Testosterone Therapy

Content written by Irwin Goldstein MD

There are seven biologically identical androgens defined as sex steroid hormones that consist of 19 carbons in the chemical structure. Androgens are naturally derived from cholesterol via synthetic processes within the ovaries and the adrenal gland and from the androgen precursor, dehydroepiandrosterone, in multiple peripheral organs such as the skeletal muscle, bone, and skin. Since androgens are synthesized in multiple locations in the body, even after menopause when ovarian estradiol synthesis is impaired the body is capable of synthesizing adequate amounts of androgens. Studies have shown that 90% of the androgen precursor dehydroepiandrosterone is synthesized in the adrenal gland, with the remaining 10% in the ovaries; the androgen precursor androstenedione is synthesized equally in the adrenal gland and ovaries (40% in each) and 20% in the peripheral organs; whereas testosterone is synthesized 50% by the peripheral organs and 25% each in the adrenal gland and ovaries. The ovaries are, surprising to most individuals, critical organs not only for estrogen but also for androgen synthesis. Women thinking of having their ovaries removed as part of a hysterectomy procedure need to be aware that the ovaries do synthesize many critical androgens; if the ovaries are removed, remaining androgen sources may not be adequate to maintain genital tissue structure and function.

Four of the seven androgens may be clinically measured: dehydroepiandrosterone (and dehydroepiandrosterone-sulfate), androstenedione, testosterone, and dihydrotestosterone. Androgen hormones are critically important for tissue structure and function, especially genital tissue structure and function. Androgen synthesis is an example of a one-direction waterfall. In androgen synthesis, conversion does not occur “upstream” into the early part of the synthetic cascade but conversion occurs only “downstream” into the remaining portion of the cascade. For example, dehydroepiandrosterone, the first or precursor androgen, is converted by an enzyme into androstenedione, which is then converted by a different enzyme into testosterone, which is then converted by a different enzyme to dihydrotestosterone. This is clinically relevant. Women with sexual health problems who have low dehydroepiandrosterone blood levels and who consider dehydroepiandrosterone treatment can raise that level and the rest of the androgen levels from this conversion. In contrast, women with sexual health problems with low testosterone blood levels who consider testosterone therapy raise only the androgen levels of testosterone and dihydrotestosterone.

It should be noted that androgens are not final sex steroids. There are three biologically identical estrogens defined as sex steroid hormones that consist of 18 carbons in the chemical structure. Estrogens are naturally derived from cholesterol via synthetic processes within the ovary and the adrenal gland. Estrogens are derived from the androgens, androstenedione and testosterone, via the enzyme aromatase. This is likely why some women with hot flashes and night sweats report improvement in symptoms following systemic androgen use without the need for or risk associated with systemic estrogen administration.

Androgens have a profound effect on many physiological functions in women including: stimulation of sexual interest, thoughts, and fantasies; regulation of genital (vaginal and clitoral) blood flow; volume and quality of vaginal lubrication; structural and functional integrity of the clitoris, prepuce, vaginal muscularis (smooth muscle layer), G-spot, and minor vestibular glands; stimulation of bone growth; increase in muscle mass; maintenance of energy and well-being; maintenance of lean body composition; control of oil gland activity in skin; and regulation of body hair growth.

Testosterone is the most well-studied androgen in terms of treatment of women’s sexual health problems. Testosterone is a critical and vital hormone that continually directs and maintains healthy structure and function in testosterone-dependent tissues, such as genitals and skin, muscles, bones, etc. Current evidence shows that testosterone achieves its multiple functions by entering body cells and copying or transcribing specific genetic information from the cell’s nucleus onto biochemical messages that ultimately result in the synthesis of critical proteins. These critical proteins help maintain the structure and function of many genital (clitoris, vaginal muscularis, labia minora, G-spot, minor vestibular glands) and non-genital (brain, bone, skeletal muscle, skin) tissues. Before puberty, when all the androgens are low, the woman’s peripheral genitals including the clitoris, prepuce (foreskin), frenulum, labia minora, labia majora, G-spot, and vestibule are not fully developed. After puberty, when androgen level increase, the woman’s peripheral genitals fully develop. The clitoris reaches adult size, sensitivity, and engorgement capability, the labia minora develop tissue mass and local lubrication occurs via a series of glands that release the lubricant onto the labia during sexual arousal. The vagina muscularis easily relaxes during sexual arousal so that the vagina increases appropriately in length and width.

Although testosterone appears to be an important factor in women’s overall sexual and general health, women with low (but not absent) testosterone levels can still have a satisfactory sex life. One possible explanation for this is based on new research showing that testosterone effects are mediated by the androgen receptor and that individuals have different shapes or polymorphisms of the androgen receptor. One such androgen receptor polymorphism that has been observed in humans is due to repeated insertions of the amino acid glutamine, of variable length, within the n-terminal domain of the androgen receptor. These repeated insertion glutamine amino acids were encoded by a variable number of CAG triplets in the exon 1 region of the androgen receptor gene, located on the X chromosome (women have two X chromosomes). Androgen receptor polymorphisms with low CAG triplets and low repeats of the amino acid glutamine are more effective in gene transcription of critical proteins. Androgen receptors with high CAG triplets and high repeats of the amino acid glutamine are less effective in gene transcription of critical proteins. Thus length of the polymorphism is inversely associated with testosterone-induced gene transcription. Women who have an efficient version of androgen receptor polymorphisms (low CAG repeats) may be able to synthesize critical testosterone-related proteins even with low (but not absent) levels of testosterone. Pathological CAG-triplet elongations have been observed in certain biologic disorders and future research may show more sexual dysfunction in women with an above average number of CAG repeats than in those with a polymorphism length within the average range.

Women’s androgen and testosterone levels decline with age, beginning at age 30, and progress steadily downward. At 40, a woman’s androgens are already half of values at age 20. At 60, androgen values are 1/3 of values at age 20. Research studies are concerned with average values in large population samples: not all women will have low testosterone. These studies do not report individual androgen blood test values.

Beyond aging, there are many other conditions or situations associated with lower testosterone blood levels. The most common reason is an elevation in the level of sex hormone binding globulin (SHBG). Sex hormone binding globulin is produced by the liver cells and released into the blood stream. The purpose of SHBG is to bind the sex steroids (androgens, estrogens, and progestins) in the circulation. Androgens such as testosterone have a very high propensity or affinity to bind onto sex hormone binding globulin. What is important to understand is that for sex steroids in general, and testosterone in particular, it is the “unbound” form of hormone and not the hormone bound to SHBG that is physiologically active. In theory, it is the “unbound” form of testosterone that gets into the cell and directs the synthesis of important proteins. Therefore, the measurement of sex hormone binding globulin is of paramount importance in assessing the level of “unbound” testosterone in a woman with sexual health problems. High sex hormone binding globulin levels pose a clinical problem in women. Sex hormone binding globulin values are increased by use of any estrogen (e.g., for contraception or treatment of menopausal symptoms), use of tamoxifen (for treatment of breast cancer), pregnancy, liver diseases (such as cirrhosis) or anti-seizure medications. Sex hormone binding globulin is lowered by androgen administration, a good bonus of testosterone use.

Low testosterone blood test values may be caused by conditions that affect the ovaries. These include natural, surgical or premature menopause, injury to the ovaries by chemotherapy or radiation treatments for cancer, or systemic hormone treatments that affect the ovaries such as oral, patch or ring contraceptives, infertility hormone treatments, endometriosis hormone treatments or uterine fibroid hormone treatments.

In summary, with aging or certain medications (e.g., oral contraceptives, infertility drugs, selective serotonin reuptake inhibitors), when testosterone levels fall, the woman’s androgen-dependent peripheral genitals such as the clitoris and prepuce may undergo atrophy and take on the same underdeveloped characteristics they had prior to beginning puberty. The hormone testosterone, similar to other sex steroid hormones, is critical throughout post-pubertal life to maintain genital tissue structure and function.

According to an international panel of experts, a syndrome of androgen (or testosterone) insufficiency exists if the woman has any of the following symptoms: a diminished sense of well-being; feelings of helplessness or unhappiness; persistent or unexplained fatigue; sexual function changes such as decreased sexual interest, sexual receptivity, sexual pleasure, and/or decreased lubrication; or bone loss, decreased muscle strength, and/or changes of memory; in conjunction with having a blood test consistent with low “unbound” testosterone values; as well as having personal distress or bother from the clinical symptoms.

Since there is no consensus as to what blood tests should be obtained when being evaluated for androgen insufficiency, the following list represents the personal opinion of the author of this section. Women should consider initially requesting blood tests for total testosterone: values include both “bound” and “unbound” forms of testosterone; and sex hormone binding globulin: values enable the calculated free testosterone to be determined. Optional androgen blood tests include: dehydroepiandrosterone-sulfate: the sulfated form of dehydroepiandrosterone, more stable than dehydroepiandrosterone; androstenedione; and dihydrotestosterone

There is a blood test called “free testosterone” (sometimes called “analog free testosterone”) that theoretically measures only the “unbound” (and the most biologically important) form of testosterone. Unfortunately, the current test is not very accurate for technical reasons related to the specificity of the antibodies used. Relying on this test exclusively for diagnosis of androgen insufficiency may be misleading. While there are other accurate tests of “unbound testosterone,” such as free androgen index and bioavailable testosterone, one recommended strategy is to use the free testosterone calculator available on the Internet. The value thus obtained is called the “calculated free testosterone.” It is reliable and an easily available measure of “unbound” testosterone.

While these androgen blood tests are important, it is rare that the healthcare provider is only interested in the androgen status of a woman with sexual health concerns. Additional sex steroid hormone blood tests that are usually obtained include the following: estradiol: the most important estrogen, more meaningful in women in the transition or post-menopause; progesterone: the least understood as it relates to sexual medicine, although it appears to be involved in sexual interest and overall mood; follicle stimulating hormone and luteinizing hormone: measurements of the integrity of the pituitary gland and its role in monitoring estradiol values in a woman; prolactin: a potent inhibitor of sexual activity in a woman; and thyroid stimulating hormone: measurement of the integrity of the thyroid gland.

The results of these multiple tests need to be examined very carefully. Usually a pattern will emerge that helps the sexual medicine healthcare professional recommend a course of action. There is a clinically important controversy—the normal ranges of these blood tests. Laboratories developed values for the “normal range” by measuring hormone blood values of healthy women without knowledge of the women’s sexual function. Thus the so-called “normal range” includes women who may not have been sexually healthy. Several studies have now examined the blood test values where women with sexual health concerns were excluded. These studies supported the consensus that if a hormone blood level falls in the lowest fourth or quartile of the current “normal range,” it is considered suspicious. Another controversy is that blood test values may not represent what is actually happening inside the tissues.When bothered by the clinical symptoms, and testosterone blood test values are consistent with a hormonal problem, androgen treatment may be considered for a woman with sexual health concerns. The two most widely used androgens for treatment of sexual health problems are dehydroepiandrosterone and testosterone, however there is no FDA-approved pharmacologic treatment for women with sexual health problems at present in the United States.

The testosterone patch has been approved in Europe by the EMEA for use in women with low desire following surgical menopause. From the perspective of testosterone treatment, this means that the safety and/or efficacy data concerning use of androgens in a specific population of women with sexual health problems has been satisfactorily established at the time of publication of this book by the EMEA but not the FDA.

There are FDA-approved versions of testosterone indicated for men for the treatment of hypogonadism. Use of these products in women with sexual health problems would be considered as an “off-label” treatment. As above, it is the responsibility of the healthcare clinician to provide patients with appropriate evidence-based information on risks and benefits so an informed decision regarding use may be made. The individual dose for women with sexual health problems is usually 10% of a man’s daily dose. It is important to repeat follow-up blood tests of “unbound” testosterone, usually at 3-month intervals, to establish the unique individual dose for each woman with sexual health concerns.

Although data supporting treatment of women with testosterone was limited until recently, reports documenting facilitation of the sexual response were published as early as 1938 by Shorr et al., in 1940 by Loeser, and in 1943 by Salmon and Geist. Even at that time it was appreciated by some that women’s sexual function had a biological component, and that appropriate management involved attention to biological and psychological concerns.There have been multiple double-blind, placebo-controlled studies of testosterone in women with sexual health concerns showing the benefits of testosterone use. The reader should be aware that of all the management strategies available to women for sexual dysfunction, including sex therapy, physical therapy, lifestyle modification, use of lubricants and devices, and change of medications, the evidence supporting these strategies is quite limited. Testosterone currently is the therapy most supported by evidence, although more research is needed.

In one study, post-menopausal women with sexual dysfunction randomized to testosterone treatment had significantly more satisfying sexual events, improved frequency of sexual activity, and improved sexual orgasm and pleasure compared to the placebo group. In another study of post-menopausal women, testosterone treatment was associated with significant improvement in a number of secondary sexual function outcome measures, including sexual arousal, orgasm, pleasure, and body image. Women assigned to testosterone also reported decreased concern or distress about sexual functioning. In a study of pre-menopausal women, those who received testosterone had significantly improved sexual motivation, fantasy, frequency of sexual activity, pleasure, orgasm, and satisfaction. Testosterone also significantly improved their scores on a validated well-being questionnaire.

The Princeton Consensus conference of 2001 recommended that women suspected of having testosterone insufficiency be managed with systemic estrogen administration prior to starting androgen therapy with testosterone. Despite these recommendations, however, many women express reluctance to use exogenous estrogen due to concerns about breast cancer, heart attack and stroke, based on clinical research data. Some women consider starting directly on androgen therapy to avoid the potential risks associated with exogenous estrogen use. There are double blind placebo controlled data supporting evidence that androgens are efficacious without concomitant estrogens in post-menopausal women with hypoactive sexual desire disorder.

The long-term safety of testosterone use in women for sexual health concerns has not yet been established. Women considering treatment with testosterone for their sexual health concerns need to be aware of the following possible healthcare risks.

With regard to hirsutism (body hair growth) and acne, 3% to 8% of women users of testosterone for management of sexual health problems noted side effects. These side effects are usually mild and dependent upon dose and duration of testosterone treatment. Virilization (voice deepening, excessive growth of the clitoris, and scalp hair recession) is a targeted effect of the high testosterone doses used for management of female to male transsexuals (10 times the dose used for treatment of female sexual dysfunction).

Concerning breast cancer, the vast majority of reports show no increase in breast cancer risk among women using testosterone for management of sexual health problems. There is no increased risk of breast cancer in women who have long-term elevated testosterone from polycystic ovary disease. Breast cancer potential was measured in monkeys using an index of breast tissue proliferation. In those treated with estradiol alone, the breast tissue proliferation was 4 times the control animals. In those animals co-treated with estradiol and testosterone, the risk was one half of the estradiol alone treated group. In a breast cancer comparison study, the cases of breast cancer per 100,000 women-years in women using estrogen and testosterone or estrogen, progesterone, and testosterone were lower than in women using estrogen and progesterone. Of note, while many studies show no increase in breast cancer in women using bioidentical testosterone, a recent study showed that those who used the non-bioidentical form of testosterone called methyl testosterone in conjunction with a fixed dose of estradiol did have a higher risk of breast cancer compared to those who did not use the non-bioidentical form of testosterone.

The side effects of growth of the uterine lining, liver function changes, sleep apnea and aggression were not associated in studies where women used the recommended doses of testosterone for sexual dysfunction.

In summary, testosterone is a sex steroid critical for sexual function and structure in women. Safety and efficacy data with the judicious use of bioidentical testosterone are ongoing and available for all patients (and partners) and healthcare providers to analyze. Decisions based on risks and benefits for use of this sex steroid when androgen insufficiency exists must be individual, but the most prudent plan is to use bioidentical testosterone in doses that maintain hormone values in an appropriate physiologic range, to have frequent and regular blood testing, and to undergo annual breast exams, mammograms, and gynecologic exams.

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