Aging, androgens, and female sexual desire: Can we restore what time takes away?

How androgen production declines with age 

The clinically relevant androgens in women include dehydroepiandrosterone (DHEA), its sulfoconjugate dehydroepiandrosterone sulfate (DHEAS), and testosterone.1 DHEAS is a pro-hormone that originates almost exclusively from the zona reticularis, or innermost zone, of the adrenal cortex. The zona reticularis contains steroidogenic architecture uniquely configured to secrete substantial amounts of DHEAS.

The production rate of DHEAS ranges from 5 to 40 mg every 24 hours, an amount exceeding all other steroids. DHEAS circulates in a large, slow turning pool at concentrations 100- to 1,000-fold higher than any other androgen. However, as a pro-androgen, it has no identifiable receptors and must be converted into testosterone and dihydrotestosterone (DHT) in order to express its androgenic presence.

DHEAS is converted into testosterone and DHT within the cells of target tissues. This intracellular production is initiated by DHEAS metabolizing enzymes (steroid sulfates) to form DHEA, which is then converted to androstenedione, testosterone, and then to DHT. DHT interacts with the signal transduction systems of the androgen receptor.1, 2, 3

DHEAS concentrations increase detectably in girls beginning at 7 to 8 years of age and are associated with adrenarche: increasing pubic and axillary hair, emerging sexual desire, increasing strength and muscle mass, increasing bone mass, maturation of the immune system, and accelerated linear growth (Table 1).

TABLE 1.

	Adrenarche (beginning at age 7 to 8)	Menopausal senescence or “reverse adrenarche” (beginning at age 40 to 50)
	Increasing sex hair	Loss of sex hair
	Increasing libido	Loss of libido
	Increasing bone density	Loss of bone density
	Increasing stature	Loss of stature
	Increasing muscle mass	Loss of muscle mass
	Immune maturation	Immunosenescence

Concentrations of DHEAS reach their peak in the 20s and 30s (figure 1). Production rates and circulating levels begin to decline during the 40s and 50s. A clinical picture, analogous to “reverse adrenarche,” emerges in which there is loss of pubic and axillary hair, decreasing sexual desire, loss of muscle mass and bone mass, immunosenescence, and decline in stature.

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Figure 1. Circulating DHEAS in girls and women from birth through age 100+. The graph is a composite of two studies. DHEAS concentrations, a direct reflection of DHEAS adrenal secretion, begin to increase in girls aged 7 to 8. Maximum lifetime concentrations are achieved during the decades of the 20s and 30s and begin a sustained decline through age 100. Outside bands enclose 95% of the data points. Adapted from Babalola AA, Ellis G: Clin Biochem 1985;18(3):184-9; and Ravaglia G, Forti P, Maioli F, et al. J Clin Endocrinol Metab 1996;81(3):1173-8.

Just as there is an age-related increase in zona reticularis mass at adrenarche, there is a decrease in zona reticularis mass and fragmentation of its cells with aging. The process closely resembles apoptosis (Figure 2). This decline in zona reticularis mass is associated with falling production of DHEAS and declining concentrations of circulating DHEAS that occur with advancing age.

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Figure 2. In a process resembling apoptosis, the number of functional zona reticularis cells decreases with age. This figure, showing 13 adrenal glands (18 to 84 years in the female), was reproduced from one of a very small number of studies of age-related changes in the reticularis. It shows increasing irregularity rather than simple involution of the zone. Adapted from Kreiner E, Dhom G: Age-related changes of the human adrenal gland. [author's translation; article in German]. Zentralbl Allg Pathol 1979;123:351-60.

Circulating testosterone during the reproductive years evolves partly from peripheral DHEAS conversion and partly from direct ovarian secretion originating from the dominant ovarian follicle. A mid-cycle rise in testosterone levels occurs in conjunction with the luteinizing hormone (LH) surge, which is linked to increased sexual desire now known to occur at that time (figure 3).

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Figure 3. Midcycle rise in ovarian testosterone in a group of healthy women. Testosterone concentrations show a midcycle increase associated with the peri-ovulatory period. LH, luteinizing hormone; T, testosterone. Adapted from Abraham GE. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab 1974;39(2):340-6.

After menopause, the ovary evolves from a follicle-laden reproductive structure to an acyclic, androgen-secreting, stroma-dominant organ that shrinks to about half its original reproductive-age size (figure 4). This remnant ovary is believed to produce considerable amounts of testosterone due to elevated LH levels in the menopause, though this is in some dispute.

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Figure 4. Schematic representation of the most salient differences between (A) the reproductive-age ovary and (B) the postmenopausal ovary. After menopause, the ovary evolves from a follicle-laden reproductive structure to an acyclic, androgen-secreting, stroma-dominant organ that shrinks to about half its reproductive-age size. The stromal compartment comprises virtually all of the postmenopausal ovary. The postmenopausal stroma is believed to synthesize and secrete considerable testosterone, although this is disputed by some. Adapted from Buster JE, Casson PR.1

Thus, testosterone concentrations do not decline sharply after menopause in women with intact ovaries. After postmenopausal oophorectomy, however, testosterone levels drop immediately by 40% to 50%.1, 2, 3

Declining androgen production is subtle in presentation, takes years to evolve, and can be difficult to recognize. Depletion of androgens is not lethal, but it may accelerate some processes traditionally associated with aging and mortality (ie, the characteristics of “reverse adrenarche” summarized in Table 1).

How sexual desire declines with age 

Decreased sexual desire as an event of aging may be acceptable to some women, but may not be acceptable to many others.1, 2, 3 Female sexual desire is influenced by several variables including good general health, an available and attractive partner, freedom from psychotropic drugs (eg, antidepressants), and a safe environment. Thus, advancing age and the endocrinology of advancing age are but one aspect of a highly complex behavior.4

Loss of sexual desire appears to be one of the most prevalent female sexual problems across all age groups. Most surveys compare women before and after menopause:

In addition to the effects of age, sexual desire declines in association with oophorectomy, menopausal estrogen therapy, treatment with corticosteroids, adrenalectomy, and hypopituitarism, all of which suppress androgen production. In a study assessing indices of sexual functioning in three age-matched groups of women who underwent hysterectomy with or without oophorectomy, the oophorectomized women experienced significant decreases in indices of sexual desire when compared to those whose ovaries were not removed.10, 11, 12, 13

Androgen therapy: What the studies show 

Androgens administered in pharmacologic doses can increase sexual desire. This discovery was first made when androgens were administered as chemotherapy for breast cancer, and enhanced sexual desire was noted as a side effect. The major problem over the years has been devising systems that can deliver androgens at levels closely approximating the rates of premenopausal androgen production. Ideally, in otherwise healthy older women, increased sexual desire should occur without hyperandrogenization.

A survey of the literature reveals at least six randomized, single- or double-blind clinical trials showing significant increases in sexual desire with testosterone vs estrogen-only treatment.13, 14 In addition, there are eight randomized, double-blind, placebo-controlled clinical trials demonstrating significant increases in sexual desire with testosterone treatment vs. placebo.15, 16 In six of these placebo-controlled trials, the treatment was a matrix patch that delivered testosterone at a rate of 300 μg per day, an amount close to the production rate of a normal premenopausal woman. There were few side effects with this dosage.

Of particular note, the psychological instruments used in the six placebo-controlled studies were devised specifically to measure attributes of sexual desire. The studies were limited, however, by a maximum duration of just 24 weeks, so the long-term effectiveness of therapy and occurrence of side effects beyond that time frame are not known.

The FDA has not approved any androgen therapies for decreased sexual desire. Nonetheless, many types of androgen preparations are widely prescribed off-label or are self- administered. These include topical gels, creams, vaginal gels, subcutaneous implants, testosterone patches developed for men, intramuscular injections, sublingual preparations, oral methyltestosterone, and oral DHEA.

Three examples of off-label androgen regimens include:

A need for approved treatments 

There is clear documentation that androgen production declines with age and that it is associated with declining sexual desire. Furthermore, there is confirmatory evidence from recent and sizable prospective, blinded, and randomized placebo-controlled clinical trials that restoration of serum testosterone approximating that of the reproductive years restores sexual desire to many women. It is not clear whether exposure to these levels for many years beyond menopause may have long-term deleterious effects. It is clear, however, that until the FDA approves one or more of these treatments, physicians and their patients have no choice but to use off-label and locally compounded treatments.