CONTROVERSIES IN OB/GYN

Does androgen insufficiency exist in women?

Yes. It is underrecognized but studies show the condition responds to testosterone treatment.

By Gloria Bachmann, MD, and Nidhi Gupta, MD

Like any other endocrine organs, the ovary and the adrenal gland—which both produce androgens—can produce hormones in quantities defined as too little (hypo) or too much (hyper). However, there is no controversy about what constitutes excessive or insufficient adrenal hormone synthesis. That is not the case, however, with insufficient androgen production in women, especially when the decline occurs after surgical or natural menopause. States of ovarian hyperandrogenism, such as polycystic ovary syndrome, are universally recognized, whereas hypoandrogenic conditions related to both the ovary and the adrenal glands remain controversial.

Because of this discrepancy, an international panel of experts on androgens and their effects in women was convened in 2001 to review the role of androgen decline in the female and also propose a working definition of postmenopausal female androgen insufficiency. An older population was chosen because their levels of gonadal hormones do not fluctuate in the same manner as in premenopausal women, who experience wide fluctuations in sex hormones during their menstrual cycles.

After reviewing the research, the panel defined female androgen insufficiency in the postmenopausal female as a condition "consisting of a pattern of clinical symptoms in the presence of decreased bioavailable T [testosterone] and normal estrogen status."¹

The impact of assays

The group also recognized that one of the major reasons that androgen insufficiency has been difficult to quantify in women is the lack of an accurate and reproducible assay for measuring lower levels of testosterone. In addition, current assays do not always measure all fractions of testosterone, including the bioactive fraction. Although the most accurate assay currently available is equilibrium dialysis, which measures free testosterone levels, this test is difficult to perform and most laboratories are not equipped to do it.

Lacking a simple and reliable testosterone assay and given the global nature of the symptoms that accompany androgen insufficiency in the female, many women who have the condition may not be accurately diagnosed. Hyperandrogenism in women is associated with many different presenting signs and symptoms, including acne, alopecia, hirsutism, menstrual disorders, infertility, insulin resistance, abnormal glucose tolerance, android obesity, dyslipidemia, voice changes, clitoral changes, and hypertension, and yet there is no controversy regarding that clinical diagnosis in women. Hypoandrogenism, however, is not universally accepted despite the fact that it, too, produces diverse symptoms in older women, such as reduced sex motivation, fantasy, enjoyment, and arousal; diminished vaginal vasocongestion; loss of pubic hair; reduced bone and muscle mass; and diminished mood, affect, and energy.

What treatment can do for these patients

Androgen replacement has been shown to produce significant improvement in estrogen-replete women who have symptoms of androgen insufficiency, confirmed by measurement of low circulating bioavailable T levels.^2,3

Clinical trials in nonhuman primates and humans have shown that giving androgens to ovariectomized females enhances sexual motivation. In the ovariectomized rhesus monkey, testosterone administration is associated with increased proceptive behavior. Testosterone implants in the anterior hypothalamus also restore proceptivity in estrogen-treated rhesus monkeys who have undergone bilateral oophorectomy and adrenalectomy.⁴

In humans, results from at least seven randomized, controlled trials using androgen show enhanced sexual function in the women treated with androgens.² In one study, increased sexual activity and pleasure-orgasm was seen in estrogenized women who received a 300-µg testosterone patch, compared with those given placebo or a 150-µg testosterone patch. The women in the higher-dose group achieved a mean bioavailable T level of 11.4 ± 9.5 ng/dL, the upper limit of the normal female range, and had significant improvement in well-being, depressed mood, and composite scores on the Psychological General Well-Being Index.³

The take-home message

Androgens have significant and varied actions in women and when levels fall, signs and symptoms of insufficiency may occur. Hypoandrogenism is recognized in men and in specific subsets of women, particularly those who are surgically menopausal. As research continues in this area, especially in the area of assays that accurately measure free T at low levels, our understanding of androgen insufficiency in woman will broaden.

REFERENCES

1. Bachmann G, Bancroft J, Braunstein G, et al. Female androgen insufficiency : the Princeton consensus statement on definition, classification, and assessment. Fertil Steril. 2002;77:660-665.

2. Sherwin BB. Randomized clinical trials of combined estrogen-androgen preparations: effects on sexual functioning. Fertil Steril. 2002;(suppl 4):S49-S54.

3. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000;343:682-688.

4. Everitt BJ, Herbert J. The effects of implanting testosterone propionate in the central nervous system on the sexual behavior of the female rhesus monkeys. Brain Res. 1975;86:109-120.

DR. BACHMANN is Associate Dean for Women's Health and Professor of Obstetrics and Gynecology and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, N.J.

DR. GUPTA is a Research Assistant in the Women's Health Institute of UMDNJ-Robert Wood Johnson Medical School, New Brunswick, N.J.

Controversies in OB/GYN focuses on controversial issues pertaining to the clinical practice of obstetrics and gynecology and reproductive medicine. The authors have been selected for their ability to articulate a particular point of view, regardless of their own personal convictions.

We hope that these short essays will provoke discussion and help Contemporary OB/GYN's readers clarify and refine their own practice management. You can join in the dialogue by completing and faxing in the response form at the end of this article or sending us your opinion (pro or con) via e-mail to jorvos@advanstar.com. A summary of the correspondence we receive will be published in a future issue.

David B. Seifer, MD, Department Editor
Department of Obstetrics, Gynecology, and Reproductive Sciences
UMDNJ-Robert Wood Johnson Medical School
New Brunswick, N.J.

CONTROVERSIES IN OB/GYN

Does androgen insufficiency exist in women?

By Gerson Weiss, MD

No. The condition is poorly defined and therapy has not been proven effective.

Androgens are potent hormones. Excess androgens in women produce dramatic symptoms, including acne, cephalic baldness, hirsutism, increased muscle mass, amenorrhea, and deepening of the voice. In women, levels of circulating androgens are a fraction of those in men and fairly close to assay detectability levels.

In premenopausal women, a portion of circulating androgens is derived from the ovaries. But this type of androgen production ceases within 2 years after a woman's final menstrual period. Postmenopausal ovaries do not contain the enzymes needed to produce steroids, and thus do not produce androgens.¹ In the absence of any ovarian androgens, most postmenopausal women have normal strength and libido and feel fine.

I'll limit my discussion to female androgen insensitivity syndrome (FAI), which is characterized by decreased libido, tiredness, weakness, and a lack of well-being. We will not consider marked pituitary or adrenal insufficiency, which involves a lack of many hormones, including androgens, and results in significant symptomatology. In situations such as those, androgens may play a role in maintaining bone density, muscle strength, and other factors, in the context of other hormonal deficiencies.

Understanding female androgen insensitivity

FAI is poorly defined and difficult to distinguish from the changes one would expect in aging or depression, which may affect 20% of postmenopausal women. In all discussions of FAI, sexual response, libido, and other aspects of sexuality are major concerns. This leads to the question, what is the role of androgens in female sexuality? Is testosterone necessary for libido? Sexuality is an extremely complex topic, involving many factors. These include, but are clearly not limited to, one's mental state, health, level of depression, physical condition, religious beliefs, upbringing, orientation, and availability of a partner.

As people age, they have less intercourse. Determinants include physical condition, availability of partners, and other factors. For example, a woman's sexuality can be affected if she feels unattractiveness because of aging or weight gain. Certainly, vaginal dryness and thinness secondary to a hypoestrogenic state, and hip osteoarthritis will limit sexual function. Among the major reasons why women have decreased sexual function are unavailability of a partner, decreased ability of a partner to perform, or decreased desirability of their partner.

Evaluating the research on testosterone

With this as background, what are the roles of testosterone in female sexuality? It is fairly clear that most women with hyperandrogenic states do not have increased libido or sexuality. As a group, women with polycystic ovarian syndrome are hyperandrogenic, yet they are not hyperlibidinous. Women with androgen-secreting tumors have male hormone levels and clear virilization, including clitoromegaly, increased muscle mass, deepening of voice, and massive hirsutism. However, when questioned before and after surgery, they will often report no changes in libido, even with circulating androgen levels 10 to 20 times that of the an average female. Likewise, XY phenotypic women with complete FAI syndrome who do not respond to androgens frequently report normal libido.

Many of the studies on exogenous androgens for female sexuality have been weakened by poor controls, small numbers, difficulty in defining endpoints, and a large placebo effect. A look at several good studies is instructive. In 2000, Shifren and colleagues reported on the use of transdermal testosterone in 75 women aged 31 to 56.² All had undergone oophorectomy and hysterectomy and were on estrogen therapy. These patients were treated for 12-week periods with either placebo, 150 µg of testosterone, or 300 µg of testosterone per day. Sexual function and mood were evaluated with the Brief Index of Sexual Functioning for Women. The baseline score was 52, compared to 72 for both placebo and 150 µg of testosterone and 81 for 300 µg of testosterone. At baseline, 23% of women engaged in sexual intercourse at least once a week, compared to 35% during low-dose treatment or placebo and 41% during high-dose therapy. Hence, low-dose therapy almost tripled circulating testosterone concentrations in serum but was not clinically different than placebo. High-dose testosterone resulted in a five-fold increase in circulating testosterone to clearly pathologically high levels but produced a modest increase over the lower dose or placebo effect. Therapy was only maintained for 12 weeks but it is highly likely that continued treatment would have produced hyperandrogenic symptoms. It is also not clear whether the effect produced was due to testosterone or to the aromatization of testosterone to estrogens, hence producing a greater estrogen effect than in the placebo group.

The issue of whether testosterone functions as an androgen or as a source of increasing estrogens may be partially explained by a study by Dennerstein and colleagues.³ They applied the Short Personal Experiences Questionnaire (SPEQ) to 438 Australian women between the ages of 45 and 55. Using SPEQ, a score of 7 or less indicates sexual dysfunction. Studying hormonal levels in the early menopause transition, the authors noted no substantive change in testosterone, free testosterone index, or sex hormone-binding globulin in the individuals with sexual dysfunction or no sexual dysfunction. They did, however, note that circulating estradiol levels were significantly higher in the group with normal sexual function, compared to the women with sexual dysfunction. This indicates that estrogen may be a factor in female sexuality and that testosterone may thus have an effect by virtue of its aromatization to estrogen.

In the final analysis

The criteria for the diagnosis of FAI are weak and not generally agreed upon. Most authors suggest some testing, but differ as to what tests should be performed. Some recommend SHBG and/or testosterone and/or free testosterone index, all of which, especially at low levels, are insensitive and imprecise measurements. Hence, there is no clear methodology for either diagnosing FAI or differentiating it from common significant illnesses, such as depression. It appears as if testosterone therapy can improve sexuality, but most of the improvement is due to a placebo effect. The additional, relatively minor improvement in sexuality produced by high doses of testosterone may be due to aromatization to estrogen. Giving exogenous testosterone raises circulating levels, which may increase risk of cardiovascular disease, low-density lipoprotein levels, liver disease, hair growth, and cephalic baldness, and decrease high-density lipoprotein levels. It is wishful thinking to envision using testosterone in women without elevating circulating levels and producing the significant side effects seen with high doses while producing profound psychological and physiological changes. One need only contemplate the Women's Health Initiative findings for estrogen to determine what potentially negative effects would occur in a similar study of exogenous androgens in women.

In summary, FAI is poorly defined and characterized. There are no clear diagnostic criteria. Therapy with androgen has yet to be proved safe and effective.

REFERENCES

1. Couzinet B, Meduri G, Lecce MG, et al. The postmenopausal ovary is not a major androgen-producing gland. J Clin Endocrinol Metab. 2001;86:5060-5066.

2. Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000;343:682-688.

3. Dennerstein L, Randolph J, Taffe J, et al. Hormones, mood, sexuality, and the menopausal transition. Fertil Steril. 2002;77(suppl 4):S42-S48.

DR. WEISS is Professor and Chair, Department of Obstetrics, Gynecology, and Women's Health at UMDNJ-New Jersey Medical School, Newark, N.J. He is Chairman of the American Board of Obstetrics and Gynecology and is a member of the Executive Committee of the American Board of Medical Specialties.

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Does androgen insufficiency exist in women?

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Gloria Bachmann, Nidhi Gupta. Does androgen insufficiency exist in women? Contemporary Ob/Gyn Jul. 1, 2004;49:58-64.