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Continuing Education Article
Age-Related Androgen Deficiency and
Type 2 Diabetes
Journal of Pharmacy Practice
24(3) 316-322
ª The Author(s) 2011
Reprints and permission:
DOI: 10.1177/0897190010397719
Gina J. Ryan, PharmD, BCPS, CD1 and Lynetta J. Jobe, DVM, PhD2
There is a higher prevalence of low testosterone levels in males with type 2 diabetes compared to those without. Additionally,
there is evidence that low testosterone levels may predict the development of type 2 diabetes. Symptoms of hypogonadism
include decreased libido, decreased bone mineral density (BMD), and decreased lean muscle mass. The majority of the
published cases in men with diabetes were attributed to age-related idiopathic hypogonadotropic hypogonadism. This paper
reviews the link between type 2 diabetes and age-related hypogonadism and the treatment options for hypogonadism. Pharmacists who provide care for males with diabetes should be aware of the increased incidence of hypogonadism, know how to screen
for it, and be able to recommend appropriate therapy.
diabetes, hypogonadism, testosterone, men’s health, andropause
Learning Objectives
After completing this continuing education program, the pharmacist should be able to:
List the symptoms of hypogonadism.
Describe the normal physiology of testosterone production.
Describe the link between diabetes and hypogonadism.
List the optimal therapy for hypogonadism.
Describe the goals of therapy for hypogonadism
List the advantages, disadvantages, and patient education points for the various testosterone preparations that are
available in the United States.
In males, hypogonadism may present with low testosterone
levels, infertility, and/or other symptoms, depending upon the
age at disease onset. The condition is rarely recognized
before puberty. In adult males, symptoms of hypogonadism
may include decreased muscle strength, altered libido, erectile dysfunction, the inability to concentrate, and occasionally
menopausal-type hot flushes. In addition to decreased muscle
bulk, signs of hypogonadism can include a loss of body hair,
gonadal atrophy, low sperm counts, and decreased bone mass
(Table 1).1 The normal range for total testosterone levels is
approximately 300 to 1000 ng/dL (10.5 to 35 nmol/L) although
the actual limits vary between laboratories. Typically, after the
age of 40, levels decline at a rate of 1% to 2% per year,2 and
almost half of all men in their eighties have hypotestosteronemia, compared with only 12% of those under 50. The term ‘‘clinical hypogonadism’’ refers to cases in which low serum
testosterone is associated with symptoms. In one study, the incidence of clinical hypogonadism is 4.1% among men 40 to
49 years old, and the rate doubles (9.4%) among those 60 to
70 years old.3 This physiological age-related decrease in
testosterone levels is known as ‘‘age-related androgen
deficiency,’’ also called andropause.1
Type 2 diabetes is also strongly associated with aging, as
observational studies have shown that 15% to 34% of patients
with this disease also have hypotestosteronemia.4-8 This article
will review the link between these 2 diseases and the treatment
options for hypogonadism.
The Pathophysiology of Male Hypogonadism
The hypothalamus secretes pulses of gonadotropin-releasing
hormone, which stimulates the release of luteinizing hormone
(LH) and follicle-stimulating hormone (FSH) by the pituitary.
Department of Pharmacy, Mercer University, Atlanta, GA, USA
University of Maryland Eastern Shore, School of Pharmacy and Health
Professions, Hazel Hall, Princess Anne, MD, USA
Corresponding Author:
Gina J. Ryan, Department of Pharmacy, Mercer University, Atlanta, GA, 30341,
Email: [email protected]
Ryan and Jobe
Table 1. Symptoms of Clinical Hypogonadism1,23
Erectile dysfunction
Menopausal-type hot flushes
Decreased muscle mass
Decreased libido
Decreased concentration
the assay used to measure the unbound hormone levels.10-12
Non-SHBG-bound testosterone levels can be estimated by
using SHBG-bound and total testosterone levels, but the accuracy of this method is questionable.10,11
The Link between Diabetes and Low Testosterone Levels
Luteinizing hormome stimulates testicular production and
secretion of testosterone, and FSH promotes spermatogenesis
and increases inhibin B production by Sertoli cells. Inhibin B
and testosterone close the negative feedback loop by inhibiting
further secretion of FSH and LH, respectively (Figure 1).
Primary hypogonadism (ie, testicular failure) is characterized by low plasma testosterone levels and elevated gonadotropin levels. Technically, secondary forms are caused by low
pituitary production of LH and FSH whereas decreased
hypothalamic production of gonadotropin-releasing hormone
is known as tertiary hypogonadism. In clinical settings, however, the term ‘‘secondary hypogonadism’’ is also commonly
applied to cases related to hypothalamic or pituitary dysfunction. ‘‘Androgen deficiency in the aging male’’ is typically
related to changes at both the testicular and hypothalamic
Testosterone secretion follows a diurnal rhythm with peak
levels normally observed in the morning. Total testosterone
levels comprise free (1%-2% of the total) and bound forms of
the hormone. Approximately 20% to 30% of total testosterone
is bound to albumin, and 40% to 50% is bound to the sex
hormone-binding globulin (SHBG).9 The effect of SHBG on
levels of total and free testosterone is not completely understood. Low circulating levels of SHBG can be expected to
cause increases in the unbound fraction. However, conflicting
reports have been published on the relationship between free
testosterone and SHBG levels, and data vary depending upon
Interstitial cells
Sertoli cells
Figure 1. Hypothalamic-pituitary-testis access.
The precise causes of hypogonadism and type 2 diabetes have
yet to be defined, but it is clear that the 2 diseases are correlated. A systematic review and meta-analysis of 43 prospective
and cross-sectional studies containing a total of 6427 men
examined the relationship between testosterone and diabetes
risk and revealed that elevated levels of the hormone reduced
the risk for type 2 diabetes by 42% (relative risk ratio: 0.58;
95% confidence interval (CI): 0.39 to 0.87). In this study, males
with type 2 diabetes had on average a 76.6 ng/dL lower testosterone level than men without diabetes.13 Statistical models
adjusting for age, race, and adiposity found that low free testosterone was 4 times more common in men (N ¼ 1413) with type
2 diabetes than compared to those without (odds ratio [OR]
4.12 [95% CI 1.25-13.55]), and that low androgen levels may
be a risk factor for development of type 2 diabetes.14 In an
8-year observational study, the risk of developing type 2 diabetes was 2.7 times higher in men (N ¼ 294) with low testosterone levels at baseline (95% CI: 1.1-6.6). These findings
suggest that the onset of type 2 diabetes may be preceded by
Androgen levels are shown to be correlated with obesity,
insulin resistance, and other alterations associated with the
metabolic syndrome. Decreased levels of free testosterone
have been found in patients with body-mass indices (BMI) over
35 kg/m2, but this parameter was not altered in those with lower
BMIs.16 In a cross-sectional study of 355 males over 30 years
old with type 2 diabetes, BMI (r ¼ .210; P<.001) and waist
circumference (r ¼ .148; P < .006) were negatively correlated with free testosterone.8 In the same study, SHBG correlated with BMI (r ¼ .309; P < .001) and waist
circumference (r ¼ .277; P < .001). Obesity can lead to hypogonadism by increasing aromatization of testosterone to estradiol (much of which occurs in adipose tissue) and/or
derangements in the hypothalamic-pituitary-adrenal-testicular
axis.17 Hyperinsulinemia and obesity also seem to be associated with decreased SHBG production,16,18-20 and patients with
type 2 diabetes have been found to have lower levels of this
globulin than age- and BMI-matched controls.21 Until more
is known about the relationships between SHBG, free testosterone, and total testosterone levels,10-12 it will be difficult to
determine the significance of the effects of diabetes-induced
reductions in SHBG. Low LH and testosterone levels are
shown to be associated with metabolic syndrome.15,19,22 The
results from a observational cross-sectional study showed that
there was an inverse relationship between total testosterone
(OR ¼ 0.43; 95% CI 0.32-0.59), SHBG (OR ¼ 0.46, 95% CI
0.33-0.64), and metabolic syndrome, as defined by the National
Cholesterol Education Program (NCEP), in 400 men between
the age of 40 and 80 years.15,19,22 Chen et al, conducted an 8-
Journal of Pharmacy Practice 24(3)
Table 2. Risk Factors for Low Testosterone
Type 2 diabetes
Sellar mass
HIV-associated weight loss
End-stage renal disease
Osteoporosis or low-trauma
Moderate or Severe Chronic
Obstructive Lung Disease
Use of medications that affect
testosterone levels:
year observational trial of 195 men, average age 76.2 years,
found that subjects with metabolic syndrome had a higher total
testosterone level compared to normal subjects (348 mg/dL vs
409 mg/dL, P ¼ .03).15,19,22 Dhindsa et al reported that the low
androgen levels observed in 103 men with type 2 diabetes are
secondary to reduced levels of FSH and LH.5 In addition, the
LH pulses in obese males are characterized by normal frequency
but lower amplitude.16 Collectively, these findings indicate that
the hypotestosteronemia associated with type 2 diabetes is not
caused exclusively by testicular failure.
Diagnosing Hypogonadism
The diagnosis of adult male hypogonadism can be difficult
because the symptoms are often vague and can overlap those
related to normal aging. The American Association of Endocrinologists (AACE) and the Endocrine Society, however, both
recommend that diagnosis of age-related hypogonadism be
based on the presence of symptoms coupled with low morning
levels of total testosterone.1,23 The Endocrine Society recommends not routinely using a screening questionnaire in the general population, but only those patients at high risk (Table 2).
Measurement of testosterone levels should be reserved for
symptomatic patients since treatment offers few benefits for
asymptomatic forms of hypotestosteronemia. Therapy should
not be given to asymptomatic patients.23 According to the
AACE guidelines, testosterone replacement for hypogonadism
should be considered when total testosterone levels drop below
200 ng/dL (7 nmol/L) and symptoms (Table 1) are present.1,23
Since the reference range of testosterone varies between different laboratories, the Endocrine Society recommends using the
lower limit of the range of the reference laboratory as the diagnostic criteria.1,23
The 10-item Androgen Deficiency in Aging Males (ADAM)
questionnaire,24 8-item the Massachusetts Male Aging Study
Questionnaire,25 and the 17-item Aging Males’ Symptoms
Scale26 are 3 questionnaires that have been developed to screen
Table 3. Contraindications to Testosterone Replacement Therapy1,23
Prostate cancer
Breast cancer
Hematocrit > 50%
Severe benign prostatic hypertrophy (BPH)
Severe congestive heart failure (Class III or IV)
Sleep apnea
Table 4. Benefits and Risks of Testosterone Replacement Therapy1,23,41
Muscle mass
Bone mineral density
Sense of well-being
Stimulates prostate cancer
Acne and oily skin
Decreased Sperm production
Decreased Fertility
patients for age-related hypogonadism. The most recent AACE
guidelines recommend against using them because; there are no
case-detection trials of these instruments; it is not known
whether they are more cost-effective than measurement of
serum testosterone; and their specificity is low.1,23
The AACE and the Endocrine Society both recommend testosterone replacement therapy for symptomatic andropause.1,23
The contraindications for testosterone therapy are summarized
in Table 3, and the risks and benefits are listed in Table 4. Despite
the suggested link between low testosterone, metabolic syndrome, and diabetes, it is unclear whether testosterone therapy
affects insulin sensitivity. Studies examining testosterone influence on insulin sensitivity have conflicting results. In a 20-week
study, Singh et al examined the effects of testosterone on insulin
sensitivity and plasma lipid levels. Sixty-one healthy eugonadal
men 18 to 35 years old received intramuscular testosterone
(25 mg, 50 mg, 125 mg, 300 mg, or 600 mg) following
suppression of endogenous testosterone production with a
gonadotropin antagonist. At the end of the study, there were no
significant changes in insulin sensitivity, compared with baseline
findings, and the only significant effect on lipid profiles was a
decrease in high-density lipoprotein levels among men treated
with the 600 mg dose.27 In another trial, a one-time injection of
500 mg of testosterone ethanate caused glucose tolerance to
decrease in 6 men. However, a single 250 mg injection of testosterone ethanate increased glucose tolerance in 8 men. In the
same study, 11 men were given daily 40 mg of testosterone undecanoate for 6 weeks and glucose tolerance also increased in 8 men
after 250 mg per day of topical testosterone gel for 3 months.28
Conflicting data have been reported regarding the effects of
testosterone replacement on blood glucose in men with type 2
diabetes. In a non-randomized, open-label trial of 10 men with
type 2 diabetes, low testosterone, and symptoms of hypogonadism, Corrales et al found that 150 mg every 14 days of intramuscular injections of testosterone enanthate had no significant effect
on glycemic control.29 Similar results emerged from a more
recent nonrandomized, uncontrolled, open-label trial in which
11 men with type 2 diabetes were treated with 100 mg of intramuscular testosterone every 3 weeks for 3 months.30 Additionally, testosterone 200 mg every 15 days for 3 months failed to
significantly affect insulin resistance, glycosylated hemoglobin,
Ryan and Jobe
Table 5. Testosterone Preparations Available in the United Statesa,23
10 -50 mg po
(Testred1, Viridaily
lon1, Android1)
Buccal, mucoadhesive, 30 mg buccal
30 mg (Striant1)
twice daily
50-400 mg IM,
every 2-4
200 mg/ml,
Testosterone cypio50-400 mg IM,
nate, 100 mg/ml or
every 2-4
200 mg/ml (Depo
Testopel (sq testos150-450 mg
terone pellets)
SC, every
3-6 months
Testosterone gel 1%, 5-10 gm of gel
(50-100 mg
one) daily
1 or 2 patches
Testosterone patch
(Androderm), 2.5
mg/24 h, 5 mg/24 h
Easy administration
Hepatotoxicity " lipid levels
Low bioavailability
9.2% rate of gum irritation42,
Not injectable, May
Accidental detachment from
provide " levels,
Avoids skin irritation
Inexpensive if selfadministered, Very
flexible dosing
Inexpensive if selfadministered, Very
flexible dosing
Facilitates compliance
Mimics diurnal rhythm,
Flexible dosing, Easy
to use, Minimal skin
irritation <5%
Easy to use, Mimics
diurnal rhythm
Patient Education
Place the rounded side against the upper gums
and hold finger over lip for 30 seconds;
system should stay in position until
removed. To remove, push system down
toward the tooth. Do not chew/swallow.
Review IM injection techniques if product will
Injection site pain, May require
be self-administered. Review side effects.
office visit for injections, Peak
and trough drug levels may be
Injection site pain, May require
office visit for injections, Peak
and trough drug levels may be
Requires minor surgery for
insertion, Pellets may be
Potential transfer to others via
direct contact
Apply to clean dry skin on abdomen, upper
arms, or thighs. Gel can be transferred to
others via direct contact
Skin irritation in 37%35
Do not place over bony prominences or
scrotum. Allow at least 7 days between
applications to the same site. Irritation may
All preparations are schedule III controlled substances.
and fasting blood glucose in a double-blind, placebo-controlled,
crossover study in 22 men with type 2 diabetes.31 However, in a
randomized, open-label, no-treatment controlled trial, 3 months
of treatment with 120 mg/day of oral testosterone undecanoate
reduced glycosylated hemoglobin levels from 10.4% to 8.5%
(P < .05) in 24 subjects with type 2 diabetes.32 In a randomized,
double-blind, placebo-controlled, crossover study, 24 men with
hypogonadism and type 2 diabetes received 200 mg of intramuscular testosterone injections every 2 weeks for 3 months.33 During
testosterone supplementation, glycosylated hemoglobin
decreased by 0.37% (P ¼ .03), and insulin sensitivity improved
(P ¼ .02). Another group of investigators found that abrupt withdrawal of sex steroid increased insulin resistance in healthy men
with idiopathic hypogonadotropic hypogonadism.34 Larger randomized, controlled, and blinded studies are needed to define the
effect of testosterone replacement on glycemic control in patients
with type 2 diabetes.
Testosterone Preparations
Table 5 shows the main characteristics of the testosterone preparations currently marketed in the United States. The most
recent guidelines from the Endocrine Society recommend that
methyltestosterone not be used because of its potential hepatoxicity.1,23 It can also causes an increase in low-density lipoprotein and a decrease in high-density lipoprotein.1,23 The other
oral form, undecanoate testosterone, is not available in the
United States. A buccal system has been developed that
adheres to the gum and provides sustained release of testosterone, which is absorbed via the buccal mucosa. This route of
administration eliminates the need for injections and provides
adequate serum levels, but it can cause local gum irritation and
has to be administered twice a day.1,23
Testosterone cypionate and testosterone enanthate are longacting parenteral preparations. The optimal initial regimen is
intramuscular injection of 50 to 100 mg every 7 to 10 days, but
slightly larger, less frequent doses (ie, 100-150 mg every
2 weeks) can be used to reduce the number of injections.1 The
latter approach carries a higher risk of immediate side effects,
and symptoms of hypogonadism are more likely to reappear
prior to the next dose. Once the optimal parenteral dose of testosterone has been established, long-term fixed-dose replacement
can be achieved with subcutaneous testosterone pellets. Insertion of these pellets requires a minor surgical procedure.1,23
Testosterone can also be administered via transdermal
patches. The scrotal patch, Testoderm1, was removed from
the market in 2005. The currently available patches are applied
to the back, abdomen, upper arms, or thighs and replaced every
24 hours. The primary advantage with the transdermal preparation is it mimicks diurnal variation. The disadvantage is skin
irritation is a common adverse effect.
Another topical option is testosterone gel (1%). This is the
testosterone product most commonly prescribed because it
allows flexible dosing and causes considerably less irritation
than injections or patches. The primary disadvantage is the gel
can be transferred to others via direct contact with the application site. This risk can be reduced, however, by instructing the
patient to cover the application site with clothing after the gel
has dried. The hands should also be carefully washed with soap
and water after each application.35
Goals of Therapy
According to the AACE and Endocrine Society, the goals of
testosterone replacement therapy include improvement of clinical symptoms, restoration of normal testosterone levels, and
reduction of the risk of adverse events. Testosterone levels and
symptoms should be monitored every 3 to 4 months during the
first year of therapy. Patients should have a prostate exam with
measurement of prostate-specific antigen levels prior to treatment and every 6 to 12 months, and lipid profiles and hematocrit levels should also be monitored on a regular basis.1,23
Adverse Events and Drug Interactions
The most common adverse effects of testosterone replacement
include erythrocytosis, acne, prostate cancer, decreased sperm
counts, and infertility.23 Gynecomastia, male-pattern balding,
breast cancer, benign prostatic hypertrophy symptoms, mood
liability, aggressive behavior, and worsening of sleep apnea
have been reported with much lower frequency.23
Testosterone may decrease the anticoagulant requirements
for patients taking warfarin. Additional monitoring is recommended if either drug is used concomitantly with testosterone.35 In patients receiving diabetes medications, serum
glucose levels may also need closer monitoring since testosterone may increase insulin sensitivity.32,33
Patient Education
General patient education should include a review of the
common adverse effects of testosterone as well as specific
instructions for administration (Table 5). Patients receiving injectable preparations should be warned about peak-and-trough effects
on mood stability. Counseling is important for men who administer self-injections to avoid soft tissue damage or skin infection.
Men using topical agents should be informed that a rash may
occur at application site.1,23
Journal of Pharmacy Practice 24(3)
Chorionic Gonadotropin Hormones
Human chorionic gonadotropin hormone (hCG) is most commonly known as the hormone that is assayed in pregnancy
tests. Human chorionic gonadotropin hormone increases after
conception and prevents disintegration of the ovary’s corpus
luteum and promotes male sexual differentiation in the fetus
by stimulating replication Leydig cells and increasing testicular testosterone secretion. The results of one study suggest
that, in adult males with oligospermia, high hCG levels stimulate spermatogensis in males.36 In one trial, low doses
of hCG increased testosterone levels in all normal subjects
(N ¼ 37), who were first made hypogonadal with treatment
of a gonadotropin-releasing hormone antagonist.37 In 40 male
subjects with partial age-related androgen deficiency (testosterone 441 ng/dL), 250 mcg of subcutaneous hCG was
administered twice weekly for 3 months in a double-blind, randomized, placebo-controlled trial.38 Subjects treated with hCG
had a 150% increase in total and free testosterone (P < .001).
And although muscle mass increased (2 kg P < .001), there was
no significant increase in muscle strength. Prostate symptoms
and prostate-specific antigen was not significantly increased
by hCG. Three men treated with hCG reported nipple tenderness, but no gynecomastia was observed. Meier et al also
reported that 3 months of twice-weekly subcutaneous 250
mcg injections of hCG increased osteoblastic collagen
sythensis in older males with partial age-related androgen
deficiency.39 Although there are no clinical trials evaluating
the effects of hCG in male patients with type 2 diabetes,
investigators reported that hCG does not alter insulin sensitivity or b-cell function.40 Larger long-term studies of various
doses are needed prior to recommending chorionic gonadotropin for treatment of age-related hypogonadism. Additionally, further studies in patients with type 2 diabetes will
help determine its effect on hCG’s effects on glycemic control. Therapy with hCG is not recommended by either AACE
or the Endocrine Society for the treatment of age-related
androgen deficiency.1,23
Approximately 15% to 33% of adult males with type 2 diabetes
have low testosterone levels, although the frequency of clinical
hypogonadism in this population has never been determined.
Both the AACE and the Endocrine Society recommend testosterone replacement therapy for patients with symptomatic
hypotestosteronemia. Pharmacists working with patients with
diabetes should be aware of the symptoms and refer patients for
screening as necessary. Once treatment has been initiated,
closer monitoring of blood glucose levels may be warranted
since testosterone may alter glycemic control.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interests with respect
to the authorship and/or publication of this article.
Ryan and Jobe
The author(s) received no financial support for the research and/or
authorship of this article.
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Continuing Education Credit
The NYSCHP is approved by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program
provides 1.5 contact hours (0.15CEUs) of continuing education. Universal Program Number is 0134-0000-11-067-H01-P. Submission of exam
for CE credit expires 06/30/2014.
A grade of 70% or above is required to earn the CE credit. Repeat examinations will be permitted once for a grade below 70%.
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