Anastrozole

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Anastrozole

Arimidex, the brand name for anastrozole is an aromatase inhibitor used to lower circulating estrogen. It was developed to help fight breast cancer as estrogen plays a role in the growth of cancer cells. Anastrozole binds reversibly to the aromatase enzyme through competitive inhibition. This suppresses the conversion of androgens into estrogen. Circulating plasma estrogen can be reduced by nearly 85% in women using anastrozole. A common misconception is that aromatase inhibition is similar in men than women. However in trials when males were administered 1mg of anastrozole daily, circulating estrogen was only reduced by about 50%. Anastrozole is rapidly absorbed orally (time to reach maximum concentration, 1 h) with a slow apparent clearance of 1.54 liters/h and a terminal half-life of 46.8 h. Because anastrozole reversibly binds to the aromatase enzyme, once you stop taking it the aromatase enzyme is free to convert androgens such as testosterone into estrogen again. This is advantageous as very low estrogen can rise into the normal range if the medication is discontinued.


Figure 1. Changes in testosterone and E2 concentrations in normal young men (15-22 yr old) before and after 10 days of oral anastrozole at 0.5 and 1 mg.

Anastrozole not only lowers circulating estrogen but it also increases LH and FSH concentrations in addition to increasing testosterone by about 58% in men. In one study elderly men with mild hypogonadism were administered 1mg daily of anastrozole for 12 weeks. This treatment normalized serum testosterone levels in those men without adversely affecting lipids, inflammatory markers of cardiovascular risk or insulin resistance.

Anastrozole can be employed during a cycle when aromatizing compounds such as testosterone are administered in order to control estrogen from getting out of control. During the course of a typical steroid cycle estrogen can rise quite high. Estrogen has been measured as much as 7 times higher than normal in men on steroids. This is excessive and can potentially cause water retention, gynecomastia (the formation of female breast tissue) or benign prostatic hyperplasia. Therefore in order to avoid these side effects estrogen must be controlled.

Reduction in breast area and breast volume have been observed in young men treated for 6 months with anastrozole (1 mg daily). These subjects had recent preexisting gynecomastia (less than one year). However boys with longstanding gynecomastia (more than one year) were unresponsive to 6 months of anastrozole treatment, possibly due to development of dense breast fibrosis. Therefore using anastrozole to treat recent gynecomastia is supported by the data.

Anastrozole may be used during a steroid cycle with aromatizing compounds and during PCT to help keep the estrogen to testosterone balance in favor of testosterone. From the data I have read and my years of experience with this compound, 0.5mg of anastrozole every other day is a good starting point on moderate amounts of testosterone. If testosterone doses are raised then 0.5mg to 1mg daily may be needed to control estrogen. Since either high and low estrogen can cause side effects such as low libido only labs can determine the appropriate amount of anastrozole. Overall anastrozole is a highly effective compound for controlling Estrogen and is well tolerated.

References
1. Effect of aromatase inhibition on lipids and inflammatory markers of cardiovascular disease in elderly men with low testosterone levels.
2. Estrogen suppression in males: metabolic effects.
3. Pharmacokinetics and pharmacodynamics of anastrozole in pubertal boys with recent-onset gynecomastia.
4. Influence of Neoadjuvant Anastrozole (Arimidex) on Intratumoral Estrogen Levels and Proliferation Markers in Patients with Locally Advanced Breast Cancer

Written by John Connor

Information is for educational purposes ONLY. Consult a medical doctor before using any medication. heavyiron does not advocate readers engage in any illegal activity. Research chemicals are not meant for human consumption.

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Effect of aromatase inhibition on lipids and inflammatory markers of cardiovascular disease in elderly men with low testosterone levels.

Dougherty RH, Rohrer JL, Hayden D, Rubin SD, Leder BZ.
Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

OBJECTIVE: Although androgen replacement has been shown to have beneficial effects in hypogonadal men, there is concern that androgens may deleteriously affect cardiovascular risk in elderly men.

DESIGN: Anastrozole is an oral aromatase inhibitor that normalizes serum testosterone levels and decreases oestradiol levels modestly in elderly men with mild hypogonadism. Thirty-seven elderly hypogonadal men were randomized to receive either anastrozole 1 mg daily (n = 12), anastrozole 1 mg twice weekly (n = 11), or daily placebo (n = 14) for 12 weeks in a double-blind fashion.

PATIENTS: Men aged 62-74 years with mild hypogonadism defined by testosterone levels less than 350 ng/dl.

MEASUREMENTS: Serum levels of fasting lipids, C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and homeostatic model assessment (HOMA) scores were measured at 4-week intervals.

RESULTS: Treatment with anastrozole did not significantly affect fasting lipids, inflammatory markers (IL-6, CRP), adhesion molecules (ICAM-1, VCAM-1) or insulin sensitivity (HOMA). There was, however, a positive correlation between changes in serum triglycerides and changes in serum oestradiol levels (P = 0.04).

CONCLUSIONS: While short-term administration of anastrozole is an effective method of normalizing serum testosterone levels in elderly men with mild hypogonadism, it does not appear to adversely affect lipid profiles, inflammatory markers of cardiovascular risk or insulin resistance.

PMID: 15670201 [PubMed - indexed for MEDLINE]

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These two studies were summarized and showed anastrozole decreased Estradiol by about 50% while raising Testosterone by about 58% in males.


Estrogen suppression in males: metabolic effects.

Mauras N, O'Brien KO, Klein KO, Hayes V.
Nemours Research Programs at the Nemours Children's Clinic, Jacksonville, Florida 32207, USA. nmauras@nemours.org


Comment in:

• J Clin Endocrinol Metab. 2001 Apr;86(4):1836-8.

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 [(13)C]leucine and (42)Ca/(44)Ca, 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.

PMID: 10902781 [PubMed - indexed for MEDLINE]

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J Clin Endocrinol Metab. 2009 Aug;94(8):2975-8. Epub 2009 May 26.

Pharmacokinetics and pharmacodynamics of anastrozole in pubertal boys with recent-onset gynecomastia.

Mauras N, Bishop K, Merinbaum D, Emeribe U, Agbo F, Lowe E.

Source

Nemours Children's Clinic, 807 Children's Way, Jacksonville, FL 32207, USA. nmauras@nemours.org

Abstract

CONTEXT:
Use of aromatase inhibitors to suppress estrogen production is being actively investigated in a variety of experimental conditions in both females and males. Anastrozole (Arimidex) is a potent and selective reversible inhibitor of the aromatase enzyme in females.
OBJECTIVE:
Our objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of anastrozole in adolescent males with gynecomastia of less than 1 yr duration. The effect of anastrozole on breast size was also assessed as an exploratory aim.
DESIGN:
We conducted a PK/PD open-label study.
SETTING:
This clinical research center study was undertaken at pediatric academic centers.
PATIENTS:
Forty-two boys with gynecomastia (mean age 13 +/- 1.8 yr; duration of gynecomastia 7.0 +/- 2.5 months; body mass index 28.3 +/- 5.9 kg/m(2)) were recruited. Interventions: Anastrozole, 1 mg, was given daily for 6 months.
MAIN OUTCOMES:
We assessed PK/PD of anastrozole after 14 d daily dosing and changes in breast size (exploratory aim) by manual tape measurements (area) and ultrasound (volume) after 6 months.
RESULTS:
Anastrozole was rapidly absorbed orally (time to reach maximum concentration, 1 h) with a slow apparent clearance of 1.54 liters/h and a terminal half-life of 46.8 h. Testosterone/estradiol ratios increased significantly with concomitant increase in LH/FSH concentrations indicating aromatase blockade. There was a reduction in breast area (approximately 63%) and breast volume (approximately 57%) in the study group as compared with baseline (P = 0.004). The drug was well tolerated.
CONCLUSIONS:
Anastrozole is a potent aromatase inhibitor in adolescent males, with rapid absorption and slow elimination kinetics after oral dosing. Exploratory analysis of changes in breast size showed breast reduction in the cohort; this deserves further study.

PMID:19470631 [PubMed - indexed for MEDLINE]

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Clin Cancer Res. 2001 May;7(5):1230-6.

Influence of neoadjuvant anastrozole (Arimidex) on intratumoral estrogen levels and proliferation markers in patients with locally advanced breast cancer.

Geisler J, Detre S, Berntsen H, Ottestad L, Lindtjørn B, Dowsett M, Einstein Lønning P.

Source
Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway.

Abstract

Anastrozole (Arimidex) is a novel, selective, and potent aromatase inhibitor used for the treatment of postmenopausal breast cancer. The drug has been shown to inhibit in vivo aromatization by 96--97% and to suppress plasma estrogen levels by 84--94%. However, the effects of anastrozole on intratumoral estrogen levels have not been studied. Here we report the effects of neoadjuvant treatment with anastrozole on intratumoral levels of estrone (E(1)), estradiol (E(2)), and estrone sulfate (E(1)S), measured by a highly sensitive RIA following a multistep purification procedure involving high-pressure liquid chromatography. Tumor tissue was obtained prior to treatment and after 15 weeks on therapy with anastrozole (1 mg once daily) from 12 postmenopausal women with locally advanced breast cancer (T(3)--T(4) and/or N(2)). Pretreatment tissue levels of E(2), E(1), and E(1)S were 217.9 (69.8--679.9), 173.6 (83.9--358.9), and 80.7 (31.4--207.3) fmol/g tissue (geometric mean values with 95% confidence interval, respectively). Treatment with anastrozole suppressed tissue E(2), E(1), and E(1)S levels by 89.0% (73.2--95.5%), 83.4% (63.2--92.5%), and 72.9% (47.3--86.1%), respectively, compared with baseline levels, with no significant difference between responders and nonresponders. Plasma levels of E(2), E(1), and E(1)S were suppressed by 86.1, 83.9, and 94.2%, respectively. Anastrozole caused a decrease in the immunoexpression of the proliferation markers Ki67 and pS2 in all of the patients, with a trend for a more profound suppression in those achieving an objective response. The mean percentage of apoptotic cells was found to be decreased in responders and increased in nonresponders after 15 weeks of anastrozole therapy. Our results reveal anastrozole to cause a significant suppression of tissue estrogen levels and to influence the biology of primary estrogen receptor-positive breast cancers in postmenopausal women.

PMID:11350888 [PubMed - indexed for MEDLINE]

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J Clin Endocrinol Metab. 2001 Jun;86(6):2869-74.
The effect of aromatase inhibition on sex steroids, gonadotropins, and markers of bone turnover in older men.

Taxel P, Kennedy DG, Fall PM, Willard AK, Clive JM, Raisz LG.
Source

Division of Endocrinology and Metabolism, Center on Aging, University of Connecticut Health Center, Farmington, Connecticut 06030-1317, USA. taxel@nso.uchc.edu

Abstract

There is evidence that estrogen decreases bone turnover in men as well as women. We therefore hypothesized that older men would show increasedbone resorption in response to inhibition of the aromatase enzyme, which converts androgens to estrogen. Fifteen eugonadal men over 65 yr were treated for 9 weeks with 2.0 mg/day of anastrozole, an aromatase inhibitor. After 9 weeks of treatment, there were significant decreases in estradiol, estrone, and sex hormone-binding globulin levels by 29%, 73%, and 16%, respectively, and total testosterone increased significantly by 56%. Despite the limited decrease of estrogen and the increase in testosterone, C-telopeptide of type 1 collagen showed a progressive significant increase of 11%, 24%, and 33% (P for trend = 0.033) above baseline at 3, 6, and 9 weeks, respectively. N-telopeptide of type 1 collagen values were highly correlated with C-telopeptide of type 1 collagen, but the change in N-telopeptide of type 1 collagen was not statistically significant. Bone-specific alkaline phosphatase and N-terminal type I procollagen peptides showed significant decreases of 8% and 11% of baseline at 9 weeks. Osteocalcin decreased significantly by 30% at 18 weeks. We conclude that aromatase inhibition can reduce estrogen levels in older men, but this effect is limited, perhaps because of feedback stimulation of testosterone production, and that endogenous estrogen derived from aromatization of testosterone plays a role inbone metabolism of older men by limiting the rate of bone resorption.


PMID: 11397902 [PubMed - indexed for MEDLINE]

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J Clin Endocrinol Metab. 2004 Mar;89(3):1174-80.
Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels.

Leder BZ, Rohrer JL, Rubin SD, Gallo J, Longcope C.
Source

Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Abstract

As men age, serum testosterone levels decrease, a factor that may contribute to some aspects of age-related physiological deterioration. Although androgen replacement has been shown to have beneficial effects in frankly hypogonadal men, its use in elderly men with borderline hypogonadism is controversial. Furthermore, current testosterone replacement methods have important limitations. We investigated the ability of the orally administeredaromatase inhibitor, anastrozole, to increase endogenous testosterone production in 37 elderly men (aged 62-74 yr) with screening serumtestosterone levels less than 350 ng/dl. Subjects were randomized in a double-blind fashion to the following 12-wk oral regimens: group 1: anastrozole 1 mg daily (n = 12); group 2: anastrozole 1 mg twice weekly (n = 11); and group 3: placebo daily (n = 14). Hormone levels, quality of life (MOS Short-Form Health Survey), sexual function (International Index of Erectile Function), benign prostate hyperplasia severity (American Urological Association Symptom Index Score), prostate-specific antigen, and measures of safety were compared among groups. Mean +/- SD bioavailable testosteroneincreased from 99 +/- 31 to 207 +/- 65 ng/dl in group 1 and from 115 +/- 37 to 178 +/- 55 ng/dl in group 2 (P < 0.001 vs. placebo for both groups and P = 0.054 group 1 vs. group 2). Total testosterone levels increased from 343 +/- 61 to 572 +/- 139 ng/dl in group 1 and from 397 +/- 106 to 520 +/- 91 ng/dl in group 2 (P < 0.001 vs. placebo for both groups and P = 0.012 group 1 vs. group 2). Serum estradiol levels decreased from 26 +/- 8 to 17 +/- 6 pg/ml in group 1 and from 27 +/- 8 to 17 +/- 5 pg/ml in group 2 (P < 0.001 vs. placebo for both groups and P = NS group 1 vs. group 2). Serum LHlevels increased from 5.1 +/- 4.8 to 7.9 +/- 6.5 U/liter and from 4.1 +/- 1.6 to 7.2 +/- 2.8 U/liter in groups 1 and 2, respectively (P = 0.007 group 1 vs. placebo, P = 0.003 group 2 vs. placebo, and P = NS group 1 vs. group 2). Scores for hematocrit, MOS Short-Form Health Survey, International Index of Erectile Function, and American Urological Association Symptom Index Score did not change. Serum prostate-specific antigen levels increased in group 2 only (1.7 +/- 1.0 to 2.2 +/- 1.5 ng/ml, P = 0.031, compared with placebo). These data demonstrate that aromatase inhibition increases serumbioavailable and total testosterone levels to the youthful normal range in older men with mild hypogonadism. Serum estradiol levels decrease modestly but remain within the normal male range. The physiological consequences of these changes remain to be determined.


PMID: 15001605 [PubMed - indexed for MEDLINE]