Long-acting Testosterone Esters Research Articles

Intramascular injection therapy of long-acting testosterone ester does not alter the dihydrotestosterone level

Intramascular injection therapy of long-acting testosterone ester does not alter the dihydrotestosterone level

Drug Insight: testosterone preparations

Testosterone has been used for substitution therapy in testicular and hypothalamopituitary diseases for almost six decades, with injectable testosterone esters and implanted testosterone pellets being the mainstay of treatment. Growing interest in the possible use of testosterone in nonclassical situations such as male contraception, aging (late-onset hypogonadism), muscle-wasting conditions like HIV, erectile dysfunction, and female hypoactive sexual disorder has stimulated research, leading to the development of several new modes of administration of testosterone. Transdermal patches, gels, mucoadhesive sustained-release buccal tablets and long-acting testosterone esters are designed to provide testosterone levels that approximate normal physiologic levels, to improve patient acceptability, and to further increase the number of treatment options available. In this Review, we briefly describe the chemistry, mechanism of action, and metabolism of testosterone. We then discuss the pharmacokinetics, advantages, and disadvantages of various formulations and summarize the various preparations currently available.

Testosterone Replacement Therapy for Male Aging: ASA Position Statement

Testosterone Replacement Therapy for Male Aging: ASA Position Statement

The effects of testosterone and oestrogen on gonadectomised and intact male rat anterior pituitary mitotic and apoptotic activity

We have used a direct, non-immunochemical and highly accurate method to quantify the effects of testosterone and oestrogen on mitotic and apoptotic activity in the young, male rat anterior pituitary in vivo. Surgical gonadectomy resulted in a 3-fold increase in mitotic activity by the fourth post-operative day, which returned gradually to levels seen in intact animals over the subsequent 3-4 weeks. Both a single dose of Sustanon, a mixture of long-acting testosterone esters in arachis oil, and the same dose divided over 7 days (starting 6 days after gonadectomy), initially suppressed mitotic activity to levels seen in intact animals, but was associated after 48-96 h with a wave of increased mitotic activity. The latter was blocked by co-administration of Sustanon with the non-steroidal aromatase inhibitor letrozole and was not seen when the non-aromatisable androgen dihydrotestosterone was substituted for Sustanon. Oestrogen alone in gonadectomised and intact rats produced a marked increase in mitosis as expected. With the exception of a transient increase in response to a single high-dose injection of Sustanon in gonadectomised animals, apoptotic activity was unaffected by all of the above. This study suggests that pituitary mitotic activity is tonically inhibited by gonadal hormone production (at least in the short term) in adult male rats. The study also suggests that supraphysiological testosterone treatment -- while unable to reduce anterior pituitary mitotic activity in untreated, intact animals --suppresses the early increase in mitotic activity induced by gonadectomy. Oestrogen, either exogenous or generated locally by aromatisation, stimulates anterior pituitary mitotic activity in a time-dependent manner.

Kontrazeption des Mannes – Geeignet für Jugendliche?

Obwohl effektive Verhütungsmethoden in Deutschland und anderen Industrienationen verfügbar sind, ist die Schwangerschaftsrate bei Teenagern weiterhin hoch. Ursächlich hierfür sind neben anderen Gründen insbesondere die Anwendung ineffektiver Methoden bzw. die fehlende Anwendung auch nur irgendeiner Verhütungsmethode. Existierende männliche Kontrazeptionsmethoden weisen entweder eine unbefriedigende Effektivität (Kondom, Koitus interruptus) auf oder sind nur bedingt reversibel (Vasektomie), was einer weiteren Verbreitung im Wege steht. Von den experimentellen Verhütungsmethoden beim Mann erscheint die hormonelle Kontrazeption zurzeit am weitesten entwickelt. Androgene sind elementarer Bestandteil der hormonellen Kontrazeptiva, da sie über eine Suppression der Gonadotropine zu einer Suppression der Spermatogenese führen und gleichzeitig den durch die Gonadotopinsuppression bedingten Androgenmangel ausgleichen. Wenn auch die Wirksamkeit einer hormonellen Methode bei Männern in klinischen Studien gezeigt werden konnte, so scheiterte die weitere Entwicklung zunächst an dem unpraktikablen Applikationsintervall bzw. an der mangelnden Effektivität der selbst anwendbaren Ansätze. Neuere effektive Ansätze in Phase II Studien konzentrieren sich daher auf die Verwendung von Androgen-Implantaten bzw. langwirksamen Testosterondepotinjektionen in Kombination mit den Gestagenen-Depots Medroxyprogesteron Azetat, Norethisteron, Desogestrel oder Etonogestrel, die zusätzlich zu den Androgenen die Gonadotropine supprimieren. Ob die hormonelle Kontrazeption beim Mann auch eine Alternative für Jugendliche darstellt bleibt nach der Markteinführung abzuwarten. Bedenken ergeben sich insbesondere hinsicht lich der Knochenreifung, da Androgene in den verwendeten Dosen einen vorzeitigen Schluss der Epiphysenfugen bewirken könnten.

The challenges of testosterone deficiency

PREVIEWIn addition to its relatively uncommon congenital causes, testosterone deficiency in men occurs in a diverse range of clinical conditions. Even healthy men are now known to begin experiencing progressive yet subtle declines in testosterone secretion after age 30. Diagnosis can be challenging, and testosterone replacement therapy does not alleviate all symptoms in all men. Nevertheless, some men can get relief with intramuscular long-acting testosterone esters, transdermal testosterone patches, or transdermal testosterone gel.

Testosterone-induced inhibition of spermatogenesis is more closely related to suppression of FSH than to testicular androgen levels in the cynomolgus monkey model (Macaca fascicularis).

We have investigated the antigonadotropic and antispermatogenic effects of exposure to a long-acting testosterone ester in the cynomolgus monkey model. Groups of five adult animals were exposed either to vehicle or to 10 mg/kg or 20 mg/kg testosterone buciclate (TB) over a 26-week period with injections given in weeks 0, 11 and 18. In week 26, testicular biopsy tissue was collected. Serum testosterone levels were in the upper normal range with 10 mg/kg TB and were approximately twofold higher with 20 mg/kg TB. The estradiol pattern followed that of testosterone and body weights increased in a testosterone-dependent manner. TB completely abolished serum LH bioactivity. Serum concentrations of FSH and inhibin-alpha were suppressed in a TB dose-dependent manner. During weeks 4-8 after the first injection, a rebound of FSH and inhibin but not bioactive LH secretion occurred. This rebound was followed immediately by a restimulation of testis size and sperm numbers. After the next TB injections these parameters were once again suppressed. Nadir testis size was 30-40% of baseline and animals were severely oligozoospermic or transiently azoospermic. Consistent azoospermia was not achieved. Quantitation of serum inhibin B, proliferating cell-nuclear antigen staining and flow cytometric analysis of germ cell populations revealed pronounced suppression of spermatogenesis in both TB-treated groups whereas androgen receptor expression remained unchanged. Testicular androgens levels, determined in week 26, did not differ among all three groups and did not correlate with sperm numbers, histological and immunocytochemical findings. All suppressive effects were fully reversed during the recovery period. We have concluded that pronounced suppression of primate spermatogenesis seemingly requires inhibition of FSH rather than testicular androgen levels, at least in this preclinical non-human primate model. For the purpose of male contraception, FSH inhibition appears mandatory.

1 Male contraception

With the powerful tools of molecular investigation, the last decade has witnessed the most remarkable scientific advance in our history, yet no new leads for male contraception have been forthcoming. All the likely methods of male contraception discussed above were derived from relatively 'old' physiological principles or serendipitous observations. The increasing gap between fundamental research (in the control of mammalian spermatogenesis) and the lack of clinical application are a testament to the low public funding priority afforded to male reproduction and the unwillingness of the pharmaceutical industry to invest in male reproductive research and development. Yet amidst such an unfavourable setting and with very limited support, it is heartening to note that the prospects of introducing a new systemic method for male contraception into the market by the end of this millenium has been greatly enhanced. Thus the results of recent studies have confirmed the contraceptive efficacy of sex steroid-induced oligozoospermia and unexpectedly revealed an ethnically distinct pattern of susceptibility to the hormonal suppression of spermatogenesis. Thus, Asian men are more responsive than are caucasian, and long-acting testosterone esters now being tested in that most densely populated part of the world may well hasten the large-scale application of this method. This is probably the most effective way to correct the misconceptions that men are unwilling or disinterested in sharing in family planning options with their partners. Together with the increased acceptance of novel non-surgical and reversible methods of vas deferens occlusion and the availability of improved non-latex condoms, the currently unfulfilled contraceptive needs of millions of men can be increasingly met in future years. The consequent increase in overall contraceptive prevalence could well make the telling difference between demographic catastrophe and maintaining good quality existence. Politicians, scientists and industrialists need to wake up to their responsibilities and the opportunities offered by this untapped resource and market potential.

Effect of testosterone enanthate on follicular growth in rats

The effects of exogenous testosterone enanthate, a long-acting testosterone ester, on estrous activity and reproductive performance in female rats were studied. An injection of 2.5–20.0 mg of testosterone enanthate delayed until 26.9–60.1 days the cycling of the estrous cycle in a dose-dependent way; the treated rats began regular 4-day estrous cycles 41.9–80.7 days after the injection. Subsequent reproductive performance was not different in the treated and control animals (P > .05). Ovarian weight during estrous inhibition decreased steadily after treatment, but the uterine weight increased for a time. The ovaries contained follicles and interstitial cell islands, but no new ovulatory corpora lutea. The injection decreased the number of small follicles (250–549 μm), but increased the number of mature large follicles (≥550 μm; P < .05). The mean testosterone concentration in the peripheral plasma during estrous inhibition was higher than that before the treatment (P < .05). Testosterone concentrations increased for a time after treatment (P < .05), but decreased steadily thereafter. These results suggest that testosterone enanthate might be used for long-term contraception; the effects seem to depend on testosterone. Continuous stimulation by the long-term activity of testosterone inhibited the growth of small follicles but stimulated the growth of large follicles. © 1996 Wiley-Liss, Inc.

Testosterone administration to mares: criteria for detection of testosterone abuse by analysis of metabolites in plasma and urine.

A pharmacological dose of a long-acting testosterone ester, testosterone hexahydrobenzoate, was administered intramuscularly to two mares. The time course for some characteristic metabolites in blood and urine was then studied using an analytical method based on gas chromatography-mass spectrometry associated with stable isotope dilution. Among the plasma analytes, testosterone glucuronide was found to be the most adequate indicator for the monitoring of exogenous testosterone up to 2 weeks postadministration if a threshold value of 200 ng/L was applied. In urine, the simultaneous measurement of the concentrations of testosterone sulfate (TS) and epitestosterone sulfate (ES) allowed the calculation of the concentration ratio, TS/ES, which was independent of urine flow and which offered the possibility of detecting testosterone misuse 20 to 30 days after dosing if a tentative threshold value of 8 was adopted. In addition to this ratio, particularly when the TS/ES ratio was close to the cutoff point, it seemed advisable to take into account the concentrations of 5 alpha-androstane-3 beta, 17 alpha-diol (glucuronide) and its 17 beta-isomer (sulfate), which should not exceed 50 micrograms/L.

Treatment of Constitutional Delayed Puberty with a Combination of Testosterone Esters

Thirteen boys who had constitutional delayed puberty (CDP) were treated with a combination of short- and long-acting testosterone esters (testosterone propionate, testosterone phenylpropionate, testosterone isocaproate). Mean age at the onset of treatment was 14.9 +/- 0.6 years and bone age delay was -2.7 +/- 0.9 years. An intramuscular dose of 200 mg testosterone was administered 4 times at 3-week intervals and the treated CDP boys were followed for 2 years. All boys with CDP entered puberty after the last dose (testicular volume > or = 4 ml) and growth rate increased from 4.5 +/- 0.5 cm/year pretreatment to 8.4 +/- 1.6 cm/year posttreatment after the 2-year follow-up period. Height for bone age SD score did not alter significantly from a mean of -1.1 pretreatment to -1.3 posttreatment as well as predicted height pretreatment (173.5 +/- 6.6 cm) and posttreatment (173.3 +/- 4.9 cm). A combination of testosterone esters in a given dose and schedule is a safe and effective treatment for prepubertal boys with CDP.

Sustained inhibition of sperm production and inhibin secretion induced by a gonadotrophin-releasing hormone antagonist and delayed testosterone substitution in non-human primates (Macaca fascicularis)

Since the concomitant administration of a gonadotrophin-releasing hormone (GnRH) antagonist and testosterone suppresses sperm production only incompletely, the feasibility of treatment with a GnRH antagonist and delayed testosterone supplementation for sustained suppression of sperm production in a non-human primate model was investigated. Adult cynomolgus monkeys (Macaca fascicularis; five/group) received daily s.c. injections of the GnRH antagonist [N-acetyl-D-2-naphthyl-Ala1,D-4-chloro-Phe2, D-pyridyl-Ala3,nicotinyl-Lys5,D-nicotinyl-Lys6, isopropyl-Lys8,D-Ala10]-GnRH of either 450 or 900 micrograms/kg for 18 weeks. During week 6 of the GnRH antagonist treatment, all monkeys were given a single i.m. injection of 40 mg of a long-acting testosterone ester (testosterone-trans-4-n-butylcyclo-hexanecarboxylate; 20-Aet-1). Within 1 week, serum LH bioactivity was suppressed in both groups and remained low throughout the entire treatment period. Similarly, concentrations of serum testosterone declined precipitously. During week 6, substitution with testosterone restored concentrations of serum testosterone into the pretreatment range. Concentrations of serum inhibin declined within 1 week and remained suppressed during the period of treatment with the GnRH antagonist. Testicular volumes were reduced to approximately 25% of pretreatment values in both groups by week 8 and stayed in that range during the remaining period of administration of the GnRH antagonist. During the first 6 weeks of administration of the GnRH antagonist, the ejaculatory response to electrostimulation and the volume of the ejaculates diminished with time.(ABSTRACT TRUNCATED AT 250 WORDS)

Testosterone prevents complete suppression of spermatogenesis in the gonadotropin-releasing hormone antagonist-treated nonhuman primate (Macaca fascicularis).

We studied the effects of administration of a GnRH antagonist combined with testosterone (T) as an approach to male contraception as well as the role of intratesticular androgens in spermatogenesis using a nonhuman primate model. Three groups of five adult cynomolgus monkeys (Macaca fascicularis) received daily sc injections of 420-460 micrograms/kg GnRH antagonist ([Ac-D2Nal1,D4ClPhe2,DPal3,Arg5,DGlu6(AA), DALa10]GnRH) for a period of 15 weeks. T supplementation, commencing on the first day of GnRH antagonist administration, was provided by single im injection of 40 mg (group 2) or 200 mg (group 3) of the long-acting testosterone ester testosterone-trans-4-n-butylcyclohexancarboxylate (20-Aet-1). Serum LH bioactivity was undetectable within 1 week of GnRH antagonist administration in all monkeys. GnRH antagonist administration alone (group 1) reduced serum T levels into the castrate range. Forty milligrams of 20-Aet-1 maintained serum T levels in the upper range of normal monkeys, while 200 mg 20-Aet-1 maintained serum T levels about 1.5-fold above normal. The response to electroejaculation was fully maintained in all T-treated monkeys. Sperm counts in the ejaculates dropped to zero among group 1 animals within 7-10 weeks of GnRH antagonist administration. In groups 2 and 3 consistent azoospermia could not be induced, and the sperm counts were significantly (P less than 0.05) higher in group 3 than in group 2. Histologically, spermatogenesis in group 1 was arrested at the spermatogonial level in 75% of seminiferous tubules. In group 2, spermatogenesis proceeded to spermatocytes in 50% of tubules and to elongated spermatids in 10% of tubules, while in group 3 elongation of spermatids occurred in 75% of tubules. The mean T and dihydrotestosterone concentrations in baseline testicular biopsies (n = 15) were 43.8 +/- 6.8 (+/- SE) and 5.7 +/- 1.5 ng/g, respectively. After GnRH antagonist with or without T administration, the mean (n = 15) intratesticular T and dihydrotestosterone levels were reduced to 20.3 +/- 4.9 and 3.2 +/- 0.5 ng/g, respectively, and differed little among the three groups. No correlation, however, could be established between testicular androgen levels and spermatogenic status (P greater than 0.30) or sperm counts (P greater than 0.60). These results demonstrate that administration of a GnRH antagonist in the presence of constant serum T levels does not induce consistent azoospermia, and that the supporting effects of T on spermatogenesis cannot be explained exclusively on the basis of the testicular androgen concentrations.

Studies on the mechanism of action of oestrogens on the pituitary-adrenal function in the male rat.

ABSTRACT A single injection of a long-acting oestrogen, polydiethylstilboestrol phosphate (PSP; 200 μg/100 g body weight), into adult male rats caused an enlargement of the adrenal glands and an approximate doubling of total adrenal 3β-hydroxysteroid dehydrogenase (3β-OHD) activity and plasma corticosterone concentration in animals sacrificed 11 to 14 days following injection. The administration of interstitial cell stimulating hormone (ICSH) of human origin or a long-acting testosterone ester (Andradurin®) into the PSP-treated animals partially or completely counteracted the effects of the PSP treatment on adrenal weight and 3β-OHD activity. Daily injections of corticotrophin (ACTH) into intact male rats for 7 days caused a significant rise in the adrenal 3β-OHD activity. Gonadectomy of male rats resulted in increased adrenal weights and elevated adrenal 3β-OHD activity. The plasma corticosterone concentration was unaffected. PSP treatment significantly augmented the effects of the gonadectomy on the adrenal weight and 3β-OHD activity and caused an elevated plasma corticosteroid concentration. The adrenal enlargement following gonadectomy was completely reversed by testosterone replacement but was not influenced by daily injections of ICSH. The data are interpreted as suggesting that the oestrogen-induced hyper-secretion of ACTH in the male rat may be mediated through an elevated activity of the corticosteroid-binding globulin, caused by a reduced plasma testosterone level and a stimulated thyroid activity.