Editing Infertility: Epidemiology and Etiology (section)

=== Testicular ===

==== <span style="color:#ff0000">Congenital</span> ====
*<span style="color:#ff0000">'''Causes of primary hypogonadism'''</span>
**'''<span style="color:#0000ff">DUNKY XX</span><span style="color:#ff0000">:</span>'''
**#'''<span style="color:#0000ff">D</span><span style="color:#ff0000">own syndrone</span>'''
**#'''<span style="color:#0000ff">U</span><span style="color:#ff0000">ndescended testis/cryptorchidism</span>'''
**#'''<span style="color:#0000ff">N</span><span style="color:#ff0000">oonan’s Syndrome</span>'''
**#'''<span style="color:#0000ff">K</span><span style="color:#ff0000">linefelter Syndrome</span>'''
**#'''<span style="color:#0000ff">Y</span> <span style="color:#ff0000">chromosome micro deletions</span>'''
**#'''<span style="color:#0000ff">XX<span style="color:#ff0000">-male</span>'''

* '''<span style="color:#ff0000">Klinefelter Syndrome</span>'''
** '''<span style="color:#ff0000">Most common known genetic cause of male infertility</span>'''
**'''Most common major abnormality of sexual differentiation'''
** '''See [https://test.urologyschool.com/index.php/Disorders_of_Sexual_Differentiation#Klinefelter_syndrome Klinefelter Syndrome Section] in [[Disorders of Sexual Differentiation]] Chapter Notes'''
** Males with Klinefelter syndrome should be counseled that few non-mosaic XXY men will have sperm in the ejaculate and medically-unassisted paternity is rare.[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
* '''<span style="color:#ff0000">Y chromosome microdeletion</span>'''
** '''<span style="color:#ff0000">Second most common known genetic cause of infertility in the male</span>'''
**Can result from errors that occur during homologous recombination during meiosis due to the palindromic structure of the chromosome
**Majority of (but not all) genes on the Y chromosome encode proteins involved in testis determination or spermatogenesis
**'''<span style="color:#ff0000">Azoospermia Factor (AZF) region[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
***'''In the long arm of the Y chromosome''' 
***'''Critical to formation of sperm'''
***'''<span style="color:#ff0000">Consists of three areas encoding genes involved in spermatogenesis (AZFa, AZFb, AZFc)</span>'''
****'''<span style="color:#ff0000">AZFa (also known as AZF1) or AZFb complete microdeletion: generally result in absence of spermatogenesis.</span>'''
*****Common phenotypic manifestations of deletions in AZFa region are azoospermia and Sertoli cell-only syndrome
*****Genes in the AZFb region have been found to support the growth and maturity of sperm and are critical for efficient progression of spermatogenesis. Common phenotypic manifestations of deletions in this region are spermatogenic arrest and azoospermia
****'''<span style="color:#ff0000">AZFc microdeletion: may result in spermatogenic impairment but not necessarily absence of spermatogenesis</span>'''
*****Genes in the AZFc region have a diverse role, but overall, they are essential to complete spermatogenesis. AZFc deletions have been associated with drastic reduction in sperm count, and there are subsets of men with AZFc microdeletions that experience progressive declines in their sperm count.
****'''Originally, the AZFb and AZFc genes were identified and thought to be separate regions. They were later found to be overlapping and are now referred to as AZF2.'''
*'''<span style="color:#ff0000">Cryptorchidism</span>'''
** If underwent orchidopexy and had unilateral cryptorchidism, 96% paternity rate; 70% if bilateral.
** The sooner orchidopexy the better, but age unknown. Better if done prior to age 10.

* '''<span style="color:#ff0000">Sertoli Cell Only syndrome</span>'''
** '''Patients present with normal levels of LH and testosterone. The low level of inhibin-B leads to elevated levels of follicle-stimulating hormone FSH.[https://www.ncbi.nlm.nih.gov/books/NBK534293/ §]'''
* '''<span style="color:#ff0000">Leydig cell insufficiency</span>'''
** '''Exogenous testosterone not indicated since insufficient testicular testosterone concentrations are achieved for spermatogenesis'''
** If azoospermia, low testosterone, and elevated LH, perform surgical sperm extraction
* '''<span style="color:#ff0000">Androgen-receptor (AR) resistance</span>'''
** '''See [[Disorders of Sexual Differentiation]] Chapter Notes'''
** Diagnosis and Evaluation: significantly elevated testosterone associated with impaired male fertility. LH is mildly elevated, FSH is normal

==== 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.