Tag Archives: subcutaneous

SEX HORMONE BALANCE FORMULA

2009/12/23 Chris Hatlestad <docgenki@yahoo.com> writes:
I came across an older response to a testosterone question on the FACT website where you responded with a formula for the T:E2 ratio or A:E ratio.  I have been following the FAI or free androgen ratio which is s-T*0.0347/SHBG with normal 0.7-1.0 and find most everyone low.  However, I like the A:E ratio concept.
What is the 30 that you multiply to the s-T?.  Also, I am typically measuring total estrogens which is E2+E3.  What about using this number and including DHEA-s in the equation for a true A:E ratio.
Also, do you do any hormone implants and if so, how do you calculate or guestimate dosing, men or women?  Sourcing for the implants beyond College Pharm?
Thanks
Chris Hatlestad, MD
Integrative Medicine & Family Medicine, Center for Environmental Medicine
10748 NE Halsey Street  Portland, OR 97220
503-261-0966 (office) 503-252-2691 (fax)
docgenki@yahoo.com
www.cemmed.com

hi Chris,
thanks.
in the SI unit scale (which USA proposed switching to, then reneged on!), basal SHBG averages about 20-30 nmol/L.  So I correct the A:E ratio back to  a basal normative SHBG of 30… SHBG  binds  1000 times more to TT than  it does to estrogen… hence the higher the SHBG, the lower the free androgen ie FAI relative to estrogen. The FAI alone ignores estrogen.  Its like ignoring T3 level in assessing thyroid function- one need the whole axis eg T3 xT4/TSH. .

on the one hand I prefer to use E1+E2+E3.
On the other, we can no longer get S- E1 measured here, there is too little demand .  and remember that empirically, it is said that E2 is about ?7 times as potent as E1 and 80 times as potent as E3.
similarly, all the other androgens would have to be brought into the calculation at their disparate   androgenic potencies.  So for cumulative functional effect one would  have a complex formula factoring in the potencies.

Hence, KISS- keep it simple –  s-T x 30/ (E2 x measured SHBG).
DHEA is of course one parent hormone, and one never knows how far it is going to convert to androgens vs estrogens. So I measure it if affordable- but like Wiebke Arlt,  find it useful to replace only in the old.  at least with 7keto DHEA one knows that it cannot be bioconverted back to TT or estrogen- it is simply a weak androgen.
My late inspiration, breast surgeon Dr Roald Maartens here used a formula of 12 hormones for managing (pre)cancer hormone-related diseases. But  not even experts  like Leon Speroff,  Bill Creaseman or David Dent could help him validate and spread his program. I tried to get his thesis validated and published posthumously, but his family jealously decided to let it die with him rather than risk someone else stealing his glory… such is science.

I have an English  copy of his unpublished MS, but I cant find anyone who can understand the dense math. His brilliant son helped him with the computer formulae and the program that one of his acolytes still uses blindly, but as I say they blocked my offer to help spread his concept.

I gave up using profitable implants 20 years ago since they may be beneficial and acceptable for many patients, but have a double digit failure/complication rate; are costly; are dependent on how tightly they are compacted ie have widely varying release time- E2 perhaps 6 to 24 months, TT perhaps 3-4 months.

When I first met the woman (whom I married 4 years later), the local Emeritus Professor of Gyne had given her 300mg E2 and 150mg TT in 3 successive implant sessions in 5 months, turning her from chronic fatigue into a bloated over-estrogenized wreck. He never could explain why he defied physiology (as was taught by eg Hans Selye over 60 years ago),  instead of giving her- as is normal with implants – at least twice as much TT as E2. (He is still bravely working in the local University menopause Clinic at over 80 years of age).   Her s-E2 level was over 3000 pmol/L while her s-T was only about 6nmol/L. Since it is major hastle trying to dissect out implants, I simply balanced the excess E2 with depotestosterone injection every fortnight till her s-E2 dropped below normal after 2 years, since when (now aged 63 years) she has been happily on fortnightly sc  20mg:1mg  TT:E2 depot injection a la William Masters & Grody’s 1953 formula. . If we had someone to make progesterone implants here, I would have used combined progesterone estradiol and testosterone implants, as Mannie Schleyer-Saunders in London did for decades with excellent results. You have brave compounding pharmacists there who do so,  so go for it with triple implants or triple subcutaneous depot-sexhormone  self-injection!

go see if you can get Leon Speroff there interested again in Maartens’ formula?   I am delighted to see that Dr Speroff  is still publishing prolifically, now validating depot hormones subcutaneously as I have been advocating at international congresses the past 6 years, and on this column.
Seasons Greetings- take care!

ndb  in sunny Cape Town

ANABOLIZING THE FAINT-HEARTED WITH PHYSIOLOGICAL TESTOSTERONE REPLACEMENT

Some 2600 years after the first recorded therapeutic use of  human hormone replacement (in China), and about a century after the first modern hormone use, two new landmark trials with Nebido long-acting testosterone undecanoate DEPOT injection confirm testosterone’s  major  cardiovascular CVS Benefits:

an elegant trial by Guiseppe Rosano’s team at University Rome – Testosterone Benefit on Functional Exercise Capacity, Insulin Resistance, and Baroreflex Sensitivity in Elderly Patients With Chronic Heart Failure;

and Kevin Channer’s 12month trial in Sheffield UK Long term benefits of testosterone replacement therapy on angina threshold and atheroma in men . These confirm the heart-healing benefit of human testosterone replacement, as  we have seen for years in practice.

These findings are in striking contrast to solo estrogen supplement, which greatly improves vasodilation and thus perfusion and hypertension, but has no demonstrable benefit on general muscle or myocardial strength and mass, or arrhythmia; but increases fat mass including in muscle. (Our) metanalysis of all studies with oral estrogen +- progestin confirm   Aloia’s landmark 1995 study,  s that oral estrogen supplement  reduces lean mass (by perhaps 2kg/year)  but increases fat mass (by about 2.5kg/year), the net effect being steady weight gain of about 1/2 kg/year -which gynecologists dismiss as irrelevant, although it turns well women into dumplings- fatness frailty.

Microbiologist Dr Paul de Kruif (1890-1971) was perhaps the first to write the history of the developmental studies on testosterone The Male Hormone (1945) describing exciting clinical experience with it already before WW2 in the hands of medical scientists like Drs  Hammond, Werner  and Lalouche.

Einfeld details the first studies showing testosterone  benefit on CVD published in 1939. And Charbot ea from Paris have just confirmed what Gimeno ea first published from Univ California in 1963, that testosterone is a potent atrial antiarrhythmic drug -which partly explains why older women – normally with  serum testosterone, and testosterone:estrogen ratio only ~ 1:10th  of that of men-  are far more at risk of torsades arrhythmia and CVD in general than men.

William Masters and team had already in 1953 reported in the first RCT of human  bioidentical HRT the dramatic global benefits of injectible testosterone-estrogen even well after 70years of age  in already-institutionalized patients- as he called them, the Third Gender, those neutered by aging’s sexhormone waning.

then Tvedegard Moller & Einfeldt in Denmark ; & Jaffe in USA, reportedtestosterone’s  cardiovascular system CVS benefits .

Ullis Ptacek and Shackman’s thorough 1999  review shows that in USA testosterone only became reputable for study after publication of the landmark trials by Shalender Bhasin ea at UCLA  Drew medical school confirmed that testosterone is highly but safely anabolic on muscle in frail and aging men.

More obliquely, Chapman, Horowitz ea from Adelaide Australia  have just published a small study showing  dramatic benefit of  (oral) Testosterone and a nutritional supplement (475kcals, 9gms protein a day)  on reducing hospital admissions in undernourished older mean 77yrs  men mean BMI 19kg lean mass 43.4kg fat mass 12.8kg, and women mean BMI 18kg/sqm, lean mass 28kg, fat mass 15.8kg; thus the females especially were cachectic; combined supplements abolished hospital admissions over a year,  compared to 70% admission rate (only one patient had elective admissions, for separate hip replacement) without any supplements.It is common cause that such oral testosterone supplement gives very shortlived spikes in serum testosterone, thus does not raise the mean level.

DURATION CONFUSION IN THE ROME TRIAL?: the Rome paper by Caminiti, Rosano ea   perhaps  has a sub-editing typo:  It (the Tables)  clearly says they measured bloodlevels and cardiovascular response  at baseline and at 3 months after commencing testosterone undecanoate injection Nebido 1gm  at baseline and then the  6week shot.

but Nebido  1gm is generally given every 3 months (after the first 3 gms   each 6 weeks apart). This is because  it lasts for 3 months when given on a regular 3monthly basis.The definitive study by Schubert ea in Germany confirmed that the trough TT level over about 30months on 1gm Nebido 3monthly is about 16.3nmol/L – but a peak initially over the first 3weeks post injection to around 30nmol/L- ie rarely outside the physiological range of young men.

Hence the 4th shot would have been due 6months after the 1st shot.  As the Rome  abstract says, it is a 3monthly  administration long term.

So we await clarification that Caminiti & Rosano’s team  actually did the final measurements 3 months after the 3rd shot ie at 6 months ( 24 or 26weeks)? when trough  testosterone TT level  as they report was  predictably  up from ~8 to ~18 nmol/L. Why  would they have done measurements at 3 months (when they gave the 3rd shot) but not at the logical endpoint of 6 months? Otherwise their ‘after’ results would be after only 2gm Nebido over the first 3 months. More plausibly, their rsults are in fact as they say after 6months, after exposure to testosterone  for 6months.

WHAT IS “LONG TERM” IN A DRUG TRIAL? It is puzzling how the authors could call 3 months of replacement long term in their trial? Short term  in the context of human lifespan is surely up to a year (even at a mean of 70yrs age as in this cohort – average life expectancy is about 15years in a first world cohort); medium term would be up to perhaps 5years; and long term surely much beyond that. The only truly longterm RCT  ever done was the 20 year UKPDS.

But the FDA now routinely colludes with the marketing hype of drug companies to claim that even 3month trials are enough to register new designer drugs for chronic use- relying on experience, major adverse effects once the drug is in routine use to indicate if too many gullible patients are being poisoned or killed by the generally non-essential  wannabe new drug before they cancel it.

But it is common cause that serious injuries and degeneration eg of bone, muscle, brain etc can take 2 years or more to heal, before one can no longer expect much more recovery towards optimal function.  Even 6months is very early to expect optimal improvement, heart remodeling  on conservative dose anabolic  HRT equivalent to about 8mg TT a day imi or sc, since 1gm every quarter  has been determined to be an average optimal dose for Nebido, maintaining the blood TT at a minimum of about 16.3nmol/L. . But it depends on individual metabolism, habits, diet, smoking, alcohol and other estrogenic intake, antiandrogens and androgen receptors.

It is common cause that the magic formula for long cardiovascular life for men and women includes not just optimal diet and lifestyle but also  maintenance of  optimal bloodpressure,  and optimal levels by  supplementing  abundant vitamins B,C,D,K, some vitamins A and E,  the essential minerals especially calmag, zinc, iodine, iron, chromium, selenium, manganese, boron; and  the ”co-vitamin” human biologicals that deplete from early adulthood  in particular  EPA+DHA, CoQ10, carnitine, ribose,  arginine, carnosine, proline, and chondroglucosamine, and all our other hormones especially  gonadal, adrenal, thyroid, serotonin, GABA; and the plant prohormone metformin. in case of resistant overweight let alone obesity or diabetes.. A new study from Japan also shows that metformin protects from experimental heart failure.       Even modest boron supplement has potent benefit in reducing excretion of and doubling serum testosterone and estradiol levels in magnesium-repleted postmenopausal women.

But as endocrinologists, specialist physicians or family practitioners experience when interviewing an older patient , the likely answer the GP or specialist receives when enquiring about sex hormones – most patients will rebuff the query with “my gyne / urologist looks after that”.

This despite the fact that most gynecologists and urologists were trained primarily as surgeons and in reproductive organ problems and symptom relief ie short term – not in the pathophysiology of all the other internal diseases and prevention and care of the aging diseases, in which internists, geriatricians, general practitioners are trained and experienced after leaving  undergraduate medical school.

This is the appalling tragedy for the aging,  perpetuated by many cynical health professionals  and drug companies for whom only disease- not prevention- pays : that the most important supplements we  need for dynamic old age – human parenteral balanced sex hormones which deplete in 100% of women and over 50% of men- are dismissed except shortterm for the transient menopause symptoms, or for poor sexual function. .

Oral HT eg premarin, progestin is rightly condemned  much beyond 10 years or age 60yrs precisely because it is too risky (as confirmed by the  monumentally misguided but useful $billion  Women’s Health Initiative) or for sexual problems- which few health professionals are both trained and comfortable to address, and about which older people seldom complain precisely because they are already so impaired by the preventable major aging diseases – cardiovascular, metabolic, mood, mental, muskuloskeletal, malignant etc.

Studies showing the major benefits of testosterone on heart failure and ischemic heart disease of course do not discuss the pros and cons of enterohepatic versus the alternative (parenteral) route;  and to what extent the CVS benefits of TT are mediated by the  muscle-anabolic TT itself as opposed to by its daughter metabolite estrogen – with which no muscle anabolism, strengthening has been described except obviously in the uterus itself, and in promoting vascularization and endothelium. It is sad fact that estrogen alone promotes increasing adiposity while shrinking muscle mass, and dissolving collagen in eg the perineum. This causes the paradox that while estrogen strengthens brain, perfusion, skin, hair and  mucosa, it doubles the incidence and severity of stress urinary incontinence SUI, which SERMS in turn double again; with progestin perhaps halving the degree of SUI.

Only for women, at the behest of the drug industry and their non-human sex hormones, do doctors ignore the physiology, that androgens are the parents of estrogens, with the corollary that having dominance of the daughter- estrogen (whether by being overweight, or taking estrogen or progestin, or in the perimenopause)  suppresses levels and necessary anabolic benefits of androgen. They willfully ignore what is long proven, that estrogen dominance  has no direct benefit antidepressant benefit- if anything, while relieving menopause symptoms, it causes inner hostility- whereas maintaining testosterone balance relieves  depression in 2/3 of postmenopausal depression.

THE CRIMINAL RISKS OF ANY INTRAMUSCULAR INJECTION WHEN ALL THAT IS REQUIRED IS SHORT NEEDLE SUBCUTANEOUS ie SC. Finally, it is a risky and potentially dangerous myth that any routine injections must be  given intramuscularly imi. Unless there is a rare special indication for intramuscular (or intravenous) injection,  insulin   and Nebido and all “imi” injections should simply be given into a pinched fold subcutaneously sc ie under loose skin, ideally the upper outer buttock,  even preferable to the loose abdominal wall skin around which diabetics are advised to rotate insulin injections.

This  works as well sc  as imi –  but why advocate  the grave multiple – potentially paralysing or even fatal- risks of unwarranted  imi injection with a needle longer than about 10mm (the skin being  at most 2 – 3mm thick)  for which health practitioners regularly end up before a court martial when the monotonously predictable mishaps occur with the routine ~25mm long “imi” needle – intramuscular hematoma/abscess if not severe (sometimes permanent)  neuralgic pain or distal paralysis or gangrene from hitting a major nerve or artery, to pulmonary embolism from intravenous injection?

For this reason, a 25g needle usually suffices for most purposes, except  Nebido or eg Primogyn depot injection when a 23g needle is less tedious and slow since these are  suspended in a thicker oil vehicle ( than water-soluble insulin which easily goes through a 27 and even 29g needle). For usual eg depotestosterone cypionate or enanthate, or Mixogen/ Primodian Depot combinations, a 25g needle is ideal.

Imagine accidentally injecting 4ml of Nebido – oil- intravenously into an older male? This cannot happen with short 23g needle subcutaneous injection into the upper outer buttock – which is painless and causes at worst a transient bump.

when even imi Voltaren diclofenac can and does suddenly kill (and in retrospect there is never justification for it imi  since  it can always safely be taken by mouth or as suppository).;

and especially when we have for at least 60 years given subcutaneous pellets sc  eg testosterone up to 1000mg  to men and  in women up to 100mg testosterone with or without estradiol 25 to 100mg?

DOES THE SOURCE, MEASUREMENT, DOSE, BALANCE, and ROUTE OF ADMINISTRATION OF HRT MATTER? 3. THE IMPORTANCE OF THE ROUTE OF HRT?

Ross & Henderson’s sentinel (JAMA 1980) paper on the strong relationship between long term oral premarin  total dose and breast cancer was  largely ignored:  that  with cumulative premarin dose >1,500 mg (ie 7yrs) the breast cancer  risk  was estimated to be 2.5 in women with ovaries (vs  0,7 sans ovaries); the risk ratio for a high cumulative dose (ie after about 15years, >3mg premarin)  rose to 5.7 relative to nonusers with normal breasts.

 

But at the same time, Finnish papers in Maturitas showed why, because of non-physiological high E1>E2 even on oral E2,  systemic ERT is preferred:

Punnonen R ea: (in E2V 2mg/d  & the Renin-Aldost system: 1980:2:91-4) that  “on oral E2v the E2 levels rose to normal and (unlike  on oral premarin, EE2) caused  no rise In BP, aldost, renin; they thus preferred such natural  ERT which does not activate the biliary, RAS renin-angiotensin system, and thrombosis”;

 but Heinonen  PK et al (1982:4: 273-6 Estrogen levels on oral E2) showed that  on E2v  4mg/d orally, blood   E2 rose 5X and  E1 rose 25X; so they recommended avoiding   oral ERT.

 

Thus the Womens’ Health Initiative confirmed three facts: 

1. starting OHT well after age 60yrs and continuing even modest dose cyclic  (premarin 0.625mg plus MPA 5mg) does more harm than good; THIS SAYS NOTHING ABOUT APPROPRIATE PHYSIOLOGICAL BALANCED COMBINED PARENTERAL TESTOSTERONE-PROGESTERONE-ESTRADIOL HRT FROM ANY POSTMENOPAUSAL AGE HAVING ANY  LIFELONG RISKS WHATSOEVER.

  

2. starting the same OHT regime soon after menopause – especially premarin alone- reduces  all major diseases and mortality by about a third, except for rare cases of deep vein thrombosis and cholelithiasis;  this outcome was confirmed in the 9year RCT in Finland (Heikkinen ea 2006) in which women on oral estradiol 1mg/d +- MPA 2.5mg from menopause had zero major adverse events.  BUT THIS SPEAKS ONLY FOR AT MOST THE 9 YEARS THAT  THESE WOMEN WERE IN THE TRIALS.

 

There are  so far some seven  major functional types of steroid hormones  in humans: calciferols; androgens; estrogens; progestins; glucocorticoids; mineralocorticoids; and  endogenous digitalis- natriuretic hormone (eg Goldstein  2006, Weidemann 2005; Kurup ea 2003) .

    

Apart from  gender-reproduction-childhood growth promotion (ie androgens, estrogens & progestins), their actions fall into many other systemic classes; which in conventional “replacement” doses  the literature and experience suggests may be compared as follows:

 

 

Muscle anab-olic

Body

fat  gain

Bone spar- ing

Mineralocor-ticoid

Immuno-enhancing

cancer prom-oting

Infec- tion risk

Mood & mind

1 Calciferols

+

 

+

+

modulating

+

2 TT, DHEA

+

inner

++

+

modulating

+++

3 Estradiol E2

– (or n)

outer

+

+

enhancing

+

+

4 progestin

N

n

n

+

modulating

++

5 Cortisones

+

+

suppressive

+

+

6 aldosterone

 

++

 

?n

?n

7 Digoxin

+ heart

? –

+

Anti-

+

Anti-

synthetic E;       

 E1, E3,

+

+

++

++

++

+

Oral AS

+

inner

++

++

modulating

+

 

+++

+=increase;    – = lessen; n = apparently neutral?  AS=anabolic steroids.

 

The active hydroxycalciferols are in a sense exocrine ie are produced from ingested  vitamin D3 and cholesterol in the skin and kidneys, not from dedicated endocrine glands; but while their synthesis needs no more than an hour of sunlight a week in sunny climates, and modest kidney function, calciferol deficiency is increasingly recognized in those who take little dairy products, and little sunshine. Thus the pituitary, skin,  parathyroids, adrenals  and  gonads are the primary  endocrine glands of growth.

 

The other steroid hormones (like the other major anabolic hormones- insulin and human growth hormone HGH) are endocrine ie are vulnerable to both intrinsic endocrine failure (Hypothalamic-Pituitary-Adrenal- pancreatic-Gonadal ),  and to  endocrine gland decrease and blockage by infections, cancer, major stress, auto-antibodies or direct trauma.

 

All these anabolic  hormones  if swallowed are destroyed  by digestion/  1st-pass hepatic metabolism; thus to achieve the same systemic effect,   comparative doses are reported as follows:

                 

 

     ORAL-hepatic

    PARENTERAL

TT men            

     women

   120mg/day      

     5-10mg/day

   7-10mg/day   

    0.5-1mg/d

Estradiol

    1-2mg/d

   0.03-0.1mg/d

progesterone

    5-10mg/d

   0.15-0.3mg/d

Cortisone acetate

    25-50mg/day

   2-5mg/day

fluodrocortone

    0.1-0.2mg/d

   0.01-.02mg/d?

HGH

  autodigested

  +- 0.1mg/kg/wk

insulin

  autodigested

  ~40u/day

 

The vulnerability  of oral steroid therapy is illustrated by oral contraception: where taking eg an oral antibiotic can compete for absorption, reducing   blood SH levels so that accidental conception occurs. Similarly, a postmenopausal  patient with rheumatoid arthritis, on oral (E+P HRT), reports that  her analgesic  requirements  rise while she is on antibiotics.

     

One  needs to go back to a standard textbook of Pharmacology of  1958, (Kranz & Carr: Pharmacological Principles of Medical Practice: Balliere, London) to find the corollary:  eg “cortisone acetate implant, or im  2-5mg daily injection as replacement for  Addisons’ Syndrome”: “For menopausal symptoms, combined E+TT is often employed…”;  “oral synthetic estrogens (have replaced natural ones due to availability,  oral form & lower cost; but) produce undesirable: nausea, cramps, migraine and male breasts.    Estrogen + TT are additive, and E doses may therefore be reduced   since the combination gives smoother transition:  73% of patients remain  symptom free.    TT 10mg imi 3 x/week may control  functional uterine bleeding better than progesterone”!.

    

It is widely overlooked that  TT is converted irreversibly by aromatase to E2 in the tissues; but   giving E2 does not do the reverse – it  suppresses the  HPAG and   TT production. Thus women need to be given TT with estrogen, but  men do not need to be given estrogen –  giving them TT increases their E2 levels by about 1/3. This source of E2 may not be enough for balance in women, but reduces their needed dose of administered estrogen;  hence in women  on a standard 20:1 TT:E2  injection combination, or on combined implants eg TT 50mg + E2  20mg/6months,  the blood TT level should be monitored to check that the mean TT is in the physiological range of  1-3.5nmol/L, but the E2 level need  not be above perhaps 0.1nmol/L – in fact, to avoid excess fat deposition and breast cancer stimulation, it must  not , since TT is supplying E2 direct in target organs.

    

Hence Ginsberg J & Prevelic GM  at Royal Free Medical School  ( Drug Therapy & Reproductive Endocrinology: London: Arnold 1996) note that in BRCA, androgen + prednisone give good results;  they advise: parenteral> oral ERT: eg  E2 patch 50u/d;  or Implants eg TT 50mg + 20mg E2 /6mo (= 300mcg TT + 110mcg E2/ day)..

 

In TOPICS IN O & G 1998: (ed Julian Bassin: Julmar Communications, Jbg 4th Ed 1998: sponsored by all the RSA gyne Drug Suppliers):  Schnitzler CM wrote that “ERT should be given for life, from as early as possible, but even from 80yrs; the elderly not exposed to the sun needing >2000u vit D/day. Sonnendeker on HRT wrote that oral  HRT raises both coagulation & renin substrates acutely; EE2 should not be used for ERT; thus he prefers oral ERT except  if coagulopathy, liver/biliary/ triglyceride/ or vascular headache  problems, when he uses non-oral ERT. Indications for androgens are: poor libido; persistent tiredness & OP; preferring the 25mg TT pellet to oral androgens or imi esters”.

 

Finally, the physiological logic of parenteral  (as opposed to oral) HRT- in this case sex hormone replacement) was already well recognized and marketed over 60 years ago – even in South Africa- in eg the handbook Sex Endocrinology (Schering, New Jersey, 1944) which recommended and listed creams, injections and implants as well as tablets.

 

SEX HORMONE THERAPY: SOURCE, MEASUREMENT, DOSE, BALANCE, and ROUTE OF ADMINISTRATION

DOES THE SOURCE,  MEASUREMENT, DOSE, BALANCE, and  ROUTE OF ADMINISTRATION OF SEX HORMONE THERAPY HRT MATTER?

Chapter 

 

1.      THE IMPORTANCE OF THE MEASUREMENT OF BLOOD LEVELS OF SEX HORMONES

 

          While urologists,  andrologists and internists  demand blood hormone  levels to diagnose male hypogonadism ,  adrenal, thyroid  or other endocrine dysfunction ,  many gynecologists still apparently  give postmenopausal HRT without ever measuring levels.

           Do baseline and achieved sex hormone levels matter ?

           Older authorities(mostly male or trained by men) did not believe so; hence we still see women presenting  on  eg implants or Premarin up to 2,5mg/day for years, with Estrogen  levels of well above 3nmol/L ->10 times what is necessary and safe),  or SHBG levels well over 200nmol/L; some of them grossly bloated and dysfunctional if not with mushrooming breast cancers or  the obesity metabolic syndrome.

 

      The textbook HORMONE REPLACEMENT THERAPY HRT (A Wayne  Meikle ed: Humana Press, USA  1999: p266) says  in Men’s Sex Hormone Replacement SHR: “the  general principle of SHR  is to normalize the (TT) level”.  “The safe course is to duplicate normal physiology as much as possible:  HRT  should allow self-administration, be convenient, affordable, minimal discomfort, with predictable responses. TT-cypionate  or TT-enanthate  100mg/week maintains physiological levels between 16-32 ie mean 24nmol/L.   Mixtures of short-and-long-acting TT  (eg Sustanon) are  thus  not recommended”.

 

At p412 Davis & Burger, for TT Replacement  in women, say:  “replace TT levels to at least the UPPER level of  normal physiological range for young ovulating women”.

     Meikle’s  authoritative  Textbook thus stresses the importance of  duplicating  normal human  physiology .  This  requires  using human systemic (ie not oral) hormones which can  and  must  be measured before and periodically on SHR –

 ie  using only systemic TT in men, systemic TT + E2 + Progesterone in women.

 

The 2000 Management of the Menopause Millenium Review (Studd JW ea, London) strongly promotes measuring hormone levels and balance in both sexes: ”calcium loss decreases with serum E2> 72pmol/L; vasomotor symptoms at >126-252pmol/L; and lipids changes at  250pmol/L- whereas breast cancer BRCA cells responds  to  E2>36pmol/L”  but does not say how these interact with TT levels;  so it is  important to monitor the serum E2, to keep it in the therapeutic window above about 100 but below 250pmol/L ie mean about 200pmol/l;  many women do not feel better on solo ERT – so few persist  on it; Studd ea  thus recommend “E2 patch rather than orally, for less hypertension, gallstones, DVT & hepatic protein formation.”      “it  is mandatory to measure BMI and % body fat;   the single best screen for Insulin resistance is a  fasting glucose/insulin(G:I) ratio below 4,5.

       “Depression is the commonest functional disorder of aging men, in whom aging sexhormone changes – PEDAM(Partial Endocrine  Deficiency of Aging  Men)-  include falling androgens, rise in SHBG, arteriosclerosis  & CVD,  and decrease in brain hormones & wellbeing – with especially decrease in melotonin & sleep, muscle strength, RBC, cognition, bone,  immunocompetence,  &  erection.”

 

       The Johannesburg gynecologist editor of Wyeth’s Menopause Update August 2001 certainly advocates frequent E2 measurements to titrate the frequency and dose of E2 implants, “aiming for a blood level of 0.35-0.45nmol/L: side effects occur when the dose exceeds the patient’s needs”.  Kopenhager in the same issue promotes “lowdose ERT – 1mg/day oral E2 causing less side-effects like headache, swelling or mastalgia, without increase in body mass”; but he overlooks the fact that 0.05ug of E2/day systemically will often suffice, that body weight says nothing about the steady gain in fatmass and loss in muscle  mass with aging and unopposed estrogen.   Prof  Frank Guidozzi from Johannesburg in the same issue makes the  point about TT replacement even for men – 250mg ester/ fortnight intramuscularly ie  a mean 12mg TT/day, or 5mg/day by patch, or 120mg undecanoate/day orally..

 

          As Fritz Schumaker said, there is a need for the right amount of  all things, from water to air.  A bit too little or a bit too much food, insulin or cortisone will be seen and felt fairly soon; whereas with thyroid, vitamin D and the sex steroids it may take months to years before it becomes apparent – when it may be too late, with broken marriage, spirits, heart or bones, or cancer.  Optimal doses, blood levels and balance  are apparent throughout nature and  for all hormones – with balance between the hormones – between the strengthening androgens and the fattening estrogenics – being the most important to balance the bloodpressure and lipids, thrombosis and bruising, fat-mass and lean-mass,  concrete and intuitive skills,  hypo-and hyper-immunity,  apathy and drive.  

 

            Well-published clinical studies for 80 years since hormone measurements began (McLeod  & Banting; Albright; Dubois, Masters, Bulbring, Hayward, Stoll, Mackay,  Wang, Henderson, Greenblatt, Speroff, Vermeulen, Roitt & Delves, Nieschlag & Behre, Motohashi,  Studd, Whitehead, Maartens et al)  have  shown the importance of  titrating doses and measuring  bloodlevels of the superhormone family – estrogens and androgens, cortisone, insulin and thyroid –  in men and women,  on every system, the mind and body.

 

OPTIMAL SEXHORMONE LEVELS

Sue Davis et al from Monash University  have been eloquent advocates of normalizing female TT levels above the 1.5nmol/L level;  this has been done by eg  Schleyer-Saunders in London, Gelfand and Gambrell in Augusta,  Morrie Gelfand et al at McGill Quebec, and Davey’s group  in Cape Town for over 30 years. There seems to be wide consensus that E2 level should be between 0.1-0.25nmol/L – but bearing in mind that breast cancer increases in proportion to the estrogen dose, and that plasma E2 reflects the (free)  plasma estrogens and androgens only in the presence of normal SHBG and in the absence  of any other estrogenics.

 

The Healthy TT level in Young Men

      Most seem to take it for granted that, at any adult age, a plasma TT anywhere above the bottom of the population range (eg 10nmol/L) is normal and adequate. Pfizer claims  in it’s Viagra trials that only impotent men with TT below about 8nmol/L were excluded,  since  those with TT level less  than about 2sd or 20% below the lower range of “normal” were not classified as hypogonadal.

    

Yet this level is 1/4 of the vigorous youthful 35-40nmol/L which we sometimes find in dynamic men even  in their mid-fifties.  Aversa A ea in  Italy (in Clin Endoc 2000:53:517-22) show how Androgens and Erection correlate, that  older  impotent men have  TT  around 13-19, mean 16nmol/L  ie half the level of young men;  those with vascular impotence having 25% higher E2 & SHBG, and  40% lower free TT (only about 45pmol/L,  versus 75pmol/L) than in  the psychogenic group; thus fTT correlates with penile elasticity;  (cf  male TT “normal range” at all age  9-35 ie mean 22nmol/L- whereas eg Greek  recruits at  army intake: mean TT level about 32nmol/L-Mantzoros et al).

        Salmimies’ paper  (1982) already 20 years ago illustrated that there is no sharp cutoff point for impotence, for response to TT:  “15 diverse hypogonadic men received im TTEnanthate (25 to 250 mg TT) or placebo injections 2 weekly, each dose for 4 weeks. All patients with pre treatment plasma TT values below 2 ng/ml(ie <7nmol/L) reported impaired sexual function. In four patients with TT between 2 and 4.5 ng/ml who reported impairment, TTE 50 to 250mg successfully improved rated sexual behaviour. Four matched men with TT level in the same 2 – 4.5ng/ml range reported high erectile function that did not change with TT E inj. These data indicate that male sexual behaviour is impaired at an individual plasma TT below between 2.0 and 4.5 ng/ml        ie : the range of erectile loss or response is at least between 7 and 16nmol/L on their assay.

But did they, does anyone,  give enough TT, achieve adequate blood levels for long enough in non-responders?

     Andy  Guay’s 2001 abstract  illustrates the same point, there is a (?semilog) linear response ; (as  is  seen eg in Gilbert Forbes’  1980’s elegant demonstration of the semilog linear response between total TT dose and lean body mass over years). In Guay’s 44 patients (apparently 50-70yrs old) studied in detail, altho 14.9pg/ml is in the lowest quintile of the “normal” fTT range, there was 100% response to Viagra. Drop the fTT 30% and the response fell 25%; drop the fTT 45% from 14.9 to 8.1 and the response drops 84%; drop the fTT 50% to 7.4 and the response drops by 91%.

      This predictable dose response curve correlates with the finding in wasting AIDS, (Rabkins’ and Wagner’s,  Bhasin’s, and Grinspoon’s groups), that some sick men with AIDS wasting do not become anabolic at 100mg TTenanthate/ week but, improve only when the dose is increased to 150 or even 200mg/week imi- ie to a mean TT level of 30 – 40nmol/L. Bhasin’s group in LA was the first to report, in 1995, that in HEALTHY men, modestly superphysiological doses of TT cypionate or enanthate  (eg 200mg/week) (which no more than double normal  TT blood levels to around 60nmol/L,  still below the danger level of 80nmol)  improve muscle mass and strength by 10-20%; and correspondingly in frail elderly – without adverse effect.

      Thus it is  obvious that there is no arbitrary TT bloodlevel cutoff point above which Viagra is justified de novo before trial of TT replacement. Since there are no absolute contraindications to physiological systemic human TT replacement [except untreated (prostate or breast) cancer]; and since there are no risks of such measured replacement except with untreated frank heart-failure, jaundice or untreated cancer, the phosphodiesterase inhibitors  PDI (with risk of sudden death) are never justified (at a local cost of about >US$130/month) until weekly subcutaneous gluteal selfinjection of depot TT has been tried for a few months at a cost of about US$3 to $5/month.

 

Our own search  a few years ago (Burman, Bornman ea)  traced over 73  published reports of studies which give TT levels in groups of  “normal” men  the past 40 years; of which about 64 reports measured TT levels in men below 39 years of age. Four  were longitudinal studies in such young men, amongst about 38 longitudinal and cross-sectional studies.  Bearing in mind Klee and Vermeulen’s recent conclusions (2000-2001) that laboratory method (RIA) has changed little the past 40 years and that all reliable measures (TT, fTT, bioavailable TT etc) correlate fairly well,  our plots confirm that  mean male TT level falls about 0.7% per year (range 0.2% to 2%pa) between youth and old age ie about 40% over 50years;  but that in healthy lean  young men under 39years, the mean TT level has remained about 24nmol/L(+-16%) for 40 years; in the 22 studies between 1958 & 1985, the range was 16-35nmol/L-mean 25; in the 42 studies since 1987, the range was 14-40nmol/L-mean 27nm; – Bornman’s Pretoria series(in young men admitted for voluntary sterilization) understandably  yielding the lowest testosterone means…

          But these figures belie that  while TT falls modestly, the TT/(E2XSHBG) product  falls drastically since both E2 and SHBG rise with aging, especially with disease: eg values may change  from  youthful (TT) 25X(SHBG norm) 20/(E2: 0.1X measured SHBG:20) = 250;  to  an aging man’s     15X20/(0.15X30)   = 66; ie the TT/E2 product has fallen by 75%.

 

Chapter 2 follows soon.