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From the Townsend Letter
December 2016

The Clinical Importance of 5alpha-Reductase in Human Health and Pathology
Part 1: Men, Testosterone Replacement, and Stress
by Alan B. McDaniel, MD
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Optimal Testosterone Replacement Treatment: Amount and Balance
To what "ideal" values and balance should men's hormones be restored by TRT? All can agree to find "the best trade-off between increased function and the likelihood of adverse events," but can we be more specific? Supraphysiological supplementation is tempting, particularly for athletes, but invoking the law of diminishing returns invites complications.41,42 Investigators of the Massachusetts Male Aging Study wrote, "Beyond a certain threshold, there may be little association between androgens and physical performance."43 Bhasin et al. recommended targeting "high normal testosterone levels."41
Recently, older men with testosterone and DHT values in the midst of the normal reference intervals were found to have the lowest death rates from any cause. These researchers stated: "Optimal androgen levels are … a survival biomarker."44 This supports using the 40th centile of the reference interval as the initial goal, the tactic recommended by the authors of a useful review.45
The balance of testosterone to its derivatives should be considered. Excessive 5α-R activity is seen to be disruptive, though how far below the normal tTEST/DHT ratio one can fall without consequence is not certain. While exceeding the intent of this article, it must be noted the balance of testosterone to estradiol (tTEST/E2) is increasingly relevant: abdominal obesity leads to increased aromatase, so that testosterone is inversely correlated with body mass index.46,47 A search of Pub Med for hypogonadism aromatase yields 170 citations (July 2, 2016). Most importantly for Case 1, he felt greatly better after correcting his multiply abnormal blood values.
Having his skin 5α-reductase identified as the cause of his problem, Case 1 considered a variety of options to negate this enzyme's excessive effect. These included adding a 5α-R blocker (discussed in the subsequent women's article) or switching from testosterone to a clomiphene trial (Case 2; see below). He settled upon a "sure thing": injected testosterone cypionate, to bypass the skin 5α-R.

He is "not afraid of needles" and injects 30 mg twice weekly, after finding that 60 mg once weekly gave him fluctuating symptoms and a low "trough" testosterone value (tested when his next injection was due on Sept. 25, 2015; Table 1). His energy, libido, and mental clarity are improved – and his diplopia is now noted only when he is very fatigued or much stressed. The prompt and sustained correction of the tTEST/DHT ratio with injected testosterone indicates that his skin was indeed the 5α-R source.
Men's Testosterone Replacement: Case 2
Case 2 was 50 years old in July 2008, when for the second time, blood tests showed that his total testosterone was below 300 ng/dL. He was "underpowered" and had other symptoms of low T. Tests also indicated some degree of secondary hypogonadism: Despite low tTEST, the LH and FSH values were inappropriately modest, at 1.5 mIU/mL (RI: 1.7−8.6) and 3.8 mIU/mL: (RI: 1.5−12.4) respectively. His biopsy-proven celiac disease was well controlled with a careful diet, and hypothyroidism from Hashimoto's disease (not resolved with diet) was corrected.
Conservative measures to improve his low testosterone – supplements with an adrenal glandular and DHEA 50 mg daily – were symptomatically and biochemically unsuccessful. He began applying topical testosterone replacement in April 2009.
He used commercial testosterone gel 1% via pump, and testosterone and DHT rose disproportionately in relation to his dose: With 4 pumps every morning (50 mg topically, approximately 5 mg absorbed), DHT became high at 100 ng/dL (RI: 30–85) and his tTEST/DHT ratio was 4.7 (low). After reducing the dose to 3 pumps (37.5 mg, approx. 3.75 mg absorbed), his DHT dropped to 77 ng/dL and tTEST/DHT= 8.1. He felt comfortable and subsequent tests showed normal free testosterone (10.4–22.3 pg/mL [RI: 7.2–24.0]), LH and FSH at 3.1, 5.7 respectively (Table 2).

Table 2, Case 2
      Case 2
For a few years, he also took 0.25 mg anastrozole (¼ tablet) every third day to improve his balance of testosterone to estradiol. It became apparent that his pretreatment tests showed poor tTEST/E2 ratio largely due to low testosterone, and the drug was discontinued uneventfully.
Because insurance did not cover his TRT expenses, Case 2 switched from the 1% gel to less-expensive compounded testosterone cream, 200 mg/mL in 2011. Some years later, he read about clomiphene treatment for secondary hypogonadism, which might again substantially reduce his cost. This was well timed, as he also had been developing symptoms: his energy was reduced and he felt tired. He noticed lower urinary tract symptoms (LUTS), including urgency and nocturia twice nightly with another waking around 3 to 4 a.m. for no apparent reason (he has no sleep apnea). He called Doc to inquire.
They updated Case 2's tests in April 2016 and reviewed his serial monitoring results: there was cause for concern. His DHT, once normal, had become high and then was even higher (Table 2). At the same time, the serial tTEST/DHT values had fallen from 7.6 in 2010 to 6.1 in 2015 … and now only 3.0 in 2016. The simultaneous decrease of total testosterone values from 568 to 396 ng/dL shows that the high DHT is due to increased 5α-R, not simply an excess of testosterone.
Having learned about 5α-R and transdermal TRT from Case 1, Doc was disturbed by the worsening laboratory abnormalities coinciding with symptoms – especially as the LUTS implied undesirable prostate stimulation. He met with his patient and offered the same options that he'd suggested for Case 1. With all the tests indicating a significant degree of secondary hypogonadism, clomiphene seemed likely to succeed. Not only might the clomiphene-stimulated endogenous testosterone avoid the induced cutaneous 5α-R, the drug was neither expensive nor Schedule III restricted! Case 2 decided to switch from transdermal testosterone cream to a trial of clomiphene.
Clomiphene for Secondary Hypogonadism
Secondary hypogonadism is diagnosed when the testicles lack stimulation from the pituitary gland and cannot function normally – in this case, to make sufficient testosterone. Normally, pituitary stimulation is initiated and directed by the brain's hypothalamus. That ancient part of the midbrain acts as a complicated (and how!) "assay office," to determine whether the amount of sex hormones in circulation is sufficient to its preference.4 In most cases of men's acquired secondary hypogonadism, hypothalamic function is responsible.
Testosterone replacement is an obvious answer to the ills of hypogonadism – but the practice may be difficult and costly, and can fail to restore semen volume and fertility. An alternative management for secondary testicular failure had been validated by 1990: injecting "replacement" gonadotropic hormones was proved to restore testicular function.48 A much simpler solution is available.
In the mid-1990s, the drug clomiphene – commonly given to sub-fertile women to stimulate their hypothalamic function – had been shown to restore testosterone production in men with secondary hypogonadism.49-51 This use of clomiphene has now been studied many times and some two dozen reports published.52 Practitioners and researchers observe (predictably) that clomiphene treatment does not shrink the testicles, as may TRT – and it can restore, rather than impair, male fertility.53
Clomiphene is a nonsteroidal estrogen-receptor modifier (SERM). The drug alters the negative feedback estrogen exerts on the hypothalamic "assay office" to increase its "appetite," and thus its release of gonadotropin releasing hormone (GnRH).54 GnRH stimulates the pituitary to produce more LH and FSH, which drive gonadal function (in this case, testicular) and thereby testosterone production. Interestingly, clomiphene is observed also to increase the important ratio of testosterone to estradiol in obese men.55
The safety of clomiphene treatment has been reviewed. One report affirmed that it significantly increased serum testosterone and symptom scores with no adverse effect on PSA or hematocrit.56 If fertility is not desired, its common restoration of motile sperm production could be considered a disadvantage. No report of neoplasms stimulated by therapeutically elevated gonadotropins, of a male version of ovarian hyperstimulation syndrome, or of the visual disturbances reported by up to 10% of female users was found in the literature reviewed.
Clomiphene is recommended as "the drug of choice" for secondary hypogonadism by writers in the Asian Journal of Andrology, but its use in the US is considered off label.57 The lightly regarded authors of Wikipedia opine: "…clomifene (British spelling) is now a generic medication in most markets; it is unlikely that a drug company would pursue FDA approval for use in men now because of limited profit incentive."58 They correctly add, however, that a single isomer of clomiphene is under phase III trials for men.59,60 Since a number of phytochemicals have known SERM effects, the efficacy of some in this role also seems plausible.
Certainly, men with primary hypogonadism (without testicular function) cannot respond to clomiphene-induced gonadotrophic hormones. Some clomiphene trials have reported that older men were less responsive and produced less testosterone than did younger men.49,50 This reduced response is likely due to deterioration of the aged testicles.
However, the practitioner should remember that testosterone replacement itself can render the testicles atrophic and dysfunctional, if it has long suppressed pituitary gonadotrophic hormones.42,61 Even modest testosterone replacement for men with secondary hypogonadism is expected to depress their dysfunctional HP-T axis, as seen in Case 2. If his testes had not been atrophic prior to treatment, it seems inevitable that they would be after the years of testosterone replacement.
Reviewing the "blogosphere," one can find considerable discussion of uncomfortably delayed response when men switch from TRT to clomiphene. The time required for atrophic testicles to respond to renewed stimulation is apparently variable and is discussed in a recent review.57 Further studies would be useful, and Case 2 exemplifies this issue.
Case 2 revisited
Case 2 had inappropriately low-normal LH and FSH values in 2008 before using TRT, and these gonadotrophic hormones were fully suppressed with TRT in April 2016. Doc advised the man against a commonly advocated practice of stopping TRT for 2 weeks to "wake up" the hypothalamus – his wasn't working well in the first place! Doc also discouraged the use of a large clomiphene dose to "jumpstart" the testes (Doc is not a morning person himself and prefers to wake up gently).
Instead, they agreed to dose clomiphene just 25 mg (½ tablet) every other day – and at the same time, to cut his testosterone topical dose in half. After 1 week of this new regimen, Case 2 was relieved that he felt no worse. Optimistically, he then completely stopped his testosterone. Unfortunately, he had forgotten Doc's instruction to add back ¼ dose of TRT in the event that he felt worse – for he did indeed.
In less than 1 week without TRT, Case 2 had lower energy and felt weaker; his libido was lost and he developed erectile dysfunction (ED). He tried to "tough it out" but had to ask for help. This triggered blood tests, done after 4½ weeks on clomiphene and 2½ weeks without TRT (6.10.2016). He reviewed the results with Doc on June 14, 2016. By then, his energy and all symptoms had already improved, though some degree of ED lingered.

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