Dr. Ron’s Research Review – August 4, 2010

This week’s research review focuses on aromatase, including:

 

Effect of Myomin in the Expression of Aromatase, to be published in Fertility & Sterility. (Chi 2010)

A recent article proposes the use of aromatase inhibitors in elderly men receiving testosterone replacement therapy to avoid the negative effects of estradiol. (Santen, Brodie et al. 2009)

The History of aromatase: saga of an important biological mediator and therapeutic target (Santen, Brodie et al. 2009)

Serum estradiol and risk of stroke in elderly men (Abbott, Launer et al. 2007)

Of Interest:

Do you know what Kallman Syndrome is?

Hint: Characteristics include: a lack of LH and FSH; and anosmia (complete inability to smell) or hyposmia (decreased ability to smell).

In the News:

What Do You Lack? Probably Vitamin D

By Jane E. Brody, NY Times, July 26, 2010 Link

Dr. Ron


Articles

Effect of Myomin in the Expression of Aromatase

            (Chi 2010) Download

Testosterone, estradiol and aromatase inhibitor therapy in elderly men

            (Leder 2007) Download

History of aromatase: saga of an important biological mediator and therapeutic target

            (Santen, Brodie et al. 2009) Download

Aromatase is the enzyme that catalyzes the conversion of androgens to estrogens. Initial studies of its enzymatic activity and function took place in an environment focused on estrogen as a component of the birth control pill. At an early stage, investigators recognized that inhibition of this enzyme could have major practical applications for treatment of hormone-dependent breast cancer, alterations of ovarian and endometrial function, and treatment of benign disorders such as gynecomastia. Two general approaches ultimately led to the development of potent and selective aromatase inhibitors. One targeted the enzyme using analogs of natural steroidal substrates to work out the relationships between structure and function. The other approach initially sought to block adrenal function as a treatment for breast cancer but led to the serendipitous finding that a nonsteroidal P450 steroidogenesis inhibitor, aminoglutethimide, served as a potent but nonselective aromatase inhibitor. Proof of the therapeutic concept of aromatase inhibition involved a variety of studies with aminoglutethimide and the selective steroidal inhibitor, formestane. The requirement for even more potent and selective inhibitors led to intensive molecular studies to identify the structure of aromatase, to development of high-sensitivity estrogen assays, and to "mega" clinical trials of the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, which are now in clinical use in breast cancer. During these studies, unexpected findings led investigators to appreciate the important role of estrogens in males as well as in females and in multiple organs, particularly the bone and brain. These studies identified the important regulatory properties of aromatase acting in an autocrine, paracrine, intracrine, neurocrine, and juxtacrine fashion and the organ-specific enhancers and promoters controlling its transcription. The saga of these studies of aromatase and the ultimate utilization of inhibitors as highly effective treatments of breast cancer and for use in reproductive disorders serves as the basis for this first Endocrine Reviews history manuscript.

Serum estradiol and risk of stroke in elderly men

            (Abbott, Launer et al. 2007) Download

OBJECTIVE: To determine if levels of serum estradiol and testosterone can predict stroke in a population-based sample of elderly men. METHODS: Serum 17beta estradiol and testosterone were measured in 2,197 men aged 71 to 93 years who participated in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent stroke, coronary heart disease, and cancer. Participants were followed to the end of 1998 for thromboembolic and hemorrhagic events. RESULTS: During the course of follow-up, 124 men developed a stroke (9.1/1,000 person-years). After age adjustment, men in the top quintile of serum estradiol (> or =125 pmol/L [34.1 pg/mL]) experienced a twofold excess risk of stroke vs men whose estradiol levels were lower (14.8 vs 7.3/1,000 person-years, p < 0.001). Among the lower quintiles, there were little differences in the risk of stroke. Findings were also significant and comparable for bioavailable estradiol and for thromboembolic and hemorrhagic events. After additional adjustment for hypertension, diabetes, adiposity, cholesterol concentrations, atrial fibrillation, and other characteristics, men in the top quintile of serum estradiol continued to have a higher risk of stroke vs those whose estradiol levels were lower (relative hazards = 2.2; 95% CI = 1.5 to 3.4, p < 0.001). Testosterone was not related to the risk of stroke. CONCLUSIONS: High levels of serum estradiol may be associated with an elevated risk of stroke in elderly men.

Kallman Syndrome - Link

Kallmann syndrome is a hypogonadism (decreased functioning of the glands that produce sex hormones) caused by a deficiency of gonadotropin-releasing hormone (GnRH), which is created by the hypothalamus. Kallmann syndrome is also called hypothalamic hypogonadism, familial hypogonadism with anosmia, and hypogonadotropic hypogonadism, reflecting its disease mechanism (a lack of the pituitary hormones LH and FSH).

Kallmann syndrome is a form of secondary hypogonadism, reflecting that the primary cause of the defect in sex-hormone production lies within the pituitary and hypothalamus rather than a physical defect of the testes or ovaries.


References

Abbott, R. D., L. J. Launer, et al. (2007). "Serum estradiol and risk of stroke in elderly men." Neurology 68(8): 563-8.

Chi, T. C. (2010). "Effect of Myomin in the Expression of Aromatase." Fertility & Sterility.

Leder, B. Z. (2007). "Testosterone, estradiol and aromatase inhibitor therapy in elderly men." J Steroid Biochem Mol Biol 106(1-5): 162-7.

Santen, R. J., H. Brodie, et al. (2009). "History of aromatase: saga of an important biological mediator and therapeutic target." Endocr Rev 30(4): 343-75.