Male Menopause, Andropause: Drug Therapy

Therapeutic target

To compensate for the partial androgen deficit of the aging male. It should be noted that male hypogonadism (symptomatic hypogonadism/gonadal hypofunction) is defined as follows [EAU guideline].

  • Total testosterone serum level < 12 nmol/l or 3.5 ng/ml (350 ng/dl) plus
  • Organ functions and quality of life impaired by androgen deficiency.

At total testosterone serum levels < 8 nmol/l (231 ng/dl), a need for therapy is given and probable; at total testosterone serum levels between these values (< 12 nmol/l and < 8 nmol/l), an indication for probationary therapy for 6-12 months with reevaluation is given.

Therapy recommendations

  • In symptomatic hypogonadism, there is a good chance of achieving an improvement in symptoms through testosterone substitution (testosterone hormone replacement therapy; testosterone replacement therapy/testosterone replacement therapy; testosterone replacement therapy, TRT).
  • With intramuscular injection, the effect lasts about 2-4 weeks, with a long-term depot even 3 months of effect are possible. After that, a new injection is required. Disadvantages are potential side effects (see below) such as hypertension (high blood pressure), polyglobulia (erythrocytosisincrease in red blood cells) or even dyslipidemia (lipid metabolism disorder).
  • Initially, substitution should be limited to 3-6 months and continuation should depend on whether there is an improvement in subjective complaints and objective findings.
  • After three, six, and twelve months, and annually thereafter, the “response to treatment” should be assessed.

Further notes

  • No testosterone substitution therapy before exclusion of prostate carcinoma (prostate cancer)!Guideline prostate cancer: “In hypogonadal patients without clinically apparent prostate carcinoma, testosterone can be substituted. To date, an increased risk of prostate cancer has not been demonstrated.”
  • For prostate cancer patients who have already undergone surgery, wait until one year after surgery and substitute only if the patient has been PSA recurrence-free during that time. Substitution should be limited to patients with a “low risk of prostate cancer recurrence (Gleason score preoperative < 8, pT1-2, PSA < 10 ng/ml)” (EAU guideline).
  • For contraindications to testosterone substitution, see below.

Contraindications

An absolute contraindication to the administration of testosterone is known and untreated or advanced prostate cancer.Testosterone leads to the promotion (rapid growth) of prostate cancer. However, hormone replacement therapy (HRT) with testosterone does not appear to lead to increased new development (initiation) of prostate cancer: A study of nearly a quarter of a million men aged 69 years on average between 2009 and 2012 from the National Prostate Cancer Registry and the Prescribed Drug Registry in Sweden demonstrated that there was no significant association between TRT and the risk of prostate cancer when testosterone replacement therapy (TRT) was administered (OR 1.03, 95% CI 0.90-1. 17); in contrast, a 35% increased risk (OR 1.35, 95% CI 1.16-1.56) for prostate cancer (low risk) was observed in the comparison group shortly after the start of testosterone replacement therapy (possibly due to more frequent medical appointments); in the men who had already been on testosterone substitution for at least one year, the risk for aggressive forms of cancer even decreased by 50% (OR 0.50, 95% CI 0.37-0.67). Other contraindications (EAU guideline).

  • Diseases such as polycythemia (disease of the bone marrow in which red blood cells proliferate uncontrollably) and when hematocrit (volume fraction of cellular elements in the blood) > 50% (due tohemoglobin and hematocrit value ↑ under testosterone substitution).
  • Unclear prostate findings
  • PSA value > 4 ng/ml
  • Severe lower urinary tract symptoms due to benign prostatic hyperplasia (prostate enlargement).
  • Mammary carcinoma (prostate cancer)
  • Untreated obstructive sleep apnea (pauses in breathing during sleep caused by obstruction of the airway; although no association between obstructive sleep apnea and testosterone substitution has been demonstrated)
  • Dilated cardiomyopathy (disease of the heart associated with enlargement of the heart muscle).
  • Severe hypertension (high blood pressure).
  • Hypercalcemia (excess calcium) in malignant (malignant) tumors.

Active ingredients (main indication)

Application form Active ingredient HWZ Special features
Oral Testosterone undecanoate 1,6 h Short-term fluctuations in serum levelsHighest plasma concentrations of testosterone undecanoate after four hours on average.

Due to high “first-pass” effect of testosterone in the liver with rapid degradation of the substance, 3 to 4 daily single doses are necessary. Poor bioavailability! Meanwhile rather of minor importance

Buccal Testosterone Short-term fluctuations in serum levels

Mucosal irritations

Intramuscular Testosterone enanthate* 4,5 d Deep intramuscular injection required in each case!
Testosterone undecanoate* The first two injections are given six weeks apart, the others every three months. * Not recommended: highly fluctuating levels, unphysiologically high after injection.

Deep intramuscular injection required! Cave: anticoagulation.Leads to stable testosterone levels.

Subcutaneous Testosterone Pellets Surgical implantation requiredDislocation risk.
Nonscrotal transdermal(as gel or patch) Testosterone Abdominal skin or upper arms/thighs: cutis serves as a reservoir from which the drug is continuously released into the bloodstream over 24 hours; after approximately four hours, serum levels are within the normal range
Testosterone Mostly agent of choice to start therapy

Gel application in the morning leads to maximum testosterone levels in the morning hours, so a physiological effect can be mimicked here. Transfer risk due to skin-to-skin contact with children or women

rarely skin irritation

Testosterone

Mode of action of testosterone hormone replacement therapy

Mode of action of testosterone hormone replacement therapy.

The effects of testosterone hormone replacement therapy affect almost all organs or organ systems:

  • Maintenance of optimal physical, sexual, emotional, and cognitive health.
  • Increase libido
  • Spermatogenesis (spermatogenesis) and formation of seminal plasma (sperm fluid from the sex glands).
  • Anti-atherogenic effects (lowering lipoprotein (a), increasing fibrinolysis).
  • Increase in lean muscle mass
  • Increase in muscle strength
  • Prevention of osteoporosis (bone loss) and age-related frailty.
  • Decrease in arthralgia
  • Catecholamine-induced lipolysis especially decrease in visceral adiposity (mobilization of triglycerides).
  • Decrease in serum leptin levels.
  • Improved insulin sensitivity*
  • Cardiac output, dilation of coronary vessels (heart disease vessels).
  • Increase erythropoiesis (formation of mature erythrocytes from hematopoietic stem cells of the hematopoietic bone marrow) and immune function.
  • Mood improvement – especially in older depressed men.
  • Certain protection against autoimmune diseases – for example rheumatoid arthritis.
  • Stimulation of the STH (growth hormone)

Dosage information

  • Instructions for transdermal application (administration of drug in patch form): patient should wait approximately 5 minutes after application before dressing; hands must be cleaned with soap and water to remove gel residue; direct physical contact with other persons (especially women and children) should be avoided within the first 6 hours after application of the gel containing testosterone.
  • Initially, substitution should be limited to 3-6 months and continuation should depend on whether there is improvement in subjective complaints and objective findings.
  • After three, six, and twelve months, and annually thereafter, the “response to treatment” should be assessed.

Side effects

  • Side effects: Irritation of the skin

Potential side effects of testosterone hormone replacement therapy.

  • Hemoglobin and hematocrit levels ↑
  • Polyglobulia (blood thickening due to increase in red blood cells) – due to unphysiological testosterone levels (rare cause).
  • Thrombocytosis (increase in platelets above normal levels).
  • Edema (water retention), fluid retention – due to decreased sodium excretion by the kidneys, arterial hypertension (high blood pressure), heart failure (cardiac insufficiency).
  • Dyslipidemia – HDL cholesterol decrease with mostly small LDL cholesterol increase.
  • Acne (e.g. acne vulgaris) – rare, at the start of therapy).
  • Worsening of sleep apnea (rare).
  • Gynecomastia (enlargement of the mammary gland in men; rare).
  • Priapism (erection lasting >4 h without sexual stimulation; 95% of cases ischemic or low-flow priapism, which is very painful) (very rare)
  • Hepatotoxicity (liver-damaging; only with 17 alpha-alkylated androgen derivatives).
  • Cardiovascular risks are controversial:
    • Increased risk of: Myocardial infarction (heart attack), apoplexy (stroke)
    • A risk assessment procedure by the EMA (European Medicines Agency) has shown no evidence that testosterone-containing medicines increase cardiovascular risk when used as licensed
    • No increased risk of: Myocardial infarction or acute coronary syndrome, apoplexy, heart failure (heart failure), or cardiovascular death.
    • Lower cardiovascular event rate and all-cause mortality lower; largest cohort to date (83,010 male insured with documented hypogonadism/gonadal hypofunction). Participants had no history of myocardial infarction or apoplexy. Results: rate of myocardial infarction was one-fourth (HR 0.76; 95% CI 0.63-0.93) and rate of apoplexy was one-third lower.
    • In older men (308) with low or low-normal testosterone levels, three years of testosterone therapy versus placebo therapy did not result in significant change in intima-media thickness (intima-media thickness measurement: ultrasound examination to detect arteriosclerotic vascular changes) or in coronary calcification, nor in improved sexual function or quality of life.
    • Genome-wide association studies (GWAS) discovered that men with certain gene variants in the JMJD1C gene have elevated testosterone levels. Based on a Mendelian randomization analysis, we examined whether the same genes that increase testosterone levels also affect cardiovascular disease risk. Here are the results:
      • Each 1 nmol/L increase in testosterone levels was associated.
        • With only a small increased risk of myocardial infarction (odds ratio 1.17; 0.78-1.75).
        • With a double risk of a thromboembolic event (odds ratio 2.09; 95% confidence interval 1.27 to 3.46)
        • With a nearly 8-fold increased risk of heart failure (odds ratio 7.81; 2.56-23.8)

      Whether testosterone therapy increases the risk of cardiovascular events requires a separate study.

    • In the first six months, the risk was increased in testosterone-treated men with hypogonadism for venous thromboembolism; incidence of thromboembolism (deep vein thrombosis, pulmonary embolism, unspecified venous thromboembolism) 15.8/10,000 person-years (compared with control group: increased by a mean of 25% (95% confidence interval -6% to +66%); in the first six months: Incidence of thromboembolic events in testosterone-treated men: 52% (-6% to +146%).

Regular check-ups

Under testosterone substitution therapy, regular check-ups including PSA test, hematocrit, rectal palpation of the prostate and rectal prostate sonography should be performed:

  • Semiannually for the first year
  • From the second year once a year

Andropause and diabetes mellitus type 2

Testosterone substitution, of men with lowered serum testosterone levels and type 2 diabetes mellitus, results in the decrease of:

  • Fasting insulin serum levels
  • Glucose serum level
  • HbA1c

Testosterone therapy also results in weight loss and improved cardiovascular risk factors in hypogonadal obese men with and without type 2 diabetes mellitus

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Estrogen Therapy in the Aging Male

In a study (Giri et al., Atherosclerosis. 1998; 137:359-366) of older healthy men, estrogen therapy with 0.5-2 mg oral micronized 17-beta estradiol resulted in the following:

  • Decrease in LDL cholesterol
  • Increase in HDL cholesterol
  • Decrease in homocysteine and fibrinogen

This occurred without increases in thrombosis markers such as thrombin-antithrombin III complex, protein C, and von Willebrand factor. However, a randomized, placebo-controlled trial – Coronary Drug Project, 1970 – failed to demonstrate the protective effect of estrogens in men after myocardial infarction (heart attack). On the contrary, the study showed a 3-fold increase in thromboembolic events and the number of nonlethal myocardial infarctions was about twice as high.Conclusion!Therapy of aging men with estrogens is not recommended at present!

Supplements (dietary supplements; vital substances)

In the presence of insomnia (sleep disturbances) due to andropause, see below Insomnia/Medicinal Therapy/Supplements.