madman
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Prescribing testosterone and DHEA: The role of androgens in women
ABSTRACT
In women, the androgens testosterone and dehydroepiandrosterone (DHEA) play important physiologic roles in reproductive tissues, mood, cognition, the breast, bone, muscle, vasculature, and other systems. This article reviews the effects of androgens in women, as well as the indications and best-practice recommendations for the use of androgen therapy.
■ KEY POINTS
Currently, the only evidence-based indication for testosterone therapy in women is for treating hypoactive sexual desire disorder in postmenopausal women. Several randomized controlled trials have established the short-term safety and efficacy of prescribed testosterone in women when doses approximate physiologic levels.
When treatment is offered, transdermal preparations are preferred, and testosterone levels should be checked before and during treatment to ensure physiologic dosing. Decisions to continue treatment are based on clinical response; hormone levels do not correlate with symptom burden and testing is intended only to ensure the safe delivery of treatment.
Clinicians should avoid diagnosing female androgen deficiency on the basis of hormonal testing, as the syndrome is not well defined, and interpreting androgen levels and their physiologic effects are complex.
Estrogens are the principal sex hormones responsible for female reproductive maturation and sexual characteristics. However, androgens are also important for female sexual health and well-being.1 The physiologic effects of androgens are in part due to their role as precursors for estrogen synthesis, but these hormones also have independent effects on female reproductive tissues, mood, cognition, breasts, bones, muscles, vasculature, and other systems.1
Here we will discuss the physiologic roles of androgens as well as the indications and best-practice recommendations for androgen therapy in women.
■ ANDROGEN SYNTHESIS, PRODUCTION, AND MEASUREMENT IN WOMEN
Peripheral conversion of precursor hormones to active testosterone is tissue-specific and depends on the membrane and cellular receptor expression as well as the activity of converting enzymes.1 Measured serum testosterone concentrations do not correlate with peripheral tissue androgen production or tissue receptor sensitivity. Therefore, androgen effects on body tissues are complex, and there is no absolute testosterone level that defines “androgen deficiency.” Low serum testosterone levels in women should be interpreted with caution.
■ ANDROGEN EFFECTS IN WOMEN
-Cardiometabolic
The effects of sex steroids on the cardiovascular system are not fully understood. Similar to the vascular benefits of estrogen during the premenopausal years (promoting vasodilation, limiting atherosclerotic plaque progression, reducing inflammation),8,9 testosterone acts directly on the vasculature in a concentration-dependent fashion, and indirectly after being converted to estradiol. At physiologic levels, testosterone enhances nitric oxide production and influences both potassium and calcium ion channels, leading to vasorelaxation.8 Low testosterone levels have been associated with unfavorable cardiovascular outcomes.8 However, testosterone promotes vasoconstriction at supraphysiologic levels.8
*However, testosterone promotes vasoconstriction at supraphysiologic levels.8
-Skin and hair
Dihydrotestosterone, converted from testosterone by 5-alpha-reductase, is the most potent androgen acting on hair follicles.15 In the scalp, dihydrotestosterone promotes miniaturization of hair follicles and shortens the antigen phase of hair growth, leading to hair loss.15
Women with female pattern hair loss tend to have higher androgen-to-estrogen ratios. Activation of androgen receptors at hair follicles on the chin, cheeks, and upper lips leads to coarse hair growth or hirsutism.16 In women with polycystic ovary syndrome, hirsutism may be related to excess ovarian testosterone production, whereas most women with idiopathic hirsutism have normal serum androgen levels, suggesting exaggerated 5-alpha-reductase activity.16 A meta-analysis found the risk of hirsutism to be 10.7% in women on testosterone therapy compared with 6.6% with placebo (P = .011).14
Androgens stimulate the growth and secretory function of sebaceous glands, leading to increased sebum production, in turn providing a growth medium for Cutibacterium acnes. 15 Although most women with acne have normal serum androgen levels, a meta-analysis reported the risk of acne to be 7.0% in women on testosterone therapy vs 4.7% with placebo (P < .001).14
-Cognition and mood
The brain, like many organs, is affected by ovarian hormone withdrawal. Studies have shown that both estrogen and testosterone have anti-inflammatory and neuroprotective effects on the brain.17 There are androgen receptors throughout the central nervous system, with actions that affect sexual desire, thermoregulation, cognition, sleep, visual-spatial skills, and language.16 A review of the protective effects of sex steroids on Alzheimer's disease suggests that testosterone reduces oxidative stress and accumulation of amyloid-beta within the brain and accelerates nerve regeneration.17
-Musculoskeletal
Androgen receptors are present on osteoblasts. Low endogenous androgen levels in menstruating and postmenopausal women have been associated with low bone mass and increased risk of vertebral and hip fractures.20,21 Conversely, higher free testosterone levels in postmenopausal women have been associated with lower hip fracture risk.22 However, lacking randomized controlled trials to assess the effect of testosterone therapy on fracture risk, the use of androgens for bone health and fracture prevention cannot be recommended.
-Breast and endometrium
Breast tissue has abundant levels of aromatase; thus, in theory, testosterone may have indirect proliferative effects on the breast by being converted to estrogen. However, in vitro breast cultures and in vivo primate studies demonstrate that testosterone’s effects on breast tissue are antiproliferative and proapoptotic, with inhibition of estrogen receptor alpha as well as breast cancer cell growth.24 These effects largely depend on the type and the dose of androgen therapy as well as the breast cancer cell line.25
■ SHOULD WOMEN BE SCREENED FOR LOW ANDROGEN LEVELS?
■ ROLE OF ANDROGEN THERAPY IN FEMALE SEXUAL HEALTH
*Female sexual dysfunction
Female sexual dysfunction is multifactorial, often influenced by biological, emotional, cultural, and interpersonal factors. It can manifest as decreased sexual desire, painful intercourse, and diminished arousal or orgasmic response, or both.
The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 30 merged the previous diagnoses of female hypoactive sexual desire disorder (HSDD) and female arousal disorder (FAD) into a single diagnosis of female sexual interest/arousal disorder (FSIAD). While HSDD and FAD have overlapping features, the Fourth International Consultation on Sexual Medicine and the International Society of the Study of Women’s Sexual Health (ISSWSH) recommend against combining these diagnoses for clinical purposes.31,32 According to the ISSWSH, HSDD can be defined by 6 or more months of any of the following32:
1. Lack of motivation for sexual activity, including
• Absent or decreased spontaneous sexual thoughts or fantasies
• Absent or decreased responsive desire to erotic cues and stimulation or inability to maintain desire or interest through sexual activity
2. Loss of desire to initiate or participate in sexual activity, including behavioral responses such as avoidance of situations that could lead to sexual activity, that is not secondary to sexual pain disorders and is combined with clinically significant personal distress that includes frustration, grief, incompetence, loss, sadness, sorrow, or worry.
■ GENITOURINARY SYNDROME OF MENOPAUSE
*DHEA therapy for GSM
*Testosterone therapy for GSM
■ PRESCRIBING TESTOSTERONE THERAPY
*Monitoring during treatment
■ TAKE-HOME POINTS
• Androgens play an important physiologic role in women and can promote sexual health.
• Clinicians should avoid making a diagnosis of androgen deficiency in women, as the syndrome is not well defined.
• Well-designed, randomized, placebo-controlled trials are needed to establish long-term safety, efficacy, and appropriate dosing of testosterone therapy in women.
• Evidence suggests that testosterone therapy in women is associated with few adverse events when serum hormone levels remain within physiologic ranges.
• Currently, the only evidence-based indication for testosterone therapy in women is for the treatment of HSDD in postmenopausal women, but only after a thorough evaluation and consideration of other causes of sexual concerns.
• Transdermal therapy is the preferred method of delivery.
• Serum testosterone levels should be monitored at regular intervals to avoid supraphysiologic dosing
ABSTRACT
In women, the androgens testosterone and dehydroepiandrosterone (DHEA) play important physiologic roles in reproductive tissues, mood, cognition, the breast, bone, muscle, vasculature, and other systems. This article reviews the effects of androgens in women, as well as the indications and best-practice recommendations for the use of androgen therapy.
■ KEY POINTS
Currently, the only evidence-based indication for testosterone therapy in women is for treating hypoactive sexual desire disorder in postmenopausal women. Several randomized controlled trials have established the short-term safety and efficacy of prescribed testosterone in women when doses approximate physiologic levels.
When treatment is offered, transdermal preparations are preferred, and testosterone levels should be checked before and during treatment to ensure physiologic dosing. Decisions to continue treatment are based on clinical response; hormone levels do not correlate with symptom burden and testing is intended only to ensure the safe delivery of treatment.
Clinicians should avoid diagnosing female androgen deficiency on the basis of hormonal testing, as the syndrome is not well defined, and interpreting androgen levels and their physiologic effects are complex.
Estrogens are the principal sex hormones responsible for female reproductive maturation and sexual characteristics. However, androgens are also important for female sexual health and well-being.1 The physiologic effects of androgens are in part due to their role as precursors for estrogen synthesis, but these hormones also have independent effects on female reproductive tissues, mood, cognition, breasts, bones, muscles, vasculature, and other systems.1
Here we will discuss the physiologic roles of androgens as well as the indications and best-practice recommendations for androgen therapy in women.
■ ANDROGEN SYNTHESIS, PRODUCTION, AND MEASUREMENT IN WOMEN
Peripheral conversion of precursor hormones to active testosterone is tissue-specific and depends on the membrane and cellular receptor expression as well as the activity of converting enzymes.1 Measured serum testosterone concentrations do not correlate with peripheral tissue androgen production or tissue receptor sensitivity. Therefore, androgen effects on body tissues are complex, and there is no absolute testosterone level that defines “androgen deficiency.” Low serum testosterone levels in women should be interpreted with caution.
■ ANDROGEN EFFECTS IN WOMEN
-Cardiometabolic
The effects of sex steroids on the cardiovascular system are not fully understood. Similar to the vascular benefits of estrogen during the premenopausal years (promoting vasodilation, limiting atherosclerotic plaque progression, reducing inflammation),8,9 testosterone acts directly on the vasculature in a concentration-dependent fashion, and indirectly after being converted to estradiol. At physiologic levels, testosterone enhances nitric oxide production and influences both potassium and calcium ion channels, leading to vasorelaxation.8 Low testosterone levels have been associated with unfavorable cardiovascular outcomes.8 However, testosterone promotes vasoconstriction at supraphysiologic levels.8
*However, testosterone promotes vasoconstriction at supraphysiologic levels.8
-Skin and hair
Dihydrotestosterone, converted from testosterone by 5-alpha-reductase, is the most potent androgen acting on hair follicles.15 In the scalp, dihydrotestosterone promotes miniaturization of hair follicles and shortens the antigen phase of hair growth, leading to hair loss.15
Women with female pattern hair loss tend to have higher androgen-to-estrogen ratios. Activation of androgen receptors at hair follicles on the chin, cheeks, and upper lips leads to coarse hair growth or hirsutism.16 In women with polycystic ovary syndrome, hirsutism may be related to excess ovarian testosterone production, whereas most women with idiopathic hirsutism have normal serum androgen levels, suggesting exaggerated 5-alpha-reductase activity.16 A meta-analysis found the risk of hirsutism to be 10.7% in women on testosterone therapy compared with 6.6% with placebo (P = .011).14
Androgens stimulate the growth and secretory function of sebaceous glands, leading to increased sebum production, in turn providing a growth medium for Cutibacterium acnes. 15 Although most women with acne have normal serum androgen levels, a meta-analysis reported the risk of acne to be 7.0% in women on testosterone therapy vs 4.7% with placebo (P < .001).14
-Cognition and mood
The brain, like many organs, is affected by ovarian hormone withdrawal. Studies have shown that both estrogen and testosterone have anti-inflammatory and neuroprotective effects on the brain.17 There are androgen receptors throughout the central nervous system, with actions that affect sexual desire, thermoregulation, cognition, sleep, visual-spatial skills, and language.16 A review of the protective effects of sex steroids on Alzheimer's disease suggests that testosterone reduces oxidative stress and accumulation of amyloid-beta within the brain and accelerates nerve regeneration.17
-Musculoskeletal
Androgen receptors are present on osteoblasts. Low endogenous androgen levels in menstruating and postmenopausal women have been associated with low bone mass and increased risk of vertebral and hip fractures.20,21 Conversely, higher free testosterone levels in postmenopausal women have been associated with lower hip fracture risk.22 However, lacking randomized controlled trials to assess the effect of testosterone therapy on fracture risk, the use of androgens for bone health and fracture prevention cannot be recommended.
-Breast and endometrium
Breast tissue has abundant levels of aromatase; thus, in theory, testosterone may have indirect proliferative effects on the breast by being converted to estrogen. However, in vitro breast cultures and in vivo primate studies demonstrate that testosterone’s effects on breast tissue are antiproliferative and proapoptotic, with inhibition of estrogen receptor alpha as well as breast cancer cell growth.24 These effects largely depend on the type and the dose of androgen therapy as well as the breast cancer cell line.25
■ SHOULD WOMEN BE SCREENED FOR LOW ANDROGEN LEVELS?
■ ROLE OF ANDROGEN THERAPY IN FEMALE SEXUAL HEALTH
*Female sexual dysfunction
Female sexual dysfunction is multifactorial, often influenced by biological, emotional, cultural, and interpersonal factors. It can manifest as decreased sexual desire, painful intercourse, and diminished arousal or orgasmic response, or both.
The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 30 merged the previous diagnoses of female hypoactive sexual desire disorder (HSDD) and female arousal disorder (FAD) into a single diagnosis of female sexual interest/arousal disorder (FSIAD). While HSDD and FAD have overlapping features, the Fourth International Consultation on Sexual Medicine and the International Society of the Study of Women’s Sexual Health (ISSWSH) recommend against combining these diagnoses for clinical purposes.31,32 According to the ISSWSH, HSDD can be defined by 6 or more months of any of the following32:
1. Lack of motivation for sexual activity, including
• Absent or decreased spontaneous sexual thoughts or fantasies
• Absent or decreased responsive desire to erotic cues and stimulation or inability to maintain desire or interest through sexual activity
2. Loss of desire to initiate or participate in sexual activity, including behavioral responses such as avoidance of situations that could lead to sexual activity, that is not secondary to sexual pain disorders and is combined with clinically significant personal distress that includes frustration, grief, incompetence, loss, sadness, sorrow, or worry.
■ GENITOURINARY SYNDROME OF MENOPAUSE
*DHEA therapy for GSM
*Testosterone therapy for GSM
■ PRESCRIBING TESTOSTERONE THERAPY
*Monitoring during treatment
■ TAKE-HOME POINTS
• Androgens play an important physiologic role in women and can promote sexual health.
• Clinicians should avoid making a diagnosis of androgen deficiency in women, as the syndrome is not well defined.
• Well-designed, randomized, placebo-controlled trials are needed to establish long-term safety, efficacy, and appropriate dosing of testosterone therapy in women.
• Evidence suggests that testosterone therapy in women is associated with few adverse events when serum hormone levels remain within physiologic ranges.
• Currently, the only evidence-based indication for testosterone therapy in women is for the treatment of HSDD in postmenopausal women, but only after a thorough evaluation and consideration of other causes of sexual concerns.
• Transdermal therapy is the preferred method of delivery.
• Serum testosterone levels should be monitored at regular intervals to avoid supraphysiologic dosing
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