormone.
•
Changes in 5'-MonoDeiodinase activities were accompanied by
an increase in serum iodothyronine (T4, T3, and rT3)
concentrations.
•
• The rise in the serum T4 was probably due to the stimulatory
effect of melatonin on the secretory activity of the thyroid gland
itself.
• The T3 and rT3 increases may result from the deiodinating
processes by the type I 5'-MD and 5-MD, respectively
Stimulatory effect of melatonin on the 5'-monodeiodinase activity in the liver, kidney, and brown adipose
tissue during the early neonatal period of the rabbit. Brzezińska-Slebodzińska E, Slebodziński AB, Styczyńska E.
J Pineal Res. 1998 Apr;24(3):137-41
Artificial long-day conditions (16 h light, 8 h dark).
•
A, Rostral; B, middle; C, caudal parts of the MBH
are shown. In each part of the MBH,
representative autoradiograms for Dio2
expression under natural photoperiod and
artificial long-day conditions, and a schematic
drawing are shown. Each graph shows the
relative OD of Dio2 mRNA level in the external
zone of the ME (ez, large arrowheads), the cellclear zone overlying the TIS (small arrowheads),
the EC (small arrows), and cARC (large arrows),
respectively. Solid bars, Natural daylength; open
bars, artificial long days. Asterisks shows the
significant difference detected by Mann-Whitney
U test (P < 0.05). Each value is the mean ± SEM
(n = 4). Iz, Internal zone of the ME; PT, pars
tuberalis; TMv, the ventral tuberomammillary
nucleus; Fx, fornix; IIIV, third ventricle.
MBH : Medio Basal Hypothalamus
Long-Day Suppressed Expression of Type 2 Deiodinase Gene in the Mediobasal Hypothalamus of the
Saanen Goat, a Short-Day Breeder: Implication for Seasonal Window of Thyroid Hormone Action on
Reproductive Neuroendocrine Axis. Shinobu Yasuo1, Nobuhiro Nakao1, Satoshi Ohkura,and Coll.
Endocrinology 2005 : Vol. 147, No. 1 432-440
Melatonin overdosage
• Deep prolonged
sleep(iness) the
whole night through
until late in the
mornig
Treatment
• ↓ dose of melatonin from at least 50 up
to 95% !
Too vivid dreams
• Melatonin
overdosage =>
stimulates too much
and too fast after 3
to 5 hours the
conversion of T4 to
T3 (normaly 6 to 8
hours after)
Treatment
• ↓ dose of melatonin from at least 50 up
to 95% !
Too dark office room
• ↓ Melatonin
production
(circadian cycle)
• ↓ Melatonin receptor
Treatment
• Respect the
cyrcadian cycle
• Daylight exposure at
least > 2.500 Lux
• Add light sources if
needed
A 30 kHz bright light therapy lamp (Innosol Rondo) used
to treat seasonal affective disorder.
Provides 10,000 lux at a distance of 25 cm.
Treatment
• Before bedtime ↑ melatonin by 50 to
150% of the routine dose.
I should increase
Melatonin by 50 to 150%
Melatonin doesn’t work for sleep
• Excess light in
bedroon at night
• Insufficient daylight
exposure during the
day
Winter daylight
Long-Day Suppressed Expression of Type 2 Deiodinase Gene in the Mediobasal Hypothalamus of the
Saanen Goat, a Short-Day Breeder: Implication for Seasonal Window of Thyroid Hormone Action on
Reproductive Neuroendocrine Axis. Shinobu Yasuo1, Nobuhiro Nakao1, Satoshi Ohkura,and Coll.
Endocrinology 2005 : Vol. 147, No. 1 432-440
Synthesis and secretion of melatonin is
dramatically affected by light exposure to
the eyes.
• Examples of the circadian
rhythm in melatonin
secretion in humans is
depicted in the figure to the
right (adapted from Vaughn,
et al, J Clin Endo Metab
42:752, 1976). The dark gray
bars represent night, and
serum melatonin levels are
shown for two individuals
(yellow versus light blue).
Note that blood levels of
melatonin are essentially
undetectable during
daytime, but rise sharply
during the dark.
The Pineal Gland and Melatonin
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/otherendo/pineal.html
10,000 lux during 90 to 100
minutes of exposure to bright light
•
11 blind patients with no conscious perception of light
and 6 normal men ranging in age from 20 to 25 years.
Plasma melatonin and
temperature were measured
repeatedly during a constant
routine (hatched bars) and
subsequent episodes of sleep
(solid bars). The light intensity
was less than 0.02 lux during
the sleep episodes, 10 to 15 lux
during the constant routine, and
approximately 10,000 lux during
90 to 100 minutes of exposure
to bright light (open columns)
22 to 23 hours after the initial
temperature minimum
(crosses). In both subjects,
plasma melatonin
concentrations decreased
markedly in response to bright
light and then increased after
the return to dim light.
Suppression of Melatonin Secretion in Some Blind Patients by Exposure to Bright Light
Charles A. Czeisler, Ph.D., M.D., Theresa L. Shanahan, B.Sc., Elizabeth B. Klerman, M.D., Ph.D., Heinz Martens, M.D., Daniel J. Brotman, A.B.,
Jonathan S. Emens, B.A., Torsten Klein, M.D., and Joseph F. Rizzo, M.D.
The New England Journal of Medicine Volume 332:6-11 January 5, 1995 Number 1
Results of Melatonin-Suppression
Tests with and without a Blindfold
•
The plasma melatonin
concentrations did not fall during
the bright-light exposure when the
blindfold was in place (left-hand
panel), but they fell abruptly during
the exposure when the patient's
eyes were not blindfolded (righthand panel).
Suppression of Melatonin Secretion in Some Blind Patients by Exposure to Bright Light
Charles A. Czeisler, Ph.D., M.D., Theresa L. Shanahan, B.Sc., Elizabeth B. Klerman, M.D., Ph.D., Heinz Martens, M.D., Daniel J. Brotman, A.B.,
Jonathan S. Emens, B.A., Torsten Klein, M.D., and Joseph F. Rizzo, M.D.
The New England Journal of Medicine Volume 332:6-11 January 5, 1995 Number 1
Melatonin doesn’t work for
sleep
• Apparent cause
• Excess adrenaline
and cortisol
decrease melatonin
secretion & effects
on sleep
Melatonin doesn’t work for
sleep
• ↑ Melatonin at
bedtime by 1.5 to 2
times of the routine
dosage
Influence of beta-blockers on
melatonin release
• Melatonin is mainly
produced during the
night by stimulation
of adrenergic beta1and alpha1receptors.
Influence of beta-blockers on melatonin release.
Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R,
Liebmann P, Lindner W. Eur J Clin Pharmacol. 1999 Apr;55(2):111-5
αMT6s in urine after intake of the drugs
30
NS
-7%
NS
+7%
NS NS
-10% +14%
25
20
Propanolol
Atenolol
Cardevilol
Verapamil
Only the specifically beta-blocking (S)-enantiomers
15of propranoal
atenolol which act via specific
P<0.01andP<0.01
Urine aMT6s after
-86%beta1-receptors decrease the
inhibition of-80%
adrenergic
intake of the drugs in
10
nocturnal production of melatonin whereas
microgthe
non-beta-blocking (R)-enantiomers have no effect.
5
26
5
0
Placebo S-Prop.
40 mg
27
4
S-Aten.
50 mg
23
29
R-SVer.
A randomized, double-blind, placebocontrolled, cross-over study in 15
healthy volunteers.
R-Prop. R-Aten. R-S-Car.
40 mg
50 mg 120 mg
Influence of beta-blockers on melatonin release. Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R,
Liebmann P, Lindner W. Eur J Clin Pharmacol. 1999 Apr;55(2):111-5
The effects of the beta-adrenergic agonist, isoproterenol, on
induced increase in melatonin production in the pineal gland of
young and old rats, at different circadian stages.
Twice greater than the old rats
2
Isoproterenol is able to stimulate
both young and old rat pineal
glands whatever the
circadian stage.
1,8
1,6
1,4
1,2
1
Basal levels of
melatonin production
0,8
0,6
0,4
0,2
0
Young rats
Old rats
The intensity of the response to 10(-6) M isoproterenol infusion was
greater in young than in old rat pineal glands (P<0.001),
Isoproterenol-stimulated melatonin production by perifused rat pineal glands: age- and time-related effects.
Naïri-Skandrani L, Djeridane Y, Charbuy H, Touitou Y. Neuro
Endocrinol Lett. 2004 Aug;25(4):257-61
In vivo, a single acute subcutaneous administration of DZP
(3 mg/kg body weight) significantly affected pineal melatonin
synthesis and plasma melatonin levels, while administration of the
metabolites under the same conditions did not.
% in
decrease
70
60
50
40
30
70%
40%
40%
20
% in decrease of
10
0
Diazepam
and its three
metabolites:
1. nordiazepam ,
2. oxazepam,
3. Temazepam.
were tested.
Pineal
melatonin
content
N-Acetylt.
Activity
Plasma
melatonin
levels
Effects of diazepam and its metabolites on nocturnal melatonin secretion in the rat pineal and Harderian
glands. A comparative in vivo and in vitro study. Djeridane Y, Touitou Y. Chronobiol Int. 2003 Mar;20(2):285-97
Melatonin therapy may reduce or stop
benzodiazenine theray prescribe in case of
sleep disorders
n = 22
100
90
80
70
60
50
40
30
20
10
0
1. 22 subjects (16 females), mean +/- S.D. age 60.1
+/- 9.5 years.
2. All patients received 3 mg of melatonin per os
daily for 6 months, 30 min before expected sleep
time.
3. Twenty of 22 patients were on benzodiazepine
treatment and they continued this treatment for part
of or for the entire melatonin administration period.
n = 13 on 20
100%
65%
n = 4 on 20
%of patients
20%
Improved
MEL.
MEL.
sleep allowing BZD Inducing a
stop
decrease in
BZD (25-66%)
Urinary 6-sulphatoxymelatonin (aMT6s)
excretion was measured
Lack of changes in serum prolactin, FSH, TSH, and estradiol after melatonin treatment in doses that
improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly
patients. Siegrist C, Benedetti C, Orlando A, Beltrán JM, Tuchscherr L, Noseda CM, Brusco LI, Cardinali DP.
J Pineal Res. 2001 Jan;30(1):34-42
Fold increase in serum melatonin concentration
compared to fluvoxamine alone
18
Thers is an increase in the
bioavailability of oral
melatonin by coadministration of fluvoxamine.
16
14
17X
12
10
12X
8
6
Area under
concentration-time
curce
Serum peak
concentration (Cmax)
of melatonin
4
2
P<.05
P<.01
0
50mg Fluvoxamine + 5 mg melatonin
Fluvoxamine, a selective
serotonin reuptake inhibitor, is
known to elevate melatonin
serum concentrations.
Increased bioavailability of oral melatonin after fluvoxamine coadministration.
Härtter S, Grözinger M, Weigmann H, Röschke J, Hiemke C. Clin
Pharmacol Ther. 2000 Jan;67(1):1-6
Melatonin and glucocorticoids
140
120
100
127
80
60
40
73
Noctural plasma
melatonin levels
pg/ml
20
0
Before
1 mg DXM
1 mg of dexametasone caused a significant reduction in plasma melatonin levels
In 9 of 11 healthy volunteers
Demisch L et al. J Pineah, Res, 1988, 5: 317-223
Effect of corticosterone, deoxycorticosterone
and dexamethasone on melatonin secretion by
the pineal gland at different circadian stages.
50
45
40
35
30
25
20
15
10
5
0
P < 0.001
High concentrations
of corticosterone
and dexamethasone
resulted in a
↓50%
significant inhibitory effect on
% decrease of
↓30%
melatonin production whatever
the
melatonin production
circadian stage, whereas lower
concentrations of both steroids did
Corticosterone Dexamethasone
not affect
melatonin
production.
0,8X10,3 mol/l
0,4X10,3 mol/l.
Kinetic changes of melatonin release in rat pineal perifusions at different circadian stages.
Excess stress
↓ Melatonin
Adrenal
gland
Adrenaline Cortisol
↑ melatonin
dosage
Oral contraceptive pill &
melatonin
OCPs decrease significantly
the melatonin peak compared
to the non users (p 0.02)
suggesting that OCPs
obliterate the circadian
rythm of melatonin
Oral contraceptives alter circadian rhythm parameters of cortisol, melatonin, blood pressure, heart rate,
skin blood flow, transepidermal water loss, and skin amino acids of healthy young women.
Reinberg AE, Touitou Y, Soudant E, Bernard D, Bazin R, Mechkouri M. Chronobiol
Int. 1996 Aug;13(3):199-211
Suppression of nocturnal plasma melatonin levels by evening
administration of sodium valproate in healthy humans.
Monteleone P, Tortorella A, Borriello R, Natale M, Cassandro P, Maj M.Biol Psychiatry. 1997 Feb 1;41(3):336-41
Institute of Psychiatry, School of Medicine, Second University of Naple
To investigate the role of gamma-aminobutyric acid (GABA) in the
modulation of human melatonin production, we studied the effects of
the acute administration of the GABAergic drug, sodium valproate
(VAL), on nocturnal blood melatonin levels in healthy subjects. To
this purpose, 4 healthy men and 3 healthy women, aged 24-33
years, underwent
three
experimental sessions
in whichnocturnal
they
Sodium
Valproate
significantly
suppressed
received orally 400 mg VAL, 800 mg VAL, or placebo, in random
blood
order,melatonin
according to levels.
a double-blind design. The drug administration
wasmaximum
done at 19:00
hours; thereafter,
blood samples
The
suppression
coincided
withwere
the collected
highest
over the night, in dark conditions with the help of a red light. As
plasma
levels
of valproic
acid. suppressed nocturnal blood
compared
to placebo,
VAL, significantly
melatonin levels, the higher dose being slightly more effective than
the lower one. at the dosage of both 400 and 800 mg, The maximum
suppression coincided with the highest plasma levels of valproic
acid. These findings support the view that endogenous GABA may
participate in the modulation of the activity of the human pineal
gland.
Effect of fluoxetine on melatonin in patients with seasonal affective
disorder and matched controls.
Childs PA, Rodin I, Martin NJ, Allen NH, Plaskett L, Smythe PJ, Thompson C. Br J Psychiatry. 1995 Feb;166(2):196-8
University Department of Psychiatry, Royal South Hants Hospital, Southampton.
• BACKGROUND. The aim was to investigate the secretion
profile of melatonin and seasonal affective disorder before and
after treatment with fluoxetine. METHOD. A six-week casecontrolled study with repeated overnight blood sampling was
conducted. (20
Ten mg
patients
fulfilling
the criteria
for major
Fluoxetine
daily)
significantly
reduced
depressive disorder, seasonal type, with a 29-item Hamilton
melatonin
both
groups.
Depressionlevels
Ratingin
Scale
(HDRS)
score of at least 20 were
compared
ten age- and
sex-matched
healthy controls
The
effect with
of fluoxetine
differs
from tricyclics
and in a
clinical laboratory. The effects of fluoxetine (20 mg/day) on the
fluvoxamine,
both of
which increase
melatonin.
HDRS and melatonin
concentration
were measured.
RESULTS.
Fluoxetine significantly reduced melatonin levels in both
groups. There was no significant difference in melatonin
secretion between the groups. CONCLUSIONS. The effect of
fluoxetine differs from tricyclics and fluvoxamine, both of
which increase melatonin.
Coffee consumption and
plasma melatonin levels
Caffeinated coffee caused a decrease in 6-SMT
excretion throughout the following night.
• Individuals who
suffer from sleep
abnormalities
should avoid
caffeinated coffee
during the evening
hours.
The effects of coffee consumption on sleep and melatonin secretion.
Shilo L, Sabbah H, Hadari R, Kovatz S, Weinberg U, Dolev S, Dagan Y, Shenkman L. Sleep
Med. 2002 May;3(3):271-3
Drinking regular caffeinated coffee, compared
to decaffeinated coffee, caused
• ↓in the total amount
of sleep
• ↓ in sleep quality
• ↑ in the length of
time of sleep
induction.
The effects of coffee consumption on sleep and melatonin secretion.
Shilo L, Sabbah H, Hadari R, Kovatz S, Weinberg U, Dolev S, Dagan Y, Shenkman L. Sleep
Med. 2002 May;3(3):271-3
Caffeine was found to increase the oral bioavailability of
melatonin probably due to an inhibition of the CYP1A2 catalysed
first-pass metabolism of melatonin
When caffeine was coadministered
the Cmax of melatonin
were increased on average
by 142% (P = 0.001)
Melatonin serum concentration after oral administration of melatonin alone (closed circles, dotted
line) or together with caffeine (3 × 200 mg) given 1 h before and 1 and 3 h after melatonin intake
(open squares, solid line). Melatonin serum concentrations were significantly (*P < 0.05; **P < 0.01)
higher at all time points between 0.5 and 6 h after melatonin intake when caffeine was
coadministered
Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity
Sebastian Härtter,1 Anna Nordmark,3 Dirk-Matthias Rose,2 Leif Bertilsson,3 Gunnel Tybring,3 and Kari Laine4.
Br J Clin Pharmacol. 2003 December; 56(6): 679–682
Higher pack-years of smoking
were associated with
significantly lower aMT6s levels
18
P for trend, 0.04
16
14
12
10
8
6
17.4
12.3
Non smoker
15+pack-year smoker
4
2
0
Urinary aMT6S ng/ml creatinine
459 healthy, primarily premenopausal (age range 33-50 yr) women from the Nurses' Health Study II (NHS II).
Urinary 6-sulfatoxymelatonin levels and their correlations with lifestyle factors and steroid hormone
levels. Schernhammer ES, Kroenke CH, Dowsett M, Folkerd E, Hankinson SE. J Pineal Res. 2006 Mar;40(2):116-24
Alcohol consumtion and
plasma melatonin levels
Melatonin doesn’t work for sleep
100
90
80
70
↓15%
↓19%
60
50
40
30
%Change in salivary
melatonin levels after
placebo
% Change in salivary
melatonin levels afer
alcohol consumption
20
10
vodka: 0.54 g/kg for men :
n=9
0.49 g/kg for women : n = 20
0
140minutes
190 minutes
Age range from 21 to 25 years
(m = 22.6)
Evening alcohol suppresses salivary melatonin in young adults.
. Chronobiol Int. 2007;24(3):463-70
Rupp TL, Acebo C, Carskadon MA
6-sulfatoxymelatonin
decreases in a dosedependent manner with increase consumption
of alcoholic beverages.
100
90
80
70
0%
9%
15%
17%
60
50
40
30
20
10
Noctural levels of
urinary 6Sulfintoxymelatonin
expressed in %
compare to non
consumer (100%)
A total of 203 randomly selected healthy
women between the ages of 20 and 74 years
0
1 drink 2 drinks 3 drinks
4 and
more
driks
Alcohol consumption and urinary concentration of 6-sulfatoxymelatonin in healthy women.
Stevens RG, Davis S, Mirick DK, Kheifets L, Kaune W. Epidemiology. 2000 Nov;11(6):660-5
0
A moderate dose of alcohol
in the evening suppress
melatonin in young adults.
-2
-4
0%
0%
-6
-8
-10
% change in salivary
melatonin compared
to baseline
-12
-14
-16
-15%
-18
-19%
-20
29 adults (nine males) ages 21 to 25
(M=22.6, SD=1.2) yrs.
140 min 140 min 190 min 190 min
Placebo alcohol placebo alcohol
Alcohol (vodka: 0.54 g/kg for men and 0.49 g/kg for women) or placebo beverage was consumed over
30 min, ending 1 h before stabilized bedtime.
Evening alcohol suppresses salivary melatonin in young adults. Rupp TL, Acebo C, Carskadon MA.
.Chronobiol
Int. 2007;24(3):463-70
Breath Alcohol Concentration
Salivary melatonin
Mean and standard error of the mean melatonin values (pg/ml) are displayed for placebo (dashed line) and alcohol
(solid line) conditions. The mean and standard error BrAC values on the alcohol night are depicted by the dotted line.
values for melatonin are labeled on the left y-axis and for BrAC on the right y-axis. Time on the x-axis is labeled in
minutes relative to the end of beverage administration, which is time 0; the stabilized at home bedtime is +60 minutes.
asterisks indicate significant (p , .05) differences in melatonin levels between conditions. The arrow indicates DLMO
phase ( Dim light melatonin onset).
Evening alcohol suppresses salivary melatonin in young adults. Rupp TL, Acebo C, Carskadon MA.
.Chronobiol
Int. 2007;24(3):463-70
Intake of ethanol between 1900-1945 h inhibited the nocturnal
melatonin secretion dose-dependently during the first half of the
night, with no changes in urinary excretion of melatonin.
P<0.05
P<0.05
P<0.05
0
-5
-10
-18%
-15
-20
-25
-30
-35
-33%
-41%
% Decrease of plasma
melatonin levels
compared to placebo
after administration of
0,05 g ethanol/kg wt.
After 1g ethanol/kg
wt.
n=9 healthy volunteers in a double
blind, cross-over study.
-40
-45
0h00
1h00
2h00
Ethanol inhibits melatonin secretion in healthy volunteers in a dose-dependent randomized double blind
cross-over study. Ekman AC, Leppäluoto J, Huttunen P, Aranko K, Vakkuri O. J Clin Endocrinol Metab. 1993 Sep;77(3):780-3
P<0.05
P<0.01
Norepinephrine
P<0.05
Ethanol-induced suppression of nocturnal
melatonin secretion and an increase in
noradrenergic activity may be closely
associated with disturbances in
sleep and performance.
Ethanol inhibits melatonin secretion in healthy volunteers in a dose-dependent randomized double blind
cross-over study. Ekman AC, Leppäluoto J, Huttunen P, Aranko K, Vakkuri O. J Clin Endocrinol Metab. 1993 Sep;77(3):780-3
Magnetic field exposure &
Melatonin secretion
This study provides further
evidence that exposure to
magnetic fields is associated
with decreased nocturnal
melatonin levels.
36
35
35.2
34
33
33.8
33.8
6-Sulfatoxymelatonin
ng/mg creatinine
32
31
31.1
30
29
Ov. Exp. Ov. not
exp.
Anov.
Exp.
Anov.
not exp.
n = 132 (20 to 45 years)
Ovulator exposed n =126
Ovulator not exposed n =119
Effect of 60-Hz Magnetic Field Exposure on Noctural 6-Ssulfatoxymelatonin, Estrogens, Luteinizing
Hormone, and Follicule-Stimulating Hormone in healthy Reproductive-Age Women: Results of a
Crossover Trial. SCOTTT DAVIS, PhD, DANA K. MIRICK, MS, CHU CHEN, PhD, AND FRANK Z. STANCZYK, PhD
Ann Epidemiol. 2006 Aug;16(8):622-31. Epub 2006 Feb 2
0
-0,5
1.0
-1
This study provides further
evidence that exposure to
magnetic fields is associated
with decreased nocturnal
melatonin levels.
-1,5
6-Sulfatoxymelatonin
ng/mg creatinine
-2
-2,5
-3.1
-3
-3,5
Medication users
(n=14)
Nonusers
(n=101)
Includes use of psychotropics, sedatives, b-blockers,
steroids, acquired immunodeficiency syndrome
chemotherapeutic agents, and thyroid preparations during
the 24 hours preceding urine collection.
Effect of 60-Hz Magnetic Field Exposure on Noctural 6-Ssulfatoxymelatonin, Estrogens, Luteinizing
Hormone, and Follicule-Stimulating Hormone in healthy Reproductive-Age Women: Results of a
Crossover Trial. SCOTTT DAVIS, PhD, DANA K. MIRICK, MS, CHU CHEN, PhD, AND FRANK Z. STANCZYK, PhD
Ann Epidemiol. 2006 Aug;16(8):622-31. Epub 2006 Feb 2
Operator
Exposure
Time-weighed average
(µW/cm2)
TWAmean
The excretion rates of aMT6s (mol/h) in operators under
high-level and low-level radiofrequency EMR exposure
and control group during fast-rotating extended shifts
TWAmax
BC
station
N = 12
6-25 MHz
3.10
137
TV
station
N = 12
66.5-900
MHz
1.89
5.24
SAT
station
N = 12
5.850-6.245
GHz
1.6
3.57
Variations of Melatonin and Stress Hormones under Extended Shifts and Radiofrequency Electromagnetic
Radiation. Katia Koicheva Vangelova and Mishel Salvador Israel. Reviews on Environmental Health. Vollume 20, No2, 2005
Interaction between melatonin
and sexual hormones
IGF1
• The study was
performed on 14
women (volunteers),
aged from 64 to 80
years (mean age
71+/-4.6 years).
• Melatonin (2 mg
daily at 19:00 h)
DHEAS
higher
DHEAS/cortisol
ratio
No change in
cortisol levels
=
Estradiol
Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol,
dehydroepiandrosterone sulfate, and somatomedin C in elderly women.
Pawlikowski M, Kolomecka M, Wojtczak A, Karasek M. Neuro
Endocrinol Lett. 2002 Apr;23 Suppl 1:17-9
Sleep disturbances
9 out of 14 patients
45
70
40
60
35
50
30
n=9
40
30
n=4
20
% of
patients
complain
ing of
sleep
disturba
10
0
64.3%
2 mg
25
20
15
10
Improve
ment in
general
sleep
quality
(%)
5
0
28.6%
Before After 6M
treatment of MEL.
44.5
6 months MEL.
2 mg
Among patients
suffering of sleep
disturbances
Improvement in parameters as sleep initiation and latency,
numbers of awakenings episodes and wake time after sleep onset
Effect of 6six months melatonin treatment on sleep quality and serum concentrations of estradiol,
cortisol, dehydroepiandrosterone sulphate, and somatomedin C in elderly women.
Marek Pawlikowski, Maria Kolomecka, Ana Wojtczak & Michal Karasek.
Neuroendocrinology Letters 2002;23(suppl 1):17-19
Effect of 6six months melatonin 2 mg treatment
on serum concentrations of estradiol, cortisol,
DHEAS and IGF1 in elderly women.
Effect of 6six months melatonin treatment on sleep quality and serum concentrations of estradiol,
cortisol, dehydroepiandrosterone sulphate, and somatomedin C in elderly women.
Marek Pawlikowski, Maria Kolomecka, Ana Wojtczak & Michal Karasek.
Neuroendocrinology Letters 2002;23(suppl 1):17-19
Interaction between melatonin
and non sexual hormones
Effects of melatonin on basal PRL
release by cultured pituitary glands and
by dissociated pituitary cells
Melatonin decreases Prolactin
secretion by pituitary gland
Effects of melatonin on basal PRL release by cultured pituitary glands and
by dissociated pituitary cells. A, Pituitary glands were cultured in the
presence of melatonin at the concentrations and durations indicated.
Medium was renewed every 3 h. Mean ± SEM (n = 12); P < 0.05 (ANOVA) for
all the four curves. B, Same as in A, with dissociated pituitary cells cultures
on polycarbonate membrane inserts; mean ± SEM (n = 12); P < 0.0001
(ANOVA) for all three curves. C, Cultured pituitary glands were challenged
for 3 h, either with melatonin (10-8 M), or luzindole (10-7 M), or both. Mean ±
SEM (n = 6); *, P < 0.05 (Student’s t test). Similar results were obtained in two
other experiments.
Melatonin modulates secretion of growth hormone and prolactin by trout pituitary glands and cells in
culture. Falcón J, Besseau L, Fazzari D, Attia J, Gaildrat P, Beauchaud M, Boeuf G.
Effects of melatonin on basal GH
release by cultured pituitary glands.
Melatonin ↑
GH release
A, Glands were cultured in the presence of melatonin, at the indicated concentrations, for 30
min, 3 h and 12 h. This resulted in a dose-dependent increase in GH release. Mean ± SEM (n =
6); P < 0.05 for all three curves (one-way ANOVA). Similar results were obtained in two other
experiments. B, Under pharmacological conditions as in A, the stimulatory effect of melatonin
(mel), detected at the concentration of 10-8 M, was antagonized in the presence of 10-7 M
luzindole. Mean ± SEM (n = 6) P < 0.05 (Student’s t test). Similar results were obtained in
another experiment.
Melatonin modulates secretion of growth hormone and prolactin by trout pituitary glands and cells in
culture. Falcón J, Besseau L, Fazzari D, Attia J, Gaildrat P, Beauchaud M, Boeuf G.
Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: qua
Lack of changes in serum prolactin, FSH, TSH, and estradiol after melatonin tre
Ex vivo studies on the acute and chronic effects of DHEA and DHEA-sulfate on melatonin synthesis in
young- and old-rat pineal glands. Djeridane Y, Touitou Y. Steroids. 2004 May;69(5):343-9
• Significant negative
correlation between the
peak serum melatonin
concentration and the
serum 17 beta-estradiol
concentration in
premenopausal women
aged 40-50 years
(r = -0.661, P<0.0005).
46 premenopausal women,
44 postmenopausal women,
11 premenopausal women with hysterectomy and
bilateral salpingo-oophorectomy for leiomyoma.
Changes in nocturnal melatonin secretion in perimenopausal women: correlation with endogenous
estrogen concentrations. Okatani Y, Morioka N, Wakatsuki A. J Pineal Res. 2000 Mar;28(2):111-8
Jet Lag
• Disturbance in circadian
hormone rythm
• Too low melatonin at night
• Too low cortisol rythm
during day
• => Disturbance of other
hormone cycle : TH, GH,
Sexual hormones, etc
• First 3 days in the new
location :
1. ↑ Melatonin 2-3 X routine
dose before bedtime
2. ↑ Cortisol therapy 22.5 X routine dose
• Folowing 3 days :
1. ↑ Melatonin 1.5-1.75 X
2. ↑ Cortisol therapy
1.5-1.75 X
Increase nightly melatonin
production by :
• Very dark bedroom
(dark curtains,
eyemask,…) => ↑ 50
to 200% melatonin
secretion
• More outdoor
daylight (especially
in the morning) >
2000 lux
• Light therapy
Increase nightly melatonin
production by :
• More relaxatio time
(especially in the
second half of the
day)
• Limit sress &
excitment in your
live (especially in
the late afternoon &
evening)
Avoid any situation that
decreases melatonin production
• 1. Coffee, thea, Cola
(caffeine)
• 2. Alcohol
• 3. B Blockers, high
dosade
glucocorticoids,
benzodiazepin,….
• 4. Chronic stress
• 5. Light at nigt
MELATONIN
supplements
can
MECHANISM
SOLUTION
↓ Cortisol
production
↓ Melatonin in untreated or
not suffciently treated
cortisol deficiency patients
= Melatonin and correct
cortisol deficiency
↓OVARIAN ACTIVITY
(only in case of excess
melatonin)
↓ Oesrtgen
production
↓ Melatonin posology
(< 10 mg)
↑ THYROID ACTIVITY
↑ T4  T3
conversion
↓ dosage of thyroid therapy
in treated hypothyroid
patients
↑ GH
production
↓ dosage of GH therapy in
treated GH deficient patients
↓ GLUCOCORTICOIDS
(fatigue, diziness,
sugar craving,…)
(Palpitation, excess
sweating, hunger, earlier
morning wake up
↑ SOMATOTROPE
ACTIVITY
Women wanted to conceive
• Pregnant women should avoid melatonin,
since its teratogenic effect is not known.
Melatonin deficiencies in women. Rohr UD, Herold J. Maturitas. 2002 Apr 15;41 Suppl 1:S85-104.
• Melatonin (75 and300 mg) inhibits ovarian
function in women. Melatonin and melatoninprogestin combinations alter pituitaryovarian function in women and can inhibit
ovulation.
Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women
and can inhibit ovulation.
Cohen M. J
Voordouw BC, Euser R, Verdonk RE, Alberda BT, de Jong FH, Drogendijk AC, Fauser BC,
Clin Endocrinol Metab. 1992 Jan;74(1):108-17
• Melatonin levels are significantly higher
in functional hypothalamic amenorrheic
patients than in normal controls.
• A dose of 75 mg melatonin was tested
as contraception : melatonin
inactivated the GnRH pulse generator.
Melatonin: a contraceptive for the nineties. Silman RE. Eur J Obstet Gynecol Reprod Biol. 1993
Apr;49(1-2):3-9
• Nursing : melatonin has not been
tested in pregnancy : unknown risks,
small amount of melatonin are
transmitted through breast milk.
Melatonin
&
Autoimmune diseases
Melatonin alters the balance of T helper (Th)-1
and Th-2 cells mainly towards Th-1 responses
Melatonin
Immunomodulation by Melatonin: Its Significance for Seasonally Occurring Diseases. Srinivasan V, Spence DW,
Trakht I, Pandi-Perumal SR, Cardinali DP, Maestroni GJ. Neuroimmunomodulation.
2008 Aug 5;15(2):93-101. [Epub ahead of print]
Melatonin stimulates the production of natural
killer cells, monocytes and leukocytes
Eosinophil
Immunomodulation by Melatonin: Its Significance for Seasonally Occurring Diseases. Srinivasan V, Spence DW,
Trakht I, Pandi-Perumal SR, Cardinali DP, Maestroni GJ. Neuroimmunomodulation.
2008 Aug 5;15(2):93-101. [Epub ahead of print]
Melatonin increases the production of relevant
cytokines such as interleukin (IL)-2, IL-6, IL-12
and interferon-gamma
Immunomodulation by Melatonin: Its Significance for Seasonally Occurring Diseases. Srinivasan V, Spence DW,
Trakht I, Pandi-Perumal SR, Cardinali DP, Maestroni GJ. Neuroimmunomodulation.
2008 Aug 5;15(2):93-101. [Epub ahead of print]
C
MEL
• MLT serum level reached the
peak at least two hours
before in RA patients than in
controls (p < 0.05).
•
Subsequently, in RA
patients, MLT concentration
showed a plateau level
lasting two to three hours,
an effect not observed in
healthy controls.
• Several clinical symptoms of
RA, such as morning gelling,
stiffness, and swelling,
which are more evident in
the early morning, might be
related to the
neuroimmunomodulatory
effects exerted by MLT on
synovitis and might be
explained by the imbalance
between cortisol serum
levels (lower in RA patients)
and MLT serum levels
(higher in RA patients).
Melatonin serum levels in rheumatoid arthritis.Sulli A, Maestroni GJ, Villaggio B, Hertens E, Craviotto C, Pizzorni C, Briata M,
Seriolo B, Cutolo M. Ann
N Y Acad Sci. 2002 Jun;966:276-83
P < 0.05 versus
healthy controls
Patients were treated with nonsteroidal anti-inflammatory drugs (naproxene or
ketoprofene) and antacids. No one had been treated with corticosteroids or
disease-modifying antirheumatic drugs during the last two months before
entry, and no TNF-α blockers had been administered.
Melatonin serum levels in rheumatoid arthritis.Sulli A, Maestroni GJ, Villaggio B, Hertens E, Craviotto C, Pizzorni C, Briata M,
Seriolo B, Cutolo M. Ann
N Y Acad Sci. 2002 Jun;966:276-83
Conclusions
• Several clinical symptoms of
RA, such as joint gelling,
stiffness, and swelling,
which are more evident in
the early morning, might be
related to the
neuroimmunomodulatory
effects exerted by MLT on
synovitis and might be
explained by the imbalance
between cortisol serum
levels (lower in RA patients)
and MLT serum levels
(higher in RA patients).