Fertility after an undescended testicle

[This page is still being written. Check back soon for the finished article!]

What about fertility?

The number one question I get asked by parents is “will my son be able to father children?”. (The number two question is “will my son get cancer” – and I’ll address that in a future article)

Good news! The majority of men who had an undescended testicle can have children.

Less good news! The chances of having children are lower than the rest of the population. Let me break it down to be clearer…

Mechanics

The testicles contain different types of cells. Germ cells produce sperm, while Leydig cells are responsible for producing the hormone Testosterone.

While a boy starts to produce sperm at puberty, the cells in his testis get ready to produce sperm from the start. Germ cells develop in the first years after birth, some data suggesting between 3 and 9 months of age. They can only develop if the testis is in the scrotum (to keep it cool) and hormones are normal.

Hadziselimovic and Herzog (15) have demonstrated that the process of transformation of neonatal gonocytes into AD spermatogonia during the first year of life is crucial for male fertility. The inhibition of this process in undescended testis leads to a deficient pool of stem cells for post pubertal spermatogenesis and infertility. Moreover, in undescended testes, germ cells loss starts at 6 months of age. Testicular biopsies at time of orchidopexy confirmed the importance of AD spermatogonia for fertility in cryptorchid patients. Tasian and coworkers (22) observed greater germ cell depletion in abdominal testes compared with palpable testes and a progressive germ cell loss for each month the testes remain undescended.

When a testicle doesn’t descend properly, its germ cells can fail to develop properly, and are at risk of dying or developing abnormally (increasing the risk of cancer).

[Part of this is due to the testicle being at a higher temperature than it was designed to be; some is due to in-built XXXX]

“In boys older than 3 years of age at biopsy, 64% had a complete lack of germ cells”
source

What’s the risk factor?

Recent research has found that for every month the testicles remain inside the body (undescended), there’s a 2% risk that many of the sperm producing cells will die, and a 1% risk that the testosterone producing cells will die.

And by risk we mean less than a third of sperm producing tubes will contain any sperm producing cells. Not that a third will contain normal numbers of sperm producing cells; any cells at all. (source)

To make that easier to understand, let’s do some worked examples:

If your son has surgery when 12 months old, there’s a 24% risk of the testicle producing few sperm (germ cell depletion), and a 12% risk of less testosterone

If he has surgery at 18 months, there’s a 36% risk of the testicle producing little sperm, and a 18% risk of lower testosterone

I had surgery when I was nearly 3 1/2 years old (42 months). I have an 84% risk that my previously undescended testicle will not produce viable sperm, and a 42% risk that its testosterone production is impaired.

Yikes!

A 2% risk/month of severe germ cell loss and 1% risk/month of Leydig cell depletion for each month a testis remains undescended, and a 50% greater risk of germ cell depletion in nonpalpable testes has been reported, thus emphasising the need for early relocation of an undescended testis (Tasian 2009).

Another descriptor of Taslan’s risk factor – closer to statistically correct?
Increasing odds of cell depletion were noted with increasing age, with boys undergoing orchidopexy at 13-24 months having an odds ratio (OR) =3.9 for cell depletion, compared to those having surgery before a year of life. With each increasing age group the OR for germ cell depletion roughly doubled, reaching an OR =16.8 for boys undergoing orchidopexy at greater than 8 years of age (31).

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010978/full

Germ cell depletion was considered severe when <33 % of the tubules contained germ cells.
— source: https://www.researchgate.net/publication/262696562_Surgical_approach_to_the_palpable_undescended_testis

It’s important to remember that older research was skewed by surgery previously being done at an older age – which as the figures below show, would reduce fertility compared with surgery done at a younger age.


If your son had non-palpable testes (abdominal)

All the above still applies, but the risk is higher.

There is a 50% greater risk of germ cell depletion.


Feyles et al. [5] compared total sperm count and sperm motility in 51 men between 18 and 26 years of age having had an orchidopexy in childhood. They used World Health Organisation (WHO) criteria of normal count [15 million/mL and sperm motility [15 % to define normalcy. Group A had their orchidopexy in the first year of life and Group B between the first and second years of life. The proportion of subjects from Group A with a normal sperm count (96 %) was significantly higher than those in Group B (75 %) [5]. The proportion of subjects with normal sperm motility was also significantly higher in Group A than in Group B (96 vs. 67 %) [5].

— source: https://www.researchgate.net/publication/262696562_Surgical_approach_to_the_palpable_undescended_testis

Antibodies to sperm – affected by the way the testicles were fixed in the scrotum. The modern approach makes a pouch in the scrotum and holds the testicle in place without stitches, is much better. The approach used before 1995, and used on me, used insoluble stitches to anchor the testicle in the scrotum. As well as giving a poorer visual appearance and being uncomfortable, these stitches could let blood and sperm mix. When this happened there is a risk that your body’s white blood cells will attack the sperm and destroy it – and this will affect both testicles.

According to research done in 2002 on rats, if the testicle was stitched in place there was up to 60% more chance of tubular atrophy. The modern way of putting the testicle inside a pouch in the scrotum removes this risk, and ensures it cannot twist.

Orchiopexy or testicular fixation for ascending testes (acquired undescended testes). The diagnosis of ascending testes (i.e. testes in an undescended location after being noted to have been completely descended) is being made with increasing frequency in recent years (Tasian 2010). The precise aetiology remains unclear. We have chosen to exclude the ascending testes from this review due to the underlying differences in the age of diagnoses, pathogenetic mechanisms and outcomes of treatment.

In another work from the 1970s, Ludwig et al. showed that boys who were operated on in the first two years of life had a 90% rate of fertility. This was in contrast to those boys operated on in years 3-4 (50% rate) and in those who had operations in years 9-12 (30%). While this study did not include the original position of the testicle at time of orchidopexy, a factor possibly not recognized as important at the time, these results certainly speak to a recommendation for earlier orchidopexy.
— source https://www.ncbi.nlm.nih.gov/pubmed/235412 – old, but shows what was currently thought

If your son had impalpable undescended testicles

In another analysis of germ cells, boys who underwent surgery before 6 months of age were compared to those having surgery between 6 and 24 months (32). Authors were able to demonstrate a negative correlation between age at orchidopexy and germ cell counts. All of the 14 boys who had surgery before 6 months of age had a normal number of GC/T compared to the lower numbers seen in those having surgery between 6 and 24 months of age. However, the data from 20 years post-operatively called into question the use of these fertility predictors as there was no association between germ cell counts on biopsy and the total sperm count on semen analysis. Interestingly, among the boys who had surgery at less than 6 months, 31% had a sperm count less than 40 million and sperm counts between groups were not statistically different (<6 months: 136×106 sperm/ejaculate; >6 months: 96×106 sperm/ejaculate, P=0.28) despite the more frequent abnormal histology in the boys undergoing orchidopexy at greater than 6 months of life. The authors then examined results based not on patient age at orchidopexy, but on presence of AdS on biopsy. Almost all males who had developed this more mature cell line had a normal sperm count. This was in stark contrast to the group who had not undergone the transformation, wherein a majority of the men had azoospermia or oligospermia. These results are muddied by the inclusion of both unilateral and bilateral UDT in the cohort, but more clearly show that this maturational step is likely paramount to future fertility and that care decisions should be made to optimize the ability of the testicle to undergo this maturational change. In another study of testicular biopsies performed at the time of orchidopexy, a lower age at surgery was correlated with presence of spermatogonia (r=0.37, P<0.0001) and decreasing tubular atrophy (r=0.59, P<0.001) (33).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708134/

The volume of the testicles at orchidopexy is often reduced the later the surgery is performed on the cryptorchid testis (25,26). However, testicular volume may not be an appropriate proxy for future fertility based on studies following paternity rates of men with cryptorchid testes. A study by Lee et al. found no relationship to testicular size at orchidopexy for unilateral UDT on future fertility as measured by actual paternity rates (27). Possible explanations for this include hypertrophy of the normally descended testicle, which could compensate for impaired fertility of the abnormal testis.
source

In English, the above quote means…

In van Brakel et al.’s [22] report on adult follow-up that included both palpable and non-palpable testes, the testic- ular volume of the pexed testes was consistently less than that of its descended counterpart. This study also found that the volume of the descended testis in those with unilateral undescended testes was significantly less than the testes of the control group. The adult testicular

https://www.researchgate.net/publication/262696562_Surgical_approach_to_the_palpable_undescended_testis

Around 9% of men who had a single undescended testicle have fertility problems

Fixing testicle = Pexed / pex = fix

Both my son’s testicles are undescended (bilateral cryptorchidism)

Unfortunately, over 50% of men who were born with both testicles undescended will have fertility problems. This number is likely to decline and be less for your son, as now surgery is regulary done before the age of 2, whereas the 25-year studies in medical journals often had children operated on aged 3-8, with a corresponding increase in damage to the testicle.

Despite surgical treatment by orchiopexy, the long-term outcome still remains problematic and controversial. Impaired fertility (33% in unilateral cases and 66% in bilateral undescended testes) and a cancer risk 5-10 times greater than normal is observed over time (2). Hadziselimovic et al (56) reported infertility in 35% of the patients with undescended testes with normal germ cell number before surgery despite early orchiopexy performed under age 6 months. They suggested that this might be explained by defective transformation of germ cells due to lack of a mini-pubertal period (56). During mini-puberty, progenitor spermatozoa are transformed into Ad (dark) spermatogonial cells owing to the peak effect of LH and testosterone, an effect which occurs particularly in the postnatal 2-3 months (24,56). The infertility rate may increase up to 90% in patients who have not undergone a mini-pubertal period (56).
https://www.researchgate.net/publication/237084024_Epidemiology_Classification_and_Management_of_Undescended_Testes_Does_Medication_Have_Value_in_its_Treatment

Men with a history of undescended testis have a reduced probability of fertility with a low sperm count and generally poorer semen quality than men with normal testicular descent (e24, 20). This subfertility is not compensated by a normally descended contralateral testis. The probability of a fertility impairment is addi- tionally increased in bilateral cryptorchidism and delayed treatment of the non-descended testicle. Almost all adult men with bilateral undescended testis have azoospermia, whereas more than 20% of boys achieve a normal sperm count after orchidopexy. Only few studies have evaluated semen quality in relation to the time of life at which treatment was performed, the original position of the testicle, and the surgical technique.

Surgical treatments in boys between the ages of ten months and four years with bilateral cryptorchidism lead to a normal sperm count in 76% of cases compared to 26% in the boys who were operated between the age of 4 and 14 years (21). This time effect is not so pro- nounced with unilateral cryptorchidism (21). This may well be due to the impaired spermatogenesis which is already characterized histologically in the first months of life by an increasing reduction in the testosterone- producing Leydig cells, delayed onset of spermatogonia, and a quantitatively and qualitatively reduced matura- tion process of the germ cells (e25). It is found that fertility may still be impaired after treatment and that early management confers distinct benefits (e24, 22).

https://www.researchgate.net/publication/26797740_The_Undescended_Testis_Diagnosis_Treatment_and_Long-Term_Consequences

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708134/ too – some quotes above are from it

although boys with one undescended testis have a lower fertility rate, they have the same paternity rate as boys with bilateral descended testes. Boys with bilateral undescended testes have a lower fertility and a paternity rate (9).
http://journal.frontiersin.org/article/10.3389/fendo.2014.00063/full

READ THIS PAPER to get a readable description of the biology http://journal.frontiersin.org/article/10.3389/fendo.2014.00063/full. Also covers cancer risk.

Several data suggest that AD spermatogonia form between 3 and 9 months of age. This developmental cycle needs normal testicular hormones and the optimal scrotal temperature of 33°C …

The failure of transformation of gonocytes into AD spermatogonia may produce infertility in boys. …Moreover, in undescended testes, germ cells loss starts at 6 months of age. Testicular biopsies at time of orchidopexy confirmed the importance of AD spermatogonia for fertility in cryptorchid patients. Tasian and coworkers (22) observed greater germ cell depletion in abdominal testes compared with palpable testes and a progressive germ cell loss for each month the testes remain undescended. …

However, early orchidopexy does not guarantee normal fertility in adulthood. Hadziselimovic showed that despite orchidopexy before 6 months of age, up to 35% of boys will grow up to be infertile regardless of the normal total germ cell count on testicular biopsies performed at the time of orchidopexy (44).

Conclusion

The greatest concern for papers predicting outcome of undescended testes is that they are just that, predictions. It takes an extremely long study to actually document fertility and paternity and the threshold of Leydig cell depletion which affects adult hormone function is not clear.

Testicular size/volume

No matter how young your son is operated on, his undescended testicle(s) will not grow to be the same size as a normally-descended testicle (source). The fact it was undescended is enough to influence this.

In men who had a unilateral undescended testicle (one undescended) the formerly cryptorchid testes usually reach a volume in the adult of only about a half of that of the contralateral side.

Interestingly the adult testicular volumes of both the previously undescended and descended sides are significantly lower than in men who were born with both descended (source). A healthy male testicle has a volume of 20ml; a study found that the contralateral side averages 16ml while the formerly cryptorchid testis size can be 8-12ml (depending on age and if hormone therapy was administered).

For men who had bilateral undescended testicles (both undescended) I don’t have any data.

Van Brakel et al. [22] from Erasmus MC Rotterdam, The Netherlands, assessed the fertility potential of 62 men aged between 20 and 38 years who had undergone orchi- dopexy between 1 and 12 years of age for both palpable and impalpable undescended testes and compared them to a group of 55 controls. Adult testicular volumes of both the previously undescended and descended sides were signifi- cantly lower in subjects than controls.

When an undescended testis has been brought into a scrotal position, catch-up growth generally occurs, but the previ- ous UDT still lags behind its descended counterpart and the final volume reached appears not to be influenced by the boys’ age at time of orchidopexy.

— source: https://www.researchgate.net/publication/262696562_Surgical_approach_to_the_palpable_undescended_testis

A smaller testicle is common in adults who were formerly surgically treated for unilateral UDT. Formerly cryptorchid testes usually reach a volume in the adult of only about a half of that of the contralateral side. Possible causal factors might include a primary abnormality resulting in impaired growth of the retained testis and compensatory hypertrophy of its counterpart.

Conclusion

Early relocation of the testis can help with sperm production and normal hormones, but in the case of unilateral (one) undescended testicles it doesn’t appear to affect your son’s fertility rate.

Another variable that can influence a patient’s fertility is the prevalence of epididymal or vasal obstructions, which were reported among 17–40% of orchidopexed patients with fertility issues (source).

Q&A

You need two testicles to father a child

Wrong! Each testicle produces sperm. A man with one testicle can get a woman pregnant. Having two is nature’s way of ensuring that if one is damaged, he still has a second one.

A history of orchiopexy https://synapse.koreamed.org/DOIx.php?id=10.4111/kju.2010.51.3.155

They reported a deficiency of germinal cells from birth, with no evidence of a progressive loss of germ cells, and suggested that the deficiency may be congenital rather than the result of hyperthermia-induced damage to the germinal epithelium.

http://onlinelibrary.wiley.com/doi/10.1046/j.1464-410x.1999.00093.x/full

Data on the function of the scrotal testis in unilateral cryptorchidism are conflicting. A damaged germ cell function of the descended testis by the presence of an undescended gonad has been described, as has a unilateral germ cell hypertrophy compensating for the deficiency of the undescended testis [ 23, 24]. Another study showed no difference in TFI between the scrotal testis in unilateral cryptorchidism and controls [ 17]. The volume of the contralateral descended testis was significantly greater in patients with an absent testis than in patients having an intra-abdominal testis, although the compensatory hypertrophy was not a reliable criterion to differentiate between an absent or an intra-abdominal testis [ 25]. Other observations indicate a primary abnormality in both testes even when one is descended. The age-matched number of spermatogonia per tubular cross-section was higher in the descended than in the contralateral cryptorchid testis, but lower than that of an age-matched normal testis [ 26].
http://onlinelibrary.wiley.com/doi/10.1046/j.1464-410x.1999.00093.x/full

http://onlinelibrary.wiley.com/doi/10.1046/j.1464-410x.1999.00093.x/full – the Orchidopexy section covers discussion over age at surgery, whether it makes a difference. Good selection of studies reference.

Whether the changes found in the contralateral descended testis are primary or related to the undescended testis is unclear.

After 6 months of age, a decline was noted in spermatogonia with more pronounced effects noted at 2 years. In boys older than 3 years of age at biopsy, 64% had a complete lack of germ cells (20).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708134/ — useful

There is evidence of similar, yet often less pronounced, histological differences in the contralateral, normally descended testis signifying more than a localized, unilateral defect. While a significant impediment to transformation from gonocytes to AdS is noted in the UDT, a delay was noted also in the contralateral testis, although in most cases transformation was complete by 12 months of age (11). The lower fertility in men with unilateral UDT reported in some publications supports a more global dysfunction that is not purely limited to the UDT and an abnormal hypothalamic-pituitary axis has been postulated as the cause of contralateral testis dysfunction (13). There is certainly a correlation with global and often multisystem defects in boys with bilateral cryptorchidism (21).

The number of cells, or cells per transverse section of tubule, in testicular biopsies is often used as a marker of fertility potential in cryptorchid boys (22). Hadziselimovic et al. examined testicular biopsies taken at orchidopexy between the ages of 10 months to 13 years and compared them to semen analysis done on the same patients when they were 21 to 25 years old (23). Unilateral UDT patients treated before the age of 3 years had 3-fold higher sperm counts than those treated after the age of 8.

In another work from the 1970s, Ludwig et al. showed that boys who were operated on in the first two years of life had a 90% rate of fertility. This was in contrast to those boys operated on in years 3-4 (50% rate) and in those who had operations in years 9-12 (30%). While this study did not include the original position of the testicle at time of orchidopexy, a factor possibly not recognized as important at the time, these results certainly speak to a recommendation for earlier orchidopexy (30).

In examination of boys undergoing unilateral orchidopexy, there was no difference in timing of surgery with regards to future fertility potential in boys operated on at 2-12 years of age
https://www.ncbi.nlm.nih.gov/pubmed/8648809/

 

Good article on texture and developmental differences: http://onlinelibrary.wiley.com/doi/10.1111/andr.12070/full