Synthesis and application research of Testosterone decanoate

Introduction

Testosterone decanoate (Figure 1) is one of the testosterone esters contained in Sustanon®, which has been used for several years in the treatment of hypogonadism. Preliminary data demonstrated that 400 mg administered every 4 weeks with etonogestrel implants resulted in good spermatogenic suppression.[1]

Testosterone decanoate synthesis

Testosterone decanoate was synthesized following the procedure for nandrolone decanoate using testosterone (1.02 g, 3.54 mmol), K₂CO₃(1.48g, 10.6mmol), decanoyl chloride (1.35g, 7.07mmol) and 1,4-dioxane (15mL). Flash chromatography (Biotage Isolera One,Luknova supersep column 40 g, gradient of 5–15 % EtOAc in isohexane).The product was isolated as white crystals, 1.31 g, 84 % yield with >98% purity (determined by HPLC UV-254). [α]_D²³ + 76.8◦ (c 1.13, DCM); ¹HNMR (400.13 MHz, CDCl₃) δ 5.72 (s, 1H), 4.60 (dd, J= 9.2, 7.8 Hz, 1H),2.48–2.33 (m, 3H), 2.31–2.24 (m, 3H), 2.17 (m, 1H), 2.01 (m, 1H), 1.84(m, 1H), 1.77 (m, 1H), 1.73–1.44 (m, 7H), 1.43–1.12 (m, 15H), 1.18 (s,3H), 1.10–0.90 (m, 3H), 0.87 (t, J = 7.1 Hz, 3H), 0.83 (s, 3H); ¹³C-NMR(101 MHz, CDCl3) δ 199.59, 174.02, 171.10, 124.08, 82.28, 53.83,50.38, 42.64, 38.74, 36.77, 35.83, 35.54, 34.70, 34.05, 32.87, 31.98, 31.62, 29.56, 29.39, 29.38, 29.26, 27.64, 25.25, 23.62, 22.80, 20.66,17.53, 14.24, 12.19.[2]

In vivo study

Effects in the male rat

The present study examined the impact of nandrolone decanoate,testosterone decanoate, and trenbolone decanoate on the male rat by evaluating the effects on recognition memory, behavioral profile, body weight development, organ weights, and plasma corticosterone levels. Long-term use of anabolic androgenic steroids (AAS) in supratherapeutic doses is associated with severe adverse effects, including physical, mental, and behavioral alterations. When used for recreational purposes several AAS are often combined, and in scientific studies of the physiological impact of AAS either a single compound or a cocktail of several steroids is often used. Because of this, steroid-specific effects have been difficult to define and are not fully elucidated. The present study used male Wistar rats to evaluate potential somatic and behavioral effects of three different AAS; the decanoate esters of nandrolone, testosterone, and trenbolone. The rats were exposed to 15 mg/kg of nandrolone decanoate, testosterone decanoate, or trenbolone decanoate every third day for 24 days. Body weight gain and organ weights (thymus, liver, kidney, testis, and heart) were measured together with the corticosterone plasma levels. Behavioral effects were studied in the novel object recognition-test (NOR-test) and the multivariate concentric square field-test (MCSF-test). The results conclude that nandrolone decanoate, but neither testosterone decanoate nor trenbolone decanoate, caused impaired recognition memory in the NOR-test, indicating an altered cognitive function. The behavioral profile and stress hormone level of the rats were not affected by the AAS treatments. Furthermore, the study revealed diverse AAS-induced somatic effects i.e., reduced body weight development and changes in organ weights. Of the three AAS included in the study, nandrolone decanoate was identified to cause the most prominent impact on the male rat, as it affected body weight development, the weights of multiple organs, and caused an impaired memory function.[2]

Effects in murine lupus

Study 1

Treatment of NZB/NZW F1 (B/W) female and castrated male mice with testosterone or 19-nortestosterone (nandrolone), either by implantation in silastic tubing or by subcutaneous injections of their decanoate esters, reduced in a dose-dependent manner symptoms associated with murine lupus (proteinuria, IgG antibodies to DNA) and prolonged survival. These phenomena were observed under both prophylactic (start at 3-4 weeks) and therapeutic treatments (start 27-29 weeks). Nandrolone and its decanoate ester were at least as potent as testosterone and testosterone decanoate. As the unwanted androgenic properties of nandrolone and its ester are significantly less pronounced than those of testosterone and its ester, also in these NZB/NZW mice, the beneficial effect on murine lupus does not seem to be associated with these properties.[3]

Study 2

Nandrolone decanoate injections (20, 40 or 80 mg/kg/3 weeks) in female or castrated male New Zealand black/white mice, starting at various ages (4, 9, 17 or 26 weeks) prolong survival, reduce proteinuria and affect the weights of various endocrine and non-endocrine organs. Nandrolone decanoate is at least equally potent as testosterone decanoate with respect to its beneficial effects on lupus-associated symptoms; in contrast, its effects on some other androgen-sensitive endocrine parameters are significantly less. These observations show that the autoimmunosuppressive effects of steroids are not quantitatively correlated to endocrine properties.[4]

Research and application in human body

Progress and prospects in male hormonal contraception

Testosterone functions as a contraceptive by suppressing the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary. Low concentrations of these hormones deprive the testes of the signals required for spermatogenesis and results in markedly decreased sperm concentrations and effective contraception in a majority of men. Male hormonal contraception is well tolerated and acceptable to most men. Unfortunately, testosterone-alone regimens fail to completely suppress spermatogenesis in all men, meaning that in some the potential for fertility remains. Because of this, novel combinations of testosterone and progestins, which synergistically suppress gonadotropins, have been studied. Two recently published testosterone/progestin trials are particularly noteworthy. In the first, a long-acting injectable testosterone ester, testosterone decanoate, was combined with etonogestrel implants and resulted in 80-90% of subjects achieving a fewer than 1 million sperm per milliliter. In the second, a daily testosterone gel was combined with 3-monthly injections of depot medroxyprogesterone acetate producing similar results. Testosterone-based hormone combinations are able to reversibly suppress human spermatogenesis; however, a uniformly effective regimen has remained elusive. Nevertheless, improvements, such as the use of injectable testosterone undecanoate, may lead to a safe, reversible and effective male contraceptive.[5]

Effects in disseminated breast cancer

It can be said that a single hormone therapy with testosterone decanoate, drostanolone, and testosterone gave similar rates of objective responses in metastatic breast cancer. The presented randomized study has been done to prove whether an additional chemotherapy to hormone applications would further improve therapeutic results. During an observation period of 10 to 16 weeks testosterone decanoate and testolactone in combination with cyclophosphamide have more benefitial effects on the patients than drostanolone plus cyclophosphamide. The combination therapy augmented the rate of objective responses from 22-25 percent to 46-55 percent.[6]

As a potential long-acting male contraceptive

The combination of etonogestrel implants with injectable testosterone decanoate was investigated as a potential male contraceptive. One hundred and thirty subjects were randomly assigned to three treatment groups, all receiving two etonogestrel rods (204 mg etonogestrel) and 400 mg testosterone decanoate either every 4 weeks (group I, n=42), or every 6 weeks (group II, n=51) or 600 mg testosterone decanoate every 6 weeks (group III, n=37) for a treatment period of 48 weeks. One hundred and ten men completed 48 weeks of treatment. Sperm concentrations of <1 x 106/ml were achieved in 90% (group I), 82% (group II) and 89% (group III) of subjects by week 24. Suppression was slower in group II, which also demonstrated more frequent escape from gonadotrophin suppression than groups I and III. Peak testosterone concentrations remained in the normal range throughout in all groups. Mean trough testosterone concentrations were initially subphysiological but increased into the normal range during treatment. Mean haemoglobin levels increased in group I, and a non-significant increase in weight and decline in high-density lipoprotein cholesterol was observed in all groups. Fourteen subjects discontinued treatment due to adverse events. Subcutaneous etonogestrel implants in combination with injectable testosterone decanoate resulted in profound suppression of spermatogenesis that could be maintained for up to 1 year. Efficacy of suppression was less in group II, probably due to inadequate testosterone dosage. This combination has potential as a long-acting male hormonal contraceptive.[1]

References

1.Brady BM, Amory JK, Perheentupa A, et al. A multicentre study investigating subcutaneous etonogestrel implants with injectable testosterone decanoate as a potential long-acting male contraceptive. Hum Reprod. 2006;21(1):285-294. doi:10.1093/humrep/dei300

2.Zelleroth S, Stam F, Nylander E, et al. The decanoate esters of nandrolone, testosterone, and trenbolone induce steroid specific memory impairment and somatic effects in the male rat. Horm Behav. 2024;161:105501. doi:10.1016/j.yhbeh.2024.105501

3.Verheul HA, Stimson WH, den Hollander FC, Schuurs AH. The effects of nandrolone, testosterone and their decanoate esters on murine lupus. Clin Exp Immunol. 1981;44(1):11-17.

4.Verheul HA, Deckers GH, Schuurs AH. Effects of nandrolone decanoate or testosterone decanoate on murine lupus: further evidence for a dissociation of autoimmunosuppressive and endocrine effects. Immunopharmacology. 1986;11(2):93-99. doi:10.1016/0162-3109(86)90029-9

5.Amory JK. Progress and prospects in male hormonal contraception. Curr Opin Endocrinol Diabetes Obes. 2008;15(3):255-260. doi:10.1097/MED.0b013e3282fcc30d

6.Rieche K, Wolff G. Comparison of testosterone decanoate, drostanolone and testololactone in disseminated breast cancer--a randomized clinical study. Arch Geschwulstforsch. 1975;45(5):485-488. 

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