“LOW” TESTOSTERONE AND INFERTILITY- DIAGNOSIS AND TREATMENT 25 Apr 2014

QUESTION(S)- I see a lot of young males (early 20s) with idiopathic low testosterone levels who wish to preserve fertility by all means. Some have had histories of TBI, cerebral disorders like aneurysms and a few have cystic fibrosis. A couple, it appears to be truly idiopathic (deny past testosterone abuse). In my training program we would put young man like this in a combination of clomid and if high estrogen ensued, we would then add an aromatase inhibitor. In looking at the literature I am having a very hard time finding guidelines or articles to advocate for this. My concern is in regards to the longterm use of clomid and possible pituitary effects (like theoretical hyperplasia) as well as the possible long term effects on bone health that has been linked to aromatase inhibitors in the setting of breast cancer survivors. In your practice, would you use testosterone in this young population?    Natalia Regales  'nregales@tgh.org'
RESPONSE--Thanks for your question. Consideration of fertility preservation is essential whenever that ability is threatened. Sometimes it can be anticipated (e.g. pre-chemotherapy) but in other men it progressively fails for no apparent reasons. Spermatogenesis will decline when androgens are given to normal or infertile men due to its action to suppress gonadotropins. Androgen should never be given to men if they are seeking fertility without consideration of these matters. One despairs when one sees patients out on testosterone to ‘boost their sperm counts’, sadly it still happens!

The use of agents like Clomid is a complicated and contentious area. Without knowing your exact patient phenotype, one can’t be definitive but I can make general comments.
First, I am not sure what you mean by ‘low’ testosterone levels; do you mean those with a low normal range (allowing for BMI obesity correction) in man who feels a bit ‘flat’ or those with clear androgen deficiency and a very low T of  say < 2ng/ml? I see many obese younger men with low normal T for whom diet and weight loss is the key and their fertility will be uncompressed. So the first issue is how confident you are that the man is truly deficient and how compelling is the case to do anything?  The diagnosis should be made in line with the guidlenes (see US Endocrine Guidelines Bhasin S et al  J Clin Endocrinol Metab. 2010 Jun;95(6):2536-59)

In men with a history of TBI, cerebral disorders or any head trauma, then hypogonadotropic hypogonadism (HH) is a critical exclusion as it is amenable to treatment to restore natural fertility. In the presence of low LH and poor semen quality, and presuming they had undergo a normal puberty, they will respond very promptly in terms of both serum T and spermatogenesis, to hCG alone (see Hayes et al Chapter 6, Male Section, ENDOTEXT) while other will need FSH added.
Men with cystic fibrosis have an absent vas and their sterility is not amenable to medical treatment. If they want children it must be by testicular sperm aspiration and ICSI.  If they are androgen deficient for whatever reason, then testicular sperm should be cryopreserved for later use.

Anabolic abusers are a challenging group. They may swear to have never used, or to have stopped using months/years ago, but be untruthful. They have characteristically undetectable LH and low SHBG but their serum T levels will vary with the type of steroid, dose and timing. As the steroid wears off, they may have a transient phase with a very low T plus androgen deficiency symptoms making them appear to have ‘idiopathic’ HH .  This dysequilibrium situation settles over months with a slowly rising LH and serum T and a regrowth of testes and spermatogenesis; one has to be patient.
On occasion things get tricky, they may seek the clinician to be complicit in the continued drug abuse strategy while seeking fertility through the use of gonadotropins. Alternatively, they have genuinely stopped 2 months ago, be azoospermic and seek ‘urgent’ fertility as their female partner turns 43 next month! If one was to intervene, then hCG is probably the best alternative as it is an approved and well understood medication that will drive up intra testicular T and quickly restore spermatogenesis; it can then be progressively withdrawn in keeping with the time course of disappearance of the anabolic agent(s).
More rarely, one sees men who it really seems have stopped use years ago and is still symptomatic with T of <2-2.5 ng/ml with low normal LH, normal MR , and other pituitary hormones,  i.e. partial HH, and who seek fertility.  As an alternative to hCG, clomid has been tried but note that neither clomid nor aromatase inhibitors are FDA approved in men. This is why there are no guidelines; efficacy and safety are unclear.

A few comments in the area;
--One would not use aromatase inhibitors long term in men due to concerns about bone and other effects. (See Finkelstein et al Gonadal steroids and body composition, strength, and sexual function in men. Engl J Med. 2013 Sep 12;369(11):1011-22).  One needs to think about T as both a hormone and a pro-hormone for E2 and DHT and estrogen is the major sex hormone determining male bone health.
Long term use of Clomid seems not evidcne based and it is usually for periods of 3-12month.  Use of empirical approaches is common. For example, in idiopathic male infertility, two thirds of US urologists use agents, such as anti-estrogens, gonadotrophins and anti-oxidants, despite a lack of evidence, the absence of recommendation in professional guidelines (Ko et al J Urol 2012 ;187:973). It use in idiopathic infertility is controversial (Chua et al Andrology 2013: 1: 749).  That said, serious side effects have not been commonly reported and I am not aware of pituitary tumours induction.
In summary:
1-
          Androgens should be used in young men with established a firm diagnosis of androgen deficiency (see US Endocrine Guidelines Bhasin S et al  J Clin Endocrinol Metab. 2010 Jun;95(6):2536-59)
2          One must be cautious in diagnosed ‘partial HH’ in young men with a low normal T/ levels who are otherwise well with normal pituitary function and MRI. Overweight and obesity are common associations that require their own redress. Also to considered are lab errors, the need for repeat testing and surreptitious drug use.
3          In the common setting of men with primary testicular failure presenting with infertility and androgen deficiency, the infertility should be addressed first because they will be made infertile by physiological T treatment. They should consider storing sperm as one does not with certainty whether spermatogenesis will return if the testosterone is then initiated but stopped in the future .
Regards, Rob McLachlan, MD, PhD, Male Section Editor, Endotext.org