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INFERTILITY: NON-SURGICAL 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
1. Increased testosterone
2. Increased sperm counts
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