Letrozole

[Guest guest]

You are welcome this is what the group is about. Pass it forwarded.

Phil

Summers <rsummers@...> wrote:

It is good to hear he came back up on the E2

now that he knows what it feels like he may get by on a very low dose

just once every 10 days to 14 days.-----

Thanks Phil. We have been thinking about dosages, and took your

advice above. He's going to try the low dose of 1/8th of a pill

every 2 weeks, probably starting this weekend or next.

This dose will equal 1/8th of the initial dose that sent his E2

plummeting. Hopefully this decrease will be enough. Time will tell.

(I imagine if his weight lowers and his natural testosterone levels

regain a toehold that the letrozole will need to be decreased

accordingly.)

It is funny that immediate effects of high E2 (no erections, etc)

have been curtailed by ALC/ALA therapy, yet the effects of low E2

were not effected by ALC/ALA and showed up right away. Not sure why

this would be, but as you said, this gives him an indicator that his

E2 has fallen too much so I guess it is good.

Thanks for the input. It's been really helpful to compare symptoms

and experiences.

[Guest guest]

Hi I feel this should work very good. Bear in mind Reto and myself are

on TRT and your husband is not. Any E2 that he is making is coming from the

converson of the T his testis make and should be about the same from one day to

the next. Just remember if his libido goes down he is going to low.

Good find on the link.

Phil

Summers <rsummers@...> wrote:

Just an update on hubby and the letrozole therapy.

Two weeks ago we had flu and pneumonia shots that knocked us both for

a loop. We suspect it was the new pneumonia vaccine. In any event

he waited a week for the vaccine side effects to wear off and took

1/8th of a tab of anti-aromatase med, letrozole. This was half of

the 1/4th bi-weekly dose that sent his E2 crashing earlier. The plan

was to decrease the dose by half, and increase the dose interval to 2

wks.

He has decided since then (with no side effects from the 1/8th pill)

that it might be more effective to keep the dose intervals to a week

but decrease the doses, so I subdivided the pills into 1/16ths (not

as difficult as I had anticipated). So today or tomorrow he plans to

take another 1/16th and see how that goes.

I did warn him, Retrogrouch, that you were unable to settle on a

dosing schedule that works consistently, and that adjustments might

need to be made continuously due to changing physiology and hormone

levels.

Research on newer anti-aromatase meds and men has been scarce to non-

existent, but I ran across this singular study abstract:

LETROZOLE NORMALIZES SERUM TESTOSTERONE IN SEVERELY

OBESE MEN WITH HYPOGONADOTROPIC HYPOGONADISM

Diabetes Obes Metab. 2005 May;7(3):211-5.

de Boer H, Verschoor L, Ruinemans-Koerts J, Jansen M.

Department of Internal Medicine, Ziekenhuis Rijnstate,

Wagnerlaan 55, 6800 TA Arnhem, The Netherlands. hdeboer@...

BACKGROUND: Morbid obesity is associated with increased

estradiol production as a result of aromatase-dependent conversion

of testosterone to estradiol. The elevated serum estradiol levels

may inhibit pituitary LH secretion to such extent that

hypogonadotropic

hypogonadism can result. Normalization of the disturbed estradiol-

testosterone

balance may be beneficial to reverse the adverse effects of

hypogonadism.

AIM: To examine whether aromatase inhibition with Letrozole can

normalize serum testosterone levels in severely obese men with

hypogonadotropic hypogonadism.

PATIENTS AND METHODS: Ten severely obese men, mean age

48.2 +/- 2.3 (s.e.) years and body mass index 42.1 +/- 2.6 kg/m(2),

were treated with Letrozole for 6 weeks in doses ranging from 7.5 to

17.5 mg per week. RESULTS: Six weeks of treatment decreased

serum estradiol from 120 +/- 20 to 70 +/- 9 pmol/l (p = 0.006). None

of the subjects developed an estradiol level of less than 40 pmol/l.

LH

increased from 4.5 +/- 0.8 to 14.8 +/- 2.3 U/l (p < 0.001). Total

testosterone rose from 7.5 +/- 1.0 to 23.8 +/- 3.0 nmol/l (p < 0.001)

without a concomitant change in sex hormone-binding globulin level.

Those treated with Letrozole 17.5 mg per week had an excessive LH

response.

CONCLUSION: Short-term Letrozole treatment normalized serum

testosterone levels in all obese men. The clinical significance of

this

intervention remains to be established in controlled, long-term

studies.

Publication Types: Clinical Trial

PMID: 15811136 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

cmd=Retrieve & db=PubMed & dopt=Abstract & list_uids=15811136

PS: I also installed the above study along with the physician info

for letrozole into a folder that Oreon created in the FILES section

entitled Aromatase Inhibitors.

[Guest guest]

, were are a few for you...the first two are studies with letro.

The third is of exemestane, a 3rd genetation AI. It is a steroidal AI

that is a suicide AI.

----------------------------------------------------------------------

Comparative assessment in young and elderly men of the gonadotropin

response to aromatase inhibition.

T'Sjoen GG, Giagulli VA, Delva H, Crabbe P, De Bacquer D, Kaufman JM.

Department of Endocrinology, Ghent University Hospital, De Pintelaan

185, 9000 Ghent, Belgium. guy.tsjoen@...

CONTEXT: Aging in men is associated with a decline in serum

testosterone (T) levels. OBJECTIVE: Our objective was to assess whether

decreased T in aging might result from increased estradiol (E2)

negative feedback on gonadotropin secretion. DESIGN AND SETTING: We

conducted a comparative intervention study (2004) in the Outpatient

Endocrinology Clinic, Ghent University Hospital. PARTICIPANTS:

Participants included healthy young and elderly men (n = 10 vs. 10).

INTERVENTIONS: We used placebo and letrozole (2.5 mg/d) for 28 d,

separated by 2 wk washout. MAIN OUTCOME MEASURES: We assessed changes

in serum levels of free E2, LH, and FSH, free T, SHBG, and

gonadotropins response to an i.v. 2.5-microg GnRH bolus. RESULTS: As

assessed after 28 d of treatment, letrozole lowered E2 by 46% in the

young men (P = 0.002) and 62% in the elderly men (P < 0.001). In both

age groups, letrozole, but not placebo, significantly increased LH

levels (339 and 323% in the young and the elderly, respectively) and T

(146 and 99%, respectively) (P value of young vs. elderly was not

significant). Under letrozole, peak LH response to GnRH was 152 and 52%

increase from baseline in young and older men, respectively (P = 0.01).

CONCLUSIONS: Aromatase inhibition markedly increased basal LH and T

levels and the LH response to GnRH in both young and elderly men. The

observation of similar to greater LH responses in the young compared

with the elderly does not support the hypothesis that increased

restraining of LH secretion by endogenous estrogens is instrumental in

age-related decline of Leydig cell function.

----------------------------------------------------------------------

Letrozole normalizes serum testosterone in severely obese men with

hypogonadotropic hypogonadism.

de Boer H, Verschoor L, Ruinemans-Koerts J, Jansen M.

Department of Internal Medicine, Ziekenhuis Rijnstate, Wagnerlaan 55,

6800 TA Arnhem, The Netherlands. hdeboer@...

BACKGROUND: Morbid obesity is associated with increased estradiol

production as a result of aromatase-dependent conversion of

testosterone to estradiol. The elevated serum estradiol levels may

inhibit pituitary LH secretion to such extent that hypogonadotropic

hypogonadism can result. Normalization of the disturbed estradiol-

testosterone balance may be beneficial to reverse the adverse effects

of hypogonadism. AIM: To examine whether aromatase inhibition with

Letrozole can normalize serum testosterone levels in severely obese men

with hypogonadotropic hypogonadism. PATIENTS AND METHODS: Ten severely

obese men, mean age 48.2 +/- 2.3 (s.e.) years and body mass index 42.1

+/- 2.6 kg/m(2), were treated with Letrozole for 6 weeks in doses

ranging from 7.5 to 17.5 mg per week. RESULTS: Six weeks of treatment

decreased serum estradiol from 120 +/- 20 to 70 +/- 9 pmol/l (p = 0.

006). None of the subjects developed an estradiol level of less than 40

pmol/l. LH increased from 4.5 +/- 0.8 to 14.8 +/- 2.3 U/l (p < 0.001).

Total testosterone rose from 7.5 +/- 1.0 to 23.8 +/- 3.0 nmol/l (p <

0.001) without a concomitant change in sex hormone-binding globulin

level. Those treated with Letrozole 17.5 mg per week had an excessive

LH response. CONCLUSION: Short-term Letrozole treatment normalized

serum testosterone levels in all obese men. The clinical significance

of this intervention remains to be established in controlled, long-term

studies.

----------------------------------------------------------------------

Pharmacokinetics and dose finding of a potent aromatase inhibitor,

aromasin (exemestane), in young males.

Mauras N, Lima J, Patel D, Rini A, di Salle E, Kwok A, Lippe B.

Nemours Children's Clinic and Research Programs, ville, Florida

32207, USA. nmuras@...

Suppression of estrogen, via estrogen receptor or aromatase blockade,

is being investigated in the treatment of different conditions.

Exemestane (Aromasin) is a potent and selective irreversible aromatase

inhibitor. To characterize its suppression of estrogen and its

pharmacokinetic (PK) properties in males, healthy eugonadal subjects

(14-26 yr of age) were recruited. In a cross-over study, 12 were

randomly assigned to 25 and 50 mg exemestane daily, orally, for 10 d

with a 14-d washout period. Blood was withdrawn before and 24 h after

the last dose of each treatment period. A PK study was performed (n =

10) using a 25-mg dose. Exemestane suppressed plasma estradiol

comparably with either dose [25 mg, 38% (P <or= 0.002); 50 mg, 32% (P

<or= 0.008)], with a reciprocal increase in testosterone concentrations

(60% and 56%; P <or= 0.003 for both). Plasma lipids and IGF-I

concentrations were unaffected by treatment. The PK properties of the

25-mg dose showed the highest exemestane concentrations 1 h after

administration, indicating rapid absorption. The terminal half-life was

8.9 h. Maximal estradiol suppression of 62 +/- 14% was observed at 12

h. The drug was well tolerated. In conclusion, exemestane is a potent

aromatase inhibitor in men and an alternative to the choice of

available inhibitors. Long-term efficacy and safety will need further

study.

[Guest guest]

Oops... i just realized that i posted the same study that you did.

>

> Just an update on hubby and the letrozole therapy.

> Two weeks ago we had flu and pneumonia shots that knocked us both for

> a loop. We suspect it was the new pneumonia vaccine. In any event

> he waited a week for the vaccine side effects to wear off and took

> 1/8th of a tab of anti-aromatase med, letrozole. This was half of

> the 1/4th bi-weekly dose that sent his E2 crashing earlier. The plan

> was to decrease the dose by half, and increase the dose interval to 2

> wks.

>

> He has decided since then (with no side effects from the 1/8th pill)

> that it might be more effective to keep the dose intervals to a week

> but decrease the doses, so I subdivided the pills into 1/16ths (not

> as difficult as I had anticipated). So today or tomorrow he plans to

> take another 1/16th and see how that goes.

>

> I did warn him, Retrogrouch, that you were unable to settle on a

> dosing schedule that works consistently, and that adjustments might

> need to be made continuously due to changing physiology and hormone

> levels.

>

> Research on newer anti-aromatase meds and men has been scarce to non-

> existent, but I ran across this singular study abstract:

>

> LETROZOLE NORMALIZES SERUM TESTOSTERONE IN SEVERELY

> OBESE MEN WITH HYPOGONADOTROPIC HYPOGONADISM

>

> Diabetes Obes Metab. 2005 May;7(3):211-5.

> de Boer H, Verschoor L, Ruinemans-Koerts J, Jansen M.

> Department of Internal Medicine, Ziekenhuis Rijnstate,

> Wagnerlaan 55, 6800 TA Arnhem, The Netherlands. hdeboer@a...

>

> BACKGROUND: Morbid obesity is associated with increased

> estradiol production as a result of aromatase-dependent conversion

> of testosterone to estradiol. The elevated serum estradiol levels

> may inhibit pituitary LH secretion to such extent that

> hypogonadotropic

> hypogonadism can result. Normalization of the disturbed estradiol-

> testosterone

> balance may be beneficial to reverse the adverse effects of

> hypogonadism.

>

> AIM: To examine whether aromatase inhibition with Letrozole can

> normalize serum testosterone levels in severely obese men with

> hypogonadotropic hypogonadism.

>

> PATIENTS AND METHODS: Ten severely obese men, mean age

> 48.2 +/- 2.3 (s.e.) years and body mass index 42.1 +/- 2.6 kg/m(2),

> were treated with Letrozole for 6 weeks in doses ranging from 7.5 to

> 17.5 mg per week. RESULTS: Six weeks of treatment decreased

> serum estradiol from 120 +/- 20 to 70 +/- 9 pmol/l (p = 0.006). None

> of the subjects developed an estradiol level of less than 40 pmol/l.

> LH

> increased from 4.5 +/- 0.8 to 14.8 +/- 2.3 U/l (p < 0.001). Total

> testosterone rose from 7.5 +/- 1.0 to 23.8 +/- 3.0 nmol/l (p < 0.

001)

> without a concomitant change in sex hormone-binding globulin level.

> Those treated with Letrozole 17.5 mg per week had an excessive LH

> response.

>

> CONCLUSION: Short-term Letrozole treatment normalized serum

> testosterone levels in all obese men. The clinical significance of

> this

> intervention remains to be established in controlled, long-term

> studies.

>

> Publication Types: Clinical Trial

> PMID: 15811136 [PubMed - indexed for MEDLINE]

> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

> cmd=Retrieve & db=PubMed & dopt=Abstract & list_uids=15811136

>

> PS: I also installed the above study along with the physician info

> for letrozole into a folder that Oreon created in the FILES section

> entitled Aromatase Inhibitors.

>

[Guest guest]

from http://forum.bodybuilding.com/archive/index.php?t-40724.html

LOTS more there......

Captin Swole

06-27-2002, 07:24 PM

The

following 3 posts are copies of Zyglamail's posts on Elite,, We need to

get him over here,, his posts are always intelligent and well

researched. Its ALOT to read but worth the effort (Note: I didnt copy

the post on Armidex because its well known). Wickedone,,,,

3rd Generation Anti-E's

Everyone by now has heard of Arimidex/Liquidex(ie anastrozole) but

there are a couple others with slightly better estrogen suppression

values as well as slight differences in the way they affect the

endocrine system.

The other two 3rd generation Anti-e's are letrozole(femara) and

exemestane(aromasin). Letrozole and anastrozole are aromatase

inhibitors while exemestane is considered an aromatase inactivator.

While all of these seem to exert an effect on our LH/FSH levels, some

also have an effect on IGF-1 levels as well. According to some studies

for example, anastrzole was shown to reduce IGF-1 levels by 18%(note

1), which is likely due to reduced estrogen. Another abstract shows

that letrozole actually increased IGF-1 levels by an average of

24%(note 2).

Following are some detailed descriptions of the 3 products.

notes:

1. J Clin Endocrinol Metab 2000 Jul;85(7):2370-7

2. J Steroid Biochem Mol Biol 1997 Nov-Dec;63(4-6):261-7

Letrozole.

DESCRIPTION

Femara (letrozole tablets) for oral administration contain 2.5 mg of

letrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen

synthesis). It is chemically described as 4,4'-(1H-1,2,4

-Triazol-1-ylmethylene) dibenzonitrile.

Letrozole is a white to yellowish crystalline powder, practically

odorless, freely soluble in dichloromethane, slightly soluble in

ethanol, and practically insoluble in water. It has a molecular weight

of 285.31, empirical formula C17H11N5 and a melting range of 184o

C-185o C.

Femara (letrozole tablets) is available as 2.5 mg tablets for oral

administration.

Inactive Ingredients.

Colloidal silicon dioxide, ferric oxide, hydroxypropyl methylcellulose,

lactose monohydrate, magnesium stearate, maize starch, microcrystalline

cellulose, polyethylene glycol, sodium starch glycolate, talc, and

titanium dioxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

The growth of some cancers of the breast are stimulated or maintained

by estrogens. Treatment of breast cancer thought to be hormonally

responsive (i.e., estrogen and/or progesterone receptor positive or

receptor unknown) has included a variety of efforts to decrease

estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit

estrogen effects (antiestrogens and progestational agents). These

interventions lead to decreased tumor mass or delayed progression of

tumor growth in some women.

In postmenopausal women, estrogens are mainly derived from the action

of the aromatase enzyme, which converts adrenal androgens (primarily

androstenedione and testosterone) to estrone and estradiol. The

suppression of estrogen biosynthesis in peripheral tissues and in the

cancer tissue itself can therefore be achieved by specifically

inhibiting the aromatase enzyme.

Letrozole is a nonsteroidal competitive inhibitor of the aromatase

enzyme system; it inhibits the conversion of androgens to estrogens. In

adult nontumor- and tumorbearing female animals, letrozole is as

effective as ovariectomy in reducing uterine weight, elevating serum

LH, and causing the regression of estrogen-dependent tumors. In

contrast to ovariectomy, treatment with letrozole does not lead to an

increase in serum FSH. Letrozole selectively inhibits gonadal

steroidogenesis but has no significant effect on adrenal

mineralocorticoid or glucocorticoid synthesis.

Letrozole inhibits the aromatase enzyme by competitively binding to the

heme of the cytochrome P450 subunit of the enzyme, resulting in a

reduction of estrogen biosynthesis in all tissues. Treatment of women

with letrozole significantly lowers serum estrone, estradiol and

estrone sulfate and has not been shown to significantly affect adrenal

corticosteroid synthesis, aldosterone synthesis, or synthesis of

thyroid hormones.

Pharmacokinetics

Letrozole is rapidly and completely absorbed from the gastrointestinal

tract and absorption is not affected by food. It is metabolized slowly

to an inactive metabolite whose glucuronide conjugate is excreted

renally, representing the major clearance pathway. About 90% of

radiolabeled letrozole is recovered in urine. Letrozole’s terminal

elimination half-life is about 2 days and steady-state plasma

concentration after daily 2.5mg dosing is reached in 2-6 weeks. Plasma

concentrations at steady-state are 1.5 to 2 times higher than predicted

from the concentrations measured after a single dose, indicating a

slight nonlinearity in the pharmacokinetics of letrozole upon daily

administration of 2.5mg. These steady-state levels are maintained over

extended periods, however, and continuous accumulation of letrozole

does not occur. Letrozole is weakly protein bound and has a large

volume of distribution (approximately 1.9 L/kg).

Metabolism and Excretion

Metabolism to a pharmacologically-inactive carbinol metabolite (4,

4'-methanol-bisbenzonitrile) and renal excretion of the glucuronide

conjugate of this metabolite is the major pathway of letrozole

clearance. Of the radiolabel recovered in urine, at least 75% was the

glucuronide of the carbinol metabolite, about 9% was two unidentified

metabolites, and 6% was unchanged letrozole.

In human microsomes with specific CYP isozyme activity, CYP 3A4

metabolized letrozole to the carbinol metabolite while CYP 2A6 formed

both this metabolite and its ketone analog. In human liver microsomes,

letrozole strongly inhibited CYP 2A6 and moderately inhibited CYP 2C19.

Special Populations

Pediatric, Geriatric and Race: In the study populations (adults ranging

in age from 35 to >80 years), no change in pharmacokinetic

parameters was observed with increasing age. Differences in letrozole

pharmacokinetics between adult and pediatric populations have not been

studied. Differences in letrozole pharmacokinetics due to race have not

been studied.

Renal Insufficiency: In a study of volunteers with varying renal

function (24-hour creatinine clearance: 9-116 mL/min), no effect of

renal function on the pharmacokinetics of single doses of 2.5mg of

Femara (letrozole tablets) was found. In addition, in a study of 347

patients with advanced breast cancer, about half of whom received 2.5mg

Femara and half 0.5mg Femara, renal impairment (calculated creatinine

clearance: 20-50 mL/min) did not affect steady-state plasma letrozole

concentration.

Hepatic Insufficiency: In a study of subjects with varying degrees of

non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh

classification A and , the mean AUC values of the volunteers with

moderate hepatic impairment were 37% higher than in normal subjects,

but still within the range seen in subjects without impaired function.

Patients with severe hepatic impairment (Child-Pugh classification C)

have not been studied (see DOSAGE AND ADMINISTRATION, Hepatic

Impairment).

Drug/Drug Interactions

A pharmacokinetic interaction study with cimetidine showed no

clinically significant effect on letrozole pharmacokinetics. An

interaction study with warfarin showed no clinically significant effect

of letrozole on warfarin pharmacokinetics.

There is no clinical experience to date on the use of Femara in combination with

other anti-cancer agents.

Pharmacodynamics

In postmenopausal patients with advanced breast cancer, daily doses of

0.1 mg to 5 mg Femara suppress plasma concentrations of estradiol,

estrone, and estrone sulfate by 75%-95% from baseline with maximal

suppression achieved within two-three days. Suppression is

dose-related, with doses of 0.5 mg and higher giving many values of

estrone and estrone sulfate that were below the limit of detection in

the assays. Estrogen suppression was maintained throughout treatment in

all patients treated at 0.5 mg or higher.

Letrozole is highly specific in inhibiting aromatase activity. There is

no impairment of adrenal steroidogenesis. No clinically-relevant

changes were found in the plasma concentrations of cortisol,

aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in

plasma renin activity among post-menopausal patients treated with a

daily dose of Femara 0.1 mg to 5 mg. The ACTH stimulation test

performed after 6 and 12 weeks of treatment with daily doses of 0.1,

0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of

aldosterone or cortisol production. Glucocorticoid or mineralocorticoid

supplementation is, therefore, not necessary.

No changes were noted in plasma concentrations of androgens

(androstenedione and testosterone) among healthy postmenopausal women

after 0.1, 0.5, and 2.5 mg single doses of Femara or in plasma

concentrations of androstenedione among postmenopausal patients treated

with daily doses of 0. 1 mg to 5 mg. This indicates that the blockade

of estrogen biosynthesis does not lead to accumulation of androgenic

precursors. Plasma levels of LH and FSH were not affected by letrozole

in patients, nor was thyroid function as evaluated by TSH levels, T3

uptake, and T4 levels.

***************************************************************************

" The problem with socialism is that eventually you run out of other people's

money. "

--Margaret Thatcher