Editing Infertility: Management (section)

== 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.'''