The role of androgens in female sexual dysfunction

Physiology of androgens 

There are several androgens present in the female: dehydroepiandrostenedione (DHEA), DHEA sulfate, 4-androstenedione, testosterone, and 5α-dihydrotestosterone (DHT). These sex steroids are synthesized from cholesterol in the ovaries and the adrenal glands. 4 Approximately one half of the testosterone in a woman's plasma is derived from precursors from the zona fasciculata of the adrenal glands and from the ovaries. The other 50% is from the peripheral conversion of androgenic precursors to testosterone in various target tissues.5 Table 1 lists the common androgens, their serum levels in pre- and postmenopausal women, and their potency relative to testosterone.6, 7

TABLE 1. Androgens in women: Serum levels and potency relative to testosterone

	Androgen	Serum level in premenopausal women	Serum level in postmenopausal women	Target level with androgen therapy	Potency relative to testosterone
	DHEA sulfate	20–250 mg/dL	10–150 mg/dL	200 mg/dL	0.001
	DHEA	350–700 ng/dL	150–300 ng/dL	500 ng/dL	0.01
	Androstenedione	60–245 ng/dL	30–120 ng/dL	undetermined	0.1
	Testosterone	10–55 ng/dL	7–40 ng/dL	55 ng/dL	1.0
	DHT	4–22 ng/dL	3–20 ng/dL	undetermined	5

Pathophysiology of androgen deficiency 

Androgens contribute to feelings of sexual desire in men and women, and are responsible for male characteristics such as hair growth and a deeper voice. Women also have testosterone, but in much lower levels than men. With aging, not only do levels of estrogen and progesterone decrease, but so do testosterone levels. Women in their sixties typically have testosterone levels that are 50% lower than those of women in their twenties. 16 The reason is twofold: diminished ovarian function, which occurs either naturally or because of medical intervention (oophorectomy, chemotherapy, or radiation to the pelvis), and dramatically decreased adrenal androgen production by 60 to 70 years of age, resulting in only 10% of DHEA sulfate compared with that of a woman of early reproductive age. 17

Because adrenal androgens provide a substantial portion of the precursors for circulating testosterone, there is an age-related gradual decline in testosterone levels independent of menopause. Testosterone also declines in patients who have had a hysterectomy with bilateral oophorectomy, and in those with conditions such as ovarian and adrenal pathology, pituitary disease, or hypothalamic disease. Medications or conditions that increase sex hormone binding globulin (SHBG), including oral contraceptive pills and cirrhosis, also can decrease testosterone. Table 2 lists the common symptoms of androgen deficiency in women.

TABLE 2. Symptoms of androgen deficiency in women

	Decreased
	• Sexual desire, fantasies, and dreams
	• Energy
	• Muscle strength and muscle mass
	• Sexual arousal, vaginal lubrication
	• Orgasmic ability
	• Bone density
	• Pubic hair
	• Sense of well-being
	Increased
	• Insomnia
	• Mood changes, including depression
	• Headache
	• Vasomotor symptoms (hot flashes and night sweats)

Androgens are essential for the development of reproductive function and the growth and maintenance of secondary sex characteristics, either directly or throughout their conversion to estrogen. They play an important part in sexual desire, or libido, for both sexes. Therefore, low androgen levels are associated with significant deterioration of sexual desire in both premenopausal and postmenopausal women. 18 Testosterone is also thought to contribute to initiation of sexual activity and permission for sexual behavior.19, 20 There are also preliminary data that androgens modulate vaginal and clitoral physiology by influencing muscular tone of erectile tissue and the vaginal walls. They facilitate vaginal smooth muscle relaxation and, by conversion to estradiol, may also enhance lubrication.21, 22

A decrease in androgen levels may also affect mood and psychosexual function. The effects of androgens on the brain are mediated through ARs as well as by aromatization of testosterone to estrogen. 23 Androgen receptors have been identified in the cerebral cortex, pituitary, hypothalamus, preoptic region, thalamus, amygdala, and brain stem. Androgen effects in the brain influence sexual behavior, libido, temperature control, sleep control, assertiveness, cognitive function, and learning. The biologic factors influencing mood disorders and menopause are based on the premise that alterations in steroid production and activity cause changes on central neurotransmitter release and, therefore, affect mood and behavior. 23 Androgens play an important role in sexual desire, and the psychological significance of loss of sexual function can have a profound impact on a woman's psychosexual health. Increasing evidence suggests that women with androgen insufficiency treated with androgen replacement therapy experience alleviation of psychological symptoms as well as improvement in libido, sexual response, energy, fatigue, and well-being. 24

Although current data of androgen's role in clitoral, labial, and vaginal physiology is poorly understood, there is improved libido, orgasmic response, and sexual satisfaction reported in women who have undergone androgen replacement therapy to alleviate menopausal symptoms. Androgens regulate hemodynamic events—sexual arousal characterized by increase in genital blood flow—leading to increased genital sensation, vaginal lengthening, and lubrication. 25 Mucin production and proliferation of vaginal epithelial cells, which are important for vaginal lubrication, are also regulated by androgens.26, 27 Immunohistochemical detection of ARs in the vagina and vulva have been demonstrated. 28 Further studies on ARs in vaginal tissues suggest that androgens play an important role in modulating the physiology, and subsequently, the genital sexual response, in women.25, 29

Measuring testosterone levels 

In women, testosterone is found predominantly in a protein-bound form, with high affinity to sex hormone-binding globulin (50%–60%) and lower affinity to albumin (30%–40%) with only about 0.5% to 3% in the free form. Both the total and free testosterone are measured in the patient's serum. Total testosterone refers to all measurable testosterone, bound and unbound. The measurement of free testosterone provides a better estimate of the biologically relevant fraction. See “Free testosterone assays,” on this page.

Free bioavailable testosterone is testosterone not bound to SHBG plus the portion of testosterone loosely bound to albumin. This portion of testosterone is loosely bound to albumin, and is easily disassociated therefore becoming free. Some physicians prefer looking at this measurement for free testosterone. 31

The Sodergard method uses total testosterone, albumin, and SHBG. The values are as accurate as those obtained by equilibrium dialysis, but this method has limited clinical practicality because the calculations are complex. 31

Free testosterone assays

There are several free testosterone assays currently in use30, 31:

•Free testosterone by equilibrium dialysis free analog testosterone assay, or immunoassay of free testosterone with a labeled testosterone analog

•Free testosterone index (FTI) or free androgen index (FAI)

•Free testosterone by mass action-Sodergard equation

•Free bioavailable testosterone

The best method for measuring free testosterone is the free testosterone by equilibrium analysis. However, for practicality, the physician can use a calculated free testosterone index (FTI) or free androgen index (FAI) using concentration of SHBG and total testosterone, because this is less expensive and less time-consuming.

Salivary testing is becoming a popular method of testing hormone levels. It is easy to perform, painless, quick, and not sensitive to the diurnal variations of testosterone levels. The North American Menopause Society came out with recommendations for the role of testosterone therapy in postmenopausal women in September 2005. 31 In them, the society does not recommend testing of testosterone levels using salivary measurements because of questionable reliability and accuracy, especially in the lower levels that are typically seen in women. Furthermore, Granger and colleagues cited problems with collection methods, blood contamination from microinjury, sex differences in the serum-saliva correlation that result in substantially underestimating the testosterone levels in females, and problems with sample storage. Therefore, they suggest a thorough and rigorous planning involving pilot testing, adjusting for sample sizes, investing in good storage to maintain the integrity of the samples, and accounting for gender and age differences if one is to use salivary testing. 32

Testosterone should be used after estrogen replacement therapy alone has failed to improve response adequately. Postmenopausal women are assumed to have low estrogen levels, and women receiving estrogen therapy have levels similar to those of reproductive-age women. Measurement of estrogen in postmenopausal women gives no additional information. 31 Normal ranges for total and free testosterone in women are shown in Table 3.

TABLE 3. Levels of total and free testosterone in pre- and postmenopausal women

		Total testosterone (ng/dL)	Free testosterone (pg/mL)
	Premenopausal	15–70	1–21
	Postmenopausal	5–51	1–21

Testosterone replacement therapy 

With all the benefits attributed to androgens, there are definite advantages to replacement therapy for the aging woman, not only for sexual function but also for general well-being and health. Several androgen formulations for women have been tried, but none has been approved by the U.S. Food and Drug Administration (FDA). Despite this, physicians have been prescribing various forms of androgens off-label for many years. Patient education is necessary to inform patients of the type, dosage, and delivery method of the androgen they are taking. Physicians must provide close monitoring of laboratory values and symptoms to track treatment success.

DHEA has gained some publicity as a dietary supplement being sold in major health and organic food stores. It may also be dispensed from a compounding pharmacy. Mortola and Yen found that a dosage of 150 mg of DHEA resulted in increased levels of testosterone in the blood with no adverse effects. 33 The same study also showed that in much higher doses (1600 mg/day) there was a decline in serum cholesterol, low-density lipoprotein (LDL), triglycerides, and high-density lipoprotein (HDL) in the first week of administration. The most common side effects of DHEA are acne and hirsutism. These are transient, and dissipate shortly after treatment is stopped. There have been several testosterone replacement therapy studies conducted in Europe and North America. Formulations for testosterone replacement include oral therapy combined with estrogens, injectables, implants, buccal tablets, transdermal patches, gels, and creams. A combined esterified estrogen-methyltestosterone formulation is currently being used for hot flashes but is not FDA-approved for female sexual dysfunction. There is, however, evidence that female patients taking this medication experience improved sexual functioning. 34 Orally administered therapies are metabolized first by the liver, potentially leading to liver toxicity. Oral testosterone, testosterone undecanoate in particular, also needs twice daily dosing with food for better absorption. 35 Research has been done in intramuscular injection of testosterone esters in doses of 50 to 100 mg every 4 to 6 weeks. However, the female patient experiences a large supraphysiologic peak achieved early, which tapers off. This results in fluctuating, suboptimal levels from one dosing period to the next; a steady state is not achieved with this administration. 36 This is not considered a suitable long-term method for replacement therapy in women.

A testosterone pellet also can be implanted under the skin in either the lower abdomen or buttock. It is typically given in a 50-mg dose, which is slowly delivered over 3 to 6 months. Rarely, 100 mg is used.

A testosterone buccal tablet is also in the market that produces a steady-state delivery of testosterone comparable to creams and gels. This method requires twice-daily dosing in men, achieving steady levels for 10 to 12 hours. The dose of each buccal pellet is 30 mg. Because this dose is for men, titrating the dose for women is, at best, a guess. Transdermal administration of testosterone is an attractive method of delivery as it avoids a first pass hepatic metabolism and does not decrease HDL levels. 37 It is comparable to premenopausal hormone production and has a minimal side-effect profile. Because aromatase activity is minimal in nongenital skin, conversion of testosterone to estrogen is minimal. Although a transdermal patch for men is available, a recent transdermal testosterone patch for the treatment of hypoactive sexual desire disorder (low libido) for postmenopausal women was recently not approved by the FDA. More long-term safety studies are underway with hopes of obtaining approval. These patches were designed to deliver 150 μg/day and 300 μg/day, which are approximately 50% and 100% of daily testosterone production, respectively, in women. Skin irritation from the adhesive is a minor side effect.

Finally, two transdermal gels are available in the market. These gels are rubbed onto the skin daily and have proven efficacy and safety. However, they are expensive. Titrating the dose for women also involves some experimenting. Women require between one fifth and one fourth the 5-mg dose of daily testosterone replacement gel for men. Physicians should monitor blood levels frequently in the beginning of the treatment. A 1% testosterone cream, which has been shown to be effective in treating symptoms of low libido, is used off-label in Australia in premenopausal women. 38 Use of testosterone gel requires daily administration to clean, dry skin over the inner thigh and lower abdomen.

Compounding pharmacies are also able to formulate testosterone gels and creams comparable to the gels in the market. In addition, they are able to formulate testosterone into sublingual drops, which are absorbed immediately into the bloodstream via the oral mucosa. These drops achieve the same blood levels as the gels and creams. Patients should be careful not to swallow the drops to avoid hepatic first pass. The key to getting compounded androgens is to find a reputable pharmacy that will mix the compounds. A typical starting dose is about 1 to 2 mg of testosterone daily. Emphasis is placed on close follow-up with lab draws to check levels 4 to 6 weeks after starting treatment and adjusting doses accordingly. There are several testosterone formulations in trials for women: a testosterone matrix patch, a testosterone gel specifically for women, and a testosterone metered-dose transdermal therapy. Most show good efficacy, but long-term studies are needed to prove safety.

Side effects of androgen replacement therapy 

The potential side effects of androgen replacement therapy include acne, hirsutism, virilization, voice change, erythrocytosis (a rise of 3%–5% above baseline), liver toxicity, and alteration of plasma lipids.39, 40 If applied to the vaginal area, there is also a risk for clitoral hypertrophy and scrotalization. It is important to be aware that these last two side effects in particular are not reversible. Acne is reversible once the medication is stopped. Hirsutism is uncommon unless supraphysiologic levels are obtained and maintained. Sleep apnea has been reported in younger males on testosterone administration presumably due to hypertrophy of laryngeal muscles.41, 42 Liver enzyme abnormalities are reported with oral androgens. HDL reduction is seen in supraphysiologic doses and long-term androgen therapy. Rhoden and Morgentaler examined several studies looking at the effect of physiologic testosterone replacement and have concluded that testosterone replacement therapy has a neutral effect on lipid profile. 43

Testosterone replacement therapy is contraindicated in women with current or past breast cancer, baseline hematocrit >52%, and severe sleep apnea. 44

Conclusion 

The physiologic decline and resulting symptoms of androgen deficiency in women are undeniable. Symptoms include declining overall sexual function and sense of well-being. Androgen replacement therapy has been shown to have beneficial effects, altering and improving the symptoms mentioned. These benefits have been demonstrated in several trials; however, research is ongoing on the formulation and safely of testosterone replacement in women.