madman
Super Moderator
Everyone needs to keep in mind when jumping on oral T (Jatenzo or native T) that many may not do well.
* serum T levels and clinical responses vary
Most on trt pursue injections due to allowing one to easily achieve healthy, high let alone absurdly high levels steady-state.
This is a given.
To top it off body composition changes would be far greater when using injections as opposed to oral T let alone Natesto.
This alone would deter most from ever jumping on Jatenzo or Natesto!
Unfortunately too many want to be jacked up on T 24/7.
When it comes to building muscle high T levels steady-state is where it's at and there is no denying such.
The sad fact of the matter is many are brainwashed into thinking that more T is better.
For many years we have been stressing the point that many are overmedicated when it comes to testosterone therapy.
Too many caught up on that neanderthal mindset you know that more T is better mentality.
Unfortunately many are jacked up on T from the get-go let alone many are also dick riding that so-called OPTIMAL bull****!
Too many get caught up in expecting to feel great 24/7 once on trt as if testosterone is going to cure all that ails them.
So much misinformation spewed on the numerous forums/gootube let alone some of those knumbskulls that LURK on here!
*neanderthal mindset that more T is better
*high T = raging libido/titanium erections
*high T = OPTIMAL as in that fairytale everyone is chasing.....you know the one with raging libido/titanium erections 24/7, unlimited amounts of energy, stellar mood (Mr. Rogers neighborhood), packing on muscle like the hulk with the recovery abilities of wolverine.....LMFAO.
Hard to say what level you will hit when using the minimum dose of 200 mg.
A not-so-impressive T level let alone Cmax or you may be one of the lucky ones.
Need to keep in mind that the studies done were short-term and used a small number of patients.
THERAPEUTIC EFFECTIVENESS OF ORAL TESTOSTERONE (1974)
Summary
200 mg. of free testosterone (2-5 µ particles compressed into conventional tablets) produced normal male serum-testosterone levels for 5-7 hours in four subjects without testicular function. Serum-testosterone levels were still at least five times higher than initial values 6-8 hours after tablet ingestion. The clinical effectiveness of oral free testosterone 100 mg. 4 times a day was established in a double-blind trial in five eunuchs. It is concluded that artificial testosterone derivatives have no advantages, either in effect or cost, over oral androgen therapy. Adequate oral doses of natural free testosterone are fully effective in replacing hormonal testicular function.
Introduction
EARLY workers stated that free testosterone was not effective when given by mouth.l2 The lack of effect was attributed to inactivation in the liver rather than to intestinal destruction or failure to be absorbed.3 Thus, the therapeutic use of oral-free testosterone was abandoned. Free testosterone is clinically effective when it is slowly absorbed by the sublingual route 2 and from suppositories in the rectum.4’ However, neither of these methods of administration became widely used. Instead, artificial derivatives of testosterone, capable of resisting inactivation in the liver, were developed for oral androgen therapy. 17a-methyltestosterone has been used for more than 20 years. However, this compound affects liver function and may cause jaundice,s, and side-effects of this sort are likely to occur. with other 17a-substituted androgens, such as fluoxymesterone. Mesterolone is a newer artificial testosterone derivative for oral use.
However, the therapeutic effects of all artificial hormones are generally deduced from animal experiments, and such effects vary widely from one species to another. Precise data on the clinical effects of androgens are difficult to obtain in men.
We have found that natural testosterone, which is now fairly cheap, is fully effective when given orally in sufficiently high doses.
Material, Methods, and Patients
Tablets of free testosterone were used in double-blind tests in eunuchs. Testosterone particle size was 3-5 A, with few particles greater than 12 JL (maximum 15 u). In the tablets used in the serum-testosterone studies, the particle size of testosterone was 2-5 11. However, in these tablets, there was a limited number of larger particles (size about 50 ju.). These large particles were less than 1% in number and accounted for about 10% of the surface area of testosterone. Testosterone tablets (25, 50, and 100 mg.) were made in a conventional way with lactose and potato starch. For the double-blind tests, the tablets were coded together with placebo tablets of identical size and shape. The code remained unbroken until the end of the tests.
Serum-testosterone was measured by a modified specific radioligand assay.6 Ether extracts from serum were completely separated into testosterone, dihydrotestosterone, and androstanediols by chromatography on ’Celite’ (kieselguhr) columns. After chromatography, the relevant eluates were subjected to radioligand assay using an antiserum showing no cross-reactions with any testosterone metabolites other than those mentioned above. Thus, 17- ketosteroids, presumably present in large amounts in some of the samples from the present study, did not interfere with the assay. The addition of labeled testosterone at the start of the assay indicated the recovery rate. The day-to-day variation was ± 12 %.
Only patients without testicular function were included in this study. The four patients in whom serum-testosterone levels were measured after testosterone tablets were ingested consisted of two men with severe eunuchoidism aged 24 and 37 years, a man of 21 who had lost both testicles in a machine accident 4 months before the study, and a female transvestite of 43 who wanted to change sex. The five male patients participating in the double-blind tablet trials all had severe eunuchoidism with complete testicular atrophy. They were aged from 23 to 44 years. These patients had all previously been on various forms of testosterone medication. In two patients this therapy was stopped 1-2 months before the trial, and in the other three, it was continued until the beginning of the trial. This difference apparently had no effect on the outcome of the double-blind test. None of the patients studied was obese.
Results
Serum-testosterone after Testosterone Tablets
Serum-testosterone levels before and after the administration of four 50 mg. testosterone tablets are shown in the accompanying figure. As expected, all patients without testicular function had very low testosterone levels in the two blood samples drawn in the morning. 200 mg. of oral free testosterone was given at 8.30 A.M. followed by bread and tea, and blood was drawn at 9 A.M. and thereafter every hour for 6 hours. In one patient further samples were drawn 8 and 232 hours after the tablets were taken. -L 2- 11 hours after the tablets were taken, serum-testosterone levels rose at least 5-fold and came well within the range for normal men. Normal levels were maintained for at least 5 hours with only a slow decline. Even after 6 hours, and in the one patient after 8t hours, serum-testosterone was more than 4 times higher than before the tablets were administered and were still within the normal range. In the patient examined the next morning, there was no more testosterone in the blood than before the tablets were taken.
Serum-testosterone levels before and after oral ingestion of 200 mg. free testosterone in 4 patients without testicular - function.
Discussion
Our results demonstrate that the effectiveness of micronized free testosterone by mouth depends on the dosage. Our clinical double-blind trials in eunuchs showed that 100 mg. testosterone per day was ineffective, whereas 400 mg. per day was fully effective.
These results accord with our finding that 200 mg. free testosterone given once orally can maintain a normal male serum-testosterone level for many hours in patients without testicular function.
The figure indicates that the half-life of testosterone in serum after ingestion of tablets is about 5-7 hours. This is surprising since the turnover of testosterone in the blood is very rapid.7,8 The reason why high testosterone levels are maintained in the blood for a considerable time after ingestion of testosterone tablets seems to be that testosterone is absorbed very slowly from the intestine. The fact that the tablets used to study serum testosterone contained a few large particles of testosterone can hardly explain the long effect since these large particles did not constitute more than about 10% of the surface area of testosterone. The extended effect is an advantage during therapy, and we intend to change our standard treatment with oral testosterone to tablets only twice a day.
We recommend an oral testosterone dose in total testicular failure of 400 mg. per day (2 X 200 mg.). This dose in mg. substance is 3-4 times higher than that recommended for methyltestosterone or mesterolone. Free testosterone is reasonably cheap and 100- 200 mg. testosterone tablets made conventionally by hospital pharmacies will cost the same as commercial tablets containing patented artificial testosterone derivatives
An oral dose of 400 mg. testosterone per day is no less than 20-40 times greater than the endogenous testosterone secretion in normal men, and could be regarded as a heavy load on liver metabolism. However, testosterone follows a metabolic pathway in the liver (reduction and coupling to glucuronic acid) which is common to various substances, including drugs and normal metabolic breakdown products. The capacity of this pathway is presumably very large. We have used oral free testosterone as a standard androgen treatment for 4 years in a considerable number of hypogonadal men, with good results and without producing any side effects.
Oral Testosterone in Oil Plus Dutasteride in Men: A Pharmacokinetic Study (2005)
Testosterone (T) is not administered orally, because it has been reported to be rapidly metabolized by the liver. We hypothesized that sufficient doses of T or T enanthate (TE), administered orally in oil, would result in clinically useful elevations in serum T.We also hypothesized that coadministration of dutasteride (D) with T or TE would minimize increases in serum DHT seen previously with oral administration. Therefore, we conducted a pharmacokinetic study of oral T and TE in oil, with and without concomitant D, in normal men whose T production had been temporarily suppressed by the GnRH antagonist acyline. Thirteen healthy men (mean age, 24 6 yr) were enrolled and assigned to oral T (n =7) and oral TE (n= 6) groups and were administered 200, 400, or 800 mg of either T or TE in sesame oil in the morning on 3 successive days 24 h after receiving acyline. Blood samples for measurement of serum T and dihydrotestosterone were obtained before T or TE administration and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h after administration. Subjects were then administered D for 4 d before repeating the sequence of T or TE doses with D. Serum T was significantly increased in a dose-dependent fashion with the administration of oral T or TE in oil. Coadministration of D with oral T or TE significantly increased the 24-hr average serum T levels compared with administration of T or TE alone [average serum T after 400 mg dose, 8.7 3.0 nmol/l (T) and 8.3 5.7 nmol/l (TE) vs. 16.1 5.8 nmol/l (T D) and 15.0 8.8 nmol/l (TE D); P < 0.05 for T vs. T and D]. The administration of oral T or TE in oil combined with D results in unexpected and potentially therapeutic increases in serum T. Additional studies of this combination as a novel form of oral androgen therapy are warranted. (J Clin Endocrinol Metab 90: 2610 –2617, 2005)
TESTOSTERONE (T) IS crucial for male health. The normal male testes produce 4 – 8 mg T daily (1, 2). Depending on age, 2.5–10% of men have T levels below the normal range (3). T has effects on a variety of tissues, including brain, liver, muscle, bone and bone marrow, blood vessels, skin, prostate, and penis. Men with T deficiency have symptoms of depression, reduced libido, and low energy and suffer from anemia, osteoporosis, and debilitating muscle weakness. These men require T replacement therapy to improve well-being, maintain bone and muscle mass, and retain healthy sexual function (4 – 8), yet there is no acceptable form of oral T for therapy in the United States.
Most T regimens in the United States depend on parenteral injections, skin patches, gels, or buccal tablets (9 –11) because currently available oral forms of T are alkylated and cause liver toxicity when used long term (11–16). Injections are administered im every 1–3 wk and can be painful (17). Some T patches can cause moderate to severe skin reactions due to the vehicle that facilitates T absorption across the skin (18). The T gels are effective and generally well accepted by patients, but are expensive, and care must be taken to avoid inadvertent exposure to women and children (19).
Oral administration of unmodified T at doses up to 100 mg have little effect on serum T levels in T-deficient men (20, 21); however, 200-mg doses of oral T have been shown to elevate serum T levels to the low normal range for up to 8 h (22, 23). At the time, these serum T levels were thought to be insufficient for clinical use, and research into using unmodified oral T was largely abandoned.
Testosterone undecanoate (TU) is a T ester currently given orally in oil and used clinically in Europe and Canada for the treatment of T deficiency. When administered orally, TU therapy results in therapeutic increases in serum T; however, it also results in elevations in serum dihydrotestosterone (DHT) well above the normal range (24 –27). Because DHT is required for cell growth within the prostate, concern has been raised about the potential for long-term harm associated with oral TU therapy from the elevated levels of serum DHT; however, no increased risk of prostate disease has been reported to date
Because the androgen TU is absorbed well in oil, we believed that other androgens such as T enanthate (TE) and potentially T itself might be well absorbed if also administered orally in oil. Moreover, because the recently available 5-reductase inhibitor, dutasteride (D), lowers serum DHT levels more than 90% by inhibiting both isozymes of 5- reductase (28), we hypothesized that oral administration of the combination of higher doses of unmodified T or the T ester, TE, in oil, when combined with D, would be safe and result in therapeutic serum T levels. In addition, we hypothesized that the concomitant administration of the 5-reductase inhibitor D with T or TE would further increase serum T levels while minimizing the elevations in serum DHT seen after oral administration of oral androgens such as TU. If effective, we believed that this novel means of T therapy would allow for selective androgen therapy in men with T deficiency. Therefore, we conducted a pilot study of the oral administration of single doses of T and TE with and without concomitant administration of D to determine the pharmacokinetics and safety of single high doses of oral T in oil in healthy men rendered temporarily hypogonadal with the GnRH antagonist acyline.
Materials and Methods
Subjects
Fourteen healthy, normal male volunteers between 18 and 45 yr of age were recruited through local news media (newspaper and radio) and college campus bulletin boards and enrolled in the study. The inclusion criteria were no prior medical illnesses, normal physical examination, routine hematology, blood chemistry, and liver function. Exclusion criteria included regular use of any medication; abnormal serum T, DHT, or estradiol (E2); or previous or current ethanol, illicit drug, or anabolic steroid abuse. A total of 16 men were evaluated for eligibility. Of these, 14 men were potentially eligible and agreed to participate in the study. The two men who did not enroll in the study were excluded for elevated bilirubin (one subject) and the use of finasteride (for the treatment of male-pattern baldness). One enrolled subject failed to appear for his acyline injection and was therefore not studied further; thus, 13 men completed the study period. The institutional review board of the University of Washington approved all study procedures, and subjects gave written informed consent before the screening.
Study design
Participants were randomly assigned to one of two groups: 1) oral T in sesame oil or 2) oral TE in sesame oil (Delatestryl, BTG Pharmaceuticals, Iselin, NJ) at a concentration of 200 mg/ml. A sample size of seven subjects per group was estimated to have an 80% power with an of 0.05 to detect a 50% in the change in serum T area under the curve between a given dose of T and T plus D or between TE and TE plus D. The oral T in sesame oil was manufactured by the compounding pharmacy at University of Washington. Briefly, micronized T (U.S.P. grade, Spectrum Quality Projects, Gardena, CA) was suspended at 100 mg/ml in sesame oil (N.F. grade, Spectrum Quality Projects) and mixed thoroughly on a magnetic stir plate to create a homogenous T/sesame oil emulsion. The compounding pharmacist then drew up the emulsion into syringes at the desired dose levels (200, 400, and 800 mg) immediately before treatment. The syringe was sent to the Clinical Research Unit, where it was vigorously mixed (by shaking) with milk and administered to the subject. The dose of oral TE in sesame oil was normalized for the T content, so that the subjects in the TE group (molecular weight, 397) were administered 276, 554, and 1108 mg TE, corresponding to 200, 400, and 800 mg T. The drug exposure period lasted 11 d (Fig. 1). On d 0, subjects received a single injection of the GnRH antagonist acyline (300 g/kg, sc), which has been shown to suppress T production in normal men for a minimum of 15 d (29). One, 2, and 3 d after acyline administration, subjects drank 200, 400, or 800 mg T or 276, 554, or 1108 mg TE. Subjects self-administered D (0.5 mg, orally, once daily) on d 5–10 after acyline injection, and doses of T and TE were repeated on days 8, 9, and 10. For safety, the subject underwent daily testing of liver function (aspartate aminotransferase, bilirubin, and alkaline phosphatase), kidney function (urea nitrogen and creatinine), and hemopoiesis (hemoglobin and hematocrit).
Measurements
After treatment on d 1, 2, 3, 8, 9, and 10, subjects had blood was drawn via a heparin-locked iv line at 30 min and 1, 2, 4, 6, 8, 10, 12, and 24 h for measurement of serum T, DHT, E2, and SHBG. Total T was measured by an RIA (Diagnostic Products Corp., Webster, TX) The assay had a sensitivity of 0.35 nmol/liter; interassay variations for low, medium, and high pools of 13.6%, 6.1%, and 6.8%, respectively; and intraassay variations of 10.0%, 5.3%, and 6.6%. The normal range was 8.7–33 nmol/liter. DHT was measured using an RIA kit (Diagnostic Systems Laboratory, Inc., Los Angeles, CA). The sensitivity of this assay was 0.043 nmol/liter, and the intraassay variations for medium and low range pools were 9.9% and 11%, respectively, with interassay coefficients of variations of 19% and 25%. The normal range for serum DHT was 1.0 –2.9 nmol/liter. SHBG was measured by RIA (Delphia, Wallac Oy, Turku, Finland). The sensitivity of this assay was 0.2 nmol/liter, and the interassay variations for low, medium and high pools were 31%, 10.6%, and 6.8%, respectively; the intraassay variations were 3.8%, 1.7%, and 2.2%. The normal range was 3.2– 47 nmol/liter. The normal ranges for T, DHT, and SHBG were determined in our laboratory using serum samples obtained from 100 normal men, aged 20 –50 yr. Serum E2 was measured in the laboratory of Dr. David Hess (Oregon National Primate Research Center, Portland, OR) with an Elecsys 2010 Platform (Roche, Indianapolis, IN). The sensitivity of this assay was 5.5 pmol/liter, intraassay variations were 3.7%, and 2.8% for medium and high range values, and the interassay coefficient of variation was 4.7%. The normal range for serum E2 in this assay in men was 40 –220 pmol/liter.
Results
Subjects
Fourteen men were enrolled in the study; seven were randomized to the T group, and seven were randomized to the TE group, but one man assigned to the TE group failed to report for his acyline injection. Therefore, seven men completed the T arm, and six completed the TE arm of the study (Table 1). Except for the subject who failed to appear for his acyline injection, all subjects completed the drug exposure period. There were no serious adverse effects during the study. Nine of the subjects experienced transient mild pruritis at the site of the acyline injection, which resolved in all cases within 1 h of the injection. Eight subjects complained of mild, transient hot flash symptoms toward the end of the study period, presumably due to low T levels; however, no subject complained of feelings of anger, aggression, or irritability during treatment. There were no adverse gastrointestinal symptoms associated with oral T or oral TE in oil. One subject developed a small area of gynecomastia (1 1 cm) immediately under the nipple during the treatment period, but this resolved during follow-up. There were no changes in serum markers of liver or kidney function or in the hematocrit or hemoglobin during the treatment phase or at follow-up. Furthermore, no significant changes in blood pressure or pulse were observed. T and gonadotropin levels returned to baseline in all subjects during the follow-up period (data not shown). No subjects were lost to follow-up.
Serum T
All subjects were suppressed to castrate levels of T by 24 h after acyline administration (d 0 T, 20.0 7.4; d 1 T, 2.3 0.5 nmol/liter; P 0.0001). There was no difference in serum T levels 24 h after acyline between groups [2.3 0.7 (T) vs. 2.3 0.8 (TE); P 0.9]. In addition, mean serum T levels before each dose of T were not significantly different from that 24 h after acyline administration.
With the administration of both oral T and oral TE in oil, serum T was significantly increased in a dose-dependent fashion (Fig. 2; P 0.01 for trend). In addition, the maximum concentrations of T, average concentrations of serum T, and area under the curve of serum T increased significantly in a dose-dependent fashion (Table 2 and Fig. 3A), with the maximum concentration of T after oil dosing exceeding the normal range for the 800-mg dose of T and the 400- and 800-mg doses of oral TE in oil. The time of maximum concentration was between 2.5 and 4.5 h in all cases, and the calculated terminal t1/2 of oral T and TE in oil was between 7.5 and 11 h. Coadministration of D with oral T or TE in oil significantly increased the resulting serum T levels compared with administration of T or TE alone (Fig. 2; P 0.01 for trend). The maximum concentration of T after oral treatment with the combination of T or TE and D exceeded the normal range for both the 400- and 800-mg doses of T and TE in oil. Similar to the administration of T or TE only, the time to maximum concentration remained between 2.5 and 4.5 h, and the calculated terminal t1/2 was between 8 and 10 h. The T area under the curve for the combination of T and D was significantly increased at all doses compared with that for T alone [200 mg, 124 28 nmol-h/liter (T alone) vs. 176 45 nmol-h/liter (T D); 400 mg, 208 74 nmol-h/liter (T alone) vs. 393 nmol-h/liter (T plus D); 800 mg, 328 82 nmol-h/liter (T alone) vs. 846 363 nmol-h/liter (T plus D); P 0.01 for all comparisons].
Discussion
In this study, we have demonstrated that single doses of T or TE when administered orally in oil can result in serum T levels that would be useful for the treatment of T deficiency. Secondly, we have demonstrated that the addition of the 5- reductase inhibitor D to oral T in oil 1) significantly increases the serum T levels achieved after a given dose of T, and 2) attenuates the supraphysiological elevations in serum DHT seen with the administration of oral T or T esters (e.g. TU) without concomitant 5-reductase inhibition.
These data contradict the prevailing wisdom in the field, which states that the oral route for T delivery is impractical due to the near-complete hepatic first-pass metabolism of orally administered T (11). Although it is true that the bioavailability of orally administered T is very low, probably around 1% (30, 31), our work demonstrates that if sufficient T is administered orally in oil, potentially therapeutic levels of serum T can be achieved after oral dosing. It is likely that liver metabolism of orally dosed T is extensive because oral T administered to men with cirrhosis results in serum T levels that are markedly elevated compared with normal controls (32, 33). Whether long-term administration of oral T in oil would induce increased hepatic metabolism of oral T and therefore reduce T bioavailability will be the subject of future research.
Previous studies of the oral administration of T may have found reduced levels of serum T in part due to 5-reductase activity in the intestine and liver (34). In this study using T or TE, and in the work of others with TU (24 –27), serum levels of DHT after oral administration are markedly elevated, implying that a large fraction of the orally administered T dose may be metabolized in the liver and intestines to DHT. Surprisingly, in this study, the coadministration of a 5-reductase inhibitor roughly doubles the average T concentration and the area under the curve for the serum T while reducing the elevations of serum DHT by approximately half. These marked elevations in serum T with concomitant 5-reductase inhibition are probably due to inhibition of the 5-reductase enzyme in the intestine and liver, which appears to account for approximately one-half of the metabolism of T after an oral dose. Importantly, the combination of elevated serum T without marked elevations in serum DHT may allow for selective oral androgen therapy, which may be useful in decreasing the risk for DHT-dependent diseases, such as benign prostate hyperplasia and prostate cancer.
It is also important to note that previous studies of oral T administration demonstrating poor oral bioavailability of T have used T in powder form at doses of 100 and 200 mg (21–23). We have tested oral T in powder form in doses as high as 400 mg without achieving therapeutic serum T levels (data not shown), implying that the administration of T in oil is crucial for the achievement of the therapeutic serum T levels seen in this study. It has been previously shown that the absorption of oral TU is markedly affected by the concomitant intake of fatty foods (27, 30). This is probably due to the fact that much of the orally administered TU is absorbed via the lymphatics (35). In an animal model of TU absorption, more than 80% of the bioavailable T is thought to be absorbed via lymphatics (36). Whether food intake will affect the absorption of oral T in oil is unknown and probably depends on how much of the dose is absorbed via lymphatics vs. via the portal circulation. Because T was administered in oil in this study, some of the doses may have been absorbed via the lymphatics. This might explain in part the unexpectedly long serum half-life of T seen with oral compared with iv administration of T, which has been reported to have a half-life of less than 1 h (31, 37). Another possibility is that there is some degree of enterohepatic circulation of the orally administered T, prolonging the apparent half-life in serum. Because of this uncertainty, the impact of food intake on the absorption and serum levels of T after the administration of oral high dose T will be the subject of future study.
It is important to note that there was no evidence of either liver or kidney toxicity associated with the doses of oral T administered in this study; however, additional long-term study of these doses combined with a 5-reductase inhibitor will be required to determine the safety of this approach to T therapy. Although one subject did report transient gynecomastia, this subject’s serum E2 level remained within the normal range. Additionally, no subject complained of impotence, decreased libido, or sexual dysfunction during the treatment period. These side effects have been reported when D is administered alone for benign prostate hyperplasia (38); however, in theory, they would be less likely when D is administered in combination with T. Additionally, the implication of long-term 5-reductase inhibition will need examination given the increase in high-grade prostate cancer (despite an overall decrease in prostate cancer incidence) seen with chronic finasteride administration in the prostate cancer prevention trial (39).
There were slight, nonsignificant increases in serum E2 seen after oral dosing of T and TE in oil. This implies that although orally administered T can undergo aromatization to E2, it does not do so at high levels, suggesting that there is probably little aromatase activity in the intestine and liver in man. This finding is reassuring in showing that orally administered T is likely to allow for the important functions of estrogen in man, such as maintenance of bone density (40), but not lead to an increased risk of estrogen-related side effects such as gynecomastia.
From a practical standpoint, a regimen using oral T in oil in the formulation used in this study may need to be administered twice daily; however, additional refinements of this approach, such as the use of slow-release capsules, may allow for more controlled release of T in the intestine and could lead to a formulation that could be administered orally once daily, a major improvement over current T replacement options.
In conclusion, we have demonstrated that single doses of T or TE, when administered orally in oil, can result in markedly elevated serum levels of T in normal men with induced hypogonadism; such levels would presumably be therapeutically effective in treating testicular failure. In addition, we have demonstrated that the addition of the 5-reductase inhibitor D to oral T in oil significantly increases the serum T levels observed with a given dose of T and attenuates the supraphysiological elevations in serum DHT seen with the administration of oral T alone. Combinations of oral T and 5-reductase inhibitors may allow for an oral, selective form of androgen therapy. Additional studies of the long-term safety, pharmacokinetics, and pharmacodynamics of this combination are warranted to determine whether it might be a clinically useful and attractive method of treating T deficiency.
TABLE 1. Baseline characteristics of study subjects by group
FIG. 2. Serum T concentrations (mean SEM) after oral administration of 200, 400, and 800 mg T in oil (A–C) and TE in oil (D–F) with and without D for 24 h in normal men treated with the GnRH antagonist acyline to temporarily suspend T production. Note the larger y-axis for the 800-mg dose. The dotted lines represent the upper and lower limits of the normal range for serum T. *, P 0.05 compared with T alone.
TABLE 2. T pharmacokinetics after administration of a single dose of oral T and oral TE in oil with and without D to normal men previously administered a GnRH antagonist
FIG. 3. Average serum T (A) and DHT (B) concentrations (mean SD) over the 24-h interval after oral treatment. The dotted lines represent the upper and lower limits of the normal range for serum T. *, P 0.05 compared with T alone
