INKLINGS
Testosterone therapy: many players and
much controversy
The use of testosterone in men has become extremely contro-
versial over the past year. Stakeholders in this topic include
physicians who prescribe testosterone, patients—both those
who feel that they benefited from treatment, and those who
feel they have been harmed by treatment, the pharmaceutical
companies, the federal government through the Food and
Drug Administration (FDA), and litigation attorneys who
have placed ads suggesting lawsuits for patients that have
been on testosterone therapy and may have had cardiovascular
events. This is reminiscent of the controversy over female hor-
mone replacement, but there is no large randomized controlled
trial to dissect for conclusions. Testosterone has been approved
in the United States since the 1950s for conditions associated
with low or absent endogenous testosterone production. Testos-
terone is the primary androgen in the male. We have all been
taught the role it plays in normal male embryologic develop-
ment. It is also important for normal male pubertal develop-
ment. In the adult, a variety of symptoms have been
associated with low testosterone. These include sexual symp-
toms, such as low libido, erectile dysfunction, decreased inten-
sity of orgasm, as well as nonsexual signs and symptoms, such
as hot flashes, osteoporosis, and loss of body hair. In addition,
many nonspecific symptoms, including lethargy, depression,
difficulty concentrating, sleep disturbances, anemia, loss of
muscle bulk and strength, increased body fat, and increased
body mass index, are commonly present in men with low testos-
terone levels. However, many of these symptoms are also found
in aging men who do not have testosterone deficiency. The term
hypogonadism generally refers to conditions with low serum
testosterone levels in the presence of symptoms of low testos-
terone. There is no universal agreement as to what constitutes
a low testosterone level, although levels below the limit of the
95% confidence interval of testosterone levels in young healthy
men are commonly suggested. This level varies between labora-
tories, but it is roughly 300 ng/dL. We know that testosterone
production declines as men age at the rate of 0.5%–1% per
year. Thus, aging men have lower testosterone levels (in gen-
eral) than young men, but there is a large overlap in testosterone
levels between older and younger populations. Whether this
age-associated decline in testosterone is pathologic and needs
treatment or is part of the normal aging process has become
controversial. There is much disagreement between those
involved in managing these patients as to whether older men
should have the same testosterone levels as younger men.
Testosterone is produced in the testes in response to stim-
ulation from LH produced in the anterior pituitary gland,
which in turn responds to GnRH from the hypothalamus.
The etiology of hypogonadism is generally categorized as pri-
mary or secondary. Primary hypogonadism is due to an
inability of the testes to produce sufficient testosterone
despite adequate LH stimulation. Secondary hypogonadism
exists when there is inadequate LH stimulation. The approved
indications for testosterone replacement have not changed
over the years. The controversy has centered on the appro-
priate hypogonadal conditions that warrant treatment. The
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FDA has viewed the approved indications as supporting treat-
ment of ‘‘classic’’ hypogonadism—both primary and second-
ary. Those are the conditions we learned in medical school
that are associated with low testosterone levels. Examples
of classic causes of primary hypogonadism include testicular
damage due to chemotherapy (interestingly, chemotherapy
does not usually result in symptomatic hypogonadism, but
it often causes infertility), mumps orchitis, and genetic (e.g.,
Klinefelter syndrome) or congenital conditions. Classic causes
of secondary hypogonadism include Kallman syndrome and
pituitary insufficiency due to pituitary tumors, surgery, or ra-
diation. We are often taught that patients with these condi-
tions present early in life with findings such as micropenis
or cryptochidism (due to insufficient androgens during
embryogenesis) or delayed or absent puberty. These findings
are commonly associated with very low testosterone levels
(<100 ng/dL). What has become very clear over the years is
that many of the patients with these conditions progress
through puberty undetected with relatively normal pheno-
types and may present later in life—some with infertility
and some with other hypogonadal symptoms. Many Klinefel-
ter syndrome patients have testosterone levels that are only
mildly low or in the lower end of the reference range. Based
on the concept of classic hypogonadism, it is assumed that
it is quite appropriate to treat these patients that have symp-
toms and low testosterone levels with testosterone therapy.
What has become evident over the past decade is that
there is a much larger group of men that have what has
been considered age-associated hypogonadism. These pa-
tients do not have the previously mentioned conditions.
Whether the low testosterone levels are normal for age or
due to other pathology is unclear. A variety of conditions
have been associated with low testosterone levels and hypo-
gonadal symptoms, including metabolic syndrome and type
2 diabetes. Whether these may be additional causes of testos-
terone deficiency or partly due to testosterone deficiency is
not known. What is clear is that many aging men have a va-
riety of comorbidities, hypogonadal symptoms, and testos-
terone levels <300 ng/dL. Because the testosterone levels of
classic and age-associated hypogonadal patients overlap,
we need to reconsider appropriate indications for treatment.
Should the cause of the hypogonadism determine whether pa-
tients should be treated, or should other criteria be used? We
may see two patients with identical symptoms and testos-
terone levels. One may have Klinefelter syndrome and the
other age-associated hypogonadism. If both are symptomatic
and have low testosterone levels, should we offer treatment to
the patient with Klinefelter syndrome and not the other? It is
not so clear that this is a rational approach. That is not to say
that contributing factors should not first be dealt with. If the
underlying factors can address the symptoms and remove the
need for testosterone replacement, that would seem to be a far
better approach. Testosterone replacement is not a replace-
ment for proper lifestyle habits and should not be a replace-
ment for good health practices. Experience in practice
indicates that the lower the testosterone level, the more likely
patients will respond to replacement therapy, and that a larger
percentage of patients with very low testosterone levels will
VOL. 103 NO. 5 / MAY 2015

be found to have classic hypogonadism. The controversy is
primarily about those with more modest reductions in testos-
terone levels. Another point of controversy is the goal of
testosterone replacement? The Endocrine Society guidelines
suggest that the goal of replacement is to obtain midnormal
levels, but many rejuvenation clinics consider anything below
the upper range of normal men to be deficient.
Because testosterone has been considered to be replace-
ment therapy, the FDA's paradigm for approval of testosterone
formulations has required demonstration that treatment re-
stores testosterone levels to the normal range. There has been
no requirement to demonstrate that treatment improves symp-
toms. In addition, safety studies have generally focused on risks
associated with the form of replacement, such as skin rashes
from topical preparations. There have been no requirements
to prove overall health safety. Although the use of testosterone
was limited primarily to intramuscular injections for many
years, a variety of alternative formulations have been approved
over the last decade. Now patients may choose from topical
patches, ointments, subcutaneous pellets, long-lasting inject-
ables, buccal applications and likely oral preparations. As these
formulations appeared, the pharmaceutical industry began
marketing directly to consumers. Patients with many of the
nonspecific symptoms were urged to have their physicians
check their testosterone levels because it was ‘‘only a number.’’
Clinics began appearing for the purpose of testosterone
replacement, with criteria for replacement often not following
published guidelines. According to the FDA, from 2009 to
2013, the amount of testosterone sold increased 65%, with
men aged 40–64 years accounting for the majority of users.
Over the past several years, there have been several
widely publicized retrospective association studies that re-
ported higher rates of cardiovascular events and death asso-
ciated with testosterone replacement therapy. These studies
have been heavily criticized for a variety of design flaws
and inappropriate statistical manipulations. However, once
these studies were published, the media began publishing ar-
ticles interpreting the relationship between testosterone and
cardiovascular events as cause and effect—missing the point
that these were not randomized trials or even treatment trials.
Promptly following the publications, ads began appearing
from law offices, asking patients who have had cardiovascu-
lar events while on testosterone therapy to contact them.
Because of the above issues, the FDA convened a
meeting of the Bone, Reproductive, and Urologic Drugs
Advisory committee and the Drug Safety and Risk Manage-
ment Advisory Committee in September 2014 to discuss two
issues. The first was whether current evidence supports the
benefit of testosterone therapy in the populations of men
that are using it, specifically age-associated hypogonadism,
and whether there should be changes in the development
paradigm to support therapy in men with age-associated hy-
pogonadism. The second issue was to determine whether
there was sufficient evidence that testosterone treatment
increased the risk of major cardiovascular events. During
the meeting there were a variety of presentations, including
from the FDA staff, outside presenters invited by the FDA,
industry representatives, representatives from medical orga-
VOL. 103 NO. 5 / MAY 2015
Fertility and Sterility®
nizations, and individual physicians and patients. What
became clear in the meeting was that there is a need for
large randomized controlled trials to determine efficacy
and safety. There is currently an ongoing multicenter ran-
domized trial study examining efficacy which will likely
yield hard data on the effect of testosterone replacement
in a variety of domains. However, the study population is
men R65 years old, which is not the population that consti-
tutes the greatest testosterone use. In addition, it is not
powered to determine safety. Of note, since the meeting,
direct-to-consumer advertisements have decreased or van-
ished. On March 3, 2015, the FDA released its decision
and now cautions that prescription testosterone products
are approved only for men who have low testosterone levels
caused by certain medical conditions. They emphasize that
the benefit and safety of testosterone therapy have not
been established for the treatment of low testosterone levels
due to aging, even if a man's symptoms seem related to low
testosterone. They are now requiring the labeling to be
changed to clarify the approved uses of these medications.
Finally they are also requiring the manufacturers to add
information to the labeling about a possible increased risk
of heart attacks and strokes in patients taking testosterone.
The entire controversy has brought several points into
focus. There is a large gap in our knowledge about testos-
terone replacement. The field is full of disagreements and
controversies. What are the indications for testosterone
replacement? Does the cause of hypogonadism matter, or
should it be based on testosterone levels and symptoms?
What levels warrant treatment? Does the threshold for treat-
ment depend of the symptom being treated? How high is the
goal for serum levels in men on treatment? Do we push older
men's levels to be the same as those of younger men? What
are the cardiovascular risks of testosterone replacement?
This last question will require large expensive randomized tri-
als which are likely to be necessary to truly answer the ques-
tion. Can we undertake such a trial without ending up with the
controversy of the Women's Health Initiative? I certainly
don't have the answers to these questions, but I think it is
important that practitioners understand this controversy to
better manage and counsel patients.
Mark Sigman, M.D.
Division of Urology, Brown University,
Providence, Rhode Island
http://dx.doi.org/10.1016/j.fertnstert.2015.03.005
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