Aromasin, Arimidex, Letrozole, Oh My!

[Mike Arnold]

Well, if you read the above trial you can see Letro performed about the same as Adex and Aromasin in men. Adex usually can lower E2 about 50% and Aromasin about 62% in men. The letro trial shows a range of 46-62%.

Once you factor in all the additional benefits of Aromasin it is the obvious choice for E2 supression. One thing about Letro is it seems to have a longer half life than aromasin so the differences you are seeing is likely due to half life. Dosing the Aromasin every 12 hours should address this issue.

I did read the study you posted, but since supression with Aromasin was about the same as Letro (in this study only), I didn't see why Aromasin would be any better for contest prep. Simply the fact that Letro was able to reduce gyno and is the only AI that can do that...certainly justifies speculation that something else is going on.

What you say makes sense concerning half-life, as it would be difficult to acheive the same results with aromasin unless you dosed it very often. You may be correct that improper dosing has been the cause for Letro giving superior results.

It will be interesting to see if Aromasin is able to reduce gyno like Letro, once proper dosing is undertaken by more people. If Aromasin is still not able to reduce gyno even when dosed properly, then I guess we would have to start looking elsewhere. Also, it will be nice once they have performed additional studies with both aromasin and Letro in men....as we all know different studies can yield different results. Frequency of use with Aromasin is a pain in the ass, but who that is serious really cares anyway.

[Sassy69]

Random Thoughts of mine on the subject...
An agonist is a releaser basically, a substance that binds to certain receptors to induce a particular response. It’s the opposite of an antagonist which binds to receptors to block a response. Don’t confuse a gonadotropin releasing hormone agonist (GnRH) and a growth hormone receptor agonist (GHR). Now the hypothalamus secrets GnRH hormone which interacts with the GnRH receptor to induce a response which is the release of FSH and LH by the putuitary. The GnRH agonist is a peptide basically which emulates the neurohormone GnRH in mechanism. A GnRH agonist is a synthetic peptide modeled after the hypothalamic neurohormone GnRH that interacts with the gonadotropin-releasing hormone receptor to elicit a biological response, the release of the pituitary hormones FSH and LH. So initially there is an increase in the secretion of FSH and LH but this downregulation of receptors which produces a huge hypogonadal effect in a matter of days. That is ultimately our therapeutic goal. So basically GnRH agonists treat estrogen production dependent disorders in women by suppressing ovarian activity and inducing a hypoestrogenic state. The best part of all this is this process is completely reversible. Lupron is a pretty popular GnRH agonist.

Another thing about Asin. Its a suicide AI which means it binds to the aromatase enzyme and permanently deactivates it. So there is almost no estrogen rebound coming off it. So i would pick Asin overe Adex anyday. But of course with the estrogen suppression comes a whole new spectrum of issues like early onset of osteoporosis etc...but hey. You know how it goes. Nothing for free in this game.

SS

So the Lupron discussion is new to me, so googling, here's some info about Lupron:

http://womenshealth.about.com/cs/hormones/a/lupron.htm

Lupron Depot (leuprolide acetate for depot suspension), a GnRH agonist, is a hormonal agent that significantly reduces estrogen levels. The medication works in two distinct phases. Phase one stimulates the ovaries causing them to produce more estradiol, the most potent of the three estrogens produced by women. In phase two, the messenger hormones that tell the ovaries to produce estrogen decline dramatically. The resulting drop in estrogen causes women to experience menopause-like side effects.
Lupron is prescribed for women with very bad endometriosis or severe menorrhagia. It also may be administered before assisted reproduction. In men, Lupron is used to treat advanced prostate cancer. It also may be used in children who are diagnosed with central precocious puberty (early puberty). Before you decide to use Lupron, make sure you understand the facts about the benefits and side effects so that you can make an informed decision.
Side Effects and Lupron Depot


Side effects that have been associated with the use of Lupron Depot frequently include hot flashes and night sweats, and less frequently palpitations, syncope, and tachycardias. Other side effects include generalized pain, headaches, vaginitis, nausea/vomiting, fluid retention[, weight gain, acne, hirsutism, joint pain, loss of sexual desire, depression, dizziness, nervousness, and breast changes such as tenderness and pain. There have been no deaths directly related to therapy with Lupron Depot. Lupron is an effective and medically accepted treatment for endometriosis. Despite the fact that many women do experience side effects during treatment with Lupron Depot, women often consider these side effects to be a necessary price to pay for the relief of the severe pain and suffering of endometriosis.

...
Much of the above is typical of AIs, but interesting about the fluid retention - as this is one of the reasons to try to suppress estrogen. As SS mentioned, rebound from Adex might end up in water retention, etc. but is this saying weight gain / water retention comes w/ the "cycle"? This would appear to negate the whole point for using it for competition?

[heavyiron]

I did read the study you posted, but since supression with Aromasin was about the same as Letro (in this study only), I didn't see why Aromasin would be any better for contest prep. Simply the fact that Letro was able to reduce gyno and is the only AI that can do that...certainly justifies speculation that something else is going on.

What you say makes sense concerning half-life, as it would be difficult to acheive the same results with aromasin unless you dosed it very often. You may be correct that improper dosing has been the cause for Letro giving superior results.

It will be interesting to see if Aromasin is able to reduce gyno like Letro, once proper dosing is undertaken by more people. If Aromasin is still not able to reduce gyno even when dosed properly, then I guess we would have to start looking elsewhere. Also, it will be nice once they have performed additional studies with both aromasin and Letro in men....as we all know different studies can yield different results. Frequency of use with Aromasin is a pain in the ass, but who that is serious really cares anyway.

Men have reported a reduction in gyno with Aromasin so I would not say Letro is the only AI that has been reported to do this. 25mg Aromasin every 12 hours is quite effective.

Check out some of these studies. I encourage you to carefully read the first study completely, not just the abstract. I have provided the full study link directly below the abstract.


Pharmacokinetics and Dose Finding of a Potent Aromatase Inhibitor, Aromasin (Exemestane), in Young Males

Nelly Mauras, John Lima, Deval Patel, Annie Rini, Enrico di Salle, Ambrose Kwok and Barbara Lippe
Nemours Children’s Clinic and Research Programs (N.M., J.L., A.R.), Jacksonville, Florida 32207; and University of Florida Health Sciences Center (D.P.) and Amersham Pharmacia Biotech (E.d.S., A.K., B.L.), Peapack, New Jersey 07977

Address all correspondence and requests for reprints to: Nelly Mauras, M.D., Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, Florida 32207. E-mail: nmauras@nemours.org.

Abstract

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 0.002); 50 mg, 32% (P 0.008)], with a reciprocal increase in testosterone concentrations (60% and 56%; P 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.

full study;
http://jcem.endojournals.org/cgi/con...ull/88/12/5951



In just 7 days steady-state plasma levels are reached with Aromasin. Because Aromasin raises testosterone so much it may exhibit androgenic side effects.


Pharmacology and pharmacokinetics of the newer generation aromatase inhibitors.

Buzdar AU.
Department of Breast Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA. abuzdar@mdanderson.org

The newer generation aromatase inhibitors (AIs) as a class show efficacy and tolerability benefits over previously established treatments in postmenopausal women with advanced breast cancer. At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) are 41-48 h, 2-4 days, and 27 h, respectively. Time to steady-state plasma levels is 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have only been reported with exemestane. Anastrozole treatment has no impact on plasma lipid levels, whereas both letrozole and exemestane have an unfavorable effect. From indirect comparisons, anastrozole shows the highest degree of selectivity compared with letrozole and exemestane, in terms of a lack of effect on adrenosteroidogenesis. To date, there are no data suggesting any major differences in clinical efficacy between the newer generation AIs anastrozole and letrozole. Based on the observed pharmacological profiles, however, it cannot be assumed that the AIs will display the same tolerability and safety profiles when given for extended periods of time in the adjuvant setting. The effects of anastrozole, letrozole, and exemestane are being investigated in the adjuvant setting, and these data will elucidate the possible long-term consequences of the pharmacological effects reported after short-term exposure.

PMID: 12538502 [PubMed - indexed for MEDLINE]


Effects of Tamoxifen and Exemestane on Cognitive Functioning of Postmenopausal Patients With Breast Cancer: Results From the Neuropsychological Side Study of the Tamoxifen and Exemestane Adjuvant Multinational Trial

Christina M. Schilder, Caroline Seynaeve, Louk V. Beex, Willem Boogerd, Sabine C. Linn, Chad M. Gundy, Hilde M. Huizenga, Johan W. Nortier, Cornelis J. van de Velde, Frits S. van Dam, and Sanne B. Schagen*
From the Departments of Psychosocial Research and Epidemiology, Neuro-oncology, and Medical Oncology, Netherlands Cancer Institute; Department of Neurology, Slotervaart Medical Center; Department of Psychology, University of Amsterdam, Amsterdam; Department of Medical Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam; Department of Medical Oncology, Radboud University Medical Center, Nijmegen; and the Departments of Medical Oncology and Surgical Oncology, Leiden University Medical Center, the Netherlands.

* To whom correspondence should be addressed. E-mail: s.schagen@nki.nl

Purpose: To evaluate the influence of adjuvant tamoxifen and exemestane on cognitive functioning in postmenopausal patients with breast cancer (BC).
Patients and Methods: Neuropsychological assessments were performed before the start (T1) and after 1 year of adjuvant endocrine treatment (T2) in Dutch postmenopausal patients with BC, who did not receive chemotherapy. Patients participated in the international Tamoxifen and Exemestane Adjuvant Multinational trial, a prospective randomized study investigating tamoxifen versus exemestane as adjuvant therapy for hormone-sensitive BC.
Results: Participants included 80 tamoxifen users (mean age, 68.7 years; range 51 to 84), 99 exemestane users (mean age, 68.3 years; range, 50 to 82), and 120 healthy controls (mean age, 66.2 years; range, 49 to 86). At T2, after adjustment for T1 performance, exemestane users did not perform statistically significantly worse than healthy controls on any cognitive domain. In contrast, tamoxifen users performed statistically significantly worse than healthy controls on verbal memory (P < .01; Cohen's d = .43) and executive functioning (P = .01; Cohen's d = .40), and statistically significantly worse than exemestane users on information processing speed (P = .02; Cohen's d = .36). With respect to visual memory, working memory, verbal fluency, reaction speed, and motor speed, no significant differences between the three groups were found.
Conclusion: After 1 year of adjuvant therapy, tamoxifen use is associated with statistically significant lower functioning in verbal memory and executive functioning, whereas exemestane use is not associated with statistically significant lower cognitive functioning in postmenopausal patients with BC. Our results accentuate the need to include assessments of cognitive effects of adjuvant endocrine treatment in long-term safety studies.


Estrogen Suppression in Males: Metabolic Effects1

Nelly Mauras, Kimberly O. O’Brien, Karen Oerter Klein and Valerie Hayes

Nemours Research Programs at the Nemours Children’s Clinic (N.M., V..H.), Jacksonville, Florida 32207; DuPont Hospital for Children (K.O.K.), Wilmington, Delaware 19803; and The Johns Hopkins University School of Hygiene and Public Health (K.O.O.), Baltimore, Maryland 21205-2179
Address all correspondence and requests for reprints to: Nelly Mauras, M.D., Nemours Children’s Clinic, 807 Nira Street, Jacksonville, Florida 32207. E-mail: nmauras@nemours.org.
We have shown that testosterone (T) deficiency per se is associated with marked catabolic effects on protein, calcium metabolism, and body composition in men independent of changes in GH or insulin-like growth factor I production. It is not clear, however, whether estrogens have a major role in whole body anabolism in males. We investigated the metabolic effects of selective estrogen suppression in the male using a potent aromatase inhibitor, Arimidex (Anastrozole). First, a dose-response study of 12 males (mean age, 16.1 ± 0.3 yr) was conducted, and blood withdrawn at baseline and after 10 days of oral Arimidex given as two different doses (either 0.5 or 1 mg) in random order with a 14-day washout in between. A sensitive estradiol (E2) assay showed an approximately 50% decrease in E2 concentrations with either of the two doses; hence, a 1-mg dose was selected for other studies. Subsequently, eight males (aged 15–22 yr; four adults and four late pubertal) had isotopic infusions of [13C]leucine and 42Ca/44Ca, indirect calorimetry, dual energy x-ray absorptiometry, isokinetic dynamometry, and growth factors measurements performed before and after 10 weeks of daily doses of Arimidex. Contrary to the effects of T withdrawal, there were no significant changes in body composition (body mass index, fat mass, and fat-free mass) after estrogen suppression or in rates of protein synthesis or degradation; carbohydrate, lipid, or protein oxidation; muscle strength; calcium kinetics; or bone growth factors concentrations. However, E2 concentrations decreased 48% (P = 0.006), with no significant change in mean and peak GH concentrations, but with an 18% decrease in plasma insulin-like growth factor I concentrations. There was a 58% increase in serum T (P = 0.0001), sex hormone-binding globulin did not change, whereas LH and FSH concentrations increased (P < 0.02, both). Serum bone markers, osteocalcin and bone alkaline phosphatase concentrations, and rates of bone calcium deposition and resorption did not change. In conclusion, these data suggest that in the male 1) estrogens do not contribute significantly to the changes in body composition and protein synthesis observed with changing androgen levels; 2) estrogen is a main regulator of the gonadal-pituitary feedback for the gonadotropin axis; and 3) this level of aromatase inhibition does not negatively impact either kinetically measured rates of bone calcium turnover or indirect markers of bone calcium turnover, at least in the short term. Further studies will provide valuable information on whether timed aromatase inhibition can be useful in increasing the height potential of pubertal boys with profound growth retardation without the confounding negative effects of gonadal androgen suppression.

Use of the aromatase inhibitor letrozole to treat male infertility.

Patry G, Jarvi K, Grober ED, Lo KC.
Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. kochman@hadassah.org.il
Abstract

OBJECTIVE: Report the case of induction of spermatogenesis with the aromatase inhibitor letrozole. DESIGN: Case report. SETTING: University Infertility center. PATIENT(S): A 31-year-old man with primary infertility, normal volume azoospermia, normal follicle stimulating hormone (FSH) levels and pattern of nonobstructive azoospermia (NOA) on a testicular biopsy. INTERVENTION(S): The patient was given the aromatase inhibitor letrozole for 4 months and had repeated FSH, testosterone, LH levels, semen analyses, and finally a testicular biopsy. MAIN OUTCOME MEASURE(S): Results of a testis biopsy. RESULT(S): Testis biopsy showed normal spermatogenesis following 4 months of letrozole therapy. CONCLUSION(S): This is the first case report on the use of letrozole to treat male infertility and the first case report on the induction of spermatogenesis in a man with NOA using any aromatase inhibitor.

PMID: 19524225 [PubMed - indexed for MEDLINE]

[Mike Arnold]

Men have reported a reduction in gyno with Aromasin so I would not say Letro is the only AI that has been reported to do this. 25mg Aromasin every 12 hours is quite effective.

Check out some of these studies. I encourage you to carefully read the first study completely, not just the abstract. I have provided the full study link directly below the abstract.


Pharmacokinetics and Dose Finding of a Potent Aromatase Inhibitor, Aromasin (Exemestane), in Young Males

Nelly Mauras, John Lima, Deval Patel, Annie Rini, Enrico di Salle, Ambrose Kwok and Barbara Lippe
Nemours Children’s Clinic and Research Programs (N.M., J.L., A.R.), Jacksonville, Florida 32207; and University of Florida Health Sciences Center (D.P.) and Amersham Pharmacia Biotech (E.d.S., A.K., B.L.), Peapack, New Jersey 07977

Address all correspondence and requests for reprints to: Nelly Mauras, M.D., Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, Florida 32207. E-mail: nmauras@nemours.org.

Abstract

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 0.002); 50 mg, 32% (P 0.008)], with a reciprocal increase in testosterone concentrations (60% and 56%; P 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.

full study;
http://jcem.endojournals.org/cgi/con...ull/88/12/5951



In just 7 days steady-state plasma levels are reached with Aromasin. Because Aromasin raises testosterone so much it may exhibit androgenic side effects.


Pharmacology and pharmacokinetics of the newer generation aromatase inhibitors.

Buzdar AU.
Department of Breast Medical Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA. abuzdar@mdanderson.org

The newer generation aromatase inhibitors (AIs) as a class show efficacy and tolerability benefits over previously established treatments in postmenopausal women with advanced breast cancer. At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) are 41-48 h, 2-4 days, and 27 h, respectively. Time to steady-state plasma levels is 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have only been reported with exemestane. Anastrozole treatment has no impact on plasma lipid levels, whereas both letrozole and exemestane have an unfavorable effect. From indirect comparisons, anastrozole shows the highest degree of selectivity compared with letrozole and exemestane, in terms of a lack of effect on adrenosteroidogenesis. To date, there are no data suggesting any major differences in clinical efficacy between the newer generation AIs anastrozole and letrozole. Based on the observed pharmacological profiles, however, it cannot be assumed that the AIs will display the same tolerability and safety profiles when given for extended periods of time in the adjuvant setting. The effects of anastrozole, letrozole, and exemestane are being investigated in the adjuvant setting, and these data will elucidate the possible long-term consequences of the pharmacological effects reported after short-term exposure.

PMID: 12538502 [PubMed - indexed for MEDLINE]


Effects of Tamoxifen and Exemestane on Cognitive Functioning of Postmenopausal Patients With Breast Cancer: Results From the Neuropsychological Side Study of the Tamoxifen and Exemestane Adjuvant Multinational Trial

Christina M. Schilder, Caroline Seynaeve, Louk V. Beex, Willem Boogerd, Sabine C. Linn, Chad M. Gundy, Hilde M. Huizenga, Johan W. Nortier, Cornelis J. van de Velde, Frits S. van Dam, and Sanne B. Schagen*
From the Departments of Psychosocial Research and Epidemiology, Neuro-oncology, and Medical Oncology, Netherlands Cancer Institute; Department of Neurology, Slotervaart Medical Center; Department of Psychology, University of Amsterdam, Amsterdam; Department of Medical Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam; Department of Medical Oncology, Radboud University Medical Center, Nijmegen; and the Departments of Medical Oncology and Surgical Oncology, Leiden University Medical Center, the Netherlands.

* To whom correspondence should be addressed. E-mail: s.schagen@nki.nl

Purpose: To evaluate the influence of adjuvant tamoxifen and exemestane on cognitive functioning in postmenopausal patients with breast cancer (BC).
Patients and Methods: Neuropsychological assessments were performed before the start (T1) and after 1 year of adjuvant endocrine treatment (T2) in Dutch postmenopausal patients with BC, who did not receive chemotherapy. Patients participated in the international Tamoxifen and Exemestane Adjuvant Multinational trial, a prospective randomized study investigating tamoxifen versus exemestane as adjuvant therapy for hormone-sensitive BC.
Results: Participants included 80 tamoxifen users (mean age, 68.7 years; range 51 to 84), 99 exemestane users (mean age, 68.3 years; range, 50 to 82), and 120 healthy controls (mean age, 66.2 years; range, 49 to 86). At T2, after adjustment for T1 performance, exemestane users did not perform statistically significantly worse than healthy controls on any cognitive domain. In contrast, tamoxifen users performed statistically significantly worse than healthy controls on verbal memory (P < .01; Cohen's d = .43) and executive functioning (P = .01; Cohen's d = .40), and statistically significantly worse than exemestane users on information processing speed (P = .02; Cohen's d = .36). With respect to visual memory, working memory, verbal fluency, reaction speed, and motor speed, no significant differences between the three groups were found.
Conclusion: After 1 year of adjuvant therapy, tamoxifen use is associated with statistically significant lower functioning in verbal memory and executive functioning, whereas exemestane use is not associated with statistically significant lower cognitive functioning in postmenopausal patients with BC. Our results accentuate the need to include assessments of cognitive effects of adjuvant endocrine treatment in long-term safety studies.


Estrogen Suppression in Males: Metabolic Effects1

Nelly Mauras, Kimberly O. O’Brien, Karen Oerter Klein and Valerie Hayes

Nemours Research Programs at the Nemours Children’s Clinic (N.M., V..H.), Jacksonville, Florida 32207; DuPont Hospital for Children (K.O.K.), Wilmington, Delaware 19803; and The Johns Hopkins University School of Hygiene and Public Health (K.O.O.), Baltimore, Maryland 21205-2179
Address all correspondence and requests for reprints to: Nelly Mauras, M.D., Nemours Children’s Clinic, 807 Nira Street, Jacksonville, Florida 32207. E-mail: nmauras@nemours.org.
We have shown that testosterone (T) deficiency per se is associated with marked catabolic effects on protein, calcium metabolism, and body composition in men independent of changes in GH or insulin-like growth factor I production. It is not clear, however, whether estrogens have a major role in whole body anabolism in males. We investigated the metabolic effects of selective estrogen suppression in the male using a potent aromatase inhibitor, Arimidex (Anastrozole). First, a dose-response study of 12 males (mean age, 16.1 ± 0.3 yr) was conducted, and blood withdrawn at baseline and after 10 days of oral Arimidex given as two different doses (either 0.5 or 1 mg) in random order with a 14-day washout in between. A sensitive estradiol (E2) assay showed an approximately 50% decrease in E2 concentrations with either of the two doses; hence, a 1-mg dose was selected for other studies. Subsequently, eight males (aged 15–22 yr; four adults and four late pubertal) had isotopic infusions of [13C]leucine and 42Ca/44Ca, indirect calorimetry, dual energy x-ray absorptiometry, isokinetic dynamometry, and growth factors measurements performed before and after 10 weeks of daily doses of Arimidex. Contrary to the effects of T withdrawal, there were no significant changes in body composition (body mass index, fat mass, and fat-free mass) after estrogen suppression or in rates of protein synthesis or degradation; carbohydrate, lipid, or protein oxidation; muscle strength; calcium kinetics; or bone growth factors concentrations. However, E2 concentrations decreased 48% (P = 0.006), with no significant change in mean and peak GH concentrations, but with an 18% decrease in plasma insulin-like growth factor I concentrations. There was a 58% increase in serum T (P = 0.0001), sex hormone-binding globulin did not change, whereas LH and FSH concentrations increased (P < 0.02, both). Serum bone markers, osteocalcin and bone alkaline phosphatase concentrations, and rates of bone calcium deposition and resorption did not change. In conclusion, these data suggest that in the male 1) estrogens do not contribute significantly to the changes in body composition and protein synthesis observed with changing androgen levels; 2) estrogen is a main regulator of the gonadal-pituitary feedback for the gonadotropin axis; and 3) this level of aromatase inhibition does not negatively impact either kinetically measured rates of bone calcium turnover or indirect markers of bone calcium turnover, at least in the short term. Further studies will provide valuable information on whether timed aromatase inhibition can be useful in increasing the height potential of pubertal boys with profound growth retardation without the confounding negative effects of gonadal androgen suppression.

Use of the aromatase inhibitor letrozole to treat male infertility.

Patry G, Jarvi K, Grober ED, Lo KC.
Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. kochman@hadassah.org.il
Abstract

OBJECTIVE: Report the case of induction of spermatogenesis with the aromatase inhibitor letrozole. DESIGN: Case report. SETTING: University Infertility center. PATIENT(S): A 31-year-old man with primary infertility, normal volume azoospermia, normal follicle stimulating hormone (FSH) levels and pattern of nonobstructive azoospermia (NOA) on a testicular biopsy. INTERVENTION(S): The patient was given the aromatase inhibitor letrozole for 4 months and had repeated FSH, testosterone, LH levels, semen analyses, and finally a testicular biopsy. MAIN OUTCOME MEASURE(S): Results of a testis biopsy. RESULT(S): Testis biopsy showed normal spermatogenesis following 4 months of letrozole therapy. CONCLUSION(S): This is the first case report on the use of letrozole to treat male infertility and the first case report on the induction of spermatogenesis in a man with NOA using any aromatase inhibitor.

PMID: 19524225 [PubMed - indexed for MEDLINE]

Thanks brother. I will definitely read them. I did not know that Aromasin had been reported to reduce glandular tisue in breast tissue, as does Letro. If this is the case and Aromasin does suppress estrogen as much as Letro, which it appears to be, then I am ALMOST ready to change my mind on the subject...LOL.

It woud be nice if they would do additional studies, though. I am sure they will eventually.

[Dr Pangloss]

I have never seen data to confirm this. In fact Letro is not as strong in men as some think. Again the circulating T in men makes AI's less effective so relying on a female trial does not have application to us.

Comparative Assessment in Young and Elderly Men of the Gonadotropin Response to Aromatase Inhibition

Guy G. T’Sjoen, Vito A. Giagulli, Hans Delva, Patricia Crabbe, Dirk De Bacquer and Jean-Marc Kaufman

Department of Endocrinology (G.G.T., H.D., P.C., J.-M.K.), Ghent University Hospital, 9000 Ghent, Belgium; Department of Public Health (D.D.B.), Ghent University, 9000 Ghent, Belgium; and Department of Internal Medicine Subdivision Endocrinology (V.A.G.), Ospedale Putignano-Noci, 70017 Bari, Italy
Address all correspondence and requests for reprints to: G. T’Sjoen, M.D., Department of Endocrinology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. E-mail: guy.tsjoen@ugent.be .

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 iv 2.5-µg 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.

http://jcem.endojournals.org/cgi/reprint/90/10/5717

please post the data that shows circulating Test decreases the efficacy of aromatase inhibitors, and that female trials are not germain to an AI's efficacy in males.

[Dr Pangloss]

your aromasin study in males only shows a 32 and 38% decrease in plasma e2 levels after 25 and 50 mg, respectively. Look a couple lines up from where you've bolded. the 62% refers to suppression of the rate of conversion, i believe. Not total E2.

Certainly not nearly as good as letro. At least in older men.

However, we're comparing accute and chronic studies. It's not really fair.

You are right that the half life is a concern with aromasin. A side-by side study with once daily dosing is probably going to show letrozole more effective. bid however, may show aromasin to be. it's difficult to tell.

Also, if you have a study demonstrating that Test interfers with AI efficacy, I'd like to see it.

cheers bro.

[Mike Arnold]

your aromasin study in males only shows a 32 and 38% decrease in plasma e2 levels after 25 and 50 mg, respectively. Look a couple lines up from where you've bolded. the 62% refers to suppression of the rate of conversion, i believe. Not total E2.

Certainly not nearly as good as letro. At least in older men.

However, we're comparing accute and chronic studies. It's not really fair.

You are right that the half life is a concern with aromasin. A side-by side study with once daily dosing is probably going to show letrozole more effective. bid however, may show aromasin to be. it's difficult to tell.

Also, if you have a study demonstrating that Test interfers with AI efficacy, I'd like to see it.

cheers bro.

See bold above: Thanks bro. There was something that didn't sit right with me regarding the belief that Aromasin is more potent than Letro for estrogen suppression, based on every individual experience I have been able to review, in addition to Letro's widely claimed superiority for contest prep, as well as the very commonly reported reduction of glandular tissue in men with gyno....which to my knowedge, has happened far more often with Letro than with any other AI by a long shot.

It was difficult for me to reliquish Letro as the #1 AI for estrogen suppression, despite the study posted above (that I didn't realize had been misinterpreted). It looks like I will be maintaining my stance on Letro as the #1 AI for estrogen supression and contest prep, as I had always done before.

However, for PCT, I still believe Aromasin is superior due to it's suicide inhibition, as estrogen rebound is not at all desirable after PCT.

Letro is #1.....that was for Heavy Iron.

[heavyiron]

please post the data that shows circulating Test decreases the efficacy of aromatase inhibitors, and that female trials are not germain to an AI's efficacy in males.

your aromasin study in males only shows a 32 and 38% decrease in plasma e2 levels after 25 and 50 mg, respectively. Look a couple lines up from where you've bolded. the 62% refers to suppression of the rate of conversion, i believe. Not total E2.



Certainly not nearly as good as letro. At least in older men.



However, we're comparing accute and chronic studies. It's not really fair.



You are right that the half life is a concern with aromasin. A side-by side study with once daily dosing is probably going to show letrozole more effective. bid however, may show aromasin to be. it's difficult to tell.



Also, if you have a study demonstrating that Test interfers with AI efficacy, I'd like to see it.



cheers bro.

Hey brother, I am pulling my conclusions from the excerpt in post #9 in this thread. It is buried in the Aromasin study. Looks like the half life in men and circulating T effect the drugs ability to reduce aromatase. The same thing was noted in an Arimidex study. If we measure E2 supression around the half life of Aromasin it paints a different picture of the effectiveness. Essentially when E2 is measured way past the half life it shows a lower effectiveness but this is an unfair way of measuring a drugs effectiveness.

[Dr Pangloss]

Hey brother, I am pulling my conclusions from the excerpt in post #9 in this thread. It is buried in the Aromasin study. Looks like the half life in men and circulating T effect the drugs ability to reduce aromatase. The same thing was noted in an Arimidex study. If we measure E2 supression around the half life of Aromasin it paints a different picture of the effectiveness. Essentially when E2 is measured way past the half life it shows a lower effectiveness but this is an unfair way of measuring a drugs effectiveness.

you are right, it is an unfair way of comparing effectiveness.

I'm intrigued by the idea that circulating T inhibits efficacy. You know, it actually suggests that we need to look at higher doses in men. I'm thinking that neither the aromasin (25 to 50 mg) or letro (2.5 mg) is saturating. That is, if Test is a competitive inhibitor of aromatase, then higher doses are warranted. I've only seen one arimidex study which suggested 1 mg ed was no better than .5 mg ed. Pretty sure that one was males.

Clearly though from the single dose of aromasin at 25 mg and 50 resulting in decreasing total estrogen suggests it doesn't look saturated. That is, at 50 mg we would have expected the same 32% decrease that the 25 yielded. And, frankly i don't believe 2.5 mg of letro is a saturating dose.

It would be really great to see aromasin and letro side-by-side in chronic study with men at saturating doses measuring total E2.

Thanks my friend, for making chem e interesting.

[Dr Pangloss]

by the way i tried to read the whole paper but your link was broken.


cheers.

[Mike Arnold]

you are right, it is an unfair way of comparing effectiveness.

I'm intrigued by the idea that circulating T inhibits efficacy. You know, it actually suggests that we need to look at higher doses in men. I'm thinking that neither the aromasin (25 to 50 mg) or letro (2.5 mg) is saturating. That is, if Test is a competitive inhibitor of aromatase, then higher doses are warranted. I've only seen one arimidex study which suggested 1 mg ed was no better than .5 mg ed. Pretty sure that one was males.

Clearly though from the single dose of aromasin at 25 mg and 50 resulting in decreasing total estrogen suggests it doesn't look saturated. That is, at 50 mg we would have expected the same 32% decrease that the 25 yielded. And, frankly i don't believe 2.5 mg of letro is a saturating dose.

It would be really great to see aromasin and letro side-by-side in chronic study with men at saturating doses measuring total E2.

Thanks my friend, for making chem e interesting.

See bold above. Yeah, it would be, but I doubt that will happen any time soon....unfortunately.

[Dr Pangloss]

See bold above. Yeah, it would be, but I doubt that will happen any time soon....unfortunately.

i believe there is a study like this in females, but as heavy has pointed out, the results in females have questionable application to males.

[heavyiron]

you are right, it is an unfair way of comparing effectiveness.

I'm intrigued by the idea that circulating T inhibits efficacy. You know, it actually suggests that we need to look at higher doses in men. I'm thinking that neither the aromasin (25 to 50 mg) or letro (2.5 mg) is saturating. That is, if Test is a competitive inhibitor of aromatase, then higher doses are warranted. I've only seen one arimidex study which suggested 1 mg ed was no better than .5 mg ed. Pretty sure that one was males.

Clearly though from the single dose of aromasin at 25 mg and 50 resulting in decreasing total estrogen suggests it doesn't look saturated. That is, at 50 mg we would have expected the same 32% decrease that the 25 yielded. And, frankly i don't believe 2.5 mg of letro is a saturating dose.

It would be really great to see aromasin and letro side-by-side in chronic study with men at saturating doses measuring total E2.

Thanks my friend, for making chem e interesting.

Since the half life of aromasin is 8.9 hours in men and maximal E2 supression was at the 12 hour mark for men we can assume every 12 hour dosing would yeild the most E2 supression. I propose 25mg of Aromasin every 12 hours in men who want maximal E2 supression from this AI.

Thank you for your thought provoking contributions and questions as well. Your influence has shaped my thinking in recent years and I am very grateful for the studies you have e-mailed me over those years.

[heavyiron]

by the way i tried to read the whole paper but your link was broken.


cheers.

Check out the Discussion section. This is what changed my mind on Aromasin dosing.


The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 5951-5956
Copyright © 2003 by The Endocrine Society

Pharmacokinetics and Dose Finding of a Potent Aromatase Inhibitor, Aromasin (Exemestane), in Young Males

Discussion

We report the first detailed study of the pharmacological effects of exemestane in male subjects. Doses of 25 and 50 mg were comparable in suppressing all circulating estrogens and had similar effects of increasing serum androstenedione and testosterone concentrations. There were 38%, 71%, and 45% decreases in estradiol, estrone, and estrone sulfate concentrations, respectively, after 10 d, approximately 24 h after administration of the last dose of 25 mg exemestane, coupled with 60% and 32% increases in testosterone and androstenedione concentrations. The rise in the aromatase substrates, testosterone and androstenedione, is probably secondary to substrate accumulation and/or to the feedback increase in gonadotropins caused by aromatase blockade. The 21% decrease in SHBG concentrations caused by 25 mg exemestane confirms the observation in postmenopausal women (20).

The maximum plasma concentration, time to achieve maximal concentrations and oral clearance for exemestane after oral administration of a single dose of 25 mg in the present study of males were similar to those reported for females (21, 22, 23). The terminal half-life in the present study (8.9 h) was considerably shorter than the published value of 27 h (23). The reason for this difference is not clear, but may be related to a true gender dependency possibly involving the volume of distribution (lower in males than females) and plasma or tissue protein binding (respectively, higher and lower in males). This finding may also be due to the lower sensitivity of the analytical methodology used in the previous studies (14 pg/ml by HPLC/RIA) (21).

The maximal suppression evoked by exemestane at the single dose of 25 mg in the present study was similar to published results in postmenopausal women, but the time course differed (24). Evans et al. (24) reported that a single 25-mg oral dose of exemestane maximally suppressed estradiol concentrations by 72% 3 d after administration, and estradiol levels returned to baseline only 8–11 d after drug administration. In the present study maximal suppression of estradiol of 62% was observed 12 h after exemestane administration and returned to baseline 3–6 d after administration. The reason for this difference is not clear, but may be related to the shorter half-life of exemestane in males, the lower exposure to exemestane, and the higher levels of the aromatase substrates androstenedione (1 ng/ml in young males vs. 0.5 ng/ml in postmenopausal women), particularly the much higher testosterone concentrations in young males than in postmenopausal women (700 ng/dl vs. 20 ng/dl, respectively) (25). This is supported by the observation that in the 10-d study in young males reported here, the suppression of estradiol is weaker (due to the very high levels of the precursor testosterone) than that of estrone (due to androstenedione levels not very different from those in postmenopausal women). A limited suppression of circulating estradiol (50%) has been reported in a similar study in young males treated with 1 mg daily anastrozole (7), a dose that reduces estradiol by 85% in postmenopausal women (23).

Aromatase inhibitors are being investigated in a variety of clinical situations besides breast cancer. As estrogen is the principal factor responsible for epiphyseal fusion, aromatase blockers are being studied in the treatment of severe short stature in boys (8, 9). This class of compounds has a theoretical advantage over using LHRH analogs to delay puberty, because they allow for progressive virilization while decreasing estrogens, potentially extending the time of epiphyseal fusion and thus the time for linear growth. Trials have not yet been performed in adolescent females due to the concerns that increased circulating gonadotropins, decreased estrogens, and increased testosterone could precipitate ovarian dysfunction and virilization, as is seen in the aromatase-deficient female (3, 26). Because of its properties of increasing circulating gonadotropins, it has been used as a treatment for oligospermic men with low testosterone/estradiol ratios with initial preliminary success (27). This class of compounds also has a theoretical application in the treatment of gynecomastia in those individuals with overexpressed aromatase activity as recently reported (28). In addition, studies conducted using estrogen receptor blockade in the treatment of gonadotropin-independent precocious puberty have shown encouraging results (29); hence, the use of aromatase blockers seems like a natural alternative worthy of clinical trials as well.

We conclude that exemestane is a potent aromatase inhibitor in men. Exemestane appears to be an alternative in the choice of inhibitors of the aromatase enzyme available for human studies. Further studies are underway to estimate dose and dosing intervals that will provide therapeutic suppression of estrogen concentrations in males. Long-term safety will also require further investigation.

full study
http://jcem.endojournals.org/cgi/con...ull/88/12/5951

[heavyiron]

See bold above: Thanks bro. There was something that didn't sit right with me regarding the belief that Aromasin is more potent than Letro for estrogen suppression, based on every individual experience I have been able to review, in addition to Letro's widely claimed superiority for contest prep, as well as the very commonly reported reduction of glandular tissue in men with gyno....which to my knowedge, has happened far more often with Letro than with any other AI by a long shot.

It was difficult for me to reliquish Letro as the #1 AI for estrogen suppression, despite the study posted above (that I didn't realize had been misinterpreted). It looks like I will be maintaining my stance on Letro as the #1 AI for estrogen supression and contest prep, as I had always done before.

However, for PCT, I still believe Aromasin is superior due to it's suicide inhibition, as estrogen rebound is not at all desirable after PCT.

Letro is #1.....that was for Heavy Iron.

I did not misrepresent the study at all, you just misunderstood it =)