This is the html version of the file
G o o g l e automatically generates html versions of documents as we crawl the web.

Google is not affiliated with the authors of this page nor responsible for its content.
These search terms have been highlighted:  dhea  absorption  mucous  membranes 

Page 1
Mayo Clin Proc, April 2004, Vol 79 (Supplement)
Formulations and Use of Androgens
Mayo Clin Proc. 2004;79(suppl):S3-S7
© 2004 Mayo Foundation for Medical Education and Research
Supplement Article
Formulations and Use of Androgens in Women
C. C
, MD,
A. L
, MD
From the Department of Obstetrics and Gynecology, Columbia Uni-
versity College of Physicians and Surgeons, New York, NY.
Address correspondence to Rogerio A. Lobo, MD, Department of
Obstetrics and Gynecology, Columbia University College of Physi-
cians and Surgeons, 622 W 168th St, PH 16-77, New York, NY
10032 (e-mail:
The physiology of normal androgen production in women
has been poorly understood. Defining an androgen insuffi-
ciency state in women, in the absence of adrenal suppres-
sion and/or bilateral oophorectomy, has been difficult.
Nevertheless, beneficial effects of androgen on many organ
systems, including bone and the brain, are well docu-
mented. This review discusses the definition of androgen
insufficiency, anticipated effects of androgen treatment on
DHEA = dehydroepiandrosterone; SHBG = sex hormone–
binding globulin
several factors of health, and treatment options for women
with androgen insufficiency.
Mayo Clin Proc. 2004;79(suppl):S3-S7
he physiology of normal androgen production in
women has been poorly understood. Aging accounts
for much of the reduction in both ovarian and adrenal
androgen production, but natural menopause does not re-
sult in an abrupt decline in testosterone production. There-
fore, defining an androgen insufficiency state in women, in
the absence of adrenal suppression and/or bilateral
oophorectomy, has been difficult. Because androgens af-
fect many organ systems, including bone, muscle, and the
brain, there are beneficial effects of androgen therapy for
documented androgen insufficiency.
Some of the difficulty in accepting that androgen in-
sufficiency may be a valid entity in women is the confu-
sion surrounding measurements. In most perimenopausal
women, testosterone and free testosterone levels are con-
sidered normal, but there is a wide range in values for
testosterone and unbound testosterone in individual
perimenopausal women.
In addition, some women with
low levels (eg, after oophorectomy) do not report having
symptoms. Finally, because testosterone is efficiently aro-
matized to estrogen in many tissues, including the brain, it
has been argued that the effects attributed to testosterone
may be due to estrogen and that estrogen replacement alone
may be sufficient.
Nevertheless, several arguments favor the legitimacy
of a clinical syndrome of androgen insufficiency in
women: (1) symptoms are highly individual; (2) even
with estrogen deficiency, there is no direct correlation
with blood levels; (3) with aging, testosterone production
decreases, although it is a relative decrease; and (4) alter-
ations in factors of mood and well-being are difficult to
An international consensus conference on androgen in-
sufficiency in women was convened in Princeton, NJ, in
2001. Because of the lack of sufficient epidemiological
data and limitations of current laboratory assays, a conser-
vative definition of androgen insufficiency in women
(Table 1) was proposed on the basis of 3 essential criteria.
First, clinical symptoms of androgen insufficiency should
be clearly present. Symptoms of androgen insufficiency
most often reported in the literature include a diminished
sense of well-being or dysphoric mood; persistent, unex-
plained fatigue; and sexual function changes, including
decreased libido, sexual receptivity, and pleasure. Second,
because estrogen effects are also strongly linked to mood,
psychological well-being, and sexual function in women,
androgen insufficiency should be diagnosed only in
women with adequate estrogen status. Third, in the absence
of a sufficiently sensitive assay or absolute threshold for
androgen insufficiency in women, free testosterone values
should be at or below the lowest quartile of the reference
range for reproductive age (20-40 years) in conjunction
with the presence of clinical symptoms and adequate estro-
gen status.
To assist clinicians in making a diagnosis and
initiating therapy, a simple management algorithm was
proposed (Table 2).
The concept of using androgen in women, with or without
estrogen, to enhance various factors of well-being dates to
the 1940s. These prospective studies primarily used meth-
yltestosterone, and it was considered beneficial for meno-
pausal symptoms and general well-being and for libido, in
In the 1960s, methyltestosterone was added to
esterified estrogens and received class approval from the
Food and Drug Administration only for menopausal symp-

Page 2
Formulations and Use of Androgens
Mayo Clin Proc, April 2004, Vol 79 (Supplement)
Table 1. Definition of
Female Androgen Insufficiency Syndrome*
Decreased libido, sexual receptivity, and pleasure
Low energy and persistent, unexplained fatigue
Dysphoric mood
Diminished psychological well-being
Blunted motivation
Bone density
Muscle mass and strength
Adipose tissue redistribution
Sexual hair
Changes in cognition or memory
*Based on the pattern of clinical symptoms and signs in the presence of
decreased bioavailable testosterone and normal estrogen status.
Data from Bachmann et al.
Table 2. Decision-making Algorithm for Initiating
Androgen Therapy in Women*
Q. Does the woman have symptoms consistent with female androgen
insufficiency (eg, low libido, decreased energy, and well-being)?
A. If yes, initiate evaluation.
Q. Is there an alternative explanation or cause for these symptoms (eg,
major depression, chronic fatigue syndrome)?
A. If yes, manage as appropriate. If no, evaluate further.
Q. Is the woman in an optimum estrogen state?
A. If yes, continue evaluation. If no, initiate estrogen replacement.
Q. Does the woman have laboratory values consistent with a diagnosis of
androgen insufficiency?
A. If yes, continue evaluation. This should include assessment of at least
two of three measures of total T, free T, or SHBG. Androgen values
should be in the lowest quartile of normal ranges for reproductive
age women. If no, consider alternative treatments or referral.
Q. Does the woman have a specific treatable cause for androgen
insufficiency (eg, oral estrogens, oral contraceptive use)?
A. If yes, treat the specific cause (eg, change medications). If no,
consider a trial of androgen replacement therapy.
*SHBG = sex hormone–binding globulin; T = testosterone.
From Bachmann et al,
with permission from the American Society for
Reproductive Medicine.
toms such as hot flashes that did not respond adequately
to estrogens alone. More recent studies
have focused on
symptoms and well-being, in addition to assessing bone
mass changes. The first studies
to clearly show benefit
used testosterone injections. Subsequently, testosterone
implants, transdermal testosterone, and oral methyltes-
tosterone were found to be effective in combination with
estrogens. The instruments used to assess well-being and
sexual function have not been standardized, and thus some
studies that showed no beneficial effect may be criticized
on this basis. Additionally, there is controversy regarding
whether the improvements observed in prospective studies
are because of pharmacological rather than physiological
testosterone replacement. Indeed, data suggest that levels
of testosterone near or above the normal physiological
range are necessary to document significant improvement.
Part of the difficulty in determining whether androgen
levels are normal, increased, or decreased is related to the
variability in measurements. Methods used to measure tes-
tosterone vary substantially, and even standardized meth-
ods such as radioimmunoassay vary depending on whether
serum is extracted and/or undergoes chromatography be-
fore radioimmunoassay is performed. Upper normal ranges
of testosterone vary from 50 to 100 ng/dL. This has chal-
lenged the notion of what constitutes a low level in
perimenopausal and postmenopausal women. In general,
testosterone levels are considered low if they are less than
20 ng/dL, and values are usually lower than 10 ng/dL after
oophorectomy. However, women taking oral estrogen have
higher levels of total testosterone because of the increase in
sex hormone–binding globulin (SHBG) levels. In this
setting, bioavailable or free testosterone levels are de-
creased, and this is the preferred moiety to measure. The
most sensitive measurement of testosterone bioavailabil-
ity is unbound or free testosterone. Commercial assays for
free testosterone are extremely inconsistent, especially
at the lower ranges of measurement, and therefore, many
investigators prefer to use the free testosterone index,
a calculated value, usually the ratio of testosterone to
Classic studies in the mid-1980s provided evidence of a
significant effect of injected testosterone vs the effect of
estrogen alone in women who had undergone oophorec-
This model of premenopausal women who have
undergone oophorectomy provides the most extreme ex-
ample of androgen insufficiency. In addition, injected es-
trogen and testosterone combined provide a rapid pharma-
cological peak effect of both sex steroids, with values often
higher than 150 ng/dL for testosterone, as well as high
levels of estrogen. This form of therapy typically results in
an accumulation of steroids, with even higher levels
reached with repeated dosing. With prolonged therapy,
symptoms precipitating the need for another injection pre-
cede normalization of testosterone levels. However, these
studies have shown that testosterone enhances sexual moti-
vation, the sense of well-being, and the energy level in this
cohort of women.
These studies showing benefit used regimens that led to
pharmacological levels of testosterone. Some evidence
shows that androgen replacement at near-physiological
levels may also be efficacious for symptoms of sexual
dysfunction and dysphoria. In women who have undergone
oophorectomy, replacement of estradiol and testosterone
with use of 50-mg implants has been shown to improve
well-being, sexual function, and bone mass.
levels were above the reference range (approximately 90
ng/dL) yet clearly lower than those observed with inject-
able testosterone. In a recent study that compared 2 doses
of transdermal testosterone for 12 weeks in addition to oral
serum testosterone levels averaged 64 and 102

Page 3
Mayo Clin Proc, April 2004, Vol 79 (Supplement)
Formulations and Use of Androgens
Figure 1. Association between change in score on sexual interest questionnaire and
change in bioavailable testosterone concentrations from baseline to week 16. Each open
circle and closed circle represents a single participant receiving esterified estrogen and
methyltestosterone or esterified estrogens alone, respectively. Most open circles cluster
in the right upper quadrant of the graph, indicating a significant correlation between an
increase in bioavailable testosterone and improvement in score on sexual interest
questionnaire for those who received combination therapy. From Lobo et al,
permission from the American Society for Reproductive Medicine.
ng/dL with the 150-µg and 300-µg testosterone patches
(reference range, 14-54 ng/dL), respectively, with con-
comitant use of oral estrogen. However, bioavailable tes-
tosterone was not elevated and was in the upper-normal
range with the 300-µg patch (11.4±9.5 ng/dL; reference
range up to 12.7 ng/dL). Only the 300-µg dose resulted in
statistically beneficial effects on sexual function and well-
Data on the use of esterified estrogen and methyltes-
tosterone are difficult to interpret regarding physiological
vs pharmacological intervention. Although benefits are at-
tributed to the addition of lower doses of methyltestoster-
one (1.25 and 2.5 mg/d), the circulating levels of methyl-
testosterone are relatively low, in the range of 20 to 30 ng/
dL. Because methyltestosterone is at least as potent as
testosterone, some androgenic biological effect is antici-
Possibly a more significant androgen effect may be
attributable to the increase in unbound testosterone with
methyltestosterone because of the reduction in SHBG lev-
els. Despite concomitant oral estrogen use, SHBG levels
are suppressed by approximately 45%.
Thus, the tes-
tosterone-SHBG ratio has been shown to increase by 25%
to 50%, which would put unbound testosterone levels into
the upper-normal range. In our recent study,
the increase
in unbound testosterone with 0.625 mg/d of esterified es-
trogen and 1.25 mg/d of methyltestosterone correlated sta-
tistically with improvement in sexual interest in postmeno-
pausal women (Figure 1).
Various other androgen preparations are potentially
viable for use in women (Table 3). In general, injected tes-
tosterone is not recommended because of the pharmacologi-
cal nature of this approach, the peaks and valleys associated
with this therapy, and the risk of steroid accumulation. How-
ever, intramuscular testosterone has been shown to be ef-
ficacious in women who have undergone oophorectomy.
Methyltestosterone or fluorinated testosterone in large
doses (as used occasionally in men) should not be used. In
lower doses, methyltestosterone (1.25-2.5 mg/d) with es-
terified estrogens (as mentioned previously) has been
shown to be beneficial for menopausal symptoms, bone
mass, and possibly sexual function and quality-of-life vari-
ables. The long-term safety of this product has also been
Testosterone undecanoate, an oral form of replacement,
is available in Europe and Canada, and it is believed to be
efficacious in that it is absorbed via the lymphatic system,
particularly if ingested with a liquid high in fat (eg, milk).
Absorption and turnover are rapid, and high testosterone
levels have been observed with 40 mg/d.
In one study,
the addition of testosterone undecanoate improved specific
Change in sexual interest questionnaire - Total
Change in bioavailable testosterone (pg/mL)

Page 4
Formulations and Use of Androgens
Mayo Clin Proc, April 2004, Vol 79 (Supplement)
Table 3. Androgen Replacement Potentially Viable
for Women*
Injectable (IM) approximately every 4 wk
Nandrolone decanoate
25-50 mg
Mixed testosterone esters
50-100 mg
Testosterone enanthate
25-50 mg
Testosterone cypionate
25-50 mg
Oral (daily)
1.25-2.5 mg
Testosterone undecanoate
40-80 mg
Subcutaneous and transdermal
Testosterone implant
50 mg every 4-6 mo
150-300 µg
every 3.5 d
Testosterone gel
1 mg/d
Other options
DHEA (oral)
25-50 mg/d
Other androgens (androstenedione, DHT)
Other routes (vaginal, sublingual, and buccal)
*DHEA = dehydroepiandrosterone; DHT = dihydrotestosterone; IM =
From Lobo,
with permission from Lippincott Williams & Wilkins.
aspects of sexual function more than treatment with estro-
gen alone.
Testosterone implants, also known as pellets (50 mg),
are required to be inserted at 4- to 6-month intervals with a
trocar (same as used with estradiol pellets). Monitoring is
necessary with this therapy, and testosterone levels
should be determined before a repeated insertion. Al-
though values vary considerably among subjects, values
remain fairly constant for each individual, a characteristic
of this method of hormonal therapy. As stated earlier,
values are usually at the upper level of the reference
range, 70 to 90 ng/dL.
Transdermal testosterone patches have become well ac-
cepted in the treatment of testosterone deficiency in men
and are currently being developed in appropriate dosage
strengths (150-300 µg/d) for androgen therapy for women.
Short-term studies have shown efficacy with the 300-µg
dose, and testosterone values are generally in the physi-
ological range with no adverse findings.
The investiga-
tional testosterone matrix patch at 300 µg/d is now in phase
3 clinical trials for the treatment of sexual dysfunction in
women who have undergone oophorectomy and in women
who have experienced natural menopause.
The hydroalcoholic gel of testosterone has been ap-
proved for men in whom the pharmacokinetics have been
well established, and its efficacy has been shown for sexual
function, mood, muscle strength, and body composi-
In men, the 5-g dose provides physiological re-
placement with steady-state levels of approximately 600
ng/dL (Figure 2).
By extrapolation, the dose required in
women would be approximately 1 g/d or less, although this
has not been established. A recent study evaluated the
pharmacokinetics and metabolism of 14 days of daily
morning application of a topical gel containing 1 mg of
micronized testosterone in 5 women who had undergone
oophorectomy and were taking estrogen. Although the hor-
mone and metabolite profile achieved with the testosterone
gel had desirable pharmacokinetics, the 1-mg dose ap-
peared excessive.
Oral micronized dehydroepiandrosterone (DHEA) has
been used in various clinical trials.
Although not the
most efficient or efficacious way to deliver testosterone,
this approach is an option because serum testosterone lev-
els may double, while DHEA and DHEA sulfate levels are
higher than the reference range. However, a recent study
did not confirm the benefit of 50 mg/d for quality-of-life
Because DHEA can lower high-density lipo-
protein cholesterol levels and potentially affect hepatic
function, vaginal or transdermal administration of DHEA
could be considered.
Other treatment approaches include administration of
testosterone vaginally, buccally, or sublingually. A sublin-
gual form (testosterone cyclodextrin) has been developed
for men. Because cyclodextrin is a carbohydrate, this
method is thought to be useful since testosterone is trans-
ported across mucous membranes.
We have also used
hydroalcoholic gels of androstenedione and dihydrotestos-
terone in various trials in women to assess androgen me-
However, these approaches have not been
subjected to efficacy trials.
The only product available in the United States for women
with androgen insufficiency is esterified estrogen in com-
Figure 2. Mean steady-state testosterone concentrations in pa-
tients who used testosterone gel (AndroGel, Unimed Pharmaceuti-
cals, Inc, a Solvay Pharmaceuticals, Inc, company, Deerfield, Ill)
once a day. Testosterone concentrations were maintained as long as
the patient continued to apply the prescribed treatment properly.
Upper limit of normal range
10 g
5 g
Testosterone concentration (ng/dL)
Time (hours) after application
Lower limit of normal range
Day 30
Day 90
Day 180

Page 5
Mayo Clin Proc, April 2004, Vol 79 (Supplement)
Formulations and Use of Androgens
1. Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL. A
prospective longitudinal study of serum testosterone, dehydroepi-
androsterone sulfate, and sex hormone-binding globulin levels
through the menopause transition. J Clin Endocrinol Metab. 2000;
2. Lobo RA. Androgens in postmenopausal women: production, pos-
sible role, and replacement options. Obstet Gynecol Surv. 2001;56:
3. Bachmann G, Bancroft J, Braunstein G, et al. Female androgen
insufficiency: the Princeton consensus statement on definition,
classification, and assessment. Fertil Steril. 2002;77:660-665.
4. Rosner W. Measurement of androgens: methods and pitfalls. In:
Androgens in Women: Physiology, Deficiency, and Emerging
Therapeutic Potentials. Chevy Chase, Md: The Endocrine Society
Continuing Medical Education Services; 2000. Available at: Accessibility verified February 12,
5. Sherwin BB, Gelfand MM, Brender W. Androgen enhances sexual
motivation in females: a prospective, crossover study of sex steroid
administration in the surgical menopause. Psychosom Med. 1985;
6. Sherwin BB, Gelfand MM. Differential symptom response to
parenteral estrogen and/or androgen administration in the surgical
menopause. Am J Obstet Gynecol. 1985;151:153-160.
7. Sherwin BB, Gelfand MM. The role of androgen in the mainte-
nance of sexual functioning in oophorectomized women.
Psychosom Med. 1987;49:397-409.
8. Davis SR, McCloud P, Strauss BJ, Burger H. Testosterone en-
hances estradiol’s effects on postmenopausal bone density and
sexuality. Maturitas. 1995;21:227-236.
9. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testoster-
one treatment in women with impaired sexual function after
oophorectomy. N Engl J Med. 2000;343:682-688.
Greene RR, Burrill MW, Oppenheimer E, Nelson D. Conditions
modifying the effectiveness of testosterone, testosterone pro-
prionate, and methyl testosterone. Endocrinology. 1942;30:734-
Hickok LR, Toomey C, Speroff L. A comparison of esterified
estrogens with and without methyltestosterone: effects on endome-
trial histology and serum lipoproteins in postmenopausal women.
Obstet Gynecol. 1993;82:919-924.
Lobo RA, Rosen RC, Yang HM, Block B, Van Der Hoop RG.
Comparative effects of oral esterified estrogens with and without
methyltestosterone on endocrine profiles and dimensions of sexual
function in postmenopausal women with hypoactive sexual desire.
Fertil Steril. 2003;79:1341-1352.
Phillips E, Bauman C. Safety surveillance of esterified estrogens-
methyltestosterone (Estratest and Estratest HS) replacement ther-
apy in the United States. Clin Ther. 1997;19:1070-1084.
Floter A, Carlstrom K, von Schoultz B, Nathorst-Boos J. Adminis-
tration of testosterone undecanoate in postmenopausal women:
effects on androgens, estradiol, and gonadotrophins. Menopause.
Floter A, Nathorst-Boos J, Carlstrom K, von Schoultz B. Addition
of testosterone to estrogen replacement therapy in oophorecto-
mized women: effects on sexuality and well-being. Climacteric.
Lobo RA, March CM, Goebelsmann U, Krauss RM, Mishell DR Jr.
Subdermal estradiol pellets following hysterectomy and oophorec-
tomy: effect upon serum estrone, estradiol, luteinizing hormone,
follicle-stimulating hormone, corticosteroid binding globulin-bind-
ing capacity, testosterone-estradiol binding globulin-binding ca-
pacity, lipids, and hot flushes. Am J Obstet Gynecol. 1980;138:714-
Javanbakht M, Singh AB, Mazer NA, et al. Pharmacokinetics of a
novel testosterone matrix transdermal system in healthy, premeno-
pausal women and women infected with the human immunodefi-
ciency virus. J Clin Endocrinol Metab. 2000;85:2395-2401.
Mazer NA, Shifren JL. Transdermal testosterone for women: a new
physiological approach for androgen therapy. Obstet Gynecol Surv.
Wang C, Berman N, Longstreth JA, et al. Pharmacokinetics of
transdermal testosterone gel in hypogonadal men: application of
gel at one site versus four sites: a General Clinical Research Center
Study. J Clin Endocrinol Metab. 2000;85:964-969.
Wang C, Swedloff RS, Iranmanesh A, et al, Testosterone Gel Study
Group. Transdermal testosterone gel improves sexual func-
tion, mood, muscle strength, and body composition parameters
in hypogonadal men. J Clin Endocrinol Metab. 2000;85:2839-
AndroGel [package insert]. Deerfield, Ill: Unimed Pharmaceuti-
cals, Inc; 2002.
Slater CC, Souter I, Zhang C, Guan C, Stanczyk FZ, Mishell DR.
Pharmacokinetics of testosterone after percutaneous gel or buccal
administration. Fertil Steril. 2001;76:32-37.
Morales AJ, Nolan JJ, Nelson JC, Yen SS. Effects of replacement
dose of dehydroepiandrosterone in men and women of advancing
age [published correction appears in J Clin Endocrinol Metab.
1995;80:2799]. J Clin Endocrinol Metab. 1994;78:1360-1367.
Casson PR, Faquin LC, Stentz FB, et al. Replacement of dehydro-
epiandrosterone enhances T-lymphocyte insulin binding in post-
menopausal women. Fertil Steril. 1995;63:1027-1031.
Barnhart KT, Freeman E, Grisso JA, et al. The effect of dehydro-
epiandrosterone supplementation to symptomatic perimenopausal
women on serum endocrine profiles, lipid parameters, and health-
related quality of life. J Clin Endocrinol Metab. 1999;84:3896-
Wang C, Eyre DR, Clark R, et al. Sublingual testosterone replace-
ment improves muscle mass and strength, decreases bone resorp-
tion, and increases bone formation markers in hypogonadal men—
a clinical research center study. J Clin Endocrinol Metab. 1996;81:
Miles RA, Cassidenti DL, Carmina E, Gentzschein E, Stanczyk FZ,
Lobo RA. Cutaneous application of an androstenedione gel as an in
vivo test of 5 alpha-reductase activity in women. Fertil Steril. 1992;
Duffy DM, Legro RS, Chang L, Stanczyk FZ, Lobo RA. Metabo-
lism of dihydrotestosterone to 5 alpha-androstane-3 alpha, 17 beta-
diol glucuronide is greater in the peripheral compartment than in
the splanchnic compartment. Fertil Steril. 1995;64:736-739.
Barrett-Connor E, Young R, Notelovitz M, et al. A two-year,
double-blind comparison of estrogen-androgen and conjugated es-
trogens in surgically menopausal women: effects on bone mineral
density, symptoms and lipid profiles. J Reprod Med. 1999;44:
bination with 1.25 or 2.5 mg/d of methyltestosterone; how-
ever, no indication has been approved by the Food and
Drug Administration for androgen insufficiency syndrome.
Although some data suggest safety and efficacy with this
other nonoral routes are being investigated.
Currently, physicians are prescribing androgen replace-
ment therapy, including testosterone supplements or
DHEA, on an “off-label” basis. Ideally, treatment recom-
mendations should be based on the results of large random-
ized, placebo-controlled clinical trials. The goal of andro-
gen treatment should be to achieve normal premenopausal
levels of testosterone, thus limiting adverse effects and
adverse experiences. To determine the safety and effective-
ness of such treatment, sensitive androgen assays are re-
quired as well as appropriate instruments to assess efficacy.