A Brief Review on How Pregnancy and Sex Hormones Interfere with Taste and Food Intake.

Many physiological and behavioral changes take place during pregnancy, including changes in taste and an increase in food intake. These changes are necessary to ensure growth and development of a healthy fetus. Both hyperphagia and taste changes during pregnancy may be induced by sex hormones estrogen and progesterone that are increased during pregnancy. Indeed, it has been shown that estrogen decreases food intake, while progesterone increases food intake. This is for instance apparent from the fact that food intake changes during the menstrual cycle with variation in sex hormones. This review will give a short overview of the effects of pregnancy and sex hormones on food intake and taste.

Introduction

Obesity and associated diseases are fast-growing problems in the Western world. In the past decades the number of obese subjects has reached epidemic proportions and the numbers are still rising (James et al. 2004). The scientific community is fighting obesity and its associated problems by studying means to regulate food intake, including modulating taste and food perception. Although it is extremely important to study the regulation of food intake in control individuals (or animals), it is equally important to study regulation of food intake during physiological or pathological changes, for instance during pregnancy or during obesity. This is essential to get a full picture of the regulation of food intake. The present review will give a short overview of the present knowledge on changes in taste and food intake during human pregnancy as well as during rat pregnancy, since most experimental studies have been done in this species.

Part I: Pregnancy and Food Intake Regulation

To ensure growth of the fetus as well as maternal well-being, many maternal physiological and behavioral adaptations occur during pregnancy (Campbell-Brown and Hytten 1998; De Swiet 1998; Manyonda 1998). These include immunological adaptations (Manyonda 1998), cardiovascular adaptations (De Swiet 1998), and metabolic adaptations (Campbell-Brown and Hytten 1998). The most profound adaptations are metabolic of nature. The mother has to supply nutrients to the fetus without endangering her own nutrient supply. Moreover, she has to establish a positive energy balance during pregnancy in preparation of the energy demands during lactation (Hytten 1980). The female body has several strategies to meet the increased energy demand such as changes in maternal metabolism, reduced physical activity, and increased food intake (Dufour and Sauther 2002; van Raaij et al. 1987). During human pregnancy in developed countries, it has been shown that food intake is not or only slightly increased (less 10% of non-pregnancy values) (Durnin 1987). However, in other populations such as in women from Thailand, increases in food intake over 10% during pregnancy have been found (Durnin 1987). In addition, rats show a large increase in food intake during pregnancy, which is about 50% over non-pregnancy values at the end of pregnancy (Cripps and Williams 1975).

The Effect of Pregnancy on Hormones Involved in Food Intake

The mechanisms that drive the pregnancy-induced increases in appetite and hyperphagia remain largely unknown. The changes may be related to changes in levels of hormones known to regulate food intake, and the most important ones are described below (see also Table 1).

Table 1

Function and origin of hormones involved in food intake

Hormone	Origin	Physiological function
Leptin	Fat cells	Suppresses appetite and food intake
Ghrelin	Fundic portion of the stomach	Increases food intake
Cholecystokinin (CCK)	Duodenum	Induces satiety
Peptide YY (PYY)	Endocrine L cells of the small intestine and colon	Suppresses food intake and increases intermeal intervals
α-Melanocyte-stimulating hormone (α-MSH)	Arcuate nucleus in the brain	Reduces food intake
Neuropeptide Y (NPY)	Arcuate nucleus in the brain	Increases food intake
Agouti-related protein (AgRP)	Arcuate nucleus in the brain	Increases food intake

Leptin

Leptin is a hormone produced by fat cells and in most cases is produced in proportion to body adiposity. Together with insulin, leptin acts in the hypothalamus to suppress appetite and food intake and it permits energy expenditure (Myers et al. 2007). Surprisingly, during normal human and rat pregnancy, leptin concentrations are increased (Amico et al. 1998; Augustine et al. 2008; Butte et al. 1997; Grattan et al. 2007). This increase has been suggested to be necessary for regulating fetal growth and development and modulating placental endocrine function (Sagawa et al. 2002). Since pregnancy is characterized by hyperphagia and an increased energy demand, it seems likely that a leptin-resistant state develops during pregnancy. This has indeed been shown to be the case in rats (Augustine et al. 2008; Grattan et al. 2007; Ladyman and Grattan 2004; Ladyman and Grattan 2005). Changes in leptin sensitivity may therefore play a role in the hyperphagia during pregnancy in the rat. Whether this also holds true for humans remains to be established.

Ghrelin

In the body, plasma ghrelin exists in two forms: acetylated ghrelin and deacyl ghrelin, with acetylated ghrelin being the bioactive form (Hosoda et al. 2000; Murakami et al. 2002). In non-pregnant subjects, ghrelin is primarily secreted by the fundic portion of the stomach. In pregnant women it is also secreted by the placenta (Fuglsang 2008). Ghrelin is an important regulator of the energy balance, e.g., it has been shown to increase food intake (Pusztai et al. 2008). The exact role for ghrelin in pregnancy-induced hyperphagia remains elusive because during human and rat pregnancy basal ghrelin decreases (Makino et al. 2002; Riedl et al. 2007; Shibata et al. 2004; Tham et al. 2009). It may be suggested that the decreased basal ghrelin is a maternal adaptation to the physiological hyperphagia during pregnancy, rather than a regulator of hyperphagia. Additionally or alternatively ghrelin may play a role in fetal development (Nakahara et al. 2006).

Cholecystokinin (CCK) and Peptide YY (PYY)

There are only a few studies dedicated to the effect of gut hormones on food intake during human pregnancy. CCK secreted from the duodenum during food intake induces satiety in addition to growth of the pancreas and gastrointestinal function (Geary 2001; Gutzwiller et al. 2000). Basal CCK levels are increased or do not differ in pregnant women as compared with non-pregnant women (Frick et al. 1990; Radberg et al. 1987). However, it is also possible that isoforms of CCK do differ between pregnant and non-pregnant women. Another candidate hormone with a potentially important function in regulating food intake in pregnancy is PYY. PYY is a member of the pancreatic polypeptide family and is produced by the endocrine L cells in the distal small intestine and colon (Valassi et al. 2008). The main circulating form is PYY3–36 (Karra et al. 2009). This form reduces food intake and prolongs intermeal intervals in several animal models (Valassi et al. 2008). A study in rats demonstrated an increase in PYY levels during pregnancy (Tovar et al. 2004). This suggests that PYY reduces food intake during pregnancy, but pregnancy may also be associated with centrally decreased PYY sensitivity as was described for leptin before (Tovar et al. 2004). More research is needed to elucidate the exact roles of CCK and PYY in the regulation of increased food intake during pregnancy.

α-Melanocyte-Stimulating Hormone (α-MSH), Neuropeptide Y (NPY), and Agouti-Related Protein (AgRP)

At the central level, α-MSH, NPY, and AgRP are produced in the arcuate nucleus, which branches into various hypothalamic sites that are implicated in regulation of feeding behavior (Bai et al. 1985). These hormones are involved in the control of food intake: α-MSH reduces food intake, while NPY and AgRP stimulate food intake (Bai et al. 1985). All three neuropeptides are under the control of amongst others leptin (Arora and Anubhuti 2006). In the arcuate nucleus, leptin induces the expression of proopiomelanocortin, which is a precursor of α-MSH, and suppresses the production of NPY and AgRP (Arora and Anubhuti 2006). During rat pregnancy, not only a leptin-resistant state develops but also an α-MSH-resistant state (Ladyman et al. 2009). In other rat models of obesity or hyperphagia, central α-MSH administration induces decreased food intake (Pierroz et al. 2002; Zhang et al. 2004). This indicates that central α-MSH resistance may be specific for pregnancy-induced hyperphagia. In contrast to α-MSH resistance during rat pregnancy, the production of NPY and AgRP is up-regulated during pregnancy in rats (Garcia et al. 2003; Rocha et al. 2003; Szczepankiewicz et al. 2009). Although the exact mechanisms are unknown, it is plausible that these three neuropeptides are involved in the hyperphagia during pregnancy in the rat.

The Effect of Sex Hormones on Food Intake

As described above, hyperphagia is a prominent feature of pregnancy in the rat and satiety and satiation signals change during pregnancy. It is also clear that the pregnancy-induced changes in satiety and satiation signals are complex and poorly studied. However, it seems likely that sex hormones are involved, since the increase in food intake is already observed early in pregnancy at a time when the energy demands of the fetus are still limited (Campbell-Brown and Hytten 1998; Cripps and Williams 1975; Ladyman and Grattan 2004). Indeed, sex hormones that are important for pregnancy, i.e., progesterone and estrogens, are important modulators of body weight and food intake in rats (Asarian and Geary 2006; Geary and Asarian 1999). It has been shown that progesterone increases food intake, while estrogens decrease food intake (Asarian and Geary 2006). The effect of sex hormones on food intake in rats is also apparent from food intake changes during the rat ovarian cycle (Geary 2001). It seems likely that also in humans food intake is regulated by ovarian hormones, since changes in food intake related to the ovarian cycle have been observed. Women eat less at the periovulatory stage, when estrogens are increased, and they eat more in the luteal phase, when progesterone levels are increased (for a review, see Geary 2001). Moreover, postmenopausal women, which are depleted of estrogens, increase their food intake and therefore usually experience weight gain (Lovejoy 1998, 2003). This increased food intake can be prevented by estrogen treatment (Lovejoy 1998).

The Effect of Sex Hormones on Hormones Involved in Food Intake

Sex hormones have direct effects on food intake and therefore plausibly act on the metabolism of leptin, PYY, ghrelin, and CCK. Only minor information is available on the relation between sex hormones and these food intake regulators. It has been shown in control, untreated animals and premenopausal women that leptin correlated positively with estrogen concentrations (Asarian and Geary 2006). Whether this is a causal effect remains to be confirmed (Asarian and Geary 2006; Lovejoy 1998). In rats, estrogens reportedly increase CCK-induced satiation (Geary 2001) and inhibit the ghrelin-induced increased food intake (Clegg et al. 2007). Since various hypothalamic regions in rats express estrogen and progesterone receptors (Ronnekleiv and Kelly 2005), it is plausible that estrogens and progesterone also affect food intake in the brain at the level of AgRP, NPY, and α-MSH in the arcuate nucleus. Some NPY-positive cells also express steroid receptors (Skinner and Herbison 1997). This has been confirmed by studies showing that estrogens down-regulate the expression of NPY and AgRP in the rat (Titolo et al. 2006). In addition, the orexigenic effect of NPY, but not of AgRP, is decreased following estrogen treatment of rats (Santollo and Eckel 2008). Unfortunately, the effects of progesterone on these neuropeptides have not been studied yet. However, it seems likely that progesterone is able to increase the production of AgRP and NPY since both neuropeptides are up-regulated during pregnancy in the rat (Garcia et al. 2003; Rocha et al. 2003).

Part II: Pregnancy and Taste Changes

It is generally accepted that taste changes during human pregnancy. Unfortunately, however, the number of studies dedicated to this subject is very limited. There are some papers on gustatory function during human pregnancy but these studies are often conflicting (Bowen 1992; Brown and Toma 1986; Dippel and Elias 1980; Kuga et al. 2002; Mahomed et al. 1993; Nordin et al. 2004). This can partly be explained by the use of different and incomparable testing methods or different timing during pregnancy. However, consistent results have been found for bitter and salt taste. Various studies have reported a decreased threshold or increased liking for salty taste during human pregnancy as compared with non-pregnant women (Bowen 1992; Brown and Toma 1986; Duffy et al. 1998; Ochsenbein-Kolble et al. 2005). The decreased taste for salt may be necessary, since pregnant women have an increased salt requirement (Campbell-Brown and Hytten 1998). Similar results have been found in pregnant rats: Pregnant rats ingest more salt during pregnancy and show an increased preference for salt (Pike and Yao 1971; Richter and Barelare 1938), suggesting that the taste threshold for salt is also decreased in pregnant rats (Di Lorenzo and Monroe 1989). A few studies have shown that the sensitivity for bitter taste is increased during human pregnancy (Duffy et al. 1998; Ochsenbein-Kolble et al. 2005). This may be an adaptation to pregnancy in order to avoid intake of bitter-tasting toxic compounds.

It is obvious that there is a significant need for detailed studies on taste changes in pregnancy to understand gustatory function during pregnancy and its possible regulation by sex hormones. A relationship with sex hormones has been suggested from studies in non-pregnant women during menstrual cycle (Bowen and Grunberg 1990; Than et al. 1994). For instance, the threshold for sucrose tasting was lower in the preovulation stage, when estrogen concentrations are high, as compared with the early follicular phase or the luteal phase (Than et al. 1994). This low sucrose threshold during high estrogen concentrations is in line with the finding of an increased sucrose threshold in postmenopausal women, when estrogen concentrations are low as compared with premenopausal women (Delilbasi et al. 2003). These data suggest a role for estrogen in sucrose tasting in humans. Taste differences between females and males have also been studied, again with conflicting results (Cooper et al. 1959; Glanville et al. 1964; Moore et al. 1982; Weiffenbach et al. 1982; Yamauchi et al. 2002).

The fundamental question that remains is the site of action of the sex hormones for inducing taste changes. As described for food intake, sex hormones could directly act in the central nervous system, e.g., in the brainstem, while alternatively estrogens or progesterone may affect taste receptors or taste buds. A human study showed that women have more fungiform papillae and more taste buds than men (Bartoshuk et al. 1994). A study in rats showed that changes in taste bud morphology occur during pregnancy (Yucel et al. 2002). Electron microscopical scanning of the lingual papillae of pregnant rats showed differences in topographical configurations of these papillae as compared to those of control rats (Yucel et al. 2002). Also in rat studies, at the level of the brainstem, some gender differences have been shown in the strength of the response to certain stimuli of the parabrachial pons (Di Lorenzo and Monroe 1989). Female rats had a greater response to sweet stimuli in the parabrachial pons than male rats (Di Lorenzo and Monroe 1989), while the responses to sweet stimuli were even further increased in pregnant rats as compared with non-pregnant females (Di Lorenzo and Monroe 1989). An effect of sex hormones on the parabrachial pons of female rats has been shown when control female rats were compared with ovariectomized female rats. It was shown that the response of the parabrachial pons to bitter taste was increased in ovariectomized rats as compared with control female rats (Di Lorenzo and Monroe 1990). These experimental studies show that sex hormones probably affect taste both at the level of the taste buds as well as in the central nervous system.

Summary and Conclusion

Although increased food intake during pregnancy may be limited in humans in developed countries (Durnin 1987), women in less developed countries, such as Thai women (Thongprasert et al. 1987), do increase their food intake during pregnancy. Additionally, rats increase their food intake by 50% during pregnancy (Cripps and Williams 1975; Ladyman and Grattan 2004). As described in this paper, not only food intake increases during pregnancy but also taste preferences change, and this may induce differences in food intake during normal pregnancy. The mechanisms by which food intake and taste changes are induced are relatively unknown. In rats it seems likely that the sex hormones affect food intake at the level of the brain, i.e., by increasing NPY and AgRP and by increasing leptin resistance. For human pregnancy it is unclear whether these data from rats can be extrapolated, since food intake was only slightly increased in pregnant women. However, since an effect of sex hormones on food intake in humans has been shown it seems likely that similar mechanisms may induce increased food intake in human pregnancy, although at a lower magnitude. Therefore further studies are mandatory to elucidate the role of sex hormones in regulating food intake in rats and humans and in pregnancy.

Although it is generally accepted that taste changes occur during pregnancy, the scientific evidence for taste changes during pregnancy are largely lacking. To combat the obesity epidemic we need to increase our knowledge of satiety, satiation signals, and taste changes in control individuals as well as in individuals with hyperphagia like obese people or pregnant women. It may be clear from the above that pregnancy is an excellent physiological model to study changes in the regulation of food intake, satiety, satiation signals, and taste changes. The advantage of using pregnancy as a model for hyperphagia is that changes in satiety/satiation signals and food intake take place in a relatively small and well-defined time frame.

This review emphasizes that when studying changes in food intake and taste, the role of sex hormones needs to be taken into account. Food intake and taste changes in women vary with their hormonal status. It is therefore imperative when studying food intake and taste to stratify according to gender and to take menstrual cycle, oral contraceptive use, and age (i.e., menopause) into account when studying women.