Editing Infertility: Nonsurgical Management

'''See 2015 CUA Azoospermia Guideline Notes'''

== General Principles'''§''' ==

* Counsel infertile men or men with abnormal semen parameters of the health risks associated with abnormal sperm production.
** 1-6% of men have undiagnosed medical diseases at the time of an infertility evaluation
** Cancer
*** Abnormal semen parameters associated with increased rsk of testicular cancer.
** Mortality
*** Abnormal semen parameters associated with increased rsk of mortality.
* Advise couples with advanced paternal age (≥40) that there is an increased risk of adverse health outcomes for their offspring.
** Effects of male age on reproductive function
*** Reproductive function
*** Sexual function
*** Testicular morphology
*** Semen parameters (except sperm concentration, semen parameters decrease as age increases)
*** Infections of the accessory glands
*** Vascular disease
*** Sperm aneuploidies
*** Aneuploidies in off-spring
*** Sperm DNA integrity
*** Telomeres
*** Epigenetics
*** Fertility
*** Miscarriage
*** C-section
*** Pre-eclampsia
*** Trophobalst disease
*** Preterm birth
*** Adverse outcome in offspring

== Selective estrogen receptor modulators (e.g. clomophene (clomid), tamoxifen) ==

* '''MOA: acts as an agonist or antagonist on different estrogen receptors.'''
** '''Agonists on receptors in bone, improving bone health'''
** '''Antagonists on receptors on the hypothalamus and pituitary, resulting in increased GnRH and ultimately''' '''increased LH, FSH, and intratesticular testosterone.'''
*** 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.
* '''Benefits'''
*# '''Increased testosterone'''
*#* Testosterone increase is more than that achieved with anastrazole
*# '''Increased sperm counts'''
*#* See Risk Calculator for expected changes for men with infertility who are given clomiphene citrate
* '''Indications'''
** '''Currently, no FDA approval for using SERMs for male hypogonadism'''
*** '''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
** 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) ==

* '''MOA: inhibit aromatase from converting testosterone to estradiol''' (E2)
** Estradiol is an indirect mediator of testosterone feedback inhibition of the HPT axis. Therefore, aromatase inhibition in men can '''result in decreased estrogen levels and ultimately increased gonadotropin production'''
* '''May restore FSH, 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'''
* '''Adverse events'''
** '''Theoretical risk of decreasing bone mineral density as they decrease E2.'''
** '''Same theoretical risk of testosterone replacement exists'''

== Hormones (gonadotropins (hCG, FSH) ==

* The advantage of injectable gonadotropin vs pulsatile GnRH for the treatment of hypogonadotropic hypogonadism is that the injectable gonadotropin bypasses the need for a pump and screening for functionality of the pituitary gland.
* '''hCG'''
** '''MOA: stimulate testosterone production by mimicking LH'''
*** '''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
** Can
** '''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.
* '''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'''

== 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.

== Vitamins ==

* Little evidence to support the routine use of vitamins to improve pregnancy rates

== References ==

* Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 24
* Khan MA, Pagani RL, Ohlander SJ. 2019 AUA Update: Exogenous Testosterone and Male Reproduction
* Gupta N, David M, Kohler TS. 2017 AUA Update: Treatment of Male Hypogonadism: Alternatives to Testosterone