ICL 4.3: Andropause

Question 1

is there a true andropause?

Answer 1

no not really, there isn’t a measurable/observable event like menopause

it’s just a normal decline in testosterone production after the 5th decade that’s usually associated with a rise in LHindiating end organ unresponsiveness

ADAM, LOH, AD, TD are all also terms for andropause

Question 2

what is testosterone deficiency syndrome?

Answer 2

declining testosterone levels after age 40 yrs

symptoms: diminished sense of well being, libido, fatigue, ED.

Question 3

what are the complications associated with testosterone deficiency syndrome?

Answer 3

1. metabolic syndrome
2. sarcopenia
3. decreased bone density

Question 4

what is hypogonadism? how is it different than testosterone deficiency?

Answer 4

male hypogonadism is defined by the Endocrine Society as “a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (T) AND sperm due to disruption of one or more levels of the hypothalamic-pituitary-testicular axis.”

in routine urologic practice the term “Testosterone Deficiency” may be used to refer specifically to the syndrome of low serum testosterone without regard to spermatogenic potential so that’s why testosterone deficiency is

Question 5

what is the prevalence of testosterone deficiency?

Answer 5

eh we don’t know, 2-77%

variability due to cut off used, assay used, heterogeneity, total vs free T

variability due to cut off used, assay used, heterogeneity, total vs free T – lots of inter and intra lab variability of levels

there’s no clear data to show what thresholds to use to define levels below which deficiency symptoms are observed and above which therapeutic benefits occur –> so don’t treat the number, treat the patient!

Question 6

what is generally accepted cut off for testosterone deficiency?

Answer 6

less than 280-300 ng/dL

Question 7

why has testosterone testing and prescriptions have nearly tripled in recent years?

Answer 7

1. direct-to-consumer advertising
2. clinical centers for men’s health not run by MDs
3. anti-aging industry

many patients were started on TRT with no clear indications, no prior levels drawn, no follow up levels

there are also many men who could have potentially befitted from treatment – did not get TRT due to unresolved concerns with prostate cancer, heart disease, CVE

Question 8

which cells make testosterone?

Answer 8

Leydig cells in the interstitum between the seminiferous tubules –> they do this under stimulation from LH, in the interstitium of the testes

there’s also a minor fraction that comes from the adrenal glands

Question 9

how do intratesticular vs. serum testosterone levels differ?

Answer 9

Intratesticular Testosterone is 500-1000 times higher than circulating T levels

if you start someone on exogenous T, their serum levels could be high but the intratesticular levels could be low due to the blood testicular barrier –> the problem is that because of the high serum levels, there will be down regulation of LH within the testicles which will cause even lower levels of testosterone production in the testicles

Question 10

which proteins bind testosterone?

Answer 10

1. pre-albumin
2. sex hormone binding globulin (SHBG)

it is only the bioavailable testosterone(free + albumin bound) testosterone that is active in tissues –> so if SHBG is high, even though total testosterone might be high, the bioavailable T is low and they might have symptoms of testosterone deficiency

Question 11

what does circulating testosterone do?

Answer 11

1. circulating T is converted to Estradiol (E2) in adipose cells using enzyme aromatase.
2. circulating T inhibits hypothalamic release of GnRH (gonadotropin releasing hormone).
3. estradiol inhibits LH release from pituitary in response to GnRH
4. T is converted to active form DHT (DiHydroTestosterone) by enzyme 5 alpha reductase in prostate, scalp etc.

Question 12

what happens to SHBG levels with age?

Answer 12

SHBG increases with age and can make isolated T level check inaccurate in patients above age 65 yrs

so it’s really unreliable to measure free T levels in older people so you have to calculate the bioavailable testosterone levels by doing the total T and subtracting the SHBG to get the bioavailable T

Question 13

what is the normal rhythm of testosterone?

Answer 13

it has a normal, circadian, seasonal rhythm

there’s a seasonal drop in the spring

in the morning, daily T rises and there’s a peak from 8-11 AM and at noon it drops so always get morning T levels

there are also hourly pulses in T based on stress, excitement, etc. but this pulsitility blunts out after 50

Question 14

what are the types of hypogonadism?

Answer 14

1. hypergonadotrophic hypogonadism

2. hypogonadotrophic hypogonadism

Question 15

what is hypergonadotrophic hypogonadism?

Answer 15

high LH

with or without high FSH

low T

tells you that the end organ isn’t responding well!

can be congenital and acquired

acquired due to aging -> TDS focus of this lecture

Question 16

what is what is hypogonadotrophic hypogonadism?

Answer 16

low LH with low testotserone

problem is usually the HPG axis not stimulating the gonads properly

Question 17

what is primary hypogonadism?

Answer 17

causes related to testes directly

1. testicular failure: aging - TDS
2. Klinefelter’s, UDT, varicocele, iatrogenic, traumatic
3. iatrogenic atrophy: infant hernia/ hydrocele repair
4. post pubertal mumps orchitis

Question 18

what is secondary hypogonadism?

Answer 18

1. pituitary adenoma
2. prolactinoma
3. narcotics
4. hemochromatosis

Question 19

how do you diagnose testosterone deficiency?

Answer 19

total testosterone level below 300 ng/dL

you must have TWO documented low levels of testosterone on separate occasions –> make sure it’s an early morning draw as T has circadian rhythm

a clinical diagnosis of testosterone deficiency is made only when patients havelow total testosterone levels AND
symptoms and/or signs of low T

once low testosterone confirmed – next step is to measure serum luteinizing hormone levels and in patients with TD, the LH is normal or high because it’s hypergonadotrophic hypogonadism

Question 20

even if patients aren’t having symptoms of TD, when should you still screen patients for TD?

Answer 20

history of:

1. unexplained anemia
2. bone density loss
3. diabetes
4. exposure to chemotherapy
5. exposure to testicular radiation
6. HIV/AIDS
7. chronic narcotic use
8. male infertility
9. pituitary dysfunction
10. chronic corticosteroid use

screen for TD with these even in the absence of symptoms or signs associated with testosterone deficiency

Question 21

what is the secondary testing you should do for TD?

Answer 21

1. serum LH
2. serum estradiol

should be measured in testosterone deficient patients who present with breast symptoms or gynecomastia prior to the commencement of testosterone therapy

3. men with testosterone deficiency who are interested in fertility should have a reproductive health evaluation (semen analysis) performed prior to treatment
4. Hct/Hb levels

prior to offering testosterone therapy, check hemoglobin and hematocrit and inform patients regarding the increased risk of polycythemia

5. PSA

should bemeasured in men over 40 years of age prior to commencement of testosterone therapy to exclude a prostate cancer diagnosis – there’s a prostate cancer that suppresses T in the body so low T with prostate cancer is a bad prognostic sign

6. obesity

obesity can increase estradiol and decrease T; suggest exercise

Question 22

what are the treatment options for TD?

Answer 22

1. weight loss
2. topical gel (risk of transference)
3. intranasal gel
4. buccal suppository (can be transferred via saliva)
5. oral (none in the US)
6. injectables

Question 23

how does weight loss help with testosterone defieicny?

Answer 23

moderate intensity exercise has been shown to improve T

105 minutes of activity weekly for 24 weeks achieving a mean T increase of 22.8±13.3 ng/dl

with 236 minutes of weekly activity, mean T increases of 59.4±13.3 ng/dl

Question 24

how do you make the decision about testosterone replacement therapy?

Answer 24

counseling is needed – shared decision making process

TRT may result in improvements in erectile function, low sex drive, anemia, bone mineral density, lean body mass, and/or depressive symptoms

inconclusive whether TRT improves cognitive function, measures of diabetes, energy, fatigue, lipid profiles, and quality of life measures

the long-term impact of exogenous testosterone on spermatogenesis should be discussed with patients who are interested in future fertility because exogenous T can effects spermatogenesis negatively

absence of evidence linking testosterone therapy to the development of prostate cancer.

Question 25

what risk factors are associated with TD?

Answer 25

low T is a risk factor for cardiovascular disease.

Question 26

what is the risks associated with TRT?

Answer 26

1. patients with history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of TRT
2. no definitive evidence linking testosterone therapy to a higher incidence of venothrombolic events despite potential for polycythemia
3. unknown risk of cardiovascular events as data is conflicting

Question 27

what are the contraindications for TRT?

Answer 27

1. discuss fertility plans with the patient /couple – do NOT prescribe TRT to men who are currently trying to conceive
2. not be commenced for a period of three to six months in patients with a history of a recent cardiovascular events or untreated severe congestive heart failure
3. existing prostate / breast cancer (controversial)
4. hematocrit level >54%
5. Untreated Obstructive Sleep Apnea (OSA)

Question 28

what do you treat TD men with who want to conceive?

Answer 28

Use aromatase inhibitors (Anastrozole), human chorionic gonadotropin, selective estrogen receptor modulators (Clomiphene), or a combination thereof in men with testosterone deficiency desiring to maintain fertility.

do NOT prescribe TRT to men who are currently trying to conceive

Question 29

how do you monitor TRT?

Answer 29

monitor T levels - measure every 6-12 months while on testosterone therapy.

discontinue TRT if no improvement in symptoms or signs in 3-6 months despite achieving therapeutic levels

Question 30

what do you need to follow up with after starting TRT?

Answer 30

1. repeat Hb and Hct
2. PSA (T didn’t cause prostate cancer but it can unmask an underlying cancer)
3. morning T levels at 2-6 and 12 months after initiation and annually afterwards
4. check bone density with men on aromatase inhibitors because their estradiol levels drop and estradiol is required for bone health and long term aromatase inhibitors can lead to osteopenia

Question 31

what are the common side effects of TRT?

Answer 31

1. polycythemia –> effect is more pronounced in elderly (>60 years) males and with injections (not creams)
2. gynecomastia
3. increased sebum productions and secretion
4. acne
5. androgenic alopecia

Question 32

how does TRT effect body composition?

Answer 32

TRT results in hypertrophy of type-I and II skeletal muscle fibers, and preferential differentiation of progenitor cells into muscle over adipose tissue

among frail men, or those with limited mobility, TRT results in improved leg strength and stair climbing speed compared to those receiving placebo.

Question 33

how does TRT effect bone and metabolism?

Answer 33

1. variable outcomes data on bone mineral density (BMD) and aging males treated with T.
2. diabetes and Metabolic Syndrome - mild improvements in measures of glycemic control
3. changes in lipids: controversial

meta-analyses showed mild improvements in triglycerides and no changes in HDL.

Question 34

how does TRT effect sexual function?

Answer 34

most studies report mild but significant improvements after TRT – it’s a facilitator of erections but not a direct cause

more so if they were hypogondal or low normal T levels as compared to eugonadal

over-supplementation of T in eugonadal males has not been shown to improve sexual function or libido.27

TRT was associated with a significant increase in sexual activity as well as significant improvements in sexual desire and erectile function

Question 35

how does TRT effect depression and mood?

Answer 35

treatment of depression in hypogonadal patients remains understudied

several studies have shown improvements in reducing symptoms of major depressive disorder, dysthymia, depression refractory to selective serotonin reuptake inhibitors, and clinical relapses, with other studies suggesting no benefit

largest RCT of hypogonadal men aged ≥65 demonstrating mildly improved mood and depressive symptoms over placebo

Question 36

how does TRT effect cardiovascular events and mortality?

Answer 36

there’s no support to support an association between TRT or increase in CVE

no increased risk of MI, stroke, or mortality with T therapy

in heart failure patients TRT demonstrated improvements in exercise capacity without increased risk of CVE. beneficial effects of T on cardiac perfusion, cardiac ischemic threshold, exercise tolerance, and cardiac output

Question 37

how does TRT effect fertility?

Answer 37

Exogenous T supplementation results in decreased gonadotropin secretion by feedback inhibition at the level of the hypothalamus and pituitary

this leads to impairment in spermatogenesis by suppression of follicle stimulating hormone (FSH)

so exogenous T decreases fertility!!!

Question 38

how does TRT effect the prostate?

Answer 38

prostate is an androgen dependent organ and T is converted to DHT in the prostate and when T levels are too high like after an injection, it gets converted to DHT and can cause an increase in PSA in hypogonadal males and increases prostate volume in patients with BPH

this can be blocked by addition of 5-alpha reductase inhibitors

there is a detrimental effect of TRT in locally advanced or metastatic prostate cancer is well established; significant progression of disease following TRT

TRT in men with localized or treated prostate cancer remains controversial.