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'''Includes [https://pubmed.ncbi.nlm.nih.gov/33295257/ 2020 AUA/ASRM Guidelines on Infertility]'''
'''Includes [https://pubmed.ncbi.nlm.nih.gov/33295257/ 2020 AUA/ASRM Guidelines on Infertility]'''
See [https://www.youtube.com/watch?v=6d0TZRTQLJ8 Video Reviewing Guidelines] (Dr. Joshua Helpern)
== Non-surgical Management ==
===Options===
# '''<span style="color:#ff0000">Selective estrogen receptor modulators (SERMs) (e.g. clomophene (clomid), tamoxifen)</span>'''
# '''<span style="color:#ff0000">Aromatase inhibitors (anastrazole or letrozole)</span>'''
# '''<span style="color:#ff0000">Gonadotropins (hCG, FSH, GnRH)</span>'''
# '''<span style="color:#ff0000">Growth Hormone</span>'''
==== Selective estrogen receptor modulators (SERMs) ====
*'''<span style="color:#ff0000">Mechanism of action: acts as an agonist or antagonist on different estrogen receptors</span>'''
**'''Agonists on receptors in bone, improving bone health'''
**'''<span style="color:#ff0000">Antagonists on receptors on the hypothalamus and pituitary, resulting in increased GnRH</span>'''
***In males, normal binding of estrogen at these receptors functions as an indirect negative feedback mechanism of endogenous testosterone production to down-regulate GnRH and subsequently pituitary gonadotropin production.
*'''<span style="color:#ff0000">Benefits</span>'''
*#'''<span style="color:#ff0000">Increased testosterone'''
*#*<span style="color:#ff0000">'''Treatment with SERMs results in increased GnRH, which then stimulates LH and FSH production by the pituitary gland; the increased LH production, in turn, stimulates Leydig cell production of testosterone'''[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
*#*Testosterone increase is more than that achieved with anastrazole
*#'''<span style="color:#ff0000">Increased sperm counts</span>'''
*#*See [https://riskcalc.org/clomiphene_citrate/ Risk Calculator] for expected changes for men with infertility who are given clomiphene citrate
*'''<span style="color:#ff0000">Indications</span>'''
**'''Not FDA-approved for use in males'''
***'''<span style="color:#ff0000">Clomiphene citrate is the most commonly used SERM for treating hypogonadism when fertility must be maintained. However, this remains an off-label use.'''
****Enclomiphene citrate, the functional stereoisomer of clomiphene citrate, is currently in commercial development. Its potential advantage is avoidance of the estrogenic side effects of its enantiomer zuclomiphene.
**'''Consider in patients with low testosterone, borderline high/high FSH (lazy pituitary)'''
*Drugs and Dosages
**Examples: clomophene (clomid), tamoxifen
**Available orally
**Clomophene dosing typically starts at 25 mg daily and can be increased up to 100 mg daily.
*'''Adverse events'''
**No specific adverse effects attributed to clomiphene or enclomiphene citrate in males.
**'''Same theoretical risk of testosterone replacement exists'''
====Aromatase inhibitors (anastrazole or letrozole)====
*'''<span style="color:#ff0000">MOA: inhibit the enzyme aromatase from converting testosterone to estradiol (E2)</span>'''
**'''Estradiol is an indirect mediator of testosterone feedback inhibition of the hypothalamus-pituitary-testis axis.'''
**'''<span style="color:#ff0000">Aromatase inhibition can result in decreased estrogen levels and ultimately increased gonadotropin production</span>'''
*'''May decrease estradiol and and LH and testosterone levels in patients with elevated estradiol (T/E ratios <10)''', such as those with obesity or Klinefelter syndrome (tend to have more adipose tissue)
*'''Limited data to improve sperm parameters'''
*'''<span style="color:#ff0000">Indications</span>'''
**'''<span style="color:#ff0000">May be considered for men with testosterone deficiency and elevated estradiol levels</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
**'''<span style="color:#ff0000">Not FDA-approved for use in males</span>'''
*Administration
**Available orally
*'''Adverse events'''
**'''Theoretical risk of decreasing bone mineral density as they decrease E2.'''
**'''Same theoretical risk of testosterone replacement exists'''
====Gonadotropic related (hCG, FSH, GnRH)====
===== Options (3): =====
# '''hCG'''
# '''FSH'''
# '''GnRH'''
#*
====== hCG ======
*'''<span style="color:#ff0000">Mechanism of Action: stimulates testosterone production from Leydig cells by mimicking LH</span>'''
**'''hCG has the same structure as the beta unit for LH'''
*'''When used in conjunction with exogenous testosterone administration, may reverse azoospermia and maintain elevated intratesticular testosterone levels'''
**'''By directly stimulating Leydig cells, intratesticular testosterone increases regardless of the extent of negative feedback on the HPG axis, improving spermatogenesis.'''
**Greater effect seen in males with initial testes length >4cm
**'''Effect improved with addition of FSH''' or hMG
***Most experts treat with hCG alone for 3 to 6 months after which spermatogenesis induction occurs in some cases.
***For patients without adequate spermatogenesis induction, treatment proceeds with the addition of FSH
*'''Indications'''
**'''FDA approved for treatment of pituitary hypogonadism in males'''
**Classically used to treat hypogonadotropic hypogonadism, such as Kallmann syndrome.
====== FSH ======
*When given alone or in combination with testosterone, has proven unsuccessful at inducing spermatogenesis or maintaining spermatogenesis in those previously induced with hCG/FSH, confirming the need for maintenance of elevated intratesticular testosterone.
* '''Indications'''
** '''<span style="color:#ff0000">Infertility associated with hypogonadotropic hypogonadism</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
** '''<span style="color:#ff0000">Not FDA-approved for use in males[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]</span>'''
* '''hCG/FSH not used frequently due to cost'''
**hCG is more expensive than clomiphene citrate and anastrozole, and requires multiple weekly subcutaneous injections.
* Adverse events
** hCG is generally well tolerated but there are reports of gynecomastia in up to a third of the patients, which should be monitored.
***If gynecomastia does occur, anastrazole would be the first line treatment option.
**'''Same theoretical risk of testosterone replacement exists'''
====== GnRH ======
* Pulsatile GnRH is not currently approved in the US or Europe[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
====Growth Hormone (GH)====
*Also known as somatotropin
*Single most important hormone for normal growth.
*Acts through its mediator, insulin-like growth factor-1 (IGF-1)
*GH and IGF-1 regulate gonadal steroidogenesis and spermatogenesis via receptors on pituitary gonadotrophs, Sertoli cells, Leydig cells and germ cells. GH and IGF1 also reduce SHBG levels, potentially increasing androgen bioavailability.
*GH for androgen replacement is off-label.
====Supplements====
*Benefits of supplements (e.g., vitamins, antioxidants, nutritional supplement formulations) are of questionable clinical utility[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
===Treatment Selection'''<span style="color:#ff0000">[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]</span>'''===
*'''<span style="color:#ff0000">Testosterone monotherapy should not be prescribed for the male interested in current or future fertility</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]'''
**Exogenous testosterone administration provides negative feedback to the hypothalamus and pituitary gland, which can result in inhibition of gonadotropin secretion.
**Depending on the degree of testosterone-induced suppression, spermatogenesis may decrease or cease altogether, resulting in azoospermia.
**Although recovery of sperm to the ejaculate occurs in most men with cessation of testosterone therapy, the time course of recovery may be prolonged and can be months or rarely years.
***In those that may want to pursue paternity in the more distant future, testosterone therapy may be offered, but the patient should be counseled about the effects on spermatogenesis and the time course required for resumption of spermatogenesis.
*'''Hyperprolactinemia'''
**Etiology of hyperprolactinemia should be treated
*'''Secondary hypogonadism (hypogonadotropic hypogonadism)[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]'''
**Patients with HH present with deficient LH and FSH secretion. In the absence of LH and FSH stimulation, the Leydig cells in the testes do not secrete testosterone, and spermatogenesis is disrupted.
**'''Causes'''
***'''Idiopathic hypogonadotropic hypogonadism (IHH)'''
****'''Congenital'''
*****'''Kallman syndrome'''
******'''Associated with anosmia and the lack of endogenous GNRH secretion'''
****'''Spermatogenesis can be initiated and pregnancies achieved in many of these idiopathic hypogonadotropic hypogonadism men when they are treated with exogenous gonadotropins (hCG, FSH) or GnRH.'''
*****'''Usual first-line drug for the treatment of idiopathic hypogonadotropic hypogonadism for restoration of testosterone and spermatogenesis is hCG'''
******hCG is FDA-approved for use in men with HH
******Degree of response correlates with the size of the testis prior to treatment
******Initial treatment consists of hCG injections (1,500-2,500 IU, twice weekly)
*******Can be followed by FSH, when indicated, after testosterone levels are normalized on hCG
***'''Acquired (adult-onset)'''
****Secondary causes of HH include pituitary or suprasellar tumors, pituitary infiltrative disorders (e.g., hemochromatosis, tuberculosis, sarcoidosis, histiocytosis), exogenous androgens, other medications (e.g., chronic narcotic exposure), hyperprolactinemia, prior head trauma, pituitary apoplexy, and severe chronic illness.
****Management
*****The first line treatment for secondary causes of hypogonadotropic hypogonadism is towards the underlying disorder. Once that has been accomplished, and the patient continues to have hypogonadotropic hypogonadism, a trial of the gonadotropin treatment regimen described above can be initiated.
******SERMs have been used off label as an alternative treatment to increase testosterone and sperm density in men with acquired hypogonadotropic hypogonadism.
*******'''SERM therapy will not be beneficial if the pathology is due to primary pituitary dysfunction, such as after surgical resection.'''
*'''<span style="color:#ff0000">Infertile men with low serum testosterone (and low or normal serum LH)'''
**'''<span style="color:#ff0000">May use aromatase inhibitors (AIs), hCG, selective estrogen receptor modulators (SERMs), or a combination thereof'''
***AIs, hCG, and SERMs act by different mechanisms to increase endogenous testosterone production. Each agent may be used separately or in combination in an effort to increase serum testosterone concentrations without impairing spermatogenesis.
****'''If elevated estradiol levels: consider use of AIs'''
****'''If low or normal serum LH: Either hCG or SERMs may be considered'''
****'''If elevated LH, consistent with primary hypogonadism, may have a limited serum testosterone response to these medications due to inherent testicular dysfunction.'''
***Although the goal of testosterone optimization in the infertile male may be symptom amelioration, symptomatic outcomes and benefits may not be comparable to those achieved using standard (exogenous) testosterone replacement therapy.
*'''<span style="color:#ff0000">Idiopathic infertility'''
**'''<span style="color:#ff0000">Use of SERMs has limited benefits relative to results of ART'''
***Any possible limited benefits of SERM administration, particularly in the patient population with idiopathic infertility, are small and, therefore, outweighed by the distinct advantages offered by other forms of medically-assisted reproduction (e.g., IVF), which include higher pregnancy rates and efficiencies with respect to the earlier timeframe of conception.
**'''May consider treatment using an FSH analogue with the aim of improving sperm concentration, pregnancy rate, and live birth rate'''
***
*'''Non-obstructive Azoospermia'''
**For any patient with NOA, it would be ideal to optimize spermatogenesis and hence the chances of sperm recovery at the time of attempted surgical sperm retrieval.[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
**'''Limited data supporting pharmacologic manipulation with SERMs, AIs, and gonadotropins prior to surgical intervention.'''


== Surgical Management ==
== Surgical Management ==
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****'''Any injury to the epididymis distal to the caput will result in complete obstruction of the entire system on that side'''
****'''Any injury to the epididymis distal to the caput will result in complete obstruction of the entire system on that side'''
**'''Hydrocelectomy and orchiopexy for torsion can result in iatrogenic injury to the epididymis'''
**'''Hydrocelectomy and orchiopexy for torsion can result in iatrogenic injury to the epididymis'''
*'''Ejaculatory Ducts'''
===Surgical Sperm Extraction===
**'''Obstruction of ejaculatory ducts can lead to azoospermia.'''
***'''Transurethral resection (TUR) of the ejaculatory ducts (TURED) can relieve the obstruction.'''
==='''Testicular Biopsy'''===
*Fresh, unfixed tissue is examined for the presence of sperm with tails and possible motility; if sperm are not found initially, examination of multiple samples is recommended.
*Fresh, unfixed tissue is examined for the presence of sperm with tails and possible motility; if sperm are not found initially, examination of multiple samples is recommended.
**Optimal care requires the availability, at the time of biopsy, of an andrology laboratory capable of processing and cryopreserving any sperm found at the time of biopsy.
** Optimal care requires the availability, at the time of extraction, of an andrology laboratory capable of processing and cryopreserving any sperm found at the time of biopsy
 
====Indications ====
==== Approaches ====
*'''Azoospermia (obstructive or non-obstructive)'''
 
*'''Ejaculatory dysfunction'''
*'''Open Testicular Biopsy: Microsurgical Technique'''
==== Options====
**'''Open biopsy remains the gold standard'''
=====Epididymal sperm retrieval=====
**Technique
*'''<span style="color:#ff0000">Techniques (2):'''
***May be performed using either general, spinal, or local anesthetic.
*#'''<span style="color:#ff0000">Microsurgical Epididymal Sperm Aspiration (MESA)'''
*'''Percutaneous Testicular Biopsy'''
*#'''<span style="color:#ff0000">Percutaneous Epididymal Sperm Aspiration (PESA)'''
**'''A blind procedure that could result in unintentional injury to either the epididymis or the testicular artery'''
=====Testicular sperm retrieval=====
**'''The midsection of the testis has relatively fewer vessels compared with superior or inferior areas'''
*'''<span style="color:#ff0000">Techniques (3):'''
**'''Should not be used when previous surgery has resulted in scarring and obliteration of normal anatomy'''
*#'''<span style="color:#ff0000">Open Testicular Sperm Extraction (TESE)'''
*'''Percutaneous Testicular Aspiration'''
*#*Allows retrieval of the largest number of sperm with potential for cryopreservation
**Technique
*#*'''Remains the gold standard'''
***Performed with a 23-gauge needle or angiocath sheath  
*#*Involves wide opening of the tunica albuginea to allow examination of multiple regions of testicular tissue, each of which are oriented in a centrifugal pattern in parallel to the intratesticular blood supply, allowing extensive search of nearly all areas of the testis with limited risk of devascularization of tissue.[https://pubmed.ncbi.nlm.nih.gov/33295257/]
**Less invasive and less painful than percutaneous biopsy
*#**'''<span style="color:#ff0000">Preferably done with an operating microscope (micro-TESE)'''
**'''Usually yields few tubules with poorly preserved architecture'''
*#***Conventional TESE has been associated with decreased postoperative testosterone levels, and males men with non-obstructive azoospermia have baseline testosterone deficiency levels.
 
*#***Less effect on testosterone levels is seen after micro-TESE than with conventional TESE, but testosterone deficiency requiring testosterone replacement remains a risk, even after micro-TESE.
==== Adverse Events ====
*#*Contraindications
*'''Most serious potential complication: inadvertent biopsy of the epididymis'''
*#**Sertoli-only cell syndrome
**If histologic evaluation of the biopsy material reveals epididymis with sperm within the epididymal tubule, obstruction of the epididymis at the site of the biopsy is certain.
*#**Spermatogenic arrest
***If there are no sperm within the epididymal tubules, the patient is either obstructed above the level of the epididymal biopsy site or has primary seminiferous tubular failure and no harm has been done.
*#*Adverse events
*'''Most common potential complication: hematoma'''
*#** Decreased postoperative testosterone levels
===Surgical Sperm Extraction===
*#'''<span style="color:#ff0000">Percutaneous core biopsy'''
====Indications====
*#*Uses the same 14-gauge biopsy gun used for prostate biopsy
#'''Azoospermia (obstructive or non-obstructive)'''
*#*'''A blind procedure that could result in unintentional injury to either the epididymis or the testicular artery'''
#'''Ejaculatory dysfunction'''
*#*'''The midsection of the testis has relatively fewer vessels compared with superior or inferior areas'''
*#*'''Should not be used when previous surgery has resulted in scarring and obliteration of normal anatomy'''
*#'''<span style="color:#ff0000">Percutaneous aspiration (testicular sperm aspiration [TESA])'''
*#*Done with a high-suction glass syringe and a 23-gauge needle or angiocath sheath
*#*'''Least invasive and least painful procedure but usually yields few tubules with poorly preserved architecture and often requires 10 to 20 passes to obtain an adequate yield'''
* '''Adverse Events'''
**'''Most common complication is hematoma'''
====Approach====
====Approach====
*'''Classified: Testicular vs. Epididymal'''
*'''<span style="color:#ff0000">If azoospermia'''
*'''Testicular sperm retrieval'''
**'''<span style="color:#ff0000">Due to obstruction, sperm may be extracted from either the testis or the epididymis.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
**Mainstay in the management of the man with non-obstructive azoospermia[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
*** Fertilization, pregnancy, and live birth rates similar for epididymal and testicular derived sperm in men with azoospermia due to obstruction
**'''Techniques (3):'''
**'''<span style="color:#ff0000">Without obstruction (non-obstructive azoospermia), microdissection testicular sperm extraction (TESE) should be performed.</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
**#'''Open''' '''Testicular Sperm Extraction (TESE)'''
**#*A surgical procedure that involves wide opening of the tunica albuginea to allow examination of multiple regions of testicular tissue, each of which are oriented in a centrifugal pattern in parallel to the intratesticular blood supply, allowing extensive search of nearly all areas of the testis with limited risk of devascularization of tissue.[https://pubmed.ncbi.nlm.nih.gov/33295257/]
**#**'''Preferably done with an operating microscope (micro-TESE)'''
**#***Conventional TESE has been associated with decreased postoperative testosterone levels, and many men with non-obstructive azoospermia have baseline testosterone deficiency levels.
**#***Less effect on testosterone levels is seen after micro-TESE than with conventional TESE, but testosterone deficiency requiring testosterone replacement remains a risk, even after micro-TESE.
**#*Contraindications
**#**Sertoli-only cell syndrome
**#**Spermatogenic arrest
**#*Allows retrieval of the largest number of sperm with potential for cryopreservation
**#'''Percutaneous core biopsy'''
**#*Uses the same 14-gauge biopsy gun used for prostate biopsy
**#'''Percutaneous aspiration (testicular sperm aspiration [TESA])'''
**#*Done with a high-suction glass syringe and a 23-gauge needle.
**#*'''Least invasive procedure but often requires 10 to 20 passes to obtain an adequate yield'''
*'''Epididymal sperm retrieval'''
**'''Techniques (2):'''
***'''Microsurgical Epididymal Sperm Aspiration (MESA)'''
***'''Percutaneous Epididymal Sperm Aspiration (PESA)'''
*'''<span style="color:#ff0000">Selection of approach</span>'''
**'''<span style="color:#ff0000">If azoospermia due to obstruction, testicular or epididymal extraction</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
***Fertilization, pregnancy, and live birth rates similar for epididymal and testicular derived sperm in men with azoospermia due to obstruction
**'''<span style="color:#ff0000">If non-obstructive azoospermia, microdissection testicular sperm extraction (TESE) should be performed.</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
**#Micro-TESE was observed to result in successful extraction 1.5 times more often than non-microsurgical testis sperm extraction
**#Micro-TESE was observed to result in successful extraction 1.5 times more often than non-microsurgical testis sperm extraction
===Vasography===
===Vasography===
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**Hematoma
**Hematoma
**Sperm granuloma
**Sperm granuloma
===Varicocele Repair/Varicocelectomy===
*'''See [https://test.urologyschool.com/index.php/Varicocele Varicocele Chapter Notes]'''
*'''<span style="color:#ff0000">Indications</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
**'''<span style="color:#ff0000">Not recommend for males with non-palpable varicoceles detected solely by imaging</span>'''
***No demonstrable benefit of varicocele repair was observed in pregnancy or bulk seminal parameters with the exception of a possible small numerical effect on progressive sperm motility that is unlikely to be clinically important.
**'''<span style="color:#ff0000">Should be considered in males attempting to conceive who have (3):</span>'''
**#'''<span style="color:#ff0000">Palpable varicocele(s) AND</span>'''
**#'''<span style="color:#ff0000">Infertility AND</span>'''
**#'''<span style="color:#ff0000">Abnormal semen parameters, except for azoospermic males</span>'''
**#*Meta-analyses demonstrate higher estimated pregnancy rates for men treated with any approach for repair of clinical varicocele compared to no treatment
**#*'''For males with clinical varicocele and non-obstructive azoospermia, couples should be informed of the absence of definitive evidence supporting varicocele repair prior to ART.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
**#**Varicocele repair defers treatment with ART for at least six months
===Vasovasostomy/Vasoepididymostomy===
===Vasovasostomy/Vasoepididymostomy===
*Microsurgical reconstruction is done by anastomosing the vas to the most distal site in continuity with the testis, documented by identifying sperm at this region of the reproductive tract. [https://pubmed.ncbi.nlm.nih.gov/33295257/ '''★''']
*Microsurgical reconstruction is done by anastomosing the vas to the most distal site in continuity with the testis, documented by identifying sperm at this region of the reproductive tract. [https://pubmed.ncbi.nlm.nih.gov/33295257/ '''★''']
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***'''If the fluid expressed from the vas is found to be thick, white, water insoluble, and toothpaste-like''' in quality, microscope examination rarely reveals sperm. Under these circumstances, '''the tunica vaginalis is opened and the epididymis inspected. If clear evidence of obstruction is found—that is, an epididymal sperm granuloma with dilated tubules above and collapsed tubules below—vasoepididymostomy is performed.''' When in doubt, or if not very experienced with vasoepididymostomy, vasovasostomy should be performed.
***'''If the fluid expressed from the vas is found to be thick, white, water insoluble, and toothpaste-like''' in quality, microscope examination rarely reveals sperm. Under these circumstances, '''the tunica vaginalis is opened and the epididymis inspected. If clear evidence of obstruction is found—that is, an epididymal sperm granuloma with dilated tubules above and collapsed tubules below—vasoepididymostomy is performed.''' When in doubt, or if not very experienced with vasoepididymostomy, vasovasostomy should be performed.
****Vasoepididymostomy should only be performed on an epididymal tubule containing sperm
****Vasoepididymostomy should only be performed on an epididymal tubule containing sperm
**'''See Table 67-2 CW12th edition for relationship between gross apperance of vasal fluid and microscopic findings'''
**'''Relationship between gross appearance of vasal fluid and microscopic findings'''
***'''UrologySchool.com Summary'''
***'''UrologySchool.com Summary'''
****'''Clear/thin, water vasal fluid: vasovasostomy'''
****'''Clear/thin, water vasal fluid: vasovasostomy'''
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===Ejaculatory Duct Obstruction===
===Ejaculatory Duct Obstruction===
====Causes====
====Causes====
*'''Congenital (most common cause)'''
*'''<span style="color:#ff0000">Congenital (most common cause)'''
**Aplastic segment at the terminal end of the vas
**Aplastic segment at the terminal end of the vas
*'''Acquired'''
*'''<span style="color:#ff0000">Acquired'''
**'''Occasionally''' '''results from chronic prostatitis or extrinsic compression of the ejaculatory ducts by prostate or seminal vesical duct cysts'''
**'''<span style="color:#ff0000">Occasionally results from chronic prostatitis or extrinsic compression of the ejaculatory ducts by prostate or seminal vesical duct cysts'''
====Diagnosis and Evaluation====
====Diagnosis and Evaluation====
*'''Findings associated with ejaculatory duct obstruction:'''
*'''<span style="color:#ff0000">Findings associated with ejaculatory duct obstruction:'''
*#'''Azoospermic or severely oligospermic and/or asthenospermic men with at least one palpable vas deferens'''
*#'''<span style="color:#ff0000">Azoospermic or severely oligospermic and/or asthenospermic men with at least one palpable vas deferens'''
*#'''Low semen volume'''
*#'''<span style="color:#ff0000">Low semen volume'''
*#'''Acidic semen pH'''
*#'''<span style="color:#ff0000">Acidic semen pH'''
*#'''Negative, equivocal, or low semen fructose levels'''
*#'''<span style="color:#ff0000">Negative, equivocal, or low semen fructose levels'''
*#'''Normal serum levels of FSH'''
*#'''<span style="color:#ff0000">Normal serum levels of FSH'''
*#'''Testis biopsy reveals normal spermatogenesis'''
*#'''<span style="color:#ff0000">Testis biopsy reveals normal spermatogenesis'''
*'''Transrectal US'''
*'''Transrectal US'''
**'''A (müllerian duct)''' '''midline cystic lesion or dilated ejaculatory ducts and seminal vesicles can be visualized  '''
**'''A (müllerian duct)''' '''midline cystic lesion or dilated ejaculatory ducts and seminal vesicles can be visualized  '''
***'''Suggestive if AP diameter of seminal vesicle >1.5cm'''
***'''<span style="color:#ff0000">Suggestive if AP diameter of seminal vesicle >1.5cm'''
**'''Microscopic examination of TRUS-guided aspiration of the cystic or dilated ejaculatory ducts or seminal vesicles can be performed.'''
**'''Microscopic examination of TRUS-guided aspiration of the cystic or dilated ejaculatory ducts or seminal vesicles can be performed.'''
***'''If motile sperm are found''', they are cryopreserved and 2 to 3 mL of indigo carmine diluted with water-soluble radiographic contrast is instilled. '''If a radiograph confirms a potentially resectable lesion, TURED is performed without the need for prior vasography'''
***'''If motile sperm are found''', they are cryopreserved and 2 to 3 mL of indigo carmine diluted with water-soluble radiographic contrast is instilled. '''If a radiograph confirms a potentially resectable lesion, TURED is performed without the need for prior vasography'''
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****'''If no sperm are found in either vas when the vasotomy is made and vasography reveals ejaculatory duct obstruction, it is best to abandon attempts at reconstruction and simply perform microsurgical epididymal sperm aspiration and cryopreservation for future IVF and ICSI.'''
****'''If no sperm are found in either vas when the vasotomy is made and vasography reveals ejaculatory duct obstruction, it is best to abandon attempts at reconstruction and simply perform microsurgical epididymal sperm aspiration and cryopreservation for future IVF and ICSI.'''
****Performance of simultaneous vasoepididymostomy and TURED is unlikely to be successful.
****Performance of simultaneous vasoepididymostomy and TURED is unlikely to be successful.
====Management====
====Management====


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**63-83% of patients will have an improvement in semen parameters after the procedure
**63-83% of patients will have an improvement in semen parameters after the procedure
**In addition to fertility, investigators have reported successful treatment with TURED for other symptoms including hematospermia, recurrent infection, or pain (i.e., scrotal, post-ejaculatory).
**In addition to fertility, investigators have reported successful treatment with TURED for other symptoms including hematospermia, recurrent infection, or pain (i.e., scrotal, post-ejaculatory).
*'''Indications'''
*'''<span style="color:#ff0000">Indications'''
**'''May be offered if a seminal vesicle aspirate reveals the presence of sperm in an azoospermic man'''
**'''<span style="color:#ff0000">May be offered if a seminal vesicle aspirate reveals the presence of sperm in an azoospermic male'''
*Technique
*Technique
**Resection of the verumontanum will often reveal the dilated ejaculatory duct orifice or cyst cavity. Resection should be carried out in this region with great care to preserve the bladder neck proximally, the striated sphincter distally, and the rectal mucosa posteriorly.
**Resection of the verumontanum will often reveal the dilated ejaculatory duct orifice or cyst cavity. Resection should be carried out in this region with great care to preserve the bladder neck proximally, the striated sphincter distally, and the rectal mucosa posteriorly.
**In men with EDO associated with Mullerian cysts, treatment involves unroofing of the cyst, resulting in decompression of the cyst and relief from extrinsic obstruction of the ejaculatory ducts.
**In men with EDO associated with Mullerian cysts, treatment involves unroofing of the cyst, resulting in decompression of the cyst and relief from extrinsic obstruction of the ejaculatory ducts.
*'''Complications (9):'''
*'''Adverse events (9):'''
*#Restenosis
*#Restenosis
*#Pain
*#Pain
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*#*Common after TUR, even when care has been taken to spare the bladder neck
*#*Common after TUR, even when care has been taken to spare the bladder neck
*#Urethral stricture
*#Urethral stricture
===Ejaculatory Stimulation===
===Ejaculatory Stimulation===
*'''Neurologic conditions associated with abnormal or absent seminal emission due to impaired sympathetic outflow:'''
 
*#'''Spinal cord injury'''
==== Indications (1) ====
*#'''Demyelinating neuropathies (multiple sclerosis)'''
*'''<span style="color:#ff0000">Infertility due to ejaculatory dysfunction[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
*#'''Diabetes'''
**'''<span style="color:#ff0000">Neurologic conditions associated with abnormal or absent seminal emission due to impaired sympathetic outflow (4):'''
*#'''Iatrogenic (retroperitoneal lymph node dissection, pelvic surgery)'''
**#'''<span style="color:#ff0000">Spinal cord injury'''
*'''With stimulation, motile sperm can be obtained for assisted reproduction techniques (IUI, IVF with ICSI).'''
**#'''<span style="color:#ff0000">Demyelinating neuropathies (multiple sclerosis)'''
**Semen collected from men with SCI is often initially senescent and of poor quality with a low sperm count and reduced sperm motility but may improve with subsequent ejaculations
**#'''<span style="color:#ff0000">Diabetes'''
*'''Stimulation can be done with penile vibratory devices or electroejaculation'''
**#'''<span style="color:#ff0000">Iatrogenic (retroperitoneal lymph node dissection, pelvic surgery)'''
**'''Approach depends on level of spinal cord lesion§'''
**'''With stimulation, motile sperm can be obtained for assisted reproduction techniques (IUI, IVF with ICSI).'''
***'''If lesion above T10, ejaculatory reflex arc will be intact so can stimulate with penile vibratory devices'''
***Semen collected from men with spinal cord injury is often initially senescent and of poor quality with a low sperm count and reduced sperm motility but may improve with subsequent ejaculations
***'''If lesion T10 or below, consider electroejaculation'''
 
==== Technique ====
 
*'''<span style="color:#ff0000">Stimulation can be done with penile vibratory devices or electroejaculation'''
**'''<span style="color:#ff0000">Approach depends on level of spinal cord lesion[https://www.ncbi.nlm.nih.gov/pubmed/12406364 §]'''
***'''<span style="color:#ff0000">If lesion above T10, ejaculatory reflex arc will be intact so can stimulate with penile vibratory devices'''
***'''<span style="color:#ff0000">If lesion T10 or below, consider electroejaculation'''
***'''If these fail, sperm retrieval is performed'''
***'''If these fail, sperm retrieval is performed'''
**'''Ejaculatory stimulation for men with spinal cord injuries may result in autonomic dysreflexia'''
**'''<span style="color:#ff0000">Ejaculatory stimulation for men with spinal cord injuries may result in autonomic dysreflexia'''
***'''Autonomic dysreflexia'''
***'''<span style="color:#ff0000">Autonomic dysreflexia'''
****'''See 2019 CUA NLUTD Guideline Notes'''
****'''See [[CUA: Neurogenic Lower Urinary Tract Dysfunction (2019)|2019 CUA NLUTD Guideline Notes]]'''
****'''An uninhibited sympathetic reflex accompanied by headache, diaphoresis, hypertension, bradycardia, and diaphoresis'''
****'''An uninhibited sympathetic reflex accompanied by headache, diaphoresis, hypertension, bradycardia, and diaphoresis'''
****'''More common with spinal cord injury at a level of T6 or above'''
****'''More common with spinal cord injury at a level of T6 or above'''
****'''Can be life-threatening.'''
****'''<span style="color:#ff0000">Can be life-threatening.'''
****'''Pretreatment, 15 minutes before the procedure, with 20 mg of sublingual nifedipine is used'''
****'''Pretreatment, 15 minutes before the procedure, with 20 mg of sublingual nifedipine is used'''
****'''Should have intravenous access and their blood pressure and pulse should be monitored every 2 minutes before, during, and for 20 minutes after ejaculatory stimulation.'''
****'''Should have intravenous access and their blood pressure and pulse should be monitored every 2 minutes before, during, and for 20 minutes after ejaculatory stimulation.'''
****'''In the event of a sympathetic outflow (autonomic dysreflexia), termination of the procedure should be sufficient to break the response; however, intravenous access allows for delivery of sympatholytic agents should they become necessary'''
****'''In the event of a sympathetic outflow (autonomic dysreflexia), termination of the procedure should be sufficient to break the response; however, intravenous access allows for delivery of sympatholytic agents should they become necessary'''
*'''Indications'''
 
**'''Ejaculatory dysfunction as cause of infertility[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
==== Varicocele Repair/Varicocelectomy ====
*'''See [https://test.urologyschool.com/index.php/Varicocele Varicocele Chapter Notes]'''
*'''<span style="color:#ff0000">Indications</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
**'''<span style="color:#ff0000">Not recommend for males with non-palpable varicoceles detected solely by imaging</span>'''
***No demonstrable benefit of varicocele repair was observed in pregnancy or bulk seminal parameters with the exception of a possible small numerical effect on progressive sperm motility that is unlikely to be clinically important.
**'''<span style="color:#ff0000">Should be considered in males attempting to conceive who have (3):</span>'''
**#'''<span style="color:#ff0000">Palpable varicocele(s) AND</span>'''
**#'''<span style="color:#ff0000">Infertility AND</span>'''
**#'''<span style="color:#ff0000">Abnormal semen parameters, except for azoospermic males</span>'''
**#*Meta-analyses demonstrate higher estimated pregnancy rates for men treated with any approach for repair of clinical varicocele compared to no treatment
**#*'''For males with clinical varicocele and non-obstructive azoospermia, couples should be informed of the absence of definitive evidence supporting varicocele repair prior to ART.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
**#**Varicocele repair defers treatment with ART for at least six months
===Assisted Reproductive Technology===
===Assisted Reproductive Technology===
====Indications====
====Indications====
*Surgically unreconstructable obstruction such as congenital absence of the vas deferens
#'''Surgically unreconstructable obstruction such as congenital absence of the vas deferens'''
*Few viable sperm in the ejaculate
#'''Few viable sperm in the ejaculate'''
*Azoospermia with varicoceles (half of these men will respond to varicocelectomy with return of enough sperm to ejaculate to achieve pregnancy using IVF with ICSI)
#'''Azoospermia with varicoceles (half of these men will respond to varicocelectomy with return of enough sperm to ejaculate to achieve pregnancy using In-vitro Fertilization (IVF) with/out Intracytoplasmic Sperm Injection (ICSI)'''
*Non-obstructive azoospermia
#'''Non-obstructive azoospermia'''
#'''Idiopathic infertility'''
====Options====
====Options====
*'''Intrauterine insemination (IUI)'''
*'''<span style="color:#ff0000">Intrauterine insemination (IUI)'''
*'''In-vitro Fertilization (IVF) with/out Intracytoplasmic Sperm Injection (ICSI)'''
*'''<span style="color:#ff0000">In-vitro Fertilization (IVF) with/out Intracytoplasmic Sperm Injection (ICSI)'''
====Intrauterine insemination (IUI)====
====Intrauterine insemination (IUI)====
*Technique
*'''Technique'''
**Involves processing a semen specimen and placing the low volume washed semen into the uterine cavity at the time of ovulation
**'''<span style="color:#ff0000">Involves processing a semen specimen and placing the low volume washed semen into the uterine cavity at the time of ovulation'''
***May be done with or without ovarian stimulation of the female partner to enhance oocyte production
**May be done with or without ovarian stimulation of the female partner to enhance oocyte production
****Pregnancy rates with IUI are increased in couples with abnormal semen parameters if the woman undergoes ovulation induction.
***Pregnancy rates with IUI are increased in couples with abnormal semen parameters if the woman undergoes ovulation induction.
*****In men with male factor infertility due to abnormal semen parameters, natural cycle intracervical or intrauterine insemination (IUI) is no better than timed vaginal intercourse.
****In men with male factor infertility due to abnormal semen parameters, natural cycle intracervical or intrauterine insemination (IUI) is no better than timed vaginal intercourse.
******Natural cycle refers to allowing the woman to ovulate on her own without pharmaceutical induced stimulation of the development of multiple follicles through ovulation induction.
*****Natural cycle refers to allowing the woman to ovulate on her own without pharmaceutical induced stimulation of the development of multiple follicles through ovulation induction.
******Natural cycle IUI is useful in infertility caused by mechanical problems such as hypospadias, retrograde ejaculation, impotence, or pure cervical factor infertility.
*****Natural cycle IUI is useful in infertility caused by mechanical problems such as hypospadias, retrograde ejaculation, impotence, or pure cervical factor infertility.
*'''Men with low total motile sperm count (<5 million motile sperm after processing) are expected to have lower pregnancy rates after IUI than using sperm from men with normal total motile sperm counts.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
*'''Males with low total motile sperm count (<5 million motile sperm after processing) are expected to have lower pregnancy rates after IUI than using sperm from men with normal total motile sperm counts.[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
**Since approximately 50% of sperm do not survive semen processing, a total motile count of at least 5 to 10 million sperm is usually required to allow for an adequate number of motile sperm for insemination.[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
**Since approximately 50% of sperm do not survive semen processing, a total motile count of at least 5 to 10 million sperm is usually required to allow for an adequate number of motile sperm for insemination.[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
====In-vitro Fertilization (IVF) with/out ICSI====
====In-vitro Fertilization (IVF) with/out ICSI====
*'''In IVF, the egg and sperm (of which there are multiple) are left in a petri dish to fertilize on their own. In ICSI, one sperm is directly injected into the egg.'''
*'''<span style="color:#ff0000">In IVF, the egg and sperm (of which there are multiple) are left in a petri dish to fertilize on their own. In ICSI, one sperm is directly injected into the egg.'''
*'''ICSI minimizes any adverse effects of sperm “quality” as measured by sperm concentration, motility, and morphology as long as viable sperm are present to inject into all oocytes'''
*'''ICSI minimizes any adverse effects of sperm “quality” as measured by sperm concentration, motility, and morphology as long as viable sperm are present to inject into all oocytes'''
**With IVF, abnormal sperm motility and morphology adversely affect fertilization rates. The application of ICSI during IVF treatment provided fertilization rates comparable to that observed with otherwise normal sperm
**With IVF, abnormal sperm motility and morphology adversely affect fertilization rates. The application of ICSI during IVF treatment provided fertilization rates comparable to that observed with otherwise normal sperm
Line 324: Line 453:
*Couple may need to undergo several cycles of IVF treatment in order to achieve a pregnancy
*Couple may need to undergo several cycles of IVF treatment in order to achieve a pregnancy
**Each attempt typically allows for a 33% live delivery rate per initiated IVF cycle
**Each attempt typically allows for a 33% live delivery rate per initiated IVF cycle
*Pregnancy and live birth results are closely related to female age, with progressively lower success with increased female age (over 35 years)
***Pregnancy and live birth results are closely related to female age, with progressively lower success with increased female age (>35 years)
*Approximately 19% of all deliveries involve twins
***≈19% of all deliveries involve twins
*'''In men undergoing surgical sperm retrieval, either fresh or cryopreserved sperm may be used for ICSI[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
*'''In men undergoing surgical sperm retrieval, either fresh or cryopreserved sperm may be used for ICSI[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
**A meta-analysis evaluating the use of sperm from men with NOA found no significant differences in fertilization, pregnancy, or live birth rates from ICSI in men for whom sperm was extracted and used with or without cryopreservation, as long as there were sperm of adequate number and survived cryopreservation and thawing.[https://pubmed.ncbi.nlm.nih.gov/29785532/]
**A meta-analysis evaluating the use of sperm from men with NOA found no significant differences in fertilization, pregnancy, or live birth rates from ICSI in men for whom sperm was extracted and used with or without cryopreservation, as long as there were sperm of adequate number and survived cryopreservation and thawing.[https://pubmed.ncbi.nlm.nih.gov/29785532/]
===Orchiopexy in Adults===
===Orchiopexy in Adults===
*'''When scrotal orchiopexy is performed for retractile or ectopic testis in adults, a dartos pouch operation should be performed.'''
*'''When scrotal orchiopexy is performed for retractile or ectopic testis in adults, a dartos pouch operation should be performed.'''
**Simple suture orchiopexy of the tunica albuginea of the testis to the dartos, as is performed sometimes to prevent torsion, will not prevent retraction of these testes into the groin. Creation of a dartos pouch will keep the testis well down in the scrotum and permanently prevent retraction. This is also the most reliable and safest technique for the prevention of testicular torsion
**Simple suture orchiopexy of the tunica albuginea of the testis to the dartos, as is performed sometimes to prevent torsion, will not prevent retraction of these testes into the groin. Creation of a dartos pouch will keep the testis well down in the scrotum and permanently prevent retraction. This is also the most reliable and safest technique for the prevention of testicular torsion
== Non-surgical Management ==
===Options===
# '''<span style="color:#ff0000">Selective estrogen receptor modulators (e.g. clomophene (clomid), tamoxifen)</span>'''
# '''<span style="color:#ff0000">Aromatase inhibitors (anastrazole or letrozole)</span>'''
# '''<span style="color:#ff0000">Gonadotropins (hCG, FSH)</span>'''
# '''<span style="color:#ff0000">Growth Hormone</span>'''
==== Selective estrogen receptor modulators (e.g. clomophene (clomid), tamoxifen) ====
*'''<span style="color:#ff0000">MOA: acts as an agonist or antagonist on different estrogen receptors.</span>'''
**'''Agonists on receptors in bone, improving bone health'''
**'''<span style="color:#ff0000">Antagonists on receptors on the hypothalamus and pituitary, resulting in increased GnRH.</span>'''
***In men normal binding of estrogen at these receptors functions as an indirect negative feedback mechanism of endogenous testosterone production to down-regulate GnRH and subsequently pituitary gonadotropin production.
*'''<span style="color:#ff0000">Benefits</span>'''
*#'''<span style="color:#ff0000">Increased testosterone'''
*#*<span style="color:#ff0000">'''Treatment with SERMs results in increased GnRH, which then stimulates LH and FSH production by the pituitary gland; the increased LH production, in turn, stimulates Leydig cell production of testosterone'''[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
*#*Testosterone increase is more than that achieved with anastrazole
*#'''<span style="color:#ff0000">Increased sperm counts</span>'''
*#*See [https://riskcalc.org/clomiphene_citrate/ Risk Calculator] for expected changes for men with infertility who are given clomiphene citrate
*'''<span style="color:#ff0000">Indications</span>'''
**'''Not FDA-approved for use in males'''
***'''Clomiphene citrate is the most commonly used SERM for treating hypogonadism when fertility must be maintained. However, this remains an off-label use.'''
****Enclomiphene citrate, the functional stereoisomer of clomiphene citrate, is currently in commercial development. Its potential advantage is avoidance of the estrogenic side effects of its enantiomer zuclomiphene.
**'''Consider in patients with low testosterone, borderline high/high FSH (lazy pituitary)'''
*Administration
**Available orally
**Typically dosing starts at 25 mg daily and can be increased up to 100 mg daily.
*'''Adverse events'''
**No specific adverse effects attributed to clomiphene or enclomiphene citrate in males.
**'''Same theoretical risk of testosterone replacement exists'''
====Aromatase inhibitors (anastrazole or letrozole)====
*'''<span style="color:#ff0000">MOA: inhibit the enzyme aromatase from converting testosterone to estradiol (E2)</span>'''
**'''Estradiol is an indirect mediator of testosterone feedback inhibition of the hypothalamus-pituitary-testis axis.'''
**'''<span style="color:#ff0000">Aromatase inhibition can result in decreased estrogen levels and ultimately increased gonadotropin production</span>'''
*'''May decrease estradiol and and LH and testosterone levels in patients with elevated estradiol (T/E ratios <10)''', such as those with obesity or Klinefelter syndrome (tend to have more adipose tissue)
*'''Limited data to improve sperm parameters'''
*'''<span style="color:#ff0000">Indications</span>'''
**'''<span style="color:#ff0000">May be considered for men with testosterone deficiency and elevated estradiol levels</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
**'''<span style="color:#ff0000">Not FDA-approved for use in males</span>'''
*Administration
**Available orally
*'''Adverse events'''
**'''Theoretical risk of decreasing bone mineral density as they decrease E2.'''
**'''Same theoretical risk of testosterone replacement exists'''
====Gonadotropic related (hCG, FSH, GnRH)====
===== Options =====
* '''hCG'''
* '''FSH'''
* '''GnRH'''
**
====== hCG ======
*'''<span style="color:#ff0000">MOA: stimulates testosterone production from Leydig cells by mimicking LH</span>'''
**'''hCG has the same structure as the beta unit for LH'''
*'''When used in conjunction with exogenous testosterone administration, may reverse azoospermia and maintain elevated intratesticular testosterone levels'''
**'''By directly stimulating Leydig cells, intratesticular testosterone increases regardless of the extent of negative feedback on the HPG axis, improving spermatogenesis.'''
**Greater effect seen in males with initial testes length >4cm
**'''Effect improved with addition of FSH''' or hMG
***Most experts treat with hCG alone for 3 to 6 months after which spermatogenesis induction occurs in some cases.
***For patients without adequate spermatogenesis induction, treatment proceeds with the addition of FSH
*'''Indications'''
**'''FDA approved for treatment of pituitary hypogonadism in males'''
**Classically used to treat hypogonadotropic hypogonadism, such as Kallmann syndrome.
====== FSH ======
*When given alone or in combination with testosterone, has proven unsuccessful at inducing spermatogenesis or maintaining spermatogenesis in those previously induced with hCG/FSH, confirming the need for maintenance of elevated intratesticular testosterone.
* '''Indications'''
** '''<span style="color:#ff0000">Infertility associated with hypogonadotropic hypogonadism</span>[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]'''
** '''<span style="color:#ff0000">Not FDA-approved for use in males[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]</span>'''
** '''Not used frequently due to cost'''
***hCG is more expensive than clomiphene citrate and anastrozole, and requires multiple weekly subcutaneous injections.
* Adverse events
** hCG is generally well tolerated but there are reports of gynecomastia in up to a third of the patients, which should be monitored.
***If gynecomastia does occur, anastrazole would be the first line treatment option.
**'''Same theoretical risk of testosterone replacement exists'''
====== GnRH ======
* Pulsatile GnRH is not currently approved in the US or Europe[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
====Growth Hormone (GH)====
*Also known as somatotropin
*Single most important hormone for normal growth.
*Acts through its mediator, insulin-like growth factor-1 (IGF-1)
*GH and IGF-1 regulate gonadal steroidogenesis and spermatogenesis via receptors on pituitary gonadotrophs, Sertoli cells, Leydig cells and germ cells. GH and IGF1 also reduce SHBG levels, potentially increasing androgen bioavailability.
*GH for androgen replacement is off-label.
====Supplements====
*Benefits of supplements (e.g., vitamins, antioxidants, nutritional supplement formulations) are of questionable clinical utility[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
===Treatment Selection'''<span style="color:#ff0000">[https://pubmed.ncbi.nlm.nih.gov/33295257/ ★]</span>'''===
*'''Testosterone monotherapy should not be prescribed for the male interested in current or future fertility[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]'''
**Exogenous testosterone administration provides negative feedback to the hypothalamus and pituitary gland, which can result in inhibition of gonadotropin secretion.
**Depending on the degree of testosterone-induced suppression, spermatogenesis may decrease or cease altogether, resulting in azoospermia.
**Although recovery of sperm to the ejaculate occurs in most men with cessation of testosterone therapy, the time course of recovery may be prolonged and can be months or rarely years.
***In those that may want to pursue paternity in the more distant future, testosterone therapy may be offered, but the patient should be counseled about the effects on spermatogenesis and the time course required for resumption of spermatogenesis.
*'''Hyperprolactinemia'''
**Etiology of hyperprolactinemia should be treated
*'''Secondary hypogonadism (hypogonadotropic hypogonadism)[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]'''
**Patients with HH present with deficient LH and FSH secretion. In the absence of LH and FSH stimulation, the Leydig cells in the testes do not secrete testosterone, and spermatogenesis is disrupted.
**'''Can be congenital (e.g. Kallman syndrome,  associated with anosmia and the lack of endogenous GNRH secretion) or acquired (adult-onset)'''
**'''Spermatogenesis can be initiated and pregnancies achieved in many of these idiopathic hypogonadotropic hypogonadism men when they are treated with exogenous gonadotropins (hCG, FSH) or GnRH.'''
***Usual first-line drug for the treatment of IHH for restoration of testosterone and spermatogenesis is hCG
****hCG is FDA-approved for use in men with HH
****Degree of response correlates with the size of the testis prior to treatment
****Initial treatment consists of hCG injections (1,500-2,500 IU, twice weekly)
*****Can be followed by FSH, when indicated, after testosterone levels are normalized on hCG
***SERMs have been used off label as an alternative treatment to increase testosterone and sperm density in men with acquired hypogonadotropic hypogonadism.
**Secondary causes of HH include pituitary or suprasellar tumors, pituitary infiltrative disorders (e.g., hemochromatosis, tuberculosis, sarcoidosis, histiocytosis), exogenous androgens, other medications (e.g., chronic narcotic exposure), hyperprolactinemia, prior head trauma, pituitary apoplexy, and severe chronic illness.
***The first line treatment for secondary causes of hypogonadotropic hypogonadism is towards the underlying disorder. Once that has been accomplished, and the patient continues to have HH, a trial of the gonadotropin treatment regimen described above can be initiated.
****'''SERM therapy will not be beneficial if the pathology is due to primary pituitary dysfunction, such as after surgical resection.'''
*'''Infertile men with low serum testosterone (and low or normal serum LH)'''
**'''May use aromatase inhibitors (AIs), hCG, selective estrogen receptor modulators (SERMs), or a combination thereof'''
***AIs, hCG, and SERMs act by different mechanisms to increase endogenous testosterone production. Each agent may be used separately or in combination in an effort to increase serum testosterone concentrations without impairing spermatogenesis.
****'''If elevated estradiol levels: consider use of AIs'''
****'''If low or normal serum LH: Either hCG or SERMs may be considered'''
****'''If elevated LH, consistent with primary hypogonadism, may have a limited serum testosterone response to these medications due to inherent testicular dysfunction.'''
***Although the goal of testosterone optimization in the infertile male may be symptom amelioration, symptomatic outcomes and benefits may not be comparable to those achieved using standard (exogenous) testosterone replacement therapy.
*'''Idiopathic infertility'''
**'''Use of SERMs has limited benefits relative to results of ART'''
***Any possible limited benefits of SERM administration, particularly in the patient population with idiopathic infertility, are small and, therefore, outweighed by the distinct advantages offered by other forms of medically-assisted reproduction (e.g., IVF), which include higher pregnancy rates and efficiencies with respect to the earlier timeframe of conception.
**'''May consider treatment using an FSH analogue with the aim of improving sperm concentration, pregnancy rate, and live birth rate'''
***
*'''Non-obstructive Azoospermia'''
**For any patient with NOA, it would be ideal to optimize spermatogenesis and hence the chances of sperm recovery at the time of attempted surgical sperm retrieval.[https://pubmed.ncbi.nlm.nih.gov/33295257/ §]
**'''Limited data supporting pharmacologic manipulation with SERMs, AIs, and gonadotropins prior to surgical intervention.'''


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