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.

 

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

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