A N E N D O C R I N E S O C I E T Y C L I N I C A L P R A C T I C E G U I D E L I N E S

Testosterone Therapy in Adult Men with Androgen Deficiency

Syndromes

• Testosterone is a steroid hormone from the androgen secreted primarily by the testicles of males and the ovaries of females, although small amounts are also secreted by the adrenal glands. it is the principal male sex hormone and an anabolic steroid.

• In men, testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass, and the growth of body hair in addition, testosterone is essential for health and well-being as well as the prevention of osteoporosis

• In adult males, levels of testosterone are about 7–8 times as great as in adult females.

• Necessary for normal sperm development, regulates acute HPA axis response under dominant challenge. It also regulates cognitive and physical energy, maintenance of muscle trophism.

Introduction:

Testosterone synthesized primarily in the Leydig cells.

Regulated by LH and FSH The amount of testosterone synthesized is

regulated by the Hypothalamic-Pituitary axis.

Factors affecting testosterone levels include: - Weight loss - Sleep- Aging - Resistance training- Zinc deficiency

- Is a name that has been given, in some parts of the english-speaking world, to a set of effects that appears in some aging men, and which have some superficial similarities to menopause effects in women. Not currently recognized by the World health Organisation and it’s ICD-10 medical classification as it does not indicate a complete cessation of reproductive ability.

- Refers to a deficiency state in which the hormone testosterone goes below the normal range in an aging male. Noted to occur as early as 40 years of age. Average age of more rapid onset is 51.

- Other: Male menopause , male climacteric , androgen decline in the ageing male (ADAM) ageing male syndrome (AMS) and late onset hypogonadism

Andropause: Not the same asmid life cirses!

• First recognized: In 1889, at age 72, distinguished French neurologist & physiologist Charles e. Brown-Sequard reported in lancet, the rejuvenating effects of self-administered extracts of dog and guinea pig testes.

• Syndrome was further clarified in 1944, Heller and Myers who identified symptoms of what they labeled the "male climacteric“. heller, c.g., myers, g.b., “the male climacteric: its symptomatology, diagnosis and treatment.” JAMA 1944; 126:472-77.

• In 1927, the University of Chicago's professor of physiologic chemistry, Fred c. Koch, established easy access to a large source of bovine testicle.

• In 1935, Butenandt & Ruzicka received the Nobel prize in chemistry after synthesizing testosterone in the laboratory.

History

- Nervousness - Depression - Impaired memory - Inability to concentrate - Easy fatigability - Anger and social withdrawal - Lack of libido - Sexual dysfunction

Signs and Symptoms:

Epidemiology :

Primary • Abnormality of the HPT axis at the testicular level. • Low testosterone level , impairment of spermatogenesis and elevated gonadotropin levels

Secondary: • Central defects of the hypothalamus or pituitary.• Testicular failure results in low testosterone levels, impairment of spermatogenesis and low or low normal

gonadotropin.

Combined primary and secondary:• Testicular failure  impairment spermatogenesis, and variable gonadotropin level.  >>> causes of the

combined type include hemochromatosis, sickle cell disease thalassemia, glucocorticoid treatment, alcoholism.

classification of hypogonadism

Specific symptoms:

- Incomplete or delayed sexual development - Reduced sexual desire. - Decrease spontaneous erections- Breast discomfort of gynecomastia. - Loss of body (axillary, and pubic) hair reduced shaving. - Small < 5 ml or shrinking testicles- Inability to father children, low to zero sperm count - Height loss, or bone fracture - Hot flushes, sweats.

Measure serum testosterone levels

Mesurment of Serum Testosterone in patients with clinical manifestations

Non-specific symptoms:

-Decrease energy. - Feeling sad or blue - Poor concentration - Sleep disturbances increased sleepiness - Mild anemia - Reduced muscular bulk - Increased body fat - Diminished physical performance

• The Endocrine Society suggests the measurement of morning testosterone levels as the initial diagnostic test. and then confirmation of the diagnosis with repeating another level of total testosterone.

• Free testosterone measurement is suggested in cases where total testosterone concentrations are near the lower limit of the normal range and in whom alterations of SHBG is suspected.

• Keep in mind that serum testosterone can be affected by illness, and certain medications, such as opiates (paticularly long acting analgesics, and methadone glucocorticoids), circadian variation of testosterone levels with peaks in the morning time.

 

From the guidelines :

For most symptoms, the average testosterone threshold corresponded to the lower limit of the normal range for young men. i.e ~ 280-300 ng/dl with a greater likelihood to have symptoms below this threshold.

Keep in mind the conditions that increase or decrease SHBG.Such as : - Moderate obesity - Nephrotic syndrome - Hypothyroidism - Use of glucocorticoid, progestins and androgenic steroids- DM- Aging.- Hepatic cirrhosis and hepatitis - HIV- Use of anticonvalsants

From the Guidelines :

Further evaluation after establishing androgen deficiency: • Serum LF , FSH. • Semen analysis (if fertility issue)

Inpatient with primary testicular failure>> karyotyping

Patient with secondary hypogonadism my require further evaluation to identify the cause of hypothalamic and/or pituitary dysfunction. • Serum prolactin • Iron saturation • Pituitary function testing, • MRI of the Sella

From the Guidelines

From the Guidelines:

The Endocrine Society recommends against screening for androgen deficiency:

“As there is lack of consensus on a case definition and the extent to which androgen deficiency is an important health problem as well as the lack of data on the performance characteristics of candidate screening tools, the usefulness of population screening cannot be evaluated at present. the recommendation not screen men in the general population places a high value on avoiding labeling, medicalization of otherwise healthy men for whom testing, treatment and monitoring would represent a burden with unclear benefit”

Screening ?

 The panel suggests that clinicians consider case detection by measurement of totla testosterone levels in men with certain clinical disorders in which prevalence of low testosterone is high + have symptoms suggestive :

• Sellar mass or any disease in the Sellar region • Treatment with medications that affect testosterone production or metabolism

such as glucocorticoids and opioids• HIV associated weight loss • End stage renal disease and HD. • Moderate to severe COPD• Infertility • Type II DM.

From the Guidelines

Recommendation against testosterone therapy :

• In obstructive sleep apnea• Severe lower urinary tract symptoms IPSS >19 uncontrolled or poorly

controlled heart failure • Patients with history of prostate of breast cancer • Patient with palpable prostate nodule or induration or with PSA of >4 ng/ml

or PSA of 3 ng/ml in patient with high risk for prostate cancer (AA, 1st degree relative).

• Patients with hct > 50 %, untreated severe

Treatment of androgen deficiency:

In men >= 40 years of age:

Who have a baseline serum PSA > 0.6 , it is recommended to examine the prostate and to measure PSA before starting treatment then at 3, 6 months after treatment.

In men above 40 with a baseline of > 0.6 if serum PSA increases by more than 1.4 during a one year period after starting testosterone therapy then urological evaluation is warranted.

Treatment of androgen deficiency:

Most common forms of testosterone treatment :

• IM injections of 150-200 mg of T-enanthate or Cypionate q 2 weeks or 75- 100 mg q1 week (relatively inexpensive, easy to self administer).

 • One or two 5 mg testosterone patches applied nightly. (easy administration, frequent irritation at the site of use).

• 5-10 g of testosterone gel applied daily over a covered area of skin

• 30 mg of bio adhesive, buccal testosterone tablet applied to buccal mucosa twice a daily.

• Testosterone pellets (dose and regimen vary with formula used)

- Testosterone level is aimed to achieve testosterone levels in a range that is midnormal for healthy young males

Evaluate patients 3, 6 months after initiation of treatment then annually.

• Monitor testosterone level Q 3-6 months after initiation of treatment• Treatment should be aimed at testosterone levels in the mid normal range • Injectable testosterone need dose adjustment if T level is >700 ng/dl < 400

ng/dl• Transdermal patch: assess level 3-12 hours after application • Buccal adhesive tablets: Assess level immediately • Transdermal gels: assess any time patient has been on treatment for at

least 1 week

Monitoring after initiation of treatment

• Check HCT at baseline, 3 and 6 months after initiation of therapy. Stop if >54 %

• Measure bone mineral density at 1-2 years after starting treatment in patient with known osteoporosis, or low trauma fractures.

• Evaluate formulation specific side effects.

Bone mineral density: No trials with consistent or precise results showed significant effect on lumbar bone mineral density.

Body composition : Increase in LBM and greater reduction in fat mass [1]

Mucsle strength and physical activity: Testosterone is associated with greater improvement in grip strength than placebo. Data on changes in lower extremity muscle strength and measures of physical function were inconsistent and were only reported on in few studies [1]

Sexual function: two placebo controlled trials yielded imprecise results regarding the effect of testosterone on overall sexual satisfaction .

Quality of life : Four placebo- controlled randomized trials reported on testosterone’s effect on quality of life. Results where imprecise.

Depression/cognitive function : the effect has been inconsistent across trials .

Testoteron replacement effects:Evidence based

REFERENCES

Importance : Rates of testosterone therapy are increasing and the effects of testosterone therapy on CVD are unknown. Randomized clinical trial on men with high prevelance of CVD was stopped prematurely due to adverse effects > TOM trial.

It is estimated that annual prescriptions for testosterone increased by more than 5 folds from 2000-2011, reaching 5.3 million prescription.

Objectives: To assess the association between testosterone therapy and all cause mortaility, myocardial infarction MI or stroke among male veterans and to determin wether this association is modified by underlying CAD.

The study

Design: A retrospective national cohort study. Approved by the Colorado Multiple Institutional Review board.

Population: the study included Men with low testosterone levels (<300ng/dl) who underwent coronary angiography in the VA system between 2005-2011.

Total number of patients 23173 out of which 14464 were excluded based on the following exclusion criteria:

- Patients who started testosterone therapy prior to coronary angiography.- Patient who are started on testosterone prior to having their testosterone level

checked- Patient with missing coronary artery anatomy. - Patients who where prescribed testosterone therapy after an MI. - Patients with HCT > 50% and patients with elevated PSA level

Patients who are included: Patient with testosterone levels < 300 ng/dl. Levels closest to the timing of the angiogrpathy procedure were obtained . CAD was present (defined as based on this study) if there was 20% or more stenosis in any of the epicardial vessels on the angiography. No evidence of CAD was defined as less than 20% stenosis in all epicardial vessels.

7486 : Received no Testosterone therapy

1223 : Received testosterone therapy

Patient where categorized as initiating testosterone therapy if they filled a prescription for gel or patch or injection following coronary angiography based on pharmacy dispensing data.

Once initiating therapy the patient is assumed to have continued treatment until an outcome event occurred or the end of the follow up.

The average follow up was approximately 840 days or 27.5 months.

Characteristics of the patients between the two groups (comorbidities).

Results : • Total number of events in the cohort : 1710 748 died, 443 had MIs, 519 Had strokes.

• Of the 7486 patients not receiving testosterone : 681 died , 420 had MI, and 486 had strokes

• Of the 1223 patients receiving testosterone therapy: 67 died, 23 had MI, and 33 had strokes .

The Kaplan- Meier estimated cumulative percentages with events among the no testosterone therapy group Vs the testosterone therapy group at 1 year after CA angiography were 10.1% Vs 11.3% ; at two years 15.4 Vs 18.5%, and at 3 years 19.9Vs 25.7%. The absolute risk differences were 1.3% (95% CI -7.1-9.7%), at 1 year. 3.1% (95% CI -4.9-11.0%) at 2 years, and 5.8% (95% CI -1.4% to 13.1%) at 3 years.