Decreased HDL Caused by Higher Dose TRT

[Nelson Vergel]

Higher dose testosterone can decrease HDL.

Click here for background information:
Why does testosterone therapy decrease HDL cholesterol in some men?


HDL (High Density Lipoprotein cholesterol) particles are sometimes referred to as "good cholesterol" because they can transport fat molecules out of artery walls, reduce macrophage accumulation, and thus help prevent or even regress atherosclerosis.

Data from the landmark Framingham Heart Study showed that, for a given level of LDL, the risk of heart disease increases 10-fold as the HDL varies from high to low. On the converse, however, for a fixed level of HDL, the risk increases 3-fold as LDL varies from low to high.

While higher HDL levels are correlated with cardiovascular health, no medication used to increase HDL has been proven to improve health.In other words, while high HDL levels might correlate with better cardiovascular health, specifically increasing one's HDL might not increase cardiovascular health. The remaining possibilities are that either good cardiovascular health causes high HDL levels, there is some third factor which causes both, or this is a coincidence with no causal link.

Pharmacologic (1- to 3-gram/day) niacin doses increase HDL levels by 10–30%,making it the most powerful agent to increase HDL-cholesterol. A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events.However, niacin products sold as "no-flush", i.e. not having side-effects such as "niacin flush", do not contain free nicotinic acid and are therefore ineffective at raising HDL, while products sold as "sustained-release" may contain free nicotinic acid, but "some brands are hepatotoxic"; therefore the recommended form of niacin for raising HDL is the cheapest, immediate-release preparation.[SUP][[/SUP]Both fibrates and niacin increase artery toxic homocysteine , an effect that can be counteracted by also consuming a multivitamin with relatively high amounts of the B-vitamins, however multiple European trials of the most popular B-vitamin formulas, trial showing 30% average reduction in homocysteine, while not showing problems have also not shown any benefit in reducing cardiovascular event rates. A 2011 niacin study was halted early because patients adding niacin to their statin treatment showed no increase in heart health, but did experience an increase in the risk of stroke.

Source

Plasma HDL Cholesterol as a Noncausal Biomarker

Abbreviations:
SNPs: A single-nucleotide polymorphism, is a variation (mutation) in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population.
CHD: Coronary Heart Disease
HDL: High Density Lipoprotein
MI: Myocardial infarction
Pleiotropic effects: occur when one gene influences two or more seemingly unrelated phenotypic traits. Therefore, a mutation in a pleiotropic gene may have an effect on several traits simultaneously due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function.

There is a strong inverse association of plasma HDL-C concentrations with CHD, which for decades lent credence to the notion that pharmacological raising of HDL-C should protect against CHD. Yet recent genetic analyses have in general failed to support a causal role for HDL-C in CHD. As related above, a genetic score comprising LDL-C–associated SNPs was found to have a strong relationship with MI risk. The same study performed a parallel Mendelian randomization study in >50 000 cases and controls using a genetic score comprising 14 GWAS SNPs primarily associated with plasma HDL-C levels. Whereas a 1-standard deviation increase in HDL-C (≈15 mg/dL) was expected to be associated with a 38% decrease in MI risk using data from observational epidemiological studies, a 1- standard deviation decrease in HDL-C because of genetic score conferred no significant change in MI risk .

The same study performed a more focused Mendelian randomization analysis on a coding SNP (Asn396Ser) in the LIPG gene, which encodes endothelial lipase, an enzyme that metabolizes HDL particles but has little effect on plasma LDL-C and triglycerides. To obtain adequate power for the analysis, the SNP was genotyped in ≈20 000 individuals with MI and 95 000 control individuals. Carriers of the LIPG Asn396Ser SNP variant had increased plasma HDL-C levels, on average ≈5.5 mg/dL. This degree of increase in HDL-C was expected to be associated with a 13% decrease in MI risk using data from observational epidemiological studies. However, carriers of the LIPG Asn396Ser variant were found to have a negligible change in MI risk (1% decrease; P=0.85; 95% confidence interval ranging from an 11% increase to a 12% decrease), essentially ruling out an effect of LIPG on the pathogenesis of CHD. In other studies, genetic analyses of both common variants in the ABCA1 gene, which encodes the ATP-binding-cassette transporter A1 involved in reverse cholesterol transport, and rare variants in the same gene that are linked to familial hypoalphalipoproteinemia and Tangier disease and have been unable to demonstrate a relationship between decreased plasma HDL-C levels in affected individuals and increased CHD risk.

In contrast to LDL-C, the collective genetic data suggest that HDL-C is not causal for CHD risk, at least in a simplistic sense. Although the data cannot rule out that there are some biological mechanisms that lead to increased plasma HDL-C levels that also protect against CHD, it seems fair to conclude that not all interventions that raise HDL-C will reduce CHD risk. Further support for this conclusion is provided by RCT (randomized controlled) data, most notably with the cholesteryl ester transfer protein (CETP) inhibitors, which substantially raise plasma HDL-C levels. Three inhibitors of CETP—torcetrapib, dalcetrapib, and evacetrapib—all raised HDL- C substantially, and each failed to reduce risk for CHD in large-scale RCTs. All 3 studies— the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial of torcetrapib, which increased HDL-C by 70%; the dal- OUTCOMES trial of dalcetrapib, which increased HDL-C by 30%; and the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High-Risk for Vascular Outcomes (ACCELERATE) trial of evacetrapib, which was projected to raise HDL-C by > 90%—were all terminated prematurely because of lack of clinical efficacy. Indeed, torcetrapib seemed to result in increased cardiovascular events and death, although this has been attributed to off-target, nonlipid-related effects of this particular medication.

Source: Circ Res. 2016 Feb 19;118(4):579-85.


The CANHEART study showed that HDL lower than 30 mg/dL increase risk of death caused by cardiovascular disease and cancer. The higher HDL levels over 70 did not seem as protective as 40-70.

Source


For more discussions on HDL and TRT, click on these links:

Testosterone Decreased HDL: What Can I Do?

 

[Nelson Vergel]

Testosterone, HDL and cardiovascular risk in men: the jury is still out

Page, Stephanie T, and Katya B Rubinow. "Testosterone, HDL and cardiovascular risk in men: the jury is still out." Clinical Lipidology Aug. 2012: 363+. Health Reference Center Academic. Web. 7 July 2015.

Testosterone-replacement therapy in older men with aging-associated hypogonadism remains an area of substantial clinical controversy. Although improvements in strength, quality of life and stamina have been observed [1] , reluctance to more broadly prescribe testosterone replacement derives, in part, from concern that replacement therapy may augment cardiovascular risk in men. One basis for this concern is the observation that exogenous testosterone can decrease serum levels of HDL-cholesterol (HDL-C). As low HDL-C is a well recognized risk factor for cardiovascular disease (CVD), this HDL-C-lowering effect could augment risk and therefore argue against widespread use of testosterone-replacement therapy in clinical practice. Importantly, however, the impact of exogenous testosterone on HDL-C levels is not uniform and appears to vary substantially with variables, including patient age and both the dose and route of androgen administration [2] . Thus, the HDL-C-lowering effects of testosterone observed in some clinical or research settings might not be relevant to the use of testosterone for physiologic replacement therapy in older men. Moreover, recent clinical data demonstrate the possible dissociation of HDL-C levels and cardiovascular risk, undermining the assumption that an intervention that reduces HDL-C necessarily translates into augmented risk. Finally, the historical focus on HDL-C alone fails to account for the remarkable complexity of HDL particle composition, particularly with regard to the modifiable protein cargo that likely confers the functional properties of HDL.

Direct evidence for the HDL-C-lowering effect of testosterone derives principally from observations of men using androgenic-anabolic steroids for athletic enhancement [3] . This effect has been achieved consistently with the administration of supraphysiologic doses of oral androgens to young men [2] , but has been far less consistent when testosterone therapy has been used at physiologic doses to restore eugonadal serum levels, particularly in older men [4,5] . Moreover, the lipid-related effects of exogenous testosterone appear highly contingent on whether parenteral or oral routes of administration are employed. Oral testosterone administration significantly reduced HDL-C levels in young, healthy men [6] , whereas when older, hypogonadal men were treated with transdermal testosterone, we found no significant changes in HDL-C after 3 months of therapy [5] . These disparate effects may be a consequence, in part, of first-pass hepatic metabolism that occurs with oral but not parenteral administration. In addition, the HDL-C-lowering effect of testosterone may be offset, at least partially, by aromatase-mediated conversion of testosterone to estradiol, as estradiol can raise HDL-C levels in men [7] , and coadministration of intramuscular testosterone with an aromatase inhibitor led to significant decreases in HDL-C [8] . Increased adiposity and associated aromatase activity in older men could thus play a mitigating role in the androgen-mediated reductions in HDL-C seen in this population. Accordingly, more clinical studies are necessary in order to better define those populations of men at greatest risk of lipid-related effects of testosterone therapy and to determine the testosterone regimens that are least likely to confer seemingly adverse changes in lipid profiles.

Even when reductions in HDL-C are observed as a consequence of androgen therapy, the implications for cardiovascular risk modification remain highly uncertain [2] . Whereas an inverse relationship between HDL-C levels and cardiovascular risk has been demonstrated clearly on a population basis [9] , the utility of HDL-C as a biomarker of individual cardiovascular risk has increasingly fallen into question. Underscoring the limitations of assessing HDL-C alone, recent clinical trials have found no decrease in cardiovascular event rate despite significant and substantial increments in HDL-C after treatment intervention in subjects with pre-existing CVD; indeed, the CETP inhibitor torcetrapib raised HDL-C levels by 72% but was associated with an increased rate of cardiovascular events [10] . Conversely, no long-term data have established that the reduced HDL-C levels observed in men receiving testosterone lead to an increased incidence of CVD. Rather, clinical data strongly suggest that men with low circulating levels of testosterone are at greater risk of CVD [11] . These apparently discrepant findings regarding HDL-C and CVD risk may eventually be resolved as the complexity of HDL biology becomes better understood. Currently, research efforts are expanding to incorporate alternative metrics of HDL composition and function, such that HDL-C content is incorporated into a larger context of particle protein, triglyceride and phospholipid content, as well as quantitative measures of HDL's pleiotropic functions.

A primary role of HDL-C is that of reverse cholesterol transport, the process whereby HDL particles accept cholesterol from peripheral tissues and transport it to the liver for excretion in bile. These peripheral cholesterol donors include lipid-laden macrophages, which may otherwise deposit cholesterol in the artery wall and contribute to atherogenesis. Rader, Rothblat and colleagues have developed an assay that measures the capacity of serum HDL to efflux cholesterol from macrophages and demonstrated reduced efflux capacity in patients with existing coronary artery disease [12] . Furthermore, investigators found marked interindividual variation in HDL-mediated efflux among subjects with identical HDL-C levels, underscoring the potential dissociation between HDL-C and HDL function [13] . As in vitro data suggest mechanisms by which testosterone could accelerate reverse cholesterol transport [14] , a lower HDL-C level could reflect altered kinetics of cholesterol transport that would actually reduce cardiovascular risk. Thus, these data illustrate the difficulty of drawing inferences about HDL function on the basis of HDL-C alone.

Ongoing research efforts are similarly exploring alternative strategies for assessing the relationship between HDL and CVD, including measurement of HDL particle number and size, determination of HDL protein cargo and assays of other HDL functions [5,15] . For example, our research has generated the novel finding that testosterone replacement in older, hypogonadal men confers changes in the protein composition of HDL particles in the absence of changes in HDL-C [5] . Although we did not observe attendant changes in HDL-cholesterol-efflux capacity, HDL particles also mediate lipid peroxidation, endothelial cell nitric oxide production and immunomodulatory functions [15,16] . The development of new methods to examine the variable composition of HDL therefore promises to offer more nuanced insights into HDL biology overall and, specifically, into the undoubtedly intricate relationships between circulating androgens and HDL composition and function.

In contrast to the historical concern that testosterone might increase cardiovascular risk in men, mounting data now demonstrate elevated risk to be associated with low androgen states [17,18] . This elevated risk is strikingly prominent among men who have undergone androgen-deprivation therapy (ADT) for treatment of prostate cancer, as these men exhibit a two- to three-fold higher incidence of stroke and myocardial infarction, as well as an increased risk of cardiovascular-related mortality after ADT exposures as brief as 6 months [19] . Furthermore, this elevated risk is manifested despite the inconsistent but not infrequent observation of increased HDL-C levels with ADT [19] . However, intervention trials have yielded inconsistent findings. In one study of frail, elderly men, those who received testosterone replacement experienced significantly more cardiovascular events despite gains in mobility and strength [20] . Nonetheless, no increased cardiovascular risk was evident in a similarly designed trial [1] . These conflicting data thus highlight the importance of extending our focus beyond a single HDL-associated metric in order to understand the full scope of testosterone's effects on HDL and the associated implications for cardiovascular risk. In addition, analogous to the Women's Health Initiative, large-scale clinical studies in men are needed to help define specific populations of men who are most likely to benefit from replacement therapy and, further, to establish optimal parameters for the timing, dose and duration of testosterone treatment. As yet, however, the role of testosterone in modifying lipoprotein function and cardiovascular risk in men remains highly uncertain and constitutes an intriguing area of emergent research.

References

1 Srinivas-Shankar U, Roberts SA, Connolly MJ et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 95, 639-650 (2010).

2 Shabsigh R, Katz M, Yan G, Makhsida N. Cardiovascular issues in hypogonadism and testosterone therapy. Am. J. Cardiol. 96, M67-M72 (2005).

3 Basaria S. Androgen abuse in athletes: detection and consequences. J. Clin. Endocrinol. Metab. 95, 1533-1543 (2010).

4 Ozata M, Yildirimkaya M, Bulur M et al. Effects of gonadotropin and testosterone treatments on lipoprotein(a), high density lipoprotein particles, and other lipoprotein levels in male hypogonadism. J. Clin. Endocrinol. Metab. 81, 3372-3378 (1996).

5 Rubinow KB, Vaisar T, Tang C et al. Testosterone replacement in hypogonadal men alters the HDL proteome but not HDL cholesterol efflux capacity. J. Lipid Res. 53(7), 1376-1383 (2012).

6 Amory JK, Kalhorn TF, Page ST. Pharmacokinetics and pharmacodynamics of oral testosterone enanthate plus dutasteride for 4 weeks in normal men: implications for male hormonal contraception. J. Androl. 29, 260-271 (2008).

7 Bagatell CJ, Knopp RH, Rivier JE, Bremner WJ. Physiological levels of estradiol stimulate plasma high density lipoprotein 2 cholesterol levels in normal men. J. Clin. Endocrinol. Metab. 78, 855-861 (1994).

8 Friedl KE, Hannan CJ Jr, Jones RE, Plymate SR. High-density lipoprotein cholesterol is not decreased if an aromatizable androgen is administered. Metabolism 39, 69-74 (1990).

9 Boden WE. High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the veterans affairs high - density lipoprotein intervention trial. Am. J. Cardiol. 86, 19L-22L (2000).

10 Barter PJ, Caulfield M, Eriksson M et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109-2122 (2007).

11 Keating NL, O'Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J. Natl Cancer Inst. 102, 39-46 (2010).

12 Khera AV, Cuchel M, de la Llera-Moya M et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364, 127-135 (2011).

13 de la Llera-Moya M, Drazul-Schrader D, Asztalos BF et al. The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arterioscler. Thromb. Vasc. Biol. 30, 796-801 (2010).

14 Langer C, Gansz B, Goepfert C et al. Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochem. Biophys. Res. Commun. 296, 1051-1057 (2002).

15 Besler C, Heinrich K, Rohrer L et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J. Clin. Invest. 121, 2693-2708 (2011).

16 Gordon SM, Hofmann S, Askew DS, Davidson WS. High density lipoprotein: it's not just about lipid transport anymore. Trends Endocrinol. Metab. 22, 9-15 (2010).

17 Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J. Clin. Endocrinol. Metab. 93, 68-75 (2008).

18 Vikan T, Johnsen SH, Schirmer H et al. Endogenous testosterone and the prospective association with carotid atherosclerosis in men: the Tromsø study. Eur. J. Epidemiol. 24, 289-295 (2009).

19 Shahani S, Braga-Basaria M, Basaria S. Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. J. Clin. Endocrinol. Metab. 93, 2042-2049 (2008).

20 Basaria S, Coviello AD, Travison TG et al. Adverse events associated with testosterone administration. N. Engl. J. Med. 363, 109-122 (2010).