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