Is Oral Testosterone The New Frontier Of Testosterone Replacement TherapyⅡ

Transdermal therapy 

Transdermal testosterone modalities are applied to the skin, which allows for the perpetual release of the hormone at a more regular rate when compared to injectable delivery systems. Gel formulations, such as Androgel or Axiron, contain alcohol and are recommended for application to the epidermis in any area besides the scrotum. 

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The alcohol content allows for rapid dissolution of the gel on the skin. Scrotum application is contraindicated due to increased levels of 5 alpha-reductase, which can subsequently contribute to prostatic hyperplasia due to the conversion of testosterone to 5-DHT [13]. Testosterone can also be delivered through transdermal means with a patch. These patches imitate the diurnal pattern of testosterone release seen in human physiology. 

Testosterone levels post-application peak at 2-6 hours and fall back within 24 hours, thus necessitating renewed application within 24 hours. As with the testosterone gel modality, transdermal patches may be applied anywhere along the skin apart from the scrotum, buttocks, or bony site. It is recommended that the application site should be regularly rotated around once a week to reduce the risk of an adverse dermatological reaction.

Serum Testosterone Levels 

Changes in serum testosterone levels with testosterone supplementation are well studied throughout the available literature involving the study of hypogonadism. When using transdermal methods, it typically takes around 4-12 weeks to improve serum testosterone levels to the acceptable range of 400-700 ng/dL [14]. In a prospective, open-label study by J. Rodriguez-Tolra et al., 50 hypogonadal males were given 50mg of testosterone gel daily. Total and free testosterone levels were measured after 12 and 24 months of therapy. Baseline total testosterone for the participants was measured at (294±104)ng/dL and free testosterone was (51.9±14.4) pg/mL. 

The measurements at 12 months for total and free testosterone were (555±291) ng/dL and (121.2±83.7) pg/mL, respectively. At 24 months the measurements were (553±250) ng/dL total testosterone and (115.4±49.0) pg/mL free testosterone [15]. Wang et al. also conducted a study of 222 subjects in which 73 participants were given 50mg testosterone gel, 78 participants were given 100mg testosterone gel, and 76 were given a testosterone patch daily. 

The 50mg/day T gel group saw increased total testosterone from (237 ± 15) ng/dL to (555 ± 34) ng/dL after 180 days of treatment. The 100mg/day T gel group saw increased total testosterone from (248 ±16) ng/dL to (713 ± 30) ng/dL after 180 days. The patch group went from (237 ± 16) ng/dL at baseline to (408 ± 25) ng/dL after 180 days [16].

Body Composition 

In J. Rodriguez-Tolra et al.'s previously mentioned study, total bone mass density was also measured during months 12 and 24 in the lumbar spine, femur, trochanter, and Ward's triangle using a DEXA scan. The study showed a significant improvement in bone mass density across all the measured areas. At 50mg/day of testosterone gel, the lumbar spine (L1-L4) showed a 4.5% increase in BMD, while the trochanter showed a 3.2% increase. 

It was also discovered that C-telopeptide decreased, which shows that bone destruction had been decelerated [15]. Measurements of lean body mass and fat mass were recorded by Wang et al., in the T gel 50mg/day group an increase in lean body mass of (1.59 ± 0.39) kg was seen after 180 days. The T gel 100mg/day group increased (3.03 ± 0.35) kg after 180 days. The T patch group had a change of (0.99 ± 0.38) kg after 180 days.

In terms of body fat mass, the T gel 50mg/day group saw a decrease of (0.90 ± 0.32) kg, the T gel 100mg/day group saw a decrease of (1.05 ± 0.22) kg, and the T patch group saw no change (0.01 ± 0.2) kg. These results were seen at 90 days and decreased in the T gel groups after 180 days [16].

Quality Of Life 

We gathered information regarding the effects of transdermal testosterone on quality-of-life factors, including mood and sexual function. According to a meta-analysis by Pankaj Jain et al., transdermal testosterone therapy was more effective than oral and injectable modalities when looking at their effects on erectile dysfunction. 

Transdermal patch delivery had a response rate of 80.9% compared to 51.3% achieved by intramuscular delivery and 53.2% achieved by oral supplementation. The authors scoured various databases for 73 articles investigating the effects of testosterone replacement therapy on erectile dysfunction to spur new research. It was suggested that this discrepancy in response rates might be due to the size of the studies; the transdermal study had 42 participants, whereas the intramuscular studies had much larger participation [17]. 

In a separate meta-analysis by Giovanni Corona et al., a study conducted with more than 700 patients using a transdermal delivery method showed a significant improvement in the patient's sexual function [18].

Adverse Effects 

Testosterone gels are more commonly used as treatment modalities for hypogonadism due to their ease of use and patient preference. However, there are serious concerns surrounding their use. Wang et al. found that skin irritation was reported in 5.5% of subjects treated with testosterone gel and 66% of subjects in the testosterone patch group [16]. 

Also, it is important to note that women and children should avoid contact with clothing or skin that may have gel residue due to reported side effects such as precocious puberty caused by the secondary transfer. Cavender et al. performed a case study where such an incident occurred in a 10-month-old male. The patient had developed precocious puberty due to the transfer of testosterone from the patient's father, who had been undergoing treatment for hypogonadism using a topical gel. 

The patient's symptoms subsided once his father's treatment had been changed to a buccal modality [19]. Another case study by Brachet and Heinrichs discovered that a 5-year-old patient had developed central precocious puberty after long-term exposure to testosterone via secondary interpersonal transfer from testosterone gel, as determined by a GnRH test. The patient's secondary exposure had begun while he was in utero [20]. 

When considering transdermal gels there is a deep concern for transference through contact that can lead to virilization, especially in children [21]. Certain transdermal gels do not allow the patient to wash the application site for hours, increasing the probability of transfer [22]. No significant changes in liver function tests were noted in the previously mentioned Wang et al. study comparing T gel uses of 50 mg, 100 mg, and T patch; however, measured PSA levels throughout treatment did show significant changes. 

The study noted a significant increase in mean serum PSA levels in the 100 mg T gel group, going from (0.89±0.08) ng/mL upon the initial measurement on day 0 to (1.19±0.12) ng/mL on day 90. The 50 mg/day group demonstrated a baseline PSA level of (0.88±0.08) ng/mL which increased to (1.19±0.12) ng/mL. There was no significant change to PSA levels noted in the T patch group; baseline levels were measured to be (0.89±0.10) ng/mL, and on day 90, the PSA levels were (0.88±0.09) ng/mL [16].

Oral therapy 

Androgens traditionally cannot be given orally due to poor bioavailability from extensive hepatic first-pass metabolism [23]. The only ester testosterone preparation available for administration by mouth is testosterone undecanoate. The greatest absorption of testosterone undecanoate occurs with the simultaneous consumption of meals high in fat concentrations. 

This is due to a "hydrophobic, long aliphatic chain ester," which "favors preferential absorption into chylomicrons entering the gastrointestinal lymphatics and largely bypassing hepatic first-pass metabolism." Despite adding an ester, multiple high daily dose regimens of 160 mg or 240 mg are deemed most effective due to undecanoate's variable and inconsistent bioavailability and short duration of action [24]. After compiling studies that were done regarding oral testosterone therapy, the following results were determined:

Serum Testosterone 

Levels In a single-blind study by Zhang et al., 160 men at least 50 years of age presented with a total morning serum testosterone measurement of < 230 ng/dL or a morning free testosterone level of <64.9 pg/mL. If the serum total morning testosterone level was between 230 and 345 ng/dL, participants were placed in either a treatment or placebo group. The treatment group received 120-160 mg of testosterone undecanoate (TU) orally daily, based on serum testosterone levels, while the placebo group received vitamin e/c capsules. 

The researchers found that serum total testosterone concentrations before and after intervention were (230 ±21) ng/L and (395±34) ng/dL, respectively, and the free testosterone concentrations before and after intervention were (30.0±5.0) pg/mL and (62.1±9.0) pg/mL [25]. Mean total serum testosterone and free testosterone concentrations of all patients at six-month follow-up remained within the reference range of adult males and were significantly higher than the corresponding baseline levels [25]. 

Park et al. conducted a similar study by administering oral testosterone undecanoate in a single-blind, placebo-controlled study to 33 participants with hypogonadism. Patients were selected using a similar criterion to the above study; 27 were given 80mg of testosterone undecanoate twice a day, while six were given placebos. In regards to serum total testosterone levels, there was an increase from (260±130) ng/dL to (400±180) ng/dL after three months of therapy, which was deemed statistically significant [26]. 

In a recent open-label study conducted by Swerdloff et al., 221 male patients between 18-65 years of age with consistent serum total T <300 ng/dL and a history of hypogonadism-like signs or symptoms were randomly assigned to either an oral testosterone undecanoate group or a 2% topical testosterone solution group. 

The oral testosterone undecanoate group started the study with a dose of 237 mg of testosterone undecanoate twice a day prior to breakfast and dinner to allow for a 12-hour window. Based on average testosterone levels measured on days 21 and 56 of the study, doses could be changed to 316 mg and then 396 mg or decreased to 198mg and 158mg of testosterone undecanoate. 

At the end of the 105-day study, 87.3% of the oral testosterone undecanoate group patients displayed serum testosterone levels of 489±128 ng/dL [27]. From these findings, it is safe to conclude that regarding serum testosterone levels, administering testosterone undecanoate orally is an effective method in bringing patients with hypogonadism to therapeutic physiological levels.

Body Composition 

Changes in bone mineral density, skeletal muscle mass, and fat mass while receiving oral testosterone therapy have been well acknowledged. Bouloux et al. found that oral testosterone undecanoate significantly increased bone mineral density in the lumbar spine (L1-L4) and the trochanter at 160 mg/d compared with placebo. After 12 months of therapy, there was a (1.68 ± 3.35) % change in the lumbar spine and a (1.37 ± 4.00)% change in the trochanter.

They also reported a dose-dependent response on both lean and body fat mass; 160 mg/day of oral TU resulted in a 1.3 kg increase in lean body mass, while 240 mg/day resulted in a 1.7 kg increase. Body fat mass was reduced by 1.4 and 1.2 kg after 12 months of treatment with oral TU 160 and 240 mg/d, respectively [28]. A study by Wittert et al. highlighted the efficacy of oral testosterone on body composition. 

After six months of therapy consisting of 160mg/day of oral TU, lean body mass decreased by (0.91 ± 0.03) kg in the placebo group and increased by (1.04 ± 0.07) kg in the testosterone group. Fat mass increased by (0.85 ± 0.19) kg in the placebo group and decreased by (0.2 ± 0.1) kg in the testosterone group [29].

Quality of Life 

Furthermore, we found that quality of life factors such as sexual function, mood, and mental status was well documented with oral therapy. The same study by Park et al. found that testosterone undecanoate treatment significantly improved sexual dysfunction compared to baseline and placebo. 

Those in the treatment group reported increased libido, decreased erectile dysfunction, and decreased ejaculation difficulty. Likewise, in terms of mood and mental status, the treatment group, on average, reported significantly decreased nervousness or depression, increased appetite, and increased memory and concentration [26]. Similarly, a study done by Haren et al. on the effects of administering testosterone undecanoate for 12 months on older men with hypogonadism revealed significant improvements in quality of life; the treatment group reported decreased sadness/grumpiness and improved erection strength [30]. 

In the study conducted by Swerdloff et al., patients included in the oral therapy group were noted to have a significant decrease in negative moods and significant increases in positive moods, sexual desire, weekly sexual activity (with and without a partner), and sexual energy with a partner [27]. The overall quality of life increased in male patients across multiple studies.

Adverse Effects 

The general adverse effects of testosterone supplementation have been widely studied, but there has been varying data on oral testosterone itself. Oral testosterone can be prepared in many ways to have reliable system absorption. Methyltestosterone, 17-alkylated testosterone, is absorbed through the portal system and can result in hepatotoxicity. 

However, testosterone undecanoate is a non-alkylated testosterone ester absorbed through the intestinal lymphatic system and bypasses the portal system, allowing for little to no hepatotoxicity. Park et al. recorded normal AST and ALT levels with TU usage showing a lack of any undesirable effect on the liver considered a very well-tolerated modality.

Conclusions 

Our research has shown that the modalities discussed have nearly equal efficacy in raising serum testosterone levels to be physiologic and therapeutic eugonadal levels. They also have shown similar efficacy in improving body composition and quality of life in mood and sexual function measures. Therefore, each modality's prescription rests on each side effect profile. 

The major complaint by patients participating in IM testosterone therapy is the pain at the injection site resulting in decreased patient compliance. Transdermal testosterone therapy, such as gels and patches, avoids this pain issue at an injection site and even has the benefit of reducing the number of clinic visits a patient must make; however, they pose other potential severe consequences and side effects. 

Oral testosterone undecanoate has been found as an equivalent alternative to gel therapy throughout the world, including in Europe; we have found that oral testosterone undecanoate has minimal side effects, which can be quelled by changing the dosage. Ease of use when considering either gels or orals allow for higher patient compliance. 

However, compared to orals, gels possess the risk of interpersonal testosterone transfer, as noted in various case studies, and increases in PSA levels not seen in the oral treatment. Based on recent approval by the FDA, we believe that more research should be done concerning oral testosterone use for hypogonadal treatment in the US due to its equal efficacy compared to the other modalities, its ease of use leading to increased patient compliance, and its mild side effect profile.

The mechanism of Cistanche boosts the testosterone effect

Cistanche has been found to boost testosterone levels in several ways. Firstly, it contains compounds known as echinacoside and acteoside, which have been shown to enhance the production of luteinizing hormone (LH) in the pituitary gland. LH stimulates the Leydig cells in the testes to produce testosterone. Cistanche also contains polysaccharides and phenylethanoid glycosides, which have been shown to have antioxidant and anti-inflammatory properties. This can help reduce oxidative stress and inflammation in the testes, which can impair testosterone production Additionally, Cistanche has been found to increase the expression of genes involved in testosterone synthesis and reduce the activity of enzymes that break down testosterone, such as 5-alpha-reductase. Overall, the combination of these mechanisms is thought to contribute to Cistanche's testosterone-boosting effects.