STUDY PROTOCOL:
Exogenous Testosterone and venous thrombosis in Patients with Underlying Clotting abnormalities

When men are given testosterone, either by application of an androgen gel or by injection, some of that testosterone is coverted by the body (aromatized) to the female hormone, estradiol. If men have an underlying inherited trait which increases their risk of blood clotting, particularly the Factor V Leiden mutation, the Prothrombin gene mutation, high Factor VIII, high homocysteine, or the lupus anticoagulant, then the estradiol can interact with the underlying clotting trait to produce blood clots in the legs, the lungs, the eyes, the brain, and the bones. ANY MEN WHO HAVE DEVELOPED CLOTS AFTER RECEIVING EXOGENOUS TESTOSTERONE BY SKIN-GEL OR INJECTION, PROBABLY HAVE AN UNDERLYING COAGULATION DISORDER, AND WOULD BENEFIT BY STUDY. CALL THE CHOLESTEROL CENTER 513-585-7945 TO TALK WITH DR GLUECK ABOUT THIS STUDY, OR SEND DR GLUECK EMAIL AT sonar16@gmail.com.

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TITLE: Exogenous Testosterone and venous thrombosis in Patients with Underlying Clotting abnormalities
DATE OF STUDY SUBMISSION: 4 – 27 - 2010
PRINCIPAL INVESTIGATORS:
- Cholesterol Center Staff:
- C.J. Glueck MD, Naila Goldenberg MD, Ping Wang PhD
Jewish Hospital Residents
- Naseer A Khan MD
- Waqas Ahmed MD and other Jewish Hospital residents to be named.
Other Principal Investigators:
- Gautam Paul MD and others to be named.
LENGTH OF STUDY: 3-6 months

1. Purpose

Our study has two aims. First, we want to quantitate the estradiol levels produced by aromatization of exogenous androgens when given to men with libido or sexual function problems. Second, we want to conduct a pilot study of patients who are treated with exogenous testosterone and subsequently develop venous thrombosis, because of the interaction of increased estradiol (arising from the aromatization of the testosterone to estradiol). We plan to study two groups of patients:

Men given conventional androgel/ Testosterone for purpose of libido enhancement and hypgonadism and their blood estrodiol levels.
Men with thrombotic events who had been on androgel/Testosterone and their blood estrodiol levels.

2. Significance in relationship to human health:

It is already known that when otherwise normal men, are given exogenous testosterone, some of the testosterone is aromatized to estradiol (E2). We also have preliminary data which shows that patients who have some underlying clotting abnormalities are at significant risk for venous thrombosis when given androgel/Testosterone . Checking estradiol levels in these patients and its relationship toward developing venous clots in these patients will help us in better understanding of the pathophysiology of the thrombotic events If these patients are treated with exogenous testosterone their risk of developing complications from venous thrombosis becomes even higher. They might develop Central retinal vein occlusion, deep vein thrombosis, pulmonary embolism and osteonecrois of hip and jaws. Central retinal vein occlusion is an important cause of vision loss and is second most common retinal vascular disorder in USA. Avascular necrosis of the femoral head is also a debilitating disease that usually leads to osteoarthritis of the hip joint in relatively young adults (mean age at presentation: 38 y). The disease prevalence is unknown, but estimates indicate that 10,000-20,000 new cases are diagnosed in the United States per year.1, 2 Similarly osteonecrosis of jaw (ONJ) has been reported as a rare complication of bone disorders and phosphorus exposure since the 1830s.[3 ] Osteonecrosis of bone in general has been associated with a wide variety of factors, including advanced age, arthritis, chronic inactivity, corticosteroids, estrogen, female sex, hemodialysis, thrombophilic disorders, hyperlipidemia, hypertension, infection, and many other disorders. [4] , [5] , [6] and intravascular coagulation appears to be the central event however the exact pathoetiology is not completely understood.

We hypothesize that giving exogenous testosterone to patients with underlying clotting abnormality increases their chances of getting venous thrombosis by the conversion of testosterone to estradiol in the body.

3. Preliminary data

Our preliminary data based on patients referred to cholesterol center with the above mentioned complications supports our hypothesis of relationship between exogenous testosterone and venous thrombosis. In otherwise healthy patients given exogenous androgens, we have observed osteonecrosis, deep venous thrombosis and pulmonary embolus, and amaurosis fugax (retinal artery thrombosis).

4.Preclinical and Prior clinical studies:

Low doses of androgen are used in women for the symptomatic treatment of sexual dysfunction and premenstrual syndrome (PMS). Testosterone has also been used by the urologists to treat sexual dysfunctions in their male patients. Buckler et al has reported the effects of low-dose testosterone treatment on lipid metabolism and clotting factors7. The relationship of exogenous testosterone leading to clotting abnormality has not been investigated in detail. Smith et al has shown that testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina 8. Their study also didn’t study the effect of exogenous testosterone leading to thrombosis in people who already have an underlying clotting abnormalities.

5. Method of Study:

5a Subjects

We will study up to 50 patients from our Jewish Hospital who received exogenous testosterone by their urologists or primary care physicians

Men given conventional androgel/ Testosterone for purpose of libido enhancement and hypgonadism and their blood estrodiol levels.
Men with thrombotic events who had been on androgel/Testosterone and their blood estrodiol levels.

5b Inclusion Criteria:

Patients receiving exogenous androgens for purpose of improving libido, increasing low endogenous testosterone, or for treatment of hypogonadotrophic hypogonadism.

Patients who develop documented diagnoses of CRVO and/or osteonecrosis of jaw/femur, DVT or PE, and then found to have underlying clotting abnormalities

5c Exclusion Criteria

Patients not on exogenous testosterone.

5d Methods of study

Eligible men and women will be selected from our outpatients at the Jewish Hospital Cholesterol Center and patients seen by urologists in the The Jewish Hospital inpatient or in private office. These will include referred to us with diagnosis of CRVO and osteonecrosis of jaw and femur, DVT , PE or any other clotting abnormality after receiving exogenous testosterone.

At study entry, a detailed medical history will be taken. Information regarding onset of the symptoms, diagnosis and treatment and the association of their disease with other risk factors will be evaluated. All medications, smoking history, exercise history will also be recorded.
Blood will be obtained for measurement of total and free testosterone and estradiol levels.

5. Risks and Benefits:

Risks:
The only potential risk will be discomfort of having blood drawn (total 30 ml). The bloods drawn in the study are the same, which would routinely be drawn clinically in the Cholesterol Center . In addition the blood will be checked for total and free testosterone and estradiol levels.

Benefits:
People having clotting abnormalities, receiving exogenous testosterone and subsequently developing thrombosis will be studied in the study. The study will open new doors in studying the relationship of exogenous testosterone with thrombosis and complications from thrombosis. The better understanding of the disease process will help prevent these complications in people receiving exogenous testosterone in near future.

7. Payment:

There will be no financial remuneration. Parking is free for Cholesterol Center patients

8. Estimated time:

Estimated time to complete study is 3-6 months.

9. Funding:

It is anticipated that The Jewish Hospital Medical Research Council will fund this project.

10. References:

Lavernia CJ, Sierra RJ, Grieco FR. Osteonecrosis of the femoral head. J Am Acad Orthop Surg. Jul-Aug 1999;7(4):250-61. [Medline].
Vail TP, Covington DB. The incidence of osteonecrosis. In: Urbaniak JR, Jones JR, eds. Osteonecrosis: Etiology, Diagnosis, Treatment. Rosemont, Ill: American Academy of Orthopedic Surgeons; 1997:43-9.
Donoghue A.M.: Bisphosphonates and osteonecrosis ,analogy to phossy jaw Med J Aust 183 (3): 163-164.2005;
Roberts A., McMahon R.: Causes of ischemic bone damage. The Maxillofacial Center for Diagnostics & ResearchAccessed November 28, 2007 http://www.maxillofacialcenter.com/NICOcause.html
Ruggiero S.L., Gralow J., Marx R.E., et al: Practical guidelines for the prevention, diagnosis, and treatment osteonecrosis of the jaws in patients with cancer. J Oncol Pract 2. (1): 7-14.2006;
Glueck C.J., McMahon R.E., Bouquot J.E., et al: A preliminary pilot study of treatment of thrombophilia and hypofibrinolysis and amelioration of the pain of osteonecrosis of the jaws Oral Surg Oral Med Oral Pathol Oral Radiol Endod 85. (1): 64-73.1998;
H. M. Buckler, K. McElhone, P. N. Durrington, M. I. Mackness, C. A. Ludlam and F. C. Wu. The effects of low-dose testosterone treatment on lipid metabolism, clotting factors and ultrasonographic ovarian morphology in womenClin Endocrinol (Oxf). 1998 Aug;49(2):173-8.
A. M. Smith, K. M. English, C. J. Malkin, R. D. Jones, T. H. Jones and K. S. Channer. Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina.Eur J Endocrinol. 2005 Feb;152(2):285-91