Low testosterone

hypogonadism

a clinical syndrome that results from failure of the testis to produce

physiological concentrations of testosterone and/or a normal number of spermatozoa due to pathology at one or more concentrations of the hypothalamic-pituitary-testicular axis

increases

Hypogonadism ________ linearly with age.

DM and metabolic syndrome

What chronic med conditions are associated with hypogonadism?

~39% prevalence in men 45 years or older

Hypogonadism in Males (HIM) study:

• ~20% incidence in men older than 60 years

• Up to 50% incidence in men 80 years and older

Baltimore Longitudinal Study on Aging:

Primary hypogonadism

caused by a disruption of the testicular level

- FSH and LH concentrations are elevated

Secondary hypogonadism

caused by a disruption at the hypothalamic or pituitary level

- FSH and LH concentrations are normal or low

physical system hypogonadism clinical presenation

-Muscle wasting/weakness or

-lack of muscle gain

-Fatigue

-Suspected bone loss or non-traumatic fracture

-Hot flashes

-Metabolic syndrome

-Iron-deficiency anemia

-Body hair loss

-Obstructive sleep apnea

sexual system hypogonadism clinical presentation

-Decreased or absent morning erections*

-Decreased or lack of libido

-Weakened erection strength/rigidity in past year

-An ejaculation or difficulty achieving orgasm

-Failure of PDE-5 inhibitors to correct erectile dysfunction

physiological system hypogonadism clinical presentation

-Depression**

-Memory/cognitive impairment

-Disinterest in/apathy to partner/spouse***

2

You need to have s/s in at least ____ systems to be classified as hypogonadism.

• Presence of signs and symptoms

• Low serum total (free plus protein-bound) testosterone concentrations

- Drawn between 8 and 10 AM on at least two occasions

- The normal range in adult men ~300-800 ng/dL

- Lab should also be drawn fasting

How do you dx hypogonadism?

2

How many occasions should serum testosterone concentrations be drawn in order to dx hypogonadism?

younger

Circadian fluctuation is more pronounced in ________

primary

If serum testosterone is elevated then think ________ dx

secondary

If serum testosterone is normal or low then think ________ dx

1-8

What is the normal serum testosterone range?

• To achieve and maintain eugonadal serum testosterone levels

• To treat signs and symptoms of adult onset hypogonadism

What are the goals of testosterone replacement therapy?

• Induce and maintain secondary sex characteristics

• Correct symptoms of testosterone deficiency

Testosterone therapy is recommended to:

against

There are recommendations _______ routinely prescribing testosterone therapy to all men 65 years of age or older with low testosterone (age-related decline)

• Weight risks and benefits if symptomatic

metastatic prostate cancer and breast cancer

What are very high risk conditions that we would recommend against using T?

-unevaluated prostate nodule or induration

-unevaluated PSA > 4

-Hematocrit > 48%

-severe LUTS associated with benign prostatic hypertrophy as indicated by AUA/IPSS > 19

-uncontrolled or poorly controlled congestive heart failure

-desire for fertility in the near term

What are the moderate to high risk conditions that we would recommend against using T?

Efficacy of testosterone

• Induces development of secondary sex characteristics

• Significant improvement in libido and erectile function

• Small benefits for positive mood aspects

• No significant benefit for fatigue

• Increases bone strength but no studies on fracture risk

erythrocytosis

CV

VTE

prostate cancer

fertility

What are the risks associated with TRT?

Erythrocytosis

• Higher risk in older men

• Significantly higher frequency with testosterone over placebo

• Level of increased risk for neuro-occlusive and cardiovascular events is unknown

Cardiovascular risk with TRT

• No RCTs long or large enough to determine major adverse cardiovascular events - limited power has led to inconclusive evidence

• Inconsistent relationships between testosterone concentrations and CAD

Venous Thromboembolism (VTE)

• Too few events reports to make significant conclusions

• Some case reports suggest increased VTE risk within the first 6 months of starting therapy

Prostate Cancer

• No powered RCTs to determine relationship

• Meta-analyses of epidemiologic students found no significant association between testosterone concentrations and prostate cancer

• However, the physiologic role of testosterone in hormone-dependent cancer is significant enough to warrant caution

suppresses

Testosterone ________ sperm production.

Testosterone, thyroid-stimulating hormone (TSH), hematocrit

D.R. is a 67-year-old man who presents for an annual visit.

Symptoms include:

• Depressed mood

• Impaired cognition and memory

• Decreased muscle strength

• Hair loss

• Diminished libido

In addition to a prostate-specific antigen (PSA) test, which one of the following groups of laboratory tests is best to recommend for D.R.?

A. Testosterone, thyroid-stimulating hormone (TSH), hematocrit

B. TSH, hematocrit, A1C

C. Testosterone, luteinizing hormone, A1C

D. Follicle-stimulating hormone (FSH), TSH, hematocrit

Discontinue testosterone until symptoms resolve

D.R. returns to the clinic for a follow-up visit after receiving testosterone cypionate 100 mg intramuscularly weekly:

• No new problems

• Reports some improved sexual function and resolution of depression

• Muscle strength has not improved, and he has noted increased fatigue and frequent bruising

• D.R. also started HCTZ 25 mg daily at his last visit

• Lab results this afternoon:

- PSA 2.1 ng/ mL

- Triglycerides 422 mg/dL

- Total testosterone 821 ng/dL

- Hematocrit 55%

- Hemoglobin 18.6 g/dL.

Which one of the following is best to recommend for D.R.?

A. Reduce the dose of testosterone to 50 mg intramuscularly weekly

B. Reduce the dose of testosterone to 100 mg every 2 weeks

C. Repeat the testosterone concentration test between 8 AM and 11 AM

D. Discontinue testosterone until symptoms resolve

A total testosterone concentration should be repeated, together with a free concentration, before a definitive diagnosis of hypogonadism can be made

• A 59-year-old man presents with:

- Depressed mood

- Impaired cognition and memory

- Decreased muscle strength

- Diminished libido

• He has been followed in the clinic for the past year for diabetes

• Currently medications:

- metformin 1000 mg twice daily

- Insulin glargine 10 units daily

• Lab results this afternoon:

- A1C 8%

- Fasting blood glucose 180 mg/dL

- Total testosterone 310 ng/dL

- Hematocrit 46%

- Hemoglobin 14.5 g/ dL

- PSA 1.8 ng/mL

Which one of the following would be best to recommend for this patient?

A. Testosterone replacement therapy (TRT) should not be implemented because the presenting symptoms are too ambiguous to make a definitive diagnosis of hypogonadism

B. Increasing the Lantus dose will help achieve goal A1C, subsequently relieving hypogonadal symptoms

C. A total testosterone concentration should be repeated, together with a free concentration, before a definitive diagnosis of hypogonadism can be made

D. Testosterone enanthate 400 mg may be given intramuscularly every 2 weeks

Decrease Androderm to 2 mg daily

A married couple presents for their follow-up visit in the family medicine clinic. The wife states that her 46-year-old husband's mood has improved after starting TRT, but he still can be borderline aggressive toward her. The husband states that his wife is just jealous that he is "getting in shape." He taps his chest and tells you his "pecs" have increased in the past month.

• Current meds:

- Testosterone patch 4 mg daily

• Testosterone concentration is 854 ng/dL

Which one of the following is best to recommend for this patient?

A. Discontinue testosterone

B. Decrease Androderm to 2 mg daily

C. Change to Androgel 1.62% 4 actuations daily

D. Change to testosterone enanthate 250 mg weekly

SC implant TRT

-pellet implants

-assess serum T at the end of the dosing interval

-looks for signs of infection, fibrosis, or pellet extrusion

injectable T

-Testosterone cypionate/enanthate

-assess serum T in the middle of the dosing interval

-ask pt about fluctuations in mood or lbido; ask about cough after injections (rare)

patch testosterone

-assess serum T 3-12 hrs after application

-evaluate for skin reaction at the application site

gel testosterone

-assess serum T any time after treatment initiated for 1 week

-advise covering application sites with clothing

-wash hands with soap and water before close contact with women or child

buccal system testosterone

-assess serum T immediately before or after application of a fresh system

-ask about taste alterations and examine gums for irritation

capsule testosterone

-assess serum T 7 days after tx initiating or dose adjustment then measure 6 hrs after morning dose

-Advise can cause blood pressure (BP) increases that can increase the risk of major adverse cardiovascular events. Ensure adequate BP

control prior to initiation and periodically monitor for new-onset HTN or exacerbations of pre-existing HTN

strong association adverse events

• Erythrocytosis

• Acne/oily skin

• Subclinical prostate cancer

• Growth of metastatic prostate cancer

• Reduced sperm production and fertility

• Blood pressure increases

weak association with adverse events

• Gynecomastia

• Male pattern balding

• Growth of breast cancer

• Induction or worsening of obstructive sleep apnea

• Fluctuation in mood/libido

• Pain at injection site

• Coughing episodes

injection T AEs:

skin reactions at site

patches T AEs:

alterations in taste and gum irritation

buccal T AEs:

-transfer to another person in close contact

-skin irritation and odor at site

-stickiness, slow drying

gels and solutions T AEs:

infection and expulsion of pellet

pellet implants T AEs:

-DRE

-voiding/IPSS

-PSA

-hematocrit

-clinical breast exam

-sleep apnea

What do you monitor during hypogonadism?

-Baseline, 3 and 6 months, and then every year

-Biopsy if abnormal at baseline or during treatment

digital rectal exam monitoring:

baseline, symptom assessment of prostate every 6-12 months

voiding/IPSS monitoring:

-baseline, 3-6 mo, and then every yr

-biopsy if: PSA > 4, PSA increases ≥ 1.4 within 1 yr

-repeat measure if: PSA increases by at least 0.7 within 1 yr

PSA monitoring:

-baseline, 3 and 6 mo, and then every yr

-if hematocrit > 53%, discontinue use

Hematocrit monitoring:

-baseline and at follow up prn clinically

-if painful gynecomastia, may need to discontinue use

Clinical breast exam monitoring:

-baseline and prn clinically

-ask pt about daytime fatigue and disordered sleep

-if sleep apnea worsens, discontinue use

Sleep apnea monitoring:

Transdermal formulations

- Can correct most deficiencies

- Require significant counseling to help patients achieve desired

effects, ensure adherence, and avoid transference

Injectable formulations

- Less expensive option

- Produce a supraphysiologic response that has been associated with mood swings, infertility, and polycythemia

- Surgical placement

- Intolerability

- Financial concerns

What are the challenges with Subcutaneous implants and buccal tablets?

- Easy administration

- Possible improved adherence to treatment regimen

- Generic currently unavailable

What are the challenges with oral capsules?

do not supplement with testosterone

If PSA ≥ 4

PSA ≥ 50% increase over 1 yr

untreated prostate cancer

AUA/IPSS score > 19

Hct > 50%

CHF

Breast cancer

injectable supplementation (high dose or once weekly frequency preferred)

Total Testosterone < 150 TRT tx:

injectable (low dose with every 2 week frequency) or transdermal

Total Testosterone 151-299 TRT tx:

reduce dose/frequency OR stop supplementation

After initial TRT of 1 month the total T is > 800 what do you do?

increase dose frequency

After TRT tx with an injectable (low dose with every 2 week frequency) or transdermal you get a total T of < 300 what do you do?

consider dual therapy (injectable + transdermal)

After TRT tx with an injectable (high dose or once weekly frequency preferred) you get a total T of < 300 what do you do?

reassess secondary causes and adherence

After TRT tx with dual therapy (injectable + transdermal) you get a total T < 300 what do you do?

Xyosted

testosterone enanthate

Xyosted (testosterone enanthate)

- Approved October 1, 2018

- Antares Pharma, Inc.

- TRT in adult males for conditions associated with a deficiency or absence of endogenous testosterone

• Primary hypogonadism (congenital or acquired)

• Hypogonadotropic hypogonadism (congenital or acquired)

- Administered as a once-weekly, subcutaneous, single dose auto injector therapy

- The device will provide the patients to take the treatment without the aid or supervision of a care provider at home

- It is approved in dosage strengths of 50 mg, 75 mg, and 100 mg

Jatenzo

testosterone undecanoate

Jatenzo (testosterone undecanoate)

- Approved March 2018

- Clarus Therapeutics, Inc.

- The first and only FDA-approved oral softgel capsule (CIII) for

testosterone replacement therapy (TRT) for adult males with

primary hypogonadism

- Admistered by mouth twice daily, morning and evening, with food

- It is approved in dosage strengths of 158 mg, 198 mg, and 237 mg

• In the absence of severe testosterone deficiency (< 150 ng/dL), signs and symptoms should be present in at least two categories before considering supplementation

• The treatment algorithm should be considered when deciding on a course of therapy

• Any supplementation choice requires vigilant monitoring, counseling, and patient adherence

In determining the optimal pharmacotherapy for the treatment of hypogonadism, practitioners should consider the following: