Editing Infertility: Epidemiology and Etiology (section)

==== Acquired (TICCS) ====
* '''<span style="color:#ff0000">Toxins</span>'''
** '''<span style="color:#ff0000">Medications</span>'''
*** '''<span style="color:#ff0000">Associated with infertility</span>'''
****'''<span style="color:#ff0000">Finasteride</span>'''
***** 5 mg/day is associated with reduced semen volume, but 1 mg/day data are inconclusive
**** '''<span style="color:#ff0000">Exogenous testosterone/anabolic steroids</span>'''
***** '''Testosterone is converted to estradiol by aromatase. This estradiol inhibits LH secretion. Consequently, there is decreased intratesticular testosterone synthesis and reduced spermatogenesis.'''
***** '''Testosterone abuse results in an acquired variant of hypogonadotropic hypogonadism''' 
*****'''Characterized by''' 
*****#'''Extremely low or undetectable serum levels of FSH and LH'''
*****#'''Atrophic testes'''
*****#'''Severe oligozoospermia or azoospermia'''
***** Anabolic androgenic steroid abuse was the most frequent cause of profound hypogonadism among young men.
***** '''Injections are the most toxic against spermatogenesis; nasal spray is the least toxic'''
***** While exogenous testosterone does not suppress luteinizing hormone or FSH during puberty in patients with Klinefelter syndrome, testosterone does suppress gonadotropins after puberty.
***** '''Should be ceased as the initial step'''
****** '''Majority recover fertility in a time-dependent manner'''
******* Recovery begins on average 4 to 5 months after initiation of medical therapy but it can take up to 2 years
********Time to recovery slower in 
*********Older males
*********Low-normal sperm count prior to starting exogenous testosterone
*********High dose exogenous testosterone
******* Probabilities of recovery at 6, 12, 16, and 24 months to be 67%, 90%, 96% and 100%, respectively.
******** Older males less likely to recover
****** Recovery of spermatogenesis can be improved with hCG +/- FSH
******* Semen quality will be sufficient for intrauterine insemination in 70% of men within 12 months of medical therapy to promote spermatogenesis
******Low-quality evidence for no impact of anabolic steroids/exogenous testosterone on permanent infertility[https://pubmed.ncbi.nlm.nih.gov/33295257/]
**** '''<span style="color:#ff0000">Estrogen</span>'''
**** '''<span style="color:#ff0000">Anti-androgens</span>'''
***Evidence inconclusive'''[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
****Anti-rheumatic medications
****Thiopurines
****Corticosteroids
***Not a risk factor'''[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
****Methotrexate
*** Other medications mentioned in Campbell's 11th edition:
**** Spironolactone
**** HIV medications
***** Protease inhibitors (indinavir) and nucleoside reverse transcriptase inhibitors (stavudine)
**** Cimetidine
**** Sulfasalazine (should be substituted with mesalazine)
**** Opioids
***** Suppresses LH release resulting in decreased intratesticular testosterone synthesis and reduced spermatogenesis
**** Anti-psychotics
***** Dopamine antagonists can result in decreased libido
***** SSRIs are associated with anorgasmia and delayed or absent ejaculation
***If there is concern about the influence of a particular medication on fertility, clinicians may consult databases with data on reproductive effects of medications such as REPROTOX® for additional information.
**'''<span style="color:#ff0000">Chemotherapy</span>'''
***Cancer (especially testicular cancer) can negatively affect spermatogenesis, even before chemotherapy
***It is unknown what duration of time after receiving chemotherapy is needed to have no residual DNA damage
**** Sperm DNA damage can be detected at least 2 years after chemotherapy.
**** Sperm banking should be prioritized early in the management of a patient with testicular cancer
** '''<span style="color:#ff0000">Radiation</span>''' '''to testes if dose > 7.5 Gy'''
** '''<span style="color:#ff0000">Social habits</span>'''
***'''<span style="color:#ff0000">Cigarette smoking</span>'''
**** Smokers have slightly reduced fertility[https://pubmed.ncbi.nlm.nih.gov/33295257/]
****Low-quality evidence (due to high risk of bias) exists to link smoking with a small impact on sperm concentration, motility, and morphology[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
*** '''Cannabis''' decreases plasma testosterone and may affect the acrosome of the spermatozoa[https://pubmed.ncbi.nlm.nih.gov/30916627/ §]
*** '''Alcohol use'''
**** Drinkers have slightly lower semen volume and slightly poorer sperm morphology, but drinking does not adversely affect sperm concentration or sperm motility[https://pubmed.ncbi.nlm.nih.gov/33295257/]
***Caffeine
****Moderate quality evidence of no association (except possibly sperm aneuploidy) between caffeine and male infertility[https://pubmed.ncbi.nlm.nih.gov/33295257/]
** '''Environmental exposure'''
*** Some heavy metals (e.g. lead) and pesticides are associated with increased risk of infertility[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
****For those patients thought to be at risk for heavy metal toxicity, serum testing may be performed; however, lead levels in the blood may not reflect the total lead burden throughout the body[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
**'''Diet'''
***Poor diet results in reduced fertility
**'''Stress'''
***Associated with reduced sperm progressive motility, but has no association with semen volume; data were inconclusive for sperm concentration and sperm morphology[https://pubmed.ncbi.nlm.nih.gov/33295257/]

* '''<span style="color:#ff0000">Infections and Inflammation</span>'''
** '''<span style="color:#ff0000">History of infections of the GU tract (testis, epididymis, prostate, urethra) is associated with infertility</span>'''
*** Viral orchitis can result in bilateral testicular atrophy
**'''No effect of HIV or hepatitis'''

* '''<span style="color:#ff0000">Childhood</span>'''
** '''<span style="color:#ff0000">Hydrocele or hernia surgery can cause obstruction</span>'''
*** Moderate-quality evidence that found the impact of hernia repair on reproductive function to be inconclusive[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
** '''<span style="color:#ff0000">Torsion</span>'''
*** '''11% of males develop anti-sperm antibodies after testicular torsion. However, fertility similar to general population'''
**** 2016 study from Israel reviewed torsion 63 patients, 41 with orchiopexy and 22 with orchiectomy, and found that pregnancy rates were similar to general population (≈90%). Mean time to pregnancy approx. 7 months, no difference between orchiopexy and orchiectomy[https://pubmed.ncbi.nlm.nih.gov/27117442/ §]

* '''<span style="color:#ff0000">Testicular cancer</span>'''
**Impacts sperm count and concentration, but evidence is inconclusive regarding impact on motility and morphology[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
*'''Increased scrotal temperature'''
** Scrotal temperature is maintained 2-4°C below body temperature.
** Increasing testis temperature impairs spermatogenesis; safe scrotal temperature is not known

* '''Age'''
**'''Older men have slightly reduced fertility'''
***'''All 7 parameters, except concentration, are associated with small age-dependent declines (i.e., semen parameters decrease as age increases)[https://pubmed.ncbi.nlm.nih.gov/33295257/]'''
*'''Obesity'''
** Moderately reduced fertility
**'''Mechanisms related to infertility (4):'''
**# Adipose tissue, which is the main source of aromatase in men and results in increased E2 levels, lowers T:E2 ratio and increases negative feedback on the HPG axis
**# Increased scrotal temperature
**# Increased total body surface area, effectively diluting testosterone concentration in testosterone sensitive areas.
**# Obesity and metabolic syndrome are associated with an overall increased inflammatory state, suppressing the HPG axis and causing mixed testicular/pituitary hypogonadism.