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How Physicians Get Misled
I came across this abstract during my search for recent testosterone studies.
The study is in the January 2007 issue of The Journal of Clinical Endocrinology and Metabolism.
To the best of my knowledge these are established and competent researchers writing in a reputable
medical journal.
It is important to understand that almost all doctors read only the
abstract of a medical study and go no further. (continued below)
J Clin Endocrinol Metab. 2007 Jan 23;
Endogenous Sex Hormones and Glucose Tolerance Status in Post-menopausal Women.
Golden SH,
Dobs AS,
Vaidya D,
Szklo M,
Gapstur S,
Kopp P,
Liu K,
Ouyang P.
Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD; Divisions of Endocrinology,
Metabolism and Molecular Medicine and Department of Preventive Medicine,Feinberg School of Medicine, Northwestern
University, Chicago, IL.
Context: In post-menopausal women, endogenous estradiol (E2) and free testosterone (T) have been positively
associated with glucose intolerance and type 2 diabetes. Most studies have not examined these associations in a
large group of post-menopausal women. Objective: Our objective was to examine the association between endogenous
sex hormones and glucose tolerance in post-menopausal women. Design, Setting, and Participants: This was a
cross-sectional study of 1,973 post-menopausal women ages 45-84 years, not taking hormone replacement therapy, in
the Multi-Ethnic Study of Atherosclerosis baseline examination. Main Outcome Measures: Impaired fasting glucose (IFG)
and diabetes were defined based on fasting blood sugar and/or treatment for diabetes. In women with normal glucose
tolerance, insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR).
Results: Increasing quartiles of bioavailable T and E2 and decreasing quartiles of sex hormone binding globulin
(SHBG) were associated with significantly increased odds of IFG and diabetes (all p for trend <0.001). Except for
the association of bioavailable T with diabetes, the other associations persisted following multivariable adjustment.
While higher dehydroepiandrostenedione (DHEA) was associated with a greater odds of IFG (p for trend=0.02), it
was not associated with diabetes. Among 1,100 women with normal glucose tolerance, E2 and DHEA were positively
associated and SHBG was inversely associated with HOMA-IR (all p<0.001) following multivariable adjustment.
Bioavailable T was associated with HOMA-IR (p<0.001) but not fasting glucose.
Conclusion: Among post-menopausal women, endogenous bioavailable T, E2, and DHEA were positively, and SHBG
negatively associated with insulin resistance.
PMID: 17244779 [PubMed - as supplied by publisher]
“Endogenous” means what is produced in the body. “Insulin resistance”
is believed to be the primary defect in type II diabetes.
My interpretation of this abstract was that testosterone in women causes
or promotes type II diabetes. That was very disconcerting because that is exactly the opposite
of what I wrote in my book, and exactly the opposite of what happens in men.
I went to the journal website itself to review the entire study.
Following is page 5 of the body of the study. (continued below)
Sex hormones and glucose tolerance
5
Both androgens and estradiol (E2) are associated with diabetes mellitus and altered glucose tolerance.
Testosterone (T) given to healthy women leads to impaired glucose metabolism(1-4). Endogenous free T is
positively correlated with insulin resistance(5-9), fasting plasma glucose(6;6;10;11), and adiposity(6;10).
Both low levels of sex hormone binding globulin (SHBG), a marker of hyperandrogenicity (12-14) that is inversely
related to insulin(15), adiposity(6;10), and glucose tolerance(13;16), and high levels of free T(6), predict the
incidence of type 2 diabetes in women. In a recent analysis in the Atherosclerosis Risk in Communities (ARIC) Study,
we found that higher free androgen index was associated with the hyperinsulinism and hyperglycemia components of
the metabolic syndrome in postmenopausal women(17). This study was limited, however, by only having sex hormone
data on a select group of women and not on the entire cohort. The association between dehydroepiandrostenedione
(DHEA), another androgen, and glucose tolerance status in post-menopausal women is less clear.
Previous studies have also shown that post-menopausal women with impaired glucose tolerance and type 2 diabetes
have higher estradiol (E2) levels than postmenopausal women with normal glucose tolerance(10;14;18). Among healthy
postmenopausal women without diabetes or glucose intolerance, E2 was significantly associated with insulin (7)and
insulin resistance(19), independent of adiposity. Bioavailable E2 is associated with incident insulin resistance
but not with the incidence of type 2 diabetes(6). One study failed to find an association between free E2 and fasting
plasma glucose levels (11) and other studies in human and rodent models suggest that E2 may have a beneficial
effect on glucose metabolism(20).
The two bold-faced sentences on the above page are an even more direct indictment of
testosterone promoting diabetes in women. (Note the 4 references.)
I continued into the discussion part of the study which follows. (continued below)
DISCUSSION
We found that among post-menopausal women not taking hormone replacement therapy, higher levels of bioavailable T
were associated with a greater odds of having IFG but was not associated with diabetes in multivariable analyses.
Higher levels of E2 and lower levels of SHBG were strongly associated with a greater odds of having both IFG and
diabetes. There was a trend toward higher levels of DHEA being associated with a greater odds of having IFG but it
was not associated with diabetes. These associations persisted following multivariable adjustment; however, adding
HOMA-IR to the model explained all of the associations of sex hormones and SHBG with IFG. In a subsidiary analysis
of post-menopausal women with normal glucose tolerance, bioavailable T was positively associated with HOMA-IR; however,
it was not associated with fasting glucose. E2 and DHEA were positively associated and SHBG negatively associated with
both fasting glucose and HOMA-IR in multivariable analyses.
In women with normal glucose tolerance in MESA, bioavailable T was more strongly associated with our measure of insulin
resistance than with fasting glucose. We have previously found that free androgen index was strongly associated with
the glucose and insulin components of the metabolic syndrome in post-menopausal women(17). In another cohort, free T
has been positively associated with fasting plasma glucose(6;10;11), higher fasting and postchallenge insulin
levels(6;7), and higher insulin/glucose ratio(8). Free androgen index has been inversely associated with insulin
sensitivity, assessed by the euglycemic-hyperinsulinemia clamp(5). Elevated free T has also predicted incident type
2 diabetes and insulin resistance, independent of age, adiposity, and systolic blood pressure(6). Recently, in the
SWAN Study, free androgen Sex hormones and glucose tolerance 16 index was positively correlated with glucose, insulin
and HOMA-IR, even after adjustment for BMI(22). In short-term clinical trials, androgen administration to healthy women
has been shown to reduce insulin sensitivity and impair glucose utilization (1;4;26). Anti-androgen therapy given to
women with polycystic ovary syndrome and hyperandrogenism has resulted in partial improvement in insulin
sensitivity(27;28) and a decrease in visceral abdominal fat(29). In post-menopausal women, androgen therapy resulted
in a gain in visceral abdominal fat but there was no change in fasting glucose or insulin sensitivity(30). As we
recently summarized(17), there are several potential mechanisms by which androgens and glucose metabolism may be
associated.
We found that E2 was positively associated with fasting glucose and HOMA-IR and with IFG and diabetes. Sutton-Tyrell
et al. did not find an association between E2 and markers of glucose metabolism in pre- and peri-menopausal women whose
E2 levels were significantly higher than those of the post-menopausal women in our study(22). Our results may have
also differed because the SWAN Study participants were predominantly Caucasian, with fewer Hispanic and Chinese subjects
compared to our MESA population. However, our results are similar to other studies in post-menopausal women showing that
impaired glucose tolerance and type 2 diabetes are associated with higher E2 levels than normal glucose
tolerance(10;14;18). E2 has also been associated with insulin (7)and insulin resistance(19), independent of adiposity,
and has predicted incident insulin resistance(6).
The literature regarding the effects of estrogen on glucose metabolism is mixed. Rodent models of E2 deficiency have
insulin resistance and rodent models of type 2 diabetes demonstrate that ovariectomy makes female rats susceptible to
beta-cell Sex hormones and glucose tolerance 17 destruction(20). These defects are reversed with E2 administration.
Several studies have shown that treating healthy women with unopposed E2 or continuous equine estrogen improves
insulin sensitivity and decreases blood glucose (31-34) and among women with diabetes, unopposed E2 (35-37)or
combination hormone replacement therapy (38) improves insulin sensitivity and glycemic control. However, although
exogenous estrogen administered via hormone replacement therapy was associated with a reduced risk of developing
diabetes in post-menopausal women with coronary artery disease(39), pregnancy, a state of high endogenous estrogen,
is associated with insulin resistance(26). Our findings that higher SHBG was associated with better insulin sensitivity
confirms findings from previous studies(15;16;22). Low SHBG has also predicted type 2 diabetes in men and women(12;14).
Insulin is a potent inhibitor of SHBG secretion in vitro in hepatoma cells and thus low levels of SHBG may reflect
underlying insulin resistance(40). In our study, this is strongly suggested by the association between SHBG and
IFG becoming non-significant after adjusting for HOMA-IR. Physiologically, SHBG binds T, dihydrotestosterone, and
E2 with high affinity and thus regulates their free concentrations and lower SHBG reflecting greater androgenicity(41).
In our study, we found that DHEA was associated with higher glucose levels, higher HOMA-IR, and an increased odds of
IFG. DHEA declines significantly with age and lower levels have been shown cross-sectionally to be associated with
diabetes, impaired glucose tolerance, and insulin resistance(26;42). Administration of DHEA to post-menopausal women
resulted in reduction in insulin and glucose levels(43). A recent study, however, found that higher DHEA levels were
associated with insulin resistance and non-alcoholic fatty liver disease(44). Taken together, the relation between
DHEA Sex hormones and glucose tolerance 18 and glucose metabolism in post-menopausal women remains unclear and requires
further study. In addition, future studies are needed to examine the relation between DHEAsulfate, a more stable marker
of long-term DHEA bioavailability, and glucose tolerance status. Finally, we found some differences in endogenous sex
hormone levels by ethnicity. Chinese women had the lowest total T and highest DHEA levels and black women had the
highest total and bioavailable T levels and the highest E2 levels in unadjusted analyses. Following adjustment for BMI,
race/ethnic differences in total and bioavailable T and E2 were no longer significant. In pre- and peri-menopausal
women, Randolph et al. similarly found that Chinese women had the highest DHEA-sulfate levels; however, in contrast
to our study, T levels were slightly lower in the African-American and Hispanic women(21). In both of our studies,
however, adiposity was an important confounder of the race/ethnic differences in sex hormone levels--they also found
that E2 and free T index did not differ by race/ethnicity once BMI was accounted for(21). In another study, Chinese
women had lower E2 levels than White women(45). In our study, as in SWAN, the associations between endogenous hormones
and glucose metabolism variables were similar for all race/ethnicities(22). Our study has several strengths. First, we
had a large sample size of nearly 2000 post-menopausal women to examine these associations. With the exception of the
Rancho-Bernardo (6;10;11) Study, the majority of other studies have been small. Second, because MESA is an ethnically
diverse sample, this allowed us to examine the association between endogenous sex hormones and insulin resistance by
race/ethnicity. The SWAN Study is the only other study that we are aware of that has examined these sex hormones and
glucose tolerance 19 associations in a multiethnic population(22). Third, as individuals with prevalent cardiovascular
disease were excluded, this is a healthier, population-based sample, compared with a clinic-based sample. Finally, in
contrast to our previous study(17), bioavailable T and other sex hormones measurements were available on the entire
cohort of women and not a pre-selected subset. Nonetheless, several limitations should be kept in mind in interpreting
our data. This was a cross-sectional analysis, which does not allow us to elucidate the temporal association between
hormones and glucose parameters; however, the structure of subsequent MESA follow-up examinations will allow for
longitudinal analyses in the future. Also, only one measurement of sex hormones was used to characterize each woman’s
hormonal status; however, it has been previously suggested that a single measure can reliably characterizes a person’s
androgen status(6;46). We also did not have data on estrone, the primary estrogen present in post-menopausal women. Our
study suggests an association of androgens and estrogens with insulin sensitivity in post-menopausal women. Longitudinal
studies are needed to determine the temporal relation between endogenous sex hormones and risk of insulin resistance and
diabetes. Additional studies are needed to further elucidate the mechanisms by which endogenous sex hormones are
related to glucose metabolism and diabetes risk. Finally, studies aimed at altering the endogenous hormonal milieu may
have implications for altering glucose metabolism and diabetes risk.
My interpretation of this discussion was that the authors were now
stating the exact opposite of what they had stated before. Rephrasing their words for simplicity,
how does one reconcile the earlier,
“Androgens (testosterone) are associated with diabetes mellitus and altered glucose tolerance.”,
with the later,
“We found that among post-menopausal women higher levels of bioavailable testosterone
were not associated with diabetes.”
And how does one reconcile the earlier,
“Testosterone given to healthy women leads to impaired glucose metabolism.”,
with the later,
“In post-menopausal women, androgen therapy resulted in no change in fasting glucose or insulin sensitivity.”
Now, what about those four references? Remember, they are the basis of the blanket statement:
“Testosterone given to healthy women leads to impaired glucose metabolism.”
The references themselves were
on page 20. (continued below)
Sex hormones and glucose tolerance
20
Reference List
1. Polderman KH, Gooren LJ, Asscheman H, Bakker A, Heine RJ. Induction of
insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 1994;
79(1):265-271.
2. Dunaif A. Insulin resistance in polycystic ovarian syndrome. Ann N Y Acad Sci
1993; 687:60-64.
3. Lando J, Wynn V, Samols E. The effect of anabolic steroids on blood sugar and plasma insulin levels in man.
Metab Clin Exp 1963; 12:294-297.
4. Diamond MP, Grainger D, Diamond MC, Sherwin RS, Defronzo RA. Effects of
methyltestosterone on insulin secretion and sensitivity in women. J Clin Endocrinol Metab 1998; 83(12):4420-4425.
Reference 1
Unbelievably, the study by Polderman was on women being given megadoses of testosterone
to change them into men!
(The most common dose I give to women is 40 mg – 60 mg every three weeks.)
Journal of Clinical Endocrinology & Metabolism, Vol 79, 265-271,
Copyright © 1994 by Endocrine Society
Induction of insulin resistance by androgens and estrogens
KH Polderman, LJ Gooren, H Asscheman, A Bakker and RJ Heine
Department of Internal Medicine, Free University Hospital, Amsterdam, The Netherlands.
Hyperinsulinemia is a common finding in hyperandrogenic women, during pregnancy, and in women using oral
contraceptives.
To test whether sex hormone treatment can induce insulin resistance in healthy subjects, we studied the effects of
administration of testosterone to 13 female to male and of ethinyl estradiol to 18 male to female transsexuals.
Utilization and production of glucose and levels of sex steroids were measured during a three-step
hyperinsulinemic-euglycemic clamp before and after 4 months of hormone administration. Females were treated with im
injections of testosterone esters (250 mg/2 weeks); males were treated with ethinyl estradiol alone
(0.1 mg/day, orally)
or a combination of ethinyl estradiol and cyproterone acetate (100 mg/day, orally). Similar insulin levels were achieved
at each of the three steps of the clamp studies before and during hormone administration. During step 1 of each clamp,
with insulin levels in the physiological range, glucose utilization decreased from 3.5 +/- 1.2 to 2.6 +/- 0.9 mmol/kg
lean body mass (LBM).h in women treated with testosterone esters (P < 0.001) and from 3.2 +/- 0.7 to 2.5 +/- 0.5 mmol/kg
lean body mass.h in men treated with ethinyl estradiol (P < 0.001). The effects of sex steroids during steps 2 and 3 of
the clamp at higher (supraphysiological) insulin levels were less clear. Endogenous glucose production (measured by
isotope dilution with tritiated glucose) was not affected by hormone administration, indicating that the observed
changes in glucose requirement were determined by a diminished peripheral glucose uptake. We conclude that sex hormone
administration, i.e. testosterone treatment in females and ethinyl estradiol treatment in males, can induce insulin
resistance in healthy subjects.
Reference 2
There was no need to look up the second reference. It is well known that women
suffering from the polycystic ovary syndrome have very high abnormal levels of testosterone. What does that
have to do with giving presumably physiologic doses of testosterone to healthy women?
Reference 3
I could not find anything on the 1963 reference.
Reference 4
The fourth reference (following) is the most outlandish. It is clearly stated to
be a study of the effect of testosterone excess on women.
Effects of Methyltestosterone on Insulin Secretion and Sensitivity In Women
Michael P. Diamond, David Grainger, Meredith C. Diamond, Robert S. Sherwin and Ralph A. DeFronzo
Department Obstetrics and Gynecology (M.P.D., M.C.D.), Division of Reproductive Endocrinology and Infertility,
Hutzel Hospital/Wayne State University School of Medicine, Detroit, Michigan 48201; Center for Reproductive
Medicine (D.G.), Wichita, Kansas 67214; Department of Internal Medicine (R.S.S.), Yale New Haven Hospital, New
Haven, Connecticut 06520; Diabetes Division, Department of Medicine R.A.D.), University of Texas Health Science
Center, San Antonio, Texas 78284-7870 ,
Address correspondence and requests for reprints to: Michael P. Diamond, MD, Professor of Obstetrics and
Gynecology, Hutzel Hospital/Wayne State University, 4707 St Antoine Boulevard, Detroit, Michigan 48201.
The frequent coexistence of hyperandrogenism and insulin resistance is well established; however, whether a
cause and effect relationship exists remains to be established. In this study we tested the hypothesis that
short-term androgen administered to women would induce insulin resistance. To test this hypothesis, regularly
menstruating, nonobese women were studied before and during methyltestosterone administration
(5 mg tid for 10–12 days) by the hyperglycemic (n = 8) and euglycemic, hyperinsulinemic (n = 7) clamp techniques.
Short-term methyltestosterone administration had no significant effects on the fasting levels of glucose,
insulin, c-peptide, glucagon, or glucose turnover. During the hyperglycemic clamp studies, the mean glucose
level during the final hour was 203 ± 2 and 201 ± 1 mg/dL in the methyltestosterone and control studies, respectively.
The insulin response to this hyperglycemic challenge was slightly but not significantly greater during
methyltestosterone treatment (first phase 59 ± 8 vs. 50 ± 8 µU/mL in controls; second phase 74 ± 9 vs. 67 ± 9 µU/mL
in controls; total insulin response 133 ± 16 vs. 117 ± 15 µU/mL in controls). In spite of this, glucose uptake was
reduced from the control study value of 10.96 ± 1.11 to 7.3 ± 0.70 mg/kg/min by methyltestosterone (P < 0.05). The
ratio of glucose uptake per unit of insulin was also significantly reduced from a control study value of
14.3 ± 1.4 to 9.4 ± 1.3 mg/kg/min per µU/mL x 100 during methyltestosterone administration. In the euglycemic
hyperinsulinemic clamp studies, insulin was infused at rates of 0.25 and 1.0 mU/kg/min to achieve insulin levels
of approximately 25 and 68 µU/mL, respectively. During low-dose insulin infusion, rates of endogenous hepatic
glucose production were equivalently suppressed from basal values of 2.37 ± 0.29 and 2.40 ± 0.27 mg/kg/min to
0.88 ± 0.25 and 0.77 ± 0.26 mg/kg/min in the methyltestesterone and control studies respectively. Whole body
glucose uptake during low-dose insulin infusion was minimally affected. During the high-dose insulin infusion,
endogenous hepatic glucose production was nearly totally suppressed in both groups. However, whole body glucose
uptake was reduced from the control value of 6.11 ± 0.49 mg/kg/min to 4.93 ± 0.44 mg/kg/min during methyltestosterone
administration (P < 0.05).
Our data demonstrate that androgen excess leads to the development of insulin resistance during both
hyperglycemic and euglycemic hyperinsulinemia. These findings provide direct evidence for a relationship between
hyperandrogenemia and insulin resistance, and its associated risk factors for cardiovascular disease.
The JCEM study title clearly states that the study was supposed
to be about “endogenous” testosterone in women. Why are these studies of women having, or being
given, abnormally high levels of testosterone being used as references? Is it evidence
against type II diabetes being associated with testosterone deficiency? Not at all. The
following study on rats demonstrated that both low levels of testosterone and high doses of testosterone
induce insulin resistance while physiologic doses decrease insulin resistance and
improve insulin sensitivity
Acta Physiol Scand. 1992 Dec;146(4):505-10.
The effects of testosterone on insulin sensitivity in male rats.
· Holmang A,
· Bjorntorp P.
Department of Medicine I, Sahlgrenska Sjukhuset, University of Goteborg, Sweden.
In order to examine the effects of testosterone (T) on insulin sensitivity, male rats were castrated or
sham-operated, and exposed to low or high doses of T to substitute normal or to produce high serum T
concentrations. Insulin sensitivity was followed by euglycaemic, hyperinsulinaemic glucose clamp measurements.
An index of insulin-stimulated glucose transport was obtained in the white gastrocnemius (WG), extensor digitorum
longus (EDL), red gastrocnemius (RG) and soleus (SOL) muscles after a bolus dose of [2-3H]deoxyglucose (2-DOG)
when steady state was obtained in the clamp measurements. Glycogen synthesis was followed similarly with [U-14C]glucose
as a labelled precursor after isolation of glycogen in the muscles mentioned, and in the liver. Castration and
high T were followed by a marked insulin resistance in the clamp measurements. This was paralleled by a diminished
insulin stimulation of glucose incorporation into glycogen down to about 50% of control values, apparently
equally pronounced in all muscles but not found in liver glycogen synthesis. 2-DOG uptake was diminished by
castration in the WG and RG muscles but was unaffected by high doses of T. Substitution of castrated rats with
a low dose of T, restoring their serum T concentrations to the normal range, completely abolished these
perturbations of insulin sensitivity. It is concluded that T is an important regulator of muscular insulin
sensitivity, which seems to be highest in a 'window' of normal serum T concentrations.
PMID: 1492567 [PubMed - indexed for MEDLINE]
In summary, and once again taking the liberty to edit and simplify, in the abstract doctors were told:
“In post-menopausal women, endogenous testosterone has been positively associated with
insulin resistance, glucose intolerance, and type II diabetes.”
While in their discussion the authors stated:
“In post-menopausal women, higher levels of testosterone were not associated with diabetes,
and testosterone therapy resulted in no change in fasting glucose or insulin sensitivity.”
To me the abstract of the JCEM study was grossly misleading, giving me
(and other physicians) the exact opposite impression of the actual facts of the study. Was this
a mistake, an oversight? Was this a purposeful deception of the medical community by one or more
of the authors? Is this an example of anti-testosterone activists at work? Have there been more
studies published with misleading abstracts? Maybe this is why testosterone replacement therapy
is so controversial.
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