Andropause - Male Menopause
Testosterone delivery systems pharmacokinetics and pharmacodynamics; When is the best time to measure levels?
By Allyn A. Brizel, M.D.
Oct 27, 2002, 10:04am

Testosterone delivery systems pharmacokinetics and pharmacodynamics; When is the best time to measure levels?

Initial evaluation for men whom are not on any testosterone replacemnt therapy

>Should be tested in the morning around 9:00am. Circadian rhythms of serum testosterone concentrations in men have been shown, in general, to be highest in the morning and lowest in the evening.
*Patients also should be advised eliminate any exercise starting the evening prior to the blood draw since this has been shown to blunt LH and increase cortisol levels resulting in a lower free and total testosterone level. Thus potentially giving you a false low reading.
*In difficult to interpert cases pooled testosterone and LH levels should be draw on three seperate occasions

Men whom are currently on testosterone replacement therapy

Transdermal Gel:
>Steady state blood levels occur following 4 weeks of application, thus repeat blood test should be done no sooner then 4 weeks upon initiation of first testosterone application. Men whom have only a moderate degree of hypogonadism you might see a dip in testosterone levels at 3 to 4 weeks due to suppression of whatever nature production of testosterone this patient might have prior to the start of therapy. Taking into account the great inter and intra patient variability in the absorption of topical gel peak levels usually occur at 18 hours following application.
> Blood draw should be done 24 hours after previous application and this time frame should be keep constant from one draw to the next.
*Testosterone application immediately following a shower or bath has been shown to increase the absorption of testosterone by 3x (1) compared to application to dry skin
*Testosterone application to 4 sites versus a single site has been shown to increase testosterone levels by 23% and DHT by 33%. (2)

Patch-Testosterone transdermal delivery systems
>The patch provides continuous release testosterone replacement with peak concentrations of sex hormones occurring approximately 8 h after application for T and BT and at 13 h for DHT and E2. (3)
>Patches are applied nightly to mimic the circadian rhythm of a normal healthy male Thus producing peak values first thing in the morning.(4)
>Blood draw for Testosterone levels for men using the patch are best done in late afternoon to estimate the trough value. Otherwise when morning draws are done you must take into account that this will give you peak value.
>Best sites for placement of patch based on the BT levels, the rank ordering of the sites were: back >thigh > upper arm > abdomen > chest > shin (3)

Subcutaneously implanted testosterone (T) pellets:
>Implanted in the sub dermal fat tissue usually in the gluteal area or lower abdomen. This form of TRT provides the most state levels over the longest period of time. With peak levels occurring at 2 weeks followed by a stable plateau lasting until day 63. Thereafter serum T gradually declines and reaches baseline concentrations around day 300.(5)
>Blood levels should be done around day 60 following pellet insertion.
*“T-pellets are the androgen formulation with the longest biological action and strongest pharmacodynamic efficacy in terms of gonadotrophin suppression. The pharmacokinetic features are advantageous compared to other T preparations and the patient acceptance is high.” (5,5a)

Testosterone Injections:
Testosterone Depot (cypionate), Testosterone enanthate
>Quantity and timing of testosterone injection varies from physician to physician with the most common dosage regimens: 100 mg once a week, 200 mg every 2 weeks, 300 mg every 3 weeks, and 400 mg every 4 weeks (6)
>In general following a 200mg testosterone injection levels peak on day 2-3 and plateau out till day 7 following which levels decline to hypogonad levels by day 14- 16. This of course will vary depending on the initial dose of testosterone given. (7,8)
>In my practice I find the best results when using injectable Depot testosterone is using lower doses more frequently e.g. starting dose 100mg each week or 200mg every 2 weeks. This greatly reduces the peak and troughs resulting in more stable blood levels. Levels are then checked and dosage adjusted accordingly.
>When injections are dosed weekly blood draw for testosterone levels should be done on the 7th day prior to the next injection. When dosed every two weeks blood draw can be done a few days later.

*I.m. treatment produced supraphysiological levels of T, bioavailable T, and estradiol (but not dihydrotestosterone) for several days after each injection. These results in increase adverse events when compared to other delivery system e.g. excessive stimulation of erythropoiesis, gynecomastia, reduction of HDL cholesterol and over-suppressing gonadotropins.

Transbuccal and Sublingual Testosterone:
>Rapid rise in testosterone with peak levels at 30 minutes and levels returning to baseline at 6 hours. Due to the rapid rise and fall in levels it most be administered three times per day. Thus this method of replacement when used alone is usually not recommended. (9)
>This rapid rise in testosterone and DHT might be taken advantage of in certain clinical situations.

References:
(1) Rolf C,Clin Endocrinol (Oxf) 2002 May;56(5):637-41
Interpersonal testosterone transfer after topical application of a newlydeveloped testosterone gel preparation

(2)Wang C,J Clin Endocrinol Metab 2000 Mar;85(3):964-9
Pharmacokinetics of transdermal testosterone gel in hypogonadal men: applicationof gel at one site versus four sites: a General Clinical Research Center Study.

(3) Meikle AW J Clin Endocrinol Metab 1996 May;81(5):1832-40
Pharmacokinetics and metabolism of a permeation-enhanced testosterone
transdermal system in hypogonadal men: influence of application site -a
clinical research center study.

(4) McClellan KJ, Drugs 1998 Feb;55(2):253-8; discussion 259
Transdermal testosterone.

(5) Jockenhovel F Clin Endocrinol (Oxf) 1996 Jul;45(1):61-71
Pharmacokinetics and pharmacodynamics of subcutaneous testosterone implants in hypogonadal men.

(5a) Handelsman DJ J Clin Endocrinol Metab 1990 Jul;71(1):216-22
Pharmacokinetics and pharmacodynamics of testosterone pellets in man.

(6) Snyder PJ,J Clin Endocrinol Metab 1980 Dec;51(6):1335-9, Treatment of male hypogonadism with testosterone enanthate.

(7) Nankin HR, Fertil Steril 1987 Jun;47(6):1004-9
Hormone kinetics after intramuscular testosterone cypionate.

(8) Navarro MA, Fertil Steril 1994 Jan;61(1):125-8
Salivary excretory pattern of testosterone in substitutive therapy with testosterone enanthate.

(9) Stuenkel CA,J Clin Endocrinol Metab 1991 May;72(5):1054-9 Sublingual administration of testosterone-hydroxypropyl-beta-cyclodextrin inclusion complex simulates episodic androgen release in hypogonadal men.


Written By
Allyn A. Brizel, M.D.
Director, Center for Clinical Age Management


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