Adipose Tissue and Reproduction

SPECIAL CONTRIBUTIONS
Adipose tissue and reproduction in women

Henry Bohler, Jr., M.D.,
a
Sriprakash Mokshagundam, M.D.,
b
and Stephen J. Winters, M.D.
b
a
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Womens Health; and
b
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Louisville School of
Medicine, Louisville, Kentucky
Adipose tissue has been viewed as the primary source of stored energy, but with the discovery of novel adipose
tissue gene products, i.e., adipokines, another equally important role has emerged. Adipose tissue is a key endo-
crine organ involved in multiple processes, including glucose homeostasis, steroid production, immunoregulation,
hematopoesis, and reproduction. The distribution of adipose tissue may also have a signicant impact on reproduc-
tive function. (Fertil Steril
2010;94:795825. 2010 by American Society for Reproductive Medicine.)

Adipose tissue is the largest endocrine organ in the human
body, with effects on glucose homeostasis, steroid produc-
tion, the immune system, hematopoesis, and reproductive
function (16). The last several years have seen an expanded
interest in understanding the role of adipose tissue in repro-
duction, partly due to the discovery of novel adipose tissue
products, adipokines (7, 8). Adipokines may include any sub-
stance released by adipose tissue, whether from adipocytes
(fat cells), inltrating macrophages, stromovascular cells,
or other parts of the adipose tissue matrix (connective tissue
and blood vessels) (1, 9, 10). These substances include cyto-
kines, hormones, growth factors, chemokines, complement
factors, and proteins involved in vascular hemostasis, the reg-
ulation of blood pressure, lipid metabolism, glucose homeo-
stasis, and angiogenesis (11, 12).
Interest in the reproductive endocrine aspects of adipose tis-
sue has increased partly owing to the polycystic ovary syn-
drome (PCOS), one of the most investigated and prevalent
endocrinopathies in women of reproductive age (1316).
Adipose tissue excess (obesity) is present in at least 50% of
PCOS patients, and is responsible for unmasking the syndrome
in those who might otherwise go undetected (11, 17, 18). With
the present obesity epidemic, the number of patients diagnosed
with PCOS is likely to increase (19).
Obesity per se may not be as important as the distribution
of adipose tissue. Upper body fat has long been associated
with metabolic and endocrine-related ovulatory dysfunction,
but for the most part lower body fat has not (20, 21). Besides
an increase in abdominal subcutaneous adipose tissue (SAT),
upper body obesity (UBO) usually includes an accumulation
of intra-abdominal or visceral adipose tissue (VAT), which
may be the most signicant factor in disrupting normal me-
tabolism (22, 23). Both an excess and scarcity of body fat
have a signicant negative impact on several aspects of repro-
duction, including fertility and optimal pregnancy mainte-
nance (2426).
For the reproductive scientist and clinician, adipose tissue
represents an intriguing endocrine organ that is evidently
vital for reproductive function in women. The present review
focuses on adipose biology, its secretory products, and
their impact in physiologic and dysfunctional reproductive
conditions.
ADIPOSE TISSUE
Adipose tissue has several components, including adipo-
cytes, preadipocytes, endothelial cells, pericytes, monocytes,
macrophages, and broblastic connective tissue (27, 28). The
lipid droplet in adipocytes may increase in size (hypertrophy)
to reach a threshold that triggers the recruitment and differen-
tiation of preadipocytes (hyperplasia) (29). The potential for
adipocyte replication extends into adulthood, and once new
adipocytes form they remain permanently (27, 28).
Food consumption, physical activity, genetics, psycho-
logic factors, gender, and ethnicity are among the important
factors that contribute to the quantity and distribution of
adipose tissue (30). The quantity of adipocytes reects the
balance between adipose deposition (lipogenesis) and break-
down (lipolysis). Lipids account for 85% of the weight of ad-
ipose tissue, and 95%of the adipocyte content is triglycerides
(TG). The remaining 5% is water and proteins, including
adipokinesendocrine and paracrine factors, including
members of the cytokine family (27).
Received January 28, 2009; revised March 20, 2009; accepted March 24,
2009; published online July 8, 2009.
H.B. has nothing to disclose. S.M. has nothing to disclose. S.W. has noth-
ing to disclose.
Reprint requests: Henry Bohler, Jr., M.D., Division of Reproductive
Endocrinology and Infertility, Department of Obstetrics, Gynecology &
Womens Healthcare, University of Louisville, 401 E. Chestnut Street,
4th Floor, Suite 410, Louisville, KY 40202 (FAX: 502-271-5984; E-mail:
h.bohler@louisville.edu).
0015-0282/$36.00 Fertility and Sterility
Vol. 94, No. 3, August 2010

795
doi:10.1016/j.fertnstert.2009.03.079 Copyright 2010 American Society for Reproductive Medicine, Published by Elsevier Inc.
Histology and Differentiation
There are two types of mature adipocytes in mammals: brown
adipocytes and white adipocytes. Brown adipocytes are more
abundant in infancy but are scarcely represented in adults
(12). Besides their color and histologic differences (brown
adipocytes are multilocular), brown adipocytes are involved
in basal heat production, whereas white adipocytes serve as
a long-term fuel reservoir and are usually the type of fat dis-
cussed or implied in investigations involving obesity
(3133). Preadipocytes are also a component of adipose tis-
sue and respond to various stimuli, particularly insulin and
fatty acids, to become mature adipocytes (34). They initiate
differentiation through the peroxisome proliferator-activated
receptor g (PPAR-g) (12).
Innervation
Adipose tissue is regulated by the sympathetic nervous sys-
tem (SNS) (35, 36). b-Adrenergic receptors (adrenoceptors)
stimulate lipolysis to generate free fatty acids (FFAs) and
glycerol, whereas activation of a2A-adrenoceptors inhibits
lipolysis. Activation varies by fat depot and is also dependent
on age, gender, species, and amount of obesity (35, 36).
Activation of b-receptors through the G
s
protein increases
adenyl cyclase activity leading to an increase in cyclic aden-
osine monophosphate (cAMP) with phosphorylation of
hormone-sensitive lipase (HSL) and perilipin (35, 36).
HSL releases FFAs and glycerol from TGs. On the other
hand, activation of G
i
by a2-adrenoceptors decreases
cAMP to inhibit lipolysis (35).
Melanocortin receptors (MCR) have been colocalized with
SNS neurons and modulate SNS signaling to adipose cells
(35, 37). MCR activation reduces food intake and body fat
and increases energy expenditure and lipolysis (35, 38, 39).
In rodents, SNS stimulation also inhibits an increase in fat
cell number, and SNS denervation leads to obesity (4042).
Further evidence demonstrating an SNS inuence on adipose
tissue includes the presence of polymorphisms with b-recep-
tors in some morbidly obese humans and possibly the weight
gain that occurs with b-receptor antagonist therapy (4345).
Whether the parasympathetic nervous system is involved in
lipolysis is less clear (4648). There are comprehensive
reviews by Bartness and Song and others (35, 36, 44).
Metabolism
Adipose tissue metabolism results in either accumulation or
release of lipids from adipocytes as FFAs (29). Lipogenesis
and lipolysis are affected by the quantity of adipose tissue
(e.g., obese compared with nonobese), gender, neuronal in-
put, the fat depot examined (e.g., intra-abdominal compared
with extra-abdominal fat), hormones, including estrogens,
androgens, insulin, growth hormone, and cortisol, and phys-
ical activity (12, 34, 49, 50). Lipolysis is preferentially acti-
vated over lipogenesis when energy is needed, and this is
especially true during exercise and fasting (28, 51). Lipolytic
activity is reduced in subcutaneous fat compared with
visceral fat, which is also more resistant to the antilipolytic
effects of insulin (22, 52, 53).
Lipoprotein lipase (LPL) is synthesized in adipocytes as
well as muscle and many other tissues and is one of the key
enzymes involved in lipid storage (34, 36). After a meal, di-
etary TGs are transported in lymph to the circulation by chy-
lomicrons, where they acquire a series of proteins that allow
for interaction with LPL (54). LPL is stimulated by insulin
and is secreted into the circulation and resides on the capil-
lary endothelium, where it hydrolyzes TGs, forming FFAs
and glycerol (55, 56). FFAs are used for oxidative metabo-
lism or enter adipocytes by a protein-facilitated process to
be stored as TGs (34, 36, 55). During fasting, the net ow
of FFAs is outward from adipocytes into the circulation,
where they are bound by albumin to be oxidized as fuel by
liver, muscle, and other cells while preserving glucose for uti-
lization by CNS neurons and erythrocytes (12, 57). Insulin
promotes the uptake of FFAs by adipocytes by increasing
LPL synthesis and release but is less effective in visceral fat
compared with SAT (36, 52). The antilipolytic effect of insu-
lin is mediated by a reduction of cAMP through phosphoino-
sitide 3-kinase with suppression of protein kinase A (Fig. 1).
Hormone sensitive lipase, the key enzyme regulating lipol-
ysis, is found in many tissues, including adipocytes.(36, 51,
52). Phosphorylated HSL hydrolyzes TGs into FFAs and
glycerol, and insulin decreases this process (36, 55). Other li-
pases, such as adipose triglyceride lipase, may also regulate
adipocyte metabolism (56, 58).
Testosterone and dihydrotestosterone (DHT) promote cen-
tral obesity because they decrease HSL expression while up-
regulating LPL action (59). Conversely, estrogen decreases
central fat accumulation while increasing fat in the femo-
ral-gluteal region (60, 61). Estrogen suppresses adipose
growth in part by diminishing LPLgene transcription through
an estrogen responselike element in the promoter region of
the LPL gene or by modulating posttranscriptional activity
(60, 61). Cortisol (in the presence of insulin) and androgens
generally stimulate LPL activity and increase central fat
quantities (34, 52, 62). Catecholamines, growth hormone,
thyroid hormone, natriuretic peptide, and tumor necrosis fac-
tor alpha (TNF-a) are among other hormones affecting lipid
storage.
Tumor necrosis factor alpha promotes lipolysis by down-
regulating membrane proteins and perilipin, a protein that
forms the protective coat of lipid droplets, which are then
susceptible to degradation by HSL (36, 63). Owing to ele-
vated TNF-a in adipocytes, plasma FFAs are increased in
obesity. There are a number of excellent reviews of this eld
(12, 34, 36, 49, 52, 64) (Table 1).
Energy Homeostasis
Besides providing thermal insulation and protection from
mechanical trauma, adipose tissue is a key source of energy
in times of nutritional insufciency (65, 66). This is
796
Bohler et al. Adipose tissue and reproduction in women Vol. 94, No. 3, August 2010
important between meals and is critical during starvation.
The greater the quantity of adipose tissue, the greater the
chance of survival when food supply is inadequate (28, 65).
The probability of successful reproduction decreases when
food is scarce; therefore, adequate energy stores in times of
limited food intake appear to be teleologically linked to the
processes of reproduction, including the onset and mainte-
nance of ovulatory cycles, pregnancy, and lactation (67, 68).
Energy homeostasis is a complex process (65, 66, 6971).
A steady state of energy ux is reached when energy intake
(food consumption) equals energy expended and there is nei-
ther a gain nor loss of weight (70, 72). Energy expended is
accounted for by basal metabolism (the energy it takes to
conduct normal physiologic processes), adaptive thermogen-
esis (the energy dissipated as heat in response to environmen-
tal changes), and physical activity or voluntary movement
(72). A unilateral increase of energy intake or expenditure
will alter white adipose tissue mass quantity (11). Obesity
results when food intake exceeds energy expended. Mutated
genes may be responsible for an excess or deciency in
adipose tissue mass, but a genetic component is thought to
play a minor role in overall energy homeostasis (72).
Adipocytes, which account for approximately 50% of adi-
pose tissue, store energy as TGs, which are energy efcient
because their water content is small compared with other sour-
ces of energy, such as protein and carbohydrates (36, 65, 66).
During lipolysis, TGs release 9 kcal/g, whereas carbohydrates
and protein release 4 kcal/g (36, 51, 65).
The primary signal indicating the quantity of energy stores is
believed to be leptin, but other hormones are known to inu-
ence energy homeostasis by encouraging feeding or signaling
satiety (7, 70, 73). The gastrointestinal hormones ghrelin and
peptide YY
336
(PYY
336
) increase and decrease food intake,
respectively (71). Other hypothalamic orexigenic neurohor-
mones include neuropeptide Y (NPY), melanin-concentrating
FIGURE 1
Hormone regulation of TGmetabolism. Fat mass is regulated by the processes of lipogenesis and lipolysis which
are controlled primarily by lipoprotein lipase (LPL) and hormone sensitive lipase (HSL), respectively. LPL is
released to the capillary endothelium where it hydrolyzes TGs in very low density lipoproteins and chylomicrons.
FFA are re-esteried with glycerol-3-phosphate to form TG in the adipocyte. HSL, so named because of its
responsiveness to catecholamines and insulin, hydrolyzes adipose tissue TGs into FFA and glycerol. Androgens
increase LPL and decrease HSL activity. Estrogens decrease LPL and increase HSL activity. *Actions are fat
depot-specic. (See text) ANP atrial natriuretic peptide; TGtriglyceride; LPL lipoprotein lipase; FFA free
fatty acids; HSL hormone sensitive lipase. Modied and used with permission fromFrayn KN, Karpe F, Fielding
BA, Macdonald IA, Coppack SW. Integrative physiology of human adipose tissue. Int J Obes Relat Metab Disord
2003;27:87588.
Bohler. Adipose tissue and reproduction in women. Fertil Steril 2010.
Fertility and Sterility
797
hormone, and agouti-related peptide (AgRP), all of which are
down-regulated by leptin (11, 71, 72, 74). Leptin receptors
are colocalized with NPY-containing neurons in the arcuate
nucleus. A decrease in hypothalamic leptin is associated with
an increase in NPY/AgRP, which, along with other neurohor-
mones, initiates food intake (11, 71, 7477). Leptin also regu-
lates endocannabinoids, which activate receptors involved in
maintaining food intake (78, 79). The activities of pro-opiome-
lanocortin/melanocortin, cocaine- and amphetamine-related
transcript neurons, andcorticotropin-releasinghormone are an-
orexigenic and are stimulated by leptin (11, 79). In the brain,
insulin also suppresses NPY (71, 72).
Glucose Homeostasis
Skeletal muscle is the primary target for insulin-stimulated
glucose disposal, and signals from body fat are thought to
disrupt insulin signaling in skeletal muscle, predisposing to
insulin resistance (12, 80). If the Glut 4 adipose-specic
transporter is reduced in mice, insulin resistance develops
not only in adipocytes but also in muscle and liver, and in
obesity and type 2 diabetes Glut 4 expression is decreased
in adipose tissue but not in skeletal muscle (80, 81). Therapy
directed at increasing insulin sensitivity selectively in adi-
pose tissue signicantly improves glucose tolerance (12).
Clearly, obesity is linked to insulin resistance and diabetes,
again due to the importance of fat cells in glucose homeosta-
sis. Adipocyte products may promote glucose uptake,
e.g., leptin, adiponectin, omentin, visfatin, or impede glucose
uptake, e.g., TNF-a, interleukin (IL) 6, resistin, and retinol-
binding protein 4 (12) (Fig. 2).
Chronic Inammation
A likely bridge between obesity and insulin resistance is the
inammatory response (82). Obesity is a chronic inamma-
tory state marked by an invasion of mononuclear phagocytes
or macrophages into adipose tissue and by an increase in
proinammatory cytokines not seen in lean individuals
(83). There is a 40% increase in macrophage inltration,
which is positively correlated (along with body mass index
[BMI]) with adipocyte size (83). Thirty percent of protein
products expressed in white adipose tissue is related to in-
ammatory and macrophage-specic genes (84). Precursors
for macrophages, most likely derived from the bone marrow,
are attracted to increasing numbers of adipocytes as a result
of an overexpression of the chemotaxin gene for monocyte
chemotactic protein 1 (82, 83, 85).
Proinammatory cytokines also are up-regulated in obesity.
They are released from adipose tissue and macrophages and
include IL-6, TNF-a, and C-reactive protein (CRP) (82, 83).
As mentioned previously, IL-6 is secreted by macrophages
as well as adipocytes and may be causally related to insulin
resistance (1, 86).
Tumor necrosis factor a originates primarily from
macrophages and in turn stimulates macrophage activity
TABLE 1
Hormone effects in adipose tissue.
Hormone Action Clinical example(s)
Insulin (36, 42) Potent antilipolytic Diabetes?
Cortisol (in the presence of
insulin) (42, 52)
Increased in visceral
fat and central obesity
Cushing syndrome,
polycystic ovary syndrome
Catecholamines (36) Lipolytic, but action
depends on the balance
of b- and a-adrenergic
receptors
Activated in fasting
and exercise
Androgens (20, 327, 332, 333,
336)
Promotes central obesity Polycystic ovary
syndrome, postmenopause,
men, female-to-male
transsexuals
Estrogens (50, 51, 334, 335, 454) Decreases central
fat; increases femoral-gluteal
fat
Reproductive-age women,
postmenopause estrogen
administration
Growth hormone (34, 36, 37) Decreases central
fat; opposes action
of cortisol insulin
Acromegaly
TNF-a (36, 53, 233) Lipolytic; promotes
insulin resistance
Increased with obesity
Note: TNF tumor necrosis factor.
798
(82, 83, 87). TNF-aexpression also is increased in obesity and
inhibits insulin-stimulated glucose uptake (1, 36, 37, 86).
However, the clinical signicance of augmented adipose tis-
sue levels of TNF-a in humans is not clear (88).
Another marker of chronic inammation is highly sensi-
tive CRP (hs-CRP), which is produced in hepatocytes and ex-
hibits inammatory effects (89). It is activated by cytokines
and is positively associated with obesity, fasting insulin,
and insulin resistance (90). Serum hs-CRP levels are an inde-
pendent marker for cardiovascular disease (89). Sex hor-
mones may affect hs-CRP levels. Transdermal estrogen
may lower hs-CRP levels perhaps through IL-6 and TNF-
a (89). Moreover, hs-CRP levels vary during the menstrual
cycle in normal-weight and overweight women, with increas-
ing levels in the early follicular phase and decreasing levels
during the late follicular phase when E
2
levels are increased.
Excess visceral adiposity is a predictor for increased in-
ammatory markers (91). In a population-based study,
women with a waist-to-hip ratio (WHR) >0.8 were more
likely to have increases in inammatory markers than those
diagnosed with obesity based on a BMI >29.9 kg/m
2
(43%
compared with 15%). Compared with those with normal
body fat distribution, women with central fat exhibited
53% higher CRP levels, 30% higher TNF-a levels, 17%
higher white blood cell counts, and 42% higher IL-6 levels
(all P<.05) (91).
ADIPOSE TISSUE PRODUCTS (ADIPOKINES)
Awide variety of proteins and other products are produced by
adipose tissue. Some of these are produced by adipocytes,
whereas others are produced by adipose stromal cells, which
are important in adipocyte development, or from macro-
phages which migrated to adipose tissue in obesity (92)
(Table 2). Collectively, these products are referred to as adi-
pokines or adipocytokines, even though not all are classic cy-
tokines or from adipocytes (1, 9, 34, 9294). Adipokine
quantities may vary by metabolic state (e.g., morbid obesity),
fat compartment (visceral fat compared with subcutaneous
fat), and cell development (preadipocytes compared with ma-
ture adipocytes) (9, 95). Some adipokines are released in sub-
stantial amounts into the circulation (e.g., leptin), whereas
others, such as TNF-a, remain primarily localized to adipose
tissue and function as paracrine or autocrine regulators (52).
Several adipokines, such as leptin, adiponectin, IL-6, plas-
minogen activator inhibitor (PAI) 1, and TNF-a, are known
to inuence the functions of reproductive tissues and will
be discussed here in detail, whereas others, such as omentin,
vaspin, and acylation-stimulating protein have been reviewed
in detail elsewhere (9, 52, 92, 94).
Leptin
Leptin is a 167amino acid polypeptide that is synthesized
predominantly by fat cells but is also expressed in stomach,
placenta, and mammary gland (96100). A mutation of the
gene (ob/ob) that produces morbidly obese mice led to its
discovery, (7). The ob/ob gene was cloned in 1994 and the
16-kDa protein product was named from the Greek leptos,
meaning thin, because leptin was initially thought to act pri-
marily as an antiobesity protein (7, 101). Morbid obesity may
occur in human subjects from congenital leptin deciency or
from a mutation in the leptin receptor, but these are rare
conditions (102, 103).
Leptin circulates in free and bound forms, and total plasma
leptin represents the sum of both (104). Like other plasma
binding proteins, it protects its ligand from rapid clearance,
and may have other functions (105). Leptin is not appreciably
stored, but instead is constitutively secreted by adipocytes;
the larger the adipocyte, the more leptin it secretes (106).
Circulating levels are increased in proportion to body fat,
which coincides with its most important function: to relay
energy status (73, 76, 101, 107).
Similar in structure to cytokines, leptin and its cognate
receptor belong to the cytokine-receptor family activating
primarily the Janus kinase 2/signal transducer and activator
of transcription 3 pathways (73, 108). The soluble leptin re-
ceptor, the major leptin-binding protein in plasma, is created
by the shedding of the ectodomain of the membrane receptor
(105, 109, 110). Leptin receptors are expressed in the hypo-
thalamic arcuate nucleus, anterior pituitary, T lymphocytes,
FIGURE 2
Adipokines that promote or inhibit glucose uptake.
Adipocytes secrete proteins with variable effects on
glucose homeostasis. Adipocyte-derived proteins
with antihyperglycemic action include leptin,
adiponectin, omentin and visfatin. Other factors tend
to raise blood glucose, including resistin, TNF-a and
RBP4. TNF-a and human resistin are probably
secreted by cells other than adipocytes within the fat
pad. TNF-a tumor necrosis factor; IL, interleukin;
RBP retinol binding protein. Modied and used
with permission from Rosen ED, Spiegelman BM.
Adipocytes as regulators of energy balance and
glucose homeostasis. Nature 2006;444:84753.
799
vascular endothelial cells, pancreas, ovary, and endometrium
(110116).
Exhibiting a pulsatile and diurnal pattern of release, leptin
levels peak at 0100 hours and reach a nadir at 0900 hours
(117, 118). The number of pulses is related to BMI and to
pulse amplitude, but the mechanism controlling pulsatile lep-
tin release is still unknown, although it is independent of go-
nadal steroids and glucose (119).
Although serum leptin levels are positively correlated with
fat mass, they fall acutely with fasting, even before weight or
percentage body fat decrease (1, 120). Despite leptins re-
pressive effect on food intake, obese patients have high serum
leptin levels and may be leptin resistant, similar to the in-
sulin resistance that is often seen in obesity (108, 121). Other
factors that inuence serum leptin levels include gender, sex
steroids, and fat distribution (122124) (Table 3). There is
a differential expression of leptin in subcutaneous and vis-
ceral adipose tissue (125). In vitro studies have demonstrated
that leptin secretion from SAT is signicantly higher than
from intra-abdominal omental fat, in both obese and nonob-
ese individuals (116). Leptin transcripts follow the same pat-
tern, probably owing to a larger cell size in subcutaneous fat
(52). Because subcutaneous fat comprises 80% of total body
fat, SAT is considered to be the most important source of
leptin (125).
Estrogens stimulate the production of leptin from adipose
cells from women, but not from men, and increase leptin
mRNA in ovariectomized rats (126). Ovariectomy in rats re-
duced leptin mRNA in white adipose tissue, and the effect
was reversed if rats were given estrogen supplementation
(124). Women have higher leptin concentrations in serum
and in cerebral spinal uid than men, partly because andro-
gens suppress leptin expression (127, 128). It is also likely
that estrogens increase the sensitivity to leptin in the brain
(61, 62) (Fig. 3).
Leptin plays a role in glucose homeostasis. Leptin receptors
have been localized in rodent and human pancreatic b-cells,
and leptin administration inhibits preproinsulin gene tran-
scription and reverses hyperinsulinemia in leptin-decient
ob/ob mice before effects on body weight (129, 130). Cultured
human pancreatic islet cells also demonstrated a suppression
of preproinsulin gene expression and secretion when treated
with leptin (129).
Insulin, on the other hand, increases rodent and human ob
mRNA in vivo and in cultured adipocytes (131). Acute
changes only were seen in rodents, whereas prolonged insulin
administration in human subjects was associated with a rise in
leptin levels invivo and an increase in ob mRNAand leptin se-
cretion from cultured adipocytes (132, 133). Thus, there is an
adipoinsular axis involved in serum glucose control (134).
Serum leptin levels in girls begin to rise between ages 7
and 8 years and reach peak levels by age 1315 years (135,
136). Although the timing of these changes suggests a role
for leptin in pubertal development, it remains controversial
whether increasing leptin initiates puberty in primates
(137140). Instead, leptin may play a permissive role in
this process (135, 138, 140, 141).
After menarche with the onset of menstrual cycles, serum
leptin levels parallel LH and E
2
(117, 142). Leptin levels are
at their nadir during the early follicular phase and increase
across the menstrual cycle, peaking during the luteal phase.
At this time, leptin receptors in the endometrium are also at
their peak (142145).
Leptin is found in follicular uid, and receptors for leptin
have been localized in the preovulatory follicle and mature
oocyte, as well as in granulosa, theca, and interstitial cells
(114). There is in vitro evidence that leptin may act as a gate-
way for steroidogenesis. Huang et al. demonstrated that leptin
inhibits FSH/insulin-like growth factor (IGF) 1 stimulation of
TABLE 2
Adipokines and their sites of origin in adipose tissue.
Site of origin in adipose tissue
Adipokines Adipocytes Macrophages Stromal cells
Leptin (7)
Adiponectin (8)
Visfatin (158)
TNF-a (36)
IL-6 (9) ?
PAI-1 (456) (9)
Resistin (216, 217, 457)
Retinol-binding protein (455)
Omentin (458)
Note: IL interleukin; PAI plasminogen activator inhibitor; TNF tumor necrosis factor.
800
E
2
in rat granulosa cells, and leptin inhibits insulin-induced P,
E
2
, and A secretion (146149).
Leptin may play a role in embryonic development, because
leptin receptors have been localized in preimplantation em-
bryos (143). Maternal and serum fetal levels are elevated in
term pregnancies (150).
Adiponectin
Discovered shortly after leptin in1995, adiponectin is a 30-kDa
protein (with 244 amino acids) that is the most abundant se-
creted protein expressed exclusively by adipocytes (151). Its
globular form is similar in structure to complement proteins
(8, 151153). It circulates in the blood in three main forms:
a low-molecular-weight (trimeric) form, a medium-molecu-
lar-weight (hexameric) form, and a high-molecular-weight
(dodeca- to octadecameric) form. The different forms have
varying effects on target tissues, with the high-molecular-
weight form affecting the liver and endothelial cells (154).
Factors that affect circulating adiponectin levels are not
fully understood, but adiponectin is secreted in pulses and
follows a circadian pattern in the circulation, declining at
night and reaching its nadir in the early morning hours
(155, 156). Circulating levels of adiponectin (825 mg/mL)
are higher in women than in men (157). It is known that an-
drogens decrease adiponectin secretion, but the mechanisms
of regulation by sex hormones remain undened (158, 159).
Other factors that might increase adiponectin levels include
dietary soy proteins and sh oils, whereas adiponectin levels
are decreased by oxidative stress and high-carbohydrate
meals (160, 161).
At least two distinct receptors have been identied for
adiponectin: AdipoR1 and AdipoR2 (162). These have the
typical seven-transmembrane structure but differ from
G-proteincoupled receptors in that the C-terminal portion
is extracellular whereas the N-terminal is cytoplasmic (163,
164). The main intracellular signaling pathway is through
AMP-activated kinase, but several other pathways are also
involved. Adiponectin receptors have been demonstrated
in reproductive tissues, including ovary, placenta, and endo-
metrium (165). In addition, the pituitary expresses both
adiponectin and its receptors, and adiponectin stimulates
LH secretion in vitro (166).
The chief action of adiponectin is to increase insulin-
stimulated glucose uptake in muscle and liver by decreasing
serumFFAs and triglycerides and by suppressing hepatic glu-
cose production (36, 164). Effects on fatty acid oxidation and
reduced TG accumulation in muscle could enhance muscle
insulin sensitivity (167).
Although it is an adipocyte-derived hormone, adiponectin
levels in serum actually decrease with obesity and increase
with weight reduction (83, 155, 163, 167). Adiponectin levels
are affected by a variety of pathologic states in addition to
obesity, including diabetes mellitus, cardiovascular disease,
metabolic syndrome, insulin resistance, and hypertension
(156, 168). Renal failure, congestive heart failure, and thiazo-
lidinedione drugs increase adiponectin levels (169).
Ledoux et al. (170) have recently demonstrated that in por-
cine granulosa cells, adiponectin at physiologically relevant
levels provokes expression of genes associated with periovu-
latory remodeling of the ovarian follicle. These genes include
cyclooxygenase-2, prostaglandin E synthase, and vascular
endothelial growth factor. Adiponectin interacts with both
LH and insulin to induce expression of cyclooxygenase-2
transcripts in granulosa cells (165).
The potential interaction between adiponectin, insulin, and
FSHin the regulation of periovulatory ovarian follicular gene
expression was recently summarized by Campos (94). She
postulated that the adapter protein APPL1 may play a key
role in the cross-talk between adiponectin, FSH, and insulin
receptor signaling in the ovary. Although overexpression of
adiponectin in mice results in infertility as well as improved
insulin sensitivity, adiponectin knockout has not been shown
to have a signicant impact on insulin sensitivity or fertility
(171).
Pregnancy is an insulin-resistant state, and gestational
diabetes complicates 3%12% of all pregnancies (172).
TABLE 3
Factors affecting leptin levels.
Factor Leptin level
Adipocyte mass
(87, 459)
Increased
Adipocyte size (7, 86) Increased
Adipocyte distribution
(visceral vs.
subcutaneous fat)
(105)
More from
subcutaneous fat
(total volume and
secretion are greater)
Secretion pattern
(97, 98)
Diurnal variation:
low at 0900 hours,
peak at 0100 hours
Glucocorticoids
(86, 460)
Increased
Insulin (111, 460) Controversial, but
possibly increased
Cytokines (TNF-a, IL-1)
(460)
Increased
Gender (103, 460) Higher levels in women
Sex steroids (104, 106) Increased with
estrogen; decreased
by androgens
Acute caloric
restriction (100)
Decreased
Acute caloric
consumption (112)
Increased
Note: Abbreviations as in Table 2.
801
Therefore, several studies have measured adiponectin levels
in pregnancy and gestational diabetes (173). Nien et al. (86)
reported no signicant differences in the median adiponectin
concentration between pregnant and nonpregnant women.
Plasma adiponectin concentrations were negatively corre-
lated with gestational age only among normal-weight preg-
nant women, whereas overweight pregnant women had
signicantly lower plasma adiponectin concentrations than
normal-weight women (86). Consistent with the increased
insulin resistance and weight gain that occur in pregnancy,
adiponectin concentrations correlated negatively with gesta-
tional age (174).
Vascular dysfunction is a major feature of preeclampsia.
High levels of circulating adiponectin have been reported
in preeclampsia and may be a compensatory mechanism to
protect the vasculature (86, 174).
Obesity has been associated with an increased risk of endo-
metrial cancer (175). Circulating adiponectin levels are in-
versely associated with the risk of endometrial cancer in
pre- and postmenopausal women (175). This relationship
remains signicant after adjustment for BMI and other
obesity-related risk factors, such as C-reactive protein,
IGF-1, IGF-binding proteins 1 and 2, SHBG, T, and estrone
(175).
Visfatin
Another adipokine with ties to reproduction is visfatin. This
52-kDA protein is expressed in a variety of cell types and
tissues, including adipose tissue and adipocytes, lympho-
cytes, bone marrow, liver, muscle, trophoblast, and fetal
membranes (88).
Because of the metabolic importance of visceral fat, Fuku-
hara et al. (88) sought to identify a secretory product which
might be unique to intra-abdominal adipose tissue. Using
a differential display method, they compared visceral fat
products with those of subcutaneous tissue and found a pro-
tein whose mRNA was much more abundant in visceral fat
(therefore the name, visfatin). Their work also revealed that
visfatin levels in mice and humans were in direct proportion
to the amount of visceral fat measured by computerized to-
mography (CT), a correlation not seen with subcutaneous
fat, and that plasma visfatin levels were elevated with obesity.
FIGURE 3
Leptin effects on the reproductive axis. When fat stores are adequate, leptin stimulates GnRHrelease. This action
is most likely indirect through other neurohormones, including kisspeptin, neuropeptide-y, and pro-
opiomelanocortin. Leptin and its receptor are also found in the pituitary. Whether estrogen has a physiologic role
in releasing leptin from fat stores is unclear. Receptors for leptin have been localized in the ovary and
endometriumimplying additional direct actions on these tissues. GnRHgonadotropin releasing hormone; LH
luteinizing hormone; FSH follicle stimulation hormone; KISS kisspeptin; POMC pro-opiomelanocortin;
NPY neuropeptide-Y.
802
The visfatin protein actually had been previously character-
ized as a growth factor for early-stage Bcells, and was known
as preB-cell colonyenhancing factor (89).
Visfatin was reported to have insulin-like properties (88).
In mice, recombinant visfatin lowered plasma glucose levels,
and mice with one mutant copy of the visfatin gene had
higher plasma glucose levels compared with wild-type
mice. Furthermore, visfatin was shown to bind to the insulin
receptor but at a different site, producing downstream effects
unlike those of insulin (88). The relationship between visfatin
and obesity and insulin action is presently less clear, however,
because there has been a retraction of a portion of the work
originally published in Science (176). Subsequent studies
have not conrmed the high level of expression in visceral
fat or the correlation between circulating levels and measures
of adiposity (177, 178). Some of the conicting ndings may
be due to the presence of many forms of visfatin in plasma
that are variably detected by immunoassays, and the connec-
tion to obesity may instead relate to inammation and other
cytokines (178, 179).
As mentioned previously, pregnancy is characterized by
a progressive increase in insulin resistance, and women
who fail to compensate with a sufcient increase in insulin
secretion develop gestational diabetes. Visfatin levels were
reported to progressively increase throughout gestation in
normal pregnancy, and rst-trimester levels predicted the in-
sulin sensitivity in the second trimester (180). Interestingly,
plasma visfatin levels in third-trimester healthy women
were not signicantly different from values in healthy non-
pregnant controls. Moreover, visfatin levels have been re-
ported to be both increased and decreased in gestational
diabetes (181, 182).
Insulin resistance increases the risk for preeclampsia, and
serum visfatin levels were reported to be reduced in women
with preeclampsia and further reduced with severe disease
(183). On the other hand, visfatin levels were increased in
women in the third trimester in pregnancies characterized by
intrauterine growthretardation(184). These associations await
conrmation, and their importance remains to be determined.
Tumor Necrosis Factor Alpha
Tumor necrosis factor a is constitutively expressed by many
cell types, including macrophages, lymphocytes, and adipo-
cytes (36). It is a 26-kDA transmembrane protein that was
originally found to cause necrosis of tumors (185). The bioac-
tive form is a 17-kDa cleavage product which interacts with
either type I or II TNF-a receptors in adipose tissue
(1, 186). Macrophages, whose numbers increase with an
increase in fat cell mass, are the predominant source of
TNF-a (187189). The production of TNF-a also parallels
fat cell size (1). The quantity of adipose tissue mass may be
partly determined by TNF-a because of its ability to impair
human preadipocyte differentiation, increase adipocyte apo-
ptosis, and increase lipolysis (27, 190, 191). In massively
obese women (BMI >45 kg/m
2
), TNF-a was more abundant
in SAT than in VAT, but the difference became insignicant
with a BMI <32 kg/m
2
(9).
Sex steroids may inuence TNF-a production. Circulating
levels were unchanged during the menstrual cycle, despite
signicant changes in hs-CRP insulin resistance, determined
by homeostatic model assessment (HOMA), and SHBG
levels (192). On the other hand, TNF-a release was signi-
cantly increased in cultured bone marrow cells in early post-
menopausal compared with younger women and may have
been decreased by estrogen treatment (193).
One of the mechanisms of insulin resistance in obesity may
be inhibition of insulin signaling by TNF-a (194, 195).
TNF-a impedes insulin signaling by inhibiting tyrosine
kinase activity and favoring serine phosphorylation of insulin
receptor substrate 1 (196). Furthermore, TNF-a decreases ad-
ipocyte secretion of adiponectin in vitro and suppresses Glut-
4 glucose transporters and insulin receptors (190, 197, 198).
Tumor necrosis factor a injected into the brain in rats
reduces GnRH and LH secretion, and thus it may be partly
responsible for the gonadotropin deciency that accompanies
acute illness (199). TNF-a also inhibits gonadotropin activa-
tion of steroidogenesis in the ovary as well as the testis and
adrenal cortex through the inhibition of cAMP production
and downstream signaling (1).
Interleukin-6
Interleukin-6 is a cytokine with multiple forms ranging in
size from 22 to 27 kDa (1, 200). Like other adipokines, IL-
6 binds to a transmembrane receptor (IL-6R) which is homol-
ogous to the leptin receptor and is expressed by adipose tissue
although at a higher level in hepatocytes). IL-6 associates
with two molecules of gp130 protein to initiate intracellular
signaling (1, 9, 201, 202).
One-third of circulating IL-6 is accounted for by adipose
tissue, and serum levels parallel adipocyte size and fat mass
(1). Omental fat produces threefold more IL-6 than does
SAT (9, 52, 194). IL-6 levels are positively correlated with
TGs, and IL-6induced release of TGs contributes to an in-
crease in serum FFAs (196). Although IL-6 levels increase
with obesity, mice decient in IL-6 develop obesity, and
intracerebral administration of IL-6 decreased body fat and
increased energy expenditure, suggesting actions at central
and peripheral sites (1). Levels of IL-6 are also increased by
TNF-a (200).
Interleukin-6 has multiple functions, but it is best known
for its association with inammation and insulin resistance
(200). It reduces downstream insulin receptor signaling, adi-
pogenesis, and adiponectin release (1, 52, 200, 203). In rat
pancreatic cells, IL-6 down-regulates glucose-stimulated in-
sulin release, but IL-6 administered to normal human subjects
increased plasma glucose without altering insulin concentra-
tions (196, 204). Finally, it is not clear whether IL-6 induces
or is the consequence of impaired glucose tolerance and insu-
lin resistance (196).
803
Willis et al. (205) investigated the production of proinam-
matory cytokines by monocytes in culture (including IL-6)
during ovulatory menstrual cycles. There was no signicant
change in IL-6 secretion during ovulation, although other cy-
tokines increased, but there was an increase in IL-6 produc-
tion in the luteal phase. This is in agreement with Van der
Hoek et al. (206) and others (83, 207209), who found no
role for IL-6 in ovulatory regulation based on experiments us-
ing perfused rat ovaries. OBrien et al. (207), however, noted
an increase in soluble IL-6 receptor in the luteal phase.
Minkunis ndings (210) depart fromthose above. In a per-
fusion system, IL-6 suppressed LH-induced ovulation as well
as FSH and LH-induced E
2
production from granulosa cells.
Deura et al. (211) also demonstrated a reduction in estrogen
production from human granulosa cells by IL-6.
The effect of IL-6 on hypothalamic and pituitary cells has
also been examined (212). Cultured rat pituitary cells and hy-
pothalamic explants known to contain GnRH neurons were
exposed to IL-6. IL-6 had no effect on GnRH release from
proestrus female hypothalamic explants, nor did it have an ef-
fect on GnRH-stimulated release of LH in dispersed pituitary
cells from proestrus females (212).
Endometriosis induces an inammatory response in the
peritoneal cavity, where an increase in peritoneal uid and
IL-6 levels has been documented in subfertile women
(213). The source of IL-6 in endometriosis is thought to be
macrophages and endometriotic stromal cells (214, 215).
IL-6 may also contribute to infertility by impairing sperm
transport. Yoshida et al. (214) demonstrated a signicant de-
crease in sperm motility and rapidly moving sperm in a dose-
dependent manner when the combination of IL-6 and soluble
IL-6R were added to sperm cultures.
Plasminogen Activator Inhibitor 1
Plasminogen activator inhibitor 1, a 50-kDa glycoprotein, is
the primary inhibitor of brinolysis and is expressed in liver,
endothelial cells, platelets, smooth muscle cells, and adipose
tissue (adipocytes and inltrating macrophages) (52, 216).
By inactivating urokinase-type and tissue-type plasminogen
activator, PAI-1 prevents the conversion of plasminogen to
plasmin, which reduces thrombin formation (52, 217). Ele-
vated levels of PAI-1 are associated with venous thrombosis,
cardiovascular disease, recurrent pregnancy loss, and preg-
nancy complications beyond the rst trimester (1, 217220).
Elevated PAI-1 levels are also associated with obesity, in-
sulin resistance, type 2 diabetes, dyslipidemia, hypertension,
and the metabolic syndrome (1, 10, 218, 221). A common
denominator in these conditions may be hyperinsulinemia,
because insulin as well as glucose, angiotensin II, and fatty
acids have been demonstrated to increase PAI-1 expression
(222). Weight loss, metformin, and thiazolidinediones, each
of which reduces insulin levels, decrease PAI-1 (1, 10,
222). Interestingly, PAI-1 may contribute to the development
of obesity inasmuch as PAI-1 knockout mice fail to accumu-
late fat even when overfed (223). Visceral fat production of
PAI-1 exceeds that of subcutaneous adipose tissue, especially
in subjects with visceral adiposity (218, 224).
Plasminogen activator inhibitor 2 is sometimes called the
placental PAI, because it is expressed at high levels by tropho-
blastic epithelium and is found in plasma only during preg-
nancy (216). An increase in the PAI-1/PAI-2 ratio in maternal
plasma is one biochemical marker of preeclampsia (225).
Resistin
During their study of the nuclear receptor PPAR-g, using thia-
zolidinedione antidiabetic drugs to study glucose homeostasis,
Steppan et al. found that a gene, later designated as Retn, was
suppressed in murine adipocytes (3, 226). They named the
protein productsecreted as a 94amino acid polypeptide
resistin for resist insulin, owing to its association with
insulin resistance, at least in mice. The product was simulta-
neously discovered by two other groups (227). Serum levels
of resistin are increased in diet-induced obese mice as well
as in those with genetic forms of obesity, e.g., leptin (ob/ob)
and leptin receptor (db/db) decient mice (3, 226, 228).
Further evidence to support a role for resistin as a link be-
tween obesity and insulin resistance includes a decrease in
blood glucose in mice treated with resistin antibodies, an im-
pairment of glucose tolerance in those treated with recombi-
nant resistin, and a decrease in resistin synthesis in response
to the PPAR agonist pioglitazone which improves insulin
sensitivity (226, 229).
Resistin belongs to a family of cysteine-rich resistin-like
molecules that include found in inammatory zone pro-
teins (1, 12, 230). Although localized in adipocytes in
mice, resistin levels in human adipocytes are low and may
not originate from adipocytes but rather from other resident
cells in adipose tissue, including macrophages and stromal
cells (12, 82, 84, 171, 231). Resistin is also produced in pan-
creatic islet cells and possibly muscle (84, 85, 229). More-
over, resistin mRNA levels are greater in human peripheral-
blood mononuclear cells than in adipocytes (229).
Resistin appears to impair insulin sensitivity in rodents, but
its role in human insulin resistance is unclear. Serum levels of
resistin in patients with insulin resistance or type 2 diabetes
mellitus are not consistently different from normal, although
a positive correlation between resistin with body fat mass has
been found (84, 85, 90, 91, 171, 228). Resistin levels in hu-
man peripheral blood mononuclear cells are increased by
proinammatory cytokines, including IL-1, IL-6, and TNF-
a, and are reduced by thiazolidines, providing a possible
link between inammation and insulin resistance (82, 229).
Sex steroids may affect the levels of resistin in adipose tis-
sue (depending on the fat depot), and these levels may or may
not parallel plasma levels. In rats, P increased Retn expres-
sion in retroperitoneal white adipose tissue, with a simulta-
neous increase in plasma concentrations, but not in
parametrial or subcutaneous fat depots. Estrogen decreased
804
Retn expression in some fat depots, but without a change in
plasma concentrations (232). On the other hand, Chen et al.
(233) found that 17b-estradiol up-regulated Retn expression
in 3T3-L1 adipocytes, increasing with dose and time.
Pregnancy is associated with an increase in sex steroids as
well as insulin resistance, and some have hypothesized that
resistin may be an insulin antagonist during pregnancy. Se-
rum resistin levels are elevated in pregnancy, may increase
with gestational age, and decline postpartum, and the princi-
pal source of the rising resistin levels may be the placenta
rather than adipose tissue (173, 234236).
Chen et al. (237) reported that when pregnancy is compli-
cated by gestational diabetes, resistin concentrations are
higher than in nondiabetic pregnant control subjects, whereas
Megia et al. (238) found lower resistin levels in gestational
diabetes compared with pregnant women with normal glu-
cose tolerance, indicating a need for further study.
Because there might be a link between resistin, insulin re-
sistance, and PCOS, Seow et al. (239) examined serum and
follicular uid levels of resistin in women with PCOS, includ-
ing those with insulin resistance who were undergoing IVF
cycles, and found no signicant difference from control sub-
jects although resistin mRNAin adipose tissue was increased.
On the other hand, Munir et al. (240) found a 40% increase in
mean serumresistin concentrations in women with PCOS and
a positive correlation with BMI and T. In addition, resistin was
found to increase ovarian androgen production by directly
stimulating ovarian theca cells, more so in the presence of
insulin. Resistin mRNA in adipose tissue as well as serum
T and glucose-stimulated insulin secretion was found to
decrease after laparoscopic ovarian electrocautery (241).
Furthermore, in a case-control study of infertility patients
treated with IVF, serum resistin levels were inversely corre-
lated with the number of oocytes retrieved, but, interestingly,
only in non-PCOS patients, and there was no correlation with
BMI or body weight (242). In summary, resistin is an impor-
tant adipokine, and its role in female reproduction is a subject
of ongoing studies.
FREE FATTY ACIDS
Plasma levels of FFAs are elevated in obesity partly because
of the corresponding increase in TNF-a, which stimulates
lipolysis (36). An increase in FFAs leads to lipid deposition
in skeletal muscle and liver and contributes signicantly to
insulin resistance (52, 203, 243). Consequently, FFAs cause
a decrease in glucose uptake peripherally and an increase
in hepatic glucose production (203, 243). Because of its
portal drainage, visceral fat is thought to contribute a greater
quantity of FFAs to the hepatic circulation (22, 244, 245).
FFAs are re-esteried in the liver, leading to steatosis, and
the resultant inammation further increases insulin resistance
and hyperinsulinemia (244, 246). FFAs also suppress insulin
secretion from pancreatic b-cells (247, 248). Finally, FFAs
added to cultured human granulosa cells decreased cell sur-
vival by causing apoptosis, and thus FFAs could contribute
to anovulation (249).
ADIPOSE TISSUE DISTRIBUTION
Upper body or central obesity refers to excess fat above the
waistline and includes extra-abdominal SAT lying just be-
neath the skin and intra-abdominal, or VAT (52). Fat below
the waistline, obviously, is subcutaneous. Altogether, the to-
tal volume of SATis greater than VAT (53). VATis composed
of mesenteric, omental, and retroperitoneal fat (52). This
includes fat deposits which surround and protect organs
such as kidneys and heart (23, 28). The products of VATenter
the portal blood system and have direct access to the liver,
whereas the venous drainage of SATis into the peripheral cir-
culation (22, 23). VATaccumulation is governed by genetics,
diet, energy expenditure, age, race, steroid hormones, and
gender (22). VAT increases with age and weight gain and
decreases with exercise and weight loss (22, 23). Generally,
men tend to accumulate more upper body fat, including
VAT and women have more lower body fat (27) (Table 4).
African-American women may have less visceral fat than
caucasian women (250255). In the Heritage Family Study,
Stanforth et al. (256) compared fat distribution between black
and white adults aged 1765 years using CT scanning and
found less VAT and more SAT in African-American than in
caucasian women, despite a higher BMI in the African Amer-
icans. Weinsier et al. (251) tracked the effect of weight loss
on VAT and SAT stratied by weight (overweight, normal
weight, and never overweight) in women with a mean age
of 36 years. In all three groups, intra-abdominal fat was
less in black than in white subjects, whereas SATwas greater
in only the black overweight women. In a longitudinal study
with a follow-up to 4 years, in which total body fat was sim-
ilar between white and black women at baseline, VAT was
less in black women at baseline and at follow-up. The in-
crease in VAT was more signicant than the increase in total
body fat over time in both groups (257). Perry et al. (258)
found higher VAT in obese white women compared with
obese black women matched for age, BMI, and percentage
body fat using magnetic resonance imaging (MRI).
In contrast, in the Coronary Artery Risk Development in
Young Adults study, VAT and total fat were greater in young
adult African-American women (259). Lovejoy et al. (250,
260) conducted two studies, one in which the mean age of
women was 35 years, and a second in which black and white
women were middle-aged. In those studies, there was no sig-
nicant racial difference in VAT (although in both studies
VAT was slightly less and SAT signicantly greater in black
women (250, 260). Differences in adipose tissue distribution
have been reported for other racial groups as well. Hispanics,
Filipinos, Japanese, and Ethiopians have dissimilar fat distri-
butions compared with each other and with caucasian women
(261264).
There are several different methods used to measure total
body fat and fat distribution. All have their advantages and
805
disadvantages, including practicality, complexity, cost, accu-
racy, and the need for an experienced anthropometrist. The
easier methods have been used to predict clinical outcome
and are correlated with the gold standards of measuring
body fat, including the measurement of body density, body
water, and body potassium(265). However, the gold standards
do not always agree and are themselves not direct measures of
body fat (265, 266). Additionally, they are better suited for use
in research than for clinical assessments.
Some of the better known and simplest means for estimat-
ing body fat and fat distribution include measurement of
BMI, waist circumference (WC), WHR, and abdominal sag-
ittal diameter (ASD) (265, 268). BMI is the ratio of weight in
kg to the square of height in meters, and is a reliable method
of estimating body fat percentage, particularly if age and gen-
der are considered (266268). A BMI of R30 denes obesity
by the World Health Organization and the U.S. National
Institutes of Health (266, 269). Because abdominal adiposity
may be more important biologically than total body fat, BMI
may not be as accurate in predicting metabolic disturbances
or reproductive dysfunction as indexes that quantify fat distri-
bution (268, 270, 271). Additionally, the reference standards
for BMI do not apply to all ethnic groups, which affects
research on clinical implications (266, 270, 272).
Waist circumference and ASD may be the most accurate
clinical indexes for estimating intra- and extra-abdominal
fat (273). While the person is standing, WC is measured
with a tape around the smallest portion of the torso, halfway
between the lowest rib and the iliac crest. The abdomen
should be bare, the patient relaxed, and the measurement
taken after an exhalation (274). AWC of R80 cm is associ-
ated with increased morbidity in women, but standards vary
with different ethnic groups (265). When estimating the
quantity of intra-abdominal fat, WC comes closer to the
true value than does WHR (273): Using a tape measure, the
widest part of the hips and buttocks are measured; the waist
is measured as described above. AWHR >.85 for women de-
nes abdominal obesity. ASD is measured with a Holtain-
Kahn abdominal caliper at the level of the iliac crest (275).
The gold standards for measuring intra-abdominal fat or
VAT are CT scanning or MRI (276278) (Fig. 4). Several
studies suggest that only one image is needed, preferably at
the L4-L5 level, to quantify VAT (279281). However, Tul-
loch-Reid et al. (282) concluded that this method is inferior
to measuring VAT volume by using multiple CT slices, be-
cause more detailed imaging correlated with the insulin
sensitivity index, whereas a single slice did not. Because of
radiation exposure by CT and the cost of both methods,
MRI and CT are more valuable as research tools than for
clinical applications.
ADIPOSITY AND PUBERTY
The environment, socioeconomic status, genetic factors,
nutrition, and body fat inuence the onset and progression
of puberty (283285). Fat accumulation accelerates during
puberty in girls and plays a major role in reaching pubertal
milestones (283, 286). Frisch and McArthur (68) were among
the rst to propose that body fat was not only needed for the
inception of menstrual cycles but also for their maintenance
and return in subjects who were amenorrheic with weight
loss. Many subsequent studies have concluded that the earlier
TABLE 4
Comparison between visceral and subcutaneous adipose tissue.
Characteristic
Visceral adipose
tissue (VAT)
Subcutaneous
adipose tissue (SAT)
Location (42) Intra-abdominal Extra-abdominal and peripheral
Drainage (42) Drained by the portal venous
system
Drained by the systemic circulation
Lipolytic activity (22) Higher mobilization of FFAs Lower
Catecholamine-induced
lipolysis (36)
More responsive Less responsive
Antilipolytic effect by insulin (461) Weaker Stronger
Expression of b-adrenoceptors
(lipolytic) (36, 461)
Increased Decreased
Expression of a2-adrenoceptors
(antilipolytic) (36, 462)
Decreased Baseline
Insulin receptor afnity and insulin
receptor substrate 1 (36)
Less than SAT Baseline
LPL activity (42) Lower Baseline
Note: FFAs free fatty acids; LPL lipoprotein lipase.
806
onset of puberty in girls is linked to nutrition and the increas-
ing prevalence of obesity (287). Moreover, others have shown
that the amount or percentage of body fat may not be as
important as where the fat is distributed (288, 289).
Although the age of menarche declined fromthe early 1800s
to the mid-1950s, it has seemingly reached a plateau in all but
one group, African Americans (290, 291). African-American
girls have continued to experience a decline in menarcheal
age of 5.5 months over the last 30 years and, not surprisingly,
they now have an earlier mean age for thelarche: 8.9 years ver-
sus 10.9 yrs for caucasian girls (283, 290, 292). Body fat is one
factor that may dene the difference in sexual maturation be-
tween African-American girls and their caucasian counterparts
(293). African-American girls on average are heavier than cau-
casian girls, even after adjusting for socioeconomic status, and
tend to have less VAT than caucasians (252, 293, 294).
The mechanisms through which nutrition, growth, and adi-
pose tissue inuence pubertal development are complex and
not fully understood; however, there is substantial evidence
linking leptin to sexual maturation (see above). Leptin levels
in girls increase during the prepubertal years and continue to
rise during puberty in parallel with an increase in BMI
(131). This effect may be partly initiated by aromatase in adi-
pose tissue, which increases estrogen production, which in
turn induces leptin. In contrast, girls decient in leptin due
to rare loss-of-function mutations in the leptin gene or with
leptin receptor gene mutation have delayed puberty and are
gonadotropin decient (102, 295). Low body fat mass due to
extreme exercise, e.g., ballet dancers or gymnasts, oftenresults
in low circulating leptin levels and pubertal delay (118, 296,
297). Puberty is also disrupted and leptin levels are lowin con-
ditions with insufcient nutritional status, such as anorexia
nervosa (107, 298, 299). Leptin levels are higher in black girls
than white even after adjusting for fat mass (300).
When prepubertal female monkeys were treated with sub-
cutaneous recombinant human leptin daily for 18 months, LH
and E
2
were increased and the age of perineal swelling was
advanced compared with untreated control subjects (301).
In male monkeys, on the other hand, no change in daytime
serum leptin levels before the onset of puberty was found.
Furthermore, IV infusion of leptin into agonadal prepubertal
male monkeys for 16 days did not enhance GnRH-stimulated
LH secretion, although GH was increased, suggesting that
circulating leptin does not initiate puberty, at least in males
(302, 303). From these studies, it seems prudent to conclude
that the role of leptin in human pubertal development requires
further investigation.
Premature adrenarche is dened as the development of pu-
bic hair before the age of 8years in girls, and it is characterized
by a premature increase in adrenal androgen production (304,
305). Premature adrenarche is associated with obesity and ac-
celerated growth and with a history of low birth weight (306).
Girls with premature adrenarche are at a higher risk for devel-
oping the metabolic syndrome, type 2 diabetes, and cardiovas-
cular disease when they reach adulthood (304). These girls
have insulin resistance and hyperinsulinemia, low SHBG,
and higher levels of IGF-1, each of which may play a role in
the link between obesity and puberty (304). In girls of low
birth weight who developed precocious adrenarche, metfor-
min improved insulin resistance, reduced androgen excess,
and led to a reduction in total and abdominal adipose tissue
compared with untreated control subjects (307). Approxi-
mately 2%3%of girls with premature adrenarche have a mu-
tation in the CYP21 gene causing nonclassic 21-hydroxylase
deciency and androgen excess (308). Variable effects of lep-
tin on ACTH production have been reported, and although
leptin receptors are found in the adrenal, leptin may interfere
with, rather than activate, ACTH signaling (309, 310).
FIGURE 4
Computerized tomography showing cross-sectional abdominal areas at the umbilicus level in two women
demonstrating variation in fat distribution despite similar BMIs. A. 49-yr-old female with a BMI of 23; B. 40-yr-old
female with a BMI of 24. VAT visceral adipose tissue; SAT subcutaneous adipose tissue. FromWajchenberg
B. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000;21:
697738.
807
ADIPOSE TISSUE DEFICIENCY AND REPRODUCTION
Amajor functionof the secretoryproducts fromadipocytes is to
signal the adequacy of energy stores to the CNS for reproduc-
tive function. An adipose tissue threshold must be reached
to initiate and continue ovulatory cycles (68). When the fat
mass is too low, gonadotropin secretion is reduced and repro-
ductive capacity is decreased (311, 312). Adeciency of leptin
appears to be the key mediator of this effect (313). There is now
an abundant literature linking leptin to gonadotropin secretion
(147, 314, 315). Notably, leptin activates reproductive function
incongenital leptindeciency and restores gonadotropinsecre-
tion in leptin deciency associated with fasting. Puberty is also
advanced in leptin-transgenic skinny mice, which have no ap-
parent adipose tissue (316). Leptin stimulates the secretion of
GnRH and directly stimulates the pituitary to release LH
(115, 317). There is accumulatingevidence that kisspeptin neu-
rons in the anteroventral periventricular nucleus mediate the
nutritional signal linking leptin to GnRH. Kisspeptin neurons
express the leptin receptor, and leptin treatment normalizes
suppressed KISS-1 expression in rodents with gonadotropin
insufciency and low leptin, including the ob/ob mouse and
the streptozotocin-induced diabetic rat (317). Aleptin-induced
increase could mediate the increase in GnRH pulsatility that
follows the administration of recombinant leptin to low-weight
women with hypothalamic amenorrhea (311).
Lipodystrophy, the complete absence of subcutaneous adi-
pose tissue, is marked by severe insulin resistance, elevated
androgens, low gonadotropins, amenorrhea, elevated andro-
gens, and low leptin levels (318, 319). When these patients
are treated with recombinant leptin glucose tolerance im-
proves, androgen levels fall, and ovulatory menstrual cycles
resume, even before there is a change in weight or fat accumu-
lation (318, 319). Gonadotropin levels were unchanged, but
the response to GnRH was more robust, after therapy (319).
Leptin improved insulin sensitivity and was accompanied
by a decrease in insulin levels and an increase in SHBG(296).
Fat quantity is also severely reduced in patients with an-
orexia nervosa (299, 312). These patients experience a de-
crease in gonadotropins and E
2
and have low leptin levels
(313, 320). Puberty is delayed or arrested, and secondary
amenorrhea is common in those with established menses.
Some women continue to have menstrual cycles, and those
who menstruate have more body fat, especially truncal fat,
and higher leptin levels (312). Interestingly, about 20%of pa-
tients with anorexia nervosa experience amenorrhea before
the onset of weight loss. Menses generally resume when
weight increases to about 90% of ideal body weight, but
amenorrhea may persist when body fat is low or there are
unresolved emotional issues (321).
In fact, calorie restriction of any cause can disturb gonado-
tropin secretion and thereby ovulation (322). Sustained calorie
deprivation sufcient to cause weight loss leads to anovulation
in previously ovulatory women; however, short-term fasting
has a lesser effect on LHsecretion than in men (323, 324). Ad-
ministration of recombinant leptin reverses the fasting-induced
decrease in LH pulsatility in normal women (325).
Strenuous physical exercise may disrupt GnRH secretion
and produce menstrual dysfunction, including amenorrhea
(311). Athletes who experience amenorrhea tend to have re-
duced body fat and lower leptin levels (297, 326). Most often,
calorie intake is insufcient for the level of exercise, produc-
ing a negative energy balance. Treatment with recombinant
leptin can reactivate the reproductive axis when amenorrhea
results from low weight or strenuous exercise (311).
ADIPOSE TISSUE EXCESS AND REPRODUCTION
Obesity
Obesity has reached epidemic proportions in the United
States, affecting all age groups and races, including women
of reproductive age (19). The prevalence of obesity (BMI
R30 kg/m
2
) in women aged 2039 years stratied by ra-
cial/ethnic groups for 19992000, 20012002, and 2003
2004 is shown in Table 5 (19). Although there appears to
have been a decrease in obesity in caucasians, obesity has
consistently increased in African Americans and Mexican
Americans, with the former most affected (19).
Obesity is associated with many comorbidities, including
detrimental effects on reproductive health (327). Anovulation
and infertility occur more frequently in obese women com-
pared with nonobese women (26, 328330). Ovulation induc-
tion with either clomiphene citrate or gonadotropins may
require a higher dose and take longer to induce oocyte matu-
ration (331). With assisted reproduction, there may be
a decreased number of oocytes retrieved and fewer live births
(332, 333). Miscarriages may also be increased, but this
nding has been inconsistent (332, 333, 335).
The negative impact of obesity on reproduction may be re-
lated to a change in a variety of hormones starting as early as
the pubertal transition. In a cross-sectional analysis, obese
peripubertal girls were found to have an increase in total
and free T, a decrease in SHBG, and an increase in insulin
levels compared with normal-weight girls of the same age
(336). Other changes include an increase in DHEAS and
LH hypersecretion. Although there may be other factors re-
sponsible for a reduction in fecundity and successful preg-
nancy, the hormonal changes associated with obesity are an
important cause for interrupting normal ovulatory menstrual
cycles (17).
Hormone Proles and Effects in Upper and Lower Body
Obesity
Global adiposity has an important effect on an individuals
overall health and metabolic status, but compartmental fat
distribution appears to be the most important characteristic
(337). The distinction between UBO and lower body obesity
(LBO) was rst made by Vague in 1947 (20), because of the
changes in sex hormones and the comorbidities that accom-
pany UBO in women. Androgen and estrogen levels may
be increased with UBO and LBO, but UBO is more closely
linked to an androgenic prole; therefore, it is referred to
as android or central obesity (338, 339). Because the
808
balance of sex steroids in women is weighted toward estro-
gen, LBO is referred to as gynoid or peripheral obesity
(339).
Kirschner et al. (340) found an increase in the production
rates of T, DHT, and A in women with UBO and LBO com-
pared with nonobese controls, but women with UBO had
higher levels. Women with LBO demonstrated more periph-
eral aromatization and had higher production rates of estrone.
The women in their study had regular menstrual cycles.
The relationship between central obesity and hyperandro-
genemia may be bidirectional (336, 341, 342). In women,
androgens appear to encourage a male-type central obesity
(62, 113). Postmenopausal women, who have a decrease in
ovarian production of estrogen and an increase in androge-
n:estrogen ratio, have less gluteofemoral adiposity and more
upper body fat (53, 343). Additionally, postmenopausal
women given hormone therapy (estrogen) maintain a fat dis-
tribution similar to premenopausal women instead of the
android body type acquired by those not treated (344).
Female-to-male transsexuals given T had similar changes
(345). After 1 year, there was a signicant reduction in sub-
cutaneous fat but no change in visceral fat. They were then
ovariectomized and examined again by MRI at year 3, at
which time visceral fat had increased compared with baseline
values (345). Moreover, the effect was at least partly reversed
by utamide, an androgen receptor antagonist. Visceral fat
was not affected. Testosterone has been shown to reduce cat-
echolamine-induced lipolysis in subcutaneous fat cells from
human subjects by reducing HSL and b
2
-adrenoceptors (59).
Androgen-induced lipogenesis is also due to an effect on
LPL (59, 346). Evidence linking androgens to LPL activity
and lipid storage include a positive correlation between
LPL activity and free T in obese women in whom there is
a negative correlation with E
2
(60, 346, 347). When DHT,
a nonaromatizable androgen, was added to cultures of subcu-
taneous adipose tissue obtained from nondiabetic women
(59), LPL increased and HSL expression decreased. Addi-
tionally, ovariectomized mice given DHT demonstrated an
increase in visceral fat TG levels and, therefore, an increase
in visceral fat quantity (53). Proteins involved in lipogenesis
were elevated, including fatty acid synthase, sterol regulatory
element binding protein, and LPL. Enzymes involved in
lipolysis (AMP-activated protein kinase and acetyl-CoA
carboxylase) were down-regulated (53). Overall, in women,
androgens appear to promote central and suppress peripheral
fat accumulation, and estrogens have the opposite effect.
Central obesity, on the other hand, may contribute to ele-
vated serum androgen levels (17, 341, 348). Circulating an-
drogen levels increase with increasing obesity and decline
when obese hyperandrogenemic women lose weight
(349353). It is possible that insulin resistance and hyperin-
sulinemia, which commonly accompany abdominal obesity
and decline with weight loss, may be the causal link between
obesity and increased androgens, because insulin may serve
as a cogonadotropin to augment the production of T from
the ovaries (354). Insulin also decreases SHBG levels, which
increases the non-SHBG (bio-available) T (355357).
Abdominal obesity and hyperandrogenemia may also be
related to an increase in FFA ux (358). FFAs not only con-
tribute to insulin resistance, compensatory hyperinsulinemia,
and, consequently, elevated androgen levels but may also add
to the androgen pool by increasing the production of andro-
gen precursors fromthe adrenal glands (247, 359). Men given
a short-term 20% lipid infusion had an increase in FFA levels
and an increase in DHEA and A, before any detectable
change in insulin resistance. The evidence suggests that
FFA may affect adrenal androgen production directly and
not through a central (ACTH) mechanism (359).
As previously noted, UBO may also be considered to be
a hyperestrogenic state (340, 360, 361). Estrogenic effects
on fat distribution are partly due to actions on the sympathetic
nervous system and directly on proteins expressed in adipose
tissue. Both estrogen receptor a (ERa) and ERb are ex-
pressed in human subcutaneous adipocytes, but the most im-
portant physiologic effects appear to involve ERa (362364).
Estradiol decreases lipolysis by augmenting the number of
a2A-adrenergic receptors in subcutaneous but not visceral
fat, which may at least partly explain why reproductive-age
women have more body fat than men, because they have
a greater number of a2A-adrenergic receptors (362, 364).
Evidence for estrogen effects on fat deposition and LPL
activity is both complex and contradictory. Studies in this
area include quantifying LPL protein synthesis, activity,
and mRNA levels in vivo and in vitro, in rodents and in hu-
mans after the removal or administration of estrogen. Ovari-
ectomy in rats results in an increase in energy intake, TG
TABLE 5
Prevalence of obesity (BMI R30 kg/m
2
) in women aged 2039 years, % (SE).
Non-Hispanic white Non-Hispanic black Mexican-American
19992000 24.4 (2.6) 45.6 (3.9) 30.6 (5.7)
20012002 25.2 (2.3) 47.2 (3.8) 31.6 (5.3)
20032004 23.8 (3.1) 50.3 (4.6) 35.7 (3.6)
Note: BMI body mass index.
809
accumulation, LPL activity, and obesity (365). These effects
are diminished and almost completely reversed by physio-
logic estrogen replacement and a selective estrogen receptor
modulator with agonist properties (365). LPL activity in-
creases after ovariectomy in adipose tissue biopsies from
rats and is decreased dose-dependently after the administra-
tion of 17b-estradiol (366). Using genetically manipulated
3T3-L1 mouse adipocytes expressing ER, Homma et al.
(60) demonstrated a reduction in fat accumulation and LPL
mRNA levels after estrogen exposure.
In humans, the impact of estrogen on LPL and lipogenesis
appears to be age, region, and gender specic. Lipogenesis
and LPL activity in the gluteal-femoral area of women ap-
pears to follow an increase in estrogen, whereas there may
be an inverse relationship in the abdominal region. There
are several examples. Body fat distribution does not differ
by gender until puberty (367). Menstrual cycling women
have higher LPL activity in the gluteal-femoral region com-
pared with the abdominal region. LPL activity increases even
further during pregnancy but decreases during lactation
(368). Postmenopausal women tend to acquire fat centrally
and lose fat peripherally. Femoral adipocytes from postmen-
opausal women given estrogen-progesterone therapy showed
increased LPL activity (344, 369). Congenital estrogen de-
ciency due to Turner syndrome is accompanied by an in-
crease in visceral fat proportionate to the years of estrogen
deciency (370). Finally, male-to-female transsexuals treated
with estrogen accumulate more peripheral and less abdomi-
nal fat (371).
The results of other studies disagree with the above nd-
ings, however. Transdermal estrogen patches in the gluteal
region decreased LPL protein and activity but not mRNA
levels in adipose tissue biopsies beneath the patch compared
with surrounding areas (372). Toth et al. (373) found that
ovariectomized rats lost rather than gained fat mass, and
women of reproductive age given ethinyl-estradiol for 2
weeks had no change in LPL activity in adipocytes taken
from the buttocks (374). Finally, the effect of estrogen on
LPL activity and thereby TG hydrolysis may be dose related
in that subcutaneous abdominal adipocytes taken before elec-
tive surgery in women exposed to high-dose 17b-estradiol
demonstrated reduced LPL protein expression, whereas low
doses increased LPL expression (347).
ADIPOSITY AND POLYCYSTIC OVARY SYNDROME
The Rotterdam ESHRE/ASRMSponsored Consensus
Workshop Group dened PCOS by at least two of the follow-
ing: 1) oligo- or anovulation; 2) clinical and/or biochemical
signs of hyperandrogenism; and 3) polycystic ovaries; with
the exclusion of other etiologies that mimic PCOS (375).
Other common features include LH hypersecretion, insulin
resistance, and obesity (17, 376, 377). Although weight
gain and central obesity are common in PCOS patients and
often precede the onset of anovulatory cycles, obesity is
not one of the diagnostic criteria for PCOS (378).
The most recent criteria for PCOS actually date back to
Irving Stein and Michael Leventhal (379), who in 1935 in-
cluded amenorrhea, hirsutism, and polycystic ovaries in their
description of the syndrome. Most of their patients were
obese, and recent studies have determined that at least 50%
of PCOS patients are either overweight or obese (380,
381). Moreover, visceral adiposity is a common nding,
even when the subject is not classied as overweight (382).
When 30 nonobese Turkish patients with PCOS were com-
pared with 30 lean women with regular menstrual cycles
and similar BMI (mean 20 kg/m
2
), age, and WHR, the
PCOS group had signicantly more visceral fat but a similar
amount of upper body subcutaneous fat (270). Despite the
lack of obesity, they exhibited the classic features of PCOS,
suggesting that excess visceral fat is an important component
of the syndrome.
Truncal obesity is clearly associated with insulin resistance
(383, 384). Lord et al. (384) recently demonstrated that an
increase in visceral adipose tissue, in particular, was signi-
cantly related to insulin resistance in a prospective cross-sec-
tional analysis. An impressive linear correlation between
visceral fat and insulin resistance (r 0.68; P<.001) was
demonstrated (384).
The prevalence of insulin resistance, dened by a higher-
than-normal concentration of insulin to effect a normal re-
sponse (usually in glucose transport), may be as high as
80% in PCOS and is considered to be an important patho-
physiologic feature of the disorder (377, 385387). Insulin
resistance in PCOS appears to be selective; that is, whereas
skeletal muscle and adipose tissue may be refractory to insu-
lin action, other tissues, including ovarian stroma and liver,
respond or may be even hypersensitive to insulin (388,
389). This may be explained by the multiple intracellular sig-
naling pathways and pleiotropic effects of insulin, which in-
clude not only activating glucose transport but also mitogenic
and steroidogenic actions (390, 391). Insulin resistance leads
to a compensatory increase in insulin secretion, resulting in
hyperinsulinemia (81).
Impaired glucose tolerance (IGT) and type 2 diabetes mel-
litus among women in the U.S. are found in approximately
30% and 7.5%, respectively, of women with PCOS but in-
creases with age (392). Women with PCOS who have IGT
are more obese than PCOS patients with normal glucose tol-
erance (NGT) (393, 394). Moreover, obese women with
PCOS and NGT are hyperinsulinemic compared with thin
women with PCOS and NGT and have higher SHBG and
lower free T levels (394).
Weight loss in previously anovulatory obese women with
PCOS is associated with improvement in insulin sensitivity,
diminished insulin levels, a decrease in T, and increased ovu-
lation rates (349, 395397). Several studies have demon-
strated an increase in ovulatory cycles in PCOS women
when insulin sensitivity is increased by metformin or a thiazo-
lodinedione (15, 398, 399). Long-termtreatment with metfor-
min reduced menstrual abnormalities, abdominal (including
810
visceral) fat, and hirsutism when added to a hypocaloric diet
(397).
Fat cells of women with PCOS may have altered lipolysis
and lipogenesis even in the absence of obesity. There is a re-
sistance to catecholamine-induced lipolysis in subcutaneous
cells in vitro, and fasting glycerol levels (a product of lipoly-
sis) are lower in women with PCOS (400). Signaling path-
ways leading to the activation of HSL may be responsible
(400). This was conrmed in a recent study in which lean
women with PCOS or obesity (without PCOS) had signi-
cantly decreased catecholamine-induced lipolysis and HSL
protein expression compared with healthy control subjects
(185).
The link between obesity and androgens outlined in previ-
ously is probably operational in PCOS as well. A male-type
fat distribution dominates the phenotype of women with
PCOS (representing more lipogenesis than lipolysis), per-
haps because of excess androgens (401). Androgens have
the potential to augment fat deposition in subcutaneous and
visceral fat and may do so by stimulating LPL and inhibiting
HSL (402, 403). Testosterone and A production are aug-
mented from ovarian theca cells and stroma in response to
LH hypersecretion and higher-than-normal levels of insulin
(404406).
The adrenal glands also contribute to the total amount of
circulating androgens and perhaps to obesity. In as many as
40%of women with anovulatory PCOS, the adrenal gland ap-
pears to be overactive based on an increase in DHEAS levels
(404, 407, 408). Explanations for adrenal gland overactivity
include an increase in sensitivity to ACTH, dysregulation
of enzymes involved in cortisol metabolism, factors that reg-
ulate 17-hydroxylase/C17,20-lyase, and dyslipidemia with
an increase in FFAs (410412).
The enzymes 5a- and 5b-reductase are expressed in adi-
pose tissue as well as in liver and skin. They reduce cortisol
to 5a- and 5b-dihydrocortisol, and T to DHT (409, 410, 413).
Because the activity of 5a-reductase is enhanced in PCOS,
based on the high ratio of 5a to 5b urinary metabolites and
direct study of T metabolism in skin, there may be a decrease
in negative feedback by cortisol and a compensatory increase
in ACTHsecretion to normalize serumcortisol while increas-
ing androgen levels (409, 414). ACTH levels are normal in
PCOS, however, and explanations for normal ACTH levels
include a resetting of the hypothalamic-pituitary-axis and
an increase in pituitary sensitivity to ACTH (409, 413).
11b-Hydroxysteroid dehydrogenase (11b-HSD), which is
also important in cortisol clearance, is dysregulated in
PCOS (410). 11b-HSD exists as two different isoenzymes,
11b-HSD1 and 11b-HSD2, that catalyze the interconversion
of bioactive cortisol and inactive cortisone (415, 416). Corti-
sol is rapidly oxidized to cortisone by 11b-HSD2 in the kid-
ney, allowing mineralcorticoid receptors to be occupied and
regulated by aldosterone instead of the far more abundant
cortisol; if 11b-HSD2 activity is reduced, the excess cortisol
mimics aldosterone and hypertension and hypokalemia
develop (410). This occurs with inactivating mutations of
the 11-HSD2 gene and when activity is reduced by glycyr-
rhetinic acid in licorice (410).
11b-Hydroxysteroid dehydrogenase 1 converts cortisone
to cortisol (415, 417). The expression and activity of 11b-
HSD1 have emerged as a key factor in obesity, the metabolic
syndrome, and possibly PCOS (410, 418, 419). Overexpres-
sion of this enzyme in rats leads to central obesity and insulin
resistance (419). In human obesity,especially central obesity,
the activity of 11b-HSD1 is tissue specic (420, 421). It is
reduced in the liver but increased in adipocytes (422). De-
creased 11b-HSD1 activity in the liver, a major site of action,
may contribute to the compensatory increase in cortisol pro-
duction, and the enhanced generation of cortisol from
cortisone in adipocytes may be partly responsible for an in-
crease in adipocyte mass and central obesity, because of an
abundance of glucocorticoid receptors in the omentum
(410, 423426). Thus, changes in the production and meta-
bolic clearance of cortisol may play an important role in
PCOS (410, 413) (Figs. 5 and 6).
PCOS AND ADIPOKINES
Because of the interactions between leptin and insulin, leptin
may have a role in the pathophysiology of PCOS. Although
many studies have found similar leptin levels between
PCOS and weight-matched control subjects, others suggest
that leptin is increased (3, 139, 427429). Interestingly, leptin
mRNA levels in subcutaneous fat may be down-regulated in
obese PCOS patients (430).
Mantzoros et al. (139) found a strong correlation between
leptin and BMI in PCOS patients but no relationship with
gonadal hormones or hyperinsulinemia. Moreover, after con-
trolling for BMI, no signicant correlation was found
between serum leptin levels and HOMA or hyperinsulinemia
after glucose challenge in either obese or normal weight
women with PCOS (431). Furthermore, neither troglitazone
nor metformin, which increase insulin sensitivity, affected
serum leptin concentrations (432, 433).
Elevated leptin levels may contribute to the lack of follic-
ular maturation in PCOS (427, 429). Leptin inhibits the IGF-
1induced rise in FSH-stimulated estrogen production by
cultured rat granulosa cells, and the elevated follicular uid
leptin concentrations in PCOS might inhibit aromatase activ-
ity and follicular growth (148, 434). Although the concentra-
tion of leptin receptors was similar in granulosa cells from
women with PCOS and those undergoing IVF because of
tubal disease, the level of phosphorylated signal transducer
and activator of transcription was lower, suggesting that it is
leptin signaling that is disrupted in PCOS (429). Poor IVF
outcome has also been associated with elevated follicular
uid leptin levels (427, 429, 435).
Several studies have examined the potential role of adipo-
nectin in the ovulatory dysfunction and metabolic abnormal-
ities in PCOS (436439). Plasma adiponectin levels are
811
inversely related to BMI in subjects with PCOS as in subjects
without PCOS, and the degree of insulin resistance appeared
to have little affect on adiponectin levels (439). However,
other studies suggest that there may be at least some correla-
tion between adiponectin levels and insulin sensitivity in
PCOS, independent of adiposity (440, 441). Adiponectin
mRNA levels in adipose tissue have been found to be propor-
tionately reduced with increasing visceral and subcutaneous
fat measured by ultrasound (430).
Adiponectin gene polymorphisms have also been studied in
PCOS. Haap et al. (442) and Zhang et al. (443) found a higher
prevalence of the 45G and 276G/T polymorphism in the
adiponectin gene in women with PCOS compared with con-
trol women. This was not, however, associated with a more in-
sulin-resistant phenotype. On the other hand, Xita et al. (444)
and Escobar-Morreale et al. (438) did not nd any association
between common polymorphisms in the adiponectin gene and
PCOS. Xita et al. (444) reported that genomic variants might
inuence adiponectin levels in PCOS.
Interventions that affect reproductive and metabolic func-
tion in PCOS may also affect adiponectin levels. It has been
postulated that some of the effects of weight loss and insulin-
sensitizing agents in PCOS may be mediated through
changes in adiponectin levels. Ibanez and de Zegher (445)
evaluated the effects of an oral contraceptive or an antiandro-
geninsulin sensitizer combination on adipocytokines and in-
ammatory markers in adolescent and young adult women
with PCOS. They found that adiponectin levels decreased
with ethinylestradiol-drospirenone and increased with uta-
mide-metformin. Furthermore, lean body weight increased
and central adiposity decreased only in the latter group, sug-
gesting that oral contraceptives may not be the optimal treat-
ment for the metabolic abnormalities in PCOS patients.
Adiponectin levels also rose and insulin-stimulated glucose
disposal increased when PCOS patients were treated with
pioglitazone (446).
Several studies have found increased visfatin gene expres-
sion and plasma levels in women with PCOS compared with
BMI-matched control women (447449). In one study, 70
lean and obese women with PCOS and 45 healthy non-PCOS
controls were evaluated using an euglycemic clamp (449).
Both lean and obese PCOS subjects had lower insulin sensitiv-
ity as expected, but serumvisfatin levels were higher than con-
trol subjects only in lean PCOS subjects. Visfatin levels were,
however, negatively correlated with SHBG and positively cor-
related with the free androgen index in the entire PCOS group
(449). PCOS patients undergoing laparoscopy for infertility
also demonstrated an up-regulation of visfatin (447). Visfatin
mRNAand protein were increased in omental as well as subcu-
taneous fat and subcutaneous adipocytes compared with infer-
tile non-PCOS control subjects with unexplained infertility.
FIGURE 5
Cortisol metabolism may be tissue-specic in obesity and polycystic ovary syndrome. In these conditions,
hepatic 11b-HSD1 activity is reduced in the liver resulting in a decrease in the regeneration of cortisol; however,
adipocyte 11b-HSD1 activity is increased (Fig. 6). 5a-R activity is increased in the liver and skin resulting in an
increase in 5a-reduced cortisol metabolites and dihydrotestosterone production from testosterone (not shown).
Inreased production of cortisol in visceral fat because of increased 11bHSD activity may contribute to insulin
reistance and low SHBG. HSD hydroxysteroid dehydrogenase.
812
Tumor necrosis factor a levels in obese women (average
BMI 35 kg/m
2
) with and without PCOS were similar before
and after weight loss in one study, whereas another study
found higher levels (450, 451). In the latter study, the authors
concluded that the increase in TNF-a may have been due to
excess central fat (451). TNF-a secretion by cultured mono-
nuclear cells fromPCOS patients in response to glucose stim-
ulation was found to be reduced rather than increased as in
women without PCOS (452).
Cytokines have also been studied in follicular cells ob-
tained at the time of oocyte retrieval during IVF. These cells
express mRNA for a variety of cytokines, including IL-6, but
there was no difference between PCOS and non-PCOS pa-
tients (453). Reduced levels of IL-6 were found in those
FIGURE 6
Possible role of VAT and SAT in the pathophysiology of polycystic ovary syndrome. An increase in central obesity
and VAT may result fromelevated serumandrogens and local cortisol production, the latter caused by increased
11-HSD1 activity in adipocytes. 5a-R activity is also dysregulated and contributes to increased cortisol
clearance. The negative feedback of cortisol may be decreased resulting in a compensatory increase in ACTH in
an effort to maintain normal cortisol levels, while increasing adrenal androgen production. FFA in the liver and
skeletal muscle contribute to insulin resistance and hyperinsulinemia, as does altered adipokine levels. Insulin
acts as a co-gonadotropin, amplifying the effect of LH to induce androgen production from the ovary leading to
anovulation. Leptin may play a role in the increase in LHsecretion although other factors and obesity dampen this
effect. VAT visceral adipose tissue; SAT subcutaneous adipose tissue; FFA free fatty acid; HSD
hydroxysteroid dehydrogenase; E cortisone; F cortisol; R reductase; SHBG sex hormone binding
globulin; ACTH adrenocorticotropic hormone; LH luteinizing hormone; GnRH gonadotropin releasing
hormone;TNF tumor necrosis factor; IL interleukin; PAI plasminogen activator inhibitor.
813
patients with high BMI and those who achieved pregnancy,
however. The authors suggested that the angiogenic action
of IL-6 may increase follicular growth by increasing FSH ac-
cess (453). Amato et al. (454), on the other hand, found an in-
crease in serum and follicular uid levels of IL-6 in PCOS
patients undergoing IVF.
The possible increased risk of rst-trimester miscarriages
and gestational diabetes in women with PCOS has been re-
lated to increased PAI-1 activity and elevated plasma levels
of PAI-1 (456, 456). Glueck et al. (455) found more PAI-1
gene 4G polymorphisms and an increase in PAI-1 activity
in women with PCOS compared with control women, a nd-
ing that was also demonstrated in a recent meta-analysis
(457). PAI-1 gene polymorphisms may be important in the
pathogenesis of PCOS, as suggested by the enlarged cystic
ovaries and slightly elevated T levels seen in transgenic
mice overexpressing PAI-1 (458). Other comorbid ndings
associated with an up-regulation of PAI-1 activity and
PCOS include obesity, insulin resistance, and hypertriglycer-
idemia (455). However, amplied PAI-1 plasma levels and
activity are associated with PCOS independent of BMI, and
there is also a positive correlation between PAI-1 activity
and serum T levels (222, 458).
Plasminogen activator inhibitor 1 protein activity as well
as insulin levels decrease in women with PCOS when they
are treated with troglitazone (222). Metformin begun in the
rst trimester and continued throughout pregnancy not only
reduced insulin and PAI-1 levels but also decreased spontane-
ous abortions and other pregnancy complications (165, 455).
Polycystic ovary syndrome has been associated with low-
grade inammation, but whether it is due to PCOS per se or to
UBO is unsettled (451, 459461). Kelly et al. (459) were the
rst to examine low-grade chronic inammatory markers in
PCOS. The PCOS group had signicantly elevated CRP
levels compared with healthy control subjects matched for
BMI which were inversely correlated with insulin sensitivity,
although central adiposity was not evaluated. Other investi-
gators found that the elevated inammatory markers in
PCOS were correlated with BMI and upper abdominal
obesity rather than with the characteristics of PCOS, such
as hyperandrogenemia (451, 461). Evidence of inammation
is usually accompanied by insulin resistance and hyperinsu-
linemia, which together are thought to increase the risk for
hypertension, type 2 diabetes, and heart and vascular disease.
Women with PCOS with elevated hs-CRP levels and insulin
resistance have evidence of endothelial dysfunction, even if
BMI is normal (23 kg/m
2
) (462). Moreover, even in the ab-
sence of inammatory markers, obese young (average age 34
years) insulin-resistant PCOS patients have more evidence of
early coronary atherosclerosis than weight-matched control
subjects (463).
Thus, there are a series of cytokine abnormalities in
women with PCOS, some of which are due to obesity but
others that could be disease specic. Cytokines may play
an important role not only in the fertility disturbance but
also in the many other reproductive problems that PCOS
women experience (Fig. 6).
CONCLUSIONS
Adipose tissue and its chief component, adipocytes, are nec-
essary for survival. They protect the body from trauma, pro-
vide the major source of stored energy, and inuence
a myriad of physiologic functions, including reproduction,
through an array of secreted products collectively known as
adipokines. Deciency or excess of these products disturbs
the dynamics of the reproductive axis and contributes to
a suboptimal environment for pregnancy, if it should occur.
Although the total amount of body fat is important, it is the
selective expression of adipokines in various adipose tissue
compartments that makes the distribution of adipose tissue
critical.
Both thinness and obesity have a negative impact on the re-
productive system. An excess of VAT, in particular, appears to
be the most important contributor to the development of
anovulatory cycles in women with PCOS. To that end it, is
vitally important to understand how obesity and adipokines
predispose to infertility and pregnancy loss. Although pre-
ferred treatments remain controversial, our increasing aware-
ness of the mechanisms linking adipose tissue to reproduction
has dramatically altered the treatment approaches for repro-
ductive endocrinologists.
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