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The clinical importance of 5alpha-reductase in human health and pathology: Part 1: men, testosterone replacement, and stress.

Introduction

Men and women have the same sex hormones, made from cholesterol by our ovaries or testicles and adrenal glands. The body assumes male and female forms depending on how much of which hormone we make. This net effect is determined by enzymes, which produce our hormones and subtly "fine-tune" the messages that they deliver. One such critical enzyme is 5alpha-reductase (5[alpha]-R): When its effects go awry, the consequences can be dramatic--altering the body via its sex hormones and the nervous system through its neurosteroids.

In this report, men whose testosterone replacement is inappropriately 5[alpha]-reduced are examined, as are their treatment options and outcomes. The normal physiology of sex hormones involved with these cases is discussed, as are the causes of the problems and their solutions. The new frontier of 5alpha-reduced neurosteroids is next considered and relevant clinical literature is cited. Finally, women's abnormal 5alpha-reduced neurosteroid production and its causal relation to premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), and dysmenorrhea is introduced, cases of which will be studied in the upcoming companion to this article.

Men's Testosterone Replacement: Case 1

Case 1 is a 36-year-old former professional athlete with autoimmune hypothyroidism and combined-type hypogonadism: low free testosterone but midrange normal gonadotrophic LH and FSH. Despite testosterone replacement therapy (TRT) with the maximum recommended dose of transdermal testosterone gel, 1.62% (4 pumps = 81 mg topically q.d., of which 10% is absorbed), he still had symptoms, including hot flashes, reduced libido, and episodic anxiety. He perceived his muscle mass reduced, despite vigorous daily workouts at the gym. Worse still, vertical diplopia had recently begun and it resisted diagnosis by a neuro-ophthalmologist. Were these complaints due to thyroid or testosterone--or something not revealed by his MRI?

He saw Doc for a thyroid tune-up. Although his immune system interfered with the free T3 test by RIA, the new dialysis, LC/MS-MS (ED/MS) method--not an immunological assay--showed how to achieve his best dose. With his thyroid treatment adjusted, the sex hormone levels in November 2014 looked acceptable (Table 1, p. 55.).

His diplopia and symptoms were greatly improved, but the man still felt subpar. Believing that he needed more testosterone, he increased his dose to 5 pumps, or 10.1 mg topical testosterone, daily--in excess of the manufacturer's recommended upper limit. (1) After a brief improvement, he relapsed and within 6 months felt awful--as bad as he ever had! Even his puzzling vertical diplopia had fully relapsed. His repeated blood test results were revealing.

The thyroid values looked fine, but his sex hormones were a bit of a shock: Estradiol (E2), total testosterone (tTEST), and free testosterone (fTEST) were all low. In contrast, his dihydrotestosterone (DHT) was high and the ratio of tTEST/DHT (comparing "total" with "total" measures) was only 2.4--normally 9 to 12 (Table 1). (2) Had the prescription hormone expired or been degraded? He got a fresh refill and repeated the tests: These results looked even worse. His LH and FSH were checked this time and were both low, too. Despite applying more testosterone, his sex hormone levels had fallen precipitously. Doc wondered, why?

Contritely, Case 1 reduced his dose to 4 pumps but a month later felt no better, as confirmed by blood tests using ED/MS to rule out more immune interference. The tests consistently showed that his testosterone was being converted excessively to DHT. Doc found evidence that DHT can suppress the hypothalamus and thereby sex hormone production; apparently Case 1's high DHT had blocked his LH and FSH. (3-5) Again, why?

A clue suggested the answer: His shoulders, to which he habitually applied the gel, had become excessively hairy. The factor responsible for this unpleasant turn of events is the enzyme 5[alpha]-R. A brief review of physiology is indicated.

Testosterone: Basic Sex Hormone Physiology

Surfing the web might lead one to believe that testosterone is the omnipotent conveyor of all things manly. It is not. Although androgenic (from the Greek, "creates men"), testosterone is best described as a prehormone. It offers itself on the altar of Differentiation to be converted either to estradiol and feminize women (via the enzyme aromatase, CYP19A1)--or conversely, by 5[alpha]-R to DHT, to the most powerfully masculinizing hormone. (6)

Compared with testosterone, DHT is about 10 times more potent at the androgen receptor (AR) in affecting its role to activate DNA transcription: DHT "fits" better to the AR, so it both stays bound longer and stimulates the receptor more strongly. (7-10) This gives a biological benefit: In contrast with the two known estrogen receptors, there is but a single AR--the activity of adjacent 5[alpha]-R (or its lack) is an important means by which our body "diversifies" androgen signaling. (9)

In the developing fetus, sex hormones have important roles. In the male child, "weak" testosterone directs the development of most male internal sex organs, while the more potent DHT produces the external genitalia and prostate gland. The fetal brain is affected by sex hormone surges at circumscribed stages, and abnormalities of their timing or intensity are reported to influence children's subsequent development and behavior. (11-16) Production of DHT is generally curtailed between the toddler years and puberty. Then, our bodies assume adult forms.

Converting testosterone to DHT provides a "one-way ticket to Macho City." Unlike testosterone, DHT cannot be aromatized to estrogens. (17) However, we have seen that DHT is indeed able to feed back upon the hypothalamus (brain) to block the production of LH and FSH and thereby inhibit the production of all sex hormones. (4,5) After DHT has served its function, it is eliminated--mostly by the liver (at which it arrives via blood, so blood tests are valid). Its breakdown products can have subtle effects, though not relevant to this discussion.

The Enzyme 5alpha-Reductase: Part 1

Enzymes are proteins (generally) made by the human body to hasten the conversion of a particular precursor (or substrate) into something different, a "product." Enzymes are coded in the DNA genome. By producing, activating, and degrading enzymes, the body controls its own structure, function and indeed, existence. The marvelous means by which all this is regulated evokes the Psalmist: we are fearfully and wonderfully wrought.

5[alpha]-R was discovered in 1951. It cuts a double bond between the #4 and #5 carbon atoms in the A ring of its substrate steroids ("made from cholesterol") (Figure 1). Some of these are hormones--not just testosterone, but also progesterone, Cortisol, and aldosterone. Others include hormone precursors (androstenedione, deoxycorticosterone) and metabolites (epitestosterone). (7)

The significance of 5[alpha]-R began to be appreciated in 1968, when its deficiency in men was proved to cause the rare and extreme genetic condition male pseudohermaphroditism. (18) We now understand that its importance is much greater. (19 20)

There are three variations (isoforms) of 5[alpha]-R (types 1-3), and two other proteins have similar effects. All five of these are shared by every eukaryotic organism-which can be quite primitive. (7) This suggests that their importance is great. The importance for practitioners that these enzyme types respond differently to sundry pharmacological blockers will be discussed in Part 2 of this article.

These isoforms of 5[alpha]-R are expressed quite specifically in diverse tissues, and they vary with developmental age, to supply key locations with their products at the time that they are required. In the fetus, these tissues include the prostate, skin (genital development), and brain. (7) The neonate widely expresses types 1 and 2, but after age 18 months, there is little 5[alpha]-R in the skin until puberty. Adult humans express 5[alpha]-R; men make far more than women.

The importance of an enzyme can be evaluated by studying animals--or humans--lacking it. Type 1 5[alpha]-R deficiency is not identified in nature, but engineered knockout mice have weak muscles and reduced bone mass. (21) Type 2 deficiency gives men pseudohermaphroditism with ambiguous external genitalia and no prostate gland. (18) Women, though, show few effects: reduced body hair, no acne, and high testosterone/DHT ratio. (22) Humans without type 3 are severely retarded, with brain and eye defects indicative of a glycosylation disorder. (23)

Laboratory Tests for 5[alpha]-Reductase Activity

Commercially available laboratory tests can clinically indicate whether a person's 5[alpha]-R activity is appropriate for their sex: men have more, women have less. Blood tests are used to find the ratio of tTEST to total DHT. In healthy men, this tTEST/DHT ratio is said to fall between 9 and 12. (2) From normal reference intervals and clinical observation, it may be argued that women's normal tTEST/DHT value is about 2.

A second laboratory metric is the balance of 5alpha- to 5beta-reduced steroid metabolites (e.g., androsterone to etiocholanolone) in GC/mass-spec studies of 24-hour urine. Men have more 5alpha; women have more 5beta. This method has been employed in published research, and the tests are available to practitioners from several American reference laboratories, at least some of which routinely report a calculated 5[alpha]/5[beta] balance. (24-27)

Case 1 Revisited

As hinted by his hairy shoulders, Case l's skin is the probable source of the 5[alpha]-R that so thoroughly reduced his applied testosterone to DHT. Beginning shortly after conception, human skin produces 5alpha-reductase. Indeed, skin cells contain enzymes needed to produce every steroid hormone--and can contribute significantly to levels of circulating steroids. (28)

Clinicians: Case 1's problem is not unique. An early study of topical testosterone therapy found that although its use increased blood testosterone, patients' DHT gained relatively even more ... and their tTEST/ DHT ratio decreased with transdermal TRT. (2) The skin is implicated also in similar results from other studies: another of transdermal use and one of subcutaneous (pellet implant) TRT. (29,30) The latter group reported high levels of DHT persisting for more than 100 days.

Case 1 had such dramatically abnormal blood tests because high DHT levels depressed his hypothalamic-pituitary LH and FSH production. This caused low testosterone, low estradiol, and the lack of their important effects. He felt bad because, yes, men also need the beneficial effects of some estrogen. (31) Besides the milder androgenic effects of testosterone at the androgen receptor, its local conversion to estradiol has significant trophic effects on vascular endothelium, bone, and possibly other tissues. (32-35)

Elevated DHT can have other, less dramatic side effects which complicate men's testosterone replacement. These include erythrocytosis, the overproduction of red blood cells and vascular events from the consequently viscous, "sludgy" blood. (36,37) There are complex relationships between testosterone, DHT, and prostate cancer as well, which also call attention to the role of proper sex hormone balance. (38-40)

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 5[alpha]-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 5[alpha]-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 5[alpha]-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 5[alpha]-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 5[alpha]-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 mlU/mL (Rl: 1.7-8.6) and 3.8 mlU/mL: (Rl: 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 (Rl: 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).

For a few years, he also took 0.25 mg anastrozole (1/4 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 5[alpha]-R, not simply an excess of testosterone.

Having learned about 5[alpha]-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 5[alpha]-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 subfertile 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 gonadotropic 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 (Yi 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 1/4 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 4 1/2 weeks on clomiphene and 2 1/2 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.

The test results showed strong hypothalamic-pituitary response to the small clomiphene dose of 25 mg every other day: LH and FSH values were both high (Table 2). In response to the elevated gonadotropic hormones, his total testosterone--288 ng/dL--was only 72% of the previous therapeutic value. However, this amount was greater than before he started TRT ... and higher even than one of his earlier levels while using TRT. Most importantly, his free testosterone (10.1 pg/mL) was normal and the highest it had been in years!

Had his testicles atrophied during TRT, or did Case 2 have combined-type hypogonadism--or does clomiphene suppress his hepatic SHBG synthesis? Although resuming a small dose of TRT was discussed, Case 2 declined; he had improved so much while waiting for the test results that he opted to continue without any: he felt confident that his testicles would increasingly respond to the gonadotropins.

His confidence was validated on the next set of tests in July 2016. With LH and FSH values still a bit elevated, both total and free testosterone values were normal (Table 2). The ratio of tTEST/DHT is again normal at 12.3, and all his androgens, including DHT, are expected to continue to increase as LH and FSH "rehab" his gonads. Currently, he pays $25 monthly for clomiphene, compared with $85 to $150 monthly for compounded testosterone from various pharmacies.

5alpha-Reductase: Part 2: Further Actions

There are other significant roles for 5[alpha]-R beyond sex hormone metabolism and prostate cancer. As above, its substrates include other steroid hormones, their precursors and even metabolites ("breakdown products"), and endocrine modification is a key 5[alpha]-reductase function. (7)

Aldosterone, when 5[alpha]-reduced, becomes even more potent in signaling the kidney to retain salt and raise our blood volume (and blood pressure). In contrast to its effects on this hormone and testosterone, 5[alpha]-R significantly reduces the potency of Cortisol. Ultimately, the same goal is achieved, though: signaling is diversified at each hormone's single receptor. (62,63)

5[alpha]-reductase takes progesterone remarkably farther, with very different consequences for men and women (the subject of the companion article). It is well known that sex hormones are "neutrally active": They alter our brain function, including our affect, thoughts, and behavior; in addition, they are neuroprotective. (64,65) Sex hormones made in the body easily enter the brain and make us act, well, hormonal.

5[alpha]-R Makes Neurosteroids

Yet some steroid hormones influencing our brain are made within the brain itself, which like the skin (its embryological progenitor) possesses all the enzymes needed to make any steroid hormone de novo from cholesterol. (66) These products are termed neurosteroids, and they are not controlled by hypothalamic-pituitary regulation. (67) Progesterone enters this "realm" of neurosteroids via 5[alpha]-R and an acquiescent companion enzyme, 3[alpha]-hydroxysteroid dehydrogenase (3[alpha]-HSD; also called 3[alpha]-oxidoreductase to confuse casual readers).

In two steps, of which 5[alpha]-R is rate-limiting, these enzymes convert progesterone within the brain to the polysyllabic neurosteroid 3[alpha],5[alpha]-tetrahydro-progesterone (also called allopregnanolone, or simply "ALLO") --see Figure 2. (7,66,67) An aldosterone precursor, deoxycorticosterone is converted by the same enzymes to a neurosteroid with similar effects called 3[alpha], 5[alpha]-tetrahydro-deoxycortone (THDOC). We shall focus on ALLO.

This key enzyme 5[alpha]-R is found together with 3a-HSD in neurons and glial cells within brain regions critical for mood, emotion, and sexual activity--no coincidence. (67,68) Their neurosteroid products, ALLO and THDOC, travel via autocrine, paracrine, or transmembrane diffusion to influence the neuronal GABAA-receptor (GABAA-R). (69) It is this receptor upon which the neurotransmitter GABA, benzodiazepines, barbiturates, and ethanol all exert their similar--and synergistic--effects. (70)

In binding to the GABAA-R, ALLO and THDOC potently enhance GABAergic inhibitory effects and influence the contrasting balance between GABA and glutamatergic (stimulatory) transmission. (67) These neurosteroid effects are regulated and modified by the actions of local enzyme production and degradation, counteracting neurosteroids (e.g., 3[beta]-THP) and the opposing effects of neuroactive steroids from the body. (65,66-68,72-73)

Under acute stress, effects of the GABAA-R inhibit hypothalamic corticotrophin-releasing factor (CRF) release, causing reduced anxiety and stress-behaviors. In rats and mice, infusions of the neurosteroids ALLO and THDOC into the brain enhance this GABAA-R activity, adding to its calming, protective effect. (74-76) Neurosteroids--especially ALLO--are thought to help adjust, even "program," the HPA-axis response to stress. (66)

With evidence that infusing ALLO into animal brains reduces anxiety and stress-behaviors--and even mitigate seizures--it is logical to ask whether deficient ALLO is related to human mood disorders. (67) Evidence shows that it can be. Circumstantially, we know that drugs used as antidepressants enhance neurosteroid levels, including clonazepine and olanzapine, lithium, fluoxetine, and some atypical anticonvulsants (valproate, lamotrigine, and carbamazepine). (77)

More directly, low ALLO is linked to dysphoria in a study by Kilts et al. from the Durham VA Medical Center. Observing that nearly half of returning veterans experience persistent pain postdeployment, they studied the first 90 male US military veterans to have blood drawn upon entering the Mental Illness Research, Education and Clinical Centers (MIRECC) Registry. They found low ALLO blood levels significantly associated with increased pain perception. (20)

Why do these men have low ALLO? Possible explanations are a lack of 5a-reductase activity or, more likely, deficient progesterone as substrate. ALLO is reported to match progesterone levels throughout women's cycles. (78,79) The men's chronic stress may be related to low progesterone. Progesterone is also the precursor of Cortisol, the most important steroid and arguably the central hormone made in the stress response. (80) It is popularly argued that progesterone can be depleted by producing Cortisol in chronic stress states, known as "progesterone steal." Personal experience with patients supports this idea, though there is a paucity of published literature.

An intriguing possibility is raised: if treatment for ALLO deficiency were to be offered, supplying progesterone would be a physiological method. This has been done successfully at Yale, in a study of people stressed by cocaine addiction. (81) It may not even be necessary to determine whether the veterans' pain was due to low ALLO or the lack of progesterone's valued neuroprotective effect. (82) The authors' clinical experience suggests exercising caution in dosing men; however, as progesterone blood levels greater than 2 ng/mL can lead to increased abdominal adiposity and some gynecomastia.

Adding another layer of complexity, GABAA-receptor sensitivity to neurosteroids (and drugs) can be adaptively altered in response to prolonged changes in neurosteroid levels. (83,84) In response to different types and amounts of stimulation, the receptors' subunit composition, phosphorylation state, and indeed total population can be altered--and then may return to their original state as circumstances allow. This also seems to be relevant for chronically stressed humans and women in particular.

"Inappropriate" neurosteroids may be related to dysfunctional GABAergic transmission, and increased susceptibility to stress and developing psychiatric disorders. A recent paper states: "Altered expression of steroidogenic enzymes may warrant future detailed investigations." (66) As we've seen, 5[alpha]-reductase is a critical, rate-limiting neurosteroidogenic enzyme and it is worthy of attention.

Summary

Men and women have the same sex hormones, in differing amounts and relative ratios--vive la difference! Enzymes produce and process our hormones, controlling our physical form, and strongly influencing our moods, thoughts, and behavior. 5alpha-reductase is a critical enzyme that plays a role almost from conception. It strengthens the effects of testosterone and aldosterone and mitigates the strength of Cortisol. It provides neurosteroids that alter the critical balance of neural stimulation and inhibition.

Oral testosterone replacement is ineffective because of the hepatic "first pass," which converts the testosterone to estrogens or DHT. It is now clear that the skin itself can have a first-pass effect. When transdermal testosterone replacement inappropriately induces 5[alpha]-R, consequences range from mild to drastic hormone imbalances and, when left uncorrected, can reduce life expectancy. This acquaintance with 5[alpha]-R provides an introduction to neurosteroids, a new frontier in psychoneuroendocrinology. Men with robust 5[alpha]-R activity but limited progesterone substrate may suffer from the lack of 5[alpha]-reduced neurosteroids.

Segue to Women

The sequel to this article will review the importance of 5[alpha]-R and ALLO among women, whose problems can be both similar to and the opposite of men's. Consider an old puzzle: PMDD, PMS, and postpartum depression (PPD) are obviously associated with changing steroid sex hormone levels. However, all searches for a causal sex hormone abnormality yielded only a "frustrating lack of evidence." (85) Through case presentations and literature review, it will be seen that investigating not just DHT but neurosteroids as "affective switches" is very rewarding. 5[alpha]-reductase blockers--even a simple herbal treatment--offer substantial relief for suffers of PMDD/PMS and dysmenorrhea. (19)

Speed of loss of testosterone-producing Leydig cells from age 18 to 804:

115,000 Leydig cells net loss per year

300 Leydig cells net loss per day

15 Leydig cells net loss per hour

1 Leydig cell net loss every 4-5 minutes

Why not use the pharmaceutical brands of testosterone gel available in prescriptions at any pharmacy?

The usual brands of testosterone gels at 1% take more time to apply (per 5 grams) and are just too poorly concentrated to reach satisfying levels in most patients. The persistence of pharmaceutical companies in keeping concentrations low is explainable: a desire to avoid at all costs getting their names cited with regard to testosterone abuse by athletes.

Liposomal formulation makes testosterone penetrate the skin better.

Correct use of a transdermal testosterone gel

* How to proceed? Apply the testosterone gel to the skin in four successive thin layers by intensively rubbing the testosterone into the skin in between the application of each new layer. When a thin layer of testosterone is applied, the alcohol of the gel easily evaporates, and the evaporation cools the skin, which reacts by the vasodilatation of the arteries and the opening of the capillaries in the skin. This stimulation of the skin's blood vessels helps the skin to absorb the testosterone more effectively. Applying a thick layer of the testosterone gel to the skin does not permit the alcohol to evaporate and open up the blood vessels. Furthermore, the alcohol that remains on the skin--imprisoned in the thick layer--dries the skin and irritates it.

* Where to apply? Apply the testosterone gel to hairless skin with high absorption capacity, such as the forehead, the sides of the neck, and above the collarbones--areas where we flush with emotion because of their greater number of blood vessels, thereby facilitating absorption.

* Avoid hairy areas Avoid applying the testosterone gel to areas with a lot of body hair, such as the beard or a hairy chest. Otherwise, the testosterone will turn into dihydrotestosterone, the male hormone that promotes body hair growth but makes men lose scalp hair. Hairy areas, such as the beard and mustache, for example, are rich in 5-alpha-reductase, the enzyme that converts testosterone into dihydrotestosterone.

Notes

(1.) AndroGel 1.62% (testosterone)--Full prescribing information [web page]. PDR.net. http://www.pdr.net/full-prescribing-information?druglabelid=5. Accessed June 27, 2016.

(2.) Cunningham GR, Cordero E, Thornby JI. Testosterone replacement with transdermal therapeutic systems. Physiological serum testosterone and elevated dihydrotestosterone levels. JAMA. 1989 May 5; 261(17):2525-2530. PMID: 2704112.

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by Alan McDaniel, MD

Alan McDaniel, MD, is a 1977 Tulane University medical graduate. He trained in general surgery and emergency medicine before becoming board-certified in otolaryngology with subspecialties in neurotology and allergy. He has practiced privately since a two-year faculty appointment at the University of Louisville. He has presented at various national meetings in the US (AAO-HNS, AAOA, ANS, AAEM, IFM, PA AS) and Mexico. His topics have included otology and neurotology, allergy, chronic fatigue, and endocrinology. He has been a faculty member for the American Academy of Otolaryngic Allergy Basic and Advanced Courses and for the American Academy of Environmental Medicine. His two-day course "New Endocrinology" has been presented at the AAEM and elsewhere since 2005, to physicians from five continents. Work with dizziness and allergy in the 1980s led Dr. McDaniel to seek solutions for chronic fatigue syndrome. In turn, these investigations extended to the endocrine aspects of this and related conditions. Since basic surgical training emphasizes the need to know several alternative approaches to an operation, he saw the logic of studying integrative and controversial medical methods. He has endeavored to understand these in the light of new facts from research, mindful that medical history shows innovation begins as a minority opinion. He is excited that applying new research to patient care offers solutions to many of the chronic and worsening problems that are epidemic in modern society.

Table 1: Case 1 Steroid Sex Hormone Test Summary

                      11:09         11:32        11:04
Test:                 11.24.14      5.14.15      6.26.15

Estrone
Reference Interval

Estradiol             16.4          < 5.1 L      12.2
Ref. Inc.             7.6-42.6                   Same

Progesterone          0.6           0.6          0.6
Ref. Inc.             0.2-1.4       Same         Same

total Testosterone    40.8          234 L        157 L
Ref. Inc.             348-1197      148-1197     Same

Free Testosterone     10.8          2.0 L        4.1 L
Ref. Inc.             8.725.1       Same         Same

DHT                                 96 H         151 H
Ref. Inc.                           30-85        Same

Ratio   E1/E2
        E2/P4         27.3          < 8.5 (L)    20.3

Ratio   tTest/E2      24.9          > 45.8 (H)   12.9 (L)
        LH/FSH        3.6/2.5                    0.6L/1.11

Other   DHT/E2        Ra Dom 1.4H   18.8 (H)     12.4 (H)

Taking:               Androgel      Androgel     Same
* Units No 1          1.62% x 4     1.62% x 5
Reconciled            8.1mg/d       10.1mg/d
                      54.7 mg/wk    70.7 mg/wk

                      By RIA           By ED/MS     11:24
Test:                 7.28.15          7.28.15      8.25.15

Estrone
Reference Interval

Estradiol                                           14.9
Ref. Inc.                                           7.6-42.6

Progesterone                                        0.8
Ref. Inc.                                           0.2-1.4

total Testosterone    184 L            240.2 L      591
Ref. Inc.             548-1197         548-0.1197   Same

Free Testosterone     8.4 L            6.32         14.6
Ref. Inc.             87-25.1          5.00-11.00   8.7-25.1

DHT                                                 30
Ref. Inc.                                           30-85

Ratio   E1/E2
        E2/P4                                       18.6

Ratio   tTest/E2                                    39.7
        LH/FSH                                      0.1L/<2 L

Other   DHT/E2                                      DHT/E2 2.0

                      %Free T-
                      2.63 (1.5-4.2)

Taking:               1.62% x 4        Same         T cyp q wk
* Units No 1                                        0.3cc-60mg
Reconciled                                          Day #4 1/2
                                                    Mid-dose

                      8:28         12:19
Test:                 9.25.15      11.11.15

Estrone
Reference Interval

Estradiol                          20.8
Ref. Inc.             Same

Progesterone          n/t          0.7
Ref. Inc.                          0.2-1.4

total Testosterone    3.67         788
Ref. Inc.

Free Testosterone     7.3 L        22.9
Ref. Inc.             Same

DHT                   2.3 L        41
Ref. Inc.             Same

Ratio   E1/E2
        E2/P4                      29.7

Ratio   tTest/E2      32.5         37.9
        LH/FSH        0.1L/<2 L

Other   DHT/E2        DHT/E2 2.0   DHT/E2 2.0

Taking:               Same         T cyp q 3.5d
* Units No 1                       15cc-30mg
Reconciled            Day #7       Day #2 30h.
                      Trough.      Mid-dose

Table 2: Case 2 Steroid Sex Hormone Test Summary

                       12:59      13:26      15:21       15:29
Test:                  7.29.08    11.5.06    6.30.09     8.20.09

Estrone                61         71         44
Reference Interval     12-32      Same

Estradiol              30         29         20          31
Ref. Int.              0-53       Same

Progesterone           1          0.8        0.7         0.8
Ref. Int.              0.3-1.2    Same

total Testosterone     197 L      2151       470         620
Ref. Int.              241-827    Same

free Testosterone      6.1 L      7.5        12.9        22.3
Ref. Int.              6.8-21.5   7.2-24.0   Same

DHT                                          100 H       77
Ref. Int.                                    30-85       Same

Ratio    E1/E2         2          2.4        22
         E2/P4 *       30         32.5       28.6        38.8

Ratio    tTest/E2 *    6.6        7.4        23.5        20
         LH/FSH                   1.5/3.8

         tTest/DHT

Taking:                           CytoAD     CytAD 2+2   CytaD 1+1
* Units Not                       2+2        No DHEA     No DHEA
Reconciled                        DHEA 25    T-gel 1%    Same
                                  Walmart    4 pump/d    3pump/d
                                             anattro2.   Same
                                             0.25mg/d

                       13:42       13:29         13:07
Test:                  2.16.10     4.17.15       4.8.16

Estrone                54
Reference Interval

Estradiol              10.8        27            16.9
Ref. Int.              7.6-42.6    Same

Progesterone           0.5         0.6           0.8
Ref. Int.              0.2-1.4     Same

total Testosterone     274 L       568           396
Ref. Int.              280-800     348-1197      Same

free Testosterone      8.8         9.8           7.8
Ref. Int.                          7.2-24.0      Same

DHT                    36          93 H          132 H
Ref. Int.

Ratio    E1/E2         5
         E2/P4 *       21.6        45            21.1

Ratio    tTest/E2 *    25.4        21            23.4
         LH/FSH        1.1L/4.0                  0.1L/0.4L

         tTest/DHT                 IT/DHT 6.1L   IT/DHT = 3l

Taking:                CytaD 0+2   CytaD 2+2     CytaD 2+2
* Units Not            No DHEA     No DHEA       No DHEA
Reconciled             Sime        Tin crm.      Tin cnm.
                       Sime        200mg/mL      200mg/mL
                       Same        0.75ml/am     0.75ml/am
                                   No Anast.

                       13:14         13:29
Test:                  6.10.16       7.20.2016

Estrone                89 H          129 H
Reference Interval     11-72         Same

Estradiol              24.3          30.8
Ref. Int.

Progesterone           0.8           0.8
Ref. Int.

total Testosterone     288 L         356
Ref. Int.

free Testosterone      10.1          8.3
Ref. Int.

DHT                    N/T           29 L
Ref. Int.

Ratio    E1/E2                       4.2
         E2/P4 *                     38.5

Ratio    tTest/E2 *    11.9 (L)      11.6 (L)
         LH/FSH        16.9H/23/OH   13 OH/23.3H

         tTest/DHT                   IT/DHT 12.3

Taking:                CytaD 2+2     Same
* Units Not            No DHEA       No DHEA
Reconciled             No TRT        No TRT
                       Clomiphene
                       25mg qod      25 x4/wk


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Please note: Some tables or figures were omitted from this article.
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Author:McDaniel, Alan B.
Publication:Townsend Letter
Article Type:Clinical report
Date:Dec 1, 2016
Words:9501
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