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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 5 2207-2213
Copyright © 2004 by The Endocrine Society

Effect of the Combination of Methyltestosterone and Esterified Estrogens Compared with Esterified Estrogens Alone on Apolipoprotein CIII and Other Apolipoproteins in Very Low Density, Low Density, and High Density Lipoproteins in Surgically Postmenopausal Women

Stephanie E. Chiuve, Lisa A. Martin, Hannia Campos and Frank M. Sacks

Department of Nutrition, Harvard School of Public Health (S.E.C., L.A.M., F.M.S.), and Channing Laboratory and Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (F.M.S.), Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Frank M. Sacks, M.D., Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115. E-mail: fsacks{at}hsph.harvard.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Androgens are known to lower plasma triglycerides, an independent risk factor for coronary heart disease (CHD). Triglycerides are carried in plasma on very low density (VLDL) and low density (LDL) lipoprotein particles. Apolipoprotein CIII (apoCIII), a strong predictor of CHD, impairs the metabolism of VLDL and LDL, contributing to increased triglycerides. The objective of this study was to assess the effect of oral methyltestosterone (2.5 mg/d), added to esterified estrogens (1.25 mg/d), on concentrations of apolipoproteins and lipoproteins, specifically those containing apoCIII, compared with esterified estrogens alone in surgically postmenopausal women. The women in the methyltestosterone plus esterified estrogen group had significant decreases in total triglycerides, apoCI, apoCII, apoCIII, apoE, and high density lipoprotein (HDL) cholesterol compared with those in the esterified estrogen group. The decreases in apoCIII concentrations occurred in VLDL (62%; P = 0.02), LDL (35%; P = 0.001), and HDL (17%; P < 0.0001). There were also decreases in cholesterol and triglycerides concentrations of apoCIII containing LDL, and apoCI concentration of apoCIII containing VLDL. There was no effect on VLDL and LDL particles that did not contain apoCIII or on apoB concentrations. In conclusion, methyltestosterone, when administered to surgically postmenopausal women taking esterified estrogen, has a selective effect to reduce the apoCIII concentration in VLDL and LDL, a predictor of CHD. Methyltestosterone may lower plasma triglycerides through a reduction in apoCIII.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MENOPAUSE IS ACCOMPANIED by a variety of changes in women, many of which are undesirable, such as hot flashes, mood swings, and insomnia (1). Estrogen therapy is effective in alleviating vasomotor symptoms (2). After menopause, there are increases in risk factors for coronary heart disease (CHD), including overweight and obesity, dyslipidemia, insulin resistance, and the metabolic syndrome (3). Although epidemiological evidence suggests that estrogen therapy offers protection from CHD (4), recent clinical trials have found no benefit of hormone therapy with oral conjugated equine estrogens and medroxyprogesterone acetate on the risk of CHD (5, 6).

Methyltestosterone combined with esterified estrogens offers similar relief of vasomotor symptoms to postmenopausal women, compared with estrogen therapy along with improvements in sexual function and quality of life (7, 8, 9), which do not occur with estrogen therapy (10). Furthermore, women with lower natural levels of testosterone may have an elevated risk of CHD (11).

Apolipoprotein CIII (apoCIII) is an emerging risk factor for CHD related to triglycerides. ApoCIII, specifically on very low density (VLDL) and low density (LDL) lipoproteins, the apoB lipoproteins, is increased in patients with CHD (12, 13), is associated with progression of coronary artery disease (14, 15), and is an independent predictor of CHD death and myocardial infarction (16). A multiple regression analysis that included apoCIII in VLDL and LDL as well as triglycerides showed that apoCIII was significant, whereas triglycerides were not (16). As both apoCIII and triglycerides were significant in univariate analysis, the multivariate analysis suggests that apoCIII accounted for the relationship between triglycerides and CHD (16). Approximately 50–75% of VLDL and 10% of LDL particles contain apoCIII. ApoCIII inhibits the lipolysis of triglycerides that are inside the VLDL particle and decreases the clearance rate of the VLDL, increasing its circulation time in plasma (17, 18). Humans who have apoCIII deficiency (19) and animals with apoCIII gene knockout (20) have very fast catabolism of plasma triglycerides and very low plasma VLDL and triglyceride concentrations. A high production rate of apoCIII by the liver in humans (21) or overexpression of human apoCIII in mice (17, 18) has the opposite effects on VLDL metabolism. Metabolism of VLDL with apoCIII results in smaller intermediate density lipoprotein and LDL particles with apoCIII that are often termed remnants. Recently, we reported that the concentration of intermediate density lipoprotein and LDL particles that contain apoCIII is a strong and independent risk factor for CHD (22).

A potential benefit of exogenous androgens is their lowering of plasma triglyceride levels (8, 23, 24, 25, 26), but little is known about the mechanisms. The purpose of this study was to examine whether methyltestosterone lowers apoCIII in surgically postmenopausal women taking esterified estrogens, a potential mechanism by which it exerts its plasma triglyceride-lowering effect.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study design

The study was a 10-wk, randomized, double-blind trial designed to determine the effects of orally administered combination tablets containing methyltestosterone (2.5 mg) and esterified estrogens (1.25 mg) compared with esterified estrogens (1.25 mg) alone on VLDL and LDL subtypes that have been linked to atherosclerosis and CHD. Subjects who were eligible began a 2-wk, single-blind, estrogen lead-in phase consisting of esterified estrogens (0.625 mg, two tablets daily, totaling 1.25 mg/d; ESTRATAB, Solvay Pharmaceuticals, Marietta, GA). After the lead-in phase, participants were assigned at random to receive methyltestosterone plus esterified estrogen (ESTRATEST tablets, Solvay Pharmaceuticals; n = 40) or to continue with esterified estrogen alone (n = 39) for 8 wk. Blood samples were drawn at screening for eligibility, at the end of the lead-in phase (d 14), and at the end of the treatment phase (d 70). Plasma was separated, frozen at –70 C, and shipped on solid CO2 to our laboratory at Harvard School of Public Health (Boston, MA). This study was a component of a trial on the effects of methyltestosterone plus esterified estrogen on female sexual function in surgically postmenopausal women (unpublished observations).

Subjects

The subjects were enrolled from seven centers in the United States. The women had to have been in a stable relationship for at least 2 yr, were surgically menopausal as defined by total hysterectomy with bilateral salpingo-oophorectomy for a minimum of 3 months, and had a serum concentration of free testosterone of 2 pg/ml or less. These women also had to have been currently treated with 0.625 or 1.25 mg oral, or topical, or transdermal estrogens for at least 3 months before beginning the study. Women were excluded from the study if they had a medical history or current diagnosis of known sensitivity or contraindications to hormone therapy with estrogens or androgens, major mental illness, or an eating disorder within the past 2 yr. Other exclusion criteria included a body mass index of 35 kg/m2or more; current or prior history of cardiovascular disease; clinically significant hematological, autoimmune, endocrine, renal, gastrointestinal, or neurological disorder; current history of breast cancer or breast cancer in an identical twin; malignant melanoma or any cancer diagnosed less than 5 yr before screening; uncontrolled hypertension or poorly controlled diabetes mellitus; gall bladder disease or gallstones; drug or alcohol abuse within the past 6 months before screening; life-threatening illness; undiagnosed abnormal vaginal bleeding; or malignancy of the genital organs. Exclusions based on physical or laboratory findings included abnormal vaginal cytology, abnormal mammographic findings, abnormal TSH levels, hematocrit less than 30% or hemoglobin less than 9.5 mg/dl, fasting serum glucose more than 140 mg/dl, fasting serum triglycerides more than 300 mg/dl, and fasting creatinine more than 2.0 mg/dl. Finally, subjects were excluded if they were taking any of the following medications: progestin; androgen; glucocorticoid therapy; alternative estrogen-like agents (such as phytoestrogens); selective estrogen receptor modulators; liver enzyme-inducing medications such as rifampicin, phenytoin, barbiturates, antidepressants, and anxiolytics; anticoagulants; or cholesterol-lowering medications. All subjects provided written informed consent in compliance with institutional review board requirements at the recruiting centers and were free to withdraw from the study at any time. The current study was approved by the human subjects committee of Harvard School of Public Health. A total of the 84 subjects gave blood samples at their visit on d 14. Of these 84 subjects, 79 had also given blood samples at their visit on d 70 and had enough blood volume available for our analysis.

Sample analysis

Each subject’s two time points, initial (at the end of the estrogen-only lead-in phase) and final (at the end of the 8-wk blinded treatment phase), were analyzed at the same time. The plasma was thawed in a 37 C water bath, and 1 ml was applied to immunoaffinity columns containing anti-apoCIII resin and incubated overnight at 4 C with constant mixing as described in detail previously (27). The unbound fraction was collected by washing the column with PBS. The bound fractions (CIII+) were eluted with 3 M NaSCN and immediately desalted with a Sephadex G-25 column. The resulting bound (CIII+) and unbound (CIII–) fractions were then further separated by ultracentrifugation using a type 25 rotor and spun at 25,000 rpm on an L8–70M instrument (Beckman Coulter Instruments, Fullerton, CA) to prepare VLDL (density, <1.006 g/ml) and LDL (density, 1.006–1.063 g/ml). HDL was collected in the bottom fraction. All lipoprotein concentrations were adjusted for loss using total plasma concentrations as the reference points. ApoB, apoCI, apoCII, and apoCIII were measured using ELISA. Triglyceride and cholesterol concentrations were measured by enzymatic methods using the COBAS MIRA Plus autoanalyzer (Roche, Somerville, NJ). Estrone, estradiol, serum weakly bound estradiol, total estradiol, SHBG, and bioavailable testosterone were measured by RIAs (Esoterix, Calabasas Hills, CA). Total testosterone was measured by immunoradiometric assay. Free testosterone was measured by equilibrium dialysis. FSH was measured by immunochemiluminometric assay, and TSH was measured with a site immunometric procedure. The average intra- and interassay coefficients of variation for each hormone across a range of concentrations were, respectively, 7.8% and 10.3% for total testosterone, 8.4% and 9.8% for free testosterone, 3.3% and 12.4% for bioavailable testosterone, 3.3% and 8.8% for SHBG, and 6.0% and 11.2% for estradiol. The interassay coefficients of variation for estrone and bound estradiol were 9.3% and 4.9%, respectively.

Statistical analysis

All procedures were performed using SAS version 8 (SAS Institute, Inc., Cary, NC). Normality was assessed using the Wilke-Shapiro test, and all variables, except HDL and total cholesterol, had significantly skewed distributions. Spearman correlations were calculated to test whether changes in circulating hormones were associated with changes in lipoprotein concentrations. For all other statistical testing, nonnormally distributed variables were log-transformed. The primary analysis of this clinical trial tested whether the changes from baseline in the methyltestosterone- plus esterified estrogen-treated group (experimental group) differed from those in the esterified estrogens only group (control group), using unpaired t test. The lipid concentrations at baseline were expressed as the arithmetic mean and SD. The mean change and SD in log units were converted back to natural units to describe the results in the text, tables, and figure. All P values were two-tailed. The sample size was determined to provide more than 80% power to detect a 25% change in apoCIII in VLDL and LDL.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline characteristics and hormone levels

The subjects in the two treatment groups had similar age, body mass index, FSH, and TSH measured at screening (Table 1Go). The changes in circulating levels of all sex hormones, with the exception of total testosterone, were significantly different between the treatment groups after 8 wk (Table 2Go). Subjects who received methyltestosterone plus esterified estrogen treatment showed significant increases in free testosterone, bioavailable testosterone, estradiol, and weakly bound estradiol and significant decreases in estrone, total estradiol, and SHBG compared with the control group that received esterified estrogens alone. Furthermore, the changes in hormones were significantly associated with changes in some lipoproteins and apolipoproteins. Among the methyltestosterone plus esterified estrogen group, changes in weakly bound estradiol were inversely correlated with changes in total apoCIII (r = –0.36; P = 0.03), HDL-apoCIII (r = –0.36; P = 0.03), and LDL-apoCIII (r = –0.45; P = 0.01). In addition, changes in estrone and SHBG were positively associated with triglycerides (r = 0.37; P = 0.03 for estrone and r = 0.37; P = 0.02 for SHBG), whereas changes in SHBG were also correlated with LDL-apoCIII (r = 0.31; P = 0.05). Changes in serum testosterone, total or free, were not significantly correlated with changes in any of the lipoproteins.


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  		TABLE 1. Baseline characteristics

 

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  		TABLE 2. Hormone levels at initial and final visits

 
Effect of methyltestosterone on plasma total lipids and apolipoproteins

Compared with esterified estrogen alone, methyltestosterone plus esterified estrogen significantly lowered plasma total triglycerides by 11%, total cholesterol by 10%, and HDL cholesterol by 24% (Table 3Go). Methyltestosterone plus esterified estrogen also significantly lowered apoCI by 13%, apoCII by 14%, apoCIII by 14%, and apoE by 13% (P = 0.06; Table 3Go). There was no significant effect of methyltestosterone plus esterified estrogen on apoB.


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  		TABLE 3. Plasma total lipid and apolipoprotein concentrations

 
Effects of methyltestosterone on VLDL, LDL, and HDL fractions

All three lipoprotein fractions contributed to the decrease in plasma total apoCIII concentration (Tables 4–6GoGoGo and Fig. 1Go). ApoCIII decreased significantly by 62%, 35%, and 17% in VLDL, LDL, and HDL, respectively, in subjects in the methyltestosterone plus esterified estrogen group compared with those given esterified estrogen alone. Other components of apoCIII containing VLDL and LDL particles decreased in the methyltestosterone plus esterified estrogen group compared with the esterified estrogen group: apoE in VLDL and LDL, apoCI in VLDL, and cholesterol and triglyceride in LDL (Tables 4Go and 5Go). Methyltestosterone plus esterified estrogen did not affect VLDL or LDL that did not have apoCIII (Tables 4Go and 5Go). There were also significant decreases in the methyltestosterone plus esterified estrogen group in HDL cholesterol, triglycerides, apoCI, apoCII, and apoE (P = 0.06; Table 6Go).


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  		TABLE 4. VLDL subfractions

 

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  		TABLE 5. LDL subfractions

 

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  		TABLE 6. HDL lipids and apolipoproteins

 


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  		FIG. 1. ApoCIII concentrations in lipoprotein subfractions: effect of the combination of methyltestosterone and esterified estrogens compared with that of esterified estrogens alone. The mean change from baseline is shown. P values are computed by unpaired t tests of the differences in the two groups. ApoCIII concentrations were measured in the VLDL and LDL apoCIII+ particles, i.e. those that were retained by anti-apoCIII immunoaffinity chromatography. ApoCIII was measured in the total HDL.

 
Adverse effects

There were no significant differences between the groups in adverse events reported, including headache (two in methyltestosterone plus esterified estrogen vs. one in estrogen alone), acne (two vs. zero), hirsutism (zero vs. one), breast pain (three vs. one).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The main finding of our study is that oral methyltestosterone reduces apoCIII concentrations in all lipoproteins, VLDL, LDL, and HDL, in surgically postmenopausal women who were concomitantly treated with esterified estrogen. Hormone therapy, using this combination of methyltestosterone and esterified estrogen, has been shown to improve the somatic symptoms of menopause similar to estrogen therapy (8). The addition of methyltestosterone increases bone mineral density more than esterified estrogen alone and improves body composition by increasing lean mass and decreasing fat mass (7, 8). This therapy also improves sexual function and quality of life (7, 8, 9). We found that the addition of methyltestosterone to esterified estrogen may also improve lipid profiles among surgically postmenopausal women by decreasing apoCIII in VLDL and LDL, a strong, independent predictor of CHD (12, 13, 14, 15, 16, 22).

ApoCIII is gaining much attention recently due to its adverse effects on lipoprotein metabolism and its association with CHD (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). ApoCIII interferes with the metabolism of plasma VLDL by inhibiting the clearance of VLDL by the liver, thus keeping them in the circulation longer (18). ApoCIII also inhibits lipoprotein lipase from hydrolyzing triglycerides that are contained in VLDL (17, 19). Methyltestosterone decreases triglycerides levels (8, 26). Our results suggest that a mechanism by which methyltestosterone decreases triglycerides is a decrease in apoCIII levels.

ApoCIII in VLDL and LDL is increased in patients with CHD (12, 13) and is associated with worsening of coronary artery lesions (14, 15). ApoCIII in VLDL and LDL predicted CHD strongly and independently of other lipid and nonlipid risk factors and accounted for the risk associated with triglycerides (16). Moreover, in patients receiving statin therapy with aggressively lowered LDL and cholesterol, apoCIII was the predominant lipoprotein risk factor for the progression of mild to moderate coronary artery lesions (14, 15). In statin-treated patients, apoCIII was still a predictor of coronary events (16, 22). Recently, we reported that LDL with apoCIII was the specific apoCIII-containing particle associated with coronary artery disease (22). The relative risk for a coronary event was 6.6 for high concentrations of LDL with apoCIII compared with 2.2 for LDL without apoCIII. LDL with apoCIII is a remnant formed from the partial lipolysis of VLDL with apoCIII. Thus, the action of methyltestosterone to reduce apoCIII in VLDL and LDL could be a protective mechanism against CHD.

We observed that methyltestosterone selectively affected LDL that had apoCIII, but not LDL without apoCIII, which is consistent with previous studies that did not find an effect on total LDL (8, 26). LDL with apoCIII comprises approximately 10% of the total LDL. Estrogen has a well established effect to reduce concentrations of plasma total LDL cholesterol (28) due to an increase in the clearance rate from plasma (29). Adding methyltestosterone to esterified estrogen may decrease LDL cholesterol, specifically the more atherogenic apoCIII containing LDL.

We found that methyltestosterone lowered the HDL cholesterol concentration, a well known effect of androgens (8, 26, 30, 31). This is an undesirable effect, because HDL cholesterol is protective against heart disease. However, HDL is composed of diverse particle types. Approximately 60–70% of apoCIII is found in HDL. HDL apoCIII is directly correlated with plasma triglycerides and VLDL, rather than inversely as is HDL cholesterol (16). This relationship may derive from HDL being a recipient of apoCIII that is transferred from VLDL. HDL is also thought to serve as a reservoir of apoCIII for transfer to VLDL, although this process has not been demonstrated in humans. The HDL apoCIII concentration trends toward increasing coronary disease risk (16, 32, 33). We found that methyltestosterone decreased the HDL apoCIII concentration. We speculate that methyltestosterone has a favorable influence on a component of HDL that is not protective and may provide a balance to the decrease in HDL cholesterol concentration.

We found significant differences in circulating hormone levels between treatment groups. As expected, serum testosterone, free and bioavailable, increased as a result of the methyltestosterone treatment. We also observed decreases in levels of estrone and total estradiol, but found increases in total and weakly bound estradiol in the methyltestosterone plus esterified estrogens group compared with the esterified estrogen group. This may be caused by the decrease in SHBG, which may lead to increases in free and bioavailable estradiol. These changes in circulating hormones were significantly correlated with the decreases seen in apoCIII and triglycerides.

This study is limited by examining methyltestosterone only in the context of estrogen therapy. There are no previous studies published on methyltestosterone and apoCIII in women to our knowledge. A study in healthy young men found no significant effect of injections of testosterone enanthate on apoCIII levels after 20 wk of treatment or on HDL concentration, except at a dose much higher than that used in the present study (625 mg/wk) (34). There is also little information on estrogen therapy and apoCIII, although estrogenic oral contraceptives have little effect on apoCIII (35). Finally, studies among naturally postmenopausal women need to be conducted to examine whether the effects of methyltestosterone, taken with esterified estrogen, on lipoproteins are similar to those in this population of surgically postmenopausal women.

The recent findings in the Women’s Health Initiative Study and the HERS study, in which hormone therapy with oral conjugated equine estrogens and medroxyprogesterone acetate was not found to be protective against and may contribute to CHD, have changed the view of hormone replacement therapy (5, 6). Oral estrogen and medroxyprogesterone acetate both have protective and deleterious effects on CHD risk factors, including lipoproteins and thrombogenic factors, and it has proven difficult to use these individual mechanisms to predict successfully the net effect on CHD itself. We did not examine the effects of these hormones on all potential mechanisms of CHD, such as thrombogenic factors or inflammation. However, we have shown that 2.5 mg methyltestosterone improved several aspects of the lipid profiles of surgically postmenopausal women who were being treated with esterified estrogens by reducing plasma total triglycerides and plasma apoCIII in all lipoprotein fractions, most importantly in the atherogenic LDL CIII. In contrast, methyltestosterone decreased HDL cholesterol, although there was also a decrease in apoCIII HDL, which may not be a beneficial component of HDL (16, 32, 33).

In conclusion, we identified new favorable effects of methyltestosterone, given in combination with esterified estrogen, on lipoprotein risk factors, which is one potential mechanism for the development of CHD. However, only a trial that uses atherosclerosis or CHD as an outcome can determine its ultimate effects on clinical CHD.


   Footnotes
 
This work was supported by an investigator-initiated grant from Solvay Pharmaceuticals, Inc. (Marietta, GA).

Abbreviations: apo, Apolipoprotein; CHD, coronary heart disease; HDL, high density lipoprotein; LDL, low density lipoprotein; VLDL, very low density lipoprotein.

Received September 8, 2003.

Accepted February 12, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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