Acts by negative feedback at the pituitary [Campbell’s 12th edition, page 1319 says both “hypothalamus or pituitary”, Wikipedia says “Inhibin does not inhibit the secretion of GnRH from the hypothalamus", 2019 AUA Update on Exogenous Testosterone and Male Reproduction agrees with Wikipedia] to inhibit FSH production
The free and loosely-bound (albumin, corticortropin-binding) testosterone fractions combined are known as bioavailable testosterone
Only bioavailable testosterone can enter cells and have an effect on the androgen receptor.
Free and total testosterone measurements are most accurate when done by equilibrium dialysis but in the absence of this assay, they can be calculated from total testosterone, SHBG and albumin.
Serum testosterone levels <300 ng/dL considered low
Calculated free testosterone <6.5 ng/dL considered low
Intratesticular testosterone levels are 50-100x those of the circulating serum levels and are necessary for appropriate spermatogenic function.
SHBG
Conditions associated with decreased SHBG (so expect higher proportion of bioavailable testosterone for same total testosterone level)
Obesity
Nephrotic syndrome
Hypothyroidism
Use of glucocorticoids, progestins, and androgenic steroids
Acromegaly
Diabetes mellitus
Conditions associated with increased SHBG [so expect lower proportion of bioavailable testosterone for same total testosterone level]
5α-reductase to dihydrotestosterone (DHT), mainly in the target organs
Following passive diffusion through the cell membrane into the cytoplasm, testosterone undergoes conversion to dihydrotestosterone (DHT) through the action of the enzyme 5α-reductase
Both testosterone and DHT exert their biologic effects by binding to the AR in the cytoplasm, promoting the association of AR coregulators. The complex then translocates to the nucleus and binds to androgen response elements in the promoter regions of target genes
The relative potency of testosterone and DHT are similar(as defined by the ability to cause half-maximal response in a prostate regrowth model), however,if the conversion of testosterone to DHT is blocked by the 5α-reductase inhibitor finasteride, 13-fold more testosterone is required for the same effect.
DHT is in high concentrations in the prostate and hair follicles
Isoforms of 5α-reductase (2):
Type 1: localized in the non-genital skin, liver, brain, prostate, and testis
Inhibited by finasteride and dusteride
Type 2: active in the classical androgen-dependent tissues (epididymis, genitalia, seminal vesicle, testis, and prostate) but also in liver, uterus, breast, hair follicles, and placenta
Inhibited by dutasteride
Half-life of testosterone in plasma is 12 minutes
Testosterone and DHT contribute to muscle, bone, skin, sperm, brain, nerve development and hematopoiesis.
Production stimulated by ACTH released by the pituitary gland in response to corticotropin-releasing facto; like cortisol, adrenal androgen secretion exhibits circadian patterns.
Almost entirely bound to albumin
Relatively weak compared to testosterone and DHT
Remain normal in men who have undergone orchiectomy and are insufficient to maintain prostatic epithelium in such men.
Androgen deprivation therapy increases cardiovascular risk by affecting various risk factors: increased body weight, decreased insulin sensitivity, altered lipid profile, and increased fat mass
Coronary artery disease
The degree of testosterone deficiency has been reported as having an inverse relationship to the severity of CAD
Exogenous testosterone therapy in men with testosterone deficiency improves myocardial ischemia, exercise capacity, and CV risk factors.
Current guidelines do not recommend offering testosterone deficiency screening to patients with heart disease, nor do they recommend supplementing testosterone therapy to improve outcome
Cerebral vascular disease
Testosterone deficiency has also been implicated in the development of cerebral vascular disease
Proposed mechanisms of testosterone’s action on the cardiovascular system (3):
Testosterone levels correlate negatively with fibrinogen
TEAAM (Testosterone's Effects on Atherosclerosis Progression in Aging Men) (JAMA 2015)edit
Population: 156 men age ≥ 60 years or older with low or low-normal testosterone levels
Randomized to 7.5g of 1% testosterone gel packets daily vs. placebo for 3 years
Coprimary outcomes:
Common carotid artery intima-media thickness
Coronary artery calcium
Secondary outcomes: sexual function and health-related quality of life
Results:
No significant difference in common carotid artery intima-media thickness, coronary artery calcium, sexual desire, erectile function, overall sexual function scores, partner intimacy, and health-related quality of life.
Hematocrit and prostate-specific antigen levels increased more in testosterone group.
