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
- Effects of male age on reproductive function
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
- Increased testosterone
- 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.
- Clomiphene citrate is the most commonly used SERM for treating hypogonadism when fertility must be maintained. However, this remains an off-label use.
- Consider in patients with low testosterone, borderline high/high FSH (lazy pituitary)
- Currently, no FDA approval for using SERMs for male hypogonadism
- 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.
- MOA: stimulate testosterone production by mimicking LH
- 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
- hCG is generally well tolerated but there are reports of gynecomastia in up to a third of the patients, which should be monitored.
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