Male Infertility in Renal Failure and Transplantation

Scott D. Lundy; Sarah C. Vij

Disclosures

Transl Androl Urol. 2019;8(2):173-181. 

In This Article

ESRD and Reproductive Hormones

Hormonal Aberrations in ESRD

The hormonal changes associated with ESRD are profound and have significant consequences on a variety of men's health issues, but the precise physiology underlying changes in the hypothalamic-pituitary-gonadal (HPG) axis remains relatively poorly understood. Testosterone, for example, has been shown to be decreased in ESRD (Figure 1), and the prevalence of hypogonadism in HD-dependent men may surpass 50%.[4] The levels of testosterone are inversely related to pro-inflammatory markers such as IL-6, implicating chronic inflammation as a potential contributing factor.[5] As expected, the changes in testosterone are accompanied by changes in luteinizing hormone (LH). Mechanistically, there appears to be a disruption of the normal cyclic GnRH release pattern.[6] This aberration in turn is thought to lead to decreased testosterone (T) levels via a blunted LH secretory burst, which in turn predisposes CKD men to chronically elevated LH and hypogonadism (hypergonadotropic hypogonadism). This theory is supported by an improvement in all parameters when ESRD patients are administered clomiphene, which improves hypogonadism by acting centrally to stimulate follicle stimulating hormone (FSH) and LH.[6] The diminished T production is also likely further exacerbated by Leydig cell dysfunction, resulting in the profound symptomatic hypogonadism seen in many male ESRD patients.

Figure 1.

Graphical representation of hormonal and seminal parameter changes with end stage renal disease and renal transplantation. Note that the width of the graphical elements represents the variability reported in the literature for each respective variable. The gray areas and dotted lines represent the range of values seen in healthy fertile males.

In addition to the above changes, prolactin is also elevated in CKD. This elevation is predominately thought to be due to a loss of the negative feedback mechanism and a modest decrease in renal clearance rate. More recent work has also demonstrated diminished anti-Müllerian hormone (AMH), suggesting a Sertoli cell defect in addition to the Leydig cell suppression.[7]

Hormonal Changes With Transplantation

A growing body of literature has suggested that renal transplantation has a significant effect in rescuing the eugonadal phenotype in at least a subset of recipients. Early work by Lim and colleagues[8] showed that transplantation resulted in a doubling in plasma testosterone levels. More detailed analysis showed an improvement in testosterone accompanied by a decrease in LH, FSH, and prolactin (Figure 1).[9] A large contemporary series by Reinhardt and colleagues published in 2018 showed that of the 40% of ESRD patients with documented hypogonadism, less than half remained so after a year following transplant. The mean testosterone was significantly improved as early as 3 months postoperatively. Interestingly, while FSH and LH remained unchanged, estrogen decreased and prolactin robustly decreased immediately after transplant.[4] This is in contrast to Hamdi and colleagues, who noted a significant change in both LH (decreased) and FSH (increased) at 6 months following transplant.[10] Finally, Prem et al. showed resolution of hypogonadism and elevated LH in the majority of patients undergoing transplantation, but in this cohort FSH levels remained aberrant.[11] It remains to be seen whether these discrepancies represent differences in the underlying etiologies of ESRD, the immunosuppressive regimen employed, or other subtle differences in these populations. It also remains to be proven whether long-term support with a functional renal transplant graft could allow hormone levels to normalize, or whether this population is likely to be hypogonadal long-term.

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