REVIEW

CURRENT
OPINION Testosterone supplementation in men: a practical
guide for the gynecologist and obstetrician
Ryan C. Owen, Osama O. Elkelany, and Edward D. Kim

Purpose of review
Prescribing habits for the treatment of symptomatic hypogonadism have recently stirred controversy
surrounding testosterone replacement therapy. As a result, the gynecologist will need to recognize this
iatrogenic form of decreased sperm production in couples seeking fertility advice. We have compiled
a review of the current literature on testosterone supplementation pertaining to the gynecologic practice.
Recent findings
Over the last decade, testosterone use has seen a recent increase including in men desiring to become
fathers. Many physicians and hypogonadal men do not recognize that testosterone replacement therapy
can have a detrimental effect on spermatogenesis. Fortunately, the cessation of treatment will yield
predictable recovery of sperm production for most men. A growing body of evidence supports the use of
selective estrogen receptor modulators, such as clomiphene citrate, or human chorionic gonadotropin for
the treatment of hypogonadism in men who wish to maintain fertility potential. Recently, the Food and Drug
Administration has recommended a labeling update on testosterone products to warn of possible increased
risk of venous thromboembolism, cardiovascular events and stroke.
Summary
Clinicians should be familiar with current practices involving testosterone replacement therapy and the
implications on male factor fertility.
Keywords
azoospermia, cardiovascular risk, hypogonadism, spermatogenesis, testosterone supplementation

INTRODUCTION INDICATIONS FOR USE

Although gynecologists will rarely treat men with Male hypogonadism, as defined by the Endocrine
hypogonadism, implications for the couple need to Society Guidelines, is a clinical syndrome that
be recognized. There has been a clear increase in results from failure of the testis to produce physio-
testosterone therapy in men of reproductive age logic levels of testosterone, resulting in androgen
who are trying to initiate pregnancy. Moreover, deficiency and a normal number of spermatozoa
there continues to be a distinct lack of awareness because of disruption of one or more levels of the
that exogenous testosterone therapy has adverse hypothalamic–pituitary–testis axis [3]. These
consequences on spermatogenesis [1]. In a recent Guidelines, which may be considered the standard
article by Ko et al. [2], it was found that 25% of of care for men with hypogonadism, classify
urologists have prescribed testosterone therapy to patients into two groups. Primary hypogonadism,
treat male factor infertility, erroneously. Addition- or primary testicular failure, is caused by an
ally, topical testosterone therapy introduces the risk
of transference to the female partner or children as
University of Tennessee Graduate School of Medicine, Knoxville,
emphasized by a boxed warning on Food and Drug Tennessee, USA
Administration (FDA) prescribing information Correspondence to Ryan C. Owen, MD, Department of Surgery, Division
labels. We provide recent updates on the treatment of Urology, University of Tennessee Graduate School of Medicine, 1928
of hypogonadism to include indications for use, Alcoa Highway, Suite 222, Knoxville, TN 37920, USA. Tel: +1
routes of administration, results on symptomatic 8653059254; fax: +1 8653054589.
relief, consequences of use and effects on spermato- Curr Opin Obstet Gynecol 2015, 27:258–264
genesis. DOI:10.1097/GCO.0000000000000192

www.co-obgyn.com Volume 27  Number 4  August 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

 Testosterone supplementation in men Owen et al.

of patients receiving treatment with a relative

KEY POINTS increase of 78%, whereas men under the age of 39
 Prior to 2014, prescriptions for testosterone nearly years represent the largest relative increase in new
doubled, with a significant number of users under the treatments totaling 99%. Most concerning, how-
age of 39. ever, is the practice of initiating TRT without first
confirming the diagnosis of hypogonadism by
 Currently, the FDA requires testosterone manufacturers
obtaining a baseline serum testosterone level.
to warn users of possible increased risk of venous
thromboembolism, cardiovascular events and stroke, According to the FDA sponsored Joint Meeting for
although this link is highly controversial. Bone, Reproductive and Urologic Drugs Advisory
Committee (BRUDAC) and the Drug Safety and Risk
 The detrimental effects of testosterone replacement Management Advisory Committee report, only half
therapy on spermatogenesis need to be recognized by
of men receiving TRT had a baseline testosterone
the gynecologist, as cessation of treatment will yield
predictable recovery of sperm production. value prior to starting therapy. Furthermore, 21% of
treated men never demonstrated testosterone
 A growing body of evidence supports the use of monitoring throughout their course of therapy
selective estrogen receptor modulators or human &&
[5 ]. The increased trend of TRT use for uncon-
chorionic gonadotropin for the treatment of
firmed cases of hypogonadism represents a serious
hypogonadism in men who wish to maintain
fertility potential. public health concern that has stimulated recent
regulatory investigation.

abnormality with the hypothalamic–pituitary– ROUTE OF ADMINISTRATION

testis axis at the testicular level. This disorder results As the market for TRT steadily increased, so did the
in low levels of testosterone, impaired spermato- routes of administration. Current FDA-approved
genesis and elevated levels of gonadotropins includ- formulations are delivered via intramuscular injec-
ing luteinizing hormone and follicle-stimulating tion, topical gel, nasal gel, transdermal patch, buc-
hormone (FSH). Secondary hypogonadism is caused cal bioadhesive or subcutaneous pellet [3]. Details
by a deficiency within the hypothalamus or pitu- regarding each route of administration are listed in
itary and results in gonadotropin levels that fall to Table 1. Each testosterone preparation has distinct
low or low-normal range. In addition, age-related advantages and disadvantages; therefore, the
decreases in testosterone have been reported. decision to use one formulation versus another is
According to Harmin et al. [4] testosterone levels based primarily on insurance formulary preferred
in men begin to decline at a rate of 1.2% per year lists, patient preference or clinical benefit. For
beginning at age 30 to 40 years. Regardless of the example, men with young children may choose
origin, hypogonadal men may exhibit reduced to use intramuscular testosterone over a gel prep-
sexual desire, decreased energy, decreased spon- aration in order to avoid the risk of transference. In
taneous erections, small or shrinking testes, another common scenario the preference for a tes-
inability to father children, hot flushes, poor con- tosterone preparation that maintains stable serum
centration or memory, sleep disturbance, reduced levels, such as a daily gel or transdermal patch, is
muscle mass and/or diminished physical activity [3]. chosen in order to avoid the peaks and troughs
In an effort to counter the hormonal imbalance associated with intramuscular administration.
in symptomatic men, testosterone replacement In 2014, two products were FDA-approved:
& &
therapy (TRT) has been utilized in a variety of for- Aveed [6 ] and Natesto [7 ]. Aveed represents a
mulations over the past half-century. Testosterone is long-acting testosterone intramuscular injection
an androgen steroid hormone, primarily secreted by with a 10-week dosing interval. A potential risk is
the testis, with additional secretion from the adrenal the possibility of pulmonary oil microembolism.
&&
gland [5 ]. Beginning in 1953, TRT has been indi- Natesto is an intranasal gel that is applied three
cated for symptomatic hypogonadism, delayed pub- times daily. Pharmaceutical products used to treat
erty and some cases of metastatic breast cancer. In symptomatic hypogonadism but not currently
clinical practice, TRT has provided adequate symp- approved by the FDA for hypogonadism include
tomatic relief for hypogonadal men. Within this human chorionic gonadotropin (hCG) or selective
decade testosterone sales have, however, increased estrogen receptor modulators such as clomiphene
&&
by approximately 65% [5 ]. From 2010 to 2013, the citrate and tamoxifen [8–10]. Additionally, testos-
number of testosterone prescriptions increased from terone undecanoate is an oral form of TRT but is not
&&
1.3 million to 2.3 million patients [5 ]. Men aged currently approved for treatment of hypogonadism
40–64 years represent the largest absolute number in the United States.

1040-872X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-obgyn.com 259

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Reproductive endocrinology

Table 1. Testosterone supplementation options

Route of administration and

Medication formulation dosage Advantages Disadvantages

Testosterone enanthate or Intramuscular injection; Cost effective; offers flexible Requires an injection; serum testosterone
cypionate 75–100 mg every week or dosing; alleviates symptoms levels may vary
150–200 mg injection every of hypogonadism
2 weeks
Long-acting testosterone Intramuscular injection; 1000 mg Requires infrequent injections Requires an injection of a large volume;
undecanoate in oil [6 ] injection followed by 1000 mg occasional cough reported; possibility
&

injection after 6 weeks. After- of pulmonary oil microembolism

ward, inject every 10–14
weeks
hCG Intramuscular/subcutaneous Helps prevent azoospermia Requires intramuscular injection or subcu-
injection; 125–500 IU every and testis atrophy; can be taneous injection; may cause mental/
other day; 2500–3000 IU taken in low doses mood changes, headache, restless-
every other day after anabolic ness, tiredness, swelling of the ankles/
steroid abuse feet, pain in the breast
1% and 1.62% testoster- Topical; 5–10 g of testosterone Easy application; has a May cause skin irritation; can be trans-
one gel gel which consists of flexible dosage ferred to other people by skin-to-skin
50–100 mg of testosterone contact or through clothes; variable
daily for 1%. 20.21–81 mg bioabsorption
testosterone for 1.62%
2% testosterone solution Topical; 3–100 mg daily with one Decreased risk of transference; May cause skin irritation; can be trans-
to four pump actuations per axillary application; flexible ferred to other people by skin-to-skin
axilla dosage contact or through clothes; variable
bioabsorption
Nasal testosterone gel [7 ] Nasal; 11 mg, one pump Easy application; corrects Headache, rhinorrhea, epistaxis, nasal
&

actuation per nostril, symptoms of hypogonadism discomfort, nasal scab, parosmia

three times daily
Testosterone patch Transdermal; one or two patches Easy to apply; relieves May cause skin irritation
that deliver 5–10 mg of testos- symptoms of androgen
terone over a 24-h period deficiency
Testosterone pellets Surgical; 150–450 mg inserted Corrects symptoms of hypogo- Pellets must be surgically implanted;
subcutaneously; dose and nadism; administered every possibility of pellet extrusion from skin,
regimen vary 3–6 months local bleeding
Bioadhesive testosterone Buccal; 30 mg twice daily Ease of buccal administration May cause gum-related side effects
tablets
Testosterone undecanoate Oral; 40–80 mg twice or three Ease of oral administration Serum testosterone levels may vary; not
times daily with a meal approved for use in the United States
Clomiphene citrate – off Oral; 25 mg every other day with Helps to raise testosterone Not as effective when luteinizing
label upward titration to 50 mg daily levels; cost effective; avoids hormone and FSH levels are
azoospermia already high; may cause weight
gain, hypertension, gynecomastia,
acne, and cataracts

FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin.

RESULTS ON SYMPTOMATIC RELIEF the results of men taking Testim (1% testosterone
Since approval of testosterone in 1953, FDA approval gel; Auxilium Pharmaceuticals, Inc., Malvern, Penn-
of testosterone products has been based on pharma- sylvania, USA). Miner et al. [11] established that
cokinetic data rather than symptomatic relief. As a improvements were seen in sexual function, mood
result, patient-reported outcomes of symptom and depression after 3 months of daily application.
benefit are scarce. Now, in order to comply with Additionally, men with improved serum testosterone
FDA regulations, testosterone products must com- levels demonstrated improvement in metabolic
plete additional trials that include primary and sec- parameters after 12 months.
ondary efficacy endpoints. Such endpoints include With escalating public concern, regulators,
serum testosterone concentration benchmarks and however, want more precise metrics assessing symp-
&&
documented symptomatic improvements [5 ].
&&
tomatic benefit [5 ]. Measurements in improve-
An example of documented improvement is rec- ment are assessed by questionnaires designed to
ognized in a 12-month observational study assessing diagnose and follow men with hypogonadism.

260 www.co-obgyn.com Volume 27  Number 4  August 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

 Testosterone supplementation in men Owen et al.

The androgen decline of aging men, Massachusetts is no evidence to suggest an increased risk for the
Male Aging Study and aging male’s symptoms are development of prostate cancer per the Endocrine
examples, although each has limitations regarding Society Guidelines. In a 2013 study by Raynaud et al.
specificity. In 2014, Ramasamy et al. [12] demon- [18], the elevation in PSA while on TRT was minor,
strated a two-point improvement in androgen with an increase from mean baseline of 0.50 ng/ml
decline of aging men score after prospectively fol- to 0.80 ng/ml. There were no observed cases of
lowing 42 men using injectable or gel TRT. Consist- prostate cancer during the study period. Ultimately,
ent with the results of Miner’s study, this article also men taking testosterone supplementation should be
revealed specific improvement in sexual desire, made aware of all side-effects. The prescribing pro-
libido and mood. vider should continue to follow each patient until
&
More recently, Cunningham et al. [13 ] utilized TRT is discontinued. Specific recommendations for
question 4 of the Psychosocial Daily Questionnaire clinical monitoring are described in the Endocrine
(PDQ-Q4) to prove that low baseline total testoster- Society Guidelines [3].
one and free testosterone were independently
associated with changes in sexual desire, activity
and erectile function. The PDQ-Q4 will also be Cardiovascular disease and testosterone
utilized as one of the primary outcome measure- replacement therapy
ments in the ongoing testosterone trial, which is Recently, the discussion regarding the use of testos-
funded primarily by the National Institute of Aging terone and associated cardiovascular disease has
&
[13 ]. The testosterone trial in older men is a stirred controversy among medical professionals
randomized, placebo-controlled, double-blind study and media outlets alike. In June of 2014, the FDA
seeking to objectively measure changes before and Drug Safety Communication task force issued a state-
after TRT. In addition to sexual function, other ment requiring all testosterone manufacturers to
primary endpoints include physical function, include a boxed warning of TRT and the risk of venous
cognitive function and changes in vitality, cardio- thromboembolism [19]. Then, in March of 2015 the
vascular plaque volume, bone mineral density and FDA issued another statement directing that all
improvements in hemoglobin. approved testosterone supplement manufacturers
Thus, with no formally accepted endpoint for include a boxed warning of the possible increased
improvement in symptoms, changes in libido may risk of cardiovascular events and stroke [20].
be the most specific. Furthermore, with new product The association of hypogonadism, its treatment
development, success through the FDA approval and cardiovascular morbidity has been debated for
&
process will have to demonstrate that testosterone several decades [21 ]. Prior to recent concern about
products provide benefit toward patient reported TRT and an alleged increase in cardiovascular
outcomes using validated questionnaires. mortality, meta-analyses and published literature
suggested that low-serum testosterone levels were
related to cardiovascular disease [22–27]. As men-
CONSEQUENCES OF USE tioned previously though, the increase in testoster-
one prescriptions prompted a review of indications
Adverse events of use as well as potential complications. During this
Adverse events of TRT include but are not limited to time period, four articles were published which
worsening of benign prostatic hyperplasia/lower observed that TRT might potentially increase the
urinary tract symptoms (BPH/LUTS), increase in &
risk of cardiovascular events [28,29 ,30,31]. Three of
prostate-specific antigen (PSA), acne, fatigue, the four articles were among the literature cited by
insomnia, aggression, polycythemia, venous throm- the FDA Drug Safety Communication update that
boembolism, hepatic adverse effects, edema, gyne- directed the current warning regarding TRT use and
comastia, worsening of obstructive sleep apnea, cardiovascular safety. The first was a retrospective
changes in lipid profile, hypercalcemia and decreased review of 8709 men undergoing coronary angiog-
&& &
thyroxin-binding globulin [5 ,6 ,14]. Men using raphy who also received a prescription for some
intramuscular testosterone might experience injec- formulation of TRT [28]. Using unconventional stat-
tion site pain. Although reported in the package istical analysis, Vigen et al. concluded that TRT was
insert for each testosterone preparation, recent evi- related to increased propensity for cardiovascular
dence suggests that worsening of BPH/LUTS may events, stroke and death. In the second study, Finkle
not occur at a higher incidence than the general &
et al. [29 ] reported a 36% increase in the rate of
population. Recent publications suggest that TRT nonfatal myocardial infarction in the 3-month time
might actually improve BPH/LUTS [15–17]. period following testosterone prescription com-
Although TRT can cause mild increases in PSA, there pared with the previous year. The third study was

1040-872X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-obgyn.com 261

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Reproductive endocrinology

a meta-analysis by Xu et al. [31] in which 27 placebo- This form of therapy should be recognized by
controlled testosterone studies were evaluated. They the practitioner overseeing the infertile couple
reported that cardiovascular events were increased and discontinued as soon as possible, as recovery
in men using testosterone compared with the of spermatogenesis will likely occur.
placebo arm.
&
A 2015 review article by Morgentaler [21 ], how-
ever, raised objection to each of the previously Pathophysiology
mentioned studies. He contended that methodo- Testosterone production originates from a properly
logical flaws invalidated the studies produced by functioning hypothalamic–pituitary–testis axis.
Vigen and Finkle et al. Additionally, two published Gonadotropin-releasing hormone from the hypo-
corrections have recently removed over 1900 indi- thalamus triggers release of luteinizing hormone
viduals from the former data set and uncovered that and FSH from the anterior pituitary, which in turn
10% of the reported all-male dataset were actually stimulates Leydig cell and Sertoli cell activation
female. He concluded that there was no credible within the testis. Testosterone is then manufactured
evidence to support the notion that TRT increases as a result of Leydig cell function, whereas spermato-
the risk of cardiovascular mortality. Additionally, genesis occurs from Sertoli cell function. When
Morgentaler’s statement reinforces the previous exogenous testosterone enters the system, it creates
findings from the FDA’s Division of Cardiovascular a negative feedback on luteinizing hormone, FSH
and Renal Products review of the topic. BRUDAC has and gonadotropin-releasing hormone release.
previously noted that ‘results were inconclusive due When this occurs, natural stimulation of Leydig
to the lack of a prespecified safety endpoint, poten- and Sertoli cell function declines. TRT, therefore,
tial ascertainment bias, the small number of major halts the progression of spermatogenesis as well as
adverse cardiac events reported, possible imbalances intratesticular testosterone (ITT) production, poten-
in baseline cardiovascular risk between the groups, tially resulting in oligozoospermia or azoospermia.
and questionable applicability to the population for
&&
whom testosterone therapy is indicated’ [5 ]. To
clarify the association between TRT and cardiovas- Recovery of spermatogenesis
cular events, higher quality prospective studies are Although detrimental effects may be quite pro-
required. The eagerly awaited results from the tes- nounced, discontinuation of TRT will likely provide
tosterone trials may provide valuable insight into successful recovery of spermatogenesis. In a multi-
this question. variate time-to-event analysis by Liu et al. [32], 1549
eugonadal men between the ages of 18 and 51 were
administered androgens versus androgens plus pro-
Secondary exposure gestagen for a total of 1284 man-years. After discon-
Topical testosterone formulations have the poten- tinuation of therapy, median time until recovery of
tial for secondary exposure [14]. It has been esti- sperm concentrations to 3, 10 and 20 million/ml
mated that approximately 10% of a topical dose is was 2.5, 3.0 and 3.4 months, respectively. In
absorbed by the patient. The transference of testos- addition, they reported factors associated with
terone may result in genital size enlargement, increased recovery rate as older age, Asian origin,
changes in distribution of body hair, increased acne, shorter treatment duration, shorter-acting testoster-
development of pubic hair or libido or other signs of one preparations, higher sperm concentrations at
virilization in women and children. These effects baseline, faster suppression of spermatogenesis and
typically regress with the cessation of exposure. lower baseline blood concentrations of luteinizing
Also, secondary exposure typically occurs as a result hormone. Furthermore, recovery to 20 million/ml
of direct exposure to unwashed or openly exposed occurred in 67% at 6 months, 90% at 12 months and
sites. Strict adherence to prescribed precautions will 100% at 24 months. Once TRT is withheld, recovery
negate risk of exposure to applied testosterone. of spermatogenesis will likely return in a predictable
time. If spermatogenesis does not recover in the
predicted time frame, a full endocrine evaluation
EFFECTS OF TESTOSTERONE may then be warranted.
SUPPLEMENTATION ON
SPERMATOGENESIS
Literature now supports the concept that TRT will Alternate treatment regimens
have a negative effect on spermatogenesis. Some for hypogonadal men
physicians, however, continue to prescribe TRT as Despite awareness of the negative effects on sper-
empiric therapy for men with fertility concerns [2]. matogenesis, a select number of men opt to

262 www.co-obgyn.com Volume 27  Number 4  August 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

 Testosterone supplementation in men Owen et al.

continue TRT because of symptomatic benefit. For spermatogenesis was maintained in a small trial of
this cohort of men, there are a number of treatment men receiving low-dose hCG with a short acting
options that allow for continued symptomatic relief testosterone preparation. Limitations of hCG use
without the fertility concern. include high-cost, frequent injections and unfa-
One option is off-label use of an oral alternative. miliarity with dosage schedule by prescribing
Clomiphene citrate is a selective estrogen receptor physicians.
modulator that competitively binds to estrogen Aromatase inhibitors have also been utilized for
receptors in the hypothalamus and pituitary nega- the treatment of hypogonadism. Responsible for the
tive feedback loop resulting in stimulation of lutei- conversion of testosterone to estradiol, aromatase is a
nizing hormone and FSH release to the testis. The cytochrome P-450 enzyme concentrated in the
increased signal to the testis stimulates natural testes, liver, brain and adipose tissue. As mentioned
production of ITT and serum testosterone. When previously, estradiol inhibits gonadotropin secretion
prescribed clomiphene citrate, improvements in and may exert direct effects on ITT production.
serum testosterone are comparable to TRT as docu- Aromatase inhibitors function by blocking the con-
mented by Taylor and Levine [33]. They compared version of androgens to estrogen, consequently
104 men treated with 50 mg of clomiphene citrate increasing serum levels of luteinizing hormone,
every other day versus 5 g of 1% testosterone gel. FSH and testosterone and resulting in functional
After a 23-month follow up period, post treatment effects similar to those of the antiestrogens. This class
serum testosterone levels were 573 ng/dl versus of drugs, which includes anastrazole and testolac-
553 ng/dl in the clomiphene citrate group and tes- tone, has been utilized to improve male fertility
tosterone gel group, respectively. and stimulate spermatogenesis. Specifically, aroma-
With successful treatment of hypogonadism tase inhibitors may have greater benefit than anties-
using clomiphene citrate, novel selective estrogen trogens in men with lower serum testosterone to
receptor modulators are being developed for the estradiol ratios (<10) and in obese patients.
indication of secondary hypogonadism. For example, Other forms of hormonal manipulations have
a second pivotal study (ZA-304) by Repros Thera- been utilized in the past for men with primary
peutics Inc. (The Woodlands, Texas, USA) compared hypogonadism or men recovering from previous
obese men with secondary hypogonadism treated anabolic steroid use. This includes human meno-
with Androxal (enclomiphene citrate), the trans-iso- pausal gonadotropin in conjunction with hCG as
mer of clomiphene citrate, to Androgel (1.62% topical FSH and luteinizing hormone analogs, respectively.
testosterone gel). Primary endpoints included per- These are, however, rarely used as TRT in men with
centage change from baseline sperm concentration secondary hypogonadism.
and percentage of patients who maintained normal
testosterone concentrations while also maintaining
sperm concentration above 10 million/ml [34]. They Role of gynecologist in counseling the male
reported a 33% reduction from baseline sperm con- partner
centration in the Androgel arm compared with 5.9% There is a paucity of clinical scenarios in which
increase in the Androxal group. In addition, 65.9% of the gynecologist will prescribe TRT. In couples
Androxal users maintained baseline testosterone struggling with infertility, however, the onus rests
levels and sperm concentrations above 10 million/ upon the counseling clinician to recognize the use
ml compared with only 33% of Androgel-treated and then discontinue TRT. Thus, the question
men. regarding TRT use should be proposed to the male
Another option is the administration of low- partner in such couples. Furthermore, if TRT is
dose hCG in addition to TRT. In a 3-week prospec- promptly discontinued, testicular function of
tive trial, Coviello et al. [35] investigated the effects spermatogenesis will likely return in a predictable
of low-dose hCG injection to normal men receiving time frame [32]. Finally, it is reasonable to con-
exogenous testosterone compared with men only clude that if men maintain spermatogenic poten-
treated with TRT. In men receiving the additional tial, then chances of pregnancy will likely
low dose hCG, ITT levels remained within normal improve, although no study is available to prove
range, whereas men receiving only TRT recognized a this notion.
profound decrease in ITT concentration. Although
the study period lasted only 3 weeks, the finding
that low-dose hCG maintains ITT concentrations CONCLUSION
with TRT implicates that spermatogenesis may be Testosterone replacement therapy is a well tolerated
preserved with this regimen. This notion was and effective treatment for men with symptomatic
confirmed when Avila et al. [36] reported that hypogonadism. The recent increase in testosterone

1040-872X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-obgyn.com 263

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Reproductive endocrinology

13. Cunningham GR, Stephens-Shields AJ, Rosen RC, et al. Association of sex
prescriptions and controversy over cardiovascular & hormones with sexual function, vitality, and physical function of symptomatic
health effects have, however, led to public concern older men with low testosterone levels at baseline in the testosterone trials. J
Clin Endocrinol Metab 2015; 100:1146–1155.
and investigation by the FDA. The take-home point Testosterone levels were consistently, independently and positively associated
for the gynecologist is to promptly recognize men with measures of sexual desire, erectile function and sexual activity using the
psychosocial daily questionnaire in symptomatic older men with low testosterone
on TRT and to discontinue use in couples trying to who qualified for the testosterone trials.
conceive. Although improved pregnancy rates are 14. AndroGel1 (testosterone gel) 1.62% [package insert]. North Chicago, IL:
AbbVie, Inc., 2014.
not guaranteed, recovery of spermatogenesis is 15. Pearl J, Berhanu D, Francois N, et al. Testosterone supplementation does not
likely to be successful. Fortunately, if the male part- worsen lower urinary tract symptoms. J Urol 2013; 190:1828–1833.
16. Page S, Hirano L, Gilchriest J, et al. Dutasteride reduces prostate size and
ner remains symptomatic, alternative treatment prostate specific antigen in older hypogonadal men with benign prostatic
options will provide symptomatic relief while main- hyperplasia undergoing testosterone replacement therapy. J Urol 2011;
186:191–197.
taining baseline sperm concentrations. 17. Shigehara K, Sugimoto K, Konaka H, et al. Androgen replacement therapy
contributes to improving lower urinary tract symptoms in patients with
hypogonadism and benign prostate hypertrophy: a randomized controlled
Acknowledgements study. Aging Male 2011; 14:53–58.
18. Raynaud J, Gardette J, Rollet J, Legros J. Prostate-specific antigen (PSA)
None. concentrations in hypogonadal men during the 6 years of transdermal
testosterone treatment. BJU Int 2013; 111:880–890.
19. Update on United States Food and Drug Administration evaluating the risk of
Financial support and sponsorship stroke, heart attack and death with FDA-approved testosterone products:
FDA adding general warning to testosterone products about potential for
There was no financial assistance provided for participa- venous blood clots. http://www.fda.gov/Drugs/DrugSafety/ucm401746.htm.
tion in this review. [Accessed 19 June 2014]
20. Update on United States Food and Drug Administration evaluating the risk of
stroke, heart attack and death with FDA-approved testosterone products:
FDA cautions about using testosterone products for low testosterone due to
Conflicts of interest aging; requires labeling change to inform of possible heart attack and stroke
E.D.K. is a speaker for Endo Pharmaceuticals. He is also with use. http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm. [Accessed
3 March 2015]
an advisor for Repros Therapeutics, Inc. R.C.O. and 21. Morgentaler A. Testosterone deficiency and cardiovascular mortality. Asian J
O.O.E. have nothing to disclose. & Androl 2015; 17:26–31.
Provides valid counter point to the notion of alleged cardiovascular effects after TRT.
22. Haring R, Völzke H, Steveling, et al. Low serum testosterone levels are
associated with increased risk of mortality in a population-based cohort of
men aged 20–79. Eur Heart J 2010; 31:1494–1501.
REFERENCES AND RECOMMENDED 23. Malkin C, Pugh P, Morris P, et al. Low serum testosterone and increased
mortality in men with coronary heart disease. Heart 2010; 96:1821–1825.
READING 24. Menke A, Guallar E, Rohrmann S, et al. Sex steroid hormone concentrations
Papers of particular interest, published within the annual period of review, have
and risk of death in US men. Am J Epidemiol 2010; 171:583–592.
been highlighted as:
25. Laughlin G, Barrett-Connor E, Bergstrom J. Low serum testosterone and
& of special interest
&& of outstanding interest
mortality in older men. J Clin Endocrinol Metab 2008; 93:68–75.
26. Khaw K, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality
due to all causes, cardiovascular disease, and cancer in men: European
1. Moss J, Crosnoe L, Kim ED. Effect of rejuvenation hormones on spermato- prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective
genesis. Fertil Steril 2013; 99:1814–1820. Population Study. Circulation 2007; 116:2694–2701.
2. Ko E, Siddiqi K, Brannigan R, Sabanegh E. Empirical medical therapy for 27. Corona G, Rastrelli G, Monami M, et al. Hypogonadism as a risk factor for
idiopathic male infertility: a survey of the American Urological Association. J cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol 2011;
Urol 2012; 187:973–978. 165:687–701.
3. Bhasin S, Cunningham G, Hayes F, et al. Testosterone therapy in men with 28. Vigen R, O’Donnell C, Baron A, et al. Association of testosterone therapy with
androgen deficiency syndromes: an Endocrine Society clinical practice guide- mortality, myocardial infarction, and stroke in men with low testosterone levels.
line. J Clin Endocrinol Metab 2010; 95:2536–2559. JAMA 2013; 310:1829–1836.
4. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum 29. Finkle W, Greenland S, Ridgeway G, et al. Increased risk of nonfatal
total and free testosterone levels in healthy men. Baltimore Longitudinal Study & myocardial infarction following testosterone therapy prescription in men.
of Aging. J Clin Endocrinol Metab 2001; 86:724–731. PLoS One 2014; 9:e85805.
5. Joint Meeting for Bone, Reproductive and Urologic Drugs Advisory Commit- One of four articles sited in the FDA update on TRT and alleged increased
&& tee (BRUDAC) and the Drug Safety and Risk Management Advisory Com- cardiovascular risk.
mittee (DSARM AC). FDA background documents for the discussion of two 30. Basaria S, Coviello A, Travison T, et al. Adverse events associated with
major issues in Testosterone Replacement Therapy (TRT) 2014. A statement testosterone administration. N Engl J Med 2010; 363:109–122.
by the FDA outlining appropriate indications for use and potential cardiovas- 31. Xu L, Freeman G, Cowling B, Schooling C. Testosterone therapy and
cular associated outcomes. http://www.fda.gov/AdvisoryCommittees/Calen- cardiovascular events among men: a systematic review and meta-analysis
dar/ucm406131.htm. [Accessed 17 September 2014] of placebo-controlled randomized trials. BMC Med 2013; 11:108.
6. Aveed1 (testosterone undecanoate) [package insert]. Malvern, PA: Endo 32. Liu P, Swerdloff R, Christenson P, et al. Hormonal Male Contraception
& Pharmaceuticals Solutions; 2014. Released within the past 18 months. Summit Group. Rate, extent and modifiers of spermatogenic recovery after
7. Natesto1 (testosterone) nasal gel [package insert]. Barbados, BBI: Trimel hormonal male contraception: an integrated analysis. Lancet 2006;
& BioPharma SRL, 2014. Released within the last 18 months. 367:1412–1420.
8. Guay AT, Bansal S, Heatley GJ. Effect of raising endogenous testosterone levels 33. Taylor F, Levine L. Clomiphene citrate and testosterone gel replacement
in impotent men with secondary hypogonadism: double blind placebo-controlled therapy for male hypogonadism: efficacy and treatment cost. J Sex Med 2010;
trial with clomiphene citrate. J Clin Endocrinol Metab 1995; 80:354–452. 7:269–276.
9. Lopez JM, Oestreicher E. Reversal of hypogonadotropic hypogonadism with 34. Repros Therapeutics Inc. Androxal1 second pivotal study achieves super-
tamoxifen in a patient with hyperprolactinemia resistant to dopamine agonists. iority in top line analysis for both co-primary endpoints versus marked topical
Fertil Steril 2005; 84:756. gel in the treatment of secondary hypogonadism. http://ir.reprosrx.com/re-
10. Kim ED, Crosnoe L, Bar-Chama N, et al. The treatment of hypogonadism in leasedetail.cfm?ReleaseID=868068. [Accessed 24 September 2014]
men of reproductive age. Fertil Steril 2013; 99:718–724. 35. Coviello A, Matsumoto A, Bremner W, et al. Low-dose human chorionic
11. Miner MM, Bhattacharya RK, Blick G, et al. 12-month observation of testos- gonadotropin maintains intratesticular testosterone in normal men with tes-
terone replacement effectiveness in a general population of men. Postgrad tosterone-induced gonadotropin suppression. J Clin Endocrinol Metab 2005;
Med 2013; 125:8–18. 90:2595–2602.
12. Ramasamy R, Scovell J, Kovac J, Lipshultz L. Testosterone supplementation 36. Avila D, Gittens P, Hwang K, et al. Low dose human chorionic gonadotropin
versus clomiphene citrate for hypogonadism: an age matched comparison of prevents azospermia and maintains fertility in hypogonadal men on testoster-
satisfaction and efficacy. J Urol 2014; 192:875–879. one replacement therapy. Fertil Steril 2010; 94:128–129.

264 www.co-obgyn.com Volume 27  Number 4  August 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.