Obesity and the role of gut and adipose hormones in female reproduction

17 Pages·2006·0.24 MB·English

Human Reproduction Update, Vol.12, No.5 pp. 585–601, 2006 doi:10.1093/humupd/dml024
Advance Access publication June 14, 2006
Obesity and the role of gut and adipose hormones
in female reproduction
Gabriella G.Gosman1,4, Heather I.Katcher2 and Richard S.Legro3
1Department of Obstetrics and Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2Department of Nutritional Sciences, Pennsylvania State University, State College, PA, USA and 3Department of Obstetrics and Gynecology, Do
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Pennsylvania State University College of Medicine, Hershey, PA, USA n
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4To whom correspondence should be addressed at: Department of Obstetrics, Gynecology and Reproductive Science, Division ed
of Reproductive Endocrinology and Infertility, University of Pittsburgh School of Medicine, Magee-Womens Hospital, 300 Halket Street, fro
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Room 2314, Pittsburgh, PA 15213, USA. E-mail: [email protected] h
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Reproductive function declines at both extremes of human energy balance. The relationship between obesity and ://a
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reproductive function is complex and incompletely understood. The literature has established the negative impact of d
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excess energy stores on ovulatory function and investigated the mechanisms whereby this occurs. Furthermore, ic
weight loss in obese anovulatory women increases ovulation and conception. Obesity and anti-obesity therapy effects .ou
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on the endometrium, implantation and early fetal development have received less attention. The discovery of adipok- .c
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ines and enterokines greatly expands the ability to investigate the relationship between obesity, therapies to produce
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weight loss and reproductive function. In this review, we discuss select adipose and enteric signals. We focus on um
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invitro, animal and human data that lend biological plausibility to adipokines and enterokines as mediators of obesity p
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and reproduction. Very little published work exists that directly addresses adipocyte and enteric signals in this spe- /a
cific role; therefore, much of this review is on the basis of a synthesis of the literature in three areas: (i) in vitro and rticle
invivo evidence regarding the reproductive effects of these signals; (ii) adipokine and enterokine changes that occur -ab
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with weight-loss therapies, focusing on hypocaloric diets, bariatric surgery and drugs that target adipocyte or enteric tra
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signals and (iii) reproductive changes produced by these weight-loss therapies. t/1
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Key words: bowel/energy balance/gut/obesity/reproduction /58
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Introduction conveying information about energy intake and food stores. b
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Energy stores are essential to human female reproduction. From gu
Obesity is a major public health problem contributing significantly e
an evolutionary viewpoint, it would be foolhardy for a mammal to s
to the leading causes of death—cardiovascular disease and cancer. t o
attempt a long-term gestation and lactational period without suffi- n
This obesity epidemic has been characterized by a rapid onset with 0
cient energy. Achieving a certain stored energy threshold is 4
exponential rises in 20 years and by an equal opportunity affliction A
important for both the initiation and the maintenance of menstrual p
of gender and age. Especially, troubling is the high rate of afflic- cycles (Frisch and Revelle, 1970; Frisch, 1987). Similarly, an ril 2
tion among children. 0
excess of energy stored, as represented by obesity, is associated 1
The deleterious effects of obesity on reproduction have been 9
with diminished fecundity (Bolumar et al., 2000). The mecha-
recognized at least since Hippocrates, who noted in his Essay on
nisms and rationale for this are less clear.
the Scythians ‘The girls get amazingly flabby and podgy ... People
Obesity is associated with many ovulatory disorders in women.
of such constitution cannot be prolific ... fatness and flabbiness are
Polycystic ovary syndrome (PCOS) is the most frequently cited
to blame. The womb is unable to receive the semen and they men-
example. Anovulation, hyperandrogenism and obesity cluster in
struate infrequently and little’. Several excellent reviews summa-
this disorder, but the individual contribution of each to reproduc-
rize the effects of obesity on female reproduction (Friedman and
tive failure is poorly understood. In the best prevalence study in an
Kim, 1985; Norman and Clark, 1998; Pasquali et al., 2003), and
unselected population applying for work at a university hospital
there may also be adverse effects of obesity on male reproduction
from Alabama, 24% were overweight (BMI 25.0–29.9 kg/m2) and
(Jensen et al., 2004).
42% were obese (BMI > 30 kg/m2) (Azziz et al., 2004). Obesity
As a species, reproduction is our prime imperative. It is no fluke
further exacerbates metabolic and reproductive abnormalities in
of nature that the control centre of reproduction, the hypothalamus,
women with PCOS and may bring out the PCOS phenotype in a
is intimately connected to afferent loops (neural and endocrine)
© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For
Permissions, please email: [email protected] 585
G.G.Gosman, H.I.Katcher and R.S.Legro
susceptible population as family studies suggest (Legro et al., negative feedback of excess estrogen may contribute to decreased
2002). In women with PCOS, many of whom demonstrate hyper- hypothalamic pituitary signalling. Excess bioavailable androgen
insulinaemia and/or insulin resistance, therapy with insulin- may also have detrimental effects on the oocyte, follicle and
sensitizing drugs such as metformin and troglitazone improves endometrium.
ovulatory function and fertility (De Leo et al., 2003). But there are The endocrinologic understanding of obesity and its comorbidi-
other disorders of anovulation associated with obesity that are ties has expanded greatly with the discovery of adipokines,
characterized by hypogonadotrophic hypogonadism (in contrast to secreted by fat (Table I), and enterokines, secreted by the gut
the relative hypergonadotrophic hypergonadism of PCOS) such as (Table II), with a wide range of effects on metabolic processes
in Prader–Willi syndrome (Burman et al., 2001). including those on appetite, energy metabolism, insulin action,
Thus, the relationship between obesity and ovulatory dysfunc- lipid metabolism, blood pressure and coagulation. Almost all of
tion is complex, and anovulation is but one mechanism of obes- the adipokines and enterokines identified to date have receptors in
ity’s effect on reproduction. Obesity also potentially adversely the hypothalamus, implying this is an important target tissue for
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affects the endometrium, implantation and early fetal development these hormones. However, the receptors for these signals are ow
(Loveland et al., 2001; Kaaks et al., 2002; Hall and Neubert, widely dispersed in a variety of tissues, allowing also for tissue- nlo
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2005). Obese women may have an increased risk of miscarriage specific effects. Some of these signals also have menstrual cycle d
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(LWasahnegn eett aall..,, 22000042);. BSoemllvee srt uedt iaels. ,s h2o0w03 d; eFceredaosrecdsa IkV eFt parle.g, n2a0n0c4y; varEianttieorno kinin ceisr,c ualnadti nmgo croen scpeenctrifaitcioalnlsy (iTnacbreleti nIIsI,) .have become an d from
rates in obese women (Fedorcsak et al., 2004; Lintsen et al., enticing target for the treatment of type 2 diabetes (Joy et al., h
2005). However, many reports show that obese women have IVF 2005), and inflammatory adipokines have become a target for the ttps
pregnancy rates that are comparable with those in normal weight prevention of atherosclerosis and potentially for the treatment of a ://a
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controls (Lashen et al., 1999; Wittemer et al., 2000; Fedorcsak wide variety of human diseases (Figure 1). However, the role of ad
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etal., 2001; Spandorfer et al., 2004; Dechaud et al., 2006). Many these hormones in the treatment of obesity-related reproductive m
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of these investigators noted that obese women have relative gona- failure remains a secondary pursuit or, in many cases, an educated .o
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dotrophin resistance and fewer oocytes retrieved. In oocyte dona- guess. The goal of this review was to attempt to integrate adipok- p
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tion, obese recipients do not seem to suffer lower implantation ines and enterokines into the traditional hormonal concept of how o
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rates (Bellver et al., 2003; Wattanakumtornkul et al., 2003; Styne- obesity disrupts and weight loss improves reproductive function. /h
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Gross et al., 2005), suggesting that this aspect of reproductive This involves making some guesses about the potential role of adi- m
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function may be preserved. Little data exist on the effect of obesity pokines and enterokines in reproduction. The overall aim was to pd
orens isptraenimt mpliacnet, afteiowne re emmbbryryooss. rIena cohb ethsee bhlyaspteorcleypstt isntaaegme itch alne pntoinr-- aorboeussitey i-nretelaretesdt irne tphreoidr upcutitvatei vdey rsofluensc atiso tnr.e aTtmhee nctr ittaerrgiae tsfo irn ifnecmluadle- /article
mal controls (Brannian et al., 2005). Better understood is the ing the adipokines and enterokines discussed in this review are the -a
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increased risk that obesity holds for developing later pregnancy following: (i) a reproductive role for the substance has been estab- tra
complications such as gestational diabetes, hypertensive disorders lished or suggested; (ii) data on obesity and/or changes with ct/1
and birth trauma, all of which impact the health of the fetus/ weight loss exist or (iii) the substance is a specific target or tool 2
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neonate (Steinfeld et al., 2000). This review focuses primarily for weight-loss therapy. /5
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onadipokine/enterokine effects on ovulatory function. In a few Where relevant, we will examine animal models, especially 5
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instances, embryonic development and early pregnancy are knockout models (Table IV). These are instructive, as they point 78
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addressed. out the redundancy of other mechanisms to maintain appetite, 7
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Hormonal derangements associated with obesity and its attend- body weight and reproductive capacity. Interestingly, only the lep- b
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ant reproductive dysfunction have been well described. Excess tin-deficient mouse has a clear phenotype of reproductive failure. g
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adipose tissue increases peripheral aromatization of androgen to We will also consider the effect of weight loss by diet therapy and s
estrogen. Diminished sex hormone-binding globulin (SHBG) bariatric surgery, because these treatments result in a marked t on
enhances bioavailable testosterone and estradiol (E2). The central improvement in reproductive function. 04 A
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Table I. Adipokines and their effect on insulin sensitivity and putative reproductive effects 0
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Hormone Circulating levels Primary effects Effect on insulin Possible effect on reproduction
in obese sensitivity
Adiponectin ↓ Increases fat oxidation and insulin sensitivity ↑ Enhanced ovulation
IL-6 ↑ Stimulates acute phase proteins and cell growth ↓ Adverse implantation
Leptin ↑ Integrative signal of energy stores, anorexic ↑ Earlier onset reproductive maturation in children
Adverse ovulation
PAI-1 ↑ Inhibits fibrinolysis ↓ Adverse implantation
Resistin ↑ Increases insulin resistance ↓ Adverse ovulation and implantation
TNF-α ↑ Mediates acute inflammation ↓ Adverse implantation
IL-6, interleukin-6; PAI-1, plasminogen activator inhibitor type 1; TNF-α, tumour necrosis factor-α.
↓ in column 2 indicates decreased concentration.
↑ in column 2 indicates increased concentration.
586
Gut and adipose hormones in female reproduction
Table II. Enterokines and their metabolic and reproductive effects
Hormone Source in Stimulus to secretion Effect on Metabolic effects Possible reproductive effects
gastrointestinal tract appetite
Cholecystokinin Upper small intestine Fat and protein ↓ Release of pancreatic enzymes, Cycle-specific appetite effects
insulin and bile
Ghrelin Stomach Lack of food in stomach ↑ Growth hormone release ↓ LH and testosterone,
stimulates prolactin
↓ Embryo development
GIP Duodenum Carbohydrate and fat Unknown Insulin release ↓ FSH release
GLP-1 Ileum and colon Carbohydrate and fat ↓ Insulin release, ↓ glucagon, ↑ GnRH and LH release
delayed gastric emptying
Oxyntomodulin Ileum and colon Carbohydrate and fat ↓ ↓ Gastric acid secretion, ↓ ghrelin Not evaluated D
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PYY Ileum, colon and rectum Mixed meal, primarily fat ↓ ↑ Peripheral glucose uptake (?) ↑ LH and FSH release w
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GIP, glucose-dependent insulinotrophic peptide; GLP-1, glucagon-like peptide 1; PYY, peptide YY. e
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Table III. Relationship between circulating adipokine/enterokine concentration and menstrual cycle phase ttp
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Adipokine/enterokine Follicular phase Luteal phase Reference a
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CCK ↓ ↑ Frick, 1990 ic
IL-6 → → Jilma et al., 1997; Brannstrom et al., 1999; Al-Harthi et al., 2000 .o
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Leptin ↓ ↑ Moschos et al., 2002; Geisthovel et al., 2004 p
→ → Moschos et al., 2002 .co
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PAI-1 ↑ ↓ Giardina et al., 2004 /h
↓ ↑ Chung et al., 1998 um
TNF-α → → Al-Harthi et al., 2000 up
↑ (Late follicular) ↑ (Mid luteal) Brannstrom et al., 1999 d/a
↓ (Early luteal) rtic
le
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CCK, cholecystokinin; IL-6, interleukin-6; PAI-1, plasminogen activator inhibitor type 1; TNF-α; tumour necrosis factor-α. b
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↓ Indicates decreased concentration. tra
↑ Indicates increased concentration. c
→ Indicates no change. t/1
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The connection between weight loss among obese women and Deitel et al., 1988; Hall et al., 1990; Weiss et al., 2001). This is /77
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restoration of reproductive function was described as early as presumably due to the massive weight loss that follows the sur- 2
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1953 by Mitchell and Rogers (1953). Obese amenorrhoeic women gery, especially when compared with conventional therapy (Sjostrom b
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who lost weight on a hypocaloric diet had improved menstrual et al., 2004). Deitel et al. (1988) evaluated gynaecologic outcomes g
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function, and a significant proportion became pregnant. Menses by questionnaire in women who underwent bariatric surgery. Oli- e
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resumed 1–4 months after the initiation of dietary therapy. It is goamenorrhoea was present in 40% of the premenopausal women t o
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well established that among obese women with PCOS, weight loss presenting for bariatric surgery. After weight stabilization (2–5 years) 0
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results in increased ovulation and pregnancy rates (Mitchell and and loss of 36% body weight, 81% of the women with abnormal A
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Rogers, 1953; Pasquali et al., 1989; Kiddy et al., 1992; Guzick menses had become eumenorrhoeic. None of the preoperatively ril 2
etal., 1994). Hormonal changes produced by weight loss include eumenorrhoeic women had menstrual dysfunction at follow-up. 0
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increased SHBG, with attendant decreases in bioavailable estro- Preoperative infertility was reported by 25% of women. After sur- 9
gens and androgens. Obese individuals do not need to attain their gery, all nine women who tried to conceive were successful (Deitel
ideal body weight to exhibit improvements in menstrual function, et al., 1988). It is likely that post-operative alterations in adipose
ovulation and fertility. Indeed, these improvements may be noted and enteric signals contribute significantly to such reproductive
in some women after a 5–15% reduction in weight (Mitchell and changes. Studies have begun to link adipokine/enterokine changes
Rogers, 1953; Pasquali et al., 1989; Kiddy et al., 1992; Guzick to post-operative changes in metabolism and appetite. Thus far,
etal., 1994). the literature has not specifically addressed adipose/enteric signal
Bariatric surgery has been shown to be the only effective strat- modulation of reproductive function in women with severe obesity
egy for sustained weight loss among the severely obese (North who undergo bariatric surgery. Likely candidate signal molecules
American Association for the Study of Obesity and the National that link bariatric surgery to reproductive changes include ghrelin,
Heart Lung and Blood Institute, 1998, 2000; Jain, 2004). Repro- glucagon-like peptide-1 (GLP-1), leptin, adiponectin, tumour
ductive comorbidities dramatically improve after bariatric surgery necrosis factor-α (TNF-α) and plasminogen activator inhibitor
(Hey and Niebuhr-Jorgensen, 1981; Printen and Scott, 1982; type-1 (PAI-1).
587
G.G.Gosman, H.I.Katcher and R.S.Legro
and lipid metabolism (Table I) (Guerre-Millo, 2004). While some
of these are unique to fat tissue (i.e. leptin), others are more widely
produced, with adipose tissue contributing substantially to circu-
lating levels (i.e. TNF-α). An absolute decrease in the amount of
fat mass will alter the secretion of all of these hormones. This usu-
ally results in a decrease in circulating levels, although some of
the hormones are inversely secreted in relation to fat mass such as
adiponectin. Some adipokines, such as adiponectin, may exert a
beneficial effect on insulin action and others, such as TNF-α, an
adverse effect.
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Adiponectin o
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Adiponectin is the most abundant protein secreted by adipose tis- nlo
sue and circulates at a level about 1000 times higher than insulin ad
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and leptin. Levels are higher in females than those in males d
(Stefan and Stumvoll, 2002). However, unlike most adipose- fro
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specific factors, it circulates in lower concentrations in obesity and h
insulin-resistant states (Arita et al., 1999). Circulating adiponectin ttps
concentrations have been reported to increase after weight loss ://a
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Figure 1. Peripheral signals relating to long-term energy stores are produced (Yang et al., 2001). Recent data suggest that adiponectin is a ad
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by adipose tissue. Feedback regarding current nutritional state comes from mediator of insulin sensitivity and an enhancer of fatty acid oxida- m
absorbed nutrients, neuronal signals and gut peptides. Hormones released by tion (Yamauchi et al., 2002) and that the high levels protect ic.o
the gut have incretin-, hunger- and satiety-stimulating actions. The incretin hor- u
against the development of type 2 diabetes (Spranger et al., 2003). p
mones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotrophic .c
Adiponectin thus appears to have beneficial effects on glucose o
peptide (GIP) improve the response of the endocrine pancreas to absorbed m
nutrients. GLP-1 also reduces food intake. Ghrelin is released by the stomach and lipid metabolism. Administration of recombinant adiponectin in /h
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and stimulates appetite. Gut hormones stimulating satiety include cholecystokinin rodent models of obesity and diabetes improves glucose tolerance m
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(CCK) released from the gut to feedback by way of the vagus nerve. Neuronal and insulin sensitivity (Yamauchi et al., 2001). In a rhesus model, p
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pathways, primarily by way of the vagus nerve, relate information about stom- adiponectin levels decrease progressively with the worsening of /a
athceh nduisctleenutsio onf atnhde cthraecmtuicsa ls oalnitda rhiuosrm (NonTaSl )m wiliiethui nin t hthee duoprpsaelr vsmagaalll bcoowmepll etxo insulin resistance and onset of type 2 diabetes (Hotta et al., 2001). rticle
(DVC) (Modified with permission from Badman and Flier, 2005; Copyright Adiponectin knockout mice are insulin resistant, develop glucose -ab
2005 American Association for the Advancement of Science (AAAS)). OXM, intolerance on a high-fat diet and demonstrate early signs of athero- stra
oxyntomodulin; PP, pancreatic polypeptide; PYY, peptide YY. sclerosis (Kubota et al., 2002). Adiponectin is expressed in human c
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and rat placenta (Caminos et al., 2005) and is positively associated 2
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Adipokines with newborn length and birthweight (Sivan et al., 2003; Mantzoros /58
et al., 2004). Adiponectin levels are higher in adolescent girls than 5
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Adipose tissue synthesizes and secretes many peptides that are boys. Adiponectin in adolescent boys declines with increasing andro- 7
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involved in the regulation of energy homeostasis, insulin action gen concentrations (Bottner et al., 2004). However, adiponectin 7
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Table IV. Metabolic and reproductive phenotypes in mouse knockouts of adipokines or enterokines g
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Knockout gene Obese Appetite Metabolic effect Capable of reproduction t on
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Adiponectin No Normal Moderate insulin resistance and glucose intolerance with high-fat diet, atherosclerosis Yes A
GCChrKel-iAn receptor NYoes ↑Normal DNioarbmeatilc insulin and body composition YYeess pril 2
0
GIP receptor Noa Normal Glucose intolerance and normal fasting glucose Yes 1
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GLP-1 receptor No Normal Fasting hyperglycaemia and glucose intolerance Yes
IL-6 Noa Normal Glucose intolerance, normal fasting glucose and normal lipid metabolism Yes
Leptin Yes ↑ Hyperinsulinaemia and diabetes No
Leptin receptor Yes ↑ Hyperinsulinaemia and diabetes No
PAI-1 Noa Normal ↑ Bleeding tendency Yes
↑ Insulin sensitivity, glucose clearance and energy expenditure
Resistin Nob Normal ↓ Hepatic glucose production Yes
↑ Glucose tolerance
TNF-α No Normal ↑ Insulin sensitivity Yes
↓ Body fat
CCK, cholecystokinin; GIP, glucose-dependent insulinotrophic peptide; GLP-1, glucagon-like peptide 1; IL-6, interleukin-6; PAI-1, plasminogen activator inhibi-
tor type 1; TNF-α; tumour necrosis factor-α.
aProtected from weight gain on a high fat diet.
bNormal weight gain on a high fat diet.
588
Gut and adipose hormones in female reproduction
does not seem to be lower in women with PCOS compared with reproductive function at the level of the hypothalamus (Lonnqvist
BMI-matched ovulatory controls (Spranger et al., 2004). et al., 1995). Furthermore, it may be the endocrine signal to the
Large losses of body weight from bariatric surgery result in signi- brain to initiate reproductive maturation (Shalitin and Phillip,
ficant increases in plasma adiponectin (Faraj et al., 2003; Morinigo 2003). Originally, leptin was proposed to act as a satiety signal to
et al., 2004; Vendrell et al., 2004). However, in most studies, moder- the hypothalamus to limit energy intake and increase energy
ate weight loss from calorie restriction (≤7% body weight) does not expenditure (Hamann and Matthaei, 1996). Subsequently, it has
alter adiponectin despite improvements in glucose and insulin (Ryan been suggested that the primary role of leptin in the adult is to
et al., 2003; Garaulet et al., 2004; Imbeault et al., 2004; Xydakis counteract a negative energy balance and stimulate a survival
etal., 2004). Studies involving a 10% decrease in body weight or response (Flier, 1998).
BMI, however, are associated with a significant increase in adi- Serum leptin concentration is proportional to total body adipos-
ponectin (Hotta et al., 2000; Esposito etal., 2003), suggesting that a ity (Considine et al., 1996). Leptin-deficient persons represent a
critical amount of total adiposity must be lost before a change in adi- tiny proportion of obese humans. Indeed, the high concentrations
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ponectin is evident. Metformin therapy did not increase adiponectin of leptin among obese individuals support the notion of leptin res- ow
concentration in women with PCOS (Spranger et al., 2004). istance (Caro et al., 1996). Leptin’s function in obesity compared nlo
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with its role in starvation suggests that leptin may be more effect- d
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IInntteerrlleeuukkiinn--66 (IL-6) is a key mediator of inflammation. Up to 30% i2v0e0 a1s) .a Tcehnutsr,a ld seicgrneaals ionfg e nleervgeyls d eoffi cliet pthtiann sehnoeurgldy eixncceresas s(eH afovoeld, d from
intake and conserve energy, for example, by decreasing thermo- h
oinfc creiracsuelda tiinn go bILes-e6 imndaiyv iodruigalisn,a aten din i nfcart etaissseude l.e Cveirlcs ualraet iansgs oILci-a6t eids gfeemneasleis leoprt ine-lidmefiincaiteinntg mriecper oadreu csttievrei lec,a apnadci ttyh.i s Biso tcho rmreacltee da nbdy ttps://a
with diminished insulin sensitivity. IL-6 knockout mice have been c
reported to have varying obesity phenotypes. In one report, IL-6 leptin replacement (Chehab et al., 1996; Mounzih et al., 1997). ade
In humans, leptin receptors are found on granulosa and theca m
knockout mice were not obese, had normal fasting glucose levels ic
and lipid metabolism but a relative glucose intolerance and had cells, oocytes, preimplantation embryos and the endometrium .ou
(Karlsson et al., 1997; Cervero et al., 2005). There are multiple p
normal lipid metabolism (Di Gregorio et al., 2004). Furthermore, .c
proposed mechanisms for leptin-deficient reproductive failure o
they experienced less weight gain on a high-fat diet than that m
including abnormal gonadotrophin secretion, impaired folliculo- /h
experienced by wild-type mice. Another report showed an u
genesis, granulosa cell apoptosis and defective implantation m
increase in maturity onset obesity by 20% compared with wild- u
taynpdAe ln impimiidca ela, b aannnoddr hmthuaimsli atwinea sds ( aaWtsas asolulceginagiteuesdst ewtht iaatthl . e,m x2ca0er0ks2se) dI.L g-l6u choasse siunptoplreersasnivcee gi(nMr eaasltoilkmy eem t ocadal.is,fe y2s ,0t h0fe1e ;rr teHipliartmoyd muisc etitpv raeel s.c,e a2np0ta 0cw4it)iy.t h Goofeu nlte eplteitcipn tb-idnaec fkriegcprieolanuctn emdm icecanent; pd/article
(Ewart-Toland et al., 1999). Thus, even with this adipokine that -a
effects on reproductive function. In rats, intracerebroventricular b
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injection of IL-6 inhibits LH secretion (Rivier and Vale, 1990), has the clearest link to reproductive success, there may be some tra
although other studies found no such hypothalamic pituitary effect genetic redundancy that compensates for its absence. ct/1
Excess leptin has important reproductive effects that are more 2
(Watanobe and Hayakawa, 2003). In a rat-perfused ovary model, /5
relevant to obesity. Excess leptin has been shown in animal mod- /5
IL-6 blocks LH-induced ovulation and LH- and FSH-induced E 8
2 els to be detrimental to reproduction at multiple levels of the 5
production (Mikuni, 1995). IL-6 suppresses aromatase activity and /7
decreases estrogen production in human granulosa tumour cells hypothalamic–pituitary–gonadal (HPG) axis. Hyperleptinaemic 782
obese rats demonstrate lower surges of LH and prolactin than nor- 7
(Deura et al., 2005). PCOS women undergoing IVF were noted to 3
mal weight, normoleptinaemic controls. Three days of starvation b
have higher serum concentrations of IL-6 during ovarian suppres- y
in the hyperleptinaemic obese rats lowers their leptin levels by g
sion than women undergoing IVF for male factor infertility. They u
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42% and produces a substantial increase in the magnitude of their s
iatnhlsceor te ihamasveed eo hifn iog ovhvueamrr si aernerut hrmiye pvaeanrlds ( tAfimomlulialcatuotil oaernt fasluyl.in,d d2 rc0oo0mn3c)e.e (nCOtirrHactSuiolSan)ts i( noAgfb IIrLLa--m66o aivst LthHan a nthde p rnoolramctainl wsueriggeh.t ,H noowremvoelre, pthtien aseumrgiec lceovnetlrso alsr e (sWtilalt alonwobeer t on 04 A
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High concentrations (similar to those found in obesity) of leptin inter- 1
studies show no change in blood levels of IL-6 throughout the men- 9
fere with the effect of multiple growth factors on gonadotrophin-
strual cycle (Brannstrom et al., 1999) (Table III).
stimulated steroidogenesis in human and animal granulosa and
Weight loss by diet and exercise is effective in lowering IL-6
theca cells. These growth factors and hormones normally play a
levels (Ryan and Nicklas, 2004), with a greater reduction
stimulatory role and include insulin-like growth factor-1 (IGF-1),
following a hypocaloric Mediterranean-style diet (high in olive
transforming growth factor-β (TGF-β), insulin and glucocorti-
oil, fruits, vegetables, whole grains and nuts) than a low-fat diet
coids (Spicer and Francisco, 1998; Agarwal et al., 1999; Barkan
(<30% fat) (Esposito et al., 2004). IL-6 levels also decrease after
etal., 1999; Brannian et al., 1999; Zachow et al., 1999). In in vitro
bariatric surgery by as much as 50% (Vendrell et al., 2004;
cultured mouse follicles, high concentrations of leptin inhibit folli-
Vazquez et al., 2005).
cle growth, increase follicle steroidogenesis and reduce denuded
oocyte development to metaphase II (MII). However, embryo
Leptin
exposure to leptin does not alter blastocyst development or
Leptin is produced primarily by white adipose tissue and is a key hatching (Swain et al., 2004). Overall, rodent data are not
signal modulating the relationship between energy stores and entirely consistent regarding leptin’s effects on ovarian/follicular
589
G.G.Gosman, H.I.Katcher and R.S.Legro
steroidogenesis, oocyte meiosis or embryo development. These antagonism of resistin by anti-resistin immunoglobulin G (IgG)
data imply that excess leptin characteristic of obesity and/or exog- in mice improves insulin sensitivity (Steppan et al., 2001a).
enous leptin administration for weight loss impacts a variety of Conversely, administration of resistin to mice reduces insulin-
reproductive tissues. stimulated glucose uptake (Steppan et al., 2001a). Knockout
The literature consistently demonstrates that leptin decreases mice for resistin display normal weight and show improved
with weight loss on low calorie diets (Bastard et al., 1999, 2000a; glucose tolerance after a meal, along with decreased hepatic glu-
Morpurgo et al., 2003; Garaulet et al., 2004; Stamets et al., 2004; cose production (Banerjee et al., 2004). There is no clear repro-
Xydakis et al., 2004). High-protein and high-carbohydrate calorie- ductive phenotype in these mice. In rats, estrogen appears to
restricted diets yield similar decreases in leptin concentrations in down-regulate resistin expression (Huang etal., 2005).
obese women with PCOS (Stamets et al., 2004). In terms of the In humans, circulating levels of resistin may not be related to
influence of dietary composition on the leptin response to feeding, obesity or insulin resistance (Heilbronn et al., 2004; Iqbal et al.,
higher fat meals are associated with less of a leptin increase than 2005). Resistin has been investigated in women with PCOS under-
D
lower fat meals (Havel et al., 1999). Because leptin signals satiety going IVF. Resistin levels in either follicles or serum do not corre- ow
and meals with high-fat content induce a smaller leptin response, late with markers of insulin sensitivity, hormonal response (E2 or nlo
a
the drive to eat may be stronger, and weight loss may be lessened gonadotrophins) or fertilization/pregnancy rates (Seow et al., d
e
onB aa hriiagthr-icfa ts udrigete r(yK ereimsu eltts ailn., d19ra9m8)a.tically decreased leptin con- 2P0C0O5S). (UThrbea nreeski setti na l.g, e2n0e0 3p)r.omoter is also not associated with d from
centrations (Faraj et al., 2003; Geloneze et al., 2003; Molina et al., Most studies have shown no effect of weight loss on resistin h
2003; Nijhuis et al., 2004; Rubino et al., 2004; Stoeckli et al., levels. In a study of 24 insulin-resistant obese subjects, there ttps
2004; Vendrell et al., 2004). This leptin response corresponds to was no change in resistin levels after a 6-month programme of ://a
c
the immediate surgically induced energy restriction and, later, combined hypocaloric diet and moderate physical activity that ad
substantial weight loss. In a study of early hormonal changes after resulted in a 6.9 ± 0.1 kg average weight loss (Monzillo et al., em
ic
gastric bypass, leptin concentrations were significantly decreased 2003). Similarly, resistin levels did not change after 14 weeks of .o
u
in the early post-operative period (3 weeks), despite no significant weight loss by diet alone, exercise alone or both diet and exercise p
.c
change in weight (Rubino et al., 2004). (Giannopoulou etal., 2005). Resistin levels were unchanged 3 and o
m
6 months after gastric bypass surgery (Vendrell et al., 2004; /h
u
Gokce et al., 2005). m
Plasminogen activator inhibitor type-1 u
p
d
PAI-1 is a prothrombotic regulator of blood fibrinolytic activity /a
(Guerre-Millo, 2004). Circulating PAI-1 is primarily produced by Tumour necrosis factor-a rtic
le
white adipose tissue, especially visceral fat. Plasma concentrations TNF-α is produced in adipose tissue by both adipocytes and other -ab
of this protein correlate strongly with all components of the meta- s
btaidooilnpi,co PcsAyytnIed- 1rc ohemlals e m b(eVigeanrga stuiheoo new t anan lid.n, 1avn9itg8roi9o ;tg oLe anhneadsviiesn a (en6t 2ian)l.h. ,i Kb1in9too9rc0yk) .oe Iufnfte acmdt idocine- cPlTaelhtaleels s mw aidnaiit phtcho oebsn eotci-tesdhsne utBrreiavM mteiIoda n taTr niaNxdn F(dhW- yαaped pieisprrbioonebcsraygubt leeiln yte a aexelxpm.,er ie2rats0s s0 (ipBo3rn;ri um Fouaafnir n iTle yeNtt lFaaol-lc.α.,,a l22c 00po00arrr24ae))--.. tract/12/5/5
finosr uPliAn Ir-e1s iasrtaen pcero otenc tae dh igagha-fiants td itehte ( Mdeav eelto aplm., e2n0t 0o4f) . oTbheesyit ys haonwd acrltihnoe uegfhf ecatdsi p(oMseo htaismsueed -Acelir taeitn layl .,c 1o9nt9r7ib; uLteosf gtroe nt heet acilr.,c u2l0a0ti0n)g, 85/778
an increased tendency to bleed but are otherwise normal, including pool. In vitro studies demonstrate that TNF-α impairs insulin 27
3
reproductive capacity (Carmeliet et al., 1993a,b). Vascular or cell action by inhibiting insulin signalling (Hotamisligil et al., 1993, b
y
migratory effects of excess levels of this hormone may impair 1994; Stephens et al., 1997; Liu et al., 1998). TNF-α also stimu- gu
implantation and contribute to pregnancy loss. PAI-1 activity has e
lates leptin secretion by adipocytes (Kirchgessner et al., 1997; s
been implicated as a marker and as a potential contributor to spon- t o
Mantzoros et al., 1997), increases PAI-1 secretion and decreases n
taneous abortion in women with PCOS (Glueck et al., 1999, adiponectin secretion (Ruan et al., 2002). Anti-TNF-α antibodies 04
2003). Lowering PAI-1 activity has been theorized to improve the improve insulin sensitivity in obese rodents. TNF-α-deficient Ap
ongoing pregnancy rate in these individuals. mice are protected against obesity-induced insulin resistance when ril 2
Plasma PAI-1 decreases with hypocaloric weight loss fed a high-fat diet. Knockout mice for TNF-α are smaller with a 01
(Andersen et al., 1995; Mavri et al., 1999; Bastard et al., 2000c; 9
lower percentage of body fat, higher insulin sensitivity, lower glu-
Arvidsson et al., 2004) and after gastric bypass and gastric restric-
cose, insulin and triglyceride levels. They also display greater sus-
tive bariatric surgery procedures (van Dielen et al., 2004; Uzun
ceptibility to bacterial infection (Ventre et al., 1997).
etal., 2004; Vazquez et al., 2004). van Dielen et al. (2004) TNF-α and its receptors are expressed in the corpora lutea of
reported a rapid drop at 3 months post-operatively, followed by
many species and, along with gonadotrophins, regulate progester-
stabilization of PAI-1 concentrations up to 2 years after surgery.
one production (Okuda and Sakumoto, 2003). Unlike IL-6, excess
TNF-α appears to have pleiotropic effects on various aspects of
Resistin reproductive function. Central nervous system injection of TNF-α
Resistin is an adipose tissue-specific hormone, which was recently inhibits LH secretion in rats (Rivier and Vale, 1990; Watanobe
identified in a screen designed to enrich for transcripts that were and Hayakawa, 2003). However, TNF-α plays an important role
up-regulated during adipogenesis but decreased with peroxisome in multiple aspects of ovarian function, including ovulation, ster-
proliferator-activated receptor-γ (PPAR-γ) agonist treatment oidogenesis, cell proliferation and differentiation and corpus
(Patel et al., 2003). Resistin impairs glucose tolerance in vivo, and luteum regression (Terranova, 1997; Wood and Strauss, 2002).
590
Gut and adipose hormones in female reproduction
Female mice with disrupted type 1 TNF-α receptor (TNFR1) have GLP-1 are released from the gut in response to a nutrient challenge
an altered reproductive phenotype. These mice have enhanced and lead to glucose-dependent insulin release from the pancreas.
responsiveness to gonadotrophins and deliver smaller litters than
wild-type animals (Roby et al., 1999). Because many reproductive
tissues express both TNF-α and its receptor, it remains to be delin- Cholecystokinin
eated how circulating versus locally produced TNF-α differen- CCK, an incretin produced by mucosal cells in the upper small
tially influences the various reproductive processes. TNF-α and its intestine, is released after a meal and inhibits food intake in
receptor are expressed in human endometrium (Tabibzadeh et al., humans (Kissileff et al., 2003). CCK is also quantitatively one of
1995), and TNF-α has been implicated as a potential factor in the most widely expressed neurotransmitters in the central nerv-
pregnancy loss (Berman et al., 2005). Women with PCOS have ous system. CCK receptor knockout mice maintain normal
higher circulating TNF-α (Puder et al., 2005). The effects of TNF- weight in adult life, suggesting that there may be redundant path-
α on non-reproductive tissues may also have reproductive conse- ways for controlling appetite and body weight (Kopin et al.,
D
quences. Aromatase gene expression in human adipose stromal 1999). Genetic background can alter the phenotype. For ow
cells is stimulated by TNF-α (Zhao et al., 1996). Thus, extrago- example, the Otsuka Long-Evans Tokushima Fatty (OLETF) nlo
nadal estrogen production may be increased in states of TNF-α mouse that lacks CCK-A receptors is obese, diabetic and hyper- ad
e
excTehses .literature describing the TNF-α response to hypocaloric pChCaKgi cf.e Tedhbisa cmk afyr obme bthecea ugsuet oofn bsoatthi etthye aanbds etnhcee hoyfp poethriaplhaemraicl d from
weight loss is inconsistent. Serum TNF-α decreased in a study by deficiency in CCK action (Bi and Moran, 2002). CCK may lead h
Bruun et al. (2003) in which subjects went from a BMI of 39 kg/ to appetite inhibition in female animals, which is cycle specific. ttps
m2 to a BMI of 33 kg/m2 over a 24-week period. However, three During the ovulatory or estrous phase, some species demonstrate ://a
c
studies found no significant decrease in serum concentration after decreased meal size and food intake (Geary, 2001). There has ad
e
weight loss (Bastard et al., 2000a; Arvidsson et al., 2004; Xydakis been no study in humans of cycle-specific CCK effects on appe- m
ic
et al., 2004). Subjects in these studies lost less weight and main- tite or ovulatory function. In one report, CCK levels were higher .o
u
tained the hypocaloric diet for a shorter period than those in the luteal phase of the menstrual cycle (Table III) (Frick et al., p
.c
reported by Bruun et al. (2003). Arvidsson et al. (2004) observed 1990). Women with PCOS had lower postprandial secretion of o
m
that TNF-α production differed based on macronutrient content of CCK in one study, which was associated with disordered appe- /h
u
a low calorie diet. Subjects on a low-fat, high-carbohydrate diet tite regulation (Hirschberg et al., 2004). m
u
had a significant decrease in TNF-α production by adipocytes A limited number of studies have evaluated changes in CCK pd
amftoedre hraytpeo-fcaatl,o rmico wdeerigathet- cloasrsb,o whyhderraetaes sduibejte cdtisd l onsiontg ewxehiigbhitt oann ya fsrixo mo bweseeig mhte lno sasn. dN wo ocmhaenng ea fwtears ao b1s0e-rwveeedk i nv ebrays allo CwC cKal olerviee lds iient /article
change in adipocyte TNF-α response. Both of these types of diets (240 kcal/day), resulting in a mean weight loss of 23 kg (Lieverse -a
b
s
had similar effects on insulin sensitivity. Weight loss and a very low et al., 1993). However, the lack of effect may be because of a tra
calorie diet are associated with decreased serum concentrations of small sample size. One small study found no change in CCK 3 ct/1
soluble TNFR1 (sTNFR1) but stable concentrations of sTNFR2 weeks after gastric bypass (Rubino et al., 2004). Postprandial peak 2
/5
(Bastard et al., 2000c). Many authors use measures of sTNFR as a CCK secretion increased after gastric restrictive bariatric surgery, /5
8
marker of the activity of the TNF system rather than measuring potentially contributing to earlier satiety (Foschi et al., 2004). 5
/7
TNF-α itself (Aderka et al., 1992; Mantzoros et al., 1997; Corica 78
2
et al., 1999; Bullo et al., 2002). 7
3
A similar change in sTNFR may occur in bariatric surgery Ghrelin b
y
patients. Six months after gastric bypass, patients have signifi- The endogenous growth hormone secretagogue, ghrelin, is pro- g
u
e
cantly decreased concentrations of sTNFR1 and stable concentra- duced primarily by the stomach and is an appetite stimulant. Ghrelin s
tions of sTNFR2 (Vendrell et al., 2004). van Dielen et al. administration increases food intake, decreases fat oxidation and t on
(2004) followed serum concentrations at 3, 6, 12 and 24 increases adiposity in rodents. In humans, ghrelin stimulates appe- 04
months after gastric restrictive procedures and found that the tite and food intake. The effects of short-term changes in this gut Ap
drop in sTNFR1 concentrations was delayed until 24 months after hormone on reproductive function have not been extensively stud- ril 2
0
surgery. However, data do not uniformly show a decline in the ied, but a recent review discusses the preliminary data (Barreiro and 1
9
TNF-α system activity after bariatric surgery. For example, Tena-Sempere, 2004).
Vazquez et al. (2004) noted no decline in TNF-α or its soluble Elevated ghrelin concentrations may diminish reproductive
receptors 4 months after gastric restriction or intestinal bypass. function by inhibiting LH and stimulating prolactin secretion
(Arvat et al., 2001; Furuta et al., 2001). Ghrelin may also have
embryotoxic effects. Pregnant rats exposed to high levels of ghre-
Enterokines
lin in the first half of pregnancy produce smaller litters (Barreiro
The gut secretes many hormones which we will refer to as enterok- and Tena-Sempere, 2004). Ghrelin inhibits the development of
ines (Table II). We focus on hormones secreted by the gut that have mouse embryos in culture (Kawamura et al., 2003) and inhibits
a variety of endocrine effects on peripheral tissues relevant to testosterone secretion by testicular Leydig cells (Tena-Sempere
reproduction. We include those substances that affect pancreatic etal., 2002). While analogous data in the ovary are not available,
insulin secretion (incretins), hypothalamic function via appetite the notion of ghrelin’s ability to suppress gonadal steroid produc-
modification (ghrelin) and cholecystokinin (CCK). Incretins such tion is intriguing. Ghrelin knockout mice have no discernible met-
as CCK, glucose-dependent insulinotrophic peptide (GIP) and abolic or reproductive phenotype compared with wild type; they
591
G.G.Gosman, H.I.Katcher and R.S.Legro
have normal size, body distribution, behaviour and fertility (Sun the peptide increases LH concentrations in male rats (Beak et al., 1998).
etal., 2003). An additional mechanism by which GLP-1 may enhancereproductive
Weight loss from hypocaloric diets increases ghrelin expression function is via improved insulin and glucose dynamics.
(Cummings et al., 2002; Hansen et al., 2002; Soriano-Guillen The effects of weight loss by diet on GLP-1 have been incon-
etal., 2004). This rise in ghrelin is postulated to contribute to sistent. In one study, an average weight loss of 18.8 kg resulted in
recidivism after hypocaloric weight loss because of its potent a very small increase in GLP-1 in response to a test meal (an
appetite stimulation. The reproductive suppressive effects of ele- increase from 80 to 88% of that of lean subjects) (Verdich et al.,
vated ghrelin concentrations may be a factor that contributes to 2001). In a second study, postprandial GLP-1 levels were lower
inconsistent initiation of ovulation among PCOS women losing after a 6-week very low calorie diet, resulting in an average weight
weight in this manner. In postprandial studies, a protein-rich meal loss of 6.1 kg (Adam et al., 2005).
increases ghrelin, whereas a high-fat or high-carbohydrate meal GLP-1 has been shown to increase after intestinal bypass
suppresses ghrelin (Erdmann et al., 2003). Although diet composi- (Rubino and Gagner, 2002; Cummings et al., 2004). Two studies
D
tion affects postprandial ghrelin levels, there is no significant have evaluated GLP-1 in the early post-operative period after gas- ow
effect of diet composition on ghrelin during a weight-loss diet in tric bypass (Clements et al., 2004; Rubino et al., 2004). Both nlo
a
women with PCOS (Moran et al., 2003). Thus, the degree of studies showed a trend towards increased post-operative GLP-1 d
e
wgherieglhint laonsds raepppreoadrusc ttoiv he afvuen cat imonu cthha gnr deaietet rc oimmppaocsti toionn c.hanges in cpountsc erenltartaitvioelnys .u nGdLigPe-s1t edm nauyt riinencrtse aisne c obnetcaacut swe itihn ttehset idniaslt abl ysmpaaslsl d from
The effects of bariatric surgery on ghrelin concentrations differ bowel and colon. In patients with type 2 diabetes mellitus who h
between restrictive and bypass procedures. Most studies have underwent jejunoileal bypass, there was an increase in fasting and ttps
demonstrated that, after gastric restrictive procedures, ghrelin con- postprandial GLP-1 at 9 months and at 20 years after surgery, ://a
c
centrations are increased (Fruhbeck et al., 2004; Nijhuis et al., which was associated with normalized fasting and postprandial ad
e
2004; Schindler et al., 2004; Stoeckli et al., 2004). This response insulin and glucose (Naslund et al., 1998). m
ic
is intuitive, because, in gastric restrictive procedures, the anatomic .o
u
integrity of the stomach is preserved, and thus, the increased ghre- Glucose-dependent insulinotropic polypetide p
.c
lin response would be expected to be similar to non-surgical o
GIP is an incretin released after oral glucose challenge from the K m
hypocaloric weight loss. This stands in contrast to intestinal /h
cells. These cells are present throughout the small intestine but are u
bypass procedures, for which many studies demonstrate that ghre- m
most densely present in the duodenum. In addition to its incretin u
2lrie0nm0 s4aii;gn Mn uaolnlrciinhngaig niogs eeddt i asprlo.u,s pt2t-0eod0p,4e ;ra aSntdtiov eegclhykr le(ilT ienrti tacolos.,n e2cte0 an0lt4.r,)a .2t iA0o0nlt3se; r deLedic ngl ihenrte ea loil.nr, escyefflnelt chpte,r soGilsiI fPien ra alatsidooi npst.oi mcAyu telgasrt ee(asYt eliirpp opaprnordop toeWritnio ollnfipe ,ao s2fe 0 Ga0cI0tP)iv airtenyad ca hpnerdos f mathtoteyte ass ycβisd-- pd/article
dynamics after gastric bypass have been posited as an explanation -a
temic circulation compared with GLP-1. GIP receptor knockout b
s
for the sustained decrease in appetite and food intake produced by mice are similar to wild-type mice in their behaviour, feeding, tra
this procedure (Cummings et al., 2004). However, some investiga- body weight and triglyceride levels but have an impaired initial ct/1
tors have found that ghrelin concentrations increase after gastric 2
insulin response and higher peak glucose levels, following an oral /5
bypass surgery (Holdstock et al., 2003; Vendrell et al., 2004). /5
glucose challenge (Miyawaki et al., 1999). Knockout mice do not 8
This discrepancy in ghrelin levels post-operatively may have two 5
gain excessive weight or develop insulin resistance on a high-fat /7
possible explanations: (i) variations in surgical technique may lead diet, possibly because of increased energy expenditure and/or use 782
to variable inclusion of portions of the gastric fundus, the greatest 7
of fat as their preferred energy source (Miyawaki et al., 2002). 3
source of ghrelin (Cummings et al., 2004) and (ii) ghrelin assays b
GIP analogues have been proposed as potential therapeutic agents y
vary from study to study, some evaluating total ghrelin and others g
for the treatment of type 2 diabetes (Gault et al., 2003). In rats, u
e
octanoylated (active) ghrelin. s
intraventricular injection of GIP results in decreased serum FSH. t o
There is little published literature on the role of GIP in ovulation n 0
Glucagon-like peptide-1 and reproduction in humans. 4 A
GLP-1 is an incretin and product of the preproglucagon gene. L GIWP leeivghelts l owsesr aep rpeedaurcse tdo ilno w19e rn GonIP-o lbeevseel sd iina boebtiecs em ianldeisv iadfutearl s6. pril 2
cells in the distal small intestine and colon secrete GLP-1. GLP-1 0
1
months on a 1000 kcal/day formula diet, resulting in a mean 9
is one of the most potent substances to increase insulin secretion
from the β-cells of the pancreas. The hormone has a trophic effect weight reduction of 18.8 kg (Verdich et al., 2001). The area
under the curve (AUC) response of GIP following a test meal
on these cells and is also anorexigenic. GLP-1 analogues are
was also reduced. GIP levels are reduced after bariatric surgery
effective therapies for diabetes mellitus (Harder et al., 2004;
in patients with type 2 diabetes (Clements et al., 2004; Rubino
Madsbad et al., 2004). GLP-1 receptor knockout mice have normal
et al., 2004).
weight and feeding behaviour; however, they have mild fasting
hyperglycaemia and abnormal glucose tolerance after a glucose
Peptide YY
challenge (Scrocchi et al., 1996). Interestingly, female GLP-1
receptor knockout mice demonstrate delayed puberty (MacLusky et Peptide YY (PYY) is a member of the neuropeptide Y (NPY) fam-
al., 2000). Animal and in vitro data suggest that GLP-1 may enhance ily and is a powerful appetite suppressant. PYY is secreted by the
reproductive function. GLP-1 receptors have been identified in gut mucosal endocrine cells postprandially in proportion to calorie
hypothalamic regions containing GnRH neurons (Small etal., 2002). intake and is converted to PYY by the enzyme dipeptidyl
3–36
In vitro, GLP-1 stimulates GnRH release. Intracisternal injection of peptidase IV (Batterham et al., 2002). PYY activates the NPY
3–36
592
Gut and adipose hormones in female reproduction
Y2 receptor (Y2R) that inhibits NPY neurons. PYY freely and reduced adipocyte leptin production. TNF-α stimulates adi-
3–36
crosses the blood–brain barrier and acts on the hypothalamic arcu- pose tissue aromatase expression (Zhao et al., 1996). Aromatiza-
ate nucleus to suppress appetite. Obese individuals have lower tion of androgens to estrogens in obese women contributes to a
endogenous levels of PYY than those observed in lean subjects hyperestrogenic environment. Chronic exposure to elevated estro-
(Batterham et al., 2003). gen production has been hypothesized to contribute to ovulatory
In mice and rats, peripheral administration of PYY reduces dysfunction among obese women (Yen, 1980; Gambineri et al.,
3–36
total food intake and body weight (Batterham et al., 2002). In 2002). Reduction in TNF-α, in addition to reduction in fat mass
humans, infusion of PYY at physiological levels decreased with these treatments, may contribute to diminished adipose tissue
3–36
food intake by 30% in lean and obese healthy volunteers com- estrogen production in these women.
pared with placebo. Lean and obese subjects demonstrate the same Bariatric surgery and hypocaloric diet diverge in their effects on
response (Batterham et al., 2003), suggesting that, unlike leptin, ghrelin. Bariatric surgery intestinal bypass procedures avoid the
sensitivity to PYY in obese subjects is intact. increased ghrelin induced by hypocaloric diet. The diminished
3–36 D
PYY3–36 inhibits NPY neurons, suggesting a potential role in ghrelin response seen with these procedures may facilitate ovula- ow
reproductive function. NPY is oversecreted in rodent models of tion, conception and pregnancy continuation. Adiponectin nlo
a
obesity, and excessive secretion of NPY has a suppressive effect increases after bariatric surgery, potentially improving ovulatory d
e
otinv eH NPPGY f uenxchtiiboint h(Kypaolrgao annadd iKsmal r(aK, a1lr9a9 6e)t . aRl.o, d1e9n9t9s )w, withh iloev eNrPacY- faupnpcetaiorsn tvoi ap erondhuacnec eidn cinresausleins sienn asidtiipvoitnye. cHtiynp owchaelonr i1c0 w%e iogfh tb loodsys d from
knockout female mice do not have suppressed circulating LH weight is lost. However, no difference in adiponectin is produced h
vafatreira bflaes teinffge c(tHs iloln a nredp rLoedvuicnteio, n2 0i0n3 a).n iPmYaYl 3i–n3 6v iatprop eaanrsd tion hvaivvoe with up to 7% body weight lost with this method. ttps://a
c
models. PYY3–36 stimulates rat pituitary production of LH and Weight-loss therapies that target enteric and adipocyte ade
FSH; however, in vivo infusion does not show a dose–response m
signals ic
effect in females (Fernandez-Fernandez et al., 2005). Infusion of .o
u
PYY delays an E -induced LH surge in ovariectomized ewes One promising strategy in drug development for the treatment of p
3–36 2 .c
(Clarke etal., 2005). obesity is the use of adipokine and enterokine targets, especially o
m
There is limited information of the role of diet and weight-loss those that modify appetite. Several drugs that target these signals /h
u
surgery on PYY. Preliminary studies indicate that PYY levels have been developed and have undergone clinical trials in humans. m
u
increase after obesity surgery, so that levels are comparable with The body of literature regarding these agents is relatively immature pd
non-obese controls (Alvarez Bartolome et al., 2002). aNnodn detoheesl ensost, abdedcraeussse rtehpersoed augcetinvtes choanvsee aqcuteionncse so no fh tohremseo ntheesr raeplieevs-. /article
ant to body weight control, their use might have an impact on ovu- -a
b
s
Adipokine/enterokine changes and potential effects lation. We will discuss human clinical information regarding tra
on female reproductive function recombinant leptin, ciliary neurotrophic factor (CNTF), oxynto- ct/1
modulin, peptide YY (PYY ) and octreotide (Table V). 2
The degree of weight loss with bariatric surgery far exceeds that 3–36 3–36 /5/5
ahtytapionceadl orwicit hd iehty panodca bloarriica trdiice tssu. rgHeoryw eavlteerr, masa nwy eo fh athvee asdhiopwokn-, Recombinant leptin 85/77
ines/enterokines in a similar direction. Very little data exist that Because of leptin’s ability to regulate nutrient intake and energy 82
7
expenditure, investigators have explored the possibility that exog- 3
compares the magnitude of these changes between the two thera- b
enously administered leptin might exhibit similar properties. In y
pies. As previously noted, human female reproductive conse- g
murine models of leptin deficiency, exogenous leptin administra- u
quences of these alterations are largely speculative without e
s
experimental data. tion improves the obesity noted in the ob/ob knockout mouse t o
Decreased leptin with these therapies may abrogate some of the (Pelleymounter et al., 1995; Weigle et al., 1995). Indeed, the same n 0
suppressive effects of excess leptin on hypothalamic, pituitary and phenomenon has been described in leptin-deficient humans 4 A
ovarian functions. Both therapies decrease PAI-1, which may (Farooqi et al., 1999; Licinio et al., 2004). Recombinant native pril 2
decrease miscarriage in obese women. GLP-1 appears to increase as 0
1
a consequence of these treatments. One could speculate that, in 9
Table V. Effect of infusion of enterokines/adipokines or related factors on
severely obese women with glucose intolerance or diabetes mellitus,
appetite and weight in human trials
increased GLP-1 after hypocaloric or surgical weight loss may con-
tribute to the restoration of normal glucose tolerance and more nor-
Drug Effect on Effect on body
mal patterns of insulin secretion. However, in a subject with normal
appetite weight
glucose tolerance, insulin resistance and relative hyperinsulinaemia,
such as many women with PCOS, increased GLP-1 may result in an Leptin Reduced Reduced at 24 weeks
(dose dependent)
exacerbation of hyperandrogenism and chronic anovulation.
CNTF (NPY antagonist) Reduced Reduced
Reports conflict over the effects of bariatric surgery and hypoca-
PYY (NPY antagonist) Reduced No long-term studies
loric diet on TNF-α. If this is indeed one of the adipokines that
Oxyntomodulin Reduced Reduced
declines with these therapies, the reduction in adipose-derived Octreotide (somatostatin agonist) Reduced Reduced
TNF-α may be one of the mechanisms whereby ovulatory function
improves. Reduced TNF-α results in reduced insulin resistance CNTF, ciliary neurotrophic factor; NPY, neuropeptide Y; PYY, Peptide YY.
593
G.G.Gosman, H.I.Katcher and R.S.Legro
human leptin expressed and purified from Escherichia coli is similar 30% decrease in calorie intake after infusion of the drug
chemically conjugated to a species of branched polyethylene gly- (Batterham et al., 2003). Reproductive effects of PYY are dis-
col (PEG) molecule. The result is a native human leptin polymer cussed in the Enterokines section.
with increased molecular size, called pegylated leptin, which is
administered via weekly subcutaneous injections (Hukshorn et al.,
Oxyntomodulin
2000; Westerterp-Plantenga et al., 2001).
Like GLP-1, oxyntomodulin is a product of the preproglucagon
Recombinant human leptin was used to treat eight women with
gene and is released from the L cells of the distal small intestine
hypothalamic amenorrhoea because of strenuous exercise or low
(Stanley et al., 2004). It is secreted 5–30 min after food ingestion
weight. Recombinant leptin treatment increased mean LH levels
in proportion to calorie intake. Long-term administration of oxyn-
and LH pulse frequency after 2 weeks and increased maximal fol-
tomodulin inhibits food intake and weight gain in rats (Dakin
licular diameter, the number of dominant follicles, ovarian volume
etal., 2002, 2004). Infusion of oxyntomodulin to normal weight
and E levels over a period of 3 months. Three patients had an
2 D
ovulatory menstrual cycle; two others had preovulatory follicular human subjects reduced hunger and produced a 19.3% reduction ow
development and withdrawal bleeding during treatment (Welt in calorie intake at a subsequent buffet meal (Cohen et al., 2003). nlo
The anorectic effects of oxyntomodulin can be blocked by the a
etal., 2004). d
appWeteietek lyb uat dnmoi nsiisgtrnaitfiiocna not f wpeeiggyhlta tleods sl eipnt ino bleesaed sp atoti ednetsc rewahseedn GmLodPu-1li nre acnedp toGrL aPn-t1ag monaiys ta ecxt evnidai nth (e9 -s3a9m),e sruegcgeepsttoirn g(D thaakti no xeytn atol.-, ed from
compared with placebo (Hukshorn et al., 2000). Recombinant 2001). Oxyntomodulin inhibits gastric acid secretion and empty- h
methionyl human leptin by daily subcutaneous injection combined ing and reduces ghrelin (Cohen et al., 2003; Konturek et al., ttps
with a low calorie diet resulted in significant weight loss in the 2005). These mechanisms may be responsible for its appetite- ://a
two highest dose cohorts after 24 weeks of therapy compared with suppressing effects. cad
A recent clinical trial evaluated whether oxyntomodulin admin- e
placebo plus low calorie diet among non-leptin-deficient obese m
istration reduces body weight in humans (Wynne et al., 2005). In ic
subjects. The mean weight loss after 24 weeks of therapy at the .o
this study, 29 overweight or obese volunteers self-administered u
highest dose was 7 kg, 95% of which was a decrease in fat mass p
subcutaneous injections of oxyntomodulin three times daily (30 min .c
(Heymsfield et al., 1999). o
m
Investigators hypothesize that exogenous leptin administration before each meal) for 4 weeks. Volunteers were asked to maintain /h
would fail to exceed the weight loss produced by currently mar- their normal diet and level of physical activity during the study um
kathneecte eld ec pohtbainrea spcittayet rhitwshteaicrya op(fis eeoseb (eCJsaiiitlnyia,. rA2y 0lnt0ee4run)r aboteitvrcoeap ushsiigec n oaffal lcitnthoger tlaaernpgdtei ntPs eraeplsotiinsdtge- agp resoriiugopnd,i. f wiBchaoendrtey ar eswd teuhicegt hicoto nnw tiranos l l ergeprdtoiunuc pea dnlo ds2 ta. 30n . 5±in ±c0 r.0e4.a 5sk ekg g ini.n T ahtdheiepr eot nrweeaactstmi anel sinnot upd/article
YY ) have been identified in the hope that, by bypassing leptin the treatment group as well as a decrease in energy intake during a -a
3–36 b
test meal. These preliminary data suggest that oxyntomodulin s
resistance, more marked weight loss can be achieved. could be an effective treatment for obesity. Reproductive effects trac
of oxyntomodulin administration are not known. t/1
Ciliary neurotrophic factor 2/5
/5
CNTF is a neuroprotective protein originally targeted and 8
5
developed for the treatment of amyotrophic lateral sclerosis Somatostatin analogues /77
(ALS). During a clinical trial of exogenous administration of 82
Somatostatin is secreted by the D cells of the pancreas. It was 7
CNTF for ALS, the compound produced marked weight loss 3
identified as a potential target for obesity therapy because of its b
(ALS CNTF Treatment Study Group, 1996). In mice, CNTF direct suppressive effect on pancreatic β-cell function, inhibiting y g
mediates appetite suppression and weight loss via a similar sig- insulin secretion. Octreotide, a synthetic analogue of somatostatin, ues
nalling mechanism to leptin (i.e. via NPY suppression) (Xu et al., provides long-acting inhibition of insulin and growth hormone t on
1998). In a phase II randomized controlled trial of recombinant secretion (Marbach et al., 1992) and has been studied extensively 04
human variant CNTF (rhvCNTF) for the treatment of obesity, the in humans. In a pilot study, octreotide was administered to 44 A
p
hsiiggnhiefsict adnot sewse oigfh tth elo dssru (g3 –ad4m kign)i staemreodn go voebr e1s2e wadeuelktss p(Erotdtiuncgeedr seevvaelurealtye iotbs eesfefe acdtsu lotns owveeirg h2t4 l owsese aknsd w foitohdo uint tdaikeeta. rOyc rterestortiicdteio pnr oto- ril 201
etal., 2003). A phase III clinical trial of rhvCNTF involving 9
duced significant insulin suppression and an average of 3.6 kg
∼2000 subjects showed significantly more weight loss with rhvC-
weight loss (Velasquez-Mieyer et al., 2003). A multicentre, rand-
NTF than with placebo. However, the development of antibodies
omized, double-blind, placebo-controlled trial of octreotide at
to the compound limited weight loss in some individuals. Should
three dose levels involving 172 obese adults (28 men and 144
CNTF prove to be an effective anti-obesity therapy, reproductive
women) with evidence of insulin hypersecretion was performed.
effects would likely be similar to PYY (see Enterokines)
3–36 Participants on the two highest doses demonstrated a significant
because of the common mechanism of NPY suppression.
decrease in weight from baseline; however, the change in body
weight was <2% in both the groups (Lustig, 2006).
Peptide YY3–36 Octreotide’s effects on reproduction have also been examined,
NPY also has been identified as a target for obesity therapy. Inhi- particularly in women with PCOS, who might benefit from octre-
bition of NPY through PYY administration has the potential to otide’s anti-incretin effects. A single dose of octreotide adminis-
decrease appetite and enhance energy expenditure. Exogenous tered to women with and without PCOS produced decreased LH
PYY administered to obese and lean human subjects resulted in a levels in both the groups; androgens were unchanged. During the
594