Infertility: Nonsurgical Management

See 2015 CUA Azoospermia Guideline Notes

General Principles§

• 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
    • Genetics (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
  • Genetic counseling may be appropriate for couples with advanced paternal age to discuss the magnitude of these risks

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
  1. Increased testosterone
     • Testosterone increase is more than that achieved with anastrazole
  2. 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
  • 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