Anastrazole and Clomiphene to Evaluate Hypogonadal Symptoms and Erectile Function

Study Overview
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Brief Summary
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This study evaluates anastrazole and clomiphene in the improvement in hypogonadal symptoms and erectile function. Each subject will receive Anastrazole 1 mg/day, clomiphene 25 mg/day and placebo in randomized schedule of 8 week intervals.

Detailed Description
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Aromatase inhibitors (AI) (Anastrazole) and selective estrogen receptor modifiers (SERMS)(clomiphene) increase testosterone production through stimulation of the hypothalamic pituitary axis. While these drugs both reduce the feedback inhibition of estrogen on the pituitary, SERMs cause an increase in serum estradiol, whereas AIs reduce estradiol levels. Using these medications, we can obtain therapeutic testosterone levels with either an increase or decrease in estradiol levels.

Official Title
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A Randomized Double Blinded Placebo Controlled Trial Between Anastrozole and Clomiphene to Evaluate Improvement in Hypogonadal Symptoms and Erectile Function Using ADAM, IIEF and EHS Validated Scales

Conditions
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Hypogonadism, Male

Intervention / Treatment
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* Drug: Anastrozole 1mg
* Drug: Clomiphene Citrate 25mg
* Drug: Placebo - Cap


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men age 18-70 Baseline morning Testosterone 150-350 ng/dL x2 leutenizing hormone (LH) 1.5-9.2 miU/mL, Follicle stimulation hormone (FSH) 1.6-8.0 miU/mL, Prolactin 4-15 ng/mL Positive Androgen Deficiency in the Aging Male (ADAM) score. A positive score is when an affirmative answer (''yes'') to either questions Do you have a decreased sex drive/libido? or Are your erections less strong? or any three other questions.10 Body mass index (BMI) <40 Sexual health inventory for men (SHIM) score >7 and <21. Patients are allowed to be taking phosphodiesterase 5 inhibitors (i.e. Viagra, Levitra, Cialis) at baseline, however we will ask them to do the SHIM survey as if they were not taking this medication. Men must attempt to have at least four sexual encounters over each of the eight-week periods Men willing not to take phosphodiesterase 5 inhibitors throughout the entire study Exclusion Criteria: Current or previous history of prostate cancer Previous or current androgen deprivation therapy for prostate cancer, Past surgical history of prostatectomy. History of testicular cancer. History of deep vein thrombosis (DVT) or blood dyscrasia History of breast cancer Men with past or current treatment for erectile dysfunction including MUSE (alprostodil), intracavernosal injections, penile prosthesis. Men not on treatment or men who are on phosphodiesterase inhibitors will be allowed to be in the study but must stop their use at the screening visit. Chronic opioid use Use of steroids within the past 3 months, including prednisone and/or cortisone injections, and inhaled steroids. Topical steroid cream is acceptable. History of or current use of anabolic steroids, i.e. testosterone, (or any analog of testosterone) dihydroepiandrosterone (DHEA), dihydroepiandrosterone sulfate (DHEAS) or any growth promoters i.e. growth hormone itself or analogs of growth hormone History of or current use of anti-androgen medications, i.e. Aldactone, Tagamet, estrogens Alcohol intake > 30 grams (drink more than 2 beers per day OR more than 1 glass of wine or cocktail daily) Having started a new medication during the past three months which may interfere with the outcome measures of the study Polycythemia (HCT >52% ) History of prostate specific antigen (PSA)> 4.0 ng/dl Hematocrit (HCT)< 36 % Liver function tests greater than 2 times upper normal limits or history of abnormal electrolytes, calcium or Parathyroid hormone without workup, at the discretion of the investigator. Previous hypogonadal treatment within last 3 months. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: anastrazole-clomiphene-placebo<br>anastrozole for eight weeks then clomiphene for eight weeks then placebo for eight weeks | Drug: Anastrozole 1mg<br> <br> Drug: Clomiphene Citrate 25mg<br> <br> Drug: Placebo - Cap<br> <br> |
| Other: anastrazole-placebo-clomiphene<br>anastrozole for eight weeks then placebo for eight weeks then clomiphene for eight weeks | Drug: Anastrozole 1mg<br> <br> Drug: Clomiphene Citrate 25mg<br> <br> Drug: Placebo - Cap<br> <br> |
| Other: clomiphene-anastrazole-placebo<br>clomiphene for eight weeks then anastrozole for eight weeks then placebo for eight weeks | Drug: Anastrozole 1mg<br> <br> Drug: Clomiphene Citrate 25mg<br> <br> Drug: Placebo - Cap<br> <br> |
| Other: clomiphene-placebo-anastrazole<br>clomiphene for eight weeks then placebo for eight weeks then anastrozole for eight weeks | Drug: Anastrozole 1mg<br> <br> Drug: Clomiphene Citrate 25mg<br> <br> Drug: Placebo - Cap<br> <br> |
| Other: placebo-clomiphene-anastrazole<br>placebo for eight weeks then clomiphene for eight weeks then anastrozole for eight weeks | Drug: Anastrozole 1mg<br> <br> Drug: Clomiphene Citrate 25mg<br> <br> Drug: Placebo - Cap<br> <br> |
| Other: placebo-anastrazole-clomiphene<br>placebo for eight weeks then anastrozole for eight weeks then clomiphene for eight weeks | Drug: Anastrozole 1mg<br> <br> Drug: Clomiphene Citrate 25mg<br> <br> Drug: Placebo - Cap<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IIEF (International Index of Erectile Function) Score - Screen | 15 item self reported erectile function. Each item is scored 0-5 with 0=negative response and 5 = positive response with totals of 0-75 | At baseline | 
| IIEF (International Index of Erectile Function) Score - Week 8 | 15 item self reported erectile function over the past 8 weeks. Each item is scored 0-5 with 0=negative response and 5 = positive response with totals of 0-75 | Week 8 | 
| IIEF (International Index of Erectile Function) Score - Week 16 | 15 item self reported erectile function over the past 8 weeks. Each item is scored 0-5 with 0=negative response and 5 = positive response with totals of 0-75 | Week 16 | 
| IIEF (International Index of Erectile Function) Score - Week 24 | 15 item self reported erectile function over the past 8 weeks. Each item is scored 0-5 with 0=negative response and 5 = positive response with totals of 0-75 | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normalized Testosterone - Screen | Normalized at >350ng/dl | Baseline | 
| Normalized Testosterone - Week 8 | Normalized at >350ng/dl | Week 8 | 
| Normalized Testosterone - Week 16 | Normalized at >350ng/dl | Week 16 | 
| Normalized Testosterone - Week 24 | Normalized at >350ng/dl | Week 24 | 
| ADAM (Androgen Deficiency in the Aging Male) Score - Screen | Self reported quantification of hypogonadism. 10 yes or no questions. A positive (yes) questionnaire result is defined as a yes or 1 and a negative (no) questionnaire result is defined as a no or 0 to question 1 or question 7 or any 3 other questions. Yes (1) represents a better outcome than No (1) In Data Entry: Yes - 1 No - 0 | Baseline | 
| ADAM (Androgen Deficiency in the Aging Male) Score - Week 8 | Self reported quantification of hypogonadism. 10 yes or no questions. A positive (yes) questionnaire result is defined as a yes or 1 and a negative (no) questionnaire result is defined as a no or 0 to question 1 or question 7 or any 3 other questions. Yes (1) represents a better outcome than No (1) In Data Entry: Yes - 1 No - 0 | Week 8 | 
| ADAM (Androgen Deficiency in the Aging Male) Score - Week 16 | Self reported quantification of hypogonadism. 10 yes or no questions. A positive (yes) questionnaire result is defined as a yes or 1 and a negative (no) questionnaire result is defined as a no or 0 to question 1 or question 7 or any 3 other questions. Yes (1) represents a better outcome than No (1) In Data Entry: Yes - 1 No - 0 | Week 16 | 
| ADAM (Androgen Deficiency in the Aging Male) Score - Week 24 | Self reported quantification of hypogonadism. 10 yes or no questions. A positive (yes) questionnaire result is defined as a yes or 1 and a negative (no) questionnaire result is defined as a no or 0 to question 1 or question 7 or any 3 other questions. Yes (1) represents a better outcome than No (1) In Data Entry: Yes - 1 No - 0 | Week 24 | 
| EHS (Erectile Hardness Score) - Screen | Self reported questionnaire rated 0-4 0=penis does not enlarge, 4=Penis completely hard and fully rigid | Baseline | 
| EHS (Erectile Hardness Score) - Week 8 | Self reported questionnaire rated 0-4 0=penis does not enlarge, 4=Penis completely hard and fully rigid | Week 8 | 
| EHS (Erectile Hardness Score) - Week 16 | Self reported questionnaire rated 0-4 0=penis does not enlarge, 4=Penis completely hard and fully rigid | Week 16 | 
| EHS (Erectile Hardness Score) - Week 24 | Self reported questionnaire rated 0-4 0=penis does not enlarge, 4=Penis completely hard and fully rigid | Week 24 | 
| LH - Screen | Luteinizing Hormone levels collected at the initial encounter and at the end of the 8, 16, and 24 week periods. | Baseline | 
| LH - Week 8 | Luteinizing Hormone levels collected at the initial encounter and at the end of the 8, 16, and 24 week periods. | Week 8 | 
| LH - Week 16 | Luteinizing Hormone levels collected at the initial encounter and at the end of the 8, 16, and 24 week periods. | Week 16 | 
| LH - Week 24 | Luteinizing Hormone levels collected at the initial encounter and at the end of the 8, 16, and 24 week periods. | Week 24 | 
| FSH - Screen | Lab Values for follicle stimulating hormone | Baseline | 
| FSH - Week 8 | Lab Values for follicle stimulating hormone | Week 8 | 
| FSH - Week 16 | Lab Values for follicle stimulating hormone | Week 16 | 
| FSH - Week 24 | Lab Values for follicle stimulating hormone | Week 24 | 
| Free Testosterone - Screen | Measure of Free Testosterone | Baseline | 
| Free Testosterone - Week 8 | Measure of Free Testosterone | Week 8 | 
| Free Testosterone - Week 16 | Measure of Free Testosterone | Week 16 | 
| Free Testosterone - Week 24 | Measure of Free Testosterone | Week 24 | 
| Estradiol - Screen | Measurement of Estradiol levels at initial encounter and at the end of Weeks 8, 16, and 24 | Baseline | 
| Estradiol - Week 8 | Measurement of Estradiol levels at initial encounter and at the end of Weeks 8, 16, and 24 An entered value of 4.9 means the measure was <5 | Week 8 | 
| Estradiol - Week 16 | Measurement of Estradiol levels at initial encounter and at the end of Weeks 8, 16, and 24 An entered value of 4.9 means the measure was <5 | Week 16 | 
| Estradiol - Week 24 | Measurement of Estradiol levels at initial encounter and at the end of Weeks 8, 16, and 24 An entered value of 4.9 means the measure was <5 | Week 24 | 
| SHBG - Screen | Lab Measure of sex hormone binding globulin at the initial encounter and at the ends of week 8, 16, and 24 | Baseline | 
| SHBG - Week 8 | Lab Measure of sex hormone binding globulin at the initial encounter and at the ends of week 8, 16, and 24 | Week 8 | 
| SHBG - Week 16 | Lab Measure of sex hormone binding globulin at the initial encounter and at the ends of week 8, 16, and 24 | Week 16 | 
| SHBG - Week 24 | Lab Measure of sex hormone binding globulin at the initial encounter and at the ends of week 8, 16, and 24 | Week 24 | 
| SEP #1-3 Cumulative - Screen | Questions 1, 2, and 3 for the Sexual Encounter Profile have been cumulatively added. 1 - yes and 0 - no have been added for questions 1-3 to determine a total value from 0-3. 0-3: cumulative score from SEP questions 1, 2, and 3 Higher values (3) are considered to be a better outcomes relative to lower numbers (0) 3 is better than 2 is better than 1 is better than 0 | Baseline | 
| SEP #1-3 Cumulative - Week 8 | Questions 1, 2, and 3 for the Sexual Encounter Profile have been cumulatively added. 1 - yes and 0 - no have been added for questions 1-3 to determine a total value from 0-3. 0-3: cumulative score from SEP questions 1, 2, and 3 Higher values (3) are considered to be a better outcomes relative to lower numbers (0) 3 is better than 2 is better than 1 is better than 0 | Week 8 | 
| SEP #1-3 Cumulative - Week 16 | Questions 1, 2, and 3 for the Sexual Encounter Profile have been cumulatively added. 1 - yes and 0 - no have been added for questions 1-3 to determine a total value from 0-3. 0-3: cumulative score from SEP questions 1, 2, and 3 Higher values (3) are considered to be a better outcomes relative to lower numbers (0) 3 is better than 2 is better than 1 is better than 0 | Week 16 | 
| SEP #1-3 Cumulative - Week 24 | Questions 1, 2, and 3 for the Sexual Encounter Profile have been cumulatively added. 1 - yes and 0 - no have been added for questions 1-3 to determine a total value from 0-3. 0-3: cumulative score from SEP questions 1, 2, and 3 Higher values (3) are considered to be a better outcomes relative to lower numbers (0) 3 is better than 2 is better than 1 is better than 0 | Week 24 |