Designed to support testosterone deficiencies, compounded subcutaneous implants containing testosterone and anastrozole are one of the newest products in our line of pellet hormone therapies for men's health. In this blog, we will provide the summary of evidence for the combination.

 

Understanding Testosterone

Background

Testosterone and its bioactive metabolites dihydrotestosterone and estradiol are critical for their contribution to libido, muscle mass, fat distribution, hematopoiesis, mood, energy, sexual function, and cognition in males, as well as increased libido in postmenopausal women.

Testosterone is derived endogenously with a characteristic four ring C18 steroid structure, synthesized primarily in men by Leydig cells, which are located within the interstitium of the testis between the seminiferous tubules.1 Gonadotropin-releasing hormone (GnRH) released by the arcuate nucleus of the hypothalamus regulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH).1 The precursor of Testosterone, Cholesterol, is formed by de novo synthesis from acetyl-CoA in which biosynthesis into testosterone involves two multifunctional cytochrome P-450 complexes involving hydroxylation’s and side-chain scissions that is regulated by Luteinizing hormone that acts as the rate-limiting step in the conversion of cholesterol (Testosterone’s precursor) to pregnenolone within the Leydig cell’s mitochondria.1 Leydig cells create a concentration of testosterone in the testis that leaves the testis by diffusing down a concentration gradient across cell membranes into the bloodstream. Once testosterone is secreted primarily from Leydig cells, most testosterone binds to SHBG (Sex Hormone Binding Globulin), a homodimer of two glycoprotein subunits containing a single high-affinity steroid binding pocket, which participates in cellular testosterone uptake via primarily multi-valent low-density lipoprotein endocytic receptors located on cell surfaces.1

Free circulating testosterone levels (bioavailable) will exert characteristic androgenic effects on androgen-sensitive target tissues, which are primarily mediated by androgen receptors, a member of the steroid nuclear receptor superfamily. Testosterone that is bound to SHBG is considered nonactive, while testosterone that is bound to albumin or “free” is considered active.2 Monitoring of testosterone often measures both bound and unbound testosterone initially due to the cost and availability of assays.2

Within the prostate and scalp of a male, the enzyme 5-alpha-reductase will further metabolize testosterone into Dihydrotestosterone, its more potent counterpart. In the testes, testosterone will be further metabolized by aromatase into estradiol which serves many physiological benefits as well as possible adverse effects such as cardiovascular disease.1

In women, testosterone is produced in various locations such as the ovary, the adrenal gland, and peripheral tissues from various precursors produced by the ovaries themselves. The primary precursor that is produced in the ovaries is androstenedione which is further converted to provide around half of all testosterone in women and almost all estrone.1 For this reason, women who are postmenopausal, have a decreased production of testosterone.

Defects in testosterone production or levels can cause clinical features notably within the genital tract, sexual characteristics, and even fertility.

Men especially have a decline in testosterone levels as age increases due to a decreased testicular production of testosterone as well as increased SHBG reducing the amount of free testosterone.1 Testosterone deficiencies can also contribute to the anabolic status of somatic tissues causing a decrease in bone mineral density and muscle mass. Testosterone replacement therapy is widely used in men with symptomatic hypogonadism and is also used off-label for women where testosterone plays important physiological roles in female reproductive and non-reproductive health.

For men, the benefits of testosterone replacement therapy can be seen in an increase of libido and energy, beneficial effects on bone density, strength and muscle. Testosterone has debated cardioprotective effects at physiological levels, where increased testosterone has been associated with increased venous thrombotic events, thought to be due to aromatization of testosterone and subsequent estrogen-induced thrombophilia.3 Endogenous testosterone also plays an important role in women’s health and is primarily used to treat postmenopausal women with hypoactive sexual desire disorder (HSDD). For men experiencing testosterone deficiencies or women experiencing HSDD, biological hormone replacement therapy is often given to restore the body’s physiological hormone levels. Biological hormone replacement therapy is often unique to each patient, tailoring its therapy based on a patient’s exact hormone levels and dosing accordingly to each level that match physiological requirements.

 

A Word About Pellets

Pellets have often been used for BHRT as a preferred method of replacing bioidentical hormones, in which its vector is a small cylindrical fused pellet that is implanted under the skin and dissolves/releases in zero-order kinetics at a constant amount of drug over time.

Pellets have often been described as the preferred method of delivery for a myriad of reasons ranging from decreasing the possibility of transmission to others in cases such as transdermal preparations and eliminating the need for frequent administration. The subcutaneous insertion of testosterone is a weight-based approach that enables the constant release of hormones, often from a very concentrated dose.4

 

Anastrozole

Background

Anastrozole is a non-steroidal aromatase inhibitor primarily used for the treatment of postmenopausal women with advanced breast cancer. Anastrozole lowers estrogen levels in postmenopausal women by inhibiting the conversion of androstenedione to estrone by aromatase in the peripheral tissues.1 Estrone is normally converted into estradiol, therefor circulating estradiol levels have been shown to decrease with the use of anastrozole. Since anastrozole targets aromatase, it can also be utilized in decreasing the aromatization of testosterone in both women and men receiving testosterone hormone therapy. Aromatization of testosterone leads to local production of estradiol producing estrogen-mediated effects, which is especially significant in patients receiving testosterone hormone replacement therapy at high concentrations, specifically male patients who tend to receive higher doses.

Elevated estradiol levels have been associated with peripheral artery disease, coronary thrombosis, and stroke.3 Additionally, current guidelines for testosterone replacement therapy have not indicated frequent monitoring of estradiol levels, leading to increases of estradiol that are clinically undetected. Estradiol monitoring has not been clinically routinely done due to challenges that surround the accuracy, precision, and sensitivity of estradiol tests.2 Indications of aromatase inhibitor therapy, specifically in men, include signs and symptoms of excess estrogen such as abdominal obesity, anxiety, irritability, aggression, fluid retention, Gynecomastia, and lack of effects from testosterone therapy.3

Medical indications for aromatase inhibitors may include benign prostatic hypertrophy, history of prostate cancer, increased risk of thrombosis, insulin resistance, obesity, or seizures.3 Anastrozole has been utilized as a synergistic component of testosterone hormone replacement therapy.

 

Low-dose Anastrozole Combined With Pellet Implants of Testosterone

Summary of Evidence

Increasing clinical experience has shown that testosterone dosing in male patients has drastically increased to maintain optimal testosterone levels for longer periods of time, which has, in turn, increased the likelihood of increased estradiol and its adverse effects on cardiovascular health and prostate health.3 The increasing strength of testosterone hormone therapy indicated a need for further studies to research the possibility of anastrozole use decreasing estradiol effects of therapy.

An institutional review board-approved cohort study was initiated in March of 2014, which prospectively investigated the occurrence of cardiovascular events and prostate cancer in men treated with testosterone and anastrozole subcutaneous pellet therapy.

For this study, the patient selection included men who were currently being treated with testosterone therapy or just beginning testosterone therapy and those receiving both testosterone and anastrozole.

No patients were excluded for any prior history of cardiac disease, prostate disease, or prostate cancer.

The study consisted of 344 men who were accrued from March 2014 to April of 2017 in which data was evaluated in April 2017.

Patient demographics included an average of 53 years old, an average weight of 207 kg, BMI of 29.31, and a baseline testosterone level of 300 ng/dl.

To determine efficacy of testosterone and anastrozole implants in controlling estradiol in high dose (> 1600 mg) testosterone implant therapy, serum levels of testosterone and estradiol were measured at four weeks post-insertion and the end of therapy when symptoms returned prior to re-insertion.

Hemoglobin and hematocrit were also monitored as their levels are directly correlated with dose-dependent testosterone and can be increased as much as 5-7% through its effects on producing erythropoietin.2

Testosterone dosing was weight-based, and duration of therapy was also dose-related as higher doses of testosterone maintained symptom control for longer periods of time.

The mean testosterone dose in the study patients was 1,827 mg and the mean Anastrozole dose was 15.3 mg with most men receiving 16 mg of anastrozole.3

The mean interval of implant insertion was 4.8 months.3

The rate at which each component was released followed zero-order kinetics, where testosterone and anastrozole simultaneously released at a ratio of 15:1 and testosterone drove the release of anastrozole at a rate identical to itself.3

The Conclusion
Results showed that low-dose anastrozole combined with pellet implants of testosterone provided sustained levels of testosterone without elevating serum estradiol and exhibited no adverse symptoms related to excess estrogen, including anxiety, breast pain, edema, fluid retention, Gynecomastia, increased thrombosis, irritability, or prostate issues.3 Furthermore, the combination of anastrozole with testosterone released 0.1 mg of anastrozole per day compared to an oral dose of 1 mg per day used in breast cancer patients. This low dose successfully prevented any excess aromatization and lessened side effects of anastrozole. No side effects were experienced following the subcutaneous insertion of anastrozole. Higher doses of testosterone, according to BMI did require higher doses of anastrozole, but no side effects were noted in these patients.

Safety
Regarding safety, in patients who received combination testosterone and anastrozole pellets, none were diagnosed with prostate cancer. There was also not an increase in venous thrombotic events. No deaths or adverse drug events other than elevated hemoglobin and hematocrit were attributed to testosterone therapy.

There were no side effects or adverse reactions to low-dose subcutaneous anastrozole, including body aches, joint pain, decreased bone mineral density, or gastrointestinal side effects that are common with oral delivery or anastrozole monotherapy.3

No side effects of estrogen deficiency, such as hot flashes, were noted in any patients.

 

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Product Information & Counseling Points for Treatment

If you would like more information about prescribing compounded implant therapies and our testosterone/anastrozole pellets, please send us your questions and requests for clinical materials and resources.

 

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If you have any questions or would like additional information, please contact Innovation Compounding at 1-800-547-1399, Monday-Friday, 9 a.m. to 5 p.m. EST, excluding all major holidays.

Medical Disclaimer This content is for informational and educational purposes only. It is not intended to provide medical advice or take the place of such information or treatment from a personal physician. All readers/viewers of this content are advised to consult their doctors or qualified health professionals regarding specific health questions. Neither Innovation Compounding, Inc. nor the publisher of this content takes responsibility for possible health consequences of any person or persons reading or following the information in this educational content. All viewers of this content, especially those taking prescription or over-the-counter medications, should consult their physicians before beginning any medication, nutritional supplement, diet, or health regimen. Innovation Compounding does not make or intend to make any claims to efficacy or safety of compounded products for specific conditions or disease states, as compounded products are not FDA-approved for these conditions.

Sources

  1. Handelsman DJ. Androgen Physiology, Pharmacology, Use and Misuse. [Updated 2020 Oct 5]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279000/ 
  2. Glaser RL, York AE. Subcutaneous Testosterone Anastrozole Therapy in Men: Rationale, Dosing, and Levels on Therapy. Int J Pharm Compd. 2019 Jul-Aug;23(4):325-339. PMID: 31315085. 
  3. Krakowsky, Y., & Grober, E. D. (2015). Testosterone Deficiency - Establishing A Biochemical Diagnosis. EJIFCC, 26(2), 105–113. 
  4. Glaser RL, York AE. Subcutaneous Testosterone Anastrozole Therapy in Men: Rationale, Dosing, and Levels on Therapy. Int J Pharm Compd. 2019 Jul-Aug;23(4):325-339. PMID: 31315085. 
  5. Morris, P. D., & Channer, K. S. (2012). Testosterone and cardiovascular disease in men. Asian journal of andrology, 14(3), 428–435. https://doi.org/10.1038/aja.2012.21 
  6. Osterberg, E. C., Bernie, A. M., & Ramasamy, R. (2014). Risks of testosterone replacement therapy in men. Indian journal of urology : IJU : journal of the Urological Society of India, 30(1), 2–7. https://doi.org/10.4103/0970-1591.124197 
  7. McCullough A. (2014). A Review of Testosterone Pellets in the Treatment of Hypogonadism. Current sexual health reports, 6(4), 265–269. https://doi.org/10.1007/s11930-014-0033-7 
  8. Glaser RL. Testosterone, anastrozole and venous thrombosis. Maturitas.2017; 103: 91. 
  9. Innovation Compounding. (2016). BHRT Prescriber Guide Innovation Compounding. Kennesaw, Ga; Innovation Compounding. 

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