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by Aftab J. Ahmed, Ph.D.
Gender-Specificity in Therapeutics
. . . relative body weight, organ size, blood pressure, fat distribution,
and hormonal activity affect absorption processing and clearance
of various drugs between the genders.
Given the gender-bias in etiology
and, indeed in some cases, clinical
presentation of disease, it is
only befitting that a greater
emphasis is being placed on
gender specificity of therapeutics. It is a relatively
recent occurrence, which is likely to have
an impact on dosing, timing and frequency of
dispensation of therapeutics and, hence,
may propel first steps toward individualized
medicine.
On the face of it, it may appear curious,
even counter-intuitive, that gender could dictate
design of therapeutic regimens, for physiological
responses to pharmaceuticals and
nutritives are expected to be uniform. Yet as a
raft of studies have underscored lately, gender
plays a significant role in therapeutic outcomes.
Two intertwined factors are central to
gender-specificity both in susceptibility to disease
and response to therapy. Thus, whereas
women are more prone to autoimmune diseases,
routinely attributed to hormonal fluctuations,
estrogen depletion alone cannot
account for such prevalence. Further, for both
the better and the worse, anatomy dictates the
therapeutic efficacy of a corrective agent. That
is, relative body weight, organ size, blood pressure,
fat distribution and hormonal activity
affect absorption processing and clearance of
various drugs between the genders.
Ultimately, absorption, distribution,
bioavailability and elimination of a drug determine
not only its effectiveness but also the
extent of side effects associated with a corrective
agent. If the total body load of a drug is
higher, or it persists in the body beyond its
clearance time, it is likely to cause side effects
and may even accumulate in sundry organs.
For instance, nevirapine, prescribed to arrest
replication of the AIDS virus, showed higher
blood levels in women compared to men,
which resulted in rash, gastrointestinal discomfort
and nausea.¹ At least partially, excessive
blood load of the drug may be due to
gender differences in liver function. In effect,
liver function influences the incidence and
severity of side effects. Likewise, damage to the
kidney by drugs may also be accounted for by
relative robustness of the renal function.
It should be noted, however, that gender
considerations solely refer to the effectiveness
of a therapeutic/corrective agent and not
necessarily to its safety profile. For instance,
women respond favorably to and report
longer-lasting relief from k-opioids,
morphine-like painkillers, than men. In fact,
k-opioids may worsen the pain in males.²
Notwithstanding the contentious debate as to
which gender tolerates the pain more stoically,
examples bespeak a broader issue in health care
delivery; namely, how best to tailor and calibrate
dispensation of therapies that maximize
benefits while curtailing the extent of side
effects and, indeed, prevent tissue accumulation
of drugs/nutritives. Implicit in this line of
reasoning is that therapeutic regimens must be
commensurate with the physiological and
metabolic context of each individual.
Thus, it is counter-productive to merely
inhibit the conversion of testosterone
to dihydrotestosterone (DHT) in
prostate maladies without giving due consideration
to increased estrogen production in
aging males. After all, the severity of damage to
the prostate is just as much a function of
increased amounts of DHT as that of estrogen
metabolism.³ By the same token, greater or
exclusive focus on estrogen replacement in
peri- and post-menopausal women can be
detrimental to general health. It is a small
wonder then that recent reports caution
against heart disease and dementia as potential
outcomes of long-term hormone replacement
therapy.
Given but these two examples, recent
emphasis on the development of “pink Viagra”
of late is intriguing, indeed. Whereas restricted
blood flow in a vast majority of men precipitates
transient or recalcitrant erectile dysfunction,
increased blood flow would be but one
component in the rather complex libidinal
response in women, for hormonal changes
contribute significantly to it. Nonetheless,
enhanced blood flow, by the neurotransmitter
nitric oxide (NO), to the pelvic floor muscle is
indispensable in both men and women.
Nutritively, NO is efficiently induced by the
amino acid citrulline. The amount of NO produced
differs between the genders, however.
Women produce 87 percent more NO upon
appropriate physiological stimulus than
men, which is to say that dispensation of
a NO inducer should be accordingly calibrated
between the genders. Thus, a modicum
of judiciousness is necessitated in premenopausal
women with inadequate or unsatisfactory
libidinal response, which could be a
result of biogenic factors other than restricted
blood flow or hormonal insufficiency.
Likewise, due attention is required for dispensation
of pharmaceuticals/nutritives during
pregnancy and lactation, since their metabolites
cross the placental barrier and more often
than not do tend to appear in the breast milk.
In short, unless such considerations are
implemented in the development of therapeutic/
corrective modalities, the cookie-cutter
approach to health care is likely to be fraught
with adverse events and conceivably avoid
long-term complications.
While gender-based analyses are still in
short supply, this focus frames broader issues
in health care. It is for good reason, then, that
clinical trials are designed with due representation
not only of the genders but also of various
ethnicities. As detailed elsewhere, far from
balkanization of health care, paradoxically, this
approach may well yield insights in nutritive
prevention.4
Aftab J. Ahmed, Ph.D., is vice president of
research and development and business development,
Marlyn Nutraceuticals, Inc. Phoenix,
Arizona. E-mail:
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Selected references:
- Burger, et al. “Pharmacokinetic Variability Caused by Gender: Do Women Have Higher Exposure than Men?” JAIDS (2000). Vol. 29, p. 101.
- Fillingim, R. “Sex-Related Differences in the Experience of Pain,” J. Pain (2000). Vol. 10, p. 14.
- Raloff, J. “Radical Prostates,” Sci. News (1997). Vol. 151, p. 126.
- Ahmed, A. “Gender-Specificity in Therapeutics: Balkanization of Healthcare?” In preparation (2003).
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