Contraception 82 (2010) 314 – 323

Review article

Metabolism and pharmacokinetics of contraceptive steroids in obese

women: a review
Alison B. Edelmana,⁎, Ganesh Cheralab,c , Frank Z. Stanczykd,e
a
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR 97239, USA
b
College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
c
School of Pharmacy, Oregon Heath and Science University, Portland, OR 97239, USA
d
Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
e
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Received 22 February 2010; revised 6 April 2010; accepted 14 April 2010

Abstract

The effect of obesity on drug metabolism and pharmacokinetics is poorly understood, and this is particularly true in regard to
contraceptive steroids. This article will review the known and theoretical physiologic and pharmacologic interactions between obesity and
contraceptive steroids.
© 2010 Elsevier Inc. All rights reserved.

Keywords: Obesity; Contraceptive steroids; Pharmacokinetics; Birth control

1. Introduction itary and ovaries. The pulsatile release of gonadotropin-

The exponential growth of obesity since the 1990s has raised
concern regarding the efficacy of medications whose dose is not
based on weight or body mass index (BMI) [1–3]. This is
particularly true of hormonal contraception where the “one dose
fits all” approach is standard practice. Most drugs, including
contraceptive steroids, have not been extensively studied in an
obese population [4]. As hormonal contraception is one of the
most common prescription medications used by reproductive-
age women [5] and the consequences of impaired efficacy is
high (unplanned pregnancy) [6], understanding the interaction
between obesity and contraceptive steroids is critical.
The present article reviews the mechanism of action,
metabolism and pharmacokinetics of contraceptive steroids
and how obesity is known or thought to affect these processes.
2. Mechanism of action of contraceptive steroids
Normal reproductive function is dependent on the
complex interrelationship between the hypothalamus, pitu-
⁎ Corresponding author. Tel.: +1 503 494 5949; fax: +1 503 494 3111.
E-mail address: edelmana@ohsu.edu (A.B. Edelman).
0010-7824/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.contraception.2010.04.016
releasing hormone (GnRH) from the hypothalamus signals
the anterior pituitary to release follicle-stimulating hormone
(FSH) and luteinizing hormone (LH), also in a pulsatile
fashion [7–11]. These in turn trigger the ovary to produce
estrogen and progesterone. These ovarian hormones also
play a key role in regulating gonadotropin secretion through
both negative and positive feedback loops depending on the
time in the cycle [7–10,12].
The main effect of contraceptive steroids is via negative
feedback inhibition of the hypothalamic–pituitary–ovarian
(HPO) axis, with supplementary effects on cervical mucus
and the endometrium. Pulsatile secretion of FSH and LH is
profoundly suppressed by exogenous estrogen [ethinyl
estradiol (EE)] and progestin, respectively [8,13–15].
However, ovulation suppression, thinning of the endometri-
um and cervical mucus thickening is due mostly to progestin
and is dose-dependent [8,11]. It is unclear whether ovulation
suppression occurs at the level of the hypothalamus, the
pituitary or both [7,13]. Pituitary sensitivity to FSH has been
found to be reduced by combined hormonal contraceptives
as tested by a GnRH challenge test [13] but rapidly returns
with discontinuation [16]. This is also evident with cyclically
dosed hormonal contraceptives [i.e., combined oral contra-
ceptives (OCs)] when gonadotropins and ovarian hormones
 A.B. Edelman et al. / Contraception 82 (2010) 314–323
are suppressed during active hormone use but reactivate
during the hormone-free interval (placebo week) [13,16].
These previous studies only focused on the influence of
contraceptive steroid hormones on the HPO axis in normal
weight and BMI subjects (animals and women) but not in
obese subjects. We recently investigated whether increased
BMI affects OC suppression of the HPO axis [17]. Ten
ovulatory women of normal BMI (b25 kg/m2) and 10 obese
women (BMI N30 kg/m2) received 100 mcg levonorgestrel
combined with 20 mcg EE for two cycles. The subjects were
closely studied at the beginning and end of their hormone-
free interval. Both BMI groups demonstrated hypothalamic–
pituitary activation at the end of the hormone-free interval,
but more obese women also demonstrated ovarian hormonal
changes associated with the recruitment and maturation of a
dominant follicle.
3. Review of hepatic first-pass metabolism
Hepatic first-pass of a contraceptive steroid has a
profound effect on the metabolism and pharmacokinetics
of the steroid (Fig. 1). After its ingestion, the steroid enters
the stomach where it undergoes dissolution. The dissolved
drug then enters the intestine where it undergoes some
transformation by bacterial enzymes and by enzymes in the
intestinal mucosa. The mixture of metabolized and unme-
tabolized steroids is then absorbed through the intestinal
mucosa and enters the portal vein blood, which perfuses the
liver. The liver has many steroid metabolizing enzymes
(reductases, dehydrogenases, hydroxylases, sulfuryl trans-
Fig. 1. Hepatic first-pass effect of a steroidal drug (oral administration).
315
ferases and glucuronyl transferases), which extensively
transform both the unmetabolized and metabolized steroids
entering the organ. Some of the contraceptive steroid that
was originally ingested remains unmetabolized. The extent
to which a steroid reaches the systemic circulation following
hepatic first-pass metabolism is referred to as its bioavail-
ability. It is important to realize that the concentration of
steroid in the portal vein blood is very high and has a
profound effect on hepatic proteins, including sex hormone-
binding globulin (SHBG), corticosteroid-binding globulin,
thyroid-binding globulin, angiotensinogen, as well as
coagulation and fibrinolytic factors.
4. Metabolism and pharmacokinetics of EE in
nonobese women
The estrogenic component of practically all currently
marketed combined oral contraceptives (COCs) consists of
EE. While around 90% of oral EE is absorbed from the
stomach and upper intestine during the first hour after ingestion
in most women, it can take as long as 2 h in some individuals to
fully absorb the compound [18]. Wide variability in the peak
blood EE level and the time taken to reach it has been observed
between individuals, the latter varying from 1 to 2 h in most
women and up to as long as 6 h in others [19,20].
Ethinyl estradiol metabolism follows similar pathways to
that of the body's endogenous estradiol, namely, oxidation
reactions at various carbons of the steroid nucleus (Fig. 2)
[21,22]. The most important of these for estradiol involves 2-
hydroxylation, 16α-hydroxylation and conjugation in the
liver. For EE, 2-hydroxylation is quantitatively the most
important metabolic pathway, while 16α-hydroxylation
appears to be compromised by the presence of the ethinyl
group at carbon 17. Additional hydroxylations at the 4, 6 and
16β positions of EE have been reported, but to a much
smaller extent than at the 2 position. Because the 2-
hydroxylation of EE is catalyzed principally by the hepatic
cytochrome P450 (CYP) pathway, specifically CYP3A4 and
CYP2C9, wide variation in levels of these enzymes between
individuals [21] contributes significantly to the intersubject
variability in EE pharmacokinetics.
After absorption, EE is rapidly conjugated in part to a
glucuronide, which is inactive and undergoes renal excre-
tion, and to the 3- and 17-sulfates, which are present in the
circulation at levels about 10 times those of EE itself [23].
The sulfates are partially deconjugated during enterohepatic
recirculation to EE (the 17-sulfate to about 11% and the 3-
sulfate to about 21%), but this adds little to the circulating
unconjugated EE.
Both bioavailability and elimination half-life, which
reflects exposure of a drug to tissues, are important to the
clinician. For both parameters, EE shows wide intersubject
variability, as well as day-to-day variability within the same
individual. The bioavailability of EE, i.e., the amount
reaching the systemic circulation following hepatic first-
316 A.B. Edelman et al. / Contraception 82 (2010) 314–323

Fig. 2. Major routes of EE metabolism.

pass metabolism, ranges from about 25% to 65% of the marketed in the near future. Estradiol differs in chemical
amount ingested. The EE elimination half-life, i.e., the time structure from EE only in that it lacks the ethinyl group.
required for its blood level to fall to 50% of the maximal Nevertheless, this difference results in extensive metabolism
value, ranges from 6 to 27 h [18]. of estradiol during its hepatic first-pass, and consequently a
Studies in different ethnic populations have shown that very low bioavailability (b10%). However, this disadvantage
plasma EE levels differ substantially between ethnic groups. of estradiol may be negated by its pharmacodynamic profile
In a study of EE metabolism in women from Nigeria, Sri and relatively low potency.
Lanka, Singapore, Thailand and the United States, Gold-
zieher et al. [24] found the lowest plasma levels of EE in
Nigerian women and the highest in women from Thailand, 5. Metabolism and pharmacokinetics of progestins in
even when corrected for body surface area. Another study nonobese women
involving 83 women in 14 geographically diverse centers
[25] found that the intercenter EE differences were of the Some 24 different synthetic progestogens (progestins) are
same order as the intracenter variability. When the urinary used therapeutically, predominantly for contraception and/or
metabolites of EE in women from these locales were hormone therapy in postmenopausal women to prevent
analyzed [26], remarkable differences were found: Nigerian
women excreted primarily EE conjugates, with little
evidence of oxidative or other metabolism, while in contrast,
diverse oxidative metabolism at the 2, 4, 6 and 16 positions
of the EE molecule, plus other unidentified metabolism, was
noted in women from the United States; metabolism in Sri
Lankan women occurred to an intermediate extent, between
those extremes.
Interestingly, no studies exist regarding the EE metabo-
lism of nonoral routes, but there is one study that compares
the pharmacokinetics of EE administered via transdermal,
oral and vaginal routes [27]. As expected, with oral
administration, there is a peak-trough pattern in serum EE
levels, whereas with transdermal and vaginal dosing, a more
constant level is observed. The area under the concentration
time (AUC) curve of EE is greatest for transdermal
administration, but it is difficult to compare the pharmaco-
kinetics of EE among these three dosing routes since the dose
of EE for each route was not equivalent (Fig. 3).
Although EE has been the principal estrogenic compo-
nent of COCs over the past 50 years, COCs using estradiol Fig. 3. Comparison of EE pharmacokinetics dosed via three different routes
instead of EE have been developed recently and should be (oral, transdermal and vaginal) [27].
 A.B. Edelman et al. / Contraception 82 (2010) 314–323
endometrial hyperplasia. Progestins can be classified into two
groups on the basis of their chemical structure: (a) those
related to progesterone and (b) those related to testosterone
(Fig. 4). Interestingly, of the 12 progestins in the progesterone
group, only two are used for contraception, namely,
medroxyprogesterone acetate (MPA) and cyproterone ace-
tate, while all 12 progestins in the testosterone group are used
for contraception.
The 12 progestins structurally related to (but not derived
from) testosterone can be divided into ethinylated (containing
an ethinyl group at carbon 17) and nonethinylated progestins.
The latter group is composed of drospirenone and dienogest,
whereas the ethinylated group is divided into estranes and 13-
ethylgonanes (containing an ethyl group at carbon 13). The
estrane group consists of norethindrone and its derivatives
(norethindrone acetate, ethynodiol diacetate norethynodrel,
lynestrenol and norethindrone enanthate), whereas the 13-
ethylgonane group contains levonorgestrel and its deriva-
tives, including desogestrel, norgestimate and gestodene.
Progestins vary widely not only in their chemical
structures but also in their metabolism and pharmacokinetics.
In addition, large intersubject variability, and often even
intrasubject variability, is observed in their metabolism,
blood levels and pharmacokinetic parameters. Many of
the progestins are prodrugs, which mean they must
be metabolized to become active (Table 1). All five
norethindrone derivatives described earlier are prodrugs,
and they are readily converted into parent compounds. In
addition, desogestrel is converted to the active product,
Fig. 4. Classification of synthetic progestins.
317
etonogestrel, and norgestimate is transformed to levonorges-
trel and norelgestromin.
The wide intersubject differences in progestin metabolism
mean that, following administration, each woman will have a
unique steroidal milieu consisting of the individual's
endogenous steroid hormones and their metabolites mixed
homogeneously with the progestin and its metabolites. The
biologic significance of the steroidal milieu is not yet
understood but may have some relationship to contraceptive
effectiveness and side effects. Major metabolic transforma-
tions include reduction (addition of two hydrogen) by
reductases at the double-bond and by hydroxysteroid
dehydrogenases at the ketone group in the A ring of the
progestins (Fig. 5). The unreduced and reduced progestins
can also undergo hydroxylation in which a hydroxyl group is
added to carbon 2 or carbon 16 of the molecule, as well as
conjugation to form sulfates or glucuronides at one or more
hydroxyl groups of the molecules.
Progestins in OCs undergo hepatic first-pass metabolism
described earlier under Section 2 (Fig. 1). They are all well
absorbed. However, as stated earlier, there is wide intersubject
variability in their blood levels and pharmacokinetic para-
meters [28]. In general, they reach a maximum concentration
(Cmax) within 1 to 3 h [time to maximum concentration
(Tmax)], and the Cmax and AUC is dose-dependent. Levo-
norgestrel, gestodene and dienogest have the highest
bioavailabilities, generally N90%, whereas the bioavailabil-
ities for other progestins that are structurally related to
testosterone are about 20% lower [28]. Norethindrone and
318 A.B. Edelman et al. / Contraception 82 (2010) 314–323
Table 1
Progestin prodrugs and their active components
Prodrug Active progestin
Norethindrone acetate Norethindrone
Ethynodiol diacetate
Norethynodrel
Lynestrenol
Norethindrone enanthate
Desogestrel Etonogestrel (3-ketodesogestrel)
Norgestimate Norelgestromin (levonorgestrel-3-oxime) and
levonorgestrel
dienogest have relatively low half-lives, generally in the range
of 8 to 12 h [28]. Cyproterone acetate appears to have the
highest half-life (50–80 h), followed by drospirenone
(approximately 30 h) and the other progestins (12–24 h) [28].
Finally, very little is known regarding the metabolism
and pharmacokinetics of contraceptive progestins used
parenterally. Also, there is a paucity of data on how
estrogen and progestin given in combination affect each
other's metabolism.
6. General knowledge about the effect of obesity on the
metabolism and pharmacokinetics of drugs
Pharmacokinetics is the study of the passage of a drug
through the body. It encompasses four physiologic process-
es, namely, absorption, distribution, metabolism and excre-
tion. Many factors alter one or more of these four processes,
leading to altered drug pharmacokinetics and thereby altered
drug therapeutics. Some of those factors include sex, age,
dietary habits, alcohol intake, starvation, coadministered
drugs, altitude, infection, disease, seasonal and circadian
rhythms, pregnancy and body weight.
Drug dosing based on body weight is a widely used
method to individualize dose. While such dose individual-
Fig. 5. Major routes of metabolism of different active progestins (norethindrone, levonorgestrel, norelgestromin, etonogestrel, gestodene, drospirenone and
dienogest).
ization has been used for a long time, this approach is purely
empirical and based on none or very scanty scientific data.
With the recent alarming rates of increase in obesity
worldwide, there is a greater need for understanding drug
dosing in patients of varying body weights and sizes.
Attempts have been made over the last decade to understand
the physiologic changes accompanying obesity that are
relevant for drug pharmacokinetics, but much is still
unknown (Table 2).
6.1. Absorption
Many factors that affect oral drug absorption are reported
to be altered in the obese population [29]. In general, cardiac
output is higher, leading to increased gut perfusion, which
may enhance the rate and amount of drug/nutrient absorbed
[30,31]. Accelerated gastric emptying has also been
observed in obese subjects that could lead to faster
absorption and thereby a decrease in Tmax [32–35]. In regard
to intestinal transit time, which is directly related to the total
amount of drug/nutrient absorbed, no conclusive data are
available in obese patients [36,37].
Enterohepatic recirculation is an important phenomenon
of drug absorption for some drugs like COCs. Thus, any
alterations in the recirculation could affect the clinical
outcome [38,39]. While human data are absent, rodent
models of obesity suggest a significant decrease in bile salt
secretion and expression of canalicular transporters such as
the bile salt export pump and organic anion transporter 1
[40]. These changes could potentially decrease the secretion
of some drugs, including COCs, into bile duct, which in
turn could lead to a decrease in the amount that re-enters
systemic circulation.
Blood flow to skin, muscle and subcutaneous fat is an
important determinant of drug absorption when administered
parenterally, subcutaneously or transdermally. While cardiac
output is increased in obese subjects, the blood flow per
 A.B. Edelman et al. / Contraception 82 (2010) 314–323 319

Table 2
Physiologic alterations due to obesity and their pharmacokinetic consequences
Physiologic alterations Pharmacokinetic consequences
Absorption ↑ Cardiac output to gut ↑ Rate and amount of drug absorption; ­ Cmax, ↓ in Tmax
Accelerated gastric emptying
Distribution Altered body composition ↑ Volume of distribution
• ↑ Lean body mass • Moderate ­ for hydrophilic drugs
• ↑ Adipose tissue • Relatively greater ­ for lipophilic drugs
• ↑ Organ sizes Alterations in free fraction of drug
• ↑ Cardiac output • ↓ In free fraction of basic drugs
• ↑ In free fraction of highly bound acidic drugs due to
potential displacement
Alterations in protein binding
• ↑ AAG
• ↑ Plasma lipids
• ↑ Free fatty acids
• ↓ SHBG
Metabolism ↑ Splanchnic flow ↓ In specific cytochrome P450 enzyme activities
↑ Number of hepatocytes ↑ In glucuronidation and sulfation
↑ Fatty infiltration Altered biliary metabolism
↑ Cholestasis Altered enterohepatic recirculation
↑ Periportal fibrosis and infiltration
↓ Biliary secretion and transporters
Excretion ↑ Kidney size ↑ In renal clearance in general
↑ Glomerular surface area ↑ Glomerular filtration rate
↑ Renal plasma flow ↑ Filtration and tubular secretion
↓ Urine pH Altered reabsorption (↑ or ↓ depends on drug pKa)
↓ Biliary secretion and transporters Altered biliary excretion
Adapted from Blouin and Warren [4].

gram of fat is significantly less in morbidly obese compared
to lean subjects, which may affect the rate and/or extent drug
absorption [41]. However, very limited information is
available regarding the effects of obesity on drug absorption
in humans. Propranolol is a lipophilic drug, similar to
contraceptive steroids. The systemic bioavailability of
propranolol is slightly higher, though statistically not
significant, in obese subjects [42]. Data from the limited
number of studies are inconclusive, and therefore, more
focused studies are needed before a conclusion can be made
on the general effect of obesity on drug absorption.
6.2. Distribution
Distribution of a drug in the body is governed by the
amount of fat and lean mass, blood flow to tissues and
plasma and tissue binding. In obese subjects, absolute fat
and lean mass is increased [43,44]. However, as a
percentage of total body weight, lean mass decreases
while fat mass increases twofold [45]. As mentioned earlier,
cardiac output increases in obese subjects; this in turn
increases blood flow to various organs, including fat.
However, the blood flow per amount of fat mass is
decreased [41]. The effect of the above alterations in fat and
lean mass is mainly dependent on the oil/water partition
coefficient (or degree of lipophilicity) of a given drug. In
general, highly lipophilic drugs partition into the greater fat
mass available in obese subjects, and correspondingly, the
measure of drug distribution (volume of distribution, Vd)
linearly correlates with absolute body weight. On the other
hand, highly hydrophilic drugs tend to prefer lean mass, and
accordingly, their Vd correlate to a greater degree with lean
body weight. However, for drugs with intermediate
lipophilicity and hydrophilicity, Vd is a function of both
ideal and absolute body weights. In addition to ideal and
absolute body weights, other body size biomarkers such as
lean body weight, fat free mass and adjusted body weight
were also shown to exhibit a correlation to Vd (and other
pharmacokinetic parameters) [46].
Drugs administered parenterally (transdermally, subcuta-
neously, etc.) first partition into fat mass at the site of
application/administration, and then they are released over
time into the systemic circulation. The site of drug
administration may be altered due to thickness of subcuta-
neous tissue (i.e., drug is deposited in subcutaneous fat
instead of intramuscularly), which may affect the amounts
and rate of drug release [47]. This larger amount of
subcutaneous fat also has a detrimental effect on the
physiologic status of a subject [48]. Depending on the
lipophilic and hydrophilic properties of a drug, its retention
in subcutaneous fat depots could be altered. A study by
Wortsman et al. [49] concluded that the lower bioavailability
of vitamin D in obese subjects is due to its slower release
from subcutaneous fat. Furthermore, the decrease in fat
blood flow could negatively affect the parenteral absorption
of a drug into the systemic circulation.
Another important determinant of drug distribution is
plasma protein binding. While plasma levels of the major
320 A.B. Edelman et al. / Contraception 82 (2010) 314–323
drug binding protein, albumin, are unaltered in obese
subjects, the lipoproteins that bind to albumin are greatly
increased. It is unclear if increased levels of lipoprotein
would compete for more protein binding sites and thus could
cause drug displacement from albumin binding sites. Plasma
levels of α1-acid glycoprotein (AAG), which primarily binds
basic drugs, are increased in obese subjects. A few studies
also suggest alterations in the binding affinity of AAG
[50,51]. Sex hormone-binding globulin, though not found in
concentrations as high as albumin and AAG, is a plasma
protein that binds specific endogenous androgens and
estrogens, as well as progestins such as levonorgestrel and
norethindrone. Decreased plasma levels of SHBG were
reported in obese subjects [52]. One of our recent studies,
however, failed to show a correlation between serum levels
of SHBG and BMI [17].
6.3. Metabolism
The liver is the major organ of metabolism. Drug
metabolism occurs in two phases: Phase 1 (oxidation,
reduction, hydrolysis, etc.) and Phase 2 (conjugation
reactions such as glucuronidation, sulfation, etc.). The
expression of Phase 1 and 2 enzymes is regulated by a
host of factors of which cytokines play a significant role.
Obesity is considered as a chronic, low-grade inflammatory
state [53,54] with elevated levels of interleukin 6, tumor
necrosis factor α and other proinflammatory cytokines
[55,56]. Cytokines are known transcriptional regulators of
expression of the CYP super family of enzymes and other
drug-metabolizing enzymes [57–60]. In addition to cyto-
kine-mediated alterations in the expression of enzymes, fatty
infiltration of the liver might affect the function of the drug-
metabolizing enzymes [61].
Studies in obese human subjects, using CYP-specific
substrates, show a decrease in CYP3A and CYP2E1
activities. No conclusive data are available for other CYP
isozymes in obese humans. However, in genetically obese
rats, elevated levels of CYP2B, CYP2E, CYP3A and
CYP4A were reported [62]. In nutritionally induced obese
rats, only CYP2E1 activity and expression was shown to be
increased [63]. In addition to Phase 1 enzymes, some of the
Phase 2 conjugation enzymes were also altered in the obese
rats. In general, glucuronidation is the most significantly
enhanced, while sulfation is moderately enhanced. Drug
metabolism also occurs in extrahepatic tissues, and a recent
rodent study suggests that white adipose tissue is one such
tissue [64]. With increasing BMI, it is possible that the
contribution of adipose tissue to drug metabolism increases,
mainly for lipophilic drugs.
Drug transporters play a vital role in metabolism and
elimination. The interplay between drug-metabolizing
enzymes and transporters determine the overall clearance
of the drug [65]. While studies in obese human subjects are
lacking, limited data from obese animal studies suggest
alterations in the expression of various drug transporters. In
general, expression of hepatic uptake transporters such as
organic anion transporting polypeptides and sodium/taur-
ocholate cotransporting polypeptide is decreased, and on the
other hand, expression of efflux transporters (multidrug
resistance-associated proteins) is increased [66]. Similar to
the liver, expression of the renal transporters is also altered in
obese mice. Enhanced expression of the monocarboxylate
transporter (MCT) is found in the brain of obese mice [67].
Various drugs containing monocarboxylic acid moieties,
such as valproic acid, pravastatin, simvastatin, lovastatin,
etc., are substrates of MCT [68,69]. Some of the undesirable
central nervous system (CNS) side effects observed with
these drugs are attributed to the transport of parent drug and/
or its metabolites across the blood–brain barrier by MCTs,
and therefore, it could potentially place obese subjects at
greater risk of CNS side effects. MCTs are also expressed in
the intestine and thus could affect drug absorption.
Expression of canalicular transporters such as bile salt
export pump and organic anion transporter 1 was also altered
[40], with an implication for clearance of drugs that are
predominantly conjugated and excreted via bile.
6.4. Elimination
The kidney is the major organ of elimination. Three
processes, namely, glomerular filtration, tubular secretion
and reabsorption, are involved in the renal elimination of
drugs either as an unchanged moiety or as a metabolite.
Many morphological and physiologic changes in the kidney
accompany obesity [70]. Increases in kidney size [71],
glomerular Bowman's space area and filtration rate [72],
tubular secretion [73] and renin plasma flow [74] were
reported. Body mass index is inversely related to urine pH
[75]. The reabsorption of drugs is mostly a passive process
and is dependent on unionized form of a drug. The amount of
drug unionized is determined by the pH of urine; thus,
altered urinary pH in obesity could impact the reabsorption
process. Human studies have conclusively demonstrated that
renal clearance of predominantly renal excreted drugs is
increased with BMI [76–79].
Biliary excretion is another route of drug elimination and
is a significant pathway for many drugs. In obesity, bile
secretion is decreased and, in addition, expression of
canalicular bile salt export pump and organic anion
transporter 1 are decreased. A net result of these changes
could be a decrease in the amount and/or rate of biliary
excretion of drugs [40].
7. Effects of obesity on the metabolism and
pharmacokinetics of contraceptive steroids
In general, the effect of obesity on drug metabolism and
pharmacokinetics is poorly understood. This is particularly
true of steroidal contraceptives administered orally, trans-
dermally or parenterally, as most studies have excluded
women over 130% of ideal body weight. Depending on the
 A.B. Edelman et al. / Contraception 82 (2010) 314–323
drug studied, BMI can affect pharmacokinetics in several
different ways, including bioavailability and hepatic clear-
ance, renal clearance and volume of distribution.
To date, there have only been three studies investigating
the pharmacokinetics of contraceptive steroids in obese
women. In our recent study, mentioned earlier, we also
measured serum levels of levonorgestrel and EE following
their oral administration [17]. The results revealed signifi-
cant differences in levonorgestrel half-life, clearance and
time to reach steady-state between obese and normal BMI
women. The levonorgestrel half-life in the obese subjects
was twice that of the normal BMI subjects, and therefore, the
time to reach steady-state was doubled (10 days in the obese
subjects versus 5 days in the normal BMI subjects).
Consistent with these changes, more obese women demon-
strated hormonal changes associated with recruitment and
maturation of a dominant follicle. This study did not monitor
ovarian activity directly with ultrasound.
In the second study, Westhoff et al. [80] showed that
following oral administration of 150 mcg levonorgestrel in
combination with 30 mcg EE, obese women had a
significantly lower AUC and maximum plasma concentra-
tion for EE than normal BMI women. Area under the
concentration time and maximum plasma concentration
differences for levonorgestrel between the two groups were
smaller and not significant. Trough levels for both
levonorgestrel and EE were similar between the groups.
Follicular diameters tended to be larger among the obese
women, but the differences were not significant. The authors
concluded that these pharmacokinetic differences should not
affect contraceptive efficacy in obese COC users. A direct
comparison of these two pharmacokinetics studies cannot be
made as this study did not report time to reach steady state.
Additionally, the AUC calculations were based on one half-
life [80] versus two [17], which could also account for the
differences between the two studies.
In the third study, Segall-Gutierrez et al. [81] investigated
the effect of obesity on follicular development and serum
MPA levels in women using subcutaneous depo-MPA
(DMPA-SC 104 mg) for contraception during two 12-
week cycles. Subjects were recruited for three BMI
categories (five subjects in each group): normal (18.5–24.9
kg/m2), obese (30.0–39.9 kg/m2) and extremely obese (N40
kg/m2). Blood samples were obtained at monthly intervals
for quantifying MPA levels for a total of 26 weeks. Large
intersubject variability was observed in serum MPA levels.
Median MPA levels remained above the level (200 pg/mL)
needed to prevent ovulation, but compared to the normal
weight subjects, the levels were lower among obese subjects
and lowest among extremely obese subjects.
8. Pharmacogenetics
A relatively new area of drug research is pharmacoge-
netics or the role of inheritance in an individual's response to
321
a drug [82,83]. In general, we expect a dependable response
to a particular drug. This is certainly true with regard to
hormonal contraception where a “one dose fits all” approach
is pervasive. However, genetic differences may cause
clinically significant variations. No studies to date have
been done to determine if a genetic variation in the response
to contraceptive steroids exists. Warfarin, a drug with similar
metabolic pathways to contraceptive hormones through the
CYP enzymes, has been found to have genetic variations in
response. If pharmacogenetics does play a role in the
response to hormonal contraceptives, it will be interesting to
see if this counteracts or compounds the effects that obesity
may have.
9. Summary
The obesity epidemic has created new concerns and
challenges in health care. Little is known about the effects of
obesity on drug pharmacokinetics and how this in turn
influences drug therapeutics; this is especially true for
hormonal contraceptives. A greater understanding of hor-
monal contraceptive pharmacokinetics and the potential
influence that obesity may have is warranted prior to
translating this information to the bedside.
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