QUESTION  -A 59-year-old man presents with more than 12 months history of lack of libido, erectile dysfunction and energy levels
. He has a history of multiple squamous cell carcinomas of face and scalp since 2014. In May 2016 he had an excision of recurrent SCC from right cheek and skin graft reconstruction in July 2016. In addition in August 2016 he was commenced on adjuvant concurrent chemo radiotherapy (weekly Cisplatin). He finished chemotherapy about 6 weeks ago.
There is no history of testicular infections or trauma. No history of chronic headache or visual problems. He is currently on no regular medications. He has three children. He is not obese. He is well virilized, no gynaecomastia. He said he has not noticed any change in testicular size but he refused testicular examination.

His blood investigations from 17/11/16 demonstrated normal total testosterone 17 nmol/l (8.3-29), his SHBG is very high 112 nmol/L (11-71), low calculated free testosterone 141 pmol/L (225-725). FSH 22 IU/L, LH 13 IU/L  (reference range: Males less than 60 years FSH less than 7, LH less than 7: Males greater than 60 years FSH less than 14, LH less than 11) . Normal prolactin, thyroid function test, kidney and liver function.

 Questions ·         I understand that testosterone, SHBG, FSH, LH is affected in different ways with chemotherapy and its multifactoral. It appears that this patient has spuriously normal total testosterone due to an elevated SHBG.
·         Is elevated FSH and LH indicating primary hypogonadism or hypogonadism is being compensated by elevated gonadotropins making his total testosterone to become normal?
·         Is testosterone replacement indicated and if yes what levels of total testosterone should I aim for or should I monitor FSH LH aiming for normal FSH LH with testosterone replacement.
·         Should I aim for a normal calculated free testosterone with replacement?
Thank you, Dr Aziz  ,

RESPONSE-Dear Colleague,   Thank you for your excellent questions in regard to evaluating testicular function and potential androgen replacement therapy in a man after chemotherapy.
Clinical Presentation  The diagnosis of androgen deficiency (AD) involves consideration of both symptoms and signs and confirmatory biochemistry.  The lead symptoms in this gentleman are poor libido and reduced energy; these are certainly common symptoms in androgen deficiency yet might be caused or exacerbated by his other health concerns.  It is stated that he has had these issues for 12 months, have these worsened in the since August and the chemotherapy?

Erectile dysfunction (ED) is generally caused by underlying neurovascular disease, but androgen deficiency mainly be involved.  In addition to burden of his recurrent malignancy and chemotherapy, one wonders if he has any of the common co-morbidities associated with ED such as a history of hypertension, hyperlipidaemia, smoking or glucose intolerance; all such factors affect endothelial function that is essential for normal erections. As he takes no related medications, I presume these factors are not evident.

He has no features of AD on examination but these might not be expected if AD is of recent onset. I would seek again to examine his testes; it is very unusual for this to be declined if the need is well explained, in his case ‘have your testes been damaged by treatment’. Also penile examine is essential to excuse Peyronies as a cause of ED.

Biochemistry  All therapeutic guidelines support using total testosterone levels to guide in the diagnosis of AD.  His serum total T is in the mid normal range. Indeed the high SHBG would be a key factor in elevating his total T level; the elevate SHBG high is discussed below. However your concern is how to interpret the low free T estimate.

I would caution that the place of free T levels (either directly measured or calculated) is controversial. Most guidelines provide ill-defined  recommendations on free T measures such as ‘ in some men in whom total T concentrations are near the lower limit of the normal range and in whom alterations of SHBG are suspected ‘ [Bhasin S et al J Clin Endocrinol Metab. 2010 ;95:2536-59], or  ‘measurement of free or bioavailable T should be considered when the serum total T is not diagnostic …… There are no generally accepted lower limits of normal for free T for the diagnosis of hypogonadism  [Wang C  J Androl. 2009 ;30:1-9].  Others overtly recommend against the use of free T for clinical decision making [Yeap BB Med J Aust. 2016; 205:173-8]. In terms of the aforementioned guidelines, this gentleman total T is nowhere near the ‘equivocal range’. But as the SHBG and freeT assessment has been given, one must address the dichotomy between total and free T.

The underlying assumption is that free T measures better reflect tissue androgen availability. This assumption has not be empirically validated and an alternative views is the free T levels relate to that fraction that is available for metabolic clearance rather than action. Such evidence as there is for a relationship between AD and a low free T, in the presence of a normal total T, comes from cross sectional observational studies [e.g. Antonio L et al  J Clin Endocrinol Metab 2016; 101: 2647-57 ] rather than controlled trials.

Nonetheless many authors suggest free T may help in the evaluation of androgen status when SHBG levels vary greatly from the reference range. In this particular man, the SHBG is indeed very high. Perhaps this a recent change related to drug therapy rather than longstanding – only a fortuitous prior measurement would answer that question. A markedly elevated SHBG can be seen in liver disease, hyperthyroidism and with certain medications, such as anti-epileptics.  Cisplatin can cause significant hepatic and renal injury. I could not find specific information about SHBG but disruption of liver function may be a factor. This would presumably remit with time. Is his liver function being monitored? Did he have liver function tests prior to their usage?

Calculated free T estimates are derived from various mathematical formulae all of which assume a set binding affinity of T for SHBG and albumen, and accurately measured total T, SHBG and albumen levels. These equations give somewhat differing absolute values, correlate reasonably but not precisely with equilibrium dialysis, and verified reference interval are not available [Sartorius G et al Ann Clin Biochem. 2009 ;46:137-43].  They are inherently vulnerable to assay variability; especially the well known testosterone immunoassay platform based variations. The accuracy of calculated free T measures when SHBG level is well outside the reference range (such as here) is not clear.

The real issue: is testosterone therapy indicated?   Putting aside his normal total testosterone, one must pay attnetion to the clinical setting and the serum LH, which one presumes reflect his “pituitary’s view” of a sufficiency of circulating androgens.  In his case the LH level of 13IU/L , that being  ~ 50% above the upper limit of normal. Accordingly this supports a degree of primary testicular failure. His grossly elevated FSH reflects seminiferous tubule damage from his chemotherapy.

But do his symptoms reflect AD and/or relate to the burden that his malignancy and various treatments, particularly in recent months when exposed to Cisplatin.  You mentioned that he stopped therapy two months ago. It would be wise to confirm his endocrinology to see if his situation is evolving, particularly in regard to SHBG and liver function.

Going to the literature there is very little on whether T treatment is effective in borderline hypogonadism related to chemotherapy exposure.  The best study was a randomised placebo-controlled study in 35 men with borderline elevation of LH and testosterone levels in the lower half of the normal male range: thus very  similar to your patient  (Howell SJ et al Clin Endocrinol. 2001 ;55:315-24). This study looked at a range of endpoints, including quality of life, and benefits of T therapy were either absent or of borderline significance.  They authors concluded that this degree of mild hypogonadism was not of clinical significance and that androgen replacement therapy couldn’t be recommended routinely.

My feeling would be to repeat the hormonal testing in a couple of months to see if his gonadal condition progresses.  I would carefully review the impact of his co-morbidities and underlying disease and treatment on his symptoms, and consider the judicious use of PDE5 inhibitors should ED be a major component of his concerns. If his LH was similar or higher than last measured, one could confidently diagnosed AD due to testicular disease, and T replacement would be justified.

Presuming he commences treatment, in line with all guidelines, monitoring of therapy is based on symptomatic improvement and the attainment of a total T within the normal range. However given his very high SHBG and its effects of total T, importance can be given to monitoring serum LH aiming to suppress into in the normal range.  The choice of androgen treatment modality and other monitoring [such as prostate health, haematocrit] also needs to be addressed (see, Handelsman D, Chapter 2: Androgen Physiology: section 4.8)
Rob McLachlan MD, PhD ,Male Reproductive Endocrinology Section Editor,