W2 Male Hypogonadism And Testosterone Deficiency (Joey)

Question 1

Slide 3 &4
What is testosterone?
50% bound to?
The other 50% bound to?
Know the HPG axis [know this]
See my drawing

Answer 1

—cholesterol derived steroid hormone
—50% bound to albumin
—other 50% bound to SHBG therefore not physiologically active

Free testosterone performs its physiologic mechanism of action by binding to androgen binding protein in the target cells’ nuclei, which in turn binds to certain regions of DNA and by acting as a transcription factor promotes transcription of certain genes → development of proteins that downstream cause physiologic effects associated with clinical T effects

Pulsatile release of GnRH -from hypothalamus
→ pulsatile release of LH and FSH from the anterior pituitary.
→ LH moves through systemic circulation to its target cells, the Leydig Cells of the testicle → testosterone production

■ Negative feedback loop is primarily via peripheral conversion of Free T to E2 by the enzyme “aromatase”
→ E2 acts centrally at both the hypothalamus and the anterior pituitary to decrease gonadotropin release.

○ FSH moves through systemic circulation to its target cells, → Cells of the testicle to promote spermatogenesis

Question 2

Which medications interact with the HPG axis? 2
Slide 5

Answer 2

5-ARI — inhibit the transition of testosterone to DHT

Aromatase (enzyme) inhibitors prevents the conversion of free T to E2 negative feedback loop

Question 3

Physiologic functions of testosterone
MOA
Testosterone increases levels of _______ to help erectile function
______ inhibits osteoclast activity

Answer 3

● Pubertal Development [virilization: male pattern hair grown, deepening of voice (2/2 thickening of the vocal folds), increased muscle mass, increase in testicular volume and phallus size, prostate and seminal vesicle growth and function - mostly T & DHT mediated]
● Promotes libido in both men and women
● Promotes erectile function (increase levels of nitric oxide synthase → incr. NO)
● Increases muscle mass and strength
● Metabolism regulation (pro-metabolism), ? > Energy Levels
● Plays minor (behind the scenes) role in erythropoiesis
● Regulation of bone mineral density in males via aromatase-mediated conversion to estradiol:
○ Estradiol inhibits osteoclast (crush bone) function → decreased bone mineral density loss → improved bone strength

Question 4

What is a testosterone deficiency?
What is the difference between primary and secondary?
[slide 8]

Answer 4

Testosterone Deficiency:
● Definition: A male with serum T levels of <300 ng/dL (must be confirmed on on 2 seperate AM lab draws before 10 am >1 week apart)
● Normal serum T levels, in general, fall somewhere between 300 ng/dL and 800 ng/dL
○ However institution specific reference ranges may vary depending on the assay

Primary
—abnormal intratesticular function
—low serum T but LH and FSH are HIGH b/c no negative feedback so system are not suppressed

Secondary
—abnormal extra-testicular function
—low serum T and LH and FSH are ALSO LOW.
—something wrong w/ the brain (pituitary/hypothalamus)

Question 5

Testosterone deficiency s/s — two main ones
Slide 9

Answer 5

—low libido
—ED
—decrease in NO synthase
—fatigue, mental or physical

Question 6

Causes of primary and secondary hypogonadism
Which medication (used to treat metastatic prostate cancer)
[slide 10]

Answer 6

Primary: Low T, High FSH
—ageing no.1 cause “andropause”
—cryptochidism
—Klinedelter syndrome
—iatrogenic
—infectious

Secondary: Low T, Low FSH
—also no.1 cause is ageing
—obesity
—Kallman syndrome (GnRH is not picking up the call!)
—medications
—iatrogenic

Medications: GnRH agonists (Lurpon):
—used to treat metastatic prostate cancer
—should increase LH and FSH and testosterone downstream, what ends up happening, it induces a tachyphylaxis phenomenon and it causes the cells to endocytose the receptors on the anterior pituitary so GnRH is less effective. Cutting the amount of receptors down.

Question 7

Workup and patient interview
Slide 11

Answer 7

—FX + for prostate, MI, dyslipidemia
—always perform CV exam
—always perform prostate exam

Question 8

Testosterone deficiency work up — labs and imagining
Slide 13

Answer 8

Labs:

● Testosterone (normal range approximately 300 ng/dL - 800 ng/dL)
—Testosterone Deficiency Dx can only be definitively made if a patient has 2 AM T levels (fasting preferred) greater than 1 week apart
—If T Deficiency is found, you should start looking to further characterize you patient’s T deficiency (primary vs secondary), attempt to determine possible causes, treatment needs
● CBC / HCT - assess for concurrent anemia and baseline data to trend for TRT safety assessment
● LFTs - assess for baseline data to trend for TRT safety assessment
● PSA - assess for baseline data to trend for TRT safety assessment (~ <4 ng/mL or low PSA vel.)
● LH - Helps determine primary or secondary T deficiency (norm is ~ 2-10)
● FSH - Helps determine primary or secondary T deficiency (norm is 2-8 ~ MIU/mL)
● PRL - assess for hyperprolactinemia as a cause of T def. (x2, before 10am, fasting, norm is ~2-18). you’re trying to rule out prolactinoma!!
● +/- genetic screening if all else negative (karyotype for klinefelter syndrome, about 1/1000-1400 M)
● HIV antigen/antibody if suspected from other signs / symptoms

Question 9

Testosterone deficiency
Treatment
3 delivery types

Answer 9

Topicals:
● Gels (“androgel,” “axiron” underarm) - daily dosing, usually good serum response, high risk of transfer to others pts report it’s messy
● Patches (“androderm”) - daily dosing, less messy, but some pt’s develop focal irritation

Injectables / Implants (“depo”)
● IM Testosterone (T cypionate, T enanthate) - weekly or biweekly dosing, kinetics has peaks and valleys, high right after shot and then it declines over the 2 weeks
● Subcutaneous Testosterone Pellets (“Testopel”) - q 3-4 month dosing, kinetics steady, but involves procedure (infection risk, can be costly: financially, time away from work, etc)

Oral — not used at all in adult population
● PO Testosterone - rarely used now as has low bioavailability and is associated with a HIGH degree of hepatic dysfunction due to excessive first pass metabolism with PO administration (occasionally prescribed in pediatric pts close conjunction with endocrinology)
● Buccal / Sublingual Testosterone - rarely used, similar issue with PO administrations

Question 10

What are some risks, SEs and consequences of TRT

Answer 10

● Elevated hematocrit / erythrocytosis (multifactorial, T mediated > in Epo & changes in ferritin)
● Hepatic Dysfunction → chronic hepatitis → cirrhosis (> risk if pt has other risk factors for cirrhosis)
● Increased prostate growth (could be concern for which pts?) & increase in PSA
○ ?? increase incidence of prostate cancer (previously thought to be the case, data around TRT and PCa always
evolving, current data shows if dosing TRT appropriately - only to point of pt’s T level being wnl, TRT has low likelihood of causing PCa May have slight increased chance if you already have a genetic predisposition to PCa, however it is understood that TRT may unmask underlying previously occult or indolent PCa)
● Decreased sperm cell count (negative feedback loop leading to < FSH), especially if you keep them at the higher T end
● Cardiovascular risks: possible, though new data is showing low T may also cause <3 dz
○ Increased T levels may promote cardiac muscle growth (ventricular) and therefore decrease cardiac output which puts increased strain on the heart → hypoxia
○ Elevations in HCT may increase viscosity of the blood → increased strain on <3
○ Increased chance of developing clots (via increased E2 - T conversion to E2 could lead to elevated E2 serum
levels which can increase chance of clot formation (avoid TRT in smokers, keep a close eye on E2 levels in pts with predisposition to clot).
○ Hepatic dysfunction could lead to dyslipidemia which can exacerbate atherosclerosis
○ Exacerbation of OSA (weight gain..?) → systemic hypoxia → increased strain on CV system

Always rule out prolactinoma, if suspicion, MRI scan of the brain and sella turcica

Question 11

Testosterone deficiency take homes

Answer 11

● When finding patients with T deficiency, always try to figure out WHY! Your workup may reveal other pathologies and
help guide your decision making re: TRT, and may reveal more aggressive etiologies for their low T (ex: prolactinoma) ● Before prescribing TRT for your patients, make sure you are accurately diagnosing them with T deficiency and
performing an objective safety assessment: gather medical history, family history of prostate cancer, TRT safety lab
panel (CBC, LFTs, PSA), exam, etc.
● T is not “fountain of youth” that many older men may think it is… always educate your patients on risks of TRT and
continue to follow them with regular labs every 3-6 months to ensure appropriate dosing and safety (do no harm)
● Given potential risks of TRT, should only be treating patients who have SYMPTOMATIC T deficiency
○ (FYI: there are rare instances when you tx w/o sx, exs: pt’s w/ T-associated male factor infertility (see next slide deck, you typically do not use testosterone to treat these pts, osteoporosis pts who have low T w/ BMD on DEXA and hx of frequent fractures refractory to other osteoporosis treatments, treatment refractory anemia in pt’s w/ low T - very rare)
● TRT can be used as a form of HRT for transmasculine individuals in conjunction with other therapies (specifics on
this are beyond the scope of this lecture)
● Testosterone is highly important in spermatogenesis, w/o normal concentration, abnormal / low sperm cells develop
(true in either direction… < T can leading to < sperm counts (next lecture), and > T can lead to < FSH, which can also
lead to < sperm counts)