Subsequent impaired fertility (with or without sperm worsening) in men who had fathered children after a left varicocelectomy: A novel population? - Beyond the Abstract

Sperm count worsening following initial improvement after left varicocelectomy: A new finding?

Recent meta-analyses have indicated that a varicocelectomy increases sperm count in dyspermic patients (Baazeem et al. 2011).

Our group assessed whether the beneficial effects on fertility of a varicocelectomy are transitory or definitive after a first fathering.

A retrospective multicenter research involving seven andrological centers was carried out. The Authors reviewed a total of 2223 files of patients who had undergone subinguinal ligation of a high grade left varicocele for dyspermia and infertility, and established the following inclusion criteria a posteriori: sperm count improvement and fathering a child after an uneventful left varicocelectomy. Only patients who had undergone three assessments for (in-) fertility (before surgery, before the first fathering and after the first fathering) were included in the study. Each assessment included clinical history, physical examination, two sperm analyses, bilateral scrotal Duplex scans and blood hormonal levels.

Forty patients were finally studied; they all had an improved sperm count and had fathered once after surgery. Fifteen had fathered twice and still had their sperm count increased after the second fathering. Twenty-five patients could not father twice; 13 patients had their sperm count decreased after the first fathering and 12 did not. An age-related female factor could be hypothesized in these lasts.Do you mean in the latter group? A decrease in testicular volume and an increase in FSH paralleled the worsening of the sperm count after fathering. No other differences could be observed between the groups. Thus, the beneficial effects of a varicocelectomy might be transitory in some cases (Cavallini et al. 2015).

It could be argued that sperm counts and/or clinical monitors of spermatogenesis parallel the decrease in the beneficial effects of surgery. No significant differences in sperm count and in current monitors of spermatogenesis could be found between the groups; thus, the phenomenon identified in this manuscript remains unknown

Something similar occurred in azoospermic non obstructive patients with high grade left varicocele. When a varicocelectomy is performed in non obstructive azoospermic patients, 20-55% of the semen samples obtained six months postsurgically had sperm; however, a 12-month post-surgical semen sample analysis revealed that approximately one-half of these were again azoospermic (Elzanaty 2013).

The pathophysiology of the association between varicocele and dyspermia remains uncertain. The primary hypotheses involved causes linked to venous varicosities: hyperthermia, venous pressure, testicular blood flow, hormonal imbalance, toxic substances and reactive oxygen species (Eisenberg 2011). This hypothesis does not explain why only approximately one-third of patients with varicoceles are infertile.

Microdeletions of the alpha-1 subunit of the sperm calcium channels in a proportion of dyspermic men with varicoceles suggest a genetic defect leading to abnormal acrosomal function. This finding seems to support a genetic “co-factor” hypothesis for the pathogenesis of oligo±astheno±terato-spermia associated with some varicoceles (Marmar 2001); in fact, the altered genes identified in males with impaired spermatogenesis and a varicocele were: ACP[1] *B/*C, MT-ATP6, MT-ATP, CACNA1C, MT-CO1, MT-CO2, MT-ND3 (Gentile et al. 2014; Matzuk et al. 2008), androgen receptor genes (Zalata et al. 2013), the ropporine expression gene (a protein related to capacitation) (Amer et al. 2015), BAX and BCL2 genes (apoptosis related genes) (Mostafa et al 2014) and the cyclooxigenase expression gene (Mostafa et al. 2015).

It is likely that varicocele-associated oligo±astheno±teratospermia might be due to the effects of venous varicosities added to the effects of defective genes. In fact:

a) only approximately 1/3 of varicocele patients had defective genes.
b) some varicocele patients have their sperm count improved after surgery because their varicosity-related pathogenetic factors are preponderant with respect to genetic co-factors for determining dyspermia;
c) some other varicoceles do not improve sperm count because their genetic co-factors are highly preponderant with respect to varicosity-related pathogenetic factors for determining dyspermia;
d) others improve sperm count provisionally after surgery because varicosity-related pathogenetic factors are corrected by surgery; however this correction might be overshadowedIs this what you want to say? by moderately preponderant genetic co-factors.

A mechanism different from this should be difficultly accepted, but no proof exists.I didn’t understand this sentence. Can you rewrite it please?

In the case that this mechanism is accepted an even more intriguing hypothesis is confirmed. Since no difference in preoperative sperm counts occurred between patients who definitively improved their sperm count after varicocelectomy and patients who improved their sperm count only provisionally after a varicocelectomy, it could be hypothesized that sperm count is only one expression of the complex process of spermtogenesis; the process requires a quantity of data in order to be fully assessed and sperm count is only one parameter. Moreover, male fertility is more linked to spermatogenesis than to sperm count.

The data which can be regarded as linked to fertility and to spermatogenesis are likely to be:
1) Genetic Data. Forty-one single-nucleotide polymorphisms (SNPs) were significantly correlated with family size or birth rate. Of these, four SNPs (rs7867029, rs7174015, rs12870438 and rs724078) were found to be associated with semen parameters in ethnically diverse men from Chicago, and three SNPs were associated with the risk of male infertility in a Japanese population (s7867029, rs7174015 and rs7174015). The populations examined range from normospermia to azoospermia (Sato et al. 2015).
2) Metabolic data. The effects of diabetes mellitus include long-term damage, dysfunction, and various organ failures. An important complication of diabetes is disturbance to the male reproductive system, mainly via epigenetic modification during sperm spermatogenesis. Diabetes affects sperm motility to a lesser extent (Ding et al 2015).
3) Clinical data: couple residual fertility. Residual fertility means the theoretical capacity of fathering which declines in relation to the time of seeking to induce pregnancy. In fact, a varicocelectomy improves sperm count (Al-Ghazo MA et al. 2011). However, improvement in the spontaneous pregnancy rates after a varicocelectomy correlates negatively with the duration of infertility. Therefore, the duration of the infertility should be considered when treating a patient with a varicocele as a cause of infertility.
4) Epigenetic data. Antioxidant medical therapy can reduce sperm aneuploidy levels and improve the results of an intracytoplasmic sperm injection (ICSI) in patients with severe idiopathic oligoasthenoteratospermia (OAT) in the absence of significant modifications of sperm count.
(Tempest et al. 2005, Cavallini et al. 2012).

1. Al-Ghazo MA, Ghalayini IF, al-Azab RS, Bani-Hani I, Daradkeh MS. Does the duration of infertility affect semen parameters and pregnancy rate after varicocelectomy? A retrospective study. Int Braz J Urol. 2011; 37:745-50.
2. Amer MK, Mostafa RM, Fathy A, Saad HM, Mostafa T. Ropporin gene expression in infertile asthenozoospermic men with varicocele before and after repair. Urology. 2015; 85: 805-8.
3. Baazeem A, Belzile E, Ciampi A, Dohle G, Jarvi K, Salonia A, Weidner W, Zini A. Varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. Eur Urol. 2011; 60: 796-808.
4. Cavallini G, Beretta G, Biagiotti G, Mallus R, Maretti C, Pescatori E, Paulis G. Subsequent impaired fertility (with or without sperm worsening) in men who had fathered children after a left varicocelectomy: A novel population? Urol Ann. 2015; 7: 79-85.
5. Cavallini G, Magli MC, Crippa A, Ferraretti AP, Gianaroli L. Reduction in sperm aneuploidy levels in severe oligoasthenoteratospermic patients after medical therapy: a preliminary report. Asian J Androl. 2012;14:591-8.
6. Elzanaty S. Non-obstructive azoospermia and clinical varicocele: therapeutic options. Int Urol Nephrol. 2013; 45: 669-674.
7. Eisenberg ML, Lipshultz LI. Varicocele-induced infertility: Newer insights into its pathophysiology. Indian J Urol. 2011;27:58–64
8. Gentile V, Nicotra M, Scaravelli G, Antonini G, Ambrosi S, Saccucci P, Adanti, Bottini E, Gloria-Bottini F. ACP1 genetic polymorphism and spermatic parameters in men with varicocele. Andrologia 2014;46:147-50
9. Marmar JL. The pathophysiology of varicoceles in the light of current molecular and genetic information. Hum Reprod Update. 2001;7:461–72. [PubMed]
10. Matzuk MM, Lamb DJ. The biology of infertility: Research advances and clinical challenges. Nat Med. 2008;14:1197–213.
11. Mostafa T, Rashed L, Nabil N, Amin R. Seminal BAX and BCL2 gene and protein expressions in infertile men with varicocele. Urology. 2014: 84: 590-5.
12. Mostafa T, Rashed L, Taymour M. Seminal cyclooxygenase relationship with oxidative stress in infertile oligoasthenoteratozoospermic men with varicocele. Andrologia. 2015 Apr 23. doi: 10.1111/and.12423. [Epub ahead of print].
13. Tempest HG, Homa ST, Zhai XP, Griffin DK. Significant reduction of sperm disomy in six men: effect of traditional Chinese medicine. Asian J Androl. 2005;7:419–25.
Zalata AA, Mokhtar N, Badawy Ael-N, Othman G, Alghobary M, Mostafa T. Androgen receptor expression relationship with semen variables in infertile men with varicocele. J Urol. 2013; 189: 2243-2247.

Written by:
Giorgio Cavallini
Department of Andrology, Gynepro-Medical Group, Via Tranquillo Cremona 8, 40137 Bologna, Italy.

Giovanni Beretta
Department of Andrology, Centro Demetra, via Giulio Caccini 18, 50141 Firenze , Italy.

AbstractSubsequent impaired fertility (with or without sperm worsening) in men who had fathered children after a left varicocelectomy: A novel population?