Medical Hypotheses (1990) 32.255-259 fQL.ongman Group UK Ltd 1990

Pickles, Peptide Hypothesis

Hormones

and Pregnancy:

A

P. HILL Department USA

of Epidemiology,

American

Health Foundation,

320 E 43rd Str., New York, NY 10017,

Abstract - In western societies a high frequency of heartburn, nausea and vomiting occur during pregnancy. The causes and mechanisms of these clinical symptoms remain poorly understood. Evidence suggests steroid hormones modulate gastrointestinal transit time and plasma peptide hormones, while peptide hormone modulated food intake and preferences. Since diurnal and episodic release of steroid and peptide hormones occur, it is postulated that. heartburn and other digestive dysfunction during pregnancy are associated with elevated steroid and peptide ((3-endorphin, NPY) hormone interaction with innate biological rhythms controlling the gastrointestinal tract.

Introduction In Western societies adequate growth of the foetus and prevention of nutritional deficiency of the mother has been afforded by established dietary allowances (1, 2). Yet a paucity of information exists in regard to energy requirements (3). effects of different caloric loads on digestion (4, 5) or mechanisms of weight control during pregnancy. It has recently been suggested that pregnant women may have a negative daily energy balance, estimated at 940 Kjoules per day, in comparison to non-pregnant women (3). Furthermore, the increase in body weight and fat deposit occurs despite digestive dysfunctions such as heartburn, nausea and vomiting. Date received 25 October 1989 Date accepted 27 November 1989

Specific metabolic changes, such as a 25% decrease in circulating amino acids (6). a marked increase in plasma triglycerides (7). development of insulin resistance and an increase in saturated fatty acids in cholesterol esters (8) indicate fundamental changes in digestive mechanisms during pregnancy. Emesis gravidarum, nausea and vomiting, occurs in the majority of pregnant women with varying severity and duration (9). Etiological factors of emesis gravidarum remain to be clarified, except a higher incidence of spontaneous abortion occur in women without symptoms of nausea and vomiting (9). This finding, together with the report that Mormon women, who maintain a modified lifestyle compared to non-Mormon women in the United States. have a lower incidence of miscarriages (10) suggests steroid modify emesis and hormones lifestyle

MEDICALHYPOTHESES

ts

CIy

wol

C

LES

Opioids.

CCK

Satiety Gastric

Emptying

CCK. Bomb&n PYY. NT

G.I. Tract

NPY vms) Stimulate

Fig. 1 Diagrammatic outline of the interaction of steroid and peptide hormones associated with food intake and digestion. Neurotensin (NT); Cholecystokinin (CCK); fi endorphin (END); Dynorphin (DYN); Peptide YY (PYY); Lower oesophageal sphincter (LES); Smooth muscle (S.M.).

Opioida

Stimulate

Fig. 2 Outline of selected peptide hormones associated with gastro-intestinal transit and pancreatic and gallbladder function. Galanin (GA); Vasoactive intestinal polypeptide (VIP): Peptide histidine isoleucine (PHI).

causality of reproductive and digestive problems. Since current data supports a concomitant release of g.i. peptide hormones with changes in myoelectric complexes (19-22), sluggish gallbladder response and a slower g.i. transit during pregnancy implies concomitant changes in the release of peptide hormones, such as Bombesin, Cholecystokinin (CCK), peptide histidine isoleucine (PHI), peptide YY (PYY) or Neurotensin (NT): Figure 2. Such changes could increase efficiency of energy utilisation, as well as modify the enterohepatic circulation of bile acids and steroid hormones.

gravidarum. In fact, emesis gravidarum may not occur in all societies (11). To correlate clinical and metabolic events during pregnancy, it is postulated that elevation of CNS peptide hormones and increased feedback by higher circulating steroid hormones on CNS peptide hormones specifically alters the activity of peptide hormones controlling gallbladder and gastric emptying and g.i. transit: Figure 1. Changes in food preferences and development of insulin resistance resulting from the differential activity of these peptide hormones. With this concept, development of emesis gravidarum could originate from modulation of innate biological rhythms of digestion by increased or altered rhythmic secretion of steroid and/or peptide hormones.

Gastro-esophageal

Gastrointestinal transit

In the fasting state, rhythmic contractions of the g.i. tract are maintained by CNS control (12, 13). These contractions are modified by meal composition (14, 15) while specific ingested components such as fibre may act to modify’ gastric emptying time, gallbladder contraction or mucosal cell proliferation. Although the optimum rate of g.i. transit is unknown, the higher frequency of constipation in women than in men and the increase in fre- quency and severity of constipation during the third trimester implicate involvement of steroid and opioid peptide hormones (16). The high frequency of digestive problems in women attending gynecological clinics (17, 18) supports a common

reflux

In healthy subjects gastro-esophageal retlux (GER) results from a transient relaxation of the lower oesophageal sphincter (LES) and an increase intra-abdominal pressure (23). An event which occurs most frequently during the evening hours (24). Activity of LES is modulated by steroid hormones (25) and by a number of peptide hormones including opioid peptides (26). The fact that GER is also a frequent cause of angina-like pain of a non-cardiac origin in women (27, 28) stresses the need to characterise the causality and mechanism associated with GER, especially when one in three women report this dysfunction during pregnancy (29). The relation of increased prevalency of GER during pregnancy to changes in specific hormones acting on LES has not been reported. Peptide hormones and digestion

Concerning the relationship of steroid hormones with digestive function, the post-ovulatory in-

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AND

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A HYPOTHESIS

crease in food intake (30) and prolonged g.i. transit in the luteal compared to the follicular phase (33) together with the decreased contraction of LES by steroid hormones (25) indicate direct effects on the g.i. tract via steroid hormone receptors present in the stomach and g.i. tract (31). Reports that an innate circadian rhythm of feeding is present in man (32-35) and that steroid hormones and CNS peptide hormones modulate digestion, suggest a combination of elevated steroid-peptide hormones should simultaneously modify MMC and gut peptide hormone release. Differential peptide hormone activity could lead to MMC dysfunction. For example gastric disrhythmia due to glucagon administration (36). or alternatively treatment of nausea in patients chemotherapy receiving which suppresses glucagon activity (37). Epidemiological data, indicating white women over 35 years of age with a history of infertility are at decreased risk of nausea and vomiting (38), supports the involvement of steroid hormones. However, since ovariectomy or steroid administration in experimental animals differentially alters opioid peptides hormones in different areas of the CNS (3) and as mu and Kappa opioid agonists both modify g.i. transit (40), it is unclear to what extent emesis gravidarum is evoked by steroid or peptide hormone changes. Aversions and preferences of pregnant women while anecdotal probably represent physiological requirements. Thus pickles, candy or aversions to coffee or alcohol may be equated with an unconscious relief from heartburn and changes in taste and water balance. Food composition

In regard to changes in food composition and development of insulin resistance, a number of peptide hormones present in the CNS and g.i. b-endorphin, dynorphin, NPY and transit, galanin are also associated with the specific intake of carbohydrate or fat (41-43). NPY and galanin (44) also alter pancreatic secretion, while galanin inhibits gastric secretion (45). Galanin (46) and NPY (44) modulate the hypothalamicpituitary (HP) axis; the latter action being estrogen dependent. Consequently, differential responses of CNS-peptide hormones to estrogen levels could reinforce food preferences and changes in g.i. tract metabolism during pregnancy. In regard to pancreatic metabolism, in the nonpregnant woman, cholecystokinin stimulates the

pancreatic response to amino acids while galanin inhibits the pancreatic response to amino acids when the amino acids concentration is low (48). Thus during pregnancy when plasma amino acid concentration is reduced by 25% (6) a differential effect of CCK versus galanin on pancreatic response to A.A. could result in hypertriglyceridemia. Concerning weight control, prevention of excess weight gain during pregnancy is a proven factor to reduce pregnancy complications (49) and appears to be related to differences in pancreatic-g.i. functions in lean and obese nonpregnant women (50-52). The lower incidence of digestive diseases in vegetarians who are leaner than the general public (53) and who have a faster g.i. transit raises the issue in a society preoccupied with weight control, whether a vegetarian diet decreases the frequency of complaints during pregnancy. Does a lifestyle which excludes smoking and consumption of coffee and alcohol or a high fibre, fish diet maintain better health of the pregnant mother? Since no comparative study of vegetarian and non-vegetarian women has been reported, the question cannot be answered. However, advent of non-invasive ultrasonography of the g.i. tract, use of markers for g.i. transit or release of specific peptide hormones in response to meals enables non-invasive study of digestive dysfunction during pregnancy. In a study of 1 million men and women in the United States, Hammond et al (54) reported 28.6% and 33.7% of non-pregnant women suffered from indigestion and constipation respectively. In the United States, Tierson and Hook (9) estimated 89.4% of pregnant women suffered from either nausea and/or vomiting and that in approximately 15%~ and 5% of these women nausea and vomiting respectively continued until delivery. In an era of preventive medicine should these symptoms in 100 000 pregnant women be neglected annually?

Conclusion

Determination of metabolic events leading to insulin resistance and excess body weight gain, apart from decreasing the risk of complications during pregnancy would also provide information on food selection and weight control in all women. Interaction between steroid and peptide hormones and concomitant changes in MMC and

MI:I)l(‘Al.

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