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OCR for page 233
APPENDIX
B
Physiological and
Pharmacological Differences
Between the Sexes
Physiological and pharmacological differences between the sexes are
discussed in Chapter 5 (see Table 5-3~. Additional examples are presented
here in Table B-1, which is a continuation of Table 5-3, as the purpose of
understanding sex differences is to achieve better health and health care,
and understanding the differences between the sexes in response to thera-
peutic agents is particularly important in that regard.
TABLE B-1 Receptor, Enzyme, and Structural Differences Between
Males and Females
Sex Difference
Clinical Relevance
The dopamine D2 receptor gene has a
TaqIA restriction fragment length
polymorphism that yields two alleles,
A1 and A2. Individuals with the A1
allele have a D2 receptor with a lower
density and diminished function.
Nemonapride, a potent D2 receptor
antagonist with antipsychotic activity,
increases the plasma prolactin
concentration more in females with
the A1 allele than males with this
polymorphism (Mihara et al., 2000~.
233
Females may be at higher risk than males
of adverse events associated with
nemonapride-induced
hyperprolactinemia.
continued on next page
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234
TABLE B-1 Continued
EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
Sex Difference
Clinical Relevance
The levels of androgen and progesterone May explain why men have deeper voices
receptors present in vocal cords are than women and why women treated
greater in males than females. with testosterone may develop a deep
Progesterone receptor levels decrease voice.
with age (Newman et al., 2000~.
Inorganic phosphate pi-class glutathione
S-transferase (pI 4.8) is approximately
1.6 times more abundant in the female
colon than in the male colon. There are
also significant differences between
males and females in substrate
specificities and inhibition kinetics
(Singhal et al., 1992~.
Atrial natriuretic peptide (ANP) levels
are twofold greater in young women
than young men. Levels do not vary
during the menstrual cycle. ANP levels
are not different in age-matched men
and menopausal women. Aldosterone
levels are higher in women than men
during the luteal phase but not during
the preovulatory phase of menses
(Clark et al., 1990~.
Clearance of methylprednisolone is
greater in men than women during the
late luteal phase of the menstrual cycle.
The 50 percent inhibitory concentration
for suppression of cortisol secretion is
significantly lower in females. No sex
differences in net cortisol or helper
T-lymphocyte suppression exist. Males
had greater net suppression of blood
basophil weight (tow et al., 1993~.
Blood samples from more men than
women (89 versus 48 percent) with
stage B-type lymphatic leukemia test
positive for the MDR1 (multiple drug
resistance) phenotype (Monteleone
et al., 1997~.
Male and female colons may metabolize
small organic molecules differently.
When women are infused with hypertonic
saline, ANP levels are increased more
during the luteal phase than the
follicular phase of the menstrual cycle.
Investigators conclude that intra-
vascular volumes were decreased
during the luteal phase compared with
those during the follicular phase
(Trigoso et al., 1996~.
More rapid elimination of methyl-
prednisolone by women compensates for
their increased sensitivity to methyl-
prednisolone-induced cortisol
suppression. The doses given to patients
were based on lean body mass.
Women have a more benign course of
disease, suggesting that sex-dependent
differences in drug resistance gene
activity may be responsible for at least
some of the disease course (Monteleone
et al., 1997~. In deciding on a treatment
for untreated patients, sex and
determination of marl gene expression
should be considered in selecting
appropriate treatment, including the
need to use P-glycoprotein inhibitors.
OCR for page 235
APPENDIX B
TABLE B-1 Continued
235
Sex Difference
Clinical Relevance
d-Fenfluramine is used as a probe for
central serotonin activity, such as in
patients with obsessive-compulsive
disease. In healthy subjects the
secretion of a plasma cortisol response
to d-fenfluramine was blunted in
females but not males. The blunted
response was more pronounced in
female patients than healthy female
subjects (Gilmore et al., 1992~.
Young adults generally discriminate
lower concentrations of citric acid and
caffeine from water than elderly
subjects. Younger subjects also detected
suprathreshold concentrations of
caffeine significantly more intense than
those judged by young males and the
elderly (Hyde and Feller, 1981)
Young ovulating females excrete more
kallikrein in their urine than males and
menopausal females. During the
follicular phase of the menstrual cycle
the levels are similar to those in males
and the levels rise during the luteal
phase. These sex differences are present
in white subjects but not African-
American subjects (Kailasam et al., 1998~.
Suggests serotonin dysfunction in female
patients with some psychiatric disorders.
These differences may influence the types
and quantities of food and drink that
people consume.
The level of renal kallikrein excretion is
diminished in essential hypertension.
Results suggest that renal kallikrein
biosynthesis responses are decreased in
African Americans, a group at increased
risk for development of hypertension.
Estrogen receptors are higher in varicose It has not been determined if these
segments than nonvaricose segments of
the same vein, especially in females.
Progesterone receptor levels are denser
in the nonvaricose segments of females
than in those of males (Mashiah et al.,
1999~.
Estrogen and progesterone receptor
transcripts are expressed in arterial
cruciate ligaments of males and
females (Sciore et al., 1998~. Males have
significantly larger knee cartilage than
females, independent of body and bone
size (Cicuttini et al 1999~.
differences are age related or are
associated with an increased incidence of
varicosities in females.
The rate of injury to ligaments in female
athletes is greater than that to ligaments
in male athletes.
continued on next page
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236
TABLE B-1 Continued
EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
Sex Difference
Clinical Relevance
Platelet phenolsulfotransferase levels Investigators recommend research into
have different seasonal profiles in males sex-dependent metabolism of the
and females (Marazziti et al., 1998b). endogenous and exogenous substrates
for the enzyme.
A positive relationship between
occurrence of buccal mucosa ridging
and tongue indentation (signs of
bruxism) and sex and age was found,
with the relationship found to be more
common in females than males
(Piquero et al., 1999~.
Peroxidase activity in tears is higher
during the preovulatory and luteal
phases of the menstrual cycle. The
activity correlates with plasma estradiol
levels (Marcozzi et al., 2000~.
May be associated with a variety of
illnesses, e.g., headache and neck
stiffness.
Is a possible cause for the greater
incidence of some ocular diseases, e.g.,
keratoconjunctivitis sicca (dry eyes), in
females
The dissociation constant (Kd) for These observations suggest that
paroxetine binding to human platelets modifications in the serotonin
is lower in young females than males; transporter might provide the basis for
the opposite is found in elderly females. the increased susceptibility of females to
The Kd was negatively correlated with depression.
age in males (Marazziti et al., 1998a).
The ratio of the incidence of irritable
bowel syndrome in females:males is
2:1 (Mayer et al., 1999~.
Obstructive sleep apnea is more
prevalent in males than females, but
the incidence increases in postmeno-
pausal women, suggesting that pro-
gesterone may provide protection
against the disorder. Jordan et al.
(2000) tested this hypothesis and found
that one potential mechanism, the
poststimulus ventilatory decline, is not
different in males and females or in
females during the follicular and luteal
phases of their menstrual cycles.
Males receiving a 21-milligram nicotine
patch take significantly longer to
relapse to smoking than females
(Swan et al., 1997~.
Positron emission tomography scans after
rectosigmoid balloon distension show
differences and may help elucidate the
reason for the sex differences.
The biological basis for this difference is
unknown.
OCR for page 237
APPENDIX B
TABLE B-1 Continued
237
Sex Difference
Clinical Relevance
Elderly people metabolize the verapamil An example of a pharmacokinetic, not a
enantiomer more slowly than young pharmacodynamic, difference.
people. Mean arterial pressure and
PR interval (an electrocardiogram
variable) reduction correlated with
S- and R-verapamil levels in blood
and are not affected by sex or age
(Gupta et al., 1995~.
The endothelial synthesis of nitric oxide
from L-arginine is stimulated by
acetylcholine. The vasodilating effect
of the brachial artery administration
of acetylcholine was markedly
impaired in hypercholesterolemic
males but not hypercholesterolemic
females compared with the effect in
eucholesterolemic controls. The
responses to acetylcholine were
normalized by L-arginine in hyper-
cholesterolemic males, whereas the
effects were similar in hyper-
cholesterolemic and control women
(Chowienczyk et al., 1994~.
Administration of 6 milligrams of
bromperidol raises plasma prolactin
levels more in females than males and
correlates with the levels of brom-
peridol and its reduced metabolite in
plasma (Yasui et al., 1998~.
In healthy subjects a plasma cortisol
response to d-fenfluramine is present
in females but not males. The response
did not differ between patients with
obsessive-compulsive disease and
control subjects but was significantly
reduced in female patients compared
with that in female controls
(Monteleone et al., 1997~.
These responses may account for why
hypercholesterolemic females appear to
be protected from the adverse effects of
nitric oxide production.
Serum prolactin level increases in males
receiving haloperidol have been
correlated with the clinical response to
this antipsychosis drug (Van Putten et
al., 1991~. Assuming that the mechanism
for the prolactin increases for these
drugs is similar in males and females, a
smaller dose for females than males may
be appropriate.
These results suggest a dysfunction of
serotonin transmission in female patients
with obsessive-compulsive disease.
continued on next page
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238
TABLE B-1 Continued
EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH
Sex Difference
Clinical Relevance
Estrogen binds to the dopamine
receptor, providing an explanation of
why postmenopausal women are more
likely than younger women to
experience the dopamine-related side
effects of drugs (Dawkins and Potter,
1991; Yonkers et al., 1992~.
Apolipoprotein E genotype differences
had no effect on the response to
tacrine in patients with mild to
moderate Alzheimer's disease,
although there was a clear sex
difference. Treatment effect size was
not different between epsilon 2-3 and
epsilon 4 in men but was larger for
epsilon 2-3 than epsilon 4 in women
(Farlow et al., 1998~.
To satisfactorily dose patients with
growth hormone, a dose adjustment
method provides the best results since
females were less sensitive to growth
hormone and larger doses are required
to achieve in females the same levels
achieved in males (Drake et al., 1998~.
The incidence of vascular thromboses
varies between the sexes. Estrogen beta
and androgen receptors are expressed
on human megakaryocytes; they are
upregulated by 1.5 and 10 nanomoles
of testosterone per liter and are down-
regulated by 100 nanomoles of
testosterone per liter (Khetawat
et al., 2000~.
Binding to receptor probably has an
antidopaminergic effect.
Could significantly improve drug selection
for each patient if the effect is
substantiated for other drugs.
Serum insulin-like growth factor type 1
level measurements provide the
surrogate endpoint for the appropriate
dose.
The ability of megakaryocytes to respond
to testosterone provides a possible
mechanism by which sex hormones may
mediate sex differences in platelet
activity and thrombotic diseases.
Representative terms from entire chapter:
clinical relevance