REVIEW

Gastrointestinal hormones and polycystic ovary syndrome

Jing Ma • Tzu Chun Lin • Wei Liu

Received: 19 February 2014 / Accepted: 16 April 2014

� Springer Science+Business Media New York 2014

Abstract Polycystic ovary syndrome (PCOS) is an endo-

crine disease of women in reproductive age. It is character-

ized by anovulation and hyperandrogenism. Most often

patients with PCOS have metabolic abnormalities such as

dyslipidemia, insulin resistance, and glucose intolerance. It

is not surprising that obesity is high prevalent in PCOS. Over

60 % of PCOS women are obese or overweight. Modulation

of appetite and energy intake is essential to maintain energy

balance and body weight. The gastrointestinal tract, where

nutrients are digested and absorbed, plays a central role in

energy homeostasis. The signals from the gastrointestinal

tract arise from the stomach (ghrelin release), proximal small

intestine (CCK release), and distal small intestine (GLP-1

and PYY) in response to food. These hormones are recog-

nized as ‘‘appetite regulatory hormones.’’ Weight loss is the

key in the treatments of obese/overweight patients with

PCOS. However, current non-pharmacologic management

of body weight is hard to achieve. This review highlighted

the gastrointestinal hormones, and discussed the potential

strategies aimed at modifying hormones for treatment in

PCOS.

Keywords Gastrointestinal hormones � Obesity � PCOS

Introduction

Polycystic ovary syndrome (PCOS) is a common reason for

female infertility, affecting up to 4–7 % of women at

reproductive age according to the National Institutes of

Health (NIH) criteria [1, 2] or 15–18 % according to the

criteria of the European Society of Human Reproductive and

Embryology/American Society for Reproductive Medicine

(ESHRE/ASRM) [3]. The etiology of PCOS remains

unclear. Recent study reported that adiponectin gene poly-

morphisms are related to the development of PCOS [4]. The

clinical features of PCOS include hyperandrogenism and

ovarian dysfunction. Women with PCOS have increased

chance of metabolism dysfunctions [5], such as hyperinsu-

linaemia and dyslipidemia, eventually develop into obesity,

type 2 diabetes mellitus (T2DM), and cardiovascular dis-

eases (CVD) [3]. Chronic low-grade inflammation is likely

the important factor of insulin resistance in PCOS [6]. High

prevalence of obesity exacerbates insulin resistance, the

abdominal fat deposition, and androgen secretion in women

with PCOS [7] (Fig. 1). Animal models of PCOS exposure to

chronic hyperandrogenism present increased food intake [8].

It suggests that impaired appetite regulation might contribute

to the pathophysiology of PCOS [9]. Therefore, dietary,

exercise, medication and surgery are always major therapies

of weight loss in patients with PCOS [10, 11]. The paper

focused on the body weight management related to gastro-

intestinal hormones modification in PCOS.

Energy intake and gastrointestinal hormones in PCOS

Modulation of appetite and energy intake is essential to

maintain energy balance and body weight. Short-term

appetite and food intake can be regulated by the hypothala-

mus, which constitutes a central control mechanism, and by a

peripheral mechanism, constituted by signals arising from

the gastrointestinal tract [12]. The crucial roles of gastric

emptying/distention and the release of peptide hormones

such as cholecystokinin (CCK), glucagon-like peptide

J. Ma � T. C. Lin � W. Liu (&)

Division of Endocrinology and Metabolism, Department

of Internal Medicine, Renji Hospital Affiliated to Shanghai

Jiaotong University School of Medicine, Shanghai, China

e-mail: sue_liuwei@live.cn

123

Endocrine

DOI 10.1007/s12020-014-0275-1

(GLP-1), and peptide tyrosine–tyrosine (PYY) in response to

nutrient intake are increasingly being recognized as impor-

tant physiological regulators of appetite (Fig. 2). A better

understanding of the appetite regulation in PCOS is required

to enable the development of effective therapies [13, 14].

Ghrelin

Ghrelin, a 28-amino acid peptide, is an orexigenic hor-

mone, which is secreted mostly from the gastric mucosa;

small quantities can be found in the duodenum and hypo-

thalamus [15]. Plasma ghrelin concentrations are high in

the fasting state and decrease with nutrient ingestion [16].

Ghrelin declines equally after gastric, intraduodenal, and

intrajejunal nutrient infusions in rodents and humans,

suggesting that gastric distension does not regulate its

suppression [17, 18]. Rather, exposure of the small intes-

tine to nutrients is required to suppress ghrelin [18]. Fasting

and postprandial fluctuations of ghrelin are also related to

insulin concentrations and sensitivity [19]. For example,

obese individuals with insulin resistance have a blunted

suppression of ghrelin in response to nutrients [20].

In both rodents [15] and humans [21], exogenous ghrelin

administration increases energy intake, while patients with

Prader-Willi syndrome, characterized by excessive feeding

behavior, have high levels of circulating ghrelin [22].

Proximal Roux-en-Y gastric bypass decreases ghrelin

secretion, which may contribute to weight loss after this

procedure [23]. Ghrelin modulates appetite via the arcuate

nucleus (ARC) of the hypothalamus [24]; it enhances

neuropeptide Y (NPY) and agouti-related peptide (AgRY)

gene expression and release in the lateral hypothalamic

nucleus (LHA), and inhibits the anorexigenic proopio-

melanocortin (POMC) neurons in the ARC [25]. In contrast

to ghrelin, leptin, an anorexigenic hormone, inhibits orex-

igenic neurons containing NPY and AgRY, while stimu-

lating POMC neurons in the ARC [26]. Leptin attenuates

the activity of ghrelin in the ARC and suppresses food

intake. Thus, ghrelin and leptin interact with each other in

the appetite center, in the so-called ‘‘ghrelin-leptin tango’’

[27]. Ghrelin receptor antagonist, JMV 2959, which is

under research, might have the benefit in the treatment of

obesity [28].

Ghrelin levels in PCOS patients are reported to be

decreased [29] or not different [30] compared to control

subjects. Postprandial fluctuations of ghrelin are related to

insulin concentrations and insulin sensitivity [31]. Ghrelin

levels are lower in obese women suffering from PCOS than

lean women with PCOS and health controls [32]. The

impaired postprandial ghrelin levels may be involved in the

development of obesity in PCOS [32]. Some studies sug-

gested that low ghrelin levels in PCOS might be a conse-

quence of the high androgen levels [33]. Moreover,

luteinizing hormone/follicle-stimulating hormone ratio is

also related to ghrelin levels [34].

GLP-1

GLP-1 is released from L-cells, most densely located in the

ileum and colon, although they have also been found more

proximally in the duodenum and jejunum [35]. Fasting

plasma concentrations of total and intact GLP-1 are lowFig. 1 The reproductive and metabolic disorder of PCOS and the

relationship with obesity

Fig. 2 Schematic

representation of

gastrointestinal regulation of

appetite

Endocrine

123

(5–10 pmol/L); in response to a meal rich in fat or carbo-

hydrate, circulating levels of GLP-1 increase up to five fold

within minutes [36]. The half-life of GLP-1 is short

(*2 min), due largely to rapid degradation by the enzyme,

dipeptidyl peptidase-IV (DPP-IV) [37]. DPP-IV, also

known as CD26, cleaves dipeptides from the N-terminal to

inactivate GLP-1 [38]. A large proportion of GLP-1 is

degraded before entering the systemic circulation, by DPP

IV expressed on blood vessels draining the intestinal

mucosa [39].

GLP-1 is one of two known incretin hormones, together

with glucose-dependent insulinotropic polypeptide (GIP).

The insulinotropic effect of GLP-1 is glucose-dependent,

via interaction with a specific receptor expressed on the cell

membrane of b-cells [40]. GLP-1 receptors are found on

b- and D-cells of the pancreas, parietal cells of the stom-

ach, pylorus, adipose tissue, lungs, and the brain. It has

been shown that GLP-1 stimulates b-cell proliferation and

induces islet neogenesis, inhibits apoptosis, and enhances

the differentiation of new b-cells from progenitors in the

pancreatic duct epithelium [41]. In healthy subjects,

endogenous GLP-1 reduces glucagon release from the

a-cells of the pancreas [42], and intravenous administration

of GLP-1 lowers glucagon secretion in patients with T2DM

[43]. Among the multiple physiological effects of GLP-1,

its effect on gastric emptying may outweigh its insulino-

tropic effect in the regulation of postprandial glycaemia

[44]. The mechanism underlying the action of GLP-1 on

motility is complex and not well understood.

Intracerebroventricular injection of GLP-1 inhibits

feeding in rats [45], as does peripheral infusion of GLP-1

and its agonist, exendin-4 [46]. Peripheral administration

of GLP-1 is associated with enhanced satiety and reduction

of food intake in healthy humans [47], the obese [48], and

patients with T2DM [49]. GLP-1 analogs, such as exena-

tide and liraglutide, and DPPIV inhibitors, such as sitag-

liptin are used for the management of glycaemia control in

type 2 diabetic patients.

The incretin effect is reported to be substantially atten-

uated, which potentially leads to insufficient insulin

secretion and potentiates postprandial hyperglycaemia in

type 2 patients [50]. A direct comparison of the incretin

response to intraduodenal glucose deliver between type 2

patients and healthy subjects has been undertaken [51]. It

has shown there were no differences in overall GLP-1

responses to each glucose load between type 2 patients and

healthy subjects. However, an early, albeit transient, peak

in GLP-1 secretion, in response to glucose in healthy vol-

unteers is missing in patients with T2DM.

Some studies reported that the incretin effect is impaired

in obesity with normal glucose tolerance compared to the

lean subjects. It seems that plasma GLP-1 level is inversely

related to BMI. In response to glucose, obese subjects have

lower plasma GLP-1 concentrations [52]. The decreased

levels of incretin hormones may explain the impaired in-

cretin effect in obese subjects [53]. Although some other

studies reported that there were no differences in plasma

GLP-1 between obese and lean people [54, 55], restored

postprandial GLP-1 secretion following weight loss sug-

gests that GLP-1 plays a role in regulation of satiation [56].

The mechanism is likely to be related to exposure of more

distal small intestinal regions (with a larger density of

L-cells) to ingested nutrients. There is evidence of inter-

action between GLP-1 and leptin at peripheral and central

level. Study showed that leptin stimulated GLP-1 secretion

in human L-cells in vitro and in obese mouse [57]. This

interaction is important for understanding the potential to

achieve and maintain weight loss in obesity [58].

Studies on the levels of GLP-1 in PCOS patients have

not been consistent. It has been reported that there was no

difference in incretin hormones between lean patients with

PCOS and controls [59, 60]. It seems that GIP and GLP-1

secretions are not related to hyperinsulinaemia in PCOS.

However, in some larger studies, during OGTT, it exhib-

ited a lower level of GIP [60] or GLP-1 [61] in obese

women with PCOS compared with lean healthy volunteers.

The enteroinsular axis might be impaired in women with

PCOS. It still needs more research studies about the GLP-1

secretion in PCOS.

CCK

CCK is secreted from the I-cells in the duodenum and

upper jejunum, and is also found in the brain. There are a

number of bioactive forms, such as CCK-8, CCK-22, CCK-

33, and CCK-58, of which CCK-33 is the major form in

human plasma and intestine [62]. The half-life of CCK is

*1-2 min. In healthy volunteers, the fasting CCK con-

centration of 1 pmol/L increases to 5–10 pmol/L in

response to a mixed meal [63], peaks at about 30 min, and

returns to the fasting value after *3–5 h [64]. Protein, and

particularly fat, are strong stimuli for CCK secretion,

whereas carbohydrate results in much less stimulation [65].

Small intestinal fat exerts a potent action on slowing

gastric emptying which, in humans, is regulated predomi-

nantly by CCK, via CCK-1 receptors, and abolished by the

CCK-1 antagonist, loxiglumide [66, 67]. CCK slows gas-

tric emptying by relaxing the proximal stomach, increasing

basal and phasic pyloric pressures and suppressing antral

motility [67, 68], mediated by a vago-vagal reflex pathway

[69]. In contrast to its actions on the stomach, exogenous

CCK increases small intestinal motor activity and shortens

the intestinal transit time [70].

CCK was the first gastrointestinal hormone found to be

related to appetite [71]. CCK exerts its effects via two

receptors, CCK-1 and CCK-2. The suppressive effect of

Endocrine

123

CCK on energy intake in rats and humans is predominantly

mediated by CCK-1 receptors [72]. CCK-1 receptor antag-

onists increase meal size, while CCK-1 receptor deficient

rats develop hyperphagia and obesity [73]. In rats, it has been

demonstrated that chronic administration of a CCK antago-

nist results in weight gain out of proportion to increased

feeding [74], but this probably reflects a synergistic effect

between CCK and leptin on energy intake and long-term

balance of body weight [75]. In humans, exogenous CCK

dose-dependently reduces energy intake at a buffet style

meal [76] and the CCK-1 antagonist, loxiglumide, increases

energy intake modestly in healthy adults [77].

Just as GLP-1, potential medications based on CCK to

treat obesity were unsuccessful due to the rapid enzymatic

degradation within minutes [78]. Following studies

develop CCK-1 receptors agonist, (pGlu-Gln)-CCK-8,

which is modified N-terminally. (pGlu-Gln)-CCK-8 is

enzymatically stable with improved therapeutic action

profile. In animals studies, (pGlu-Gln)-CCK-8 markedly

reduces energy intake and body weight [79]. Meantime,

(pGlu-Gln)-CCK-8 injection is associated with modulation

of blood glucose and IR [80]. Further development of

(pGlu-Gln)-CCK-8 is hindered by renal filtration [81].

Recently, potential therapy of (pGlu-Gln)-CCK-8 is the

PEGylated form of (pGlu-Gln)-CCK-8. (pGlu-Gln)-CCK-

8[mPEG] provides antiobesity and antidiabetes effects with

prolonged half-life of CCK-8 [82]. Further studies of

(pGlu-Gln)-CCK-8[mPEG] in human are needed for the

future treatment for obesity and diabetes.

CCK levels are lower in women with PCOS [9, 83].

Obese PCOS patients with hyperandrogenism had lower

levels of CCK compared to obese PCOS women without

hyperandrogenism [83]. It suggests the postprandial CCK

is negatively correlated with the levels of free testosterone

[9]. So far, there are just a few studies about CCK levels in

PCOS. It needs further studies to clarify the mechanism

under the correlation between hyperandrogenism and

plasma CCK in PCOS patients.

PYY

PYY is co-located with GLP-1 in the L-cells of the distal

gut and is involved in the so-called ‘‘ileal brake’’ [84].

Plasma concentrations of PYY are low in the fasting state,

and increase about 30 min after exposure of the small

intestine to nutrients [85]. PYY is secreted in a load-

dependent fashion, with fat being the most potent stimulus,

followed by carbohydrate and then protein [86, 87]. The

secretion of PYY in response to small intestinal fat is

mediated partly by CCK [88]. Because of its capacity to

slow gastric emptying, PYY is also likely to improve

postprandial glycaemia, although there is no evidence for

an insulinotropic effect.

PYY circulates as two main forms, PYY3-36 and

PYY1-36, with the former being active in suppressing

appetite [89]. In addition to delaying gastric and gall-

bladder emptying, inhibiting gastric and pancreatic secre-

tion, and slowing colonic transit [90], peripheral adminis-

tration of PYY3-36 reduces food intake in rats, monkeys,

and humans [91–93]. In humans, both pharmacological and

‘‘physiological’’ intravenous PYY3-36 infusions elicit

fullness and suppression of food intake, the latter lasting

over 12 h, despite the plasma PYY concentration falling to

baseline [94]. In addition, there is a synergistic effect of

exogenous PYY3-36 with GLP-17-36 on reduction of

energy intake [93], whereas exogenous PYY reduces cir-

culating ghrelin concentrations [95]. It remains contentious

whether the suppressive effect of PYY3-36 on energy

intake in humans represents an aversive effect; there are no

specific antagonists of PYY which are available for use in

humans.

Injection of PYY3-36 into the ARC in rats decreases

NPY expression while stimulating expression of POMC,

which would account for reduced food intake [94]. The

putative pre-synaptic NPY Y2 receptor (Y2R) in the ARC

of the hypothalamus appears to mediate these effects [96].

Like GLP-1, plasma concentrations of PYY are slightly

lower in the fasting and postprandial states and hunger is

greater, in obese compared to lean individuals [97]. Low

PYY levels predict a trend to overweight, but in obese

children, PYY is normalized following weight loss [98].

However, the obese are as sensitive as lean subjects to

suppression of food intake by exogenous PYY3-36 [95].

Again, like GLP-1, obese patients have elevated PYY

levels after jejunoileal bypass surgery, which may con-

tribute to loss of appetite [99]. Thus, the analogs and

degradation inhibitor of PYY3–36 have the potential for

the treatment of obesity [100, 101].

There is no difference in fasting PYY between lean

patients with PCOS and controls [102]. However, fasting

and postprandial PYY levels are lower in obese patients

with PCOS [103]. It has been observed that there is an

inverse correlation between fasting levels of PYY and

HOMA-IR in women with PCOS. The impaired post-

prandial PYY levels may contribute to insulin resistance

[103]. Metformin treatment in PCOS increased PYY levels

which are parallel with improvement of insulin sensitivity

[102].

Weight management in the treatment of PCOS

Weight loss is primary therapy for overweight or obese

patients with PCOS. Even slight weight loss as 5 %

reduction significantly improves IR and ovulation

resumption [104]. Body weight loss increases the effi-

ciency of several infertility treatments in PCOS. Current

Endocrine

123

therapies for weight loss are all related to changes of gut

hormones.

Diet

Lifestyle adjustment (diet, exercise, and behavioral modi-

fication) is always the first-line treatment for overweight/

obese females with PCOS [105]. Both Low Glucose Index

(GI) diet and hypocarloric diet interventions have benefi-

cial effects for obese PCOS patients [106]. Low GI diet

improves irregular menstrual patterns compared with con-

ventional diet [107]. The effect of a hypocaloric diet on

insulin resistance was even better than metformin [108].

Compared to glucose ingestion, protein causes less glu-

cose/insulin fluctuation [109]. Whey protein supplement

profoundly slows gastric emptying of the carbohydrate and

stimulates the release of GLP-1 [110]. Fat restriction is

equally effective in weight loss and menstrual cycle

improvement as low carbohydrate diet. Fatty acids also

play a role in the treatment of metabolic disorder in PCOS.

It has been reported that diet supplied with LC n - 3

PUFA suppressed plasma bioavailable testosterone con-

centrations [111]. However, the dietary strategies alone

normally are not sufficient.

Acupuncture

Acupuncture is an important part of the traditional Chinese

treatment. Manual and electrical acupuncture activates the

afferent nerve fibers [112] to reduce abdominal visceral

adipose tissue and BMI in patients with PCOS [113]. After

a few weeks of treatment of acupuncture, the reduction of

body weight is related to decreased serum insulin and

leptin levels, and increased plasma PYY and CCK levels in

obese women [114, 115]. When the acupuncture is com-

bined with low-calorie diet, lipid profile is improved [116].

Acupuncture is an effective treatment for obesity with less

adverse effect [117].

Metformin

Metformin is widely used in treatment of T2DM, in par-

ticular, in overweight or obesity. The primary effect of

metformin is believed to suppress hepatic gluconeogenesis,

reduce glucose absorption, improve insulin sensitivity, and

increase peripheral glucose uptake. Since hyperinsulina-

emia plays an important role in the pathogenesis of PCOS,

metformin intervention is used to restore endocrine func-

tion in PCOS. It has been observed that combination of

metformin and lifestyle modification resulted in a signifi-

cantly weight loss compared to lifestyle modification alone

[118]. Clinical trials confirmed that metformin is effective

in the improvement of ovarian function and menstrual

cycle, and reduction of serum androgen levels in obese

patients with PCOS [119]. The weight reduction is related

to the increase in plasma PYY, ghrelin, and GLP-1 levels

[102, 120, 121]. Unfortunately, many of the above-dis-

cussed effects of metformin were not observed

consistently.

Berberine

Berberine (BBR), a type of isoquinoline derivative alka-

loid, is extracted from Chinese medical herbs. Normally, it

is used as an oral drug for the treatment of gastrointestinal

infections. Recent studies showed that 3 months of treat-

ment of BBR decreased WC, waist-hip ratio, TC, TG, and

LDL-C, increased HDL-C and SHBG, and improved

insulin resistance in women with PCOS [122]. Compared

to metformin, BBR brings more potential benefits to

patients with PCOS both in metabolic and endocrine

parameters [123]. The possible mechanisms of BBR

include upregulating hepatic low-density lipoprotein

receptor mRNA expression, activating AMP-activated

protein kinase in both adipose and muscle tissues, stimu-

lating glycolysis in peripheral tissue cells, promoting

secretion of insulin, inhibiting liver gluconeogenesis, and

promoting secretion of intestinal GLP-1 [124]. The effect

of BBR on antimicrobial activity may be involved in the

development of anti-obesity treatment [125]. The major

side effects of BBR include diarrhea, constipation, flatu-

lence, and abdominal pain.

GLP-1 agonists

GLP-1receptor agonists were used as a medication in the

treatment of diabetes. Recent studies provided data about

the safety and efficacy of GLP-1 receptor agonist on weight

loss in overweight and obese adults and adolescents [126–

128]. Peripheral GLP-1 administration is associated with

enhanced postmeal satiety and reduced food intake at the

subsequent meal [129]. A meta-analysis showed that

energy intake was reduced by 174 kcal or 11.7 % in

ad libitum following intravenous GLP-1 infusion [130].

Exenatide treatment for 3 months reduced BMI and

improved insulin resistance of adolescents with severe

obesity [131]. During the treatment, subjects experienced

more gastrointestinal adverse events such as nausea,

vomiting, and diarrhea after exenatide compared with

placebo. However, the symptoms decreased over time. It

appeared that gastrointestinal symptoms were not corre-

lated with weight loss reduction [132]. The overall patient

satisfaction with GLP-1R agonist treatment is fairly high

[133]. A further reduction in BMI was observed in longer-

term use of exenatide [134]. In patients with PCOS, exe-

natide was more effective than metformin in promoting

Endocrine

123

weight loss [135]. The combination of exenatide/liraglutide

and metformin was superior to exenatide/liraglutide or

metformin monotherapy in improving menstrual cyclicity,

ovulation rate, free androgen index, and insulin sensitivity

[135, 136].

Surgical therapy

Patients with PCOS require a combination therapy of life

modification and drug treatment. However, weight loss

with these approaches is often difficult to achieve for

patients. Bariatric surgery could be an alternative treatment

in metabolic dysfunction restoration and pregnancy out-

comes improvement [137]. For example, the mean weight

loss in 12 women with PCOS was 41 kg after bariatric

surgery (either biliopancreatic diversion or Laparoscopic

adjustable gastric banding) [138]. Following the weight

loss, various clinical problems such as dyslipidemia, fer-

tility, and/or hirsutism related to PCOS were significantly

improved [139]. The mechanism of weight loss induced by

bariatric surgery is not certain. One possible mechanism is

that the gastric volume is reduced [140, 141]. The other

mechanism is the changes of gastrointestinal hormones

[140]. In postoperative state, a quick delivery of nutrients

to the small intestine leads to an overstimulation or pro-

liferation of the endocrine cells, or reduced degradation of

the secreted hormones [142]. Therefore, the increased

postprandial PYY and GLP-1 response [141, 143, 144]

were observed. Plasma PYY and GLP-1 start increasing as

early as 2 days after surgery and before important weight

loss [144]. Recent study reported that weight loss after

Roux-en-Y gastric bypass (RYGB) surgery is also related

to reductions of brain activation in response to high caloric

foods [145].

Conclusion

PCOS is one of most common endocrine diseases in

women of reproductive age with clinical feature of poly-

cystic ovaries, hyperandrogen, and insulin resistance.

Woman with PCOS has a high prevalence of T2DM and

CVD. Most patients are overweight or obese. Therefore,

weight loss is important in the treatment of PCOS. Current

therapy for weight loss is less than ideal, and bariatric

surgery is invasive. Gastrointestinal hormones are crucial

in regulation of food intake and body weight. Dietary or

pharmacological strategies based on regulation of gastro-

intestinal hormones are likely to be of fundamental

importance in the management of obesity. Therapy aimed

at the gastrointestinal hormones will be the new direction

of treatment for PCOS.

Acknowledgments This work was supported by grant from the

Shanghai Jiaotong University, School of Medicine, Science and

Technology Fund (Grant No. 12XJ10015).

Disclosure There are no conflicts of interest to disclose.

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