Editing Infertility: Management (section)

===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/ §]