Treatment options
What is the aim of testosterone therapy?
The aim of testosterone therapy – also known as testosterone treatment - is to restore testosterone levels to what is optimal for each individual patient.1,2 Resolution of symptoms is a critical indicator of testosterone treatment efficacy.3-7 The key with testosterone treatment is to achieve therapeutic testosterone levels; in other words, a high enough increase in testosterone levels from baseline.
Symptom resolution occurs at various times depending on the type of symptom and the organ system involved.8,9 The table summarizes how long it takes for various health benefits to manifest with testosterone treatment. Our interactive tool illustrates this visually:
It should be underscored that many of these beneficial effects are not subjectively perceptible; such as improvements in lipids, glycemic control and bone mineral density. Therefore, it is important to measure these parameters, in addition to the assessment of symptomatic response and regular monitoring of PSA and hematocrit during testosterone treatment.
Table 1: Onset of effects of testosterone treatment and time course until maximum effects are achieved.8
| Testosterone therapy effect | Time required to achieve effect |
|---|---|
| Sexual interest (libido) | 3 weeks plateauing at 6 weeks, with no further increments expected beyond. |
| Erections/ejaculations | Up to 6 months. |
| Quality of life | 3–4 weeks, but maximum benefits take longer |
| Depressive mood | 3–6 weeks with a maximum after 18–30 weeks. |
| Erythropoiesis | 3 months, peaking at 9–12 months and then stabilizing |
| PSA and prostate volume rise | Small increase within the normal range is a physiological response. This increase reaches a plateau at 12 months; further increase should be related to aging rather than therapy. |
| Lipids (primarily reduction in triglycerides and LDL | 4 weeks, maximal after 6–12 months. |
| Insulin sensitivity | Improvements in glycemic control become evident only after 3–12 months |
| Body composition: Reduced fat mass / increased lean body mass and strength | 3 months, peaking at 9–12 months and then stabilizing. |
| Bone mineral density | Can be detectable after 6 months, but continuing improvement is seen for at least 3 years with ongoing testosterone treatment. |
In all types of male hypogonadism – regardless of underlying cause - testosterone therapy is the primary form of treatment.3-5 testosterone therapy is characterized by a wide margin of safety and good tolerability.3-5 Treatment can be initiated when a diagnosis of hypogonadism has been confirmed and contraindications ruled out. Proper regular monitoring during testosterone treatment is essential.
Currently available treatment options for testosterone therapy for male hypogonadism are summarized below.3-5,10 Not all preparations are available in all countries. A number of different androgen preparations and dosage forms are available; treatment should be individualized to each patient’s medical needs and preferences in terms of choice of testosterone product.
Long acting – testosterone undecanoate
Regimen: Injections every 3rd month = 4 times per year
Description: The long-acting injectable formulation of testosterone undecanoate was developed to overcome the shortcomings of conventional testosterone injections, usually requiring only four injections per year to maintain testosterone levels constantly in the eugonadal range, without the non-physiological peaks and troughs associated with conventional short-acting testosterone injections.12
Preparations like testosterone undecanoate are easier to administer (compared to older preparations such as testosterone Enathate) and provide more stable physiological levels of testosterone, avoiding the roller-coaster spikes and drops in testosterone levels and risk of ensuing mood swings and excessive hematocrit elevations.
Patients value the consistent, reliable efficacy and the long duration of effect, which means they are not dependent on taking frequent medication.13,14
Consequently, testosterone undecanoate is likely to become the standard preparation for long-term testosterone therapy. One of such preparations is injectable longacting testosterone undecanoate (Nebido®).
Short acting – testosterone enathate (or cypionate)
Regimen: Injections weekly or every second week
Description: Intramuscular injections of testosterone enanthate (or cypionate) have historically been the standard form of testosterone therapy in male hypogonadism. The commonly used T-enanthate and T-cypionate preparations produce peak levels at 1–3 days which gradually decline to trough levels at 2–3 weeks; through levels may be as low as 25% of the peak value, and these fluctuations can be accompanied by mood swings. Moreover, high peak levels are associated with an increased risk for excessive hematocrit elevation (polycythemia).11
Short-acting testosterone injections are increasingly being replaced by more modern treatment options, such as transdermal testosterone formulations and the long-acting injectable form, testosterone undecanoate, such as Nebido®.
Regimen: Daily
Description: The transdermal gel/solution contains native testosterone in a clear and colorless formulation which is absorbed by the skin within a few minutes after the morning application to the upper arms, shoulders and abdomen, without leaving any residue.
Blood levels of testosterone concentration remains very reliably within the normal range for 24 hours after application.12 A new testosterone formulation is an underarm transdermal preparation (Axiron®).
Regimen: Daily
Description: Testosterone patches are transdermal formulations of native testosterone applied to the skin of the abdomen, back, shoulders, upper arms or thighs (or scrotum, in the case of scrotal patches).
Although a steady absorption of testosterone is provided over a 24-hour period, some men may require two patches daily to achieve therapeutic testosterone levels.
Regimen: Implanted every 3–6 months
Description: A subcutaneous testosterone pellet (Testopel®) is available for the treatment of hypogonadism.15 Implants (pellets) are inserted in subcutaneous fat of the buttock, lower abdomen, or thigh every 3–6 months.
Pellets are placed using sterile technique in an office or hospital setting and cannot be injected by the patient at home. Treatment with implants is the most invasive of available testosterone treatment options.
Risks with subcutaneous testosterone pellets include infection, fibrosis, and pellet extrusion. Benefits include eliminating risk of skin-to-skin transfer, infrequent dosing, and relatively stable serum testosterone levels.
Regimen: Daily
Description: Oral testosterone undecanoate has the convenience of oral administration without the same potential for liver toxicity as another oral testosterone formulation, 17-α-testosterone.1-4
However, the short duration of action requires dosing 2-3 times daily, and clinical responses are less consistent than with the long-acting injectable formulation of testosterone undecanoate.1,2
Regimen: Daily
Description: Nasal and buccal testosterone preparations may be useful in limited clinical settings where other testosterone preparations are not effective or appropriate. Nasal testosterone spray is relatively new on the market.
Use of nasal and buccal preparations is limited because of the potential for nasal/sinus16 and gingival irritation 17, and limited published data on use of the nasal preparation. Furthermore, animal studies suggest possible increases in central nervous system testosterone levels with nasal testosterone above that seen with other formulations.18 The clinical implications of this are unknown.
Surveys that compared which treatment options patients prefer show that testosterone treatment satisfaction and compliance is highest with testosterone undecanoate injections, followed by testosterone gel.19 On a global level, patients starting on long-acting depot testosterone treatment are gaining ground19, and long-acting testosterone undecanoate injections are preferred among non-North American clinicians.20
Among patients who switched from other testosterone preparations, reasons for switching to long-acting testosterone undecanoate were reported to be:13
- More comfortable.
- Steady testosterone levels.
- Less side effects (less elevation in hematocrit and PSA).
- Easier compliance.
The high treatment satisfaction and compliance with long-acting testosterone undecanoate injections needs to be underscored, because compliance to long-term treatment essential for achievement of all beneficial health effects of testosterone therapy.8
A second issue that merits clarification is the possible contribution of weight loss to elevation of testosterone levels in testosterone deficient men (most of whom are obese). The Endocrine Society (ES) 2018 in particular states that weight loss is an “easy” way to treat hypogonadism.21 It is common knowledge that achievement – and importantly – maintenance of weight loss, is not an easy task. Furthermore, while it is well documented that obesity contributes to the development of hypogonadism, and that weight loss can increase testosterone levels, the amount of weight loss that can be realistically achieved and maintained with diet and exercise is in most cases not large enough to translate into sustained symptomatic improvement.
This was shown in a study of the Diabetes Prevention Program, which examined the effect of an intensive lifestyle intervention on changes in testosterone and mood among middle-aged men.22 While the intensive lifestyle intervention, which resulted in a weight loss of 7.97 kg after 1 year, increased endogenous testosterone from 10.98 nmol/L to 12.13 nmol/L (+1.15 nmol/L, 10% increase ), there were no significant improvements in mood. This is not surprising considering that the testosterone elevation was quite small, despite the intensive lifestyle intervention. In the European Male Ageing Study (EMAS) study, spontaneous resolution of secondary hypogonadism was accompanied by a 45% increase in testosterone levels, from 9.2 nmol/L at baseline to 13.3 nmol/L), but this was still not sufficient to drive improvements or resolution of sexual symptoms.23
It seems like a 2-fold increase of testosterone levels into the mid-normal physiological range is required for symptomatic improvements, as has been demonstrated in randomized controlled trials of testosterone therapy showing improvements in sexual function24 physical strength25 and depressive symptoms.26 This is supported by a notable randomized controlled trials of diet+exercise vs diet+exercise+testosterone treatment, showing that only testosterone treated patients had improvements in hypogonadal symptoms.27 Hence, weight loss alone does not necessarily cause resolution of symptoms related to hypogonadism testosterone deficiency.
Recommendations
References
- Maganty A, Shoag JE, Ramasamy R. Testosterone threshold - does one size fit all? The aging male : the official journal of the International Society for the Study of the Aging Male. 2015;18(1):1−4. Return to content
- Carruthers M. The paradox dividing testosterone deficiency symptoms and androgen assays: a closer look at the cellular and molecular mechanisms of androgen action. The journal of sexual medicine. 2008;5(4):998-1012 Return to content
- Dohle GR, Arver S, Bettocchi C, Jones TH, Kliesch S, Punab M. 2017 EAU Guidelines on Male Hypogonadism. Return to content
- Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. The journal of sexual medicine. 2015;12(8):1660-1686. Return to content
- Morales A, Bebb RA, Manjoo P, et al. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. Appendix available at: http://www.cmaj.ca/content/suppl/2015/10/26/cmaj.150033.DC1/15-0033-1-at.pdf (accessed Jan 10, 2016). CMAJ. 2015;187(18):1369-1377. Return to content
- Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559 Return to content
- Morgentaler A, Zitzmann M, Traish AM, et al. Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions. Mayo Clin Proc. 2016;91(7):881-896 Return to content
- Saad F, Aversa A, Isidori AM, Zafalon L, Zitzmann M, Gooren L. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol. 2011;165(5):675−685 Return to content
- Lunenfeld B, Mskhalaya G, Zitzmann M, et al. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. The aging male : the official journal of the International Society for the Study of the Aging Male. 2015;18(1):5-15 Return to content
- Behre HM, Nieschlag E. Testosterone preparations for clinical use in males Testosterone: Action, Deficiency, Substitution. 4 ed: Cambridge University Press; 2014:309-335. Return to content
- Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab. 1999;84(10):3469-3478. Return to content
- Gooren LJ. Advances in testosterone therapy. Front Horm Res. 2009;37:32-51. Return to content
- Wolf J, Keipert D, Motazedi H, Ernst M, Nettleship J, Gooren L. Effectiveness and tolerability of parenteral testosterone undecanoate: a post-marketing surveillance study. The aging male : the official journal of the International Society for the Study of the Aging Male. 2017;20(4):225-234. Return to content
- Bayer Pharma AG. Global Nebido® Satisfaction Study. 2009. Return to content
- McCullough AR, Khera M, Goldstein I, Hellstrom WJ, Morgentaler A, Levine LA. A multi-institutional observational study of testosterone levels after testosterone pellet (Testopel((R))) insertion. The journal of sexual medicine. 2012;9(2):594-601. Return to content
- Rogol AD, Tkachenko N, Bryson N. Natesto , a novel testosterone nasal gel, normalizes androgen levels in hypogonadal men. Andrology. 2016;4(1):46-54. Return to content
- Wang C, Swerdloff R, Kipnes M, et al. New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men. J Clin Endocrinol Metab. 2004;89(8):3821-3829. Return to content
- de Souza Silva MA, Mattern C, Topic B, Buddenberg TE, Huston JP. Dopaminergic and serotonergic activity in neostriatum and nucleus accumbens enhanced by intranasal administration of testosterone. Eur Neuropsychopharmacol. 2009;19(1):53-63. Return to content
- Gooren L. Diagnosing hypogonadism and treating decisions in different parts of the world: shifts in patterns between 2006 and 2015. The aging male : the official journal of the International Society for the Study of the Aging Male. 2016;19(1):46-53. Return to content
- Behre HM, Christin-Maitre S, Morales AM, Tostain J. Transversal European survey on testosterone deficiency diagnosis. The Aging Male. 2012;15(2):69-77 Return to content
- 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. Return to content
- Kim C, Barrett-Connor E, Aroda VR, et al. Testosterone and depressive symptoms among men in the Diabetes Prevention Program. Psychoneuroendocrinology. 2016;72:63-71. Return to content
- Rastrelli G, Carter EL, Ahern T, et al. Development of and Recovery from Secondary Hypogonadism in Aging Men: Prospective Results from the EMAS. J Clin Endocrinol Metab. 2015;100(8):3172-3182. Return to content
- Corona G, Isidori AM, Buvat J, et al. Testosterone supplementation and sexual function: a meta-analysis study. The journal of sexual medicine. 2014;11(6):1577-1592. Return to content
- Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf). 2005;63(3):280-293 Return to content
- Zarrouf FA, Artz S, Griffith J, Sirbu C, Kommor M. Testosterone and depression: systematic review and meta-analysis. Journal of psychiatric practice. 2009;15(4):289-305. Return to content
- Ng Tang Fui M, Hoermann R, Prendergast LA, Zajac JD, Grossmann M. Symptomatic response to testosterone treatment in dieting obese men with low testosterone levels in a randomized, placebo-controlled clinical trial. Int J Obes (Lond). 2017;41(3):420-426. Return to content
