Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
| Status: | Recruiting |
|---|---|
| Conditions: | Obesity Weight Loss, Endocrine |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 40 - 65 |
| Updated: | 7/12/2018 |
| Start Date: | April 15, 2018 |
| End Date: | April 14, 2024 |
| Contact: | Reina Villareal, MD |
| Email: | reina.villareal@bcm.edu |
| Phone: | 1737947534 |
The investigators have preliminary data suggesting that obese patients with hypogonadotropic
hypogonadism (HHG) have minimal benefit from testosterone therapy likely because of its
conversion to estradiol by the abundant aromatase enzyme in the adipocytes. The increased
conversion of androgens into estrogens in obese men results in a negative feedback of high
estradiol levels on hypothalamus and pituitary, inhibiting the production of
gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and follicle stimulating
hormone (FSH) and, as a consequence, of testosterone by the testis. Testosterone
administration could increase estradiol production, further promoting the inhibitory feedback
to the hypothalamic-pituitary-gonadal axis. Although weight loss from lifestyle modification
has been shown to reduce estradiol and increase testosterone levels, the effect is at best
modest and weight regain results in recurrence of hypogonadism. The use of aromatase
inhibitors, in combination with weight loss, could be an effective alternative strategy due
to its action at the pathophysiology of the disease.
Intervention Subjects (body mass index of ≥35, testosterone <300 ng/dl) will be randomized to
the active (anastrozole) or control (placebo) group. Anastrozole 1 mg tablet / day will be
self-administered with or without food, at around the same time every day (active group);
placebo 1 tablet/day with or without food to take at around the same time every day (control
group). The study duration will be 12 months.
Both groups will undergo lifestyle intervention consisting of diet and supervised exercise
program. Target weight loss will be at least 10% of baseline body weight during the
intervention. Subjects will attend weekly group behavior modification sessions which will
last ~75-90 min for the first 3 months and decreased to every two weeks from 3 to 12 months.
Subjects will attend supervised research center-based exercise sessions during the first 6
months followed by community fitness center-based sessions during the next 6 months for at
least 2 d/wk, with recording of home-based exercises for the other 2-4 days/week.
hypogonadism (HHG) have minimal benefit from testosterone therapy likely because of its
conversion to estradiol by the abundant aromatase enzyme in the adipocytes. The increased
conversion of androgens into estrogens in obese men results in a negative feedback of high
estradiol levels on hypothalamus and pituitary, inhibiting the production of
gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and follicle stimulating
hormone (FSH) and, as a consequence, of testosterone by the testis. Testosterone
administration could increase estradiol production, further promoting the inhibitory feedback
to the hypothalamic-pituitary-gonadal axis. Although weight loss from lifestyle modification
has been shown to reduce estradiol and increase testosterone levels, the effect is at best
modest and weight regain results in recurrence of hypogonadism. The use of aromatase
inhibitors, in combination with weight loss, could be an effective alternative strategy due
to its action at the pathophysiology of the disease.
Intervention Subjects (body mass index of ≥35, testosterone <300 ng/dl) will be randomized to
the active (anastrozole) or control (placebo) group. Anastrozole 1 mg tablet / day will be
self-administered with or without food, at around the same time every day (active group);
placebo 1 tablet/day with or without food to take at around the same time every day (control
group). The study duration will be 12 months.
Both groups will undergo lifestyle intervention consisting of diet and supervised exercise
program. Target weight loss will be at least 10% of baseline body weight during the
intervention. Subjects will attend weekly group behavior modification sessions which will
last ~75-90 min for the first 3 months and decreased to every two weeks from 3 to 12 months.
Subjects will attend supervised research center-based exercise sessions during the first 6
months followed by community fitness center-based sessions during the next 6 months for at
least 2 d/wk, with recording of home-based exercises for the other 2-4 days/week.
After age of 40, testosterone (T) production in men gradually decreases at a rate of 1.6% per
year for total and to 2-3% per year for bioavailable T. This reduction in T production in men
parallels the age-associated loss of muscle mass that leads to sarcopenia and impairment of
function and the age-associated loss of bone mass that leads to osteopenia and fracture risk.
Hypogonadism is a condition associated with multiple symptom complex including fatigue,
depressed mood, osteoporosis, gain of fat mass, loss of libido and reduced muscle strength,
all of which deeply affect patient quality of life. The prevalence of hypogonadism among
obese men was estimated to be as much as 40% and could as much as 50% if they are also
diabetic, with levels of androgens decreasing proportionately to the degree of obesity.
In obese men, the age-related decline in T is exacerbated by the suppression of the
hypothalamic-pituitary-gonadal axis by hyperestrogenemia. The high expression of aromatase
enzyme in the adipose tissue enhances the conversion of androgens into estrogens which in
turn exerts a negative feedback on hypothalamus and pituitary, inhibiting the production of
gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and follicle stimulating
hormone (FSH) and, as a consequence, of T by the testis resulting in hypogonadotropic
hypogonadism (HH). Considering the high aromatase expression in the adipose tissue, the
administration of T among obese men with HHG could increase the conversion of the substrate T
to estradiol (E2) and fuels the negative feedback on hypothalamus and pituitary, producing a
greater suppression of GnRH and gonadotropins. Thus, men with obesity induced HHG may benefit
from other treatment strategies that target the pathophysiology of the disease.
Although weight loss intervention improves hormonal and metabolic abnormalities related to
obesity, the increase in T levels induced by weight loss are often lost due to weight regain,
which is very frequent among patients undergoing massive weight loss. One possible approach
is the use of aromatase inhibitors (AI) to stop the conversion of T to E2 thereby
interrupting the vicious cycle of E2 inhibition of the hypothalamic-pituitary-gonadal axis
and restoring T production to normal levels. Since weight loss remains the standard of care
for obese patients, the investigators propose the following OBJECTIVES:
1. To evaluate the effect of an AI plus WL (AI+WL) compared to WL alone on the changes in
hormonal profile in severely obese men with HHG.
2. To evaluate the effect of an AI+WL compared to WL alone on the changes in muscle
strength and muscle mass, and symptoms of hypogonadism in severely obese men with HHG.
3. To evaluate the effect of an AI+WL compared to WL alone on the changes in body
composition and metabolic risk factors in severely obese men with HHG.
4. To evaluate the effect of an AI+WL compared to WL alone on the changes in bone mineral
density (BMD), bone markers, and bone quality in severely obese men with HHG.
As secondary aim, the investigators will elucidate the mechanism for the anticipated positive
effects of AI+WL on obesity-associated HHG.
This is a randomized double-blind placebo-controlled study comparing the effect of weight
loss + anastrozole to weight loss + placebo for 12 months on the hormonal profile and
symptoms associated with hypogonadism in severely obese men with a body mass index (BMI) of
more or equal to 35 kg/m2.
year for total and to 2-3% per year for bioavailable T. This reduction in T production in men
parallels the age-associated loss of muscle mass that leads to sarcopenia and impairment of
function and the age-associated loss of bone mass that leads to osteopenia and fracture risk.
Hypogonadism is a condition associated with multiple symptom complex including fatigue,
depressed mood, osteoporosis, gain of fat mass, loss of libido and reduced muscle strength,
all of which deeply affect patient quality of life. The prevalence of hypogonadism among
obese men was estimated to be as much as 40% and could as much as 50% if they are also
diabetic, with levels of androgens decreasing proportionately to the degree of obesity.
In obese men, the age-related decline in T is exacerbated by the suppression of the
hypothalamic-pituitary-gonadal axis by hyperestrogenemia. The high expression of aromatase
enzyme in the adipose tissue enhances the conversion of androgens into estrogens which in
turn exerts a negative feedback on hypothalamus and pituitary, inhibiting the production of
gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and follicle stimulating
hormone (FSH) and, as a consequence, of T by the testis resulting in hypogonadotropic
hypogonadism (HH). Considering the high aromatase expression in the adipose tissue, the
administration of T among obese men with HHG could increase the conversion of the substrate T
to estradiol (E2) and fuels the negative feedback on hypothalamus and pituitary, producing a
greater suppression of GnRH and gonadotropins. Thus, men with obesity induced HHG may benefit
from other treatment strategies that target the pathophysiology of the disease.
Although weight loss intervention improves hormonal and metabolic abnormalities related to
obesity, the increase in T levels induced by weight loss are often lost due to weight regain,
which is very frequent among patients undergoing massive weight loss. One possible approach
is the use of aromatase inhibitors (AI) to stop the conversion of T to E2 thereby
interrupting the vicious cycle of E2 inhibition of the hypothalamic-pituitary-gonadal axis
and restoring T production to normal levels. Since weight loss remains the standard of care
for obese patients, the investigators propose the following OBJECTIVES:
1. To evaluate the effect of an AI plus WL (AI+WL) compared to WL alone on the changes in
hormonal profile in severely obese men with HHG.
2. To evaluate the effect of an AI+WL compared to WL alone on the changes in muscle
strength and muscle mass, and symptoms of hypogonadism in severely obese men with HHG.
3. To evaluate the effect of an AI+WL compared to WL alone on the changes in body
composition and metabolic risk factors in severely obese men with HHG.
4. To evaluate the effect of an AI+WL compared to WL alone on the changes in bone mineral
density (BMD), bone markers, and bone quality in severely obese men with HHG.
As secondary aim, the investigators will elucidate the mechanism for the anticipated positive
effects of AI+WL on obesity-associated HHG.
This is a randomized double-blind placebo-controlled study comparing the effect of weight
loss + anastrozole to weight loss + placebo for 12 months on the hormonal profile and
symptoms associated with hypogonadism in severely obese men with a body mass index (BMI) of
more or equal to 35 kg/m2.
Inclusion Criteria:
- obese men with body mass index (BMI) of ≥35 kg/m2
- age between 40 to 65 years old
- average fasting testosterone level from 2 measurements taken between 8 to 10 AM on 2
separate days of <300 ng/dl
- Luteinizing Hormone (LH) of <9.0 mIU/L
- Estradiol of ≥17 pg/ml
- Symptoms consistent with androgen deficiency as assessed by Androgen Deficiency in
Aging Male (ADAM) questionnaire
Exclusion criteria:
- pituitary or hypothalamic disease,
- drugs affecting gonadal hormone levels, production and action or bone metabolism
(bisphosphonates, teriparatide, denosumab, glucocorticoids, phenytoin)
- diseases affecting bone metabolism (e.g. hyperparathyroidism, untreated
hyperthyroidism, osteomalacia, chronic liver disease, significant renal failure,
hypercortisolism, malabsorption, immobilization, Paget's disease),
- prostate carcinoma or elevated serum prostate specific antigen (PSA)> 4 ng/ml,
- Hematocrit > 50%,
- untreated severe obstructive sleep apnea,
- Cardiopulmonary disease (e.g. recent myocardial infarction, unstable angina, stroke)
or unstable disease (e.g., New York Heart Association Class III or IV congestive heart
failure
- severe pulmonary disease requiring steroid pills or the use of supplemental oxygen
(that would contraindicate exercise or dietary restriction)
- History of deep vein thrombosis or pulmonary embolism
- severe lower urinary tract or prostate symptoms with International Prostate Symptom
Score (IPSS) above 19
- excessive alcohol or substance abuse
- unstable weight (i.e. >±2 kg) in the last 3 months
- condition that could prevent from completing the study
- screening bone mineral density (BMD) T-score of <-2.0 at the spine, femoral neck or
total femur
- history of osteoporosis or fragility fracture
- Diabetes mellitus with a fasting blood glucose of >140 mg/dl, and/or Hemoglobin A1C
(A1C) >8.5%.
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