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Metabolic effects of progesterone
Metabolic effects of progesterone RONALD K. KALKHOFF, M.D. lvlilwaukee, Wisconsin Progesterone has important effects on carbohydrate, lipid, and protein metabolism. This steroid induces hyperinsulinemia, possibly by direct action on pancreatic islets, while promoting glycogen storage in the liver. Paradoxically, it antagonizes the effects of insulin on glucose metabolism in adipose tissue and skeletal muscle. Progesterone stimulates deposition of body fat but has catabolic effects on protein metabolism. Provisional evidence is offered that the steroid may influence ketone body production by the liver as well. When these steroid actions are considered together, their most relevant expression appears to be the physiologic changes observed during normal pregnancy. (AM. J. 0BSTET. GYNECOL. 142:735, 1982.)
SINCE RECEPTORS for progesterone and related steroids have been localized to several organ systems, it is not surprising that the hormone is extracted from blood by a variety of tissues from all regions of the body.' The purpose of this review is to define selected effects of this steroid on metabolic processes beyond the genital tract and to establish that the resultant biologic events are most relevant to important transitions that must occur during normal pregnancy.
Plasma insulin and pancreatic islet physiology Parenteral injections of progesterone into different mammalian species increase basal plasma insulin concentrations and augment the plasma insulin response to administered glucose and tolbutamide. 2· 3 Despite the presence of hyperinsulinemia, there are no appreciable effects on carbohydrate tolerance, although the hypoglycemia that follows intravenous insulin is blunted. 2 Progesterone administration also induces pancreatic islet hypertrophy and exaggerated insulin secretion in vitro in response to glucose. 4 Morphologic changes in islets are similar to those observed during pregnancy. 5 It might appear that the steroid contributes to the de-
velopment of insulin resistance and that islet changes are compensatory "feedback" adjustments to peripheral tissue insulin antagonism. The matter, however, is not that simple. Provisional evidence for the existence of sex steroid receptors in pancreatic islets has been reported." Moreover, in vitro cultures of islets with progesterone result in heightened insulin secretion, suggesting a direct {3-cytotropic action of this hormone.7 One might conclude, then, that the emergence of endogenous insulin resistance during progesterone exposure may be countered by a simultaneously mcreased secretion of pancreatic islet insulin.
Reprint requests: Ronald K. Kalkhoff, M.D., 8700 W. Wisconsin Ave., Milwaukee, Wisconsin 53226.
Carbohydrate metabolism Liver. It is estimated that up to 65% of the metabolic clearance of progesterone resides in the splanchnic bed.' Since the liver is a major organ for steroid metabolism, one might expect progesterone to have substantial effects on hepatic metabolic pathways. Progesterone administration to the intact female rat increases liver glycogen content, augments in vivo conversion of substrate precursors to glycogen, and suppresses hepatic gluconeogenesis. 8 These effects are greatly enhanced when progesterone and 17{3-estradiol are administered in combination. Progesterone also blunts the hyperglycemic effects of cortisol administration,2 partially blocks cortisol-induced alanine transaminase activity, 9 and lowers the plasma glucose response to intravenous arginine infusions. 10 Since all of these effects are insulin-like and since progesterone induces hyperinsulinemia, one cannot distinguish possible direct effects of progesterone on these processes from indirect actions mediated by augmented insulin secretion. In any event, progesterone does not have characteristics of an insulin antagonist at the liver site
0002-9378/82/060735+04$00.40/0 © 1982 The C. V. Mosby Co.
735
From the Endocrine-Metabolic Section, Department of Medicine, Medical College of Wisconsin and Milwaukee County Medical Complex. Work that was performed in the author's laboratory was supported by National Institutes of Health research grant AM 10305 from the United States Public Health Seroice, Bethesda, Maryland, and by a grant from TOPS Club, Inc., Obesity and Metabolic Research Program, Milwaukee, Wisconsin.
736
Kalkhoff
March 15, 1%2 Am.
with respect to carbohydrate metabolism. and it appears to facilitate insulin and promote glycogen storage in this organ. Adipose tissue and skeletal muscle. Progesterone administration to rats reduces sensitivity of adipocytes 1 " 12 and skeletal muscle 13 to insulin-induced glucose uptake and oxidation. In fat tissue. glucose conversion to lipid is blunted, II. 12 e\·en though triglyceride content and fat cell size are increased.n Sutter-Dub and colleagues 12 ha\·e demonstrated some of these effects rather astutely. Estrogens oppose this action of progesterone in both tissues. I i,6-Estradiol increases insulin sensitivity of adipose tissue 11 · 14 and muscle 13 • 14 with respect to glucose uptake, oxidation, and lipogenesis and reduces adi pocyte cell size .11 When estrogens and progesterone are administered in combination, the two acts are offset. 1 I. 1" suggesting that the molar concentration ratio of the two hormones ultimately determines the extent of action of one over the other. When progesterone is considered by itself, its primary effect on carbohydrate metabolism appears to be opposite that of insulin in adipose tissue and muscle and insulin-like in the liver. The result may be to divert glucose utilization away from muscle and fat to other tissues, particularly in the fed state, and to promote more storage of the substrate as glycogen in the liver. Lipid metabolism
Although progesterone administration to human subjects and animals has little effect on plasma free fatty acids or triglyceride, this steroid does influence lipid metabolism per se. Intact female rats exposed to progesterone develop hyperphagia and weight gain with substantial increases in carcass fat. 13 The progesterone effect ostensibly requires estrogen priming, since no action is observed in progesterone-treated, mariectomized animals. These observations are consistent with reports that adipocytes have high-affinity cytoplasmic binding sites for both estrogens and progestins. 1H Progestins enlarge adipocyte cell size but do not affect cell number. 11 The means by which depot triglyceride storage is enhanced may reside in the stimulation of lipoprotein lipase (LPL), 17 an enzyme that promotes hydrolysis of circulating plasma triglyceride and fat cell uptake of free fatty acids derived from this process. Progesterone also induces increased LPL activity in the liver and mammary gland. 17 The latter effect is undoubtedly relevant to preparation of the breast for lactation subsequent to parturition. It i; well established that in most instances estrogens and progesterone oppose each other's action on lipid metabolism. Estrogen reduces adipocyte cell size 11 and adipose LPL activity 17 while promoting increased he-
J Obstel. Gvnecol.
patic synthesis and release of triglyceride-rich. vet\ low-density lipoproteins. 17 · 1 ~ In the linT, progesterone partially reduces the estrogen effect on triglvceride entry into the plasma compartment. 10 · 1" Thus. it appears that one effect of progesterone action ou lipid metabolism is to favor storage of depot fat in adipm.e and breast tissue and to partiallY reduce the Inpertriglyceridemic action of estrogem. Protein metabolism
Pregnancy as well as administration of estrogens or combined oral contraceptive agents is associated with significant alterations of plasma proteins. 20 Many of these effects have been linked to estrogenic action on hepatic synthesis and release of these moieties. Plasma albumin and haptoglobin concentrations are depressed in these instances, whereas ceruloplasmin, corticosteroid, testosterone, and thyroxine-binding globulim, fibrinogen and plasminogen, are increased. There i' little evidence, however. that progesterone has any major effects on these substances. The work of Landau and Poulous 21 suggests that progesterone has catabolic action in man. The basic effects are a lowering of several plasma amino acids and an increased total urinary nitrogen excretion without an associated aminoaciduria. They conclude that loss of protein from muscle may not be pronounced, since increased urinarY nitrogen is largeh urea. This contrasts the more intense catabolic effects of glucocorticoids on skeletal muscle and the aminoaciduria associated with their administration. In the perfused hindlimb of female rats, progestcrone has little effect on phenylalanine release. an index of net protein degradation; neither is alanine release altered throughout a wide range of insulin concentrations. This contrasts the observed failure of insulin to reduce release of either amino acid during late pregnancy in the same animal model. 1 " Landau and Poulous suggest that progesterone enhances the outflow of selected amino acids predominantly to the liver. Such an action may supply added substrate for increased hepatic synthesis of specific proteins, the formation of which is stimulated by estrogen. It also could provide additional carbon skeleton for increased glycogen formation. This interpretation must be tempered by a consideration of estrogen action as well. Although progesterone may represent a relatively mild catabolic hormone, estrogens have been documented to possess weak anabolic properties in lean tissue. 22 Any influence progesterone mav have on protein metabolism, then, can only he assessed in light of its molar concentration relative to that of estrogens and other hormones that synergize with or antagonize progesterone effects.
Volume 142 Number 6, Part 2
Ketone body metabolism Premenopausal women are more sensitive to the metabolic effects of starvation than are age-matched men. 23 There is a more brisk rise of plasma free fatty acids and plasma ketones and a more rapid fall of plasma glucose. During human and rat gestation, these phenomena are greatly exaggerated. 24 • 25 Recently, it has been demonstrated that the adminisn·ation of pharmacologic doses of estrogen and progesterone to intact female rats or to postmenopausal women accelerates hyperketonemia during the initial 24 to 36 hours of total fasting. 26 • 27 Neither sex steroid by itself has this action. It is know that female rat liver has a higher content of fatty acid-binding protein than the liver of male rats. This peptide has been shown to facilitate hepatic uptake and delivery of free fatty acids to mitochondria and microsomal sites for oxidation and triglyceride biosyntheses, respectively. 28 Moreover, the female rat has a higher liver content of carnitine, a compound that binds free fatty acids prior to transfer from the cytosol into mitochondria. 29 Although estrogens augment hepatic release of triglyceride, they may also suppress liver production of ketones.'l
Metabolic effects of progesterone
737
milieu of early to mid-gestation, including the ovulation-conception period, is especially dominated by increased plasma concentrations of progesterone and estrogens. For reasons stated here and elsewhere, 31 this setting is propitious for the stimulation of hyperphagia, pancreatic islet hypertrophy, hyperinsulinemia, and body fat and glycogen deposition. Maternal tissue accretion and weight gain are the hallmarks of this period in the absence of significant metabolic demands of a small conceptus. During the latter half of pregnancy, tissue anabolism is challenged by the emergence of high plasma titers of catabolic, contra-insulin hormones, including plasma free cortisol and human placental lactogen. Unidirectional substrate storage gives way to a bidirectional anabolic-catabolic phase or accelerated turnover of maternal fuel reserves. Carbohydrate, lipid, and protein reservoirs shift into the circulation as maternal weight gain levels off, and geometric growth of the fetus ensues along with its unrelenting consumption of blood nutrients. At this stage, progesterone continues its effects by acting in concert with prolactin and other hormones to prepare breasts for lactation by continuing to promote hyperinsulinemia and fuel storage in the fed state in the face of mounting insulin antagonism and "accelerated starvation" 20 in the fasted state, and possibly by helping to condition the liver to elaborate ketones more promptly as an alternative fuel in the event of prolonged fasting. Undoubtedly, other roles for this steroid will be uncovered in the future that will also establish its importance as a hormone of anticipation for the expectant mother during her metabolic adjustments to advancing pregnancy.
REFERENCES I. Billiar, R. B., Takaoka, Y., Reddy, P. S., et a!.: Specific
2. 3. 4.
5.
tissue metabolism of progesterone in vivo in the anesthetized female rhesus monkey during the follicular and luteal phases of the menstrual cycle, Endocrinology 108:1643, 1981. Beck, P.: Progestin enhancement of the plasma insulin response to glucose in rhesus monkeys, Diabetes 18:146, 1969. Kalkhoff, R. K., Jacobson, M., and Lemper, D.: Progesterone, pregnancy and the augmented plasma insulin response,]. Clin. Endocrinol. Metab. 31:24, 1970. Costrini, N. V., and Kalkhoff, R. K.: Relative effects of pregnancy, estradiol and progesterone on plasma insulin and pancreatic islet insulin secretion, ]. Clin. Invest. 50:992, 1971. Aerts, L., Van Assche, F. A., Faure, A., eta!.: Effects of treatment with progesterone and oestradiol-17 f3 on the endocrine pancreas, in ovariectomized rats: Ultrastructural variations in the B cells,]. Endocrinol. 84:317, 1980.
6. Green, I. C., Howell, S. C., El Seifi, S., eta!.: Binding of 3 H-progesterone by isolated rat islets of Langerhans, Diabetologia 15:349, 1978. 7. Howell, S. L., Tyhurst, M., and Green, I. C.: Direct effects of progesterone on rat islets of Langerhans in vivo and in tissue culture, Diabetologia 13:579, 1977. 8. Mattlte, M. L., and Kalkhoff, R. K.: Sex steroid influence on hepatic gluconeogenesis and glycogen formation, Endocrinology 92:762, 1973. 9. Harding, A. R., Rosen, F., and Nichol, C. A.: Effects of pregnancy on several cortisol responsive enzymes in liver, Am.]. Physiol. 211:1361, 1966. 10. Bhatia, S. K., Moore, D., and Kalkhoff, R. K.: Progesterone suppression of the plasma growth hormone response,]. Clin. Endocrinol. Metab. 35:364, 1972. II. Salans, L. B.: Influence of progestin and estrogen on fat cell size, number, glucose metabolism and insulin sensitivity, Proceedings of the 53rd Meeting, Endocrine Society, San Francisco, Calif, 1971, p. A-59.
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March 15, 1982
Kalkhoff Am.
12. Sutter-Dub, M-Th., Dazey, B., et al.: Progesterone and insulin-resistance: studies of progesterone action on glucose transport, lipogenesis and lipolysis in isolated fat cells of the female rat, J. Endocrinol. 88:455, 1981. 13. Rushakoff, R. J., and Kalkhoff, R. K.: Effects of pregnancy and sex steroid administration on skeletal muscle metabolism in the rat, Diabetes 30:545, 1981. 14. McKerns, K. W., and Bell, P. H.: The mechanism of action of estrogenic hormones on metabolism, Recent Prog. Horm. Res. 16:97, 1960. 15. Hervey, E .. and Hervey, G. R.: The effects of progesterone on body weight and composition in the rat, J. Endocrinol. 37:361, 1967. 16. Gray. J. M., and Wade, G. N.: Cytoplasmic progestin binding in rat adipose tissue, Endocrinology 104:1377, 1979. 17. Kim, H. J., and Kalkhoff, R. K.: Sex steroid influence on triglyceride metabolism, J. Clin. Invest. 56:888, 1975. 18. Chan, L.,Jackson, R. L., O'Malley, B. W., eta!.: Synthesis of verv low-density lipoproteins in the cockerel. Effects of estrogen, J. Clin. Invest. 58:368, 1976. 19. Kenagy, R., Weinstein, I., and Heimberg, M.: The effects of 17,8-estradiol and progesterone on the metabolism of free fatty acid by perfused livers from normal female and ovariectomized rats, Endocrinology 108:1613, 1981. 20. sOng, C. S., and Kappas, A.: The influence of estrogens, progestins and pregnancy on the liver, Vitam. Horm. 26:147, 1968. 21. Landau, R. L., and Poulous, J. T.: The metabolic influence ofprogestins, Adv. Meta b. Disord. 5:119, 1971. 22. Knowlton, K., Kenyon, A., Sandiford, I., et al.: Comparative studv of metabolic effects of estradiol benzoate and testostero~e propionate in man, J. Clin. Endocrinol. Metab. 2:142, 1942.
J. Obstet. Gvneco!.
23. Merimee, T. ]., and Fineburg, S. E.: Homeostatis during fasting. II. Hormone substrate differences between men and women, J. Clin. Endocrinol. Metab. 37:698. 1973. 24. Felig, P.: Maternal and fetal fuel homeostasis in human pregnancy, Am.J. Clin. Nutr. 26:998, 1973. 25. Freinkel, N., Phelps, R. L., and Metzger. B. E.: Intermediary metabolism during normal pregnancy, in Sutherland, H. W., and Stowers,]. M., editors: Carbohydrate Metabolism in Pregnancv and the Newborn, Berlin, 1979, Springer. 26. Morrow, P. G., Marshall, W. P .. Kim, H. J.. et al.: ~\feta bolic response to starvation. I. Relative effects of pregnancy and sex steroid administration in the rat. Metabolism 30:268, 1981. 27. Morrow, P. G., Marshall, W. P., Kim, H. J., et al.: :\1etabolic response to starvation. II. Effects of sex steroid administration to pre- and postmenopausal women, Metabolism 30:274, 1981. 28. Ockner, R. K., Lysenko, N., Manning. J. A., et al.: Sex steroid modulation of fatty acid utilization and fatty acid binding protein concentrations in the liver,]. Clin. Invest. 65:10!3, 1980. 29. Borum, P.R.: Variation in tissue carnitine concentrations with age and sex in the rat, Biochem. J. 176:677, 1978. 30. Weinstein, 1., Soler-Argilaga, C., and Heimberg, M.: Effects of ethynyl estradiol on incorporation of I-I'C oleate into triglyceride and ketone bodies by the liver, Biochem. Pharmacal. 26:77, 1977. 31. Kalkhoff, R. K., Kissebah, A. H., and Kim, H. J.: Carbohydrate and lipid metabolism during normal pregnancy: Relationship to gestational hormonal action. Semin. Perinatal. 2:291. 1978.
SINCE RECEPTORS for progesterone and related steroids have been localized to several organ systems, it is not surprising that the hormone is extracted from blood by a variety of tissues from all regions of the body.' The purpose of this review is to define selected effects of this steroid on metabolic processes beyond the genital tract and to establish that the resultant biologic events are most relevant to important transitions that must occur during normal pregnancy.
Plasma insulin and pancreatic islet physiology Parenteral injections of progesterone into different mammalian species increase basal plasma insulin concentrations and augment the plasma insulin response to administered glucose and tolbutamide. 2· 3 Despite the presence of hyperinsulinemia, there are no appreciable effects on carbohydrate tolerance, although the hypoglycemia that follows intravenous insulin is blunted. 2 Progesterone administration also induces pancreatic islet hypertrophy and exaggerated insulin secretion in vitro in response to glucose. 4 Morphologic changes in islets are similar to those observed during pregnancy. 5 It might appear that the steroid contributes to the de-
velopment of insulin resistance and that islet changes are compensatory "feedback" adjustments to peripheral tissue insulin antagonism. The matter, however, is not that simple. Provisional evidence for the existence of sex steroid receptors in pancreatic islets has been reported." Moreover, in vitro cultures of islets with progesterone result in heightened insulin secretion, suggesting a direct {3-cytotropic action of this hormone.7 One might conclude, then, that the emergence of endogenous insulin resistance during progesterone exposure may be countered by a simultaneously mcreased secretion of pancreatic islet insulin.
Reprint requests: Ronald K. Kalkhoff, M.D., 8700 W. Wisconsin Ave., Milwaukee, Wisconsin 53226.
Carbohydrate metabolism Liver. It is estimated that up to 65% of the metabolic clearance of progesterone resides in the splanchnic bed.' Since the liver is a major organ for steroid metabolism, one might expect progesterone to have substantial effects on hepatic metabolic pathways. Progesterone administration to the intact female rat increases liver glycogen content, augments in vivo conversion of substrate precursors to glycogen, and suppresses hepatic gluconeogenesis. 8 These effects are greatly enhanced when progesterone and 17{3-estradiol are administered in combination. Progesterone also blunts the hyperglycemic effects of cortisol administration,2 partially blocks cortisol-induced alanine transaminase activity, 9 and lowers the plasma glucose response to intravenous arginine infusions. 10 Since all of these effects are insulin-like and since progesterone induces hyperinsulinemia, one cannot distinguish possible direct effects of progesterone on these processes from indirect actions mediated by augmented insulin secretion. In any event, progesterone does not have characteristics of an insulin antagonist at the liver site
0002-9378/82/060735+04$00.40/0 © 1982 The C. V. Mosby Co.
735
From the Endocrine-Metabolic Section, Department of Medicine, Medical College of Wisconsin and Milwaukee County Medical Complex. Work that was performed in the author's laboratory was supported by National Institutes of Health research grant AM 10305 from the United States Public Health Seroice, Bethesda, Maryland, and by a grant from TOPS Club, Inc., Obesity and Metabolic Research Program, Milwaukee, Wisconsin.
736
Kalkhoff
March 15, 1%2 Am.
with respect to carbohydrate metabolism. and it appears to facilitate insulin and promote glycogen storage in this organ. Adipose tissue and skeletal muscle. Progesterone administration to rats reduces sensitivity of adipocytes 1 " 12 and skeletal muscle 13 to insulin-induced glucose uptake and oxidation. In fat tissue. glucose conversion to lipid is blunted, II. 12 e\·en though triglyceride content and fat cell size are increased.n Sutter-Dub and colleagues 12 ha\·e demonstrated some of these effects rather astutely. Estrogens oppose this action of progesterone in both tissues. I i,6-Estradiol increases insulin sensitivity of adipose tissue 11 · 14 and muscle 13 • 14 with respect to glucose uptake, oxidation, and lipogenesis and reduces adi pocyte cell size .11 When estrogens and progesterone are administered in combination, the two acts are offset. 1 I. 1" suggesting that the molar concentration ratio of the two hormones ultimately determines the extent of action of one over the other. When progesterone is considered by itself, its primary effect on carbohydrate metabolism appears to be opposite that of insulin in adipose tissue and muscle and insulin-like in the liver. The result may be to divert glucose utilization away from muscle and fat to other tissues, particularly in the fed state, and to promote more storage of the substrate as glycogen in the liver. Lipid metabolism
Although progesterone administration to human subjects and animals has little effect on plasma free fatty acids or triglyceride, this steroid does influence lipid metabolism per se. Intact female rats exposed to progesterone develop hyperphagia and weight gain with substantial increases in carcass fat. 13 The progesterone effect ostensibly requires estrogen priming, since no action is observed in progesterone-treated, mariectomized animals. These observations are consistent with reports that adipocytes have high-affinity cytoplasmic binding sites for both estrogens and progestins. 1H Progestins enlarge adipocyte cell size but do not affect cell number. 11 The means by which depot triglyceride storage is enhanced may reside in the stimulation of lipoprotein lipase (LPL), 17 an enzyme that promotes hydrolysis of circulating plasma triglyceride and fat cell uptake of free fatty acids derived from this process. Progesterone also induces increased LPL activity in the liver and mammary gland. 17 The latter effect is undoubtedly relevant to preparation of the breast for lactation subsequent to parturition. It i; well established that in most instances estrogens and progesterone oppose each other's action on lipid metabolism. Estrogen reduces adipocyte cell size 11 and adipose LPL activity 17 while promoting increased he-
J Obstel. Gvnecol.
patic synthesis and release of triglyceride-rich. vet\ low-density lipoproteins. 17 · 1 ~ In the linT, progesterone partially reduces the estrogen effect on triglvceride entry into the plasma compartment. 10 · 1" Thus. it appears that one effect of progesterone action ou lipid metabolism is to favor storage of depot fat in adipm.e and breast tissue and to partiallY reduce the Inpertriglyceridemic action of estrogem. Protein metabolism
Pregnancy as well as administration of estrogens or combined oral contraceptive agents is associated with significant alterations of plasma proteins. 20 Many of these effects have been linked to estrogenic action on hepatic synthesis and release of these moieties. Plasma albumin and haptoglobin concentrations are depressed in these instances, whereas ceruloplasmin, corticosteroid, testosterone, and thyroxine-binding globulim, fibrinogen and plasminogen, are increased. There i' little evidence, however. that progesterone has any major effects on these substances. The work of Landau and Poulous 21 suggests that progesterone has catabolic action in man. The basic effects are a lowering of several plasma amino acids and an increased total urinary nitrogen excretion without an associated aminoaciduria. They conclude that loss of protein from muscle may not be pronounced, since increased urinarY nitrogen is largeh urea. This contrasts the more intense catabolic effects of glucocorticoids on skeletal muscle and the aminoaciduria associated with their administration. In the perfused hindlimb of female rats, progestcrone has little effect on phenylalanine release. an index of net protein degradation; neither is alanine release altered throughout a wide range of insulin concentrations. This contrasts the observed failure of insulin to reduce release of either amino acid during late pregnancy in the same animal model. 1 " Landau and Poulous suggest that progesterone enhances the outflow of selected amino acids predominantly to the liver. Such an action may supply added substrate for increased hepatic synthesis of specific proteins, the formation of which is stimulated by estrogen. It also could provide additional carbon skeleton for increased glycogen formation. This interpretation must be tempered by a consideration of estrogen action as well. Although progesterone may represent a relatively mild catabolic hormone, estrogens have been documented to possess weak anabolic properties in lean tissue. 22 Any influence progesterone mav have on protein metabolism, then, can only he assessed in light of its molar concentration relative to that of estrogens and other hormones that synergize with or antagonize progesterone effects.
Volume 142 Number 6, Part 2
Ketone body metabolism Premenopausal women are more sensitive to the metabolic effects of starvation than are age-matched men. 23 There is a more brisk rise of plasma free fatty acids and plasma ketones and a more rapid fall of plasma glucose. During human and rat gestation, these phenomena are greatly exaggerated. 24 • 25 Recently, it has been demonstrated that the adminisn·ation of pharmacologic doses of estrogen and progesterone to intact female rats or to postmenopausal women accelerates hyperketonemia during the initial 24 to 36 hours of total fasting. 26 • 27 Neither sex steroid by itself has this action. It is know that female rat liver has a higher content of fatty acid-binding protein than the liver of male rats. This peptide has been shown to facilitate hepatic uptake and delivery of free fatty acids to mitochondria and microsomal sites for oxidation and triglyceride biosyntheses, respectively. 28 Moreover, the female rat has a higher liver content of carnitine, a compound that binds free fatty acids prior to transfer from the cytosol into mitochondria. 29 Although estrogens augment hepatic release of triglyceride, they may also suppress liver production of ketones.'l
Metabolic effects of progesterone
737
milieu of early to mid-gestation, including the ovulation-conception period, is especially dominated by increased plasma concentrations of progesterone and estrogens. For reasons stated here and elsewhere, 31 this setting is propitious for the stimulation of hyperphagia, pancreatic islet hypertrophy, hyperinsulinemia, and body fat and glycogen deposition. Maternal tissue accretion and weight gain are the hallmarks of this period in the absence of significant metabolic demands of a small conceptus. During the latter half of pregnancy, tissue anabolism is challenged by the emergence of high plasma titers of catabolic, contra-insulin hormones, including plasma free cortisol and human placental lactogen. Unidirectional substrate storage gives way to a bidirectional anabolic-catabolic phase or accelerated turnover of maternal fuel reserves. Carbohydrate, lipid, and protein reservoirs shift into the circulation as maternal weight gain levels off, and geometric growth of the fetus ensues along with its unrelenting consumption of blood nutrients. At this stage, progesterone continues its effects by acting in concert with prolactin and other hormones to prepare breasts for lactation by continuing to promote hyperinsulinemia and fuel storage in the fed state in the face of mounting insulin antagonism and "accelerated starvation" 20 in the fasted state, and possibly by helping to condition the liver to elaborate ketones more promptly as an alternative fuel in the event of prolonged fasting. Undoubtedly, other roles for this steroid will be uncovered in the future that will also establish its importance as a hormone of anticipation for the expectant mother during her metabolic adjustments to advancing pregnancy.
REFERENCES I. Billiar, R. B., Takaoka, Y., Reddy, P. S., et a!.: Specific
2. 3. 4.
5.
tissue metabolism of progesterone in vivo in the anesthetized female rhesus monkey during the follicular and luteal phases of the menstrual cycle, Endocrinology 108:1643, 1981. Beck, P.: Progestin enhancement of the plasma insulin response to glucose in rhesus monkeys, Diabetes 18:146, 1969. Kalkhoff, R. K., Jacobson, M., and Lemper, D.: Progesterone, pregnancy and the augmented plasma insulin response,]. Clin. Endocrinol. Metab. 31:24, 1970. Costrini, N. V., and Kalkhoff, R. K.: Relative effects of pregnancy, estradiol and progesterone on plasma insulin and pancreatic islet insulin secretion, ]. Clin. Invest. 50:992, 1971. Aerts, L., Van Assche, F. A., Faure, A., eta!.: Effects of treatment with progesterone and oestradiol-17 f3 on the endocrine pancreas, in ovariectomized rats: Ultrastructural variations in the B cells,]. Endocrinol. 84:317, 1980.
6. Green, I. C., Howell, S. C., El Seifi, S., eta!.: Binding of 3 H-progesterone by isolated rat islets of Langerhans, Diabetologia 15:349, 1978. 7. Howell, S. L., Tyhurst, M., and Green, I. C.: Direct effects of progesterone on rat islets of Langerhans in vivo and in tissue culture, Diabetologia 13:579, 1977. 8. Mattlte, M. L., and Kalkhoff, R. K.: Sex steroid influence on hepatic gluconeogenesis and glycogen formation, Endocrinology 92:762, 1973. 9. Harding, A. R., Rosen, F., and Nichol, C. A.: Effects of pregnancy on several cortisol responsive enzymes in liver, Am.]. Physiol. 211:1361, 1966. 10. Bhatia, S. K., Moore, D., and Kalkhoff, R. K.: Progesterone suppression of the plasma growth hormone response,]. Clin. Endocrinol. Metab. 35:364, 1972. II. Salans, L. B.: Influence of progestin and estrogen on fat cell size, number, glucose metabolism and insulin sensitivity, Proceedings of the 53rd Meeting, Endocrine Society, San Francisco, Calif, 1971, p. A-59.
738
March 15, 1982
Kalkhoff Am.
12. Sutter-Dub, M-Th., Dazey, B., et al.: Progesterone and insulin-resistance: studies of progesterone action on glucose transport, lipogenesis and lipolysis in isolated fat cells of the female rat, J. Endocrinol. 88:455, 1981. 13. Rushakoff, R. J., and Kalkhoff, R. K.: Effects of pregnancy and sex steroid administration on skeletal muscle metabolism in the rat, Diabetes 30:545, 1981. 14. McKerns, K. W., and Bell, P. H.: The mechanism of action of estrogenic hormones on metabolism, Recent Prog. Horm. Res. 16:97, 1960. 15. Hervey, E .. and Hervey, G. R.: The effects of progesterone on body weight and composition in the rat, J. Endocrinol. 37:361, 1967. 16. Gray. J. M., and Wade, G. N.: Cytoplasmic progestin binding in rat adipose tissue, Endocrinology 104:1377, 1979. 17. Kim, H. J., and Kalkhoff, R. K.: Sex steroid influence on triglyceride metabolism, J. Clin. Invest. 56:888, 1975. 18. Chan, L.,Jackson, R. L., O'Malley, B. W., eta!.: Synthesis of verv low-density lipoproteins in the cockerel. Effects of estrogen, J. Clin. Invest. 58:368, 1976. 19. Kenagy, R., Weinstein, I., and Heimberg, M.: The effects of 17,8-estradiol and progesterone on the metabolism of free fatty acid by perfused livers from normal female and ovariectomized rats, Endocrinology 108:1613, 1981. 20. sOng, C. S., and Kappas, A.: The influence of estrogens, progestins and pregnancy on the liver, Vitam. Horm. 26:147, 1968. 21. Landau, R. L., and Poulous, J. T.: The metabolic influence ofprogestins, Adv. Meta b. Disord. 5:119, 1971. 22. Knowlton, K., Kenyon, A., Sandiford, I., et al.: Comparative studv of metabolic effects of estradiol benzoate and testostero~e propionate in man, J. Clin. Endocrinol. Metab. 2:142, 1942.
J. Obstet. Gvneco!.
23. Merimee, T. ]., and Fineburg, S. E.: Homeostatis during fasting. II. Hormone substrate differences between men and women, J. Clin. Endocrinol. Metab. 37:698. 1973. 24. Felig, P.: Maternal and fetal fuel homeostasis in human pregnancy, Am.J. Clin. Nutr. 26:998, 1973. 25. Freinkel, N., Phelps, R. L., and Metzger. B. E.: Intermediary metabolism during normal pregnancy, in Sutherland, H. W., and Stowers,]. M., editors: Carbohydrate Metabolism in Pregnancv and the Newborn, Berlin, 1979, Springer. 26. Morrow, P. G., Marshall, W. P .. Kim, H. J.. et al.: ~\feta bolic response to starvation. I. Relative effects of pregnancy and sex steroid administration in the rat. Metabolism 30:268, 1981. 27. Morrow, P. G., Marshall, W. P., Kim, H. J., et al.: :\1etabolic response to starvation. II. Effects of sex steroid administration to pre- and postmenopausal women, Metabolism 30:274, 1981. 28. Ockner, R. K., Lysenko, N., Manning. J. A., et al.: Sex steroid modulation of fatty acid utilization and fatty acid binding protein concentrations in the liver,]. Clin. Invest. 65:10!3, 1980. 29. Borum, P.R.: Variation in tissue carnitine concentrations with age and sex in the rat, Biochem. J. 176:677, 1978. 30. Weinstein, 1., Soler-Argilaga, C., and Heimberg, M.: Effects of ethynyl estradiol on incorporation of I-I'C oleate into triglyceride and ketone bodies by the liver, Biochem. Pharmacal. 26:77, 1977. 31. Kalkhoff, R. K., Kissebah, A. H., and Kim, H. J.: Carbohydrate and lipid metabolism during normal pregnancy: Relationship to gestational hormonal action. Semin. Perinatal. 2:291. 1978.