Testosterone metabolite; androgen; male hormonal contraception

Testosterone Undecanoate is the undecanoate ester form of the androgen testosterone, with gonadotropin-secretory inhibiting and hormone replacement activity. As testosterone inhibits the secretion of gonadotropins from the pituitary gland, administration of testosterone decreases the secretion of luteinizing hormone (LH). By inhibiting LH secretion, the growth of Leydig cells, which are normally stimulated by LH to produce testosterone, may be suppressed. In addition, this agent promotes the maintenance of male sex characteristics and can be used for testosterone replacement in hypogonadal males.

This study evaluates the efficacy of vas ligation in enhancing sperm retrieval in nonobstructive azoospermia cases, by accumulating intratesticular spermatozoa. Fifty-six mature male rats with equally sized testes were included in this study. Forty-six were in the study group, and 10 were in the control group. Bilateral testicular fine needle aspiration was performed for all, to confirm presence of spermatozoa in all testes. Nonobstructive azoospermia was induced in all 56 rats, using Dienogest (40 mg/kg) + Testosterone Undecanoate (25 mg/kg) every month for three months. Monthly aspirations confirmed nonobstructive azoospermia from all rats, within the three months treatment. This was followed by unilateral vas ligation and was performed for 46 rats of the study group, with no ligation performed in the control group. After a further period of 90 days (2 spermatogenic cycles) with the same medical treatment maintained, bilateral testicular sperm extraction was performed. Sperm retrieval was evaluated, comparing the outcome of vas-ligated testicles to the nonligated. Upon evaluation, spermatozoa were found in 14/46 of the vas-ligated testes (30.4%), compared to none of the nonligated (0/66), p = .0005. Ligation of the vas deferens in rats with nonobstructive azoospermia may enhance the results of sperm retrieval via sperm accumulation.[1]

Forty-six rats were randomised into the study group and 10 to the control group. Nonobstructive azoospermia was induced in all 56 rats, by monthly intramuscular injection of Dienogest (40 mg/kg) + Testosterone Undecanoate (25 mg/kg), as per Meena et al. (Meena et al., 2013). Monthly FNA's were performed until NOA was confirmed from all rats. This occurred at variable time points within the third month of the treatment course.[1]

Absorption, Distribution and Excretion
Testosterone undecanoate is a lipophilic molecule that is absorbed via the intestinal lymphatic system after oral administration. It is subsequently released into the systemic bloodstream via the thoracic duct, bypassing the portal venous circulation and first-pass metabolism in the liver, unlike endogenous testosterone. In men with hypogonadism, the mean (standard deviation) peak plasma concentration (Cmax) after twice-daily oral administration of 237 mg was 1008 (581) ng/dL. The peak plasma concentration (Tmax) occurred approximately 5 hours after oral administration. Testosterone exposure is reduced when taken on an empty stomach. Following intramuscular injection of 750 mg testosterone undecanoate, serum testosterone concentrations peaked after a mean of 7 days (range 4 to 42 days) and then declined slowly. The mean (standard deviation) peak plasma concentration (Cmax) was approximately 90.9 (68.8) ng/dL on day 4 after injection of testosterone undecanoate. Steady-state serum testosterone concentrations were reached after the third injection (week 14). Forty-two days after injection, testosterone undecanoate was almost undetectable. Approximately 90% of the intramuscular dose of testosterone is excreted in the urine as glucuronic acid and sulfate conjugates or metabolites. Approximately 6% is excreted in the feces, primarily in unconjugated form. Testosterone inactivation mainly occurs in the liver.
Currently, there is no relevant information.
Although existing information is limited, an early study reported that after oral administration of 25 mg of testosterone and 40 mg of testosterone undecanoate in women, the metabolic clearance of testosterone was 24.5 mL/min/kg.
Metabolism/Metabolites

Testosterone undecanoate can be reduced to dihydrotestosterone undecanoate by 5α-reductase. In the bloodstream, the ester bond connecting testosterone and undecanoate is cleaved by endogenous nonspecific esterases. As with all fatty acids, the undecanoate side chain undergoes β-oxidation to produce acetyl-CoA (CoA), ultimately generating propionyl-CoA. Testosterone is metabolized into various 17-ketosteroids via two distinct metabolic pathways, ultimately forming the main active metabolites: estradiol and dihydrotestosterone (DHT).
Biological Half-Life
The elimination half-life of testosterone undecanoate is approximately two hours. After conversion to testosterone, the half-life varies, with reported values ranging from 10 to 100 minutes. Castor oil-based testosterone undecanoate for intramuscular injection has a half-life of 33.9 days, maintaining serum levels within the normal range for over 6 weeks.

Protein Binding
Approximately 40% of circulating testosterone binds to sex hormone-binding globulin (SHBG), and about 2% of the drug exists in free form in plasma proteins. The remainder is loosely bound to albumin and other plasma proteins.

[1]. Effect of vas ligation on testicular sperm extraction results in nonobstructive azoospermic rats: Shaeer's lock-in technique. Andrologia. 2021 Oct;53(9):e14170.

Pharmacodynamics
Once in the bloodstream, testosterone undecanoate is broken down to release testosterone, which mediates a range of biological effects. Testosterone is an endogenous male hormone that plays a crucial role in male sexual differentiation: it is involved in the regulation of hematopoiesis, body composition, and bone metabolism. As a hormone replacement therapy, testosterone undecanoate is an exogenous source of testosterone for men with hypogonadism. Testosterone therapy aims to improve the symptoms and signs of testosterone deficiency, including decreased libido, erectile dysfunction, and muscle and bone loss. Because athletes and bodybuilders may abuse testosterone, it is a controlled substance in the United States. Using testosterone at doses higher than recommended can lead to withdrawal symptoms that last for weeks or months. Withdrawal symptoms include low mood, major depressive disorder, fatigue, cravings, restlessness, irritability, anorexia, insomnia, decreased libido, and hypogonadotropic hypogonadism. In women, testosterone use can lead to hirsutism, masculinization, a deeper voice, clitoral enlargement, breast atrophy, male pattern baldness, and menstrual irregularities. In adolescents, testosterone use can cause premature closure of the epiphyses, resulting in halted growth and precocious puberty.

C30H48O3

456.7003

456.36

C, 78.90; H, 10.59; O, 10.51

5949-44-0

65157

Typically exists as solid at room temperature

1.0±0.1 g/cm3

550.7±50.0 °C at 760 mmHg

39-42 °C(lit.)

230.3±30.2 °C

0.0±1.5 mmHg at 25°C

1.522

9.15

0

3

11

33

739

6

O(C(C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])=O)[C@@]1([H])C([H])([H])C([H])([H])[C@@]2([H])[C@]3([H])C([H])([H])C([H])([H])C4=C([H])C(C([H])([H])C([H])([H])[C@]4(C([H])([H])[H])[C@@]3([H])C([H])([H])C([H])([H])[C@@]21C([H])([H])[H])=O

UDSFVOAUHKGBEK-CNQKSJKFSA-N

InChI=1S/C30H48O3/c1-4-5-6-7-8-9-10-11-12-28(32)33-27-16-15-25-24-14-13-22-21-23(31)17-19-29(22,2)26(24)18-20-30(25,27)3/h21,24-27H,4-20H2,1-3H3/t24-,25-,26-,27-,29-,30-/m0/s1

[(8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl] undecanoate

Testosterone undecanoate; 5949-44-0; Andriol; Testosterone undecylate; Nebido; Undestor; Pantestone; Restandol; Jatenzo; T undecanoate; BRN 3176734; BRN-3176734; BRN3176734;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)