Testosterone therapy in women: Myths and misconceptions : Simpatra.Marketplace

Rebecca Glasera,b,∗, Constantine Dimitrakakisc,d

A b s t r a c t

Although testosterone therapy is being increasingly prescribed for men, there remain many questions and

concerns about testosterone (T) and in particular, T therapy in women. A literature search was performed

to elucidate the origin of, and scientific basis behind many of the concerns and assumptions about T and

T therapy in women.

This paper refutes 10 common myths and misconceptions, and provides evidence to support what

is physiologically plausible and scientifically evident: T is the most abundant biologically active female

hormone, T is essential for physical and mental health in women, T is not masculinizing, T does not cause

hoarseness, T increases scalp hair growth, T is cardiac protective, parenteral T does not adversely affect

the liver or increase clotting factors, T is mood stabilizing and does not increase aggression, T is breast

protective, and the safety of T therapy in women is under research and being established.

Abandoning myths, misconceptions and unfounded concerns about T and T therapy in women will

enable physicians to provide evidenced based recommendations and appropriate therapy.

1. Introduction

Testosterone (T) therapy is being increasingly used to treat

symptoms of hormone deficiency in pre and postmenopausal

women. Recently, especially with the advent of the T patch, additional

research has been, and is currently being conducted on the

safety and efficacy of T therapy. However, particularly in the United

States (U.S.), there still exist many misconceptions about T and T

therapy in women. This review addresses, and provides evidence

to refute, some of the most common myths.

A major source of misconceptions regarding T therapy in women

arises from epidemiological studies implicating elevated (endogenous)

T levels with certain diseases. This data is misleadingly

delivered to produce a pathogenic model of these diseases without

enough evidence or plausibility to support a causative role.

False conclusions repeated often enough, especially when supported

with anecdotal observations, create ‘myths’ that become

widely accepted, even in the absence of any biological or physiological

rationale.

Another source of confusion concerning the safety of T therapy

in both men and women is the extrapolation of adverse events

(e.g., mental status changes, aggression, cardiac and liver problems,

endocrine disturbances, abuse potential) from high doses of oral

and injectable anabolic-androgenic steroids to T therapy, despite

a lack of evidence. In this review, testosterone (T) refers only to

bio-identical (human identical molecule) testosterone, not to oral,

synthetic androgens or anabolic steroids.

In England and Australia, T is licensed and has been used in

women for over 60 years. However, as of 2013, in the U.S., there

is no licensed T product for women and human/bio identical T is

regulated as a ‘schedule 3’ drug and included as a ‘class X’ teratogen.

2. ‘Top 10’ myths about testosterone use in women

2.1. Myth: Testosterone is a ‘male’ hormone

Even in scientific publications, T has been referred to as the ‘male

hormone’. Men do have higher circulating levels of T than women;

however, quantitatively, T is the most abundant active sex steroid in

women throughout the female lifespan (Fig. 1) [1]. T is measured

in 10-fold higher units than estradiol (E2), i.e., nanograms/dl or

micromolars compared to picograms/ml or picomolars for E2. In

addition, there are exponentially higher levels of proandrogens:

dihydroepiandrosterone sulfate (DHEAS), dihydroepiandrosterone

(DHEA) and androstenedione, supplying significant amounts of T

Fig. 1. Throughout the female lifespan, testosterone (T) is the most abundant active

steroid. T levels are significantly higher than estradiol (E2) levels, adapted from Ref.

[1]. to the androgen receptor (AR) in both sexes. In fact, the measured

ranges of androgen precursors are similar in men and women.

Despite any clear rationale, estrogen was assumed to be the

hormone of ‘replacement therapy’ in women. However, as early

as 1937, T was reported to effectively treat symptoms of the

menopause [2]. From a biologic perspective, women and men are

genetically similar, having both functional estrogen receptors (ERs)

and functional androgen receptors (ARs). Interestingly, the AR gene

is located on the X chromosome. T, in balance with lower amounts

of E2, is equally important for health in both sexes. In addition, T is

the major substrate for E2 and has a secondary effect in both sexes

via the ER.

Fact

Testosterone is the most abundant biologically active hormone

in women

2.2. Myth: Testosterone’s only role in women is sex drive and

libido

Despite many recent publications, T’s role in sexual function and

libido is only a small fraction of the physiologic effect of T in women.

Functional AR’s are located in almost all tissues including the breast,

heart, blood vessels, gastrointestinal tract, lung, brain, spinal cord,

peripheral nerves, bladder, uterus, ovaries, endocrine glands, vaginal

tissue, skin, bone, bone marrow, synovium, muscle and adipose

tissue [3,4].

Testosterone and the pro-androgens decline gradually with

aging in both sexes. Pre and post-menopausal women, and aging

men, may experience symptoms of androgen deficiency including

dysphoric mood (anxiety, irritability, depression), lack of well

being, physical fatigue, bone loss, muscle loss, changes in cognition,

memory loss, insomnia, hot flashes, rheumatoid complaints,

pain, breast pain, urinary complaints, incontinence as well as sexual

dysfunction. These symptoms of androgen deficiency are becoming

increasingly recognized in women, and treated with T therapy

[5–7]. Rating scales for symptoms of androgen deficiency have been

developed in an effort to standardize severity of symptoms and

to measure treatment effectiveness. Functional, biologically active,

ARs are located throughout the body in both sexes: to assume that

androgen deficiency does not exist in women, or that T therapy

should not be considered in women, is unscientific and implausible.

Fact

Testosterone is essential for women’s physical and mental

health and wellbeing

2.3. Myth: Testosterone masculinizes females

It has been recognized for over 65 years, that T effect is dose

dependent and that in lower doses, T ‘stimulates femininity’ [8].

Although pharmacologic doses of T and supra-pharmacological

doses of T used to treat female to male transgender patients, may

result in increased facial hair growth, hirsutism, and slight enlargement

of the clitoris; true masculinization is not possible. Unwanted

androgenic side effects are reversible by lowering the T dose: however,

because of the dose dependent beneficial effects of T, many

women prefer to treat the side effects rather than lower the dose

[9,10].

As previously mentioned, in the U.S. androgens are listed as a

‘class X’ teratogen. Although 400–800 mg/d of danazol, a potent

synthetic androgen, can result in clitoromegaly and fused labia

(without long term effects) in some female fetuses; there is no

evidence that T, delivered by pellet implant (i.e., a daily dose of

1–2 mg) or topical T has any adverse effect on a fetus, even in animal

studies [11,12]. Animal studies have shown that virilization of

a female fetus requires extremely high doses of T (>30 times normal

232 R. Glaser, C. Dimitrakakis / Maturitas 74 (2013) 230– 234

maternal levels, >50–500 times ‘human’ T doses) administered over

an extended period of time [12–14].

There is a significant rise in (endogenous) maternal T levels during

pregnancy, up to 2.5–4 times non-pregnancy ranges. However,

the placenta buffers hormone diffusion and is a source of abundant

aromatase, which metabolizes maternal T [15,16]. T stimulates ovulation,

increases fertility and has been safely used in the past to treat

nausea of early pregnancy without adverse effects [8].

Fact

Outside of supra-pharmacologic doses of synthetic androgens,

testosterone does not have a masculinizing effect on females or

female fetuses

2.4. Myth: Testosterone causes hoarseness and voice changes

Hoarseness is common, affecting nearly 30% of persons at some

point in their life, with 6.6% of the adult population affected at any

given time. Hoarseness is more prevalent in women than men. Most

common causes of hoarseness are inflammatory related changes

due to allergies, infectious or chemical laryngitis, reflux esophagitis,

voice over-use, mucosal tears, medications and vocal cord polyps.

There is no evidence that T causes hoarseness. In addition, there is

no physiological mechanism by which T could be expected to do so.

T deficiency is listed as a ‘cause’ of hoarseness [17]. Physiologically,

this is consistent with the anti-inflammatory properties of T.

Although a few anecdotal case reports and small questionnaire

studies have reported an association between 400 and 800 mg/d

of danazol and self-reported, subjective voice ‘changes’ [17,18]; a

prospective, objective study demonstrates the opposite. 24 patients

receiving 600 mg of danazol therapy daily were studied at baseline,

3 months and 6 months. The authors reported that there were no

vocal changes that could be attributed to the androgenic properties

of danazol [19]. This is consistent with the findings of our current,

1 year, prospective study examining voice changes on pharmacologic

doses of subcutaneous T implant therapy in women (under

publication).

Although high doses of anabolic steroids in female rats can cause

irreversible vocal cord changes, there is no evidence that this is true

for T replacement doses in humans. If a patient experiences voice

changes or hoarseness on T therapy, a standard workup should be

performed.

Fact

There is no conclusive evidence that testosterone therapy

causes hoarseness or irreversible vocal cord changes in women

2.5. Myth: Testosterone causes hair loss

There is no evidence that T or T therapy is a cause of hair

loss in either men or women. Although men do have higher T

levels than women, and men are more likely to have hair loss

with age, it is unreasonable to assume that T, an anabolic hormone,

causes hair loss. Hair loss is a complicated, multifactorial,

genetically determined process that is poorly understood. Dihydrotestosterone

(DHT), not T, is thought to be the active androgen

in male pattern balding. Female ‘androgenic’ alopecia refers to a

(male) pattern of hair loss in women, rather than the etiology.

Although some women with PCOS and insulin resistance have

higher T levels, and do have hair loss, this does not prove causation.

Hair loss is common in both women and men with insulin

resistance [20,21]. Obesity and insulin resistance increase 5-alpha

reductase, which increases conversion of T to DHT in the hair follicle

[22]. Also, obesity, age, alcohol, medications and sedentary lifestyle

increase aromatase activity, lowering T and raising E. Increased

DHT, lowered testosterone, and elevated estradiol levels can

contribute to hair loss in genetically predisposed men and women;

as can many medications, stress and nutritional deficiencies.

Approximately one third of women experience hair loss and

thinning with aging, coinciding with T decline. We have previously

reported that two thirds of women treated with subcutaneous T

implants have scalp hair re-growth on therapy. Women who did

not re-grow hair on T were more likely to be hypo or hyperthyroid,

iron deficient or have elevated body mass index. In addition, none

of 285 patients treated for up to 56 months with subcutaneous T

therapy complained of hair loss, despite pharmacologic serum T

levels on therapy [10].

Fact

Testosterone therapy increases scalp hair growth in women

2.6. Myth: Testosterone has adverse effects on the heart

Men have higher levels of testosterone than women: men have a

higher incidence of heart disease; however, it is illogical to assume

that T causes or contributes to cardiovascular (CV) disease in either

sex. Unlike anabolic and oral, synthetic steroids, there is no evidence

that T has an adverse effect on the heart. In addition, it is not

physiologically plausible.

There is overwhelming biological and clinical evidence that T is

cardiac protective [23]. T has a beneficial effect on lean body mass,

glucose metabolism and lipid profiles in men and women; and has

been successfully used to treat and prevent CV disease and diabetes

[24]. T acts as a vasodilatorin both sexes, has immune-modulating

properties that inhibit atheromata, and has a beneficial effect on

cardiac muscle [25–27].

Low T in men is associated with an increased risk of heart disease

and mortality from all causes [28,29]. In addition, low T is an independent

predictor of reduced exercise capacity and poor clinical

outcomes in patients with heart failure. Similar to men, T supplementation

has been shown to improve functional capacity, insulin

resistance and muscle strength in women with congestive heart

failure [30].

Testosterone is a diuretic. However, T can aromatize to E2,

which can have adverse effects including edema, fluid retention,

anxiety, and weight gain. Medications, including statins and

anti-hypertensives, increase aromatase activity and elevate E2,

indirectly causing side effects from T therapy.

Fact

There is substantial evidence that testosterone is cardiac protective

and that adequate levels decrease the risk of cardiovascular

disease

2.7. Myth: Testosterone causes liver damage

Although high doses of oral, synthetic androgens (e.g., methyltestosterone)

are absorbed into the entero-hepatic circulation and

adversely affect the liver; parenteral T (i.e., subcutaneous implants,

topical patch) avoids the entero-hepatic circulation and bypasses

the liver. There are no adverse affects on the liver, liver enzymes or

clotting factors [31]. Non-oral T does not increase the risk of deep

venous thrombosis or pulmonary embolism unlike oral estrogens,

androgens and synthetic progestins.

Despite the concern over liver toxicities with anabolic steroids

and oral synthetic androgens, there are only 3 reports of hepatocellular

carcinoma in men treated with high doses of oral

synthetic methyl testosterone. Even benign tumors (adenomas)

were exceedingly rare with oral androgen therapy.

Fact

Non-oral testosterone does not adversely affect the liver or

increase clotting factors

2.8. Myth: Testosterone causes aggression

Although anabolic steroids can increase aggression and rage,

this does not occur with T therapy. Even supra-pharmacologic

doses of intramuscular T undecanoate do not increase aggressive

behavior [32].

As previously mentioned, T can aromatize to E2. There is considerable

evidence in a wide variety of species, that estrogens, not

T, play a major role in aggression and even hostility through action

at ER alpha [33,34].

In women, we previously reported that subcutaneous T therapy

decreased aggression, irritability and anxiety in over 90% of patients

treated for symptoms of androgen deficiency [5]. This is not a new

finding: androgen therapy has been used to treat PMS for over 60

years.

Fact

Testosterone therapy decreases anxiety, irritability and aggression

2.9. Myth: Testosterone may increase the risk of breast cancer

As early as 1937 it was recognized that breast cancer was an

estrogen sensitive cancer; that T was ‘antagonistic’ to estrogen and

could be used to treat breast cancer as well as other estrogen sensitive

diseases including breast pain, chronic mastitis, endometriosis,

uterine fibroids and dysfunctional uterine bleeding [8]. However,

some epidemiological studies have reported an association between

elevated androgens and breast cancer. Notably, these studies suffer

from methodological limitations, and more importantly, do not

account for associated elevated E2 levels and increased body mass

index. In addition, the ‘cause and effect’ interpretation of these

inconsistent observational studies conflicts with the known biology

of T’s effect at the AR. AR signaling exerts a pro-apoptotic,

anti-estrogenic, growth inhibiting effect in normal and cancerous

breast tissue [35,36].

Clinical trials in primates and humans have confirmed that T has

a beneficial effect on breast tissue by decreasing breast proliferation

and preventing stimulation from E2 [37,38]. It is the T/E2 ratio,

or the balance of these hormones that is breast protective. T does

not increase, and likely lowers the risk of breast cancer in women

treated with estrogen therapy [39]. Although T is breast protective,

it can aromatize to E2 and have a secondary, stimulatory effect via

estrogen receptor (ER) alpha.

T combined with an aromatase inhibitor (subcutaneous

implant) has been shown to effectively treat androgen deficiency

symptoms in breast cancer survivors and is currently being investigated

in a U.S. national cancer study as potential therapy for these

symptoms, as well as, aromatase induced arthralgia [40,41].

Fact

Testosterone is breast protective and does not increase the risk

of breast cancer

2.10. Myth: the safety of testosterone use in women has not been

established

There are many excellent reviews on the safety of parenteral

T therapy in women [6,7]. Testosterone implants have been used

safely in women since 1938. Long-term data exists on the efficacy,

safety and tolerability of doses of up to 225 mg in up to 40 years of

therapy [9,42]. In addition, long term follow up studies on suprapharmacologic

doses used to ‘female to male’ transgender patients

report no increase in mortality, breast cancer, vascular disease or

Testosterone therapy in women: Myths and misconceptions

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