ICL 4.3: Andropause Flashcards
is there a true andropause?
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
what is testosterone deficiency syndrome?
declining testosterone levels after age 40 yrs
symptoms: diminished sense of well being, libido, fatigue, ED.
what are the complications associated with testosterone deficiency syndrome?
- metabolic syndrome
- sarcopenia
- decreased bone density
what is hypogonadism? how is it different than testosterone deficiency?
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
what is the prevalence of testosterone deficiency?
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!
what is generally accepted cut off for testosterone deficiency?
less than 280-300 ng/dL
why has testosterone testing and prescriptions have nearly tripled in recent years?
- direct-to-consumer advertising
- clinical centers for men’s health not run by MDs
- 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
which cells make testosterone?
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
how do intratesticular vs. serum testosterone levels differ?
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
which proteins bind testosterone?
- pre-albumin
- 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
what does circulating testosterone do?
- circulating T is converted to Estradiol (E2) in adipose cells using enzyme aromatase.
- circulating T inhibits hypothalamic release of GnRH (gonadotropin releasing hormone).
- estradiol inhibits LH release from pituitary in response to GnRH
- T is converted to active form DHT (DiHydroTestosterone) by enzyme 5 alpha reductase in prostate, scalp etc.
what happens to SHBG levels with age?
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
what is the normal rhythm of testosterone?
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
what are the types of hypogonadism?
- hypergonadotrophic hypogonadism
2. hypogonadotrophic hypogonadism
what is hypergonadotrophic hypogonadism?
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
what is what is hypogonadotrophic hypogonadism?
low LH with low testotserone
problem is usually the HPG axis not stimulating the gonads properly
what is primary hypogonadism?
causes related to testes directly
- testicular failure: aging - TDS
- Klinefelter’s, UDT, varicocele, iatrogenic, traumatic
- iatrogenic atrophy: infant hernia/ hydrocele repair
- post pubertal mumps orchitis
what is secondary hypogonadism?
- pituitary adenoma
- prolactinoma
- narcotics
- hemochromatosis
how do you diagnose testosterone deficiency?
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
even if patients aren’t having symptoms of TD, when should you still screen patients for TD?
history of:
- unexplained anemia
- bone density loss
- diabetes
- exposure to chemotherapy
- exposure to testicular radiation
- HIV/AIDS
- chronic narcotic use
- male infertility
- pituitary dysfunction
- chronic corticosteroid use
screen for TD with these even in the absence of symptoms or signs associated with testosterone deficiency
what is the secondary testing you should do for TD?
- serum LH
- serum estradiol
should be measured in testosterone deficient patients who present with breast symptoms or gynecomastia prior to the commencement of testosterone therapy
- men with testosterone deficiency who are interested in fertility should have a reproductive health evaluation (semen analysis) performed prior to treatment
- Hct/Hb levels
prior to offering testosterone therapy, check hemoglobin and hematocrit and inform patients regarding the increased risk of polycythemia
- 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
- obesity
obesity can increase estradiol and decrease T; suggest exercise
what are the treatment options for TD?
- weight loss
- topical gel (risk of transference)
- intranasal gel
- buccal suppository (can be transferred via saliva)
- oral (none in the US)
- injectables
how does weight loss help with testosterone defieicny?
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
how do you make the decision about testosterone replacement therapy?
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.
what risk factors are associated with TD?
low T is a risk factor for cardiovascular disease.
what is the risks associated with TRT?
- patients with history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of TRT
- no definitive evidence linking testosterone therapy to a higher incidence of venothrombolic events despite potential for polycythemia
- unknown risk of cardiovascular events as data is conflicting
what are the contraindications for TRT?
- discuss fertility plans with the patient /couple – do NOT prescribe TRT to men who are currently trying to conceive
- 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
- existing prostate / breast cancer (controversial)
- hematocrit level >54%
- Untreated Obstructive Sleep Apnea (OSA)
what do you treat TD men with who want to conceive?
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
how do you monitor TRT?
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
what do you need to follow up with after starting TRT?
- repeat Hb and Hct
- PSA (T didn’t cause prostate cancer but it can unmask an underlying cancer)
- morning T levels at 2-6 and 12 months after initiation and annually afterwards
- 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
what are the common side effects of TRT?
- polycythemia –> effect is more pronounced in elderly (>60 years) males and with injections (not creams)
- gynecomastia
- increased sebum productions and secretion
- acne
- androgenic alopecia
how does TRT effect body composition?
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.
how does TRT effect bone and metabolism?
- variable outcomes data on bone mineral density (BMD) and aging males treated with T.
- diabetes and Metabolic Syndrome - mild improvements in measures of glycemic control
- changes in lipids: controversial
meta-analyses showed mild improvements in triglycerides and no changes in HDL.
how does TRT effect sexual function?
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
how does TRT effect depression and mood?
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
how does TRT effect cardiovascular events and mortality?
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
how does TRT effect fertility?
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!!!
how does TRT effect the prostate?
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.
