A Review of Testosterone Therapy Options for Men

US Pharm. 2023;48(6):17-21.

ABSTRACT: Testosterone is the treatment of choice for testosterone deficiency (defined as low serum testosterone combined with symptoms of low testosterone) and hypogonadism (low testosterone with infertility). Since 1935, scientists have explored various dosage formulations, including topicals, transdermal patches, intranasal gel, injectables, and implantable pellets. Many products are available in both branded and generic form. For some of these products, recommended dosing varies between the clinical guidelines and/or product labeling. Given the numerous products available and the plethora of direct-to-consumer pharmaceutical advertising, it is crucial for pharmacists to understand the differences between testosterone therapy options for men and educate patients on their profiles and administration techniques.

Testosterone is the treatment of choice for testosterone deficiency and hypogonadism. Since its chemical synthesis in 1935, scientists have explored various dosage formulations of testosterone.¹ The Evaluation and Management of Testosterone Deficiency guideline published by the American Urological Association (AUA) in 2018 described the need to clarify testosterone deficiency and hypogonadism.² The term testosterone deficiency refers to low serum testosterone combined with symptoms of low testosterone, and hypogonadism is defined as low testosterone with infertility.²

In men, low testosterone is defined as two separate measurements of total serum testosterone levels <300 ng/dL drawn in the morning after an overnight fast. Morning testosterone levels are required because peak testosterone values occur between 3 am and 8 am, with a daily decline occurring within 30 minutes of waking.²

The target range for total testosterone in men is 450 ng/dL to 600 ng/dL.² Initial testosterone monitoring following therapy initiation is determined based on the testosterone formulation. Routine monitoring of testosterone should occur every 6 to 12 months to ensure maintenance of target levels.²

Testosterone therapy is available in multiple forms, including topical gel, topical solution, transdermal patch, intranasal gel, injectable, and implantable pellets. Many products are available in both branded and generic form. This article will refer to products by brand name to minimize confusion with similar-sounding generic names.

Topical

Multiple topical testosterone products are available in both branded and generic form. All topical products carry the risk of accidental exposure, which could potentially cause virilization in women and children. Recommendations for reducing the risk include covering the application site with clothing, washing the hands with soap and water immediately after application, and washing the site with soap and water if direct skin-to-skin contact is anticipated.^3-8 The amount of time the skin is in contact with the product is important for absorption. Patients should avoid washing the product off via showering, swimming, or bathing for the interval specified for the product.

AndroGel: AndroGel 1% is available in 25-mg and 50-mg packets; the pump is no longer manufactured. The gel is applied to the shoulders, upper arms, and/or stomach area.³ The patient should avoid washing the area for at least 5 hours after application. The starting dose for AndroGel 1% is 50 mg applied once daily. Serum testosterone is monitored at intervals, with dose adjustments in 25-mg increments to a range of 50 mg to 100 mg daily.³

AndroGel 1.62% is available as packets or a pump (20.25 mg/pump).⁴ The pump must first be primed by pushing the pump down slowly 3 times; any gel dispensed while priming must be discarded down the drain to avoid accidental exposure. The only application sites for AndroGel 1.62% are the shoulders and the upper arms. The patient should avoid washing for at least 2 hours after application. AndroGel 1.62% has a starting dose of 40.5 mg once daily. The dose can be adjusted to between 20.25 mg and 81 mg daily based on the predose morning serum testosterone concentration. Testosterone should be monitored at 14 days and 28 days after treatment initiation or following a dose adjustment. The prescribing information (PI) provides a titration table based on serum testosterone results.⁴

Fortesta: Fortesta 2% is a testosterone gel pump (10 mg/pump) available in branded and generic versions.⁵ The pump must be primed before use by pushing the pump 8 times, and any gel dispensed while priming should be discarded in a manner to avoid accidental exposure. The patient should use one finger to apply the gel to the front and inner thighs. The application site should not be washed for a minimum of 2 hours after application. The starting dose of Fortesta is 40 mg once daily in the morning. The dose is evaluated and titrated based on the serum testosterone concentration drawn 2 hours after application. Testosterone should be monitored at 14 days and 35 days after treatment initiation or following dose adjustment. The dosing range is 10 mg to 70 mg daily. The PI includes a titration table based on serum testosterone results.⁵

Testim and Vogelxo: Testim 1% and Vogelxo 1% are topical testosterone gels that are therapeutically equivalent.⁹ Testim 1% is available as tubes and Vogelxo 1% is available as tubes, packets, and a pump (12.5 mg/pump).^6,7 These products are also available as generics. The gel is applied to the shoulders and the upper arms. Patients using Testim 1% or Vogelxo 1% should avoid washing the application site for 2 hours after application. When using the tube formulation, the patient should be instructed to squeeze the gel out of the tube by starting at the bottom and squeezing to the top. Once the gel has been expelled from the tube, the cap should be replaced and thrown away out of reach of women and children to avoid accidental exposure.^6,7 The Vogelxo 1% pump must be primed by pumping it 3 times, and any gel dispensed while priming should be discarded.⁷ The starting dose is 50 mg applied once daily in the morning. Fourteen days after therapy initiation, testosterone should be retested in the morning before application of the gel. The dose may be increased by 50 mg to a maximum dose of 100 mg daily.^6,7

Axiron: The branded and generic versions of Axiron are topical testosterone solutions supplied as a pump with an applicator device (30 mg/pump).⁸ The pump needs to be primed by depressing the pump 3 times, with any product dispensed during priming discarded to avoid accidental exposure. When the pump is ready to use, the patient should position the nozzle over the applicator cup and depress the pump fully one time. The liquid should be dispensed directly into the applicator. The applicator should not hold more than 30 mg (1 pump) of testosterone at a time. Keeping the applicator upright, the patient should place it in the armpit and wipe it up and down the area. If the solution drips, it can be wiped back into the applicator. The solution should not be rubbed into the skin with the fingers or hand. If a dosage of 60 mg or greater is prescribed, the process is then repeated with the other armpit. If multiple doses are to be applied to the same armpit, the solution should be allowed to dry between doses. After use, the applicator and cap should be washed and placed back on the bottle for storage. The patient should avoid washing for 2 hours after application. Deodorants and antiperspirants do not interact with Axiron absorption. If a stick or roll-on product is being used, it is recommended to apply it before applying Axiron to avoid accidental contamination. The starting dose of Axiron is 60 mg (2 pumps) administered once daily in the morning by applying one pump under each arm with the included applicator. At day 14 after therapy initiation or following a dose change, testosterone monitoring should be performed 2 to 8 hours after applying Axiron. Based on testosterone levels, the dose can be adjusted in 30-mg increments to a range of 30 mg to 120 mg daily.⁸

Transdermal Patch

Androderm: Androderm is available as 2-mg and 4-mg patches.¹⁰ The patch is applied daily in the evening to the back, abdomen, upper arms, or thighs, avoiding bony areas and parts of the body that may be subject to prolonged pressure while sitting or sleeping. The application site should be rotated daily, with a minimum of 7 days between same-site application. Recommendations include avoiding skin areas that are oily, perspire easily, or are covered with hair, as the patch may not stick well. The patch should not be taped to the skin. If the patch falls off before noon, a new patch should be applied and changed at the regular evening dosing time; if it falls off after noon, no patch should be applied until the evening dosing time. The patient should avoid washing the application site for a minimum of 3 hours after new patch application. The patch does not have to be removed for intercourse or while bathing; however, because of its aluminum content, the patch should be removed prior to MRI. The starting dose is 4 mg daily delivered in one 4-mg patch. At day 14 of therapy, serum testosterone should be monitored in the early morning, following patch application the evening before. Based on results, the dose may be adjusted to between 2 mg and 6 mg per day. If a 6-mg dose is indicated, the patient can wear a 2-mg patch and a 4-mg patch. A common side effect of Androderm is skin irritation at the application site; topical OTC hydrocortisone may be used to treat the irritation. Applying triamcinolone acetonide 0.1% cream to the skin under the Androderm patch has been shown to reduce the incidence and severity of skin irritation. The triamcinolone acetonide cream formulation has exhibited no absorption concerns; however, the ointment formulation significantly reduces testosterone absorption and should be avoided.¹⁰

Nasal Gel

Natesto: Natesto (5.5 mg/pump) is nasal testosterone available as a pump. The nasal pump requires priming by inverting the pump and depressing it 10 times; any gel dispensed while priming should be discarded. Before dispensing a dose, the patient should first blow the nose and place the right index finger on the pump of the actuator and advance the actuator tip upward into the left nostril until the finger on the pump reaches the base of the nose. To ensure that the gel is applied to the nasal wall, the actuator should be tilted so that the opening in the actuator tip is in contact with the lateral wall of the nostril. The patient should depress the pump and then remove the actuator from the nose while wiping the tip along the inside of the lateral nostril wall to fully transfer the gel. The process is then repeated with the other nostril. Finally, the patient should press on the nostrils at a point just below the bridge of the nose, and lightly massage. The patient should refrain from blowing the nose or sniffing for 1 hour after administration.¹¹ The starting dose is 11 mg (2 pumps, 1 in each nostril) intranasally three times a day, at least 6 to 8 hours apart. Serum testosterone should be monitored after 1 month of therapy. The use of Natesto is not recommended in patients who have chronic nasal conditions or alterations in nasal anatomy. The most common side effects of Natesto are headache, rhinorrhea, epistaxis, nasal discomfort, nasopharyngitis, bronchitis, upper respiratory tract infection, sinusitis, and nasal scabs. Natesto is not recommended for use with drugs that are administered nasally, other than sympathomimetic decongestants (e.g., oxymetazoline).¹¹

Oral Capsule

Testosterone undecanoate for oral administration is available as Jatenzo, Kyzatrex, and Tlando. This oral form of testosterone is absorbed by the intestinal lymphatic system via a pathway that bypasses the liver.^12-14 All three of these products carry a black box warning for blood pressure increases that can heighten the risk for major adverse cardiovascular events. Per product labeling, it is recommended to consider the patient’s baseline cardiovascular risk and ensure that the blood pressure is adequately controlled. The blood pressure should be checked approximately 3 weeks after initiation and periodically thereafter.^12-14 Two reputable guidelines have concluded that evidence is insufficient to state whether testosterone therapy increases or decreases the risk of cardiovascular events.^2,15

Jatenzo: Jatenzo is available as 158-mg, 198-mg, and 237-mg capsules. The starting dose is 237 mg orally twice daily with food. Serum testosterone should be tested after 7 days of therapy, with the sample drawn 6 hours after the morning dose. The PI includes specific dose-titration recommendations based on the results. The dosing range is 158 mg to 396 mg twice daily.¹²

Kyzatrex: Kyzatrex is available as 100-mg, 140-mg, and 200-mg capsules. The starting dose is 200 mg orally twice daily with food. After 7 days of therapy, dosing may be adjusted based on serum testosterone drawn 3 to 5 hours after the morning dose. The PI includes specific dosing titration recommendations based on the results. The dosing ranges from 100 mg once daily in the morning to a maximum of 400 mg twice daily.¹³

Tlando: Tlando is available as 112.5-mg capsules. The recommended starting dose is 225 mg orally twice daily with food. Serum testosterone is tested at 3 to 4 weeks of therapy, with the sample drawn 8 to 9 hours after the morning dose. Based on the result, Tlando may be continued or discontinued. There is no dose adjustment for this product.¹⁴

Injectable

Depo-Testosterone (testosterone cypionate): Depo-Testosterone is available as branded or generic testosterone cypionate in strengths of 100 mg/mL (10-mL vial) and 200 mg/mL (1-mL and 10-mL vials). This agent is administered intramuscularly into the gluteal muscle. Product dosing varies: The PI recommends 50 mg to 400 mg every 2 to 4 weeks; the AUA guideline lists a starting dose of 100 mg and a range of 50 mg to 400 mg administered every 1 to 2 weeks; and the Endocrine Society guideline recommends a starting dose of 150 mg to 200 mg administered every 2 weeks or 75 mg to 100 mg administered weekly.^2,15,16 Peak testosterone levels are in the supraphysiological range after injection and then decline to subtherapeutic range by the end of the dosing interval, and the peaks and valleys can cause fluctuations in symptoms.¹⁵ To limit the time spent outside the normal range, smaller doses at more frequent intervals are preferred.² Serum testosterone should be monitored after cycle 4.²

Delatestryl, Xyosted (testosterone enanthate): Delatestryl is available as a 200-mg/mL (5-mL vial) intramuscular gluteal injection. Per the PI, the dosing range is 50 mg to 400 mg every 2 to 4 weeks, with a maximum dose of 400 mg/month.¹⁷ The AUA guideline lists a starting dose of 100 mg, with a range of 40 mg to 200 mg every 7 to 14 days.² The Endocrine Society guideline recommends a starting dose of 150 mg to 200 mg every 2 weeks or 75 mg to 100 mg/week.¹⁵ There have been rare postmarketing reports of transient reactions, including the urge to cough, coughing fits, and respiratory distress, immediately after the injection.¹⁷ Testosterone should be monitored after cycle 4.²

Xyosted is available as an autoinjection in strengths of 50 mg/0.5 mL, 75 mg/0.5 mL, and 100 mg/0.5 mL.¹⁸ The starting dose is 75 mg administered subcutaneously to the abdominal area once weekly. The patient should pinch the skin, push the autoinjector into the skin until there is a click, and count to 10.¹⁹ Dosing is adjusted based on the testosterone trough measured 7 days after the most recent dose following 6 weeks of therapy. The PI includes a dosing titration guide. Xyosted carries a black box warning for an increase in blood pressure that can heighten the risk of cardiovascular events.¹⁸ Evidence is insufficient to state whether testosterone therapy increases or decreases the risk of cardiovascular events.^2,15

Aveed (testosterone undecanoate oil for injection): Aveed is an intramuscular gluteal injection of testosterone undecanoate that is available only through a Risk Evaluation and Mitigation Strategies (REMS) program.²⁰ This product carries a black box warning for serious pulmonary oil microembolism reactions (the urge to cough, dyspnea, throat tightening, chest pain, dizziness, syncope) and episodes of anaphylaxis. These reactions were reported to occur during or immediately after the injection. Most of these events lasted a few minutes and resolved with supportive measures; however, some events lasted up to several hours, and some required emergency care and/or hospitalization.²⁰ The REMS program requires training for healthcare providers, certification for prescribers and for the healthcare setting, specific patient counseling, and patient observation for 30 minutes post injection.²¹ The dosing of Aveed is 750 mg (3 mL) at initiation, at 4 weeks, and every 10 weeks thereafter. Testosterone monitoring is recommended after cycle 4.⁴

Implantable Pellet

Testopel (testosterone pellets): Testopel is a cylindrically shaped 75-mg testosterone pellet with a diameter of 3.2 mm and a length of 9 mm.²² In an in-office procedure, the pellets are inserted under the skin in the hip or another fatty area. The dosing for pellet implantation has less flexibility, as the pellets must be removed in order to discontinue therapy. The PI lists a dosage of 2 to 6 pellets every 3 to 6 months.²² Data from a large multi-institutional series noted that higher doses demonstrated therapeutic levels; therefore, the AUA states that a common starting dose is 10 pellets, with a common dosing range of 6 to 12 pellets every 3 to 4 months.² Implantation-site infection and pellet extrusion are concerns.²² Testosterone should be monitored at 2 and 12 weeks after each insertion.²

Conclusion

The abundance of testosterone therapy options enables patients to select a product that best aligns with their preferences. Topical products are easy to apply and dose-adjust, but they carry a risk of transference to women and children. Although the transdermal patch is easy to apply, it can cause skin irritation at the application site. Testosterone nasal gel requires multiple applications per day and has nasal side effects. Oral testosterone is easy to administer, but it must be taken with food. Although injectable therapy has flexible dosing, there is a risk of symptom fluctuations. Testosterone pellets have a long duration of action; however, they require an in-office procedure. Given the plethora of treatment options and direct-to-consumer pharmaceutical advertising, it is crucial for pharmacists to understand differences between these therapies and educate patients on their profiles and administration techniques.

REFERENCES

1. Nieschlag E, Nieschlag S. Testosterone deficiency: a historical perspective. Asian J Androl. 2014;16(2):161-168.
2. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423-432.
3. AndroGel 1% (testosterone) product information. Morristown, NJ: ASCEND Therapeutics US, LLC; November 2022.
4. AndroGel 1.62% (testosterone) product information. Morristown, NJ: ASCEND Therapeutics US, LLC; November 2022.
5. Fortesta (testosterone) product information. Malvern, PA: Endo Pharmaceuticals Inc; March 2014.
6. Testim 1% (testosterone) product information. Malvern, PA: Auxilium Pharmaceuticals, Inc; September 2009.
7. Vogelxo (testosterone) product information. Maple Grove, MN: Upsher-Smith Laboratories, LLC; September 2016.
8. Axiron (testosterone) product information. Indianapolis, IN: Eli Lilly USA, LLC; November 2010.
9. Han DH. FDA: Vogelxo therapeutically equivalent to Testim. Medical Professionals’ Reference. www.empr.com/home/news/fda-vogelxo-therapeutically-equivalent-to-testim. Accessed March 27, 2023.
10. Androderm (testosterone) product information. Madison, NJ: Allergan USA, Inc; May 2020.
11. Natesto (testosterone) product information. Englewood, CO: Aytu BioScience, Inc; October 2016.
12. Jatenzo (testosterone undecanoate) product information. Northbrook, IL: Clarus Therapeutics, Inc; March 2019.
13. Kyzatrex (testosterone undecanoate) product information. Raleigh, NC: Marius Pharmaceuticals; July 2022.
14. Tlando (testosterone undecanoate) product information. Ewing, NJ: Antares Pharma, Inc; March 2022.
15. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744.
16. Depo-Testosterone (testosterone cypionate) product information. New York, NY: Pfizer Inc; July 2018.
17. Delatestryl (testosterone enanthate) product information. Malvern, PA: Endo Pharmaceuticals Solutions Inc; October 2016.
18. Xyosted (testosterone enanthate) product information. Ewing, NJ: Antares Pharma, Inc; September 2018.
19. Xyosted instructions for use. Ewing, NJ: Antares Pharma, Inc; September 2018.
20. Aveed (testosterone undecanoate) product information. Malvern, PA: Endo Pharmaceuticals Inc; June 2020.
21. Aveed REMS Program. AVEED^® REMS (Risk Evaluation and Mitigation Strategy) Program. www.aveedrems.com. Accessed March 29, 2023.
22. Testopel (testosterone) product information. Malvern, PA: Endo Pharmaceuticals Inc; August 2018.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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