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"obesity and hormonal abnormalities". in: international textbook of obesityInternational Textbookof Obesity. Edited by Per Bjorntorp.
Copyright 2001 John Wiley & Sons Ltd Print ISBNs: 0-471-988707 (Hardback); 0-470-846739 (Electronic) Obesity and Hormonal
Endocrinology, S. Orsola-Malpighi Hospital, Univesity Alma Mater Studiorum, Bologna, Italy INTRODUCTION
The impressive growth of knowledge that has fol-lowed the discovery of leptin in 1996 is under con- Obesity is associated with multiple alterations in tinuous investigation. Other chapters of this book the endocrine system, including abnormal circula- review this exciting topic, which will probably rad- ting blood hormone concentrations, which can be ically modify our clinical and therapeutic approach due to changes in the pattern of their secretion to obesity and related metabolic disorders in the and/or metabolism, altered hormone transport and/or action at the level of target tissues. In recentyears a great stimulus in both basic and clinicalresearch has, on one hand, produced a great deal ofknowledge on the pathophysiology of obesity, and, THE HPG AXIS IN FEMALES (Table 17.1)
on the other, led to the discovery of new hormones,such as leptin (1) and orexins (2).
Sex Steroid and Gonadotropin
This chapter reviews the main alterations in the Concentration and Metabolism
classic endocrine systems, speciﬁcally those relatedto the hypothalamic-pituitary-gonadal (HPG) axis, An increase in body weight and fat tissue is asso- the growth hormone/insulin-like growth factor 1 ciated with several abnormalities of sex steroid bal- (GH/IGF-1) axis, and the hypothalamic-pituitary- ance in premenopausal women. They involve both adrenal (HPA) axis. The discussion will focus on androgens and estrogens and their main transport human endocrinology, and animal studies will be protein, sex hormone-binding globulin (SHBG).
referred to only when relevant to the organization Changes in SHBG, which binds testosterone and of current knowledge. Several other endocrine sys- dihydrotestosterone (DHT) with high aﬃnity and tems will not be discussed, and readers are referred estrogens with lower aﬃnity, also lead to an alter- to extensive recent reviews in the ﬁeld (3,4).
ation of androgen and estrogen delivery to target The recent discovery of the product of the ob tissues. The concentrations of SHBG are regulated gene, leptin, has pointed to the role of adipose tissue by a complex of factors, which include estrogens, as an endocrine organ, capable of interacting with iodothyronines and growth hormone (GH) as the central nervous system and other peripheral stimulating, and androgens and insulin as inhibi- tissues by an integrated network, mainly devoted to ting factors (5). The net balance of this regulation is the regulation of the energy balance and fuel stores.
probably responsible for decreased SHBG con- International Textbookof Obesity. Edited by Per Bjo¨rntorp.
2001 John Wiley & Sons, Ltd.
Table 17.2 Main alterations of the hypothalamic-pituitary-gonadal axis in obese women
Increased SHBG-bound and non SHBG-bound androgen production rate andmetabolic clearance rateReduced SHBG synthesis and concentrationsIncreased percentage free testosterone fractionNormal gonadotropin secretionIncreased estrogen production rateAltered active/inactive estrogen balance Worsened androgen imbalanceTreatment with androgens increases visceral fat in postmenopausal women Half PCOS women are overweight or obeseObesity may have a pathogenetic role in the development of hyperandrogenism inPCOSObese women with PCOS have a prevalence of visceral fat distributionHyperinsulinemia represents a pathogenetic factor of hyperandrogenismThe metabolic syndrome is part of the obesity—PCOS association In simple obesity, improvement of androgen and SHBG imbalanceIn obese women with PCOS reduction of hyperinsulinemia and insulin resistance,hyperandrogenism, and improvement of all clinical features, including fertility rate PCOS, polycystic ovary syndrome; SHBG, sex hormone-binding globulin.
centrations in obesity, in inverse proportion to the tion has been found in premenopausal women be- increase in body weight (4,5). Body fat distribution tween lipid intake and SHBG levels (12). Moreover, has important eﬀects on SHBG concentrations in experiments performed in men have demonstrated obese women. In fact, those with central obesity that high lipid intake signiﬁcantly decreased SHBG usually have lower SHBG concentrations in com- concentrations, although contradictory data have parison to their age- and weight-matched counter- been reported by others (see reference 12 for review).
parts with peripheral obesity (6). Insulin seems to Although the urinary excretion rate of 17-keto- play a dominant role in this context. Numerous steroids may be higher than normal in obese epidemiological studies have, in fact, demonstrated women (4), the levels of the main androgens are a signiﬁcantly negative correlation between insulin usually high only in obese women with amenorrhea and SHBG blood levels, suggesting a cause—eﬀect and are normal in those with regular menstrual relationship (7). Moreover, studies in vitro have cycles (12). Gonadotropin secretory dynamics also shown that insulin inhibits SHBG hepatic synthesis appear to be normal in eumenorrheic obese women (8), and suppression (9) or stimulation (10) of insulin (4). The reduction of SHBG increases the metabolic secretion in vivo has been found to be inversely clearance rate of circulating SHBG-bound steroids, associated with changes in SHBG concentrations, speciﬁcally testosterone, DHT and androstane 3, at least in hyperandrogenic obese women. Not sur- 17 -diol (3A-diol), which is the principal active prisingly, reduced SHBG concentrations are there- metabolite of DHT (13). However, this is compen- fore commonly associated with obesity, particularly sated for by elevated production rates. The metab- in the central phenotype, type 2 diabetes, hyperan- olism of the androgens not bound to SHBG is also drogenic states such as polycystic ovary syndrome modiﬁed by obesity. In fact, both production rates (PCOS), and cardiovascular atherosclerotic dis- and metabolic clearance rates of dehydroepiandros- eases (11), all conditions characterized by hyperin- terone (DHEA) and androstenedione are equally sulinemia and insulin resistance. On the other hand, increased in obesity (14,15), so that no diﬀerence in not all obese women have reduced levels of SHBG, blood concentrations of the hormones is usually in spite of similar circulating androgen and estrogen found in comparison to normal-weight individuals.
concentrations, similar body weight and pattern of Androgen production and metabolism may also fat distribution. It has been suggested, for example, show several diﬀerences in relation to the pattern of that dietary factors may help to explain these dis- body fat distribution. Kirschner et al. (15), for crepancies. In fact, a signiﬁcantly negative correla- example, found that premenopausal women with central obesity had higher testosterone production tain normal circulating hormone concentrations.
rates than those with peripheral obesity, whereas no Most sex steroid and SHBG alterations can be diﬀerences in androstenedione and DHT produc- improved by reducing body weight (17).
tion rate values were found. Accordingly, metabolicclearance rates of testosterone and DHT were sig-niﬁcantly higher in the former than in the latter. The The Impact of Body Fat Distribution
maintenance of normal circulating levels of thesehormones in obesity suggests the presence of a Due to the greater reduction of SHBG concentra- servo-mechanism of regulation which adjusts both tions, percentage free testosterone fraction tends to the production rate and the metabolic clearance be higher in centrally obese women than in those rate of these hormones to body size. In women with with peripheral obesity (18). Moreover, there are obesity, the rates of androgen production increase hardly ever systematic diﬀerences in the concentra- but, due to the appreciable quantity of circulating tions of principal C19 androgens between women blood passing through the adipose tissue, andro- with central and peripheral obesity, although the gens may be cleared (metabolized) not only in the former may have higher androstenedione levels liver but also in the fat. In turn, this will result in a than the latter (19). This may be due to the fact that reduction in hormone uptake by androgen-sensi- androgen production rates are higher in women tive tissues. Although speculative, this hypothesis with central obesity than in their peripheral may explain why most obese women seem to be counterparts (see above). An inverse correlation protected against the biological eﬀects of excessive exists between waist-to-hip ratio (WHR) (or other androgen production, such as hirsutism and men- indices of body fat distribution) and testosterone or SHBG concentrations, regardless of body fatness Obesity can also be considered a condition of and body mass index (BMI) (18). Therefore, a condi- exaggerated estrogen production. It has been dem- tion of ‘relative functional hyperandrogenism’ may onstrated that the conversion of androgens to es- be present in women with the central obesity trogen in peripheral tissues is signiﬁcantly corre- phenotype. This may play an important role in the lated with body weight and the amount of body fat development of visceral fat deposits. Androgen re- (16). Several other factors can contribute to this ceptors are expressed in the adipose tissue, with a condition of ‘functional hyperestrogenism’ (12).
higher density in intra-abdominal than subcu- Due to reduced SHBG synthesis and lower circu- taneous deposits, at least in rats (20). In concert with lating SHBG concentrations in obesity, the free GH and catecholamines, testosterone activates the estradiol fraction increases, thus increasing expo- sure of target tissues to this hormone. Moreover, adipocytes, thus favoring increased free fatty acid the metabolism of estrogens is altered in obese release (20). These events are suggested as participa- women. A decreased formation of inactive es- ting in the development of insulin resistance and tradiol metabolites, such as 2-hydroxyestrogens, compensatory hyperinsulinemia, both conditions which are virtually devoid of peripheral estrogen invariably associated with central obesity. In- activity, is observed, together with a higher than creased insulin levels can in turn produce an inhibi- normal production of estrone sulfate (which repre- tion of SHBG synthesis, which further aggravates sents an important reservoir of active estrogens, the androgen imbalance. Since hyperinsulinemia particularly estrone), due to the concurrent reduc- per se appears to play a role in the development of tion of its metabolic clearance and increased pro- visceral fatness, hyperinsulinemia and ‘functional duction rate. The ﬁnal result of these metabolic hyperandronism’ in the central obesity phenotype derangements on estrogens is an increased ratio of may participate in a coordinated fashion to increase active to inactive estrogens in obese women. In visceral fat deposits in obese women. This is further spite of these alterations, blood estrogen concen- supported by the ﬁnding that exogenous androgen trations are usually normal or only slightly elev- administration in obese postmenopausal women ated in both premenopausal and postmenopausal has been shown to cause a signiﬁcant gain in vis- obese women (3,4). This may be related to the fact ceral fat (as measured by computed tomography that enlarged body fat may act as deposits for ex- scan) and a relatively greater loss of subcutaneous cess formed estrogen, thus contributing to main- fat in comparison with placebo (21).
Obesity and Hyperandrogenism in
that hyperinsulinemia and insulin resistance are in- Premenopausal Women: a Link with the
variably associated with obesity and, particularly, abdominal-visceral obesity, represents the basis forthe hypothesis supporting its role in the develop-ment of hyperandrogenism in PCOS women. Suﬃ- Approximately half the women with PCOS are cient data demonstrate that suppression of insulin overweight or obese (12). This association has levels by diet (28,29) or chronic insulin sensitizing aroused a great deal of interest in recent years, agent administration, such as metformin (23), trog- particularly since the discovery that PCOS women litazone (30), or -chiro inositol (31) can improve are often hyperinsulinemic and that the degree of not only the hyperandrogenic state but also the hyperandrogenism may be positively and signiﬁ- degree of hirsutism and the fertility rate. These data cantly correlated with that of hyperinsulinemia (10).
obviously add further emphasis to the role of obes- The association between obesity and hyperan- ity-related hyperinsulinemia as a co-factor respon- drogenism develops during puberty, and common sible for increased androgen production in obese pathogenetic mechanisms primarily appear to in- volve a dysregulation of insulin secretion and action As reported above, obesity is associated with and also of the GH/IGF-I system (22). Recently, supranormal estrogen production. Since estrogens however, it has been suggested that in obese women exert a positive feedbackregulation upon gonado- with PCOS, higher than normal ovarian secretion tropin release, increased ovarian androgen produc- of androgens is associated with birthweight and tion in obese PCOS women could be partly favored maternal obesity, suggesting that intrauterine fac- by increased luteinizing hormone (LH) secretion tors may play a role in the development of the secondary to prevailing hyperestrogenemia (32).
syndrome later in life (23). Premenopausal women Obesity, as well as PCOS, is also characterized by with PCOS are clinically characterized by several increased opioid system activity, and studies in vitro signs and symptoms related to hyperandrogenism and in vivo have shown that -endorphin is able to and hyperinsulinemia, including chronic anovula- stimulate insulin secretion. Moreover, the adminis- tion, hirsutism and acne. Hyperandrogenism, hy- tration of -endorphin can reduce LH release at the perinsulinemia and insulin resistance and all clini- hypophyseal level in normal but not in PCOS cal features tend to be more severe in PCOS women women (33). The possibility that increased opioid with abdominal body fat distribution (24). Altered activity may favor the development of hyperin- lipid proﬁle represents another associated meta- sulinemia and, in turn, of hyperandrogenism, is fur- ther supported by the ﬁnding that both acute and Pathophysiological aspects of the association be- chronic administration of opioid antagonists, such tween obesity and PCOS have been extensively re- as naloxone and naltrexone, suppresses both basal viewed in recent years (12,25,26). There may be and glucose-stimulated insulin blood concentra- various mechanisms by which obesity may inﬂu- tions in a small group of obese women with PCOS ence hyperandrogenism in premenopausal women and acanthosis nigricans (34). Finally, there are with PCOS. The pivotal role of insulin was ﬁrst theoretical possibilities that diet may play some role suggested on the basis of the signiﬁcant positive in the development of the obesity—PCOS associ- correlation observed between the degree of hy- ation, although very few studies have addressed this perandrogenism and that of hyperinsulinemia in issue. In fact, a higher than usual lipid intake has women with PCOS (9). In vitro studies have subse- been described in PCOS women by some authors quently demonstrated that insulin is capable of (35). Mechanisms by which high lipid intake may be stimulating androgen secretion by the ovaries, re- responsible for altered androgen balance in suscep- ducing aromatase activity in peripheral tissues and, tible women with obesity and PCOS have been ﬁnally, reducing SHBG synthesis in the liver (9,26,27). In vivo, numerous studies have demon-strated that both acute and chronic hyperin-sulinemia can stimulate testosterone productionand that suppression of insulin levels can converselydecrease androgen concentrations (9,26). The fact Table 17.2 Main alterations of the hypothalamic-pituitary-gonadal axis in obese men
Reduced testosterone (free and total), and C19 steroidsReduced SHBG concentrationsReduced luteinizing hormone secretionIncreased estrogen production rateAltered aromatase activity (?) Men with hypogonadism have typically enlarged visceral fat depotsRelationship with waist-to-hip ratio (and other indices of fat distribution) controversialAssociation between androstane 3, 17 -diol glucuronide and visceral fatness Improved sex hormone imbalance (increase of testosterone)SHBG can be restored to normal when near-normal body mass index is achieved Reduction of visceral fatImprovement of all parameters of the metabolic syndrome Effects of Weight Loss and Reduction of
THE HPG AXIS IN MALES (Table 17.2)
Insulin Concentrations in Obese
Hyperandrogenic Women with PCOS
Sex Steroid and Gonadotropin
Concentration and Metabolism
There is long-standing clinical evidence concerningthe eﬃcacy of weight reduction upon both the clini- Contrary to what occurs in obese women, with cal and endocrinological features of obese women increasing body weight testosterone (total and free) blood concentrations progressively decrease in genemia (namely testosterone, androstenedione, obese men (36). Reduced testosterone levels are as- and dehydroepiandrosterone sulfate (DHEA-S)) sociated with a progressive decrease of SHBG con- (28,29) appears to be the key factor responsible for centrations as body weight increases (38). Sper- these eﬀects. However, weight loss primarily im- matogenesis and fertility are not aﬀected in the proves insulin sensitivity and reduces hyperin- majority of obese men, although they may be reduc- sulinemia, and changes in testosterone and insulin ed in subjects with massive obesity (3). Serum tes- concentrations are signiﬁcantly correlated, regard- tosterone is also inversely correlated with body less of body weight variations (28,29). Recent stu- weight in men with Kinefelter’s syndrome (3), thus dies have suggested that hyperinsulinemia may be supporting the causal relationship between obesity responsible for increased activity of the ovarian and hypotestosteronemia. Serum levels of other sex cytocrome P450c17 system, which has been im- steroids have also been examined in obese men.
plicated in ovarian hyperandrogenism in many Androstenedione concentrations are usually nor- PCOS women (36). Reduction of insulin concentra- mal or slightly reduced (39) and are not correlated tions by diet (37), metformin (27), or -chiro inositol with the degree of obesity (4). Likewise, concentra- (31) has been demonstrated to reduce this enzyme tions of DHT are usually normal (4). Other C19 activity and, consequently, ovarian androgen pro- steroids, such as DHEA and 3 A-diol and andros- duction. Finally, weight loss and/or insulin sensi- tenediol ( 5-diol), may be reduced in obesity (39).
tizers also signiﬁcantly improved ovulation and fer- As previously reported for women, estrogen pro- tility rate (28,29,31,37), further supporting the role duction rates are increased in male obesity in pro- of hyperinsulinemia in the pathogenesis of hyperan- portion to body weight, and blood concentrations drogenism in women with obesity and PCOS. The of all major estrogens, particularly estrone, may be eﬀects of dietary-induced weight loss on androgen normal (3,4) or slightly increased (4). Altered estro- levels (except SHBG) seem to be peculiar to obese gen metabolism in obesity presumably reﬂects the hyperandrogenic women, since they have not been aromatase activity of the adipose tissue, which is reported in non-PCOS obese women (17).
responsible for active conversion of androgens intoestrogens.
Gonadotropin secretion is also impaired in obes- pears to be largely justiﬁed by the coexistence of ity. In fact, pulsatility studies have shown that obese peripheral (i.e. reduced SHBG synthesis) and cen- men have a reduced LH secretory mass per se- tral (i.e. reduced LH secretion) factors. On the other cretory burst without any change in burst number, hand, both SHBG and testosterone are signiﬁcantly implying a reduction of total LH secretion from the and negatively correlated with insulin levels, even pituitary, probably due to impaired secretion of the after adjusting for BMI and WHR values (43). The gonadotropin releasing hormone at the hypo- inverse relationship with SHBG can be easily ex- thalamic level (40). The absence of clinical signs of plained by the fact that insulin inhibits SHBG syn- hypogonadism can be explained by the fact that the thesis in the liver. A conﬁrmatory role for the insu- testosterone free-fraction represents only 2% of to- lin eﬀect in vivo has been reported, since suppression tal testosterone, and that obesity predominantly of insulin concentrations by diazoxide has been aﬀects circulating bound testosterone, due to the found to increase circulating SHBG in both nor- concurrent decreases of SHBG production.
mal-weight and obese individuals (46). The inverserelationship between testosterone and insulin de-serves further consideration. In fact, low testos-terone levels can be found in streptozotocin-in- The Impact of Body Fat Distribution
duced diabetic rats (47) and in males with type 1diabetes (48). In insulin-deﬁcient rats and humans There are contradictory data on the relationship insulin replacement restores testosterone concen- between body fat distribution and T in male obes- trations to normal (47). In obese men, moderate ity. Although some clinical (41) and epidemiological hyperinsulinemia, such as that obtained during a (42) studies found an association between testos- hyperinsulinemic euglycemic clamp, increased tes- terone and WHR values, others in which anthropo- tosterone concentrations, whereas suppression of metry (43) or magnetic resonance (44) were used insulin by short-term diazoxide administration pro- failed to conﬁrm these results. This suggests that the duced the opposite phenomenon (49). Taken to- relationship between sex steroids and WHR may be gether, these data support the concept that insulin the result of the shared covariance of WHR and may have a ‘direct’ stimulatory eﬀect on testos- total adiposity, rather than a direct relationship.
terone production, similar to that demonstrated in This is not surprising, since obesity in males is women. Therefore, reduced testosterone levels in almost always associated with a parallel increase in obese males appear to result from several comple- abdominal and visceral fat, which means that the mentary factors, including lower gonadotropin se- central distribution of body fat in males depends on cretion and the balanced eﬀects of insulin on SHBG the actual presence of obesity. Other studies con- (inhibition) and testosterone (stimulation).
ﬁrmed that reduction of C19 steroid precursors,such as DHEA, androstenedione, dominantly associated with body fatness ratherthan with excess visceral fat accumulation (39).
The Effects of Weight Loss and
Conjugation of steroids with glucuronic acid has Testosterone Replacement Therapy
been suggested to play a major role in the intracel-lular levels of unconjugated steroids as well as their Weight reduction by both dietary intervention or biological activity. Recent studies have shown that surgical procedures can increase testosterone and 3A-diol glucuronide (3A-diol-G) levels are signiﬁ- SHBG concentrations, provided substantial weight cantly higher in obese men, particularly in those loss is achieved (3). When massively obese men with the visceral phenotype (39). Since glucuronide return to a near-normal BMI, SHBG concentra- conjugates have been considered better markers of tions fall within the reference values for normal- peripheral androgen metabolism than circulating weight individuals (50). Although there are no kin- free steroids, the association between 3A-diol-G etic data on estrogen production following weight and visceral fatness suggests that increased visceral loss in obese men, it is likely that estrogen metab- adipose tissue accumulation is a condition in which olism and peripheral production improve as weight Hypotestosteronemia in male obesity thus ap- Correction of hypotestosteronemia can also be Table 17.3 Main alterations of the growth hormone/insulin-like growth factor 1 (GH-IGF-I) axis in obesity
Reduced GH levels in proportion to body fatBlunted response to any stimuli (including GHRH, GHRP-6 superanalogs, etc.)Reduced pituitary GH secretionIncreased GH metabolic clearance rate Children and adults with GH deﬁciency typically have visceral obesity IGF-I concentration normal or reduced (particularly in visceral obesity)Increased free IGF-I fraction Improvement of basal and stimulated GH levels (in proportion to body fat loss)Possible eﬀects of nutrition on GH secretion Reduction of visceral fat, in both GH-deﬁcient (children and adults) patients and inobese individuals achieved by exogenous testosterone administration.
(53) have shown that GH metabolic clearance rate Recent studies have in fact demonstrated that it is increased in obesity, in proportion to body may have a beneﬁcial eﬀect not only by reducing weight. The blunted response to growth hormone body fat, particularly visceral fat (51), but also on all releasing hormone (GHRH) rules out the possibil- major parameters of the metabolic syndrome, by ity that a hypothalamic GHRH deﬁcit may be re- reducing hyperlipidemia and hyperinsulinemia and sponsible for reduced GH in obesity. Short-term improving peripheral insulin sensitivity (51). Al- fasting increases GH levels in obese subjects re- though much more research is needed in this area, gardless of body weight loss (56), thus suggesting this promising approach appears to have potential that GH deﬁciency in obesity may be a functional therapeutic applications in the near future.
reversible state. Pre-treatment with the cholinergicagonist pyridistigmine (57), which suppresses en-dogenous somatostatin, improves GH release, in-dicating that enhanced somatostatinergic tone may THE GH/IGF-I AXIS (Table 17.3)
be responsible, at least in part, for pretreatmentreduced GH levels. However, when eliminating the Basal GH Levels and Secretion and
presumed higher than normal somatostatin tone Dynamic Studies
with pyridostigmine, the GH response in obese in-dividuals after any stimuli is still lower than nor- Basal GH levels are markedly reduced in obesity mal (57). GHRP-6 is a potent synthetic exapeptide (52,53). This is particularly due to a signiﬁcant re- which speciﬁcally stimulates GH release in a duction of GH secretory burst mass in the pituitary dose—response fashion, by interacting with speciﬁc (52). The extent of this alteration appears to be hypophyseal and hypothalamic receptors. GH re- inversely proportional to the excess body fat (4).
sponse to GHRP-6 or other peptides of the same Indirect evidence for this is that in subjects with family can be decreased by pretreatment with increased body weight due to enlarged lean body GHRH antiserum, which indicates a degree of de- mass, such as body builders, GH output and pe- pendency of the GHRP-6 action on GHRH. Re- ripheral concentrations are not reduced and GH cent studies have shown that GH response to response to insulin-induced hypoglycemia is in fact normal. Obese subjects are also characterized by GHRH, regardless of cholinergic stimulation by blunted GH secretion to all stimuli of GH release, pyridostigmine, and that the combination of these including GHRH, insulin-induced hypoglycemia, peptides elicited the largest GH discharge ever seen L-dopa, arginine, glucagon, exercise, opioid pep- after any stimulus (54). Therefore, other than in- tides, clonidine, nicotinic acid, or states such as deep creased somatostatinergic tone, impaired GH se- cretion in obesity appears to be a functional revers- Mechanisms responsible for reduced GH levels in obesity are probably multiple. Studies per- somatotrophic function. Whether GHRH resis- formed in both rhesus monkeys (55) and humans tance or other mechanisms acting at the pituitary levels are co-responsible for blunted GH release in Effect of Weight Loss
Other factors have been implicated in reducing Weight reduction signiﬁcantly improves basal and GH levels. Obesity is a condition of altered and stimulated GH levels, in proportion to the amount supranormal free fatty acid (FFA) production. In- of body weight lost (3). However, there are no stu- creased FFAs are postulated to inhibit basal GH dies conﬁrming that weight loss can completely secretion, by mechanisms independent of eﬀects on restore GH secretion to normal. This is probably somatostatinergic tone (3). This is further supported due to the fact that it is diﬃcult to regain a normal by the fact that FFA inhibition by antilipolytic weight, particularly in subjects with massive obes- agents such as acipimox have been demonstrated to ity. On the other hand, nutrition itself is an import- potentiate GH responsiveness to GHRH, with or ant factor regulating GH secretion and metabolism.
without pyridostigmine pretreatment (58).
As mentioned above, short-term fasting can par- Sex steroids, speciﬁcally testosterone and es- tially restore baseline and stimulated GH concen- tradiol, have positive eﬀects on GH secretion (3) trations (56). Starvation is associated with increased probably by inﬂuencing the pulsatile mode of GH GH levels. Therefore, in conditions of energy deﬁcit, release (52). Basal GH secretory bursts, which are absolute or relative GH increase appears to repre- reduced in obesity, are positively correlated with sent an adaptative mechanism by which the body estradiol and testosterone concentrations (50), provides fuels from lipolytic pathways to support which further indicates a close relationship between energy balance. Since weight loss in obese patients sex steroid imbalance and GH secretory dynamics can be achieved by varying degree of energy restric- tion, it would be interesting to investigate howmuch the positive eﬀect of partial weight loss onGH secretion is due to a reduction of body fat andhow much to energy restriction per se, particularlyin carbohydrates.
Serum (IGF-I) Levels
Levels of IGF-I in obesity have been variously re-ported to be increased, normal, or decreased (3,4).
Effects of GH Administration
However, although obese children have lower thannormal GH levels in basal conditions and after GH has a potent lipolytic activity and therefore, stimulatory testing, they grow normally, which sug- suppressed GH levels in obesity can be viewed as an gests that IGF-I action in the target tissues for unbalanced lipogenetic condition, which could growth is indeed adequate for growth and develop- probably be responsible for the perpetuation of the ment before, during, and after puberty (3). Interest- obese state once established. In fact, obese subjects ingly, it has been found that free IGF-I levels are have elevated insulin levels as a consequence of the actually increased in obese subjects (59). An in- insulin resistance state with respect to carbohydrate crease in free IGF-I levels could be involved in the metabolism, but the adipose tissue remains sensitive decline in GH levels with increasing body fat, via to the antilipolytic eﬀects of insulin. Evidence from feedbackinhibition of GH secretion at the pituitary animal and human studies supports the hypothesis level. Serum IGF-I levels are particularly reduced in that GH administration in obesity may stimulate subjects with visceral obesity (60) and an inverse lipolytic pathways and can provide a valuable ad- relationship has been found with the amounts of junct to diet in inducing weight loss. Ventromedial visceral fat, independent of total fat mass (61) in a hypothalamic lesions in rats produce obesity, hy- cohort of subjects ranging from normal weight to perinsulinemia and decreased GH secretion. When obesity. Since insulin regulates IGF-I metabolism administered to hypophysectomized ventromedial- via its stimulatory eﬀects on the synthesis of IGF lesioned rats, GH prevents both hyperphagia and binding protein 1 (IGF-BP-I), altered IGF-I in development of obesity (62). Genetically obese obesity, particularly the visceral phenotype, may Zucker fa/fa rats also have decreased GH secretion reﬂect prevailing hyperinsulinemia in the blood cir- and GH treatment results in reduced lipid deposi- tion (62). In GH-deﬁcient children, many of whom Table 17.4 Main alterations of the hypothalamic-pituitary-adrenocortical axis in obesity
Increased cortisol metabolic clearance rateIncreased ACTH pulse frequencyNormal cortisol axis diurnal rhythmNormal 24-hour ACTH/cortisol concentrationsReset to lower resilient axis (?)Altered cortisol suppression after overnight dexamethasone (?) High glucocorticoid receptor density in the visceral adipose tissueAltered cortisol production in the visceral adipose tissue (increased/decreased activity of the11 -HSD)Reduced ACTH pulse amplitudePositive relationship between visceral fat and daily urinary free cortisol excretion rateLower suppression to submaximal dexamethasone administration (?)relationship with perceived stress-dependent free salivary cortisol levelsIncreased CBG binding capacity in parallel to insulin resistance Increased ACTH/cortisol response to CRH, CRH;AVP, ACTH, acute stress,insulin-induced hypoglycemia (?), meals (?)Increased ACTH respone to CRH;AVP (normal-weight individuals: reduced) during mildincrease of NE blood levels (reference 94) ACTH, adrenocorticotropin; CBG, corticosteroid-binding globulin; CRH, corticotropin-releasing hormone; AVP, arginine vasopressin.
are obese, GH administration reduces body fat (63).
of the metabolic syndrome, due to the biological The same occurs in subjects with adult GH deﬁ- eﬀects of prevailing hypercortisolemia. The main ciency (64), and in elderly subjects who underwent metabolic abnormality of cortisol excess is insulin therapy with GH to increase lean body mass and resistance, which develops by cellular mechanisms improve ﬁtness (65). Exogenous GH administration that have been largely elucidated (68). Brieﬂy, also reduced fat stores, particularly in the visceral glucocorticoids inhibit glucose uptake by periph- depots, in GH-deﬁcient adult subjects (66). These eral tissues, stimulate gluconeogenesis, and cause eﬀects can be additive to those dependent on diet increased postabsorptive glucose and insulin. In restriction, but they may also occur in conditions of insulin-sensitive tissues, glucocorticoids impair eucaloric intake (67). Interestingly, the magnitude post-receptor insulin function by mechanisms that of this eﬀect appears to be independent of initial involve interaction with glucose transporters (68).
body weight and endogenous GH status (67). One Treatment of hypercortisolism by pituitary or ad- limitation of GH administration is related to the renal surgical procedures can completely reverse possibility that long-term GH treatment worsens glucose tolerance and insulin resistance, although Subjects with visceral obesity may be character- the contrary has been reported by some studies (66).
ized by several Cushing-like features, i.e. abdominal Perhaps the administration of GH in a manner that striae, buﬀalo hump, facial plethora, etc., and have stimulates normal physiological secretion rather associated abnormalities of the metabolic syn- than pharmacological doses would circumvent or drome. Theoretically, these abnormalities may be lessen its eﬀects on carbohydrate metabolism in the related, at least in part, to alterations of cortisol metabolism and hyperactivity of the HPA axis.
THE HPA AXIS (Table 17.4)
ACTH and Cortisol Concentrations in
Similarities Between Visceral Obesity
and Cushing’s Syndrome
It is well recognized that cortisol metabolism may Patients with Cushing’s syndrome have typically be increased in obesity. This may be due to the enlarged visceral fat deposits and show all features coordinated interference of several factors. First, the concentrations of corticosteroid-binding glubulin normal plasma cortisol levels and daily circadian (CBG) may be reduced in obesity, although not rhythms, others found either lower than normal systematically (3). Moreover, glucocorticoid recep- single samples or lower 24 h integrated cortisol tors have been demonstrated in adipose tissue by levels in obese men (3). In all these studies, however, diﬀerent techniques, all of which show that they are ACTH dynamics were not investigated. Studies in signiﬁcantly more dense in visceral than in subcu- obese women are very scarce. Recently, it has been taneous adipose tissue (69). Finally, adipose tissue demonstrated that premenopausal women with vis- can metabolize cortisol to cortisone and vice versa, ceral obesity may have several abnormalities of a reaction that is catalyzed by the 11 -hydroxys- ACTH (but not cortisol) pulsatile secretion (78), teroid dehydrogenase (11 -HSD) enzyme system.
speciﬁcally higher than normal ACTH pulse fre- Bujalska and coworkers (70) found that the produc- quency and reduced ACTH pulse amplitude, par- tion of cortisol from cortisone in the omental fat ticularly during the morning, without any signiﬁ- taken from normal-weight and obese patients undergoing surgical procedures was signiﬁcantly concentrations. The mechanisms responsible for higher than in the subcutaneous fat, due to the these alterations are still unclear. Recently it has increased expression of the 11 -HSD isoform type 1 been demonstrated that a highly signiﬁcant inverse relationship between rapid ﬂuctuations in plasma rogenase/oxoreductase), this activity being further leptin and those of ACTH and cortisol exists in enhanced by tissue exposure to cortisol and insulin.
normal men, and that obese individuals, in whom The increased ‘production’ of cortisol could ensure higher than normal leptin levels are present, main- a constant exposure of glucocorticoids to omental tain unaltered both leptin diurnal variability and tissue, therefore playing a potential role in deter- pulsatile secretion (79), with higher pulse height mining diﬀerentiation and mass increase of such a resulting in higher mean daily leptin concentrations tissue, as recently suggested (71) and, in addition, in the blood. Therefore one of the central eﬀects of may represent an inappropriate feedbacksignal at leptin in the central nervous system might be the the neuroendocrine levels, able to modify both the acute suppression of the HPA axis. Whether in- basal activity of the HPA axis and its response to creased brain leptin concentrations in obesity may stimulatory and/or inhibitory factors. The concept be in some way responsible for altered ACTH pul- that obesity may be associated with increased activ- satility, particularly in the visceral phenotype, re- ity of the 11 -HSD has been recently supported by human studies which demonstrated an increasedratio of daily urinary cortisol-to-cortisone meta-bolite secretion in obese subjects, particularly inthose with the abdominal phenotype (72), although Effects of Meals on ACTH and Cortisol
controversial ﬁndings have also been reported (73).
In unselected obese subjects, normal values have been reported for plasma cortisol, plasma unbound Meals are potent stimulators of adrenocortical cortisol, 24 h mean plasma cortisol, urinary free- function. In fact, food ingestion, particularly at cortisol excretion, and circadian rhythms of plasma noon, elicits sustained cortisol release regardless of and urine cortisol (74). On the other hand, a higher its pulsatile rhythm (80). The increase in cortisol than normal 24 h urine free-cortisol excretion has concentrations appears to be higher in women with been reported in women with visceral obesity, and a visceral obesity than in those with subcutaneous positive correlation with anthropometric par- obesity and controls (78,81,82). Theoretically, this ameters of visceral fat distribution was found could reﬂect an altered responsiveness of the ad- (75—77), suggesting that cortisol production may renals to ACTH in obesity. Whatever the mechan- increase as the amounts of visceral fat enlarge.
ism of action, these ﬁndings suggest that women The impact of obesity on adrenocorticotropin with visceral obesity are inappropriately exposed to (ACTH) and cortisol pulsatile rhythm has been supranormal cortisol levels, which, in turn, may poorly investigated and available data, which pre- have a negative impact on the regulation of post- dominantly refer to obese men, often yielded con- prandial fuel metabolism and on insulin action in ﬂicting results. Although several studies reported The Activity of the HPA Axis: Dynamic
CRH ﬂow towards the pituitary. Another quite convincing theory, however, claims that the HPAhyperactivity may represent part of an altered re- Studies in obese subjects not selected on the basis of sponse to acute and/or chronic stress which can be the pattern of body fat distribution have demon- independent of the mechanisms responsible for strated that both ACTH and cortisol response to feedbackregulation (69). Several studies have in fact corticotropin-releasing hormone (CRH) was either demonstrated that a similar neuroendocrine adap- normal or reduced (74) when compared to normal- tation takes place during the reaction behaviour in weight controls. On the other hand, Weaver and laboratory animals exposed to various socioen- coworkers (83) found that obese women represen- vironmental stressors. For example, Shively and her ting a wide spectrum from ‘gynoid’ to ‘android’ colleagues (89) exposed cynomolgus macaques to obesity had signiﬁcantly higher ACTH response to chronic physical and psychological stress, and sub- insulin-induced hypoglycemia with respect to con- sequently showed that the animals developed high trols, although no signiﬁcant relationship between visceral fat deposition, which was combined with fat distribution and hormonal response was re- insulin resistance, hyperinsulinemia and impaired ported. Recently, however, several studies have re- glucose tolerance, adrenal hypertrophy, enhanced ported data supporting the concept that obese cortisol response to ACTH stimulation, altered women with visceral body fat distribution may have lipid proﬁles and incidence of coronary artery hyperactivity of the HPA axis (75,76,84). This alter- atherosclerosis signiﬁcantly greater than controls.
ation is characterized by exaggerated ACTH and Theoretically, women with visceral obesity may cortisol response to intravenous administration of have hyperactivity of the HPA as a consequence of CRH alone (76) or combined with arginine vaso- maladaptation to chronic stress exposure. In this pressin (AVP) (84), and by higher than normal corti- model, a key role is represented by the combination sol response to intravenous ACTH stimulation or of events involving maladaptation to altered coping acute stress challenge (75,84,85). In addition, vis- reaction to chronic stress. In fact, these abnormali- ceral obese women also have hyperactivity of the ties include increased or unbalanced ACTH and HPA axis to opioid blockade which can be com- cortisol response. Recent data from epidemiological pletely reversed by increasing the serotoninergic studies by Bjo¨rntorp’s group appear to be consist- receptor activation by dexfenﬂuramine (86). Other ent with the hypothesis and with the aforemen- studies indicate that obese men also have a higher tioned animal data. In fact, they found a strong than normal ACTH (but not cortisol) response to association between symptoms of mental distress combined CRH/AVP administration and that this (such as anxiety, depression, etc.), smoking habits alteration may be signiﬁcantly correlated with the and alcholic consumption, as well as certain psy- insulin concentrations, regardless of BMI and WHR values (87). In addition, a decrease in the economic conditions and abdominal obesity in inhibition of cortisol secretion by single low-dose both males and females (90—93). Furthermore, in a (0.5 mg overnight) dexamethasone administration large cohort of middle-aged men they recently dem- and an inverse correlation between the decrease of onstrated a signiﬁcant interaction between diurnal serum cortisol and the WHR has been found by cortisol secretion (measured in saliva) related to other investigators (88). This supports the concept perceived stress and several anthropometric, endoc- that increased sensitivity and/or responsiveness by rine and metabolic variables (82). Moreover, they CRH receptors in the brain could be due, at least in found that a non-stressed HPA axis was character- part, to the deﬁcient control of CRH receptors by ized by increased cortisol variance, whereas chroni- the inhibitory feedbackaction of glucocorticoids on cally stressed subjects presented decreased cortisol variance, mostly due to evening nadir elevation, The mechanisms responsible for neuroendocrine morning zenith decrease and inadequate sup- abnormalities are still unclear and need to be eluci- pression of morning cortisol by overnight dexa- dated. First, they could be due to a primary neuro- methasone (82). In addition, there are data consist- endocrine alteration leading to increased sensitivity ent with a dysregulation of the noradrenergic con- to CRH or ACTH-secreting cells or to increased trol of the HPA axis during acute mild stress insubjects with obesity, particularly the abdominal All these ﬁndings suggest chronic neuroendoc- REFERENCES
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CURRENT INTELLIGENCE BULLETIN 23 ETHYLENE DIBROMIDE AND DISULFIRAM TOXIC INTERACTION TABLE OF CONTENTS Identifiers and Synonyms for Disulfiram Identifiers and Synonyms for Ethylene Dibromide J. Donald Millar Correspondence Background---Ethylene Dibromide Background---Disulfiram Laboratory Animal Study of Toxic Interaction NIOSH Recommendations IDENTIFIERS AND SYNONYMS FOR D