Testosterone In Pill Form

Testosterone In Pill Form

Sex Med. 2015 Sep; 3(3): 165–173.

Comparison of the Effects of Testosterone Gels, Injections, and Pellets on Serum Hormones, Erythrocytosis, Lipids, and Prostate-Specific Antigen

Alexander W Pastuszak

^*Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

^†Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, USA

Lissette P Gomez

^*Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

^†Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, USA

Jason M Scovell

^*Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

Mohit Khera

^*Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

Dolores J Lamb

^*Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

^†Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, USA

^‡Department of Cell Biology, Baylor College of Medicine, Houston, TX, USA

Larry I Lipshultz

^*Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

^†Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, USA

This article has been cited by other articles in PMC.

Supplementary Materials

Figure S1 Changes in lipid parameters during TTh.

Changes in (A) total cholesterol, (B) Triglycerides, (C) LDL Cholesterol, and (D) HDL Cholesterol were assessed over time as a function of T formulation.

Table S1 Summary serum data during follow-up.

GUID: 0189721C-2B7C-4147-BABD-64BAED48A501

Abstract

Introduction

Numerous testosterone (T) formulations are available, each with differing effects on serum parameters.

Aim

The aim of this study was to compare the long-term effects of topical, injectable, and implantable pellet T formulations in hypogonadal men.

Methods

Retrospective review of hypogonadal men treated with a single T formulation was performed: 47 men on T gels, 57 on injectable T, and 74 on T pellets were identified. Total T (TT), calculated free T (FT), estradiol (E), hemoglobin (Hgb), hematocrit (Hct), prostate-specific antigen (PSA), total cholesterol (Tchol), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol were evaluated at baseline and every 3–6 months for 3 years. Serum parameters were compared using a mixed model linear regression for repeated measures.

Main Outcome Measures

Effects of topical, injectable, and pellet T formulations on serum hormone levels, Hgb, Hct, lipid parameters and PSA.

Results

Men in the injectable T group were younger (42.5 ± 12.3 years) than in the gel (54.1 ± 9.8 years) or pellet groups (53.8 ± 13.0 years), and baseline FT, Hgb, and Hct were higher in the injectable T group than in gel or pellet groups. Increases in TT and FT were observed throughout follow-up in all groups. Increases in E were observed at in all T groups and throughout follow-up in injectable and gel groups. No PSA increases were observed. Erythrocytosis (Hct > 50%) was more common with injectable T (66.7%) than with T gels (12.8%) or pellets (35.1%, P < 0.0001). Transient changes in cholesterol, TG, and LDL were observed, and no significant changes were seen in HDL for any group.

Conclusions

All T formulations increase serum T and FT. More significant increases in E occur with injectable T and T gels. Changes in Hgb and Hct are most significant with injectable T, and effects on lipids are variable and inconsistent. Selection of T formulations must account for individual patient preferences and the effects of each formulation.

Keywords: . Testosterone Therapy, Testosterone Pellets, Testosterone Gel, Testosterone Injections, Erythrocytosis, Lipid Panel, Prostate Cancer

Introduction

Hypogonadism affects approximately 2–4 million men in the United States, and is characterized by low serum testosterone (T) levels in association with signs and symptoms of hypogonadism including fatigue, decreased libido, erectile dysfunction, depression, anemia, and decreased muscle mass and bone density [1],[2]. In addition to ameliorating hypogonadal symptoms [1],[3], T therapy (TTh) can lead to increased muscle mass and bone density 4–6, and reversal of the metabolic syndrome [2],[7]. However, TTh is associated with potential adverse effects including elevated serum estrogen levels, gynecomastia, local reactions, alterations in serum lipids, erythrocytosis, testicular atrophy, male infertility, and cardiovascular effects 1,2,8–11.

Numerous T formulations are Food and Drug Administration approved in the United States for the treatment of hypogonadism. Several commonly used T formulations include injectables, transdermal gels, and implantable pellets [12]. While all T preparations are effective, the likelihood of associated side effects is determined by dosage, pharmacokinetics, and method of administration [12],[13]. As such, the selection of T preparation should be a joint decision between the patient and physician, and includes consideration of treatment efficacy, cost, acceptability of the therapy by the patients, and likelihood of specific adverse effects [2],[12]. However, a relative dearth of long-term data directly comparing the effects of T formulations in men on TTh limits physicians' ability to counsel their patients. To better understand how various T formulations impact not only serum T levels, but also the likelihood of related adverse effects, we retrospectively compared the long-term effects of injectable, transdermal, and subcutaneous T pellet formulations in hypogonadal men.

Aims

We sought to compare the long-term effects of topical, injectable, and implantable pellet T formulations in hypogonadal men on serum hormone, hemoglobin (Hgb), hematocrit (Hct), lipid, and prostate-specific antigen (PSA) levels. Our goal was to assess the unique and common effects of each T formulation in order to better inform selection of T formulations for individual patients. We hypothesized that different T formulations would have varying effects on both serum hormone parameters as well as the likelihood of adverse events.

Methods

Patient Identification and Data Acquisition

After approval by the Institutional Review Board of Baylor College of Medicine, retrospective review of hypogonadal men treated with a single T formulation between 2007 and 2012 was performed. Only men that were T naïve or those who had been off of T for 3 or more months prior to restarting TTh were included in the analysis. Men were diagnosed with hypogonadism using both clinical symptoms of hypogonadism, including erectile dysfunction, decreased libido, and/or decreased energy, as well as evidence of low serum T (≤350 ng/dL). All included men were diagnosed with secondary hypogonadism. We identified 47 men treated with T gels, 57 with injectable T, and 74 with subcutaneous T pellets that met our inclusion criteria. Men using T gels applied drug daily based on manufacturer's recommendations (Testim® 50–100 mg T [one to two packets applied to the shoulder area daily; Endo, Ballsbridge, Ireland], Androgel® 1.62% 20.25–80.1 mg T [two to four pumps applied to the skin daily; AbbVie, North Chicago, IL, USA]), and men on T pellets (75 mg crystalline T/pellet) were implanted with 10–14 pellets to achieve a peak serum T level of 500–800 ng/dL every 3–6 months [14]. Men on injectable T formulations injected 100–200 mg of T cypionate or enanthate intramuscularly weekly. If men developed serum estradiol (E) levels >5 pg/mL, the upper limit of our lab's reference range, they were treated with oral aromatase inhibitor (AI).

Patient demographics, total T, free T (FT), E, Hgb, Hct, PSA, total cholesterol (Tchol), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were evaluated at baseline and every 3–6 months for 3 years. All samples were analyzed in the Laboratory for Male Reproductive Research and Testing at Baylor College of Medicine on a single Beckman Coulter Access2 assay system (Beckman Coulter, Brea, CA, USA). Hormone levels were determined using enzyme-linked immunoassay. As the definition for erythrocytosis in the literature ranges from 50–54%, we defined erythrocytosis as Hct ≥50%, which we use in clinical practice to identify patients requiring therapeutic phlebotomy or T dose adjustment.

Statistical Analysis

Baseline and follow-up serum values were compared within each group using a mixed model linear regression for repeated measures. Erythrocytosis rates were determined and compared between groups, and the time to development of erythrocytosis in each group was determined by averaging the time it took for subjects to develop Hct ≥50%. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) for Mac Version 22 (IBM Corporation, Armonk, NY, USA) with P < 0.05 considered statistically significant.

Main Outcome Measures

The primary outcomes of this study were the effects of T topical, injectable, and pellet formulations on serum hormone levels. Secondary outcomes included the effects of the above T formulations on Hgb, Hct, lipid parameters, and PSA levels.

Results

At baseline, men in the injectable T group were younger (42.5 ± 12.3 years) than in the T gel or T pellet groups (54.1 ± 9.8 and 53.8 ± 13.0 years, respectively, P < 0.001) (Table1). More men in the T pellet group had hypertension and hyperlipidemia at baseline, and more men in the T gel group had erectile dysfunction. Baseline FT, Hgb and Hct were slightly higher in the injectable T group than in the T gel or T pellet groups (Table2). No significant differences were observed in other serum parameters at baseline. Increases in mean T and FT levels were observed beginning at 3 months after TTh initiation and persisted throughout 3 years of follow-up in all T formulation groups (Figure1, Supplementary Table S1). Overall, TT and FT levels were significantly higher in men receiving injectable T than in T gel or pellet groups.

Table 1

Cohort demographics

	T gels	Injectable T	T pellets
	n = 47	n = 57	n = 74	P value
Characteristics (mean [SD])
Age at start of rx (years)	54.1 (9.8)	42.5 (12.3)	53.8 (13.0)	0.001
Follow-up (months)	26.2 (10.6)	29.8 (8.8)	28.2 (8.6)	0.145
Range of follow-up (months)	2.7–55.8	7.1–41.1	4.3–41.0
T naïve men	41 (87.2)	36 (63.2)	33 (44.6)
Men off T for ≥3 months	6 (12.8)	21 (36.8)	41 (55.4)
Comorbidities (n[%])
Diabetes mellitus	3 (6.4)	5 (8.8)	11 (14.9)	0.288
Hypertension	6 (12.8)	3 (5.3)	18 (24.3)	0.009
Hyperlipidemia	5 (10.6)	5 (8.8)	25 (33.8)	0.003
Prostate cancer	6 (12.8)	4 (7.0)	8 (10.8)	0.609
Erectile dysfunction	32 (68.1)	19 (33.3)	37 (50)	0.002

Table 2

Baseline serum values

Baseline hormones	T gels mean (SD)	Injectable T mean (SD)	T pellets mean (SD)	P value
Total testosterone (ng/dL)	300 (89.6)	306 (164.0)	268 (167.4)	0.297
Free testosterone (ng/dL)	5.9 (1.6)	7.5 (5.0)	5.7 (3.8)	0.033
Estradiol (pg/mL)	2.66 (0.96)	2.71 (1.36)	2.80 (1.77)	0.876
PSA (ng/mL)	0.879 (0.72)	0.725 (0.53)	1.237 (1.48)	0.096
Hemoglobin (g/dL)	15.1 (1.1)	15.6 (1.3)	14.9 (1.2)	0.008
Hematocrit (%)	44.6 (3.1)	46.0 (3.7)	44.3 (3.3)	0.024
Total cholesterol (mg/dL)	191 (45.1)	180 (40.1)	189 (40.2)	0.404
Triglycerides (mg/dL)	206 (205.4)	180 (116.9)	205 (215.2)	0.743
LDL cholesterol (mg/dL)	106 (35.4)	100 (37.5)	106 (33.2)	0.655
HDL cholesterol (mg/dL)	47 (11.1)	43 (12.1)	47 (11.6)	0.16

Changes in serum testosterone (T) and free testosterone (FT) levels during testosterone therapy (TTh). Changes in (A) serum total T, and (B) serum FT were assessed as a function of time and T formulation. *P < 0.05, **P < 0.001.

Significant increases in E were observed in the injectable T group beginning at 3 months and persisted throughout the follow-up period. E levels were also consistently increased from baseline in the T gel group throughout follow-up, as well as after 3–6 months of follow-up with T pellets (Figure2). Men with E levels >5 pg/mL were treated with AIs, with 1, 12, and 22 men in the T gel, injectable T, and T pellet groups requiring therapy. A sensitivity analysis excluding AI-treated men did not significantly affect E levels during follow-up in any group (data not shown). E levels in AI-treated men normalized in all patients. Multivariate analysis demonstrated that only T level (P = 0.01), and not age (P = 0.126) or body mass index (BMI) (P = 0.813), affected E levels in all T formulation groups, with higher E levels in subjects with higher T levels.

Changes in serum estradiol (E levels during testosterone therapy (TTh). Changes in serum estradiol were assessed as a function of time and testosterone (T) formulation. *P < 0.05, **P < 0.001.

A significant concern in men on TTh is that exogenous T will increase the risk of developing prostate cancer (CaP) or its progression. We evaluated the risk of CaP incidence or progression as a function of T formulation. There were 18 men in our cohort with a prior history of CaP, and all had been treated with either radical prostatectomy or radiation therapy; no men were on active surveillance. No significant PSA increases were observed in any T formulation group, regardless of whether patients had a history of CaP (Table3). Only one subject in the T pellet group had a new diagnosis of CaP during the study, and was diagnosed with Gleason 3 + 4 CaP 2 years after TTh initiation. There were no CaP recurrences in any of the subjects with a history of CaP during the follow-up period.

Table 3

Changes in PSA by T formulation and CaP status

T formulation	Baseline PSA (ng/mL)	Final follow-Up PSA (ng/mL)	P value
	Mean (SD)	Mean (SD)
Gels (n = 47)	0.90 (0.72)	1.02 (0.83)	0.52
With CaP (n = 6)	0.06 (0.12)	0.01(0.001)	0.51
Without CaP (n = 41)	1.05 (0.67)	1.23 (0.76)	0.43
Injectables (n = 57)	0.73 (0.53)	0.73 (0.47)	0.99
With CaP (n = 4)	0.01 (0.00)	0.01 (0.00)	1.00
Without CaP (n = 53)	0.78 (0.51)	0.86 (0.39)	0.55
Pellets (n = 74)	1.24 (1.48)	1.41 (1.31)	0.54
With CaP (n = 8)	0.65 (1.45)	0.04 (0.05)	0.81
Without CaP (n = 66)	1.31 (1.48)	1.46 (1.28)	0.60

Erythrocytosis is a common adverse effect of TTh, with variable incidence as a function of T formulation. Significant increases in Hgb were observed by 6 months after TTh initiation in the injectable T and T gel groups, and by 9 months after TTh initiation in the T pellet group (Figure3). At 9 months, when Hgb plateaus in all groups, the mean ± SD increase in Hgb was 1.06 ± 1.40 g/dL in the injectable T group, and this increase was comparable with the mean increase in the T gel and pellet groups 0.79 ± 0.94 and 0.81 ± 1.15 g/dL, respectively, (P = 0.598, Table4). Similarly, significant increases in Hct were observed by 3 months after TTh initiation in the T pellet groups and by 6 months in the injectable T and T gel groups (Figure3). These increases in Hgb and Hct persisted throughout follow-up. However, the rate of erythrocytosis, defined as Hct ≥50% in our study, was more common in the injectable T group (66.7%) than in the T gel (12.8%) and T pellet (35.1%) groups (P < 0.0001) (Table5). Erythrocytosis occurred significantly earlier in the injectable T group (10.5 ± 9.1 months) when compared with the T gel (14.0 ± 12.6 months) and T pellet (16.4 ± 10.7 months) groups (P = 0.01).

Changes in hemoglobin (Hgb) and hematocrit (Hct) during testosterone therapy (TTh). Changes in (A) Hgb and B) Hct were assessed over time as a function of testosterone (T) formulation. *P < 0.05, **P < 0.001.

Table 4

Changes in Hgb and Hct after TTh initiation

Group	Baseline mean (SD)	9 months	Change	P value
		Mean (SD)	Mean (SD)
Hgb (g/dL)				0.598
T gels	15.1 (1.1)	15.8 (1.1)	0.79 (0.9)
Injectable T	15.6 (1.3)	16.4 (1.1)	1.06 (1.4)
T pellets	14.9 (1.2)	15.7 (1.5)	0.81 (1.2)
Hct (%)				0.074
T gels	44.6 (3.1)	46.6 (3.0)	2.55 (2.6)
Injectable T	46.0 (3.7)	48.3 (2.7)	6.47 (12.4)
T pellets	44.3 (3.3)	46.5 (4.0)	2.62 (3.5)

Table 5

Rates and timing of erythrocytosis as a function of T formulation

	T gels	Injectable T	T pellets
	n = 47	n = 57	n = 74	P value
Hct >50% (n[%])	6 (12.8)	38 (66.7)	26 (35.1)		<0.0001
Time to increase in Hct (months) (mean [SD])	14.0 (12.6)	10.5 (9.1)	16.4 (10.7)	0.01

Exogenous T is known to variably affect lipid profiles, although no consistent effects have been determined as a function of T formulation. In our cohort, we observed transient decreases in mean Tchol in the T gel group at 9 and 36 months, and the T pellet group at 3, 18, and 24 months (Supplementary Figure S1). The T pellet group also demonstrated a transient decrease in TG at 36 months, and in LDL at 3 and 18 months, respectively. No significant changes were observed in HDL for any T formulation group.

Discussion

Serum T levels decline at a rate of 0.4–2.6% per year as men age, resulting in hypogonadal levels in approximately 20% of men over 60, 30% of men over 70, and 50% of men over 80 15–17. The improved recognition of the sequelae of hypogonadism coupled with an aging male population has led to a significant rise in the treatment of androgen deficiency [18]. A recent study found that 3.8% of men 60 years or older were prescribed T, and the use of T has increased by over 170% between 2007 and 2013 [2],[19],[20]. Given its widespread use, it is essential to understand the long-term benefits and adverse effects of TTh. Furthermore, because multiple TTh options are available, understanding the effect profile of each is useful when selecting T formulations for individual patients. In this study, we evaluated the long-term effects of injectable, gel, and pellet T formulations to determine the impact on serum hormones and the rates of common adverse effects of each T formulation.

As expected, all T formulations resulted in increases in serum T and FT levels, which were sustained throughout 3 years of therapy. All forms of TTh resulted in a significant increase in E levels, although this increase was present throughout follow-up in men treated with injectable T and T gels, yet lasted only up to the 6-month follow-up point in men using T pellets. These findings are supported by prior work observing an increase in E during TTh using injectable and gel T formulations [20]. The increase in E results from peripheral aromatization of T in adipose tissue and is typically more prevalent in older men on TTh, in part because of higher fat mass in older men [21]. In our study, there was no correlation between age and/or BMI and E levels, and the only variable impacting E level on multivariate analysis was T level, suggesting that higher T levels drive aromatization in our cohort. This is further supported by the decrease in E levels after initiation of AI therapy in men with elevated E levels. In our cohort 1, 12, and 22 subjects were treated with an AI in the T gel, injectable, and T pellet groups, respectively, resulting in normalization of E levels in all treated men. However, the clinical consequences of elevated E levels in men remain poorly understood. While an increase in E can lead to gynecomastia, this is uncommon (2.2%) and is often reversible upon discontinuation of TTh or treatment using an AI 22–24. Furthermore, an increase in E levels may be beneficial, as very low E levels are associated with insulin resistance, an increased risk of fractures, and a higher risk of mortality in elderly men, and elevated levels of E are associated with increased libido in men on TTh 25–28.

One significant concern with TTh is potential for the development or progression of CaP, given the androgen-responsive nature of prostate tissue. In our cohort, we found no significant increases in PSA with any T formulation, irrespective of whether treated men had a history of CaP. The apparent lack of influence of TTh on PSA levels is consistent with several prospective studies that failed to demonstrate a significant increase in PSA [1],[3],[6]. However, small increases in PSA levels in men initiating TTh during the first few months following therapy initiation have been observed [29]. Furthermore, a recent study observed overall higher PSA levels in men on T [25]. However, these increases in PSA levels are not related to the risk of CaP, and support the stimulation of prostate tissue containing unsaturated androgen receptors, as described in the prostate saturation theory proposed by Morgentaler [26]. Across numerous studies, the incidence of CaP in men on TTh is low (1.1–2.3%), similar to the prevalence in the general population 1,3–6,27,28,30. In the setting of hypogonadal men with a history of CaP treated with TTh, no definitive data supporting a detrimental effect of TTh exist. In hypogonadal men on TTh with CaP treated using radical prostatectomy or radiation, small increases in PSA have been observed, with no increases in CaP recurrence rates over those seen in eugonadal men 31–34. Similar results have been observed in men with CaP on active surveillance [35]. Overall, however, these studies have been limited by their retrospective nature and small sample sizes, precluding definitive conclusions.

Erythrocytosis is the most frequent dose-limiting adverse effect of TTh; an increase in blood viscosity can exacerbate preexisting vascular disease [9]. For this study, we defined erythrocytosis as Hct ≥ 50%, which is the cutoff value we use in clinical practice for T dose adjustment or recommendation of therapeutic phlebotomy. While all forms of TTh may lead to increases in Hct, the rate of erythrocytosis in our study was significantly higher with injectable T (66.7%) when compared with T pellets (35.1%) and T gels (12.8%). Our findings are consistent with a study by Dobs et al. comparing injectable and transdermal T formulations, in which a higher incidence of erythrocytosis (43.8%) with injectable T relative to transdermal T (15.4%) was observed [27]. However, the above study used an Hct cutoff of 52% to define erythrocytosis. When adjusting our Hct cutoff to 52%, we observe 18 (31.58%) men on injectable T, 3 (6.38%) on T gels, and 9 (12.16%) on T pellets with erythrocytosis, similar to the rates observed by Dobs et al. Our results are also comparable to a recent study examining the effects of T pellets, which observed a 20.3% rate of erythrocytosis using a Hct cutoff of 50% [14].

Erythrocytosis also occurred significantly earlier in men on injectable T formulations when compared with the other two formulations. While the mechanism of T-induced erythrocytosis is unclear, erythrocytosis is associated with supraphysiologic T and E levels [1],[2],[12],[27], as well as hepcidin, dihydrotesosterone and erythropoietin levels, and androgen receptor CAG repeat length 9,36–38. It should be noted that mean T levels in men treated with injectable T were higher than those treated with gels or pellets, which may contribute to the increased likelihood of erythroctyosis in this group. However, it is unclear whether this increased rate of erythrocytosis is related to peak T levels or overall higher serum T levels. In our cohort, men on injectable T had the highest increases in serum T and E levels, whereas data were not available for the other factors associated with erythrocytosis. Nevertheless, our data support an increased risk for erythrocytosis in men on injectable T formulations. While studies directly examining the effects of T dose on Hct are lacking, Wang et al. found a direct relationship between T gel dose and the rate of erythrocytosis, observing an increase in erythrocytosis rate from 11.3% to 17.9% when increasing T gel dose from 50 to 100 mg per day [28]. Thus, care should be taken when selecting and dosing T formulations and Hgb/Hct should be monitored regularly.

Sex steroids play a key role in the regulation of lipid metabolism. Activation of hepatic lipase (HL) leads to a decrease of LDL and HDL, and increased lipoprotein lipase (LPL) activity leads to an increase in HDL and decreased Tchol [35]. Because TTh increases HL and LPL activity, and further activation of LPL can result from elevated E levels seen with TTh, TTh may have favorable effects on lipid parameters [35]. However, studies examining the effects of TTh on lipid profiles have been variable and inconclusive, identifying both favorable (decreases in Tchol and LDL with injectable T) 39–41 and unfavorable (decreases in HDL and increases in Tchol and LDL with injectable and pellet T) [42],[43] effects on lipid parameters. A recent meta-analysis examining 51 studies using various T formulations (28 injectable T, 17 transdermal T, and 6 oral T) found that the only change in lipids during TTh was a small, but significant decrease in HDL [10]. We did not observe an effect on HDL in our cohort and no consistent, significant changes in any lipid parameter were observed. This may be due to the fact that the lipid levels in our cohort were not consistently drawn from fasting patients, as they had been in the previous study observing a decrease in Tchol and LDL levels with TTh [35]. Furthermore, changes in the diets of subjects in our study were not tracked, so the influence of diet on lipid parameters in our cohort cannot be determined.

The strengths of this study include the selection of T-naïve men or men who had been off of TTh for 3 or more months, that all men in the study were treated using a single T formulation for the duration of follow-up, the study's single-center design, the long follow-up period, and the reproducibility associated with utilizing a single laboratory for evaluation of all serum variables. Furthermore, the ability to compare T formulations within a single clinic setting is significant. Our study is limited by several factors, including its retrospective design, precluding the ability to randomize the cohort to treatment and limiting the ability to evaluate the impact of confounding factors, the lack of fasting lipid parameters in all patients, the use of AIs, and the relatively small sample size necessitated by the rigorous patient selection schema. Furthermore, the 3 T formulation groups are imperfectly matched, with differing ages and comorbidities between groups, as well as varying levels of T and FT observed during follow-up, limiting the ability to compare the groups.

In summary, this study supports prior findings associating different T formulations with variable adverse effect rates. Specifically, injectable T formulations are associated with significant increases in E and higher erythrocytosis rates relative to T gels and pellets, possibly related to elevated mean or peak T levels. PSA levels are not affected by T formulation, and inconsistent variations in lipid levels occur, also apparently independently of T formulation. Understanding the differences in effect profiles for each T formulation is useful for individualizing TTh and identifying parameters that require regular monitoring.

Conflict of Interest

The author(s) report no conflicts of interest.

Supporting Information

Figure S1 Changes in lipid parameters during TTh.

Changes in (A) total cholesterol, (B) Triglycerides, (C) LDL Cholesterol, and (D) HDL Cholesterol were assessed over time as a function of T formulation.

Table S1 Summary serum data during follow-up.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599554/

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Best Reviews For Men Over 50 Years To Increase Testosterone

Best Reviews For Men Over 50 Years To Increase Testosterone

The Shortest Men of Hollywood

Photo Courtesy: Paramount Pictures/IMDb

Men aren't immune to stereotypes, especially when "tall, dark and handsome" is considered an ideal. That's one reason why it's impressive that these famous actors have managed to carve out careers in a line of work where appearance is so important.

Perhaps you were aware that these guys are on the shorter side — but did you realize they're as short as they actually are? Find out who the smaller-statured leading men in Hollywood are and how they measure up.

Dustin Hoffman

Dustin Hoffman is, by appearances, an unlikely leading man. Not only is he not the "traditionally handsome" Cary Grant type, but part of that knock is that D-Hoff measures 5 feet 6 inches tall. However, Hoffman has always owned his height, taking roles that suit him and becoming a massive star as a result.

Photo Courtesy: Gorup de Besanez/Wikimedia Commons

The list of smash hits starring Dustin Hoffman is not short, and older readers (and younger movie buffs) will recognize classics like Rain Man, The Graduate, Midnight Cowboy and Tootsie. Newer fans will know him from Meet the Fockers, among others.

Ken Jeong

Jeong — an actual physician who later became a comedian — broke onto the scene in The Hangover, and he's continued to rely on his comedic chops (as opposed to his height) to remain relevant ever since.

Photo Courtesy: Gage Skidmore/Flickr

The multitalented Jeong measures in at 5 feet 5 inches tall, making him far shorter than the typical leading man. But that hasn't stopped Jeong from carving out a respectable career — recently as a judge on The Masked Singer.

Ben Stiller

Ben Stiller has not only made it big in Hollywood but has also found brief success in the world of professional modeling (not just as Derek Zoolander — ever heard of him?). And he's only 5 feet 7 inches tall. As the son of Seinfeld actor Jerry Stiller, Ben likely never had delusions of tall genetic grandeur, but being a leading man at his height is impressive.

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And make no mistake — Stiller is a bonafide leading man, even if he's not the stereotypical hunk. Beyond Zoolander, the likes of Meet the Parents, Tropic Thunder, Along Came Polly, and Night at the Museum cement Stiller as a box office draw.

Al Pacino

Al Pacino has played some larger-than-life characters throughout his storied career, Michael Corleone in The Godfather trilogy being chief among them. But you may be surprised to learn that none of those characters were taller than 5 feet 7 inches — Pacino's height.

Photo Courtesy: Ludmila Joaquina Valentina Buyo Follow/Flickr

That's right. Tony Montana may have been big on moving weight, but he wasn't big in the height department. Pacino, commanding the screen in movies like Serpico, Dog Day Afternoon, Donnie Brasco, Any Given Sunday and so many others, is a testament to shorter guys' ability to succeed in Hollywood.

Michael J. Fox

Michael J. Fox was nothing short (pun intended) of a superstar in his young days in Hollywood, with the Back to the Future series exposing him as a witty, charming leading man with boyish good looks that proved to last. Despite being diagnosed with Parkinson's in 1991, Fox continued to act.

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Fox's height never held him back — he stands at a reported 5 feet 4 inches tall. Lately, his progressing Parkinson's has led him to do more voiceover work in movies like Stuart Little and Atlantis: The Lost Empire.

Dave Franco

Dave Franco, even with some recent success, might forever be known as James Franco's little brother. It turns out that "little," in this case, could refer not just to Dave's status as the younger Franco, but also to his height.

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Dave measures in at 5 feet 7 inches tall, which is below the average American male's height of 5 feet 10 inches. In Hollywood, where height can be a determining factor in the roles actors get (especially leading roles), Franco has still found a way to carve out a career. Movies like Neighbors, Now You See Me and 21 Jump Street have proven that.

Joe Pesci

Fans of the Mafia genre have to know Joe Pesci, both by name and by appearance. He seems to always play a character who's slightly off his rocker, whether it's Nicky Santoro in Casino, Tommy DeVito in Goodfellas or Vinny Gambini in My Cousin Vinny.

Photo Courtesy: Alberto E. Rodriguez/Getty Images

These characters were inseparable from the perception that each of them had a bit of a Napoleon complex, which was made more believable by Pesci's real-life height of 5 feet 3 inches. If anything, Pesci's small stature added to the gusto that each of his movie-stealing characters possessed.

Jack Black

It's a common perception that being on the shorter side is far less of a ding to your job options if you happen to be funny. This has proven true for Jack Black, who has commanded several leading roles in critically and financially successful movies — despite Black standing only 5 feet 6 inches tall.

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He broke onto the scene with a series of cameos in movies like Orange County and Mars Attacks! but now is more of a leading man, stealing the show in School of Rock, Shallow Hal, Nacho Libre, Tropic Thunder and Goosebumps.

Martin Scorsese

Martin Scorsese is among the greatest film directors of all time, and many believe he may just be the best — with all respect to Stanley Kubrick. And while directors' heights aren't as scrutinized as actors', you should know that Marty has made a few on-screen cameos in his flicks.

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Whether it's Hugo, Gangs of New York, The Aviator, Mean Streets or another one of his films, keep an eye out for the 5-foot 3-inch Scorsese to make a subtle appearance as a bit character.

Marc Anthony

Marc Anthony should give the shorter male population the world over hope of hooking their dream dates, as he was once married to Jennifer Lopez and a former Miss Universe. At 5 feet 5 inches tall, Anthony has also managed to pull some prominent roles on the silver screen.

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Though he's known primarily as a Latin-music singer, he has appeared in several movies, including Hackers. He even had a role alongside Denzel Washington in the edge-of-your-seat thriller Man on Fire, in which Anthony played the father of the kidnapped Dakota Fanning.

James McAvoy

James McAvoy has become an increasingly recognizable Hollywood leading man by taking on roles that attract large audiences. He has played a young Charles Xavier in several of the X-Men films and has recently become synonymous with Kevin Wendell Crumb in the movies Split and Glass.

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Yet McAvoy, who stands at 5 feet 7 inches tall, has also taken on more critically praised roles in films like The Last King of Scotland while dabbling in the action genre with Wanted, which he starred in alongside Angelina Jolie. The guy really does it all.

Daniel Radcliffe

The actor best known for playing Harry Potter was always a bit more believable as a teenager, even once he had grown out of his teens in real life. That's in part because he's only 5 feet 5 inches tall.

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Radcliffe has admitted to personal struggles with fame and alcohol, but he has continued to put out impressive performances in largely niche movies such as Swiss Army Man, receiving consistent critical praise as he proves that he's much more as an actor than Harry Potter — not that Harry Potter is anything to turn our noses up at.

Tom Cruise

Tom Cruise is the poster boy for those who believe you don't have to be over 6 feet tall to be a bonafide movie megastar. In fact, considering that Cruise is only 5 feet 7 inches tall, you apparently don't even need to be the height of the average American male to become an international superstar.

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Cruise is not without his share of controversy, but there's no denying that, even as he nears age 60, he's still a box office draw. He continues to pump out Mission Impossible films, along with blockbuster flicks like Jack Reacher, Edge of Tomorrow and American Made.

Kevin Hart

Kevin Hart is one of those movie stars who isn't succeeding in spite of his short stature but arguably succeeding because of it. He stands at 5 feet 4 inches tall, and he's made self-deprecation about his height a staple of his routines from the outset of his comedy career.

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Whether he's mocking himself in stand-up comedy sets or taking roles alongside relative giants like The Rock, Hart knows how to make his lack of height an asset in a way that few actors before him have done.

Seth Green

Seth Green has become more of a behind-the-scenes presence in the entertainment industry as the years have gone by, but he remains one of the more recognizable "short guys" in show business. Green primarily produces animated comedy shows today, but his list of on-screen appearances remains impressive.

Photo Courtesy: 20th Century Fox/IMDb

He played a prominent role as Dr. Evil's son, Scott Evil, in the Austin Powers movies, appeared in the hit TV show Entourage and appeared prominently in films like The Italian Job, Party Monster, Sex Drive and Can't Hardly Wait. And to think Green is only 5 feet 4 inches tall.

Zac Efron

Zac Efron is known as a major heartthrob in Hollywood, but he's lacking one quality commonly found in the heartthrob population: height. He's not exactly super-short at 5 feet 8 inches tall, but he's also not quite as tall as the typical leading man.

Photo Courtesy: Paramount Pictures/IMDb

Despite people's misconceptions about what height a leading man is "supposed to" measure in at, Efron has carved himself a nice career by appearing in films like Baywatch, Neighbors, Dirty Grandpa and Mike and Dave Need Wedding Dates.

Jonah Hill

Jonah Hill was once known for being a bit chubby (a fact he's made clear doesn't sit well with him), but fans may not realize that he's also not very tall. There's no meanness involved here, but it's clear that Jonah Hill isn't cut from the cloth of the classic leading men, height-wise — and that's totally fine.

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Hill has gotten by on his great sense of humor and surprisingly versatile acting abilities. At 5 feet 7 inches tall, Hill has played a Wall Street trader, a baseball executive and a horny high schooler. How's that for acting chops?

Aziz Ansari

Aziz Ansari found his breakthrough in comedy, where being short can be an asset when you play it the right way like Kevin Hart does. But Ansari has begun to appear more in TV shows and movies that aren't traditional comedies, and he's served as the leading man in some of them — a 5-foot 6-inch leading man, in fact.

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His roles in Parks and Recreation and the show he created, directed and starred in, Master of None, involved the right amount of comedy. And height was not a major issue in any of that comedy. Ansari knows he's not the traditional hunk type, and he makes his stature work.

Josh Hutcherson

Josh Hutcherson is known for his role as Peeta Mellark in The Hunger Games movie series, but he has appeared as the leading man in several other movies. He measures in at 5 feet 7 inches tall.

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He has a varied resume that includes comedies like RV, The Disaster Artist and Kicking and Screaming. He's been in fun flicks like Journey 2: The Mysterious Island and in dramas like Escobar and Burn. He's even done action movies, including The Hunger Games and its subsequent iterations. Nothing is stopping this guy.

David Spade

There are lots of comedic actors on this list, and it's no coincidence. It always helps to be funny if you're under the traditional height for a leading man. David Spade is no exception, as it was his ability to make audiences laugh on Saturday Night Live that earned him his Hollywood break.

Photo Courtesy: Emma McIntyre/ Emma McIntyre/E! Entertainment/NBC Universal/Getty

And Spade, at 5 feet 5 inches, is still relying on his humor to push out movies. His comedy-movie resume remains impressive, with Tommy Boy, Dickie Roberts: Former Child Star, Joe Dirt and the Grown Ups movies standing out for so many reasons.

Elijah Wood

Most movie fans know Elijah Wood as Frodo, a main character in the Lord of the Rings films, but Wood has put on a number of noteworthy performances. He's gotten those roles despite being synonymous with a character as iconic as Frodo and standing only 5 feet 6 inches tall.

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One of his most memorable performances came relatively early on in his career in Green Street Hooligans, in which he portrays an impressionable bad boy who gets sucked into the world of soccer hooliganism.

Emile Hirsch

Emile Hirsch seemed destined for a bright career in Hollywood, starring in a few major films early on in his career and displaying a versatile range of comedic and dramatic performances that seemed primed to launch him into long-term stardom.

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Five-foot 6-inch Hirsch's acting stock has cooled off considerably since he won audience and critical acclaim for leading roles in films like Into the Wild, Alpha Dog and even The Girl Next Door. It started to seem as though he couldn't handle leading roles any longer — he ran into some personal troubles — but he made a comeback in 2019's Once Upon a Time in Hollywood.

Martin Freeman

Martin Freeman is a British actor who has become increasingly well-known among American audiences for roles in movies like Black Panther and the popular television series Fargo. He has shown a versatile range and a knack for injecting dark comedy into several of his roles.

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Freeman is often cast as somewhat nerdy, mildly timid characters, and his 5-foot 6-inch frame at times lends itself to such portrayals. Still, Freeman has very much found his footing as an actor, playing roles in popular films such as Love Actually and The Hobbit, in which he played Bilbo Baggins.

Danny DeVito

Danny DeVito is in a class with the likes of Joe Pesci — his height is inseparable from his identity as an actor, and it has its own particular charm. DeVito's ability to own his 4-foot 10-inch stature is one thing that's made him so successful; he's been eager to poke fun at himself in movies like Twins, in which he played Arnold Schwarzenegger's unlikely brother.

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Aside from Twins, DeVito has padded his resume and bank account with timeless roles in movies such as Matilda, Batman Returns, One Flew Over the Cuckoo's Nest, Space Jam, Get Shorty and Hoffa.

Frankie Muniz

Frankie Muniz was introduced to most audiences as Malcolm, the titular character in Malcolm in the Middle — a timeless comedy series that also shone a light on Bryan Cranston. Muniz went on to star in a slew of movies aimed at teens and young adults, Agent Cody Banks being probably the most well-known.

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And while Muniz has since ventured into race car driving as a passion career, he remains one of the shorter actors to have found success in Hollywood. He measures in at around 5 feet 5 inches tall.

Macaulay Culkin

"KEVIN!" If you don't know what movie that comes from, then you've missed out on arguably the best Christmas movies of all-time in Home Alone and Home Alone 2. Both starred Macaulay Culkin as the clever protagonist, Kevin McAllister.

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Culkin hasn't grown a whole lot since his days playing Kevin, as he measures in at 5 feet 7 inches even as he continues a more relaxed acting career as an adult. Some of Culkin's later films include Party Monster, Saved! and Changeland.

Emilio Estevez

Emilio Estevez is the son of Martin Sheen and the brother of Charlie Sheen, and he's also kind of short. Well, by Hollywood standards anyway. The man Saturday Night Live rebranded as "Emilioooooo!" is 5 feet 7 inches tall.

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Considering that there's something of a height bias in most industries (and life in general), Emilio has done quite well for himself, starring in the cult classic The Breakfast Club and the Mighty Ducks series, which remains close to many a Disney kid's heart to this day.

Peter Dinklage

Peter Dinklage gained near-household name recognition playing Tyrion Lannister on the smash-hit series Game of Thrones. In Dinklage's case, his 4-foot 4-inch height was a serious advantage in gaining this role of a lifetime.

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Dinklage did well with the roles he played before landing his spot on Game of Thrones, too. The Station Agent is perhaps his most critically acclaimed film to date, but he also appeared in Elf, The Chronicles of Narnia and Death at a Funeral before Game of Thrones.

Jet Li

Jet Li is one of the most decorated martial artist actors of our time, following in the footsteps of other idols like Bruce Lee. His films are almost always high-flying affairs, even though he's stationed close to the ground at a height of 5 feet 6 inches.

Photo Courtesy: Warner Bros/IMDb

His stature arguably makes him even better suited to do the crazy stunts that his movies almost always require. Those movies include the action-packed Kiss of the Dragon, Cradle 2 The Grave, Fearless, Lethal Weapon 4, Romeo Must Die and The Expendables.

Mark Wahlberg

Mark Wahlberg is far from the shortest leading man in Hollywood, but considering his stardom and typical role as the macho man, some fans may be surprised to learn that Wahlberg's reported height is 5 feet 8 inches. That's below the national average for American men and below the average for leading men in Hollywood.

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Really, it's a testament to his good looks, big muscles and don't-mess-with-me attitude that so few fans notice that Wahlberg is rather small in the height department. Roles in films like Transformers: Age of Extinction and Patriots Day reinforce Wahlberg's abundant machismo.

Best Reviews For Men Over 50 Years To Increase Testosterone

Source: https://www.life123.com/lifestyle/shortest-men-hollywood?utm_content=params%3Ao%3D740009%26ad%3DdirN%26qo%3DserpIndex

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