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Improvement of oral glucose tolerance in
gestational diabetes by pyridoxine.
Bennink HJ, Schreurs WH
Br Med J 1975 Jul 5;3(5974):13-5
Fourteen pregnant women were shown by the oral glucose
tolerance test to have gestational diabetes. In 13 an
increased urinary xanthurenic-acid excretion after an oral
load of L-tryptophan indicated a relative pyridoxine
deficiency. All patients were treated with vitamin B6
(pyridoxine) 100 mg/day for 14 days by mouth, after which the
pyridoxine deficiency disappeared and the oral glucose
tolerance improved considerably. Only two patients then had
sufficiently impaired glucose tolerance to justify the
diagnosis of gestational diabetes; Our results substantiated
our hypothesis that increased xanthurenic-acid synthesis
during pregnancy may cause gestational diabetes. Treatment
with vitamin B6 makes the production of xanthurenic-acid
normal by restoring tryptophan metabolism and improves the
oral glucose tolerance in patients with gestational
diabetes.
Vitamin B6 status in pregnancy.
Heller S, Salkeld RM, Korner WF
Am J Clin Nutr 1973 Dec;26(12):1339-48
No abstract.
[Study of vitamin B6 metabolism during various
stages of experimental diabetes]
Shuvalova TI, Smurnov MI
Probl Endokrinol (Mosk) 1970 Jan-Feb;16(1):79-81
No abstract.
[Studies on vitamin B6 deficiency during pregnacy
and in various pathological states using pyridoxine saturation
test]
Karlin R, Croizat P, Revol L, Pommatau E, Viala JJ, Dumont
M
Pathol Biol 1968 Nov;16(21):917-24
No abstract.
[Studies on carbohydrate metabolism in vitamin
B6-deficient albino rat]
Watanabe K
Nippon Naibunpi Gakkai Zasshi 1968 May
20;44(2):154-67
No abstract.
[Contribution to the study of latent B6
avitaminoses in pregnant women]
Karlin R, Dumont M
Gynecol Obstet (Paris) 1967 Jun-Aug;66(3):339-46
No abstract.
[Effect of vitamin B6 on the lecithin-cholesterin
ratio and protein fraction of the blood serum of patients with
diabetes mellitus]
Shifrin MA
Ter Arkh 1966 Jan;38(1):96-9
No abstract.
[Clinical studies on the relation between endocrine
function and vitamin B6 metabolism. II. Vitamin B6 metabolism
in patients with pituitary, adrenal diseases and diabetes
mellitus]
Azechi S
Naika Hokan 1966 Apr;13(4):205-16
No abstract.
Dehydroepiandrosterone, dehydroepiandrosterone
sulfate, obesity, waist-hip ratio, and noninsulin-dependent
diabetes in postmenopausal women: the Rancho Bernardo
Study.
Barrett-Connor E, Ferrara A
Department of Family and Preventive Medicine, University of
California, San Diego, La Jolla 92093, USA.
J Clin Endocrinol Metab 1996 Jan;81(1):59-64
Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone
sulfate (DHEAS) levels were determined in morning specimens
from 659 fasting postmenopausal women who were not using
estrogen therapy or antidiabetic medication. All women had
concurrent oral glucose tolerance tests and measurements of
body mass index (BMI) and waist-hip ratio (WHR). DHEA levels
were weakly and inversely associated with BMI but not with WHR
or glucose tolerance status. DHEAS levels were not associated
with BMI but were positively associated with WHR, diabetes,
and impaired glucose tolerance. In analyses adjusted for or
stratified by WHR, the DHEAS association with abnormal
carbohydrate tolerance was reduced but still independent of
fat distribution. Because this was a cross-sectional study, it
was not possible to determine whether DHEAS levels were raised
by central obesity or vice versa. At a minimum, these data
strongly suggest that the positive association of DHEAS with
both central obesity and abnormal glucose tolerance does not
support the thesis that DHEAS protect against diabetes or
obesity in older women as had been suggested by animal
studies.
Differences in substrate metabolism between
selperceived 'large-eating' and 'small-eating' women.
Clark DG, Tomas FM, Withers RT, Brinkman M, Berry MN, Oliver
JR, Owens PC, Butler RN, Ballard FJ, Nestel PJ
CSIRO, Division of Human Nutrition, Adelaide,
Australia.
Int J Obes Relat Metab Disord 1995
Apr;19(4):245-52
OBJECTIVE: To compare different aspects of intermediary
metabolism in self perceived 'small-eating' females and
selperceived near normal weight 'large-eating' females and
relate the data to those reported for Pima Indians who have
the world's highest prevalence of non-insulin dependent
diabetes mellitus and obesity.
DESIGN: Make repeat measurements of rates of oxygen
consumption, carbon dioxide production and blood metabolites
in 'large-' and 'small-eating' females at rest, during
different activities and after ingestion of a standardised
liquid meal.
SUBJECTS: Nine self perceived, 'large-eating' females and
nine self perceived 'small-eating' females.
MEASUREMENTS: Resting metabolic rates (RMR), respiratory
quotient (RQ) values and plasma insulin, glucagon insulin-like
growth factor (IGF-1), dehydroepiandrosterone sulphate
(DHEA-SO4) and glucose.
RESULTS: RMR (adjusted for FFM) averaged 3891 +/- 93 J/min
in the 'small-eaters' and 3375 +/- 107 J/min in the
'large-eaters' for ten consecutive measurements conducted at
30 min intervals during the control period for the measurement
of the thermic effect of food. Over this period the average RQ
for the 'small-eating' women (0.81) was significantly greater
than that of the 'large-eating' women (0.78). The two groups
responded similarly to an oral glucose tolerance test but the
concentration of DHEA-SO4 in plasma was 35% higher in the
'small-eaters'.
CONCLUSION: The 'small-eating' women may have a greater
risk of weight gain but they counteract this tendency by
maintaining high activity levels.
[43 cases of primary empty sella syndrome: a case
series]
Bragagni G, Bianconcini G, Mazzali F, Baldini A, Brogna R,
Iori I, Sarti G
Divisione di Medicina Generale, USL 30 di Cento.
Ann Ital Med Int 1995 Apr-Jun;10(2):138-42
Primary empty sella syndrome (ESS) is an
anatomo-radiological picture characterized by the presence of
an arachnoid herniation filled with liquor that compresses the
pituitary against the sellar wall. ESS occurs particularly in
obese, hypertensive, cephalalgic women. It is often
asymptomatic but may be associated with ophthalmologic,
neurologic and non-characterizing endocrine disorders. We
report here 43 cases of primary ESS observed and assessed in
our Departments of Internal Medicine from June 1983 to May
1993. The following endocrinological diagnostic procedures
were carried out: hormonal (RIA) basal profile: FT3, FT4, TSH,
PRL, ACTH, FSH, LH, 8.00 a.m. and p.m., blood cortisol, aldo,
PRA, DHEA-S, FTe, E2, P, PTH, CT, and calcemia and
phosphoremia; provocative tests: TRH, GnRH, etc.; inhibition
tests: high dose dexamethasone. Clinical, neurologic (skull
radiographs, sellar stratigraphy, computed tomography scan and
magnetic resonance), and ophthalmologic (fundus, visual
fields) assessments were also made. Our findings fit with the
data in the literature concerning common symptoms of ESS,
associated endocrinopathies and other illness. We found
obesity (62.7%), oligo-amenorrhea (16.6%), galactorrhea
(14.6%), hyperPRL (11.6%), hypopituitarism (9.3%),
hypogonadism (4.6%), diabetes insipidus (2.3%),
(micro-)polycystic ovary syndrome (19%), hyperACTH (2.3%). In
9.3% of the cases, endocrinopathy referred to pituitary
adenomas. Moreover, we noted a high frequency of psychological
disorders, to our knowledge not previously reported in the
literature, including anxiety or dysthymic disorders with
altered behavior (chiefly oral compulsion). We also make the
hypothesis that obesity (occurring in 62.7% of our patients)
and hypertension (62.7%) may be related to hypothalamic
alterations.
Differential expression of hepatic oestrogen,
phenol and dehydroepiandrosterone sulphotransferases in
genetically obese diabetic (ob/ob) male and female mice.
Borthwick EB, Burchell A, Coughtrie MW
Department of Biochemical Medicine, University of Dundee,
Ninewells Hospital and Medical School, UK.
J Endocrinol 1995 Jan;144(1):31-7
Sulphotransferases (STs) are a family of closely related
enzymes playing a key role in regulation of the
bioavailability and activity of important endogenous molecules
such as steroid hormones. A relationship between the
expression of steroid STs and the diabetic state has been
demonstrated in various laboratory animal models, and steroid
sulphates such as dehydroepiandrosterone sulphate are known to
have anti-diabetic properties. In order to further our
understanding of the molecular basis for the association of
steroid hormone sulphation and diabetes, we have examined the
expression of oestrogen, phenol and dehydroepiandrosterone
(DHEA) STs in mice carrying the obesity mutation (ob), which
in the homozygous state (ob/ob) produces mice which are obese
and diabetic. Our data show that, in male mice, ST activities
towards oestrone (E1), oestriol (E3), DHEA and the xenobiotic
1-naphthol are elevated in ob/ob mice, whereas in female mice,
only the oestrogen ST activities were elevated, with the DHEA
and 1-naphthol ST activities reduced. Using antibodies
directed against oestrogen ST, it was demonstrated that the
induction of E1 and E3 ST activity in ob/ob mice correlated
with the expression of an ST isoenzyme not constitutively
expressed in control mouse liver.
[Isolated gonadotropin deficiency and secretory
discrepancy of cortisol and adrenal androgen by
hemochromatosis secondary to congenital dyserythropoietic
anemia]
Okano J, Yanase T, Takayanagi R, Mimura K, Nawata H
Third Department of Internal Medicine, Faculty of Medicine,
Kyushu University, Fukuoka
Nippon Naibunpi Gakkai Zasshi 1994 Jan
20;70(1):57-64
A 37-yr-old woman was admitted to our hospital for
evaluation of diabetes mellitus, liver cirrhosis and primary
amenorrhea. Serological and hematological examinations
revealed that she suffered from hemochromatosis secondary to
congenital dyserythropoietic anemia (CDA), characterized by
ineffective hematopoiesis and erythropoietic dysplasia. Iron
deposition was suggested by MRI on the pancreas, liver and
pituitary gland. Endocrinological examinations demonstrated
that she had isolated gonadotropin deficiency and ovarian
failure, resulting in hypogonadotropic hypogonadism. In
addition, despite normal responses of serum cortisol and
plasma aldosterone to ACTH and furosemide-standing tests,
respectively, serum dehydroepiandrosterone (DHEA) responded
poorly to ACTH test, suggesting selective damage of zona
reticularis in adrenocortical steroidogenesis in association
with hemochromatosis.
Decreased testosterone and dehydroepiandrosterone
sulfate concentrations are associated with increased insulin
and glucose concentrations in nondiabetic men.
Haffner SM, Valdez RA, Mykkanen L, Stern MP, Katz MS
Department of Medicine, University of Texas Health Science
Center, San Antonio, TX 78284
Metabolism 1994 May;43(5):599-603
Although many studies indicate that increased androgenicity
is associated with insulin resistance and hyperinsulinemia in
both premenopausal and postmenopausal women, relatively few
data are available on this relationship in men. We examined
the association of sex hormone-binding globulin (SHBG), total
and free testosterone, dehydroepiandrosterone sulfate
(DHEA-SO4), and estradiol to glucose and insulin
concentrations before and during an oral glucose tolerance
test in 178 men from the San Antonio Heart Study, a
population-based study of diabetes and cardiovascular disease.
Total and free testosterone and DHEA-SO4 were significantly
inversely associated with insulin concentrations. Free
testosterone and DHEA-SO4 were also significantly inversely
correlated with glucose concentrations. SHBG was weakly
positively associated with glucose concentrations. Estradiol
was not related to glucose or insulin concentrations. After
adjustment for age, obesity, and body fat distribution,
insulin concentrations remained significantly inversely
correlated with free testosterone (r = -.23), total
testosterone (r = -.21), and DHEA-SO4 (r = -.21; all P <
.01). In conclusion, we observed that increased testosterone
and DHEA-SO4 are associated with lower insulin concentrations
in men. This is in striking contrast to women, where increased
androgenicity is associated with insulin resistance and
hyperinsulinemia.
Enhanced adrenocortical activity as a contributing
factor to diabetes in hyperandrogenic women.
Buffington CK, Givens JR, Kitabchi AE
Department of Medicine, University of Tennessee,
Memphis.
Metabolism 1994 May;43(5):584-90
The high incidence of non-insulin-dependent diabetes
mellitus (NIDDM) in women with polycystic ovarian syndrome
(PCO) is believed to occur secondary to the insulin resistance
associated with their androgenicity. In the present study, we
have examined the interrelationships between glucose
tolerance, androgenicity, and various in vivo and in vitro
parameters of insulin sensitivity in 11 obese PCO patients
with NIDDM, 14 PCO patients without diabetes, and 14
weight-matched controls. Both groups of PCO patients were
hypertestosteronemic, hyperinsulinemic, and insulin-resistant
when compared with a group of weight-matched controls.
However, PCO patients with NIDDM differed from those without
diabetes in that they had elevated basal and
corticotropin-stimulated adrenal steroids (cortisol,
dehydroepiandrosterone [DHEA], dehydroepiandrosterone sulfate
[DHEAS]). The hyperglycemia of our diabetic patients was not
related to their elevated testosterone levels or to their
degree of insulin resistance, but was significantly and
positively correlated with adrenal hypersecretion, which in
turn was associated with postreceptor defects in insulin
action. These findings would suggest that enhanced
adrenocortical activity may be an important factor underlying
the development of NIDDM in women with PCO.
Obesity, body fat distribution and sex hormones in
men.
Haffner SM, Valdez RA, Stern MP, Katz MS
Department of Medicine, University of Texas Health Science
Center at San Antonio 78284-7873.
Int J Obes Relat Metab Disord 1993
Nov;17(11):643-9
An unfavourable body fat distribution may cause metabolic
abnormalities including diabetes and dyslipidemia. These
effects may be mediated by alterations in sex hormones. In
women the available data suggest that upper body adiposity is
related to increased androgenicity (especially as indicated by
low concentrations of sex hormone binding globulin). Few data,
however, are available on these relationships in men. We
therefore examined the association of total testosterone, free
testosterone, oestradiol, dehydroepiandrosterone sulphate
(DHEA-SO4) and sex hormone binding globulin (SHBG) to
waist-to-hip ratio (WHR) and conicity index in 178 men from
the San Antonio Heart Study, a population-based study of
diabetes and cardiovascular disease. The conicity index is
equal to the abdominal circumference divided by 0.109 x the
square root of (weight/height). The conicity index and WHR
were significantly inversely related to DHEA-SO4 and free
testosterone. SHBG was only weakly associated with body mass
index (r = -0.18, P < 0.05). After adjustment for age and
body mass index, DHEA-SO4 remained inversely correlated with
WHR (r = -0.22, P < 0.01) and conicity index (r = -0.31, P
< 0.001) and free testosterone remained inversely
associated with conicity index (r = -0.21, P < 0.01). Thus,
in men, the association between unfavourable body fat
distribution and increased androgenicity is inverse in
contrast to the situation in women.
Relationship of sex hormones to lipids and
lipoproteins in nondiabetic men.
Haffner SM, Mykkanen L, Valdez RA, Katz MS
Department of Medicine, University of Texas Health Science
Center, San Antonio.
J Clin Endocrinol Metab 1993 Dec;77(6):1610-5
Although many studies show that increased androgenicity is
associated with increased triglyceride (TG) and decreased high
density lipoprotein cholesterol in both pre- and
postmenopausal women, relatively few data are available on the
association of sex hormones to lipids and lipoproteins in men.
We examined the association of sex hormone-binding globulin
(SHBG), total and free testosterone, dehydroepiandrosterone
sulfate (DHEA-SO4), and estradiol with lipids and lipoproteins
in 178 nondiabetic men from the San Antonio Heart Study, a
population-based study of diabetes and cardiovascular disease.
The TG concentration was significantly inversely related to
SHBG (r = -0.22), free testosterone (r = -0.15), total
testosterone (r = -0.22), and DHEA-SO4 (r = -0.16). High
density lipoprotein (HDL) cholesterol was significantly
positively correlated to SHBG (r = 0.21), free testosterone (r
= 0.15), total testosterone (r = 0.17), and DHEA-SO4 (r =
0.16). Total testosterone was significantly related to total
cholesterol (r = -0.17) and low density lipoprotein
cholesterol (r = -0.15). After adjustment for age, body mass
index, waist to hip ratio, and glucose and insulin
concentrations, TG concentrations remained significantly
related to SHBG (r = -0.20), free testosterone (r = -0.15),
and DHEA-SO4 (r = -0.18), and HDL cholesterol remained
significantly associated with SHBG (r = 0.17), free
testosterone (r = 0.15), total testosterone (r = 0.14), and
DHEA-SO4 (r = 0.16). In conclusion, we observed a less
atherogenic lipid and lipoprotein profile with increased
testosterone concentrations. This was not explained by
differences in glucose or insulin concentrations. However, sex
hormones explained only a small percentage of the variation in
total TG and HDL cholesterol concentrations. These findings
are in striking contrast to data from women, in whom increased
androgenicity is strongly associated with increased TG and
decreased HDL cholesterol levels.
Adrenal steroid and adrenocorticotropin responses
to human corticotropin-releasing hormone stimulation test in
adolescents with type I diabetes mellitus.
Ghizzoni L, Vanelli M, Virdis R, Alberini A, Volta C,
Bernasconi S
Department of Pediatrics, University of Parma, Italy.
Metabolism 1993 Sep;42(9):1141-5
To determine whether abnormalities of
hypothalamic-pituitary-adrenal axis function occur in type I
diabetes mellitus, corticotropin, cortisol,
17-hydroxyprogesterone (17-OHP), androstenedione (D4-A),
dehydroepiandroste rone (DHEA), and DHEA sulfate (DS) levels
were measured after an intravenous (IV) injection of 1
microgram/kg human corticotropin-releasing hormone (CRH) in
diabetic adolescents and normal age-matched subjects. CRH
produced a consistent increase in corticotropin blood levels
that was comparable in the two groups. In contrast, both
baseline and stimulated cortisol concentrations were greater
in diabetic patients. Levels of 17-OHP increased after CRH
administration, and the magnitude of increase was similar in
all subjects. Stimulation with CRH determined an attenuated
integrated DS response in diabetics compared with normal
subjects with a different pattern of the hormone secretion,
whereas no differences in D4-A concentrations were detected
between the two groups. DHEA serum levels of subjects from
both groups underwent similar changes following administration
of CRH. In conclusion, patients with type I diabetes have a
discrete response of adrenal steroids to CRH stimulation that
appears to be independent of corticotropin secretion. This
phenomenon might be related to a direct effect of insulin on
enzyme systems involved in the biosynthetic pathway of adrenal
steroids or, alternatively, to an intra-adrenal
CRH/corticotropin mechanism acting on the adrenal cortex in a
paracrine manner.
Excess androgenicity only partially explains the
relationship between obesity and bone density in premenopausal
women.
Haffner SM, Bauer RL
Department of Medicine, University of Texas Health Science
Center, San Antonio.
Int J Obes Relat Metab Disord 1992
Nov;16(11):869-74
Obese subjects have increased bone density relative to
non-obese subjects yet this relationship is not fully
understood. We examined whether alterations in sex hormones or
binding proteins might explain the effect of obesity on
osteoporosis in 83 premenopausal women from the San Antonio
Heart Study, a population-based study of diabetes. We measured
total testosterone, oestradiol, oestrone, sex hormone binding
globulin (SHBG), and serum dehydroepiandrosterone sulphate
(DHEA-SO4). Bone density was assessed by a Hologic dual photon
absorptometer. Lumbar spine and femoral neck density were
positively correlated with body mass index (BMI). In addition,
femoral neck density was positively correlated with DHEA-SO4.
BMI was negatively correlated with SHBG. After adjustment for
sex hormones by multiple linear regression a positive
association between bone density and obesity still exists
suggesting that the association between obesity and bone
density is at least partially independent of sex steroids in
premenopausal women.
Lower endogenous androgen levels and dyslipidemia
in men with non-insulin-dependent diabetes mellitus
Barrett-Connor E
Department of Community and Family Medicine, University of
California, San Diego, La Jolla 92093-0607.
Ann Intern Med 1992 Nov 15;117(10):807-11
OBJECTIVE: To compare plasma androgen levels in diabetic
and nondiabetic men and to determine their relation to
diabetic dyslipidemia.
DESIGN: A population-based, case-control study.
SETTING: Community.
PARTICIPANTS: Men 53 to 88 years of age from the Rancho
Bernardo, California, cohort who were screened for diabetes
using an oral glucose tolerance test.
MEASUREMENTS: Plasma androgen levels were compared in 44
men with untreated non-insulin-dependent diabetes mellitus and
88 age-matched men who had a normal glucose tolerance test.
The relation of lipid and lipoprotein levels to androgen level
and diabetic status was assessed before and after adjusting
for covariates.
RESULTS: Men with diabetes had significantly lower plasma
levels of free (4.96 nmol/L compared with 5.58 nmol/L) and
total testosterone (14.7 nmol/L compared with 17.4 nmol/L),
dihydrotestosterone (428 pg/mL compared with 533 pg/mL), and
dehydroepiandrosterone sulfate (DHEA-S) (1.92 mumol/L compared
with 2.42 mumol/L) than nondiabetic men. They also had
significantly lower high-density lipoprotein (HDL) cholesterol
and significantly higher triglyceride levels. Differences were
not explained by obesity, alcohol use, or cigarette habit.
Overall, the total testosterone level, but not the free
testosterone level, was positively correlated with the HDL
cholesterol level (P = 0.009) and negatively correlated with
the triglyceride level (P = 0.0001). Similar associations were
seen in analyses restricted to the men without diabetes.
CONCLUSIONS: Lower levels of endogenous androgens are seen
in older diabetic men, and low androgen levels are associated
with diabetic dyslipidemia.
Increased testosterone in type I diabetic subjects
with severe retinopathy.
Haffner SM, Klein R, Dunn JF, Moss SE, Klein BE
Department of Medicine, University of Texas Health Science
Center, San Antonio.
Ophthalmology 1990 Oct;97(10):1270-4
Diabetic retinopathy rarely occurs before puberty,
suggesting that changes in sex hormones may influence the
development of this condition. The authors measured serum
testosterone, estradiol, DHEA-S, and sex hormone binding
globulin levels in 26 men and 22 women with type I diabetes
from the Wisconsin Epidemiologic Study of Diabetic Retinopathy
(WESDR), a population-based study of diabetic complications.
The mean age was 23 years and the mean duration of diabetes
was 14 years. Subjects with proliferative or preproliferative
retinopathy (greater than or equal to retinopathy level 51-80)
were matched by duration of diabetes (+/- 2 years) and sex to
subjects with minimal or no retinopathy (less than or equal to
retinopathy level 21). Seven stereoscopic retinal photographs
of each eye were obtained and photographs were read by the
University of Wisconsin Reading Center. Serum testosterone
concentrations were significantly higher in male diabetic
subjects with proliferative retinopathy (648 +/- 36 ng/dl)
than in male diabetic subjects with minimal or no retinopathy
(512 +/- 43 ng/dl) (P = 0.017). No other statistically
significant differences in sex hormones between subjects with
and without proliferative retinopathy were observed. Although
these results should be regarded as preliminary because of the
small number of subjects, they support the hypothesis that
testosterone concentrations may be associated with the
development of retinopathy in type I diabetic patients.
Increase in plasma 5 alpha-androstane-3 alpha,17
beta-diol glucuronide as a marker of peripheral androgen
action in hirsutism: a side-effect induced by cyclosporine
A.
Vexiau P, Fiet J, Boudou P, Villette JM, Feutren G, Hardy N,
Julien R, Dreux C, Bach JF, Cathelineau G
Diabetology and Endocrinology Department, Hopital
Saint-Louis, Paris, France.
J Steroid Biochem 1990 Jan;35(1):133-7
Dose-dependent hypertrichosis is a common dermatological
side-effect affecting the majority of patients treated with
cyclosporine A (CSA). Previous studies have not demonstrated
the influence of CSA on specific sex hormone levels. The aim
of this study is to investigate whether CSA increases the
activity of 5 alpha-reductase, an enzyme which transforms
androgens into dihydrotestosterone in peripheral tissues. The
metabolite which best reflects this activity is 5
alpha-androstane-3 alpha,17 beta-diol glucuronide (Adiol G).
The study was carried out on 49 insulin-dependent diabetes
patients participating in the double-blind
"Cyclosporine-Diabete-France" clinical trial, of which 28 were
treated with CSA (16 males and 12 females), and 21 received
only placebo (10 males and 11 females). All patients underwent
extensive clinical and laboratory evaluations prior to and
during the present study. In addition to Adiol G, testosterone
(T), dehydroepiandrosterone sulfate (DHEA S) and sex
hormone-binding globulin (SHBG) were assayed. Levels of Adiol
G increased significantly in CSA-treated groups: males, 11.86
+/- 2.58 vs 7.83 +/- 2.30 nmol/l; females, 4.48 +/- 2.70 vs
2.10 +/- 1.22 nmol/l; P less than 0.02 (comparison of means).
There were no significant differences in this parameter before
and during treatment in either the male or female placebo
groups (paired t-test). During the treatment period, T, DHEA
S, SHBG and the T/SHBG ratio did not significantly change with
respect to their baseline values in any of the groups studied
(comparison of means). Comparison (using paired t-test) showed
a significant increase of DHEA S in CSA-treated groups: males,
delta = 3.08 +/- 3.33 nmol/l, P less than 0.01; females, delta
= 0.98 +/- 1.13 nmol/l, P less than 0.05. In conclusion, it is
possible that CSA induces hypertrichosis or hirsutism by
increasing 5 alpha-reductase activity in peripheral tissues.
Nevertheless the role of increased DHEA S as a possible Adiol
G precursor cannot be excluded.
[Dehydroepiandrosterone. Renaissance after 13
years]
Sonka J
Cas Lek Cesk 1989 Sep 8;128(37):1157-60
DHEA, a steroid precursor of androgens and estrogens has
also an inhibitory effect on several enzymes, namely on 11
beta-hydroxylase, NADH oxidase and glucose 6-phosphate
dehydrogenase. The latter is the rate limiting enzyme of the
pentose phosphate cycle. This metabolic pathway provides the
cells with extramitochondrial NADPH and pentose phosphates.
NADPH is used for the synthesis of fatty acids and steroids.
Together with ribose 5-phosphate, NADPH (as coenzyme of folate
reductases) is required for the synthesis of nucleic acids. A
deficient production of DHEA has been found to be responsible
for several diseases obesity, diabetes type 2, hypertension,
arteriosclerosis and hyperuricemia as well as malignant growth
(low DHEA syndrome). DHEA administration favourably modified
several of these metabolic disorders. These studies were
started in our laboratory in 1962 and stopped in 1976 because
we were short of DHEA. At that time the response to our
results was rather theoretical, but the last years a new wave
of interest in DHEA called for two consecutive symposia, where
important findings were presented (Paris in January and Jena
in April 1989). It is a damage that this new trend, started in
our laboratory, could not be pursued up to now without
interruption.
[Effect of androgen on the onset of diabetes in the
KK mice treated with monosodium aspartate]
Higuchi N, Sasaki M, Arai T, Oki Y
Department of Veterinary Biochemistry, Nippon Veterinary and
Zootechnical College, Tokyo, Japan.
Jikken Dobutsu 1989 Jan;38(1):25-9
Obese diabetes was induced by monosodium aspartate (MSA)
administration in KK male mice and the diabetic KK mice were
divided into two groups, younger (12-week-old) and older
(35-week-old). The diabetic KK mice were castrated and
administered with androgen and effect of androgen on
glycosuria appearance was investigated. Androgen dependent
tear proteins (Mtp-M) were detected by the method of
polyacrylamide gel electrophoresis. Blood androgen level was
estimated by observation of change of the pattern of Mtp-M. In
the younger mice group, glycosuria disappeared temporarily
after castration and then appeared naturally again. The Mtp-M
declined with castration, but did not disappear in this
experimental period. In the older mice group, glycosuria and
Mtp-M disappeared completely and blood glucose level decreased
considerably after castration. However, in the castrated older
mice, the glycosuria and the Mtp-M appeared again after the
administration of dehydroepiandrosterone (DHEA), and the
increasing of blood glucose level was observed. These results
strongly suggested that androgen had an important role in the
onset of diabetes in the KK mice treated with MSA.
The influence of genetic background on the
expression of mutations at the diabetes locus in the mouse. V.
Interaction between the db gene and hepatic sex steroid
sulfotransferases correlates with gender-dependent
susceptibility to hyperglycemia.
Leiter EH, Chapman HD, Coleman DL
Jackson Laboratory, Bar Harbor, Maine 04609.
Endocrinology 1989 Feb;124(2):912-22
Steroid sulfurylation represents a potential mechanism for
controlling the level of active steroids within a tissue. We
have elucidated an inbred strain background-dependent
interaction between the diabetes (db) mutation and steroid
sulfotransferase (ST) enzymes, potentially modulating the
level of active steroid hormones or their precursors in the
liver. Gonadectomized mutants were analyzed to correlate how
strain- and gender-dependent variation in ST activities
interacted with db to achieve diabetogenesis. Both sexes on
the C57BL/KsChp (BKs) background developed severe early-onset
hyperglycemia, and gonadectomy failed to prevent diabetes. In
contrast, C3HeB/FeChp (C3HeB)-db/db males, but not females,
were diabetes susceptible, and the male susceptibility was
completely dependent upon endogenous testes-derived
testosterone. The female resistance, in turn, was dependent
upon ovarian sex steroids. The differential requirements of
BKs- and C3HeB-db/db males and females for gonadal sex
steroids could be explained on the basis of the differential
strength of the interaction between the db mutation and
hepatic ST activities. Hepatic ST from normal adult females
sulfurylated dehydroepiandrosterone (DHEA), whereas this
activity disappeared in cytosols of normal adult males by 8
weeks of age. This sexually dimorphic inability to sulfurylate
(pre)androgens was controlled by testosterone. Diabetogenic
susceptibility in BKs mutant mice of both sexes was associated
with marked depression of preandrogen/androgen sulfurylation
[female mutants exhibiting at least a 5-fold reduced DHEA
sulfurylation at a near-physiological concentration (0.2
microM)]. This reduced preandrogen/androgen sulfurylation
occurred concomitant with a 10-fold acceleration of estrone
(E1) sulfurylation at a limiting (0.2 microM) concentration,
essentially producing a hyperandrogenized hepatic tissue
state. These extreme shifts in ST substrate preferences were
not observed in the diabetes-resistant C3HeB-db/db females.
Kinetic analysis of semipurified hepatic ST from BKs-db/db
females showed a 10-fold decrease in Km for E1 (apparent Km =
0.9 microM in mutants vs. 9.0 microM in normals). Whereas the
Km for DHEA did not differ from the control value, hepatic ST
from BKs-db/db females showed a 10-fold decreased maximal
velocity for DHEA sulfurylation (1230 vs. 12750 pmol/mg.h in
control preparations). The antihyperglycemic effects of
dietary E1 therapy were associated with enhanced androgen
sulfurylation in BKs-db/db females and restoration of androgen
sulfurylation in BKs-db/db males.
Therapeutic effects of dehydroepiandrosterone
(DHEA) and its metabolites in obese-hyperglycemic mutant
mice.
Coleman DL
Jackson Laboratory, Bar Harbor, ME 04609.
Prog Clin Biol Res 1988;265:161-75
Dehydroepiandrosterone (DHEA) fed at 0.4%, and its
metabolites, 3 alpha-hydroxyetiocholanolone (alpha-ET) and 3
beta-hydroxyetiocholanolone (beta-ET), fed at 0.1%, had marked
anti-hyperglycemic and anti-obesity properties in mutant mice
with single gene obesity mutations (diabetes, db; obese, ob;
viable yellow, Avy). The therapeutic effects differed
depending on the mutation as well as the inbred background on
which the mutation was maintained. These steroids prevented
onset of hyperglycemia and reduced the rate of weight gain in
C57BL/6J-db/db and ob/ob mice, whereas in C57BL/KsJ-db/db
mice, only hyperglycemia was prevented. The viable yellow
(Avy) mutant, exhibiting a more slowly developing obesity
condition, responded to all steroids with a marked decrease in
rate of weight gain associated with decreased plasma insulin
concentrations. Steroid treatment of most mouse mutants was
associated with normal or increased food intake, a feature
that suggests a decrease in metabolic efficiency. In order to
assess any potential energy wastage by steroid stimulation of
futile cycles we looked at the rates of lipogenesis,
gluconeogenesis and oxygen consumption in steroid-treated
normal and mutant mice. With the possible exception of the
rate of gluconeogenesis that in obesity mutants was
consistently reduced to normal by treatment, no metabolic
changes were of sufficient magnitude to account for the marked
decrease in metabolic efficiency. All treatments potentiated
the action of insulin. This potentiation may change the
hormonal balance such that minor changes in the rates of many
metabolic pathways may interact to produce a large decrease in
metabolic efficiency.
Hormonal intervention: "buffer hormones" or "state
dependency". The role of dehydroepiandrosterone (DHEA),
thyroid hormone, estrogen and hypophysectomy in aging.
Regelson W, Loria R, Kalimi M
Department of Medicine, Medical College of Virginia, Richmond
23298.
Ann N Y Acad Sci 1988;521:260-73
No abstract.
Modulation of growth, differentiation and
carcinogenesis by dehydroepiandrosterone.
Gordon GB, Shantz LM, Talalay P
Department of Pharmacology and Molecular Sciences, Johns
Hopkins University School of Medicine, Baltimore, Maryland
21205.
Adv Enzyme Regul 1987;26:355-82
Dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one;
DHEA) and its conjugates are abundant circulating steroids
that originate largely from the adrenal cortex. Their levels
decline profoundly with age in human beings of both sexes, as
the incidence of most cancers rises. Low levels of these
steroids have been associated with the presence and risk
ofdevelopment of cancer. Administration of DHEA to rodents
produces protection against spontaneous tumors and chemical
carcinogenesis, suppresses weight gain without significantly
affecting food intake, ameliorates the severity of diabetes in
genetically diabetic mice, and restrains autoimmune processes.
DHEA and related steroids also depress the mitogenic effects
of carcinogens, tumor promoters and plant lectins, and block
viral and carcinogen-induced cell transformations. DHEA and
certain congeners are also potent and quite specific
inhibitors of mammalianglucose-6-phosphate dehydrogenases. We
have observed that the conversion of 3T3-L1 and 3T3-F442A
preadipocyte clones to the adipocyte phenotype, in response to
appropriate differentiation stimuli (fetal calf serum,
insulin, dexamethasone, and 1-methyl-3-isobutylxanthine), is
blocked by DHEA and other steroidal inhibitors of
glucose-6-phosphate dehydrogenase. The structural requirements
for blocking adipocyte differentiation and for inhibiting
glucose-6-phosphate dehydrogenase are closely correlated.
Evidence is reviewed suggesting that the inhibition of
glucose-6-phosphatedehydrogenase is central to the
anticarcinogenic and differentiation-blocking actions of DHEA
and related steroids. The 3T3 preadipocyte clones provide a
valuable system for the analysis of the mechanisms of the
effects of DHEA on growth, differentiation and carcinogenesis.
(94 Refs.)
Androgenic and estrogenic metabolites in serum of
mice fed dehydroepiandrosterone: relationship to
antihyperglycemic effects.
Leiter EH, Beamer WG, Coleman DL, Longcope C
Metabolism 1987 Sep;36(9):863-9
The steroid prehormone, dehydroepiandrosterone (DHEA) has
potentanti hyperglycemic effects when fed in the diet of
genetically diabetic C57BL/KsJ-db/db mice. The purpose of this
investigation was to analyze changes in sex steroid levels in
serum of mice fed DHEA, and to compare the antihyperglycemic
potencies of the various metabolites in order to clarify the
mechanism of DHEA action. Steroid radioimmunoassays showed
that dietary DHEA entered the blood in high concentrations and
was actively metabolized to both androgens (testosterone, T;
dihydrotestosterone, DHT) and estrogens (estrone, E1; 17
beta-estradiol, E2). This metabolism did not require intact
adrenal glands or gonads. In C57BL/KsJ normal (+/+) males,
conversion of DHEA to androgens was the prominent feature; in
db/db males, DHEA feeding not only increased serum T and DHT,
but also serum E1 and E2 levels. The db/db mice had increased
amounts of adipose tissue that sequestered more intravenously
injected 3H-E2; this additional body fat could account for
increased aromatization of DHEA-derived estrogen precursors.
Comparisons of the relative antihyperglycemic potencies of
androgenic and estrogenic steroid metabolites of DHEA in db/db
mice showed that the estrogens and metabolites with estrogenic
properties (androstenediol) or those convertible to estrogens
(DHEA sulfate) were the most potent. Although 17 beta-E2 was
effective by injection or per os, DHEA was effective only when
administered per os, implicating alimentary tract conversion
of DHEA to more biologically active reactants. Based on the
pivotal position of DHEA as a prehormone for androgens,
estrogens, andetiocholanolones, an explanation of the
seemingly paradoxical effects exerted by this compound in
blocking autoimmune disease, hyperglycemia, obesity, and
neoplasia was proposed.
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