Diagnostics and Management of Male Infertility in Primary Ciliary Dyskinesia

Abstract

Primary ciliary dyskinesia (PCD), a disease caused by the malfunction of motile cilia, manifests mainly with chronic recurrent respiratory infections. In men, PCD is also often associated with infertility due to immotile sperm. Since causative mutations for PCD were identified in over 50 genes, the role of these genes in sperm development should be investigated in order to understand the effect of PCD mutations on male fertility. Previous studies showed that different dynein arm heavy chains are present in respiratory cilia and sperm flagellum, which may partially explain the variable effects of mutations on airways and fertility. Furthermore, recent studies showed that male reproductive tract motile cilia may play an important part in sperm maturation and transport. In some PCD patients, extremely low sperm counts were reported, which may be due to motile cilia dysfunction in the reproductive tract rather than problems with sperm development. However, the exact roles of PCD genes in male fertility require additional studies, as do the treatment options. In this review, we discuss the diagnostic and treatment options for men with PCD based on the current knowledge.

Keywords: ICSI; PCD; male fertility; sperm.

Figure 1

The conserved axonemal core structure is present in motile cilia and sperm flagella. The sperm tail can be divided into three parts: the midpiece, principal piece, and end piece. Outer dense fibers (ODFs) run along the mid and principal piece, and mitochondria (MS, mitochondrial sheath) surround the ODFs in the midpiece. In the principal piece, ODFs 3 and 8 are replaced by transfers ribs (TR) and form part of the fibrous sheath (FS). The annulus is a diffusion barrier between the midpiece and principal piece, and the sperm tail is connected to the head by the head-tail coupling apparatus (HTCA). The axoneme runs along the whole tail and appears ultrastructurally identical in the sperm flagellum and motile cilia, containing nine outer doublet microtubules (OD) and a central pair (CP). Radial spokes (RD) connect the ODs to the CP and nexin links connect the adjacent ODs. The head-tail coupling apparatus (HTCA) connects the sperm tail to the head and is formed by the centriole attachment to the nucleus. The annulus is a diffusion barrier between the midpiece and principal piece. The sperm illustration and TEM images are reproduced with the Creative Commons CC by license [1].

Figure 2

PCD gene expression in the human testis. Variable expression of known PCD genes are detected in NGS data by Fagerberg et al. [18]. RPKM reads per kilobase of transcript per million reads mapped.

Figure 3

Sperm development and maturation. Male germ cells develop in seminiferous tubules of the testis. After release into the lumen of the seminiferous tubules, sperm are transported through the efferent ductules and epididymis and stored in the cauda epididymis. Efferent ductules contain motile cilia, which were shown to be crucial for male fertility in mouse models [53]. Spc = spermatocyte, Rs = round spermatid, Sc = Sertoli cell, Sp = spermatid.

Figure 4

Schematic diagram of the diagnostic and treatment pipeline for male infertility in PCD. In PCD patients, a 55% fertilization rate was reported for ejaculated sperm and 65% for testicular sperm. Pregnancy rates vary between 35 and 45% for ejaculated and testicular sperm, respectively [90]. DFI = DNA fragmentation index, LAISS = laser-assisted immotile sperm selection, microdissection testicular sperm extraction (mTESE).