Julian Kaye, PhD

Topical or depot formulations of testosterone replacement therapy (TRT), indicated for hypogonadal men with low serum testosterone levels, are associated with several potential impediments to proper and efficient use, including inadvertent testosterone transfer, messy application (for testosterone gels), poor long-term adherence/retention rates, and superphysiologic testosterone levels in some patients.

According to the authors of “Efficacy and Pharmacokinetics of LPCN 1021, a Novel Oral Testosterone Replacement Therapy (TRT), in Hypogonadal Men: Study of Androgen Replacement (SOAR),” 

 at ENDO 2015, because of these factors there is a need for testosterone formulations “that are more user-friendly, limit blood level dose excursions and avoid testosterone transdermal transfer.”

Christina C. Wang, MD, professor in the Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Harbor-UCLA Medical Center & Los Angeles Biomedical Research Institute, presented results from the SOAR phase 3 trial involving LPCN 1021, a novel oral testosterone undecanoate formulation

SOAR is a randomized, active-controlled, 12-month, open-label, multicenter, dose-titration trial that included men age 18-80 with testosterone levels <300 ng/dL (measured on two separate days in the morning) who were diagnosed prior to age 65. Treatment-naïve patients and participants who received TRT patients after washout, were randomized to either oral LPCN 1021 (n=210) or to Androgel 1.62% (n=105).

Initial LPCN 1021 dose was 225 mg BID taken with a meal. The dose could be titrated up (eg, if testosterone C

 <300 mg/dL) or titrated down (eg, if testosterone C

 was >1500 mg/dL) at weeks 4 and 8 based on 24-hour pharmacokinetics (PK). Researchers assessed efficacy at week 13 based on testosterone C

 from serum samples. Safety assessment was continued out to 52 weeks.

Wang and her colleagues observed that “LPCN 1021 reliably restored and maintained testosterone levels in the eugonadal range (300-1140 ng/dL) in 88.2% of hypogonadal men. Mean (SD) testosterone C

 was 447 (166) ng/dL, consistent with other non-oral TRT therapies.”

The researchers noted there was no significant dose timing effect, suggesting consistent intra-day performance. Overall variability was low (37% CV for C

); 82.9% of subjects had peak serum testosterone (C

 1800-2500 ng/dL, and 2% had serum testosterone levels >2500 ng/dL. The authors described the cases in the last group as “sporadic, transient, and isolated, with no associated clinical events.” Eighty-five percent of subjects required one or fewer dose adjustments, suggesting “a safe and effective titration algorithm.” No serious adverse events were reported during the study.

Based on these findings, the authors concluded that LPCN 1021 is associated with “acceptable C

 excursions, consistent with US FDA required targets met by other non-oral TRT products.” Several characteristics of LPCN 1021 may improve patient adherence compared to topical, transdermal, injectable, or implanted TRT products.

After the presentation, one questioner remarked that it is difficult to titrate dosage in regular clinical practice and asked if there is a clinical plan for administration of the product during routine practice, including a recommended interval for sampling for testosterone.

Wang said she was an investigator and could not speak for the sponsor (Lipocine). She said that when the clinical trials are concluded, the PK data will have to be evaluated to determine the optimal time for administration and monitoring. She also noted that the ambulatory effects on testosterone sampling had to be taken into consideration.

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Treatment with LPCN 1021 restored and maintained testosterone levels at rates comparable to approved non-oral products. 

Novel Oral Testosterone Replacement Therapy Is Safe and Effective in Clinical Trials

Prior studies have reached mixed conclusions regarding the cardiovascular (CV) safety profile of testosterone replacement therapy in men. According to the authors of a 

 presented at ENDO 2015, this uncertainty particularly holds true for older men with preexisting coronary heart disease. This has been “heightened by recent retrospective analyses of observational data. Prior studies, including relatively small prospective clinical trials of hypogonadal men, have yielded conflicting results.”

For the study, Salim Janmohamed, BSc, MB BS, FRCP, and colleagues examined data from two large, international, double-blind, placebo-controlled randomized clinical trials that evaluated the effect of the lipoprotein phospholipase A2 inhibitor darapladib on ischemic events. The trials enrolled men and women with a history of stable coronary heart disease (n=15,828; the STABILITY trial) or recent acute coronary syndrome (n=13,026; the SOLID-TIMI 52 trial).

Participants received treatment that met the ‘standard of care’ for cardiovascular risk factors. Researchers monitored participants for major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarct and non-fatal stroke). Patients in the STABILITY and SOID-TIMI 52 trials were followed for a median period of 3.7 and 2.5 years, respectively, after the conclusion of the studies.

Analysis of study data showed that darapladib “did not significantly reduce the risk of CV events.” Researchers assessed the risk of MACE in men who received testosterone replacement therapy (TRT) for less than one year and in men who received TRT for 12 months or longer and compared this to men who did not receive TRT, using combined data from both trials. Calculations were adjusted for a variety of factors, including treatment group, age, BMI, HDL/Total Cholesterol ratio, systolic blood pressure, GFR, diabetes, aspirin use, statin use, smoking status, and geographic region.

Janmohamed pointed out that TRT use among male trial subjects was low (n=217, 1%) and that most (83%) usage was by US men. The majority of MACE events (n=1412, 57%) were myocardial infarctions. Men exposed to TRT for less than or equal to 12 months had a hazard ratio of 0.48 (95% CI: 0.15, 1.49) (p=0.21) compared to those not exposed to TRT. Men exposed to TRT for greater than 12 months had a hazard ratio of 0.47 (95% CI: 0.25, 0.87) (p=0.02) compared to those not exposed to TRT.

Based on their analysis, the authors concluded these data “suggest that TRT is not associated with an increased risk of MACE in men with well-characterized coronary heart disease. The incidence of MACE was 11.1% in non-testosterone treated males and 7.9% in males on TRT.”

This retrospective analysis had several limitations, particularly the small numbers of male subjects exposed to TRT in each trial and the lack of ascertainment of gonadal status. However, the authors wrote that “these data do not corroborate recent observational reports that testosterone therapy is associated with increased CV risk.”

Discussion during the question and answer session was focused around the ages and the overall health of the subjects; particularly those men receiving TRT. Janmohamed said the latter tended to be overweight and diabetic.

There were also questions and comments about participants’ baseline characteristics. TRT patients were likely to have adverse baseline parameters and therefore an increased risk of disease. One audience member opined that testosterone deficiency is associated with poor health.

Disclosure: the authors of this study were all 

Study results show that men with stable coronary heart disease or acute coronary syndrome who received testosterone replacement therapy did not experience higher rates of major adverse cardiovascular events than men who did not receive testosterone replacement therapy.

Testosterone Replacement Therapy Not Associated with Increased Risk of Cardiovascular Events in Men

Studies have shown that both low and high circulating testosterone levels are associated with atherosclerosis in men and are risk factors for cardiac and cerebrovascular events.

At ENDO 2015, Reshmi Srinath, MD, fellow in the Department of Endocrinology, Diabetes & Metabolism at Johns Hopkins University School of Medicine, presented results from the Atherosclerosis Risk in Communities (ARIC) 

, a large ongoing prospective multicenter cohort of people aged 45-64 years at baseline initiated in 1987 to evaluate risk factors associated with incident cardiovascular disease (CVD).

Srinath and her colleagues evaluated a cohort of male ARIC participants who were free of CVD (including stroke) and without prior testosterone therapy to determine if low testosterone is independently associated with incident cerebrovascular events and the presence of ischemic changes on brain magnetic resonance imaging (MRI).

In the cohort (n=1558) researchers measured plasma total testosterone by liquid chromatography mass spectrometry (LC-MS) using samples obtained in the morning. The mean [SD] plasma total testosterone for the group was 401 [165] ng/dL.

They used the Cochran-Armitage test for trend and general linear regression models to assess the cross-sectional association of testosterone quartile with demographic characteristics and cardiovascular risk factors. They performed proportional hazard regression analysis to assess the association of testosterone quartiles with incident stroke through 2011.

A subset of participants underwent brain MRI at visit 5 (2011-2013) with semiquantitative evaluation of white matter hyperintensities (WMH) as well as cerebral infarcts (cortical or subcortical). Linear and logistic regression models were used to assess the association of testosterone quartiles with these ischemic changes. Multivariable regression analysis was adjusted for age, race and ARIC study center, body mass index (BMI), waist circumference, smoking status, diabetes, hypertension, LDL and HDL.

Srinath presented the following results: In the 1558 males (mean [SD] age = 63.1 [5.6] years, BMI = 28.2 [4.27] kg/m

) the median (interquartile range) plasma testosterone was 377.6 (288.4 - 480.1) ng/dL. Lower testosterone was significantly associated with higher BMI, greater waist circumference, the presence of diabetes, hypertension, lower HDL, and never smoked. Median follow-up for incident stroke was 14.1 years.

Following multivariable adjustment, there was no association of testosterone quartile (Q) with incident stroke (hazard ratios [95% CIs]) for Q1-Q3, each vs. Q4: 1.08 [0.56-2.08], 0.85 [0.44-1.66], 0.65 0.33-1.30]). Similarly there was no association of testosterone quartile with WMH (results not provided), or with cortical and subcortical infarcts on brain imaging (odds ratios [95% CIs] for Q1-Q3, each vs. Q4: 0.65 [0.28-1.49], 0.65 [0.29-1.45], 0.54 [0.26-1.16]).

Srinath and her collaborators concluded that, after controlling for key CVD risk factors, there was no association between endogenous testosterone and incident stroke and ischemic changes/WMH on brain MRI imaging in men within the ARIC cohort.

Srinath noted that this study had certain limitations. For example, only a single sample was taken from each subject for plasma testosterone determination, although the time of day was standardized, and there were a limited number of stroke events.

A member of the audience suggested considering a study to examine risk in testosterone deficiency. A questioner mentioned his own study in older men that found that low testosterone was a predictor for stroke and asked if the cohort in the present study was younger and/or homogeneous. Srinath said the mean age was about 63 years and white and black subjects were equally distributed.

Another asked if SHBG was measured. Srinath said the assay was not available for the study and therefore free testosterone could not be determined.

Researchers reported no association between endogenous testosterone and incident stroke and ischemic changes in men evaluated via brain MRI imaging.

Testosterone Levels Not Associated with Stroke Risk 

of cardiovascular disease (CVD) compared to premenopausal women, suggesting that testosterone may increase the risk of and/or that estradiol may protect against CVD. Studies that have examined the roles played by androgens and estrogens in known CVD risk factors and other metabolic factors have produced highly variable results.

At Endo 2015, Elaine Wei-Yin Yu, MD, MSc, assistant professor of medicine at Massachusetts General Hospital in Boston, MA, presented results from a study that examined the effects of testosterone and estradiol on cholesterol, leptin, and fasting glucose levels, among other markers of CVD risk in a cohort of men treated with testosterone replacement therapy.

Yu and her colleagues at Massachusetts General Hospital recruited two cohorts of healthy men aged 20-50 years. All men received the gonadotropin releasing hormone superagonist (GnRH agonist) goserelin acetate (3.6 mg q4wk) to suppress endogenous testosterone and estradiol. Men in Cohort 1 (n=198) were randomized to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily for 16 weeks. Men in Cohort 2 (n=202) received the same regimen plus 1 mg/d of the aromatase inhibitor anastrozole to block the conversion of testosterone to estradiol. Yu mentioned that aromatase activity accounts for 80% of endogenous estrogen production in men.

The researchers measured fasting serum leptin, lipids, glucose and HOMA-IR (homeostatic model assessment and insulin resistance) every 4 weeks. They measured intramuscular fat (at the thigh) at baseline and 16 weeks. Changes were assessed between testosterone dose groups within Cohort 2 to assess testosterone effects, and between Cohorts 1 and 2 to assess estradiol effects.

Yu said the dosing regimen was designed to achieve mean serum testosterone levels ranging from prepubertal to high-normal and were similar in both cohorts. Mean testosterone levels were, respectively, 44, 191, 337, 470, and 805 ng/dL in Cohort 1 vs. 41, 231, 367, 485, and 924 ng/dL in Cohort 2 at testosterone doses of 0, 1.25, 2.5, 5, and 10 gm of testosterone/day; p=NS at each dose level.

Mean serum estradiol levels increased progressively with testosterone dose escalation in Cohort 1 (3.6, 7.9, 11.9, 18.2, and 33.3 pg/mL) but remained <3 pg/mL in all dose groups in Cohort 2 (P<0.001 between cohorts).

Both serum HDL and leptin levels showed a marked inverse association with testosterone dose in both cohorts (p<0.001 for all). This relationship was not altered by suppressing estrogen production, indicating that testosterone alone regulates these measures.

In contrast, fasting glucose, HOMA-IR, and intramuscular fat increased similarly in all men in Cohort 2, regardless of testosterone dose group, and were significantly higher than in Cohort 1 (P<0.05 for all groups), indicating that estradiol primarily regulates these measures. Changes in blood pressure, LDL, and body weight were not significantly associated with either testosterone or estradiol levels.

Based on these observations, Yu and her colleagues concluded that although worsening of insulin resistance and accumulation of body fat due to low estrogen levels are consistent with the higher rates of CVD seen in men, other risk factors such as changes in LDL and blood pressure do not appear to be regulated by gonadal steroids. In the abstract summarizing their findings, the researchers wrote, “Even though leptin is made by adipocytes, its circulating level is regulated exclusively by androgens in men. These findings may contribute to a better understanding of the roles of androgens and estrogens in gender differences in CVD.”

On this last point, a member of the audience commented that there was no group of patients treated with estradiol alone to investigate this further. Yu confirmed that there was no estrogen-treated cohort in the study.

Study results presented at ENDO 2015 suggest that some risk factors associated with cardiovascular disease are regulated by testosterone and estradiol, others (such as changes in LDL cholesterol and blood pressure) are not.

Julian Kaye, PhD

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