Testosterone Insufficiency and Treatment in Women: International Expert Consensus Resolutions

While it is general knowledge that testosterone is used to improve sexual function in women, its non-sexual effects in women require more in depth review and acknowledgement. To provide a broader scope for this discussion an expert consensus conference addressing Testosterone insufficiency (TI) in women was held in Orlando, Florida, USA on April 24, 2017.

Participants representing a wide range of specialties were invited on the basis of their clinical and/or research expertise with the usage of Testosterone therapy and diagnosis and treatment of Testosterone insufficiency (TI) in women.

The goal is a review that provides reasonable and prudent rationale for the consideration of testosterone as part of a woman’s disease prevention and hormone optimization program based on the present scientific and clinical evidence.

Historical Background

Clinical use of testosterone dates to 1939 but became popularized by Greenblatt in 19491. Since then, testosterone therapy for women became a routine component of HRT in Europe and Australia but still limited in the United States.

Despite the plethora of data in support of the extensive benefits of testosterone supplementation in women, the lack of an F.D.A. approved testosterone product for women, has left medical education in the dark. In the most recent, Shifren and Davis2, review of androgens in postmenopausal women the importance of testosterone therapy in premenopausal women remains limited primarily to sexual dysfunction.

Our Consensus panel with more than 100,000 patient YEARS experience with testosterone supplementation in women is excited to share the studies we reviewed and our clinical and evidence based recommendations.

The format of the consensus group followed Morgentaler et al.3 on testosterone deficiency and treatment in men.The goal of our review is to raise awareness, open discussion and focus researchers and clinicians on the broader scope for the use of testosterone and its effects on multiple organ systems.

As a consequence of the Women’s Health Initiative (WHI) a 79% decline in utilization of hormone therapy occured.4 The WHI study didn’t consider differences in action and risk associated with various forms and routes of administration of hormones, the age of the participants or pre- existing conditions and omitted testosterone as a component of hormone optimization. In contrast Sherwin5 conducted a randomized trial comparingestrogen, testosterone and placebo in 1985 with 115 pre-menopausal women post hysterectomy and oophorectomy. Testosterone treated group showed superior energy improvement, wellbeing, decrease in somatic complaints and psychological symptoms.

Terminology

Optimization of an individual’s testosterone balance and replaces “Testosterone replacement therapy”. “Testosterone insufficiency (TI)” replaces “low T” consistent with Morgentaler Consensus recommendations in men.

Participants

The panel consisted of ten international specialists in obstetrics and gynecology, endocrinology, internal medicine, age management medicine, and urology. Participants were invited on the basis of established clinical experience with women’s health, TI and treatment. The choice of multiple specialties and geographic diversity was intentional contributing diverse opinions and minimizing regional and specialty-based biases. All experts volunteered their time.

Methods

Two months before the conference each participant was assigned one statement developed by a working group and asked to provide, 3 to 5 Pub Med, Medline, Cochrane review references pro and con to the statement. At the conference each participant presented his/her statement, interpretation and references. Collaborative discussion and debate led to the resolutions being unanimously agreed upon by the participants. This review summarizes the resolutions followed by abstracts and supporting evidence.

RESOLUTION 1. Testosterone is Not a Male-Exclusive Hormone. It is the Most Abundant Gonadal Hormone Throughout a Woman’s Life.

Although testosterone is known as the “male” hormone, in 2002 Dimitrakakis, et al.6 stated testosterone (T) is the most abundant biologically active gonadal hormone throughout the female lifespan. According to Panay and Fenton7 young women’s ovaries produce approximately three- to four- times more testosterone than estrogen daily. Measured ranges of androgen precursors are similar in women and men.

Burger8 noted that quantitatively, women produce more androgen than estrogen. Only T and DHT bind to the androgen receptor. Other androgens; DHEA, DHEA-S and Androstenedione are essentially pro-androgens.

In charting average estradiol (E2) and testosterone levels across the female lifespan, T consistently exceeds E2, usually by 250-300 pg/ml, and between ages 24-30 T levels are 400 pg/ml higher than E2. Both women and men have functional estrogen receptors (ERs) and functional androgen receptors (ARs), with the AR gene located on the X chromosome.9

Although T is the major substrate for E2, in proper balance with E2 it is equally important for health in both sexes. Testosterone was reported to effectively treat symptoms of menopause as early as 193710. Oddly estrogen is the hormone of choice for “replacement therapy” in women despite lack of clear evidence to that fact.

RESOLUTION 2. Serum Testosterone Levels do not correlate with Symptoms of Testosterone deficiency in women. Optimal ranges of SerumTestosterone levels in women have not been established.

Established reference ranges for total testosterone, free testosterone and pre-androgens, below which a woman might be considered androgen “deficient” were not found in the literature. Biochemical definition of a “female androgen deficiency syndrome” is also lacking in the literature reviewed. Normal ranges posted by various labs reflect averages for a given population and do not correlate with clinical picture.

In 2002,11 an expert panel published the Princeton consensus guideline on Female Androgen Deficiency. The recommended definition of androgen deficiency included: [1] a diminished sense of well-being or dysphoric mood; [2] persistent, unexplained fatigue; lethargy and [3] sexual function changes, including decreased libido, sexual receptivity, and pleasure. No biochemical marker diagnosing androgen deficiency was established.

In discussing androgen production in women, Burger noted that although women produce 200-300 micrograms testosterone per day, serum levels follow circadian, diurnal and menstrual cyclical variation making it difficult to define normal ranges. Other variations occur due to stress, sleep, exercise, insulin levels and more. According to Davison12 there is a wide range of normal. Traditional medicine requires clinical practice to follow “normal” values for the “mean.” However “normal” values do not always apply to the individual woman thus leaving reference levels unreliable. Seeking rigid guidelines for optimal T levels is also counter to the accepted concept that hormone optimization is not a “one size fits all” treatment (NAMS position statement 2013). Thus, TI is a clinical syndrome defined solely by clinical symptoms and its successful treatment measured solely by symptomatic improvement.

Carruthers et al.13 also noted poor correlation between symptoms and serum levels of androgens. Kelleher and Handelsman14 noted considerable variation among individuals in the serum levels of testosterone when deficiency symptoms exist.

Glaser15 noted “higher doses of testosterone correlated with greater improvement in symptoms” in 300 pre and post menopausal women studied. No laboratory correlation was found.

Kratzik16 reported neither the total AMS (Aging Male Score) nor the MRS (Menopause Rating Scale) score correlated with total testosterone serum levels.

Most testosterone in the blood is bound to sex hormone–binding globulin (SHBG). Circulating levels of SHBG are affected by genetics, aging, HRT and other factors17.

Genetic variations in the androgen receptor (AR) gene were noted by Westberg.18 The cysteine, adenine, guanine (CAG) terminal domain of the AR gene varies in both sexes. Longer chains represent less active receptors and lower levels of serum androgens. Serum levels of androgens in premenopausal women are influenced by variants in the AR gene. There is no “normal” testosterone level in women.

Due to the difficulty in establishing clear laboratory criteria for a deficiency syndrome, the consensus proposes the term “Female Testosterone Insufficiency” to represent symptom driven clinical syndrome.

RESOLUTION 3. Female Testosterone Insufficiency is a Clinical Syndrome that May Occur During Any Decade of Adult Life.

Guay et al.19 demonstrated a precipitous age-related decline in all androgens (total T, free T, DHEA-S and Free Androgen Index) in premenopausal women without sexual dysfunction age 20 to 49 years old.

In a subsequent study, Guay20 found that premenopausal women with complaints of sexual dysfunction had lower adrenal androgen precursors and testosterone than age-matched controls. No differences were noted in the ovarian androgen precursors between groups.

Turna et al.21 demonstrated that low total testosterone, free testosterone and DHEA-S levels correlated positively with full-scale FSFI score and FSFI- desire, FSFI-arousal, FSFI-lubrication and FSFI-orgasm scores. Slemenda et al.22 found hip bone loss associated with lower androgen concentrations in premenopausal women.

Zumoff et al.23 noted declining testosterone levels in premenopausal women. By age 40 a woman has half the mean plasma testosterone levels of a 21-year-old.

Androgen insufficiency (AI) may explain why despite taking standard estrogen/progestin hormone replacement therapy, 67% of women with premature ovarian failure have diminished bone density associated with increased hip fracture risk as discussed by Kalantaridou and Calis.24Pathophysiological states affecting ovarian and/or adrenal function may result in androgen insufficiency in premenopausal women. Young women with hypothalamic amenorrhea, premature ovarian failure, oophorectomy, premenstrual syndrome, acquired immunodeficiency wasting syndrome, adrenal insufficiency, hypopituitarism and on certain medications (oral estrogen, oral contraceptives and corticosteroids) may have testosterone deficiency. Additionally, testosterone insufficiency (TI) in young women may be under diagnosed because the symptoms are generally nonspecific, awareness of TI is low and the measurement of plasma total and free testosterone, not helpful.

RESOLUTION 4. Testosterone Therapy May be Breast Protective.

Studies have shown that testosterone may protect the breast from cancer. Hofling et al.25 showed that addition of Testosterone to a standard estrogen/ progestogen regimen may modulate the stimulatory effects of the estrogen/ progestogen on breast cell proliferation.

As early as 1937,26 it was recognized that breast cancer was an estrogen sensitive cancer; testosterone was ‘antagonistic’ to estrogen and was used to treat breast cancer as well as other estrogen sensitive diseases including breast pain, chronic mastitis, endometriosis, uterine fibroids and dysfunctional uterine bleeding.

Dimitrakakis and Glaser27 stated “testosterone and DHEA-s levels in saliva were statistically significantly lower in breast cancer patients compared to controls and more profound in post-menopausal women with breast cancer.”

Clinical trials in primates and humans 28 have confirmed that testosterone has a beneficial effect on breast tissue by decreasing breast cell proliferation and preventing stimulation by E2.

Although testosterone is breast protective, it can aromatize to E2 and have a secondary, stimulatory effect via estrogen receptor (ER) alpha.29

Friedman,30 reports that testosterone down regulates the Estrogen alpha receptor and may inhibit the proliferative effect of estrogen through this process.

Starting in the 1940s, androgen therapy was used to induce regression of breast cancer metastasis with promising results. Over time the use of androgen-based hormonal therapies were largely abandoned primarily due to testosterone’s masculinizing side- effects in some women albeit decreasing the dose or discontinuing use eliminated the side-effects.31-39

More recently, studies using exogenous Testosterone have shown that Testosterone in combination with estrogen may reduce, the risk of breast cancer. Dimitrakakis et al.40 followed 508 postmenopausal women receiving testosterone in addition to customary HRT in South Australia and found the addition of Testosterone reduced breast cancer incidence—to numbers lower than those observed in the general population who never took hormones.

Glaser et al.41 in the Dayton Study reported 8-year data using both testosterone and testosterone with anastrozole pellets finding a marked reduction in the incidence of breast cancer 76/100,000 women years in comparison to an age matched S.E.E.R. incidence rate of 297/100,000 women years.

RESOLUTION 5. Testosterone Insufficiency in Women Negatively Affect Sexuality, General Health and Quality of Life.

TestosteroneSupplementation May Positively Influence Sexuality, General Health and Quality of Life. Maclaran and Panay42 state testosterone has wide-ranging effects via androgen receptors, found throughout the body, including brain, skin, adipose tissue, vascular system and bone. Exogenous testosterone positively affects bone density, body composition, energy levels and psychological well-being.

Laumann et al.43 evaluated over 1700 women and estimated sexual dysfunction at 43%. It is biologically plausible that androgen insufficiency may play a role in a portion of these women. The percentage of these women complaining of low libido was substantial and varied little between 27-32% at various decades.

Basson et al.44 “It remains possible that testosterone deficit hinders desire and response but that its systemic production is of little relevance. Testosterone is produced de novo within the central nervous system starting from cholesterol. This production appears to be quite widespread within the central nervous system.” The molecular structure of the androgen receptor in women with and without sexual disorders has not been studied. “Not only would relative resistance of the androgen receptor theoretically impair testosterone activity and contribute to sexual dysfunction, but this could be accompanied by relatively high serum testosterone levels due to lessening of the hypothalamic pituitary ovarian axis negative feedback.” Goldblatt et al.45 conducted a randomized, placebo controlled crossover efficacy study using testosterone crème (10 mg/day) in premenopausal females with low libido and serum testosterone levels in the lower third of the reproductive range. It included women on oral contraceptives aged 30 to 45 years with total testosterone levels less than 2.2 nmol/l. (62.8 ng/dl). The treatment group showed improvement in wellbeing, mood and sexual function and a corresponding increase in serum testosterone and FAI.

Davis et al.46 showed that a daily 90ul dose of transdermal testosterone in sexually active women age 35 to 45 years with low libido and low circulating testosterone improved sexual satisfaction scores.

OCs reduce the level of free testosterone in a woman’s body by suppressing the production of testosterone in the ovaries and adrenals. OCs increase SHBG (sex hormone-binding globulin) levels, inhibiting the conversion of free testosterone to dihydrotestosterone (DHT). Due to increase in SHBG levels, free T levels decrease twice as much as total Testosterone47 according to a meta-analysis of the effect of combined OC on T levels in healthy women.

Glaser et al.48 demonstrated beneficial effects of testosterone therapy on somatic, psychological, and urologic complaints in both pre- and post- menopausal women. The validated Menopause Rating Scale (MRS) showed significant improvement in all 11 symptoms on the screening questionnaire during treatment period.

RESOLUTION 6. Testosterone Insufficiency May Be Associated with an Increased Risk of CVD in Women.

Testosterone insufficiency may increase cardiovascular risk in women. In 2007, Debing et al.49 reported on a study of endogenous sex hormone levels in postmenopausal women undergoing carotid artery endarterectomy. Significant association between low serum androgen levels and severe ICA atherosclerosis in postmenopausal women were found. Findings suggest that higher, yet physiologic levels of androgens in postmenopausal women may have a protective role against the development of atherosclerosis of ICA. In their review of the literature, Glaser and Dimitrakakis50 found substantialevidence that testosterone is cardio protective and adequate levels decrease the risk of cardiovascular disease. Unlike anabolic and oral, synthetic steroids, there is no evidence that human identical testosterone supplementation has an adverse effect on the heart. In fact, testosterone appears to improve blood flow to the coronaries and reduces atherogenic inflammatory markers and improves lipid profiles.

Jones and Saad51 note there is overwhelming biological and clinical evidence that testosterone supplementation is cardio protective.

Golden,52 reported that total levels of testosterone in women correlated inversely with carotid atherosclerosis. Her data confirmed reports by Bernini et al.53 showing women with highest endogenous testosterone levels had significantly lower risk for carotid atherosclerosis.

Møller and Einfeldt54 note testosterone therapy has beneficial effects on lean body mass, glucose metabolism and lipid profiles in men and women; and has been successfully used to treat and even prevent CV disease and diabetes.

Rosano et al.55 and Worboys et al.56 report that testosterone acts as a vasodilator in both sexes, has immune-modulating properties that inhibit formation of atheromata with beneficial effects on cardiac muscle.

Low Testosterone is an independent predictor of reduced exercise capacity and poor clinical outcomes in patients with heart failure. Testosterone supplementation has been shown to improve functional capacity, insulin resistance and muscle strength in women with congestive heart failure. 57

Miller et al.58 provide data suggesting that physiological level testosterone replacement in women with hypopituitarism for 12 months may improve insulin resistance. Chronic low-dose testosterone administration does not increase cardiovascular disease markers.

Spoletini et al.59 note in postmenopausal women, testosterone replacement within physiologic range is associated with improved overall wellbeing. A definitive explanation of how androgens impact cardiovascular health in postmenopausal women and whether they may be used as treatment has yet to be established. Evidence of favorable effect of androgens on surrogate cardiovascular markers in postmenopausal women, such as HDL cholesterol, total cholesterol, body fat mass, and triglycerides exists.

RESOLUTION 7. Testosterone Optimization May Be Brain Protective and May Enhance Cognitive Function.

C.J. Pike et al.60 reported the loss of the sex steroids in women is associated with increased risk of Alzheimer’s’ disease. Like estrogen, testosterone has neuroprotective effects on the brain. Testosterone increases neuronal resistance to the insults of Alzheimer’s disease and it reduces neuronal cell apoptosis preserving the life span of neurons as well as the reduction of beta amyloid production and accumulation.61

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