Testosterone

Testosterone is a natural hormone belonging to the pharmacological class of androgen receptor agonists.

Testosterone is approved for use by the FDA for treating conditions related to testosterone deficiency, such as Hypogonadism.

Testosterone is absorbed primarily from the gastrointestinal tract and skin (approx 10%). Testosterone enters breast milk, especially after intramuscular injection, firmly binding to plasma proteins. The liver metabolizes it, and the body excretes it through urine and faeces.

The most common side effects of Testosterone include acne, breast enlargement in males, voice change, and injection site reactions (pain, swelling, redness).

Dosage forms of testosterone Testosterone are available as an oral capsule, injectable solution and pellet implant.

The molecule is available in India, the United States, Canada, the United Kingdom, Italy, Australia, Germany, France, Japan and Spain.

Testosterone is a natural hormone belonging to the pharmacological class of androgen receptor agonists.

In the cytoplasm, the androgen receptor is attached to several chaperones and heat shock proteins, including HSP90, HSP70, and others. Following its attachment to an androgen, the androgen receptor separates from HSP90 and experiences a conformational alteration to decelerate its separation from the androgen receptor. When the androgen-receptor complex reaches the nucleus, it attaches itself to DNA. It enlists the help of additional transcriptional regulators to create a pre-initiation complex, which triggers the production of particular genes.

The development of male sex organs such as the prostate, seminal vesicles, penis, and scrotum is caused by antagonistic interactions between testosterone and its active metabolite, dihydrotestosterone (DHT).

Secondary sexual traits like body and facial hair, laryngeal expansion, thickening of the vocal cords, and modifications in the distribution of muscle and fat are also brought on by antagonistic interactions with the androgen receptor. The prostate, seminal vesicles, penis, and scrotum are examples of male sex organs that develop as a result of testosterone and its active metabolite dihydrotestosterone (DHT) opposing the androgen receptor.

Secondary sexual features such as changes in muscle and fat distribution, thickening of the vocal cords, growth of the larynx, and facial and body hair are also brought on by antagonistic interactions with the androgen receptor.

IM esters, including cypionate and enantate, have a duration of 2-4 weeks; undecanoate lasts 10 weeks. Transdermal gel provides 24-hour effectiveness.

Dosage forms of testosterone Testosterone are available as oral capsules, injectable solutions and pellet implants.

Oral Capsules: To be swallowed whole with water/liquid. Do not chew, crush or break it.

Injectable solution: To be administered parenterally, either IM or SC as applicable.

Pellet implant: Insert pellet implant subcutaneously as directed for hormonal therapy.

Testosterone can be used for the following health conditions:

• Treatment of Hypogonadism: It is used in the treatment of primary Hypogonadism and hypogonadotropic Hypogonadism. Testosterone antagonizes the androgen receptor to induce gene expression that causes the growth and development of masculine sex organs and secondary sexual characteristics.
• Other uses: It is also used for treating delayed puberty in males, inoperable mammary cancer in women, androgen deficiency in HIV-positive patients and delayed growth and puberty in adolescent boys. 

In treatment of Hypogonadism

Primary hypogonadism results from testicular failure due to various conditions like cryptorchidism, torsion, orchitis, orchiectomy, Klinefelter Syndrome, chemotherapy, or toxic damage. This leads to low serum testosterone and elevated gonadotropins (FSH, LH). On the other hand, hypogonadotropic Hypogonadism is caused by deficiencies in gonadotropins, LHRH, or pituitary-hypothalamic function due to factors such as tumours, trauma, or radiation. Men with this type typically have low testosterone but normal or low gonadotropin levels. Testosterone therapy can help in both conditions.

Testosterone is indicated in the treatment of:

• Primary Hypogonadism and hypogonadotropic Hypogonadism.
• Androgen deficiency, inoperable mammary cancer, delayed puberty and growth in adolescent boys.

Orally: Usually, capsules are used to deliver oral testosterone. The procedure is taking the prescribed pills with water and adhering to the doctor's recommended dosage and administration schedule.

Parenterally: For subcutaneous (SC) administration, exclusively administer injectable testosterone solution (enanthate) in the abdominal region, avoiding intramuscular (IM) or intravenous (IV) injection. Before use, visually inspect for clarity and absence of particles. Confine IM administration of Injectable testosterone solutions (cypionate) to the gluteal muscle, alternating injection sites between buttocks. Check prescribing information when switching testosterone products. Before administration, inspect for particles and discolouration. Redissolve any crystals formed due to storage at low temperatures by warming and shaking the vial.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

• Capsule: 100mg, 112.5mg, 150mg, 158mg , 198mg , 200mg, 237mg
• Injectable solutions (cypionate): 100mg/mL, 200mg/mL
• Injectable solution (enanthate): 50 mg/0.5Ml, 75 mg/0.5mL, 100 mg/0.5mL 200mg/mL
• Pellet implant: 12.5mg, 25mg, 37.5mg, 50mg, 75mg

Testosterone are available as oral capsules, injectable solutions and pellet implants.

Dose Adjustment in Adult Patients:

Oral capsule

Kyzatrex

Individualize dosage based on the patient’s serum testosterone level response to the drug.

Starting dose: 200 mg PO BID (in AM and PM) with food.

Jatenzo

Starting dose: 237 mg PO BID with food. • Adjust the dosage according to serum testosterone levels 6 hours after morning.

Orlando

Starting dose: 225 mg PO BID with food.

Based on the serum testosterone levels, continue or discontinue therapy H5

Jatenzo

Starting dose: 237 mg PO BID with food

Adjust the dose according to serum testosterone levels 6 hours after the morning dose.

Injectable solution

Xyosted

Starting dose: 75 mg SC qweek

Adjust dose based on total testosterone minimum (trough) concentrations

Testosterone enanthate (generic): 50-200 mg IM every 2-4 weeks for 4-6 months

It's crucial to incorporate high-fiber foods like vegetables, fruits and whole grains while limiting processed and fried foods. Making better dietary choices is achieved by favouring plant-based proteins over animal proteins. Limiting alcohol and caffeinated beverages is essential for optimal symptom management. Necessary measures include abstaining from smoking and excessive alcohol use, as well as maintaining a healthy weight through moderate exercise. Maintain adequate hydration due to potential fluid retention and consider taking calcium and vitamin D supplements for prolonged therapy, promoting bone health.

The dietary restriction should be individualized as per patient requirements.

Testosterone may be contraindicated in the following conditions: -

• Anyone who has previously experienced hypersensitivity to any of the product's constituents
• Expectant mothers or those who are pregnant.
• Men with confirmed or suspected prostate cancer as well as breast cancer.
• Testosterone can raise blood pressure, which increases the risk of MACE in men with hypogonadal disorders (such as "age-related hypogonadism") that are not linked to structural or genetic etiologies. The effectiveness of these treatments has not been shown.

• Polycythemia: Throughout treatment, periodically check the hematocrit. If necessary, stop injecting testosterone cypionate.
• Cardiovascular Risk: The risk of major adverse cardiovascular events (MACE) may increase with testosterone cypionate injection use. When patients decide whether to start or continue treatment, inform them about this risk.
• Exacerbation of Benign Prostatic Hyperplasia (BPH) and Possible Risk of Prostate Cancer: Patients with BPH should be closely observed for a worsening of BPH symptoms and indicators. Assess patients for prostate cancer, making sure to track prostate-specific antigen (PSA) both before and after starting androgen therapy.
• Venous thromboembolism (VTE): Patients who use testosterone products have been known to suffer VTE, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). If VTE is suspected, stop injecting testosterone Cypionate and start the proper investigation and treatment.
• Abuse of Testosterone and Serum Testosterone Monitoring: Serum testosterone concentration should be checked if testosterone use is suspected, especially when it is combined with other anabolic androgenic steroids and at doses greater than those advised for the approved indication.
• Potential adverse effects on Spermatogenesis: An injection of testosterone cypionate may result in azoospermia.
• Edema: Patients with a history of cardiac, renal, or hepatic illness may experience edema with or without congestive heart failure (CHF). Stop injecting testosterone Cypionate and start an appropriate treatment.
• Sleep Apnea: Testosterone Cypionate injection may exacerbate sleep apnea in patients with risk conditions.
• Lipid Alterations: The serum lipid profile may be impacted by testosterone. Monitor the patient's lipid concentrations. Change the dosage of the medication(s) used to decrease cholesterol or stop using testosterone Cypionate injection.
• Adverse Effects on Bone Maturation: In pediatric patients, testosterone may accelerate the ageing of the bones and cause the epiphyses to close too soon, which may impair adult stature. Every six months, determine the impact on bone maturation by measuring the wrist and hand's bone ages.

It is unsafe to consume Testosterone with alcohol.

It is not recommended for use.

It is not recommended for use during pregnancy.

Limit processed foods, exercise, hydrate, and quit smoking.

The adverse reactions related to Testosterone can be categorized as:

• Common Adverse Effects: Acne, fluid retention, sleep apnea, and mood swings.
• Less Common Adverse Effects: Hair loss, headache, polycythemia, gynecomastia, changes in libido, changes in cholesterol levels, breast enlargement, and testicular atrophy.
• Rare Adverse Effects: Liver problems, heart issues, prostate complications and mental health changes.

Reports on Postmarketing

Cardiovascular conditions: stroke and myocardial infarction

Disorders of the veins: Venous thromboembolism

Reproductive system: Benign prostatic hyperplasia and azoospermia

The clinically relevant drug interactions of Testosterone are briefly summarized here.

• Androgens may lower blood glucose levels, reducing the need for insulin in diabetic patients.
• With androgens, alterations in anticoagulant activity may be observed. It is advised to monitor prothrombin time and INR more often.
• Increased fluid retention may occur from the combination of testosterone, corticosteroids, or adrenocorticotrophic hormone (ACTH). Use caution, especially in individuals with liver, kidney, or heart illness.
• When used in conjunction with testosterone cyanide injection, patients with diabetes may require less insulin and blood glucose control.
• Anticoagulant activity may change if testosterone cyanide injection is used concurrently with it. Prothrombin time and the International Normalized Ratio should be regularly monitored.
• Increased fluid retention may occur from concurrent use of testosterone cyanide injection. Use with caution, especially in individuals who are suffering from liver, kidney, or heart illness.

The common side effects of Testosterone include:

• Headache
• Increased facial or body hair growth or male-pattern baldness
• Anxiety
• Increased or decreased interest in sex;
• Numbness or tingly feeling; or
• Injection site reactions (pain, swelling, redness)
• Acne
• Voice change
• Breast enlargement in male

• Pregnancy

During treatment, large doses of exogenous androgens can suppress spermatogenesis through feedback inhibition of the hypothalamic-pituitary-testicular axis. Some men undergoing testosterone replacement therapy have experienced reduced fertility, with potential irreversibility. It is crucial to consider and discuss the potential impact on fertility when prescribing and administering high doses of exogenous androgens. Regular monitoring and consultation with healthcare professionals are essential to address and manage observed effects.

Animal data

Exposing animals to in utero testosterone resulted in offspring experiencing hormonal and behavioural changes, along with structural impairments in reproductive tissues for both females and males. However, these studies failed to meet current standards for nonclinical development toxicity studies. Acknowledging these findings and adhering to contemporary guidelines for comprehensive nonclinical developmental toxicity assessments is imperative.

Infertility

During treatment, large doses of exogenous androgens can suppress spermatogenesis through feedback inhibition of the hypothalamic-pituitary-testicular axis. Some men undergoing testosterone replacement therapy have experienced reduced fertility, with potential irreversibility. It is crucial to consider and discuss the potential impact on fertility when prescribing and administering high doses of exogenous androgens. Regular monitoring and consultation with healthcare professionals are essential to address and manage observed effects.

• Nursing Mothers

It is not indicated for women. Contraindicated in breastfeeding patients.

• Pediatric Use

As per the FDA, safety and effectiveness in the pediatric population below 12 years of age have not been established.

Dosage adjustment

Hypogonadism

≥12 years

Testosterone cypionate: 50 to 400 mg IM every 2-4 weeks

Testosterone enanthate (generic): 50 to 400 mg IM every 2-4 weeks

Pellet: 150 to 450 mg SC every 3-6 months; 150 mg of pellet is approximately equivalent to 25 mg of testosterone propionate weekly

Delayed Puberty in Males

≥12 years: 50 to 200 mg IM every 2-4 weeks for 4-6 months.

• Geriatric Use

There is insufficient long-term safety data to assess the potential risks of cardiovascular disease (CVD)and prostate cancer.

Dose Adjustment in Kidney Impairment Patients:

Mild to moderate Renal impairment: Should be used only if the benefits outweigh the risks; Caution.

Severe Renal impairment: Not recommended.

Dose Adjustment in Hepatic Impairment Patients:

Patients with liver function disorders should take caution while administering Testosterone capsules because the drug is extensively metabolized in the liver.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Testosterone.

Signs and Symptoms

One case of an acute overdose with an approved injectable testosterone medication has been reported; the patient experienced a cerebrovascular accident and serum testosterone levels as high as 11,400 ng/dL.

Management

There is no specific antidote or treatment for excessive Testosterone intake, so treatment typically involves symptomatic and supportive measures. Testosterone should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

In cases where ingestion occurred recently, gastric lavage may be intended, followed by supportive treatment to manage symptoms. It is essential to monitor vital signs, electrolytes, and organ function. Hospitalization and observation at a medical facility are required in severe cases, especially if extensive drug intake is suspected.

Pharmacodynamics:

The growth and development of male sex organs, as well as secondary sexual traits, are caused by testosterone's antagonistic action on the androgen receptor, which also induces gene expression. With a half-life ranging from 10 to 100 minutes, testosterone's duration of activity varies from patient to patient. Given that the typical range of testosterone levels in an adult male is 300–1000 ng/dL, the therapeutic index is broad. Discuss with patients the possibility of children being exposed to testosterone topical products again.

Pharmacokinetics:

• Absorption: Testosterone is absorbed from the gastrointestinal tract and through the skin, with approximately 10% absorption. Intramuscular injection (IM) of testosterone undecanoate shows slow absorption, taking about 7 days for peak plasma concentration (4-42 days). Transdermal patches exhibit quicker absorption, reaching peak plasma concentration in 8 hours (4-12 hours). Orally administered testosterone peaks at approximately 4-5 hours, and food intake enhances its absorption.

• Distribution: Testosterone enters breast milk and exhibits a high plasma protein binding of 98%, primarily to sex hormone-binding globulin (40%) and albumin.

• Metabolism: Primarily metabolized in the liver, testosterone forms dihydrotestosterone (DHT) and estradiol, which are primary active metabolites. The oral route undergoes extensive first-pass metabolism.

• Excretion: Testosterone is excreted via urine (90%, as sulfuric and glucuronic acid conjugates and metabolites) and faeces (approximately 6% as unchanged drug). The elimination half-life varies, ranging from about 10-100 minutes to about 8 days for cypionate.

• Morgentaler A, Traish A, Barua RS, Dandona P, Dhindsa S, Khera M, Saad F. Recognizing the True Value of Testosterone Therapy in Health Care. Androg Clin Res Ther. 2022 Dec 28;3(1):217-223. doi: 10.1089/andro.2022.0021. PMID: 36643964; PMCID: PMC9814113.
• Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Resnick SM, Budoff M, Mohler ER 3rd, Wenger NK, Cohen HJ, Schrier S, Keaveny TM, Kopperdahl D, Lee D, Cifelli D, Ellenberg SS. Lessons From the Testosterone Trials. Endocr Rev. 2018 Jun 1;39(3):369-386. doi: 10.1210/er.2017-00234. PMID: 29522088; PMCID: PMC6287281.
• Kalfa N, Gaspari L, Ollivier M, Philibert P, Bergougnoux A, Paris F, Sultan C. Molecular genetics of hypospadias and cryptorchidism recent developments. Clin Genet. 2019 Jan;95(1):122-131.
• Bozzola M, Bozzola E, Montalbano C, Stamati FA, Ferrara P, Villani A. Delayed puberty versus hypogonadism: a challenge for the pediatrician. Ann Pediatr Endocrinol Metab. 2018 Jun;23(2):57-61.

• https://www.ncbi.nlm.nih.gov/books/NBK216178/
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216318s000lbl.pdf
• https://www.ncbi.nlm.nih.gov/books/NBK526128/