DHT and Prostate Health

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I have recently resumed using topical DHT. It has been a few years since I have last used it and the concentrations are now higher than before. Naturally, I was curious as to any implications this may have on prostate health. Research has uncovered some fascinating information.

Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels

Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels​

Ronald S. Swerdloff,[IMG alt="corresponding author"]https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/corrauth.gif[/IMG] 1 Robert E. Dudley, 2 Stephanie T. Page, 3 Christina Wang, 1 , 4 and Wael A. Salameh 1
Author information Article notes Copyright and License information PMC Disclaimer
See "Is Dihydrotestosterone a Classic Hormone?" in volume 38 on page 170.


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Abstract​

Benefits associated with lowered serum DHT levels after 5α-reductase inhibitor (5AR-I) therapy in men have contributed to a misconception that circulating DHT levels are an important stimulus for androgenic action in target tissues (e.g., prostate). Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels. To assess the clinical significance of modest elevations in serum DHT and the DHT/testosterone (T) ratio observed in response to common T replacement therapy, a comprehensive review of the published literature was performed to identify relevant data. Although the primary focus of this review is about DHT in men, we also provide a brief overview of DHT in women. The available published data are limited by the lack of large, well-controlled studies of long duration that are sufficiently powered to expose subtle safety signals. Nonetheless, the preponderance of available clinical data indicates that modest elevations in circulating levels of DHT in response to androgen therapy should not be of concern in clinical practice. Elevated DHT has not been associated with increased risk of prostate disease (e.g., cancer or benign hyperplasia) nor does it appear to have any systemic effects on cardiovascular disease safety parameters (including increased risk of polycythemia) beyond those commonly observed with available T preparations. Well-controlled, long-term studies of transdermal DHT preparations have failed to identify safety signals unique to markedly elevated circulating DHT concentrations or signals materially different from T.

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Circulating levels of DHT in response to testosterone replacement therapy (TRT) do not correlate with those found in androgen sensitive tissue due to homeostatic control of intracellular DHT.

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Essential Points​

• Circulating levels of DHT in response to testosterone replacement therapy (TRT) do not correlate with those found in androgen sensitive tissue (e.g., prostate, adipose, muscle) due to local regulatory mechanisms that tightly control intracellular androgen homeostasis.
• The modest increases observed in serum DHT and in the DHT/T ratio observed after TRT are unlikely to be a cause of clinical concern, particularly when viewed in the context of changes observed in these parameters for currently marketed T-replacement products and those under development for which DHT data are available.
• While well-controlled, long-term studies designed to specifically examine the effects of androgen exposure on risk for prostate need to be conducted, the current clinical data base is relatively reassuring that circulating levels of androgens (or changes in such) apparently do not play as pivotal a role as once thought in the development of prostate disease.
• Robust epidemiologic or clinical trial evidence of a deleterious DHT effect on CVD is lacking. There is some evidence that DHT therapy in men with CVD may improve clinical status—a finding that needs confirmation. Data from a longitudinal data base of older normal (i.e., not hypogonadal) indicated an association between serum DHT and incident CV disease and mortality. Conversely, others have reported that higher DHT levels in older men were associated with decreased all-cause mortality and reduced ischemic heart disease mortality. Additional exploration in prospective, placebo-controlled intervention studies of TRT with CVD as the primary endpoint is needed to resolve the long-term effects of androgens on CVD risks.
• DHT does not play a substantive role in body composition compared to T under normal conditions. Thus, elevated levels of DHT in response to TRT are unlikely to appreciably impact lean or fat mass. Nonetheless, data from animals suggest a role for DHT in adipose tissue that inhibits biochemical pathways involved in lipid synthesis and promotes several transcripts associated with apoptosis of adipocytes. Whether these DHT-induced effects also occur in human adipose tissue remains an area for future study.
• There is very limited data available regarding DHT and effects on cognition. Further research is needed, particularly in light of animal data where DHT positively modified synaptic structure and significantly delayed cognitive impairment in a well-regarded animal model for Alzheimer’s disease.
• Recent data indicating that higher levels of DHT were inversely associated with insulin resistance and risk of diabetes merit further mechanistic investigation to understand whether this action is separate from that of T.

This review on dihydrotestosterone (DHT) biology and the clinical implications of serum DHT concentrations clarifies concepts that are of importance in clinical practice.

 

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DHT is the 5α-reduced metabolite of testosterone (T) that is principally converted from T in target organs such as prostate, skin, and liver. Synthesis can also occur from other precursors, but these pathways, although potentially important in some tissues (e.g., in prostate), are minor. Intracellular DHT is a more potent androgenic agonist than T, and its presence in some tissues such as the prostate is necessary for the full organ development and function. Circulating DHT levels are of much less importance than T for optimizing the intracellular DHT concentrations due to the presence of a rate-limiting enzyme, 5α-reductase (SRD5A; types I and II). Inhibition of these enzymes with 5α-reductase inhibitors (5AR-Is) decreases intratissue DHT levels and thus, in certain tissues (i.e., prostate), diminishes the agonist action of T, thus reducing prostate size and function. These inhibitors have been used to reduce prostate hypertrophy and the symptoms of lower urinary tract obstruction in benign prostate hypertrophy (BPH). 5AR-Is have been associated with reduced risk of prostate cancer, but they have not been approved for this purpose (1–3). Suppression of intracellular DHT levels with 5AR-Is results in reduced levels of DHT in the blood due to reduced leakage of DHT from peripheral target organs and reduced conversion of T to DHT from Leydig cells in the testes.
The clinical benefits associated with lowered serum DHT levels after 5AR-Is appear to have led to the misconception that circulating DHT is an important stimulus for androgenic action in the prostate gland. However, studies in which serum DHT concentrations were markedly elevated by exogenous administration of DHT had almost no effect on prostate DHT concentrations, prostate size, and lower urinary tract symptoms (see “Intraprostatic Control Of DHT in the Presence of Fluctuating Levels of Circulating Androgens” and associated references). The reason for this highlights fundamentally important control mechanisms in androgen target tissues that finely regulate pathways for androgen synthesis and degradation to maintain DHT homeostasis. These intracellular processes do not appear to be affected by circulating DHT concentrations. Furthermore, it is well documented that DHT can be synthesized in androgen-sensitive tissues such as prostate from substrates other than T (e.g., from 17-hydroxypregnenolone and 17-hydroxyprogesterone in what is termed the “backdoor” pathway and from 5α-androstane-3α, 17-β-diol via the intracrine reverse synthesis pathway) (4). We will also explore the implications of modest increases in serum DHT that are seen with T replacement therapy (TRT; including, for completeness, DHT preparations) for male hypogonadism and discuss why these likely have minimal clinical implications for men treated with androgens.
Serum DHT levels are dependent upon the concentration of serum T achieved with TRT and the expression of normal levels of functional SRD5A in tissues. In adult eugonadal men, serum DHT levels are about one-tenth that of total serum T concentrations. As would be expected, the pattern of rise in DHT generally tracks with the increase in T, but the magnitude of change is substantially less. Differences in circulating DHT in response to various routes of T and prodrug (e.g., T esters) administration have been reported. In some cases, this can result in supraphysiologic DHT concentrations, thus leading to an important clinical question: What are the potential health effects of supraphysiological serum DHT concentrations in the setting of androgen therapy (e.g., TRT)?
To assess the clinical significance of modest elevations in serum DHT and DHT/T ratio observed with some delivery systems of TRT, we performed a comprehensive review of the published literature to identify relevant data. We examined not only studies in which elevated DHT was documented, but also those where 5AR-Is were used to suppress DHT production. Where appropriate, we have also included data from salient animal studies, although the focus of our analyses is principally on human data. In the case of some currently available TRT preparations, no pertinent published DHT data were available, and thus they are not included in this review. This points to a weakness in some studies of TRT or SRD5A inhibition, namely, the absence of data on circulating DHT levels. A notable case in this regard is the Prostate Cancer Prevention Trial (1), which evaluated the effects of 5AR-I treatment but did not directly measure serum DHT in the men treated with finasteride. Instead, serum 5α-androstane-3α, 17β-diol glucuronide, a distal metabolite of DHT, was used as a surrogate measure of intraprostatic DHT (5).
Our review is focused primarily on DHT actions in men given historical concern about potential adverse effects of elevated DHT on prostate. However, for completeness, we have included additional potential tissue targets of DHT as well a brief section summarizing what is known regarding DHT in women.
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Overview of DHT Biochemistry/Physiology​

Endogenous formations and localization​

DHT is one of four principle androgens in humans and is synthesized primarily via the irreversible action of microsomal SRD5A (both types I and II) on T (Fig. 1). This saturable process follows Michaelis-Menton kinetics and is not affected by age (9). Localization of SRD5As in prostate tissue (type II), skin (type I), liver (types I and II), and hair follicles (primarily type I) catalyzes the formation of DHT from T in these tissues. These enzymes (expressed in the nucleus and cytoplasm of, for example, prostate epithelial cells) (10) are encoded by the 5α-reductase type 2 (SRD5A2) gene, and polymorphisms of this gene (leading to increased 5α-reductase activity and DHT concentrations in prostate) have been hypothesized to increase risk of prostate cancer (11). The SRD5A3 gene has also been linked to increased DHT production in hormone refractory prostate cancer cells (12), and this gene may be particularly important in metastatic prostate cells, which have been shown to express more SRD5A1 and SRD5A3 but significantly less SRD5A2 (13). Conversion of T to DHT via SRD5A activity in peripheral tissue is the main source of circulating DHT (14, 15), but it is important to note that little DHT synthesized in the prostate or liver enters the general circulation due to efficient intracellular mechanisms that initially metabolize DHT to 3α- and 3β-, 17β-androstanediol that have little androgen activity (16, 17). As noted previously, DHT can also be synthesized in tissues by “backdoor pathways” that enable formation of DHT in the absence of T or androstenedione as precursors (18, 19). In yet a third synthetic pathway to DHT, namely, the 5α-androstanedione pathway, 5α-androstanedione is converted by 17β-hydroxysteroid B3 to DHT (11). As discussed later, these alternate synthetic pathways, which are not influenced by circulating DHT, may have particular clinical significance within prostate tissue.

 

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[IMG alt="An external file that holds a picture, illustration, etc.Object name is er.2016-1067f1.jpg"]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459338/bin/er.2016-1067f1.jpg[/IMG]
Figure 1.
Metabolism pathways for deactivation of DHT to inactive glucuronides. Enzymes and genes associated with pathways are noted next to arrows. Relative thickness/size of arrows represents primary direction of reaction. Compiled from (6, 7, 8). 3α-DH, 3α-dehydrogenase; 3β-DH, 3β-dehydrogenase; HSD2, 17β-hydroxysteroid dehydrogenase type 2; HSD3, 17β-hydroxysteroid dehydrogenase type 3; HSD5, 17β-hydroxysteroid dehydrogenase type 5; HSD7, 17β-hydroxysteroid dehydrogenase type 7; HSD8, 17β-hydroxysteroid dehydrogenase type 8; HSD10, 17β-hydroxysteroid dehydrogenase type 10; HSD11, 17β-hydroxysteroid dehydrogenase type 11; SRD5A1, 5α-reductase type 1; SRD5A2, 5α-reductase type 2 (the 5α-reductase gene that predominates in androgen-sensitive tissue); SRD5A3, 5α-reductase type 3; UGT2, B7, UDP-glucuronyltransferase type 2 isozyme B7; UGT2, B15, UDP-glucuronyltransferase type 2 isozyme B15; UGT2, B17, UDP-glucuronyltransferase type 2 isozyme B17.

 

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Binding affinity for AR​

Binding of T and DHT to the androgen receptor (AR) stabilizes the AR and slows what would otherwise be rapid degradation. At low circulating androgen levels, DHT binding is favored over T but at higher relative T concentrations (e.g., eugonadal state), stabilization of the AR is driven by T more than DHT (20). Nonetheless, DHT is the most potent endogenous androgen based on four critical aspects of its binding to the AR. First, DHT has a relative binding affinity for the AR that is roughly 4 times that of T (21). Second, the rate of dissociation from the AR is about 3 times slower than T (22). Third, binding of DHT to the AR transforms the AR to its DNA-binding state (23). And lastly, DHT upregulates AR synthesis and reduces AR turnover (24). Collectively, these processes amplify the androgenic action of DHT and increase its potency compared with T. However, this may lead to the incorrect conclusion that binding of DHT to the AR always occurs preferentially over T. This is too simplistic a view and ignores the importance of intracellular control of T and DHT concentrations that are mediated by a host of local metabolic pathways. Organ differences in receptor binding of T and DHT result, in part, from relative differences in intracellular concentrations of these androgens rather than from differences in receptor affinities alone (22). Indeed, it has been clearly demonstrated that high concentrations of intracellular T can shift AR binding away from DHT by mass action (25). Moreover, despite there being a single AR, physiological differences in T and DHT action are well known and likely reflect variations in AR receptor distribution, ligand-induced conformational changes to AR that effect stabilization, local hormone synthesis and metabolism, AR-ligand interactions with chromatin, cooperativity of receptors with other transcription factors, and actions of coactivators and corepressors (26, 27). Thus, local tissue control of androgen levels in conjunction with numerous other factors drive AR-induced transcriptional responses. And as elucidated later in this review, tissue concentrations of androgens (particularly in the prostate) are partly distinct from circulating levels.

Protein binding​

Like T, circulating DHT is principally bound to sex hormone–binding globulin (SHBG) and, more weakly, to albumin. In general, protein-bound DHT is inactive except in some reproductive tissues in which megalin, an endocytic receptor, acts as a pathway for cellular uptake of DHT when bound to SHBG (28). Studies of interactions between a wide array of natural and synthetic androgens and SHBG indicate that the molecular structure of DHT favors tight linkage to the steroid binding site on SHBG (29). Compared with T, DHT has roughly a fivefold greater binding affinity to SHBG (30). Binding of circulating DHT to SHBG is highest in young males 0.5 to 2 years of age (90%) and thereafter declines to about 70% at age 15 and to 40% in young adult men (age 18) (31). The increase of SHBG that occurs with aging (approximately 1% per year) increases DHT binding in older men (32–35). Dissociation rate constants from SHBG for DHT and T have been measured in human serum and correspond to half times of dissociation of 43 (DHT) and 12 (T) seconds, thus further demonstrating the tenacity to which DHT binds to SHBG (36). Accordingly, concentrations of free circulating DHT in eugonadal men are very low and would be expected to remain so even when total DHT levels increase in response to TRT.
This leads to an important question: Can an increase in circulating levels of SHBG-DHT give rise to DHT-mediated effects? It is well known that SHBG can bind to cell membranes and interact with the SHBG receptor (RSHBG), thus potentially providing a means for its bound ligand to enter the cell. In the case of SHBG-DHT, studies have shown that this complex does not bind to the RSHBG (37). However, once formed, the SHBG-RSHBG can be activated by an agonist steroid to initiate downstream events beginning with the activation of adenylyl cyclase and the generation of cyclic adenosine monophosphate (cAMP) (37). Generation of cAMP in this scenario has been shown to be steroid specific. For example, when DHT or estradiol were exposed to unbound SHBG in a human prostate cancer cell line (namely, LNCaP), rapid increases in intracellular cAMP were observed. However, when this experiment was conducted with human prostatic explants, estradiol caused a rise in cAMP but DHT did not (37).

Metabolism​

DHT formed in peripheral tissues is extensively metabolized before its metabolites appear in the circulation (38, 39). Metabolism of DHT to inactive steroids occurs primarily via the initial actions of 3α-17β-hydroxysteroid dehydrogenase (3α-HSD) and 3β-17β-hydroxysteroid dehydrogenase (3β-HSD) in liver, intestine, skin, and androgen-sensitive tissues. Subsequent conjugation by uridine 5′-diphospho (UDP)-glucuronyltransferase (UGT) is the major pathway for urinary and biliary elimination of DHT metabolites and, locally, is the principal irreversible step to protect tissues from high concentrations of this potent androgen (Fig. 1). Of the UGTs, only UGT2 isozymes participate in DHT metabolism. In this regard, UGT2B7, B15, and B17 have remarkable capacities to conjugate androgens and are abundant in androgen-sensitive tissues (6). Differential expression of UGT2 isozymes has been reported and likely plays a role in tissue DHT concentrations independent of circulating androgen levels, particularly in androgen-sensitive tissue. For example, transcripts of UGT2B7, B15, and B17 have been identified in liver, intestine, skin, breast, uterus, and ovary, but adipose tissue expresses only UGT2B15, whereas in prostate, UGT2B15 and B17 are expressed only in luminal and basal cells, respectively. This differential localization combined with other local differences in androgen-metabolizing enzymes provides a finely tuned mechanism for control of intracellular androgen concentrations (7). Polymorphisms of UGT2B15 (that is highly effective in conjugating DHT and its metabolites) have been identified (40) and are postulated to protect prostate tissue from high DHT concentrations and thus lower prostate cancer risk (41, 42). Conversely, increased prostate cancer risk had been observed in white but not African American men with UGT2B17 deletion polymorphism (43). So although it is generally true that DHT concentration in tissue is finely regulated (and, as discussed later, probably not effected to any relevant degree by circulating levels observed in response to androgen therapy), it is equally true that polymorphisms in genes responsible for androgen metabolism may perturb this homeostatic mechanism, thus leading to clinically relevant consequences—both positive and negative.
Finally, the metabolism of DHT must also be considered in light of its metabolic clearance. The overall metabolic clearance of DHT and its metabolism in muscle and adipose tissue of normal men were evaluated in response to intravenously infused DHT (15, 44). The overall mean metabolic clearance of DHT was roughly 70% that of T, thus indicating a modestly longer residence time for DHT. Metabolism of DHT was substantially greater in adipose tissue compared with T, and there was little conversion of T to DHT in muscle. Metabolism of intravenously administered DHT compared with transdermally applied DHT revealed that skin is a major site of peripheral DHT metabolism to 3α-androstanediol, whereas intravenously-administered DHT yielded greater concentrations of 3α-androstanediol-glucuronide (45). Splanchnic tissues have a high capacity to metabolize DHT to DHT-glucuronide, which has importance when oral androgens like T undecanoate (TU) are administered (46). A large fraction of DHT produced in the liver is metabolized to DHT-glucuronide prior to subsequent entry into the circulation (17).

Analytical methods for DHT quantification​

In adult eugonadal men, serum DHT concentrations are most accurately measured by liquid chromatography tandem-mass spectrometry (LC-MS/MS), and consistent normal ranges based on this assay platform have been reported across several studies of men spanning a wide age range. A DHT reference range of 14 to 77 ng/dL (0.47 to 2.65 nmol/L) for healthy adult men (18 to 59 years; n = 113) has been reported by Shiraishi et al. (47). Handelsman et al. (48) evaluated age-specific population profiles of circulating DHT in community-dwelling men (<65 years; n = 2606) and observed a serum DHT range of 23 to 102 ng/dL (0.8 to 35 nmol/L). In a cohort of healthy older men (71 to 87 years; n = 394), a DHT reference range of 14 to 92 ng/dL (0.49 to 3.2 nmol/L) has been reported (49). Finally, a normal DHT range of 11 to 95 ng/dL (0.38 to 3.27 nmol/L) has been published by a well-regarded commercial clinical laboratory that utilizes LC-MS/MS for the assay of DHT (Mayo Clinical Medical Laboratory, Rochester, MN). In eugonadal men, DHT concentrations are roughly 7- to 10-fold lower than circulating concentrations of T. Also of note is that plasma T and DHT tend to be highly correlated with a correlation coefficient of 0.7 (49).
Prior to the advent of LC-MS/MS for measurement of DHT, less-precise direct DHT immunoassay methods were used in older studies [e.g., direct radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA)]. We now know that these older assays yielded consistently higher T and DHT values compared with LC-MS/MS by up to 25% (50), particularly at low hormone levels. Others have reported that serum DHT measured by RIA overestimated DHT based on LC-MS/MS by as much as 40% (47). These discrepancies are likely due to lack of specificity of the DHT antibody used in the RIA and failure to remove T from the assay that contributes to cross-reactivity. Because of this, some caution must be exercised in the interpretation of DHT values not measured by LC-MS/MS or by RIA in the absence of Celite column chromatography or other methods to remove T prior to DHT immunoassay. However, when DHT is administered exogenously in pharmacologic amounts, circulating DHT levels increase dramatically, whereas there is a parallel drop in luteinizing hormone and T. Consequently, the use of older RIA methods in situations where DHT levels were high likely yielded reasonably accurate measures of DHT and DHT/T ratios because the mass excess of DHT would have minimized the impact of cross-reactivity with T. In this review, we have noted how T and DHT were measured in each of the studies considered. Findings from studies in which DHT and DHT/T ratios were reported based on LC-MS/MS are more informative and should be afforded more weight.

 

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Serum DHT and DHT/T Ratios in Men After Transdermal DHT Administration​

Data regarding the clinical impact of sustained supraphysiologic concentrations of DHT in men repeatedly exposed to daily transdermally administered DHT gel provide valuable clinical safety information. Here we summarize the findings from three placebo-controlled studies in which men were treated with a transdermal DHT gel formulation for 3, 6, or 24 months.

Transdermal DHT gel in older men with partial androgen deficiency treated for 3 and 6 months​

The efficacy and safety of a transdermal DHT gel was studied by Ly et al. (51) and Kunelius et al. (52) in placebo-controlled studies in older men with partial androgen deficiency who were treated for 3 and 6 months, respectively. Table 1 summarizes the effect of DHT treatment on serum T, DHT, and DHT/T ratio in response to DHT gel. T and DHT concentrations and DHT/T ratios remained stable in the placebo gel group. As would be expected, serum T concentrations in men treated with DHT gel were significantly suppressed to about one-third of baseline whereas serum DHT concentrations increased dramatically, rising about 10-fold. In parallel, the DHT/T ratio increased about 16- to 40-fold across the two studies. Despite such high serum DHT levels, DHT gel treatment did not significantly increase total, central, or peripheral prostate volumes, as measured by ultrasonography, nor was serum prostate-specific antigen (PSA) elevated. In addition, International Prostate Symptom Scores (IPSS) remained unchanged in men treated with DHT gel for 6 months. Exogenous DHT therapy was associated with a modest increase in hematocrit (without exceeding the normal upper limit) but was without effect on serum lipids or other parameters of cardiovascular (CV) risk.

Table 1.​

Effect of DHT Treatment on Mean (± Standard Deviation) Serum T and DHT Concentrations and Prostate and CV Risk Factors

Study Description and Population​	Duration (Months)​	N (Completed)​	T (ng/dL) [nmol/L]​	DHT (ng/dL) [nmol/L]​	DHT/T[SUP]c[/SUP]​	Assay Method​	Effect of DHT on Prostate and CV Risk Factors​
Daily application of DHT gel (70 mg/d)​	3​	17[SUP]a[/SUP], DHT gel​	Baseline: 432 ± 89 [14.98 ± 3.09]​	Baseline: 41 ± 12 [1.41 ± 0.41]​	0.09​	RIA​	Increase in Hgb/HCT but remained in normal range​
Older men; age, >60; T <450 ng/dL (51, 53)​	1 mo: 210 ± 14 [7.28 ± 0.49]​	1 mo: 490 ± 58 [16.87 ± 2.0]​	2.44​	HDL cholesterol did not change​
2 mo: 187 ± 14 [6.48 ± 0.49]​	2 mo: 505 ± 58 [17.39 ± 2.0]​	2.70​	No evidence of stimulatory effects on prostate volume or PSA concentrations​
3 mo: 144 ± 57 [4.99 ± 1.98]​	3 mo: 534 ± 99 [18.39 ± 3.41]​	3.71​	No impairment in brachial artery size or flow in response to glyceryl trinitrate–induced dilatation​
No change in inflammatory biomarkers (CRP, sVCAM, and sICAM)​
Daily application of DHT gel (125–250 mg/d)​	6​	54[SUP]b[/SUP], DHT gel​	Baseline: 464 ± 132 [16.26 ± 4.58]​	Baseline: 44 ± 17 [1.51 ± 0.59]​	Baseline: 0.09​	RIA​	No effect on serum lipids​
​	3 mo: 270 ± 136 [9.36 ± 4.68]​	​
	6 mo: 170 ± 112 [5.89 ± 3.88]​	6 mo: 238 ± 133 [8.19 ± 4.58]​	6 months: 1.4​
​	14, DHT gel (125 mg/d)​	​	Baseline: 44 ± 20 [1.51 ± 0.69]​	​
3 mo: 276 ± 200 [9.50 ± 6.89]​	Increase in HCT (2.3%) and Hgb (0.9 g/L) at 6 months​
6 mo: 247 ± 189 [8.50 ± 6.51]​
Older men; mean age, 58 (52)​	​	27, DHT gel (187.5 mg/d)​	​	Baseline: 44 ± 17 [1.51 ± 0.59]​	​
3 mo: 261 ± 113 [8.99 ± 3.89]​
6 mo: 238 ± 139 [8.19 ± 4.79]​	Serum PSA, prostate volume, and IPSS remained unchanged​
​	19, DHT gel (250 mg/d)​	​	Baseline: 44 ± 20 [1.51 ± 0.69]​	​
3 mo: 267 ± 119 [9.19 ± 4.10]​
6 mo: 232 ± 81 [7.99 ± 2.79]​
Daily application of DHT gel (70 mg/d)​	24​	37, DHT gel​	Baseline: 493 ± 176 [17.1 ± 6.1]​	Baseline: 64 ± 61 [2.2 ± 2.1]​	Baseline: 0.13​	LC-MS/MS​	No effect on lipids​
No effect on carotid IMT​
Decreased (–1.1 kg) fat mass by DEXA​
Healthy men older than 50 years with no known prostate disease (54)​	Increased HCT > 50% in 8 subjects who discontinued​
24 mo: 69.2 ± 43.5 [2.4 ± 1.5]​	24 mo: 733 ± 497 [25.2 ± 17.1]​	24 months: 10.6​	Although both increased, neither PSA nor central prostate volume growth increased significantly; no change in IPSS score​
Daily application of DHT gel (10 g of 0.7% DHT gel)​	1​	12, DHT gel​	210 ± 20 [7.3 ± 0.7]​	210 ± 50 [7.2 ± 1.7]​	1​	LC-MS/MS​	No effects on serum lipids​
HDL did not change​
Healthy men; age 35–55 (55)​	All subjects had PSA <1.5-fold baseline at end of study, and none had a PSA >4.0 ng/mL at any time during the study​
Prostate volume and IPSS unaffected by DHT treatment​

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Abbreviations: DEXA, dual-energy X-ray absorptiometry; HCT, hematocrit; HGB, hemoglobin; IMT, initma-media thickness; sICAM, soluble intercellular adhesion molecule; sVCAM, soluble vascular cell adhesion molecule.
a18 enrolled.
b60 enrolled.
cCalculated from T and DHT provided by authors.

Transdermal DHT gel in middle-aged eugonadal men treated for 24 months​

A placebo-controlled trial of DHT gel to evaluate the effect of DHT specifically on prostate growth rate has been published and is arguably the most significant report concerning the longer-term effects of supraphysiologic DHT exposure (54). DHT administration yielded a sustained increase in mean serum levels of DHT with a parallel decrease in mean concentrations of serum T. No changes in androgen levels were observed after placebo (Fig. 2). For men using DHT gel, mean serum DHT increased about 10-fold and mean serum T levels decreased by about 86% after 24 months of daily DHT gel application (Table 1).
[IMG alt="An external file that holds a picture, illustration, etc.Object name is er.2016-1067f2.jpg"]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459338/bin/er.2016-1067f2.jpg[/IMG]
Figure 2.
Mean (± standard error of the mean) serum DHT and T response to transdermal DHT therapy over 24 months of treatment in middle-aged men. Shaded region of each graph represents normal ranges for DHT or T. To convert T and DHT to ng/dL, values must be divided by 0.0347 or 0.0345, respectively. Redrawn from Idan et al. (54).
The effect of sustained serum DHT levels resulted in only minor changes to serum PSA and prostate volume, none of which were statistically or clinically significant. Three men in the DHT-treated group were discontinued due to a rise in PSA to >4 ng/mL, but none was diagnosed with prostate cancer. One man in the placebo group required a transurethral resection of the prostate for BPH. Discontinuation of men treated with DHT occurred primarily due increased hematocrit (>50%), which was asymptomatic and resolved after stopping treatment. No serious adverse effects due to DHT occurred.
Overall, these studies of men treated with supraphysiologic doses of DHT do not support the hypothesis that modest elevations of DHT and DHT/T ratios observed with commonly used TRT preparations (including injectable T esters, transdermal T, and oral TU) will yield deleterious effects in men, particularly in androgen-sensitive tissues like prostate. Consistent with this conclusion are recent data from a longitudinal, observational cohort study of 3638 men in which circulating DHT (measured by LC-MS/MS) was not associated with incident prostate cancer (56).

 

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Association of Circulating Levels of DHT and DHT/T Ratio With Prostate Disease​

Although androgens support the growth, proliferation, and progression of aggressive prostate cancer, there is no consensus that elevated levels of circulating androgens contribute to the risk of developing prostate cancer. On the contrary, there is strong evidence that circulating levels of DHT are not associated with increased risk of prostate cancer (57–59). This is because intraprostatic levels of androgens appear to be controlled by an internally regulated system that senses and adapts to circulating levels of T and DHT. So although it is possible (but not proven) that intraprostatic levels of T and DHT (along with estradiol) may play an important role in the development of prostate pathology, cross-sectional and longitudinal data do not demonstrate that elevated levels of circulating DHT increase the risk of prostate disease, even when high DHT levels or DHT/T ratios were sustained for long periods (54, 60).
It is generally accepted that intraprostatic DHT is derived primarily from the conversion of T to DHT by the enzyme SRD5A (61). Intraprostatic SRD5A activity is regulated by the SRD5A2 gene, and polymorphisms of this gene (particularly SRD5A2 V89L and A49T) have been studied for associations with prostate cancer risk. Notably, a recent meta-analysis of SRD5A2 gene polymorphisms and prostate cancer risk found that prostate cancer risk was not associated with V89L and was probably not associated with A49T (62). Furthermore, polymorphisms in CYP17 (MspA1) and SRD5A2 (V89L) genes have not been shown to increase serum T or androstanediol-glucuronide, a surrogate for upstream metabolism of the DHT (63). Thus, polymorphisms in genes associated with the synthesis of DHT do not appear to alter circulating levels. However, this has not been confirmed by the direct measurement of serum DHT in men with these polymorphisms.
In eugonadal men, the serum concentration of T probably plays a minor contributory role as a source for intraprostatic T. But in hypogonadal men, intraprostatic T concentrations are dissociated from circulating T concentrations (see Table 2). Marks et al. (66) reported that when hypogonadal men were treated with intramuscular T replacement for 6 months, average serum concentrations of T rose to about 640 ng/dL (22.19 nmol/L), whereas there was no significant effect on the intraprostatic levels of either T or DHT compared with baseline. There also was no effect of T therapy on prostate tissue biomarkers (e.g., AR, Ki-67, or CD34) or gene expression (e.g., AR, PSA, PAPA2, VEGF, NXK3, or clusterin). Lastly, there was no change in prostate histology or the incidence of prostate cancer or severity thereof, although this study was not powered for prostate cancer end points. Thus, at least for serum T, increased circulating levels have essentially no impact on intraprostatic androgen levels.

Table 2.​

Serum and Intraprostatic DHT and DHT/T Ratios and PSA Observed in Response to Various Hormonal Manipulations

Study Description​	Length of Exposure​	N​	End-of-Rx Average Serum T (ng/dL) [nmol/L]​	End-of-Rx Average Serum DHT (ng/dL) [nmol/L]​	Mean Serum DHT/T Ratio​	DHT Assay Method​	Intraprostatic T (ng/g)​	Intraprostatic DHT (ng/g)​	Intraprostatic DHT/T Ratio​	PSA Baseline/ End of Rx (ng/mL)​
Case report: Pr CA in hypogonadism (64)​	2 y TRT​	1​	19 [0.66]​	2 [0.07]​	0.10​	LC-MS/MS​	0.5​	2.77​	5.54​	Not reported/49.0​
Medical castration healthy men (65)​	4 wk​	4​	357 ± 86 (SEM) [12.4 ± 3.0]​	40 ± 14 [1.4 ± 0.5]​	0.1​	RIA​	1.9 ± 0.3​	9.1 ± 4​	5​	0.5 ± 0.2/0.5 ± 0.2​
Double placebo​
Acyline plus placebo​	4 wk​	4​	26 ± 14 (SEM) [0.9 ± 0.3]​	8.72 ± 2.88 [0.3 ± 0.1]​	0.33​	RIA​	0.4 ± 0.1​	2.0 ± 0.5​	3.5​	0.8 ± 0.1/0.3 ± 0.1​
Acyline plus T gel​	4 wk​	4​	481 ± 167 (SEM) [16.7 ± 5.8]​	140 ± 67 [4.8 ± 2.3]​	0.30​	RIA​	1.5 ± 0.2​	6.4 ± 0.8​	4.5​	0.8 ± 0.1/0.8 ± 0.1​
DHT Rx (55)​	4 wk​	15​	410 ± 50 (SD) [14.2 ± 1.7]​	30 [1.03]​	0.07​	LC-MS/MS​	0.6 ± 0.2​	2.8 ± 0.2​	4.6​	1.1 ± 0.6/1.0 ± 0.5​
Placebo​
DHT​	4 wk​	12​	210 ± 20 (SD) [7.3 ± 0.7]​	210 ± 50 [7.2 ± 1.7]​	1​	LC-MS/MS​	0.4 ± 0.1​	3.1 ± 0.5​	7.75​	0.7 ± 0.4/0.8 ± 0.5​
TRT mild hypogonadism (66)​	6 mo​	19​	273 (89–715)​	26 (7–40)​	0.09​	RIA​	0.88 (0.02–20.12)​	5.10 (0.7–22.37)​	5.6​	0.97 (0–2.47)/1.10 (0.02–6.9)​
Placebo​
TE​	6 mo​	21​	640 (272–1190) [22.19]​	47 (20–121) [1.62]​	0.07​	RIA​	1.55 (0.1–23.1)​	6.82 (1.57–39.82)​	4.4​	1.55 (0.3–5.8)/2.29 (0.4–7.1)​
Male contraceptive trial (67)​	10 wk​	8​	400 (median) [13.87]​	50 [1.72]​	0.12​	LC-MS/MS​	0.4 ± 0.6 (SD)​	6.3 ± 1.9 (SD)​	15.75​	0.7 (0.6–1.0)/0.8 (0.7–1.12)​
Placebo​
T gel​	10 wk​	7​	440 (median) [15.26]​	180 [6.20]​	0.4​	LC-MS/MS​	0.7 ± 0.6 (SD)​	6.0 ± 2.8 (SD)​	8.57​	0.7 (0.4–1.1)/0.9 (0.3–1.2)​
T gel plus duasteride​	10 wk​	7​	700 (median) [24.27]​	50 [1.72]​	0.07​	LC-MS/MS​	4.5 ± 1.5 (SD)​	0.7 ± 0.2 (SD)​	0.15​	0.9 (0.7–1.1)/0.7 (0.7–1.1)​

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DHT measured by immunoassays without preparatory chromatography generally overestimate DHT levels and correlates poorly with LC-MS/MS data.
Abbreviations: Pr CA, prostate cancer; Rx, treatment; SD, standard deviation; SEM, standard error of the mean.
DHT and DHT/T ratios have been measured (or can be calculated) in a number of TRT clinical trials. The effects of various TRTs on prostate are summarized in Table 3. Although TRT has been associated with adverse prostate events, this table indicates that even striking elevations in DHT and DHT/T ratio for prolonged periods (e.g., up to 24 months) have not been associated with clinically meaningful negative effects on prostate. However, it is important to emphasize that these trials were not designed and powered to detect long-term effects of elevated DHT on prostate tissue.

Table 3.​

Serum DHT Concentrations and DHT/T Ratios Observed With Androgen Replacement Therapies and Reported Effects on Prostate

Form of ART​	Length of Exposure​	N​	Age​	End-of-Treatment Mean Serum T (ng/dL) [nmol/L]​	End-of-Treatment Mean Serum DHT (ng/dL) [nmol/L]​	End-of-Treatment Mean DHT/T Ratio​	DHT Assay Method​	Observed Effects on Prostate​	PSA or Change in PSA in Response to ART​
Oral TU (CLR-610) (68)​	28 d​	15​	46.7 ± 11​	516 ± 58 [17.9 ± 2]​	110 ± 15 [3.8 ± 0.5]​	0.21​	LC-MS/MS​	None​	Not reported​
Nasal T gel (69)​	90 d with 180- and 360-d extensions​	BID: 228 TID: 78​	54.4 ± 11​	375-421 [13–15]​	33–40 [1.14–1.38]​	<0.1​	LC-MS/MS​	AE of PSA increased in six subjects in TID group at day 90​	BID dosing:​
180 d: +0.01 ng/mL​
360 d: +0.06 ng/mL​
TID dosing:​
180 d: +0.09 ng/mL​
360 d: +0.21 ng/mL​
Transdermal T gel (70, 71)​	3 y​	123​	51.5 ± 0.9​	432–577 [15–20]​	130–210 [4.48–7.23]​	0.26–0.30​	RIA​	AE of PSA increased in seven subjects; three with diagnosis of prostate cancer​	Baseline:​
0.85 ± 0.06 ng/mL​
6 mo:​
1.11 ± 0.08 ng/mL (with no further significant increase)​
Transdermal T solution (72)​	120 d​	155​	51.5​	389–507 [13.5–17.6]​	98 [3.37]​	0.17–0.26​	LC-MS/MS​	AE of PSA increased in one subject with diagnosis of prostate cancer​	Mean increase of 0.02 μg/L​
Scrotal T patch (73)​	8 y​	25​	Not reported​	404 [14]​	175 [6.03]​	0.43​	RIA​	None​	Not reported​
Nonscrotal​	24 wk​	33​	44.3 ± 11.1​	564 ± 149 [19.6 ± 5.2]​	50 ± 20 [1.72 ± 0.7]​	0.09​	RIA​	AE of one subject with diagnosis of prostate cancer​	Wk 24: no change from baseline​
T patch​
Parenteral TE (74)​	33​	44.9 ± 11.6​	812 ± 181 [28.2 ± 6.3]​	66 ± 26 [2.3 ± 0.9]​	0.08​	AE of one subject with diagnosis of prostate cancer​	Baseline:​
0.9 ± 0.7 ng/mL​
Wk 24:​
1.4 ± 2.2 ng/mL​
Oral TU, 80 mg BID​	Several months​	5​	Range, 60–72​	233 ± 148 [8.06 ± 5.13]​	93 ± 42 [3.20 ± 1.46]​	0.40​	RIA​	None​	Not reported​
DHT gel, 125 mg BID (46)​	12​	98.1 ± 94 [3.4 ± 3.26]​	520 ± 272 [17.9 ± 9.38]​	5.3​
Oral TU, 80–200 mg/d (75)​	10 y​	33​	Range, 15–62​	188 ± 40.4 [6.5 ± 1.4]​	90 ± 41 [3.1 ± 1.4]​	0.48​	RIA​	None​	Measured during last 2 y only; within normal limits​
T pellets (1200 mg in single s.c. dose)[SUP]a[/SUP] (76)​	300 d​	14​	32.77 ± 2.59​	742 ± 48 [25.7 ± 1.7 ]​	145 ± 18 [4.9 ± 0.62]​	0.20​	RIA​	Not reported​	Not reported​
Transdermal DHT gel (70 mg DHT/d) (51)​	3 mo​	17​	68.2 ± 1.15​	144 ± 57 [4.99 ± 1.98]​	534 ± 99 [18.4 ± 3.4]​	3.7​	RIA​	None​	Mean increase of 1.0 ng/mL​
Transdermal DHT gel (125–250 mg DHT/d) (52)​	6 mo​	54​	58.4 ± 5.3​	170 ± 1112 [5.89 ± 3.88]​	238 ± 133 [8.19 ± 4.58]​	1.4​	RIA​	None​	No change​
Transdermal DHT gel (70 mg/d) (54)​	24 mo​	56​	60.5 ± 0.7​	69.2 ± 43.5 [2.4 ± 1.5]​	733 ± 497 [25.2 ± 17.1]​	10.6​	LC-MS/MS​	None​	Mean increase of 0.2 ng/mL​
Parenteral TE​	5 mo​	11​	Young: 18–35​	550 [19.01]​	125 mg TE/d: 50 ± 2.5 [1.72 ± 0.09]​	0.09​	LC-MS/MSRIA[SUP]c[/SUP]​	Not reported​	Not reported​
Weekly dose of 125 mg (hypogonadism induced with GnRH agonist)[SUP]b[/SUP] (9)​	11​	Older: 60–75​	778 [26.9]​	125 mg TE/d: 70 ± 5.0 [2.41 ± 0.17]​	1.0​	Not Reported​	Not Reported​
Parenteral TU (750 mg TU at 0 and 4 weeks and then every 10 weeks) (77)​	84 wk​	93​	54 ± 0.9​	495 ± 142 [17.2 ± 4.9] (Cavg days 0–70 after third injection)​	25 ± 10 [0.86 ± 0.34]​	0.05​	LC-MS/MS​	AE of one subjects with diagnosis of prostate cancer​	Baseline: 1.0 ng/mL​
84 weeks: 1.4 ng/mL​

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Abbreviations: AE, adverse event; ART, androgen replacement therapy; BID, twice daily; Cavg, average T concentration; s.c., subcutaneous; TID, three times daily.
aCalculated during period when serum T in response to T pellets was measured and in the eugonadal range (i.e., between 21 and 175 days after dosing).
bTE dosages of 25, 50, 125, 300, and 600 mg/wk evaluated, but only data for 125 mg/wk included in this table as this is the typical dosage used for the treatment of adult male hypogonadism.
cCorrelation between LC-MS/MS and RIA assay was 0.99.
In addition, we have been unable to identify a single epidemiological study that has implicated serum DHT as a factor positively associated with an increased risk of prostate cancer. Data from 18 prospective studies that included 3886 men with incident prostate cancer and 6438 control subjects were pooled and analyzed by the Endogenous Hormones and Prostate Cancer Collaborative Group (78) in an effort to determine what associations, if any, existed between serum androgens (among other factors) and prostate cancer. Results from this analysis failed to identify any correlation with DHT (nor with the terminal metabolite of DHT, androstanediol-glucuronide) and prostate cancer. Given the potential for the prostate gland to regulate intraprostatic concentrations of T, DHT, and estradiol, along with metabolism of these hormones, this finding is not surprising. Moreover, it is becoming increasingly clear that intraprostatic genetic control mechanisms and genetic susceptibility to gene mutations, translocations, and various loci recently identified (79–82) are responsible for such control. These genetic events are beyond the scope of this review but are likely to be much more important in prostate cancer risk than circulating levels of T or DHT.
Based on our review of the available DHT safety data in young and older men (the majority of which is included in this review), we conclude that the modest increase in DHT concentrations and DHT/T ratios commonly associated with TRT pose a low probability of risk for prostate disease. And although long-term safety evaluations appropriately powered to assess disease end points (including prostate cancer and urinary retention) are needed to formally evaluate this risk, such studies will be problematic given the challenge of evaluating DHT effects in the presence of other endogenous androgens, most notably T. To this end, use of an injectable or transdermal DHT preparation in a prospectively designed outcomes study merits consideration.
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Intraprostatic Control of DHT in the Presence of Fluctuating Levels of Circulating Androgens​

The prostate is not a passive recipient of circulating T and DHT but rather has the ability to synthesize and metabolize these androgens. Therefore, except when serum T levels are extremely low, intraprostatic DHT levels are primarily controlled by intraprostatic factors rather than circulating T and DHT levels. To understand the various paths by which DHT can accumulate in the prostate, we briefly review here T and DHT synthesis and metabolism, and the evidence that these intraprostatic pathways are the primary controls of intraprostatic DHT levels.

 

[BadassBlues]

DHT sources in the prostate​

Although DHT enters many tissues through diffusion from the systemic circulation, DHT in the circulation does not diffuse into the prostate because DHT concentrations in the prostate are markedly higher than the systemic circulation (intraprostatic DHT is on average 6- to 10-fold higher than circulating DHT) (83, 84). The vast majority of DHT in the prostate is derived from three sources: (1) the classical pathway whereby testicular and adrenal T diffuses into the prostate and is converted, in situ, into DHT by SRD5A (shown in solid gray arrow in Fig. 3); (2) synthesis directly from 17-hydroxypregnenolone and 17-hydoxyprogesterone (known as the backdoor pathway and shown in short gray arrows in Fig. 3); and (3) intracrine reverse synthesis (back conversion) from the DHT metabolite 5α-androstane-3α,17β-diol (3α-diol) through the oxidative function of 3α-HSD (upward arrow in Fig. 3). The prostate also can metabolize DHT to inactive glucuronides by various irreversible pathways (see Figs. 1 and and3).3). The control of these processes undoubtedly plays a role in regulating DHT levels in prostate tissue and, more specifically, in certain cell types within prostate. In addition, some DHT may enter the prostate if it is bound to SHBG because megalin on prostatic cells can bind SHBG and transport the DHT-SHBG complex into the cell (28). However, the contribution of this pathway is considered to be relatively modest (85). Collectively these various pathways of DHT synthesis and metabolism, many of which are tightly regulated, maintain a steady DHT/T ratio in the prostate cells that is relatively indifferent to high or low circulating DHT levels.

[IMG alt="An external file that holds a picture, illustration, etc.Object name is er.2016-1067f3.jpg"]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459338/bin/er.2016-1067f3.jpg[/IMG]
Figure 3.
The classical and “back-door” pathways of androgen biosynthesis. In the classical pathway (solid gray arrow), C21 precursors (pregnenolone and progesterone) are converted to the C19 adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione by the sequential hydroxylase and lyase activities of CYP17A1. Circulating adrenal androgens [including dehydroepiandrosterone-sulfate (DHEA-S)] enter the prostate and can be converted to T by a series of reactions involving the activity of HSD3B, HSD17B, and aldo/keto reductase (AKR1C) enzymes. T is then converted to the potent androgen DHT by the activity of SRD5A. In the back-door pathway to DHT synthesis (short gray arrows), C21 precursors are first acted upon by SRD5A and the reductive 3α-hydroxysteroid dehydrogenase (3α-HSD) activity of AKR1C family members, followed by conversion to C19 androgens via the lyase activity of steroid 17α-monooxygenase (CYP17A) and subsequently to DHT by the action of HSD17B3 and an oxidative 3α-HSD enzyme. Redrawn from Mostaghel and Nelson (4).

Impact of changes in systemic T and DHT on intraprostatic T and DHT in hypogonadal men​

Prostate cancer occurs in men with low circulating T, and it has been estimated that 14% to 35% (86, 87) of men with prostate cancer are hypogonadal at the time of diagnosis. Furthermore, and for reasons that are not understood, it has been reported (reviewed in Raynaud) (88) that low T levels are associated with higher Gleason scores on prostate core biopsies and positive surgical margins after prostatectomy (86–89). These data suggest that low circulating T and DHT levels do not lower the risk of prostate cancer and, in fact, may predispose to more aggressive tumors, supportive of the concept that intraprostatic synthesis of DHT can come from sources other than circulating T. An alternate explanation is that SRD5A is so finely modulated that intraprostatic DHT levels only fall when the substrate (i.e., T) is very low. This possibility is discussed later. From an oncology perspective, regardless of the mechanism(s) at play in prostate that control DHT synthesis, the fact that DHT can be synthesized within prostate tissue helps to explains why androgen deprivation therapy (ADT) is not totally effective in controlling prostate cancer. Notably, blockade of residual androgen synthesis (including DHT) through all pathways mentioned previously by abiraterone (CYP17 inhibitor) has been shown to prolong survival in men with prostate cancer (90, 91).

 

[aloetard]

Great posts. Thank you! My prostate definitely has taken a beating with the high TOT dosing. BPH sucks. Fortunately my PSA continues stay rock bottom at 0.4. History of prostate cancer in my family so I am rolling the dice with TOT. Probably better to alternate TOT and TRT than blast all the time. That way you are getting the latest supraphysiologic androgen treatment for resistant prostate cancer as part of your protocol.

 

[BadassBlues]

Great posts. Thank you! My prostate definitely has taken a beating with the high TOT dosing. BPH sucks. Fortunately my PSA continues stay rock bottom at 0.4. History of prostate cancer in my family so I am rolling the dice with TOT. Probably better to alternate TOT and TRT than blast all the time. That way you are getting the latest supraphysiologic androgen treatment for resistant prostate cancer as part of your protocol.

The interesting thing to me was that the highest incidence of prostate cancer is in hypogonadal men.

 

[Guided_by_Voices]

I'm curious if you find the gel to have a better or different affect from DHT-like compounds like proviron? Many people seem to get a panacea of benefit from DHT-related things (and I'm happy for you if you're one of them) but at least at low doses, I have never felt any benefit, but I haven't tried the gel.

 

[Gman86]

Great posts. Thank you! My prostate definitely has taken a beating with the high TOT dosing. BPH sucks. Fortunately my PSA continues stay rock bottom at 0.4. History of prostate cancer in my family so I am rolling the dice with TOT. Probably better to alternate TOT and TRT than blast all the time. That way you are getting the latest supraphysiologic androgen treatment for resistant prostate cancer as part of your protocol.

What symptoms of BPH do u have?

 

[Gman86]

When u say u’ve resumed using topical DHT, are u referring to the dht gel ur applying to ur penis every day?

 

[BadassBlues]

I'm curious if you find the gel to have a better or different affect from DHT-like compounds like proviron? Many people seem to get a panacea of benefit from DHT-related things (and I'm happy for you if you're one of them) but at least at low doses, I have never felt any benefit, but I haven't tried the gel.

I have never tried Proviron, so I couldn't give any kind of opinion. I would like to at some point. I can tell you however, that the libido boost and the mood enhancement from the topical are nothing short of fantastic (for me). It's a little annoying at times when I am working or doing something and am horny as Hell

 

[aloetard]

What symptoms of BPH do u have?

Benign prostatic hyperplasia (BPH) - Symptoms and causes

www.mayoclinic.org

Spoiler: Click here

Common symptoms of BPH include:

Frequent or urgent need to pee, also called urination.
Peeing more often at night.
Trouble starting to pee.
Weak urine stream, or a stream that stops and starts.
Dribbling at the end of urination.
Not being able to fully empty the bladder.

 

[Gman86]

Benign prostatic hyperplasia (BPH) - Symptoms and causes

www.mayoclinic.org

Do u have all those symptoms? Jc, cuz I definitely get up to pee quite a bit each night, but don’t have any of the other symptoms, that im aware of. So jc if u have one or two, or like all of them

 

[aloetard]

Do u have all those symptoms? Jc, cuz I definitely get up to pee quite a bit each night, but don’t have any of the other symptoms, that im aware of. So jc if u have one or two, or like all of them

The bolded ones. This one is the most annoying...

What can I do about urinary dribbling? - Harvard Health

Dripping urine after going to the bathroom is common as men age, but a simple "milking" technique can help prevent this....

www.health.harvard.edu

Have to spin the wang for a minute after urinating. Like a helicopter blade.

 

[Gman86]

The bolded ones. This one is the most annoying...

What can I do about urinary dribbling? - Harvard Health

Dripping urine after going to the bathroom is common as men age, but a simple "milking" technique can help prevent this....

www.health.harvard.edu

Have to spin the wang for a minute after urinating. Like a helicopter blade.

What do u think ur BPH is from, just using too many androgens per week?

Seems like I only have the one symptom of needing to pee quite a few times throughout the night. So don’t think I have BPH. At least hope I don’t. Don’t have any of the other symptoms. And if I stop drinking water like 4-5 hours prior to going to bed, sometimes I only have to wake up once to pee while I’m sleeping. It’s very rare that I don’t get up at all