Androgens and Women

Testosterone 

  • Although testosterone is the most abundant biologically active hormone in women and its receptor, the androgen receptor, is located throughout the body, its role in female physiology is poorly understood.

  • Pharmacologic testosterone support has been utilized in the treatment of sexual dysfunction since the 1950s, and despite studies documenting its safety, there are no robust studies to support its widespread use.

  • Despite findings that testosterone stimulation of the androgen receptor in the breast leads to decreased breast tissue proliferation, concerns remain concerning the risk of breast cancer induction by pharmacologic testosterone support.

  • Androgen deficiency is a true medical condition in both pre- and post-menopausal women and unfortunately, there remains a scarcity of research on the topic. In addition to this lack of research, management of androgen deficiency in women can be missed unless a practitioner is astute to the the symptoms of androgen deficiency. The symptoms are many times non-specific and measurements of blood androgen levels may not reflect actual tissue levels. Additionally, normal serum levels have not been established for women.

  • Despite the above obstacles, the importance of androgens in women’s health is now being increasingly recognized and the conversation concerning androgen replacement for women is now gaining momentum. For women, both physical and mental health can be impacted by androgen levels. Past studies evaluating androgens in women have mainly focused on testosterone’s impact on hypoactive sexual desire disorder (HSSD). Some safety and efficacy data has been generated from the use of injectable testosterone and testosterone implants. Multiple studies have demonstrated an improvement in quality of life and sexuality in women who had used a continuous release of testosterone (T) from a subcutaneous implant delivery system.

    • Glaser R, York AE, Dimitrakakis C. Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS). Maturitas. 2011;68:355.

    • Kelleher S, Howe C, Conway AJ, Handelsman DJ. Testosterone release rate and duration of action of testosterone pellet implants. Clin Endocrinol. 2004;60:420–428.

    • Loeser A. Male hormone in gynaecology and obstetrics and in cancer of the female breast. Obst Gynecol Surv. 1948;3:363–381.

    • Greenblatt R, Hair L. Testosterone propionate pellet absorption in the female. J Clin Endocrinol. 1942;2:315–317.

    • Greenblatt RB. Testosterone propionate pellet implantation in gynecologic disorders. J Am Med Assoc. 1943;121:17–24.

    • Greenblatt RB, Suran RR. Indications for hormonal pellets in the therapy of endocrine and gynecic disorders. Am J Obst Gynecol. 1949;57:294–301.

  • Due to the dearth of studies of the impact that testosterone has on women’s health, controversy continues concerning the impact and safety of testosterone support for women. Safety concerns mainly relate to risks of cardiovascular disease and induction of malignancies, especially breast cancer. There are currently no clinical guidelines for the evaluation and management of androgens and testosterone in women.

Testosterone Production and Metabolism in Women

  • In the premenopausal woman, the ovary is responsible for about 50% of the testosterone that a woman has through production of testosterone and its metabolic precursors, androstenedione and DHEA. The other 50% arises from the adrenal glands through the production of testosterone’s metabolic precursor DHEA and DHEA-S. 

  • Testosterone levels begin to decline in a woman in her 30s, and as ovarian function further declines in perimenopause and menopause, testosterone levels also decline

Reported Symptoms of Androgen Deficiency in Women

  • Decreased sex drive

  • Depression

  • Weakness 

  • Low energy

  • Loss of lean body mass / muscle

  • Sleep disruption

  • Low bone mass

  • Low muscle mass

    • Davis SR, Wahlin-Jacobsen S. Testosterone in women—The clinical significance. Lancet Diabetes Endocrinol. 2015;3:980–992.

Testosterone Levels in Women

  • As in men, testosterone levels naturally decline with age, and a consensus of what constitutes a normal level for women does not exist. 

  • Some have suggested the following for androgen deficiency

    • Plasma total testosterone level of <25 ng/dL in women under 50 years old, and <20 ng/dL in women aged 50 or older 

    • Free testosterone assay by direct radioimmunoassay of a level of <1.5 pg/mL in women under the age of 50, and a level of <1.0 pg/mL in women over the age of 50

    • If the values are even slightly above these levels, a trial androgen support can be considered 

    • DHEA-S levels of <150 ng/dL in women under the age of 50 and DHEA-S levels <100 ng/DL in women aged 50 or older

  • Lower testosterone levels are associated with

    • Oral contraceptives

    • Steroid use

    • Anti-androgen medications

    • Oral estrogen therapies

    • Opioids

Treatment of Low Androgens in Women

  • Due to lack of studies and data, treatment of low androgens in women remains controversial. There are currently no FDA approved testosterone treatments on the market for women.

  • Since there are no FDA approved medications and any support of testosterone and DHEA in women must come from compounding pharmacies, or the measured use of male testosterone preparations, careful monitoring of serum levels should be undertaken.

Side Effects of Androgen Supplementation

  • Acne

  • Male pattern baldness

  • Excess hair growth

  • Deep voice

  • Enlarged clitoris

  • Since serum levels of E2 do not reflect the local production of estrogen, the clinical signs and symptoms of excess estrogen should be monitored, including breast pain, fluid retention, anxiety, emotional disturbances, irritability, aggression, and lack of effect from T therapy.

    • Glaser R, York AE, Dimitrakakis C. Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS). Maturitas. 2011;68:355–361,18.

    • Glaser RL, Dimitrakakis C. Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: A prospective, observational study. Maturitas. 2013;76(4):342–349.

    • Glaser RL, York AE, Dimitrakakis C. Reduced incidence of breast cancer with testosterone implant therapy: A 10-year cohort study. Proceedings of the 2018 San Antonio Breast Cancer Symposium. AACR; Cancer Res. 2019;79(4 Suppl.):Abstract nr P6-13-02.

    • Glaser RL, York AE, Dimitrakakis C. Incidence of invasive breast cancer in women treated with testosterone implants: A prospective 10-year cohort study. BMC Cancer. 2019;19:1–10.

  • Testosterone does increase red blood cell production, which can lower iron levels and contribute to iron deficiency—indirectly affecting hair. thyroid, iron, and ferritin levels are monitored.

  • The most common dose effects are acne and facial hair. Generally these side effects occur in women who are over replaced, however they can occur in the normal range in some women who may be more sensitive to testosterone replacement. With levels that are over replaced, fluid retention can occur as well as an abnormal lipid profiles. As some testosterone is converted into estrogens, there has traditionally been a concern over women who have had an estrogen dependent malignancy such as breast cancer, severe liver disease, or significant clotting issues. Women who are pregnant, or may become pregnant should not be prescribed testosterone or DHEA.

  • One major concern about testosterone therapy is hair loss, however studies have shown this not necessarily to be the case. In a questionnaire study of 285 patients, 48 of 76 (63%) patients complained of age-related hair loss before therapy and these patients were many times noted to have lower baseline T levels prior to initiating testosterone therapy. Some of these patients reported hair regrowth on T pellet therapy.

    • Glaser R, Dimitrakakis C. Testosterone therapy in women: Myths and misconceptions. Maturitas. 2013;74:230–234.

    • Glaser RL, Dimitrakakis C, Messenger AG. Improvement in scalp hair growth in androgen-deficient women treated with testosterone: A questionnaire study. Br J Dermatol. 2012;166:274–278.

  • A prospective study specifically designed to investigate the effect of T implant therapy on the female voice demonstrated that therapeutic doses of T—resulting in “supra physiological” T levels—had no adverse effect on the female voice, including lowering or deepening of the voice.

    • Glaser R, York A, Dimitrakakis C. Effect of testosterone therapy on the female voice. Climacteric. 2016;19:198–203.

Androgen Supplementation

These products are not widely used for women because they are not standardized and levels of testosterone have to be monitored carefully.

  • Cream

    • Although not officially approved for use by women in the United States, various pharmacies can compound testosterone in a cream or 1% gel form, as these have been approved for men. These can be applied to the inner thighs, back of the knee, inner arm, vagina or vulva.

  • Troche

    • A preparation that is absorbed under the tongue and can be used once or twice a day.

  • Suppository

    • Vaginal suppositories can be employed. They are typically used once a day.

  • IM injections

    • Intramuscular injection of testosterone esters has been used in men for decades, and very small doses have been used in women. They are usually used on a monthly basis.

  • Pellets 

    • Used more widely in England and the Australia, there is some use in the United States. They are typically associated with the delivery of higher levels of testosterone and are inserted every 3 to 4 months.

  • Over the counter (OTC) DHEA.

    • As DHEA is the precursor for testosterone, DHEA may have some benefit for women.

    • Data has been published using an OTC oral DHEA for androgen replacement

    • The dose usually begins with a 50-mg dose of OTC oral DHEA each morning, and the total and free testosterone, and estrogen levels monitored regularly. If therapeutic testosterone levels are not reached and symptoms persist, the dosage may be increased to 75-mg  to 100 - mg DHEA a day.  

Androgen Replacement can Improve Quality of Life

  • DHEA has recently been used to treat women who have adrenal insufficiency and it has been found to improve general energy, well-being and sexuality. It has also been noted to improve sexual function when used for prolonged periods of time (12months).

  • Benefits of testosterone therapy have  been reported with testosterone pellets include:

    • Improvement in QOL on both pre and post menopausal women such as improvement in depressive mode, anxiety, irritability, hot flashes, vaginal dryness and urology symptoms.Higher doses of testosterone correlate with greater improvement in symptoms. In a study of the effectiveness of testosterone, there were no adverse drug events reported in 285 patients treated for >1 year (mean 28.1 ± 10.4 months). These benefits are consistently seen in clinical practice

      • https://www.liebertpub.com/doi/10.1089/andro.2021.0003#core-B46.

    • It has been hypothesized through the actions of the adrogen receptor that testosterone is neuroprotective. This neuroprotective effect is consistent with experience reported in the literature that  “self-reported” memory issues are improved on therapy, and returned toward the end of the testosterone implant cycle. Essential tremors are also improved on testoserone therapy. Testosterone has been also demonstrated to improve migraine headaches for some women.

      • https://www.liebertpub.com/doi/10.1089/andro.2021.0003#core-B46

Androgens and Breast Cancer

  • It is foundational to understand the physiology of testosterone in women’s health and wellbeing. Interestingly, testosterone implant therapy has been used in women since 1937 in doses of 50–400 mg without excessive androgenic effects and demonstrated safety in women with a history of breast cancer.

    • https://www.liebertpub.com/doi/10.1089/andro.2021.0003#core-B1.

  • Testosterone is the direct precursor for estrogen, as aromatases in tissues convert testosterone into estrogen.The main source of estrogen in postmenopausal women is the local conversion of testosterone to biologically active estrogen. Unlike adipose tissue, which can contribute to the circulating pool of estrogens, estrogens from local aromatization would not be measurable in serum.

    • Labrie F, Martel C, Balser J. Wide distribution of the serum dehydroepiandrosterone and sex steroid levels in postmenopausal women: Role of the ovary. Menopause. 2011;18:30–43. Simpson ER. Sources of estrogen and their importance. J Steroid Biochem Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol. 2001;45:S116–S124.

  • Although some epidemiological studies have shown an “association” between endogenous T levels and breast cancer risk, there is no evidence that T treatment causes breast cancer. Other factors associated with naturally higher levels of T may be contributing to this elevated risk.

    • Davis SR, Baber R, Panay N, et al. Global consensus position statement on the use of testosterone therapy for women. J Clin Endocrinol Metab. 2019;104:4660–4666. 17. Glaser R, Dimitrakakis C. Testosterone and breast cancer prevention. Maturitas. 2015;82:291–295. Glaser RL, Dimitrakakis C. Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: A prospective, observational study. Maturitas. 2013;76(4):342–349. Glaser RL, York AE, Dimitrakakis C. Reduced incidence of breast cancer with testosterone implant therapy: A 10-year cohort study. Proceedings of the 2018 San Antonio Breast Cancer Symposium. AACR; Cancer Res. 2019;79(4 Suppl.):Abstract nr P6-13-02.

  • One of the major safety concerns of androgen therapy is whether androgens have a stimulatory effect on the breast that could lead to breast carcinomas. The proposed mechanisms for such stimulation include local estrogen production from the aromatase enzyme complex present in the breast tissue or by the direct stimulation of the androgen receptor. Predominant data from in vitro studies have shown that androgens actually have apoptotic and antiproliferative effects and not stimulatory effects. Animal models have shown similar results to in vitro studies, finding that androgens inhibit breast cancer growth. Prospective and retrospective epidemiological analyses have shown mixed outcomes, with no clear consensus regarding androgen use and breast cancer risk

  • Animal studies have shown that the addition of T to estrogen/progestogen hormone replacement therapy attenuates the proliferative effects of estrogens on breast tissue. 

    • Dimitrakakis C, Zhou J, Wang J, et al. A physiologic role for testosterone in limiting estrogenic stimulation of the breast. Menopause. 2003;10:292–298. In a retrospective, observational study that followed 508 postmenopausal women receiving testosterone in addition to usual hormone therapy in South Australia, breast cancer incidence was not increased, and lower when compared to those who did not use testosterone, with an average follow-up of 5.8 years.Dimitrakakis C, Jones RA, Liu A, Bondy CA. Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy. Menopause. 2004;11:531–535. This lead the investigators to conclude that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk.

  • A prospective study of 1267 individuals undergoing testosterone implant therapy, at 10 years there was a reduced incidence of invasive breast cancer in women treated with testosterone therapy. Withdrawal of T therapy led to an increasing trend toward diagnosis of clinically active tumors over time suggesting that T may reduce the progression of undetected cancers.

    • Glaser RL, York AE, Dimitrakakis C. Reduced incidence of breast cancer with testosterone implant therapy: A 10-year cohort study. Proceedings of the 2018 San Antonio Breast Cancer Symposium. AACR; Cancer Res. 2019;79(4 Suppl.):Abstract nr P6-13-02. Glaser RL, York AE, Dimitrakakis C. Incidence of invasive breast cancer in women treated with testosterone implants: A prospective 10-year cohort study. BMC Cancer. 2019;19:1–10.

  • The use of testosterone in combination with an aromatase inhibitors has also been reported on, in which a lower risk of breast cancer was again noted in those treated with testosterone and an AI. The combined use of T and an AI provides women with the beneficial effects of T without compromising these results with the conversion of T to estrogens and their possible adverse effects in estrogen-dependent diseases, for example, hormone receptor-positive breast cancer.

    • Glaser RL, Dimitrakakis C. Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: A prospective, observational study. Maturitas. 2013;76(4):342–349.

  • Data presented at the American Society of Clinical Oncology conference demonstrated the beneficial effects of T on the relief of severe hormone deficiency symptoms in breast cancer survivors utilizing testosterone with an AI. During this treatment strategy estrogen levels were also closely monitored and were not noted to be elevated. In addition, a reduced incidence of breast cancer recurrence was noted in the patients treated with T + AI.

    • Glaser RL, York AE, Dimitrakakis C. Efficacy of subcutaneous testosterone on menopausal symptoms in breast cancer survivors. J Clin Oncol. 2014;10(32):109 E2 levels were monitored and remained low.

The androgens Receptor may be a Tumor Suppressor in Breast Cancers

Safety Studies for Testosterone

  • the preponderance of data suggests that testosterone use in females is not associated with an increased risk of breast carcinoma.

    • https://pubmed.ncbi.nlm.nih.gov/18714077/

  • In a study of 641 women who became menopausal as a result of surgery and received transdermal testosterone therapy and estrogen, found no significant increase in the occurrence of major adverse effects over an approximately 4-year follow-up;

    • Gynecol Endocrinol. 2011;27:39-48

  • The ADORE Trial, a randomized, placebo-controlled trial, included 272 naturally menopausal women who received transdermal testosterone (300 µg) or placebo for HSDD twice a week for 6 months, and most participants were not taking other hormone therapy. No occurrences of breast cancer, myocardial infarction, or death were reported during the trial; however, there was no post-termination follow-up. There were significant improvements in various measures of satisfying sexual episodes in the testosterone-treated group.

  • In a double-blind, placebo-controlled 52-week trial of 464 postmenopausal women with low libido who were not taking estrogen and received transdermal testosterone (150 or 300 µg/day) or placebo. four cases of breast cancer occurred in the testosterone group; however, one case developed within the first 4 months of the study and one case had symptoms prior to randomization. One of the patients reported having a sister who was also at risk of breast cancer, and one patient took 300 µg/day of testosterone for 104 weeks as part of a treatment extension. There were no occurrences of breast cancer in the placebo group. Compared with placebo, there was a significantly greater increase in satisfying sexual episodes in the testosterone 300 µg/day group (P < .001) but not the testosterone 150 µg/day group (P = .11).

Testosterone Use in Transgender Men

  • Safety data can also be derived from the treatment of transgender men with testosterone. Significantly higher (male) doses of tesotsterone do not increase the risk of cardiovascular events, stroke, cancer—and increase insulin sensitivity.

    • Sharma R, Oni OA, Chen G, et al. Association between testosterone replacement therapy and the incidence of DVT and pulmonary embolism. A retrospective cohort study of the Veterans Administration Database. Chest. 2016;150(3):563–571.

    • Jones TH, Kelly DM. Randomized controlled trials–mechanistic studies of testosterone and the cardiovascular system. Asian J Androl. 2018;20(2):120–130.

    • Gooren LJ, t'Sjoen G. Endocrine treatment of aging transgender people. Rev Endocr Metab Disord. 2018;19:253–262.

    • Irwig MS. Cardiovascular health in transgender people. Rev Endocr Metab Disord. 2018;19:243–251.

    • Shadid S, Abosi-Appeadu K, De Maertelaere A-S, et al. Effects of gender-affirming hormone therapy on insulin sensitivity and Incretin responses in transgender people. Diabetes Care. 2020;43:411–417.

    • Traish AM, Gooren LJ. Safety of physiological testosterone therapy in women: Lessons from female-to-male transsexuals (FMT) treated with pharmacological testosterone therapy. J Sex Med. 2010;7:3758–3764.

Society Guidelines

  • While some safety data exists for testosterone and benefits can be significant, the data is not extensive. The Global Consensus Position Statement on the Use of Testosterone Therapy for Women—which was widely publicized by specialty societies—lists hypoactive sexual desire disorder/dysfunction as the “only evidence-based” indication for testosterone therapy.

    • Davis SR, Baber R, Panay N, et al. Global consensus position statement on the use of testosterone therapy for women. J Clin Endocrinol Metab. 2019;104:4660–4666. 

  • Concerns have been similarly raised by clinicians who are actively engaged in the clinical care of women over the Endocrine Society Guidelines relating to androgen replacement. Unfortunately, studies concerning testosterone and tesotsterone implant therapy often include heterogeneous populations, have variable dosing, and have different outcome measurements leading professional societies to be hesitant concerning the risks and benefits of testosterone replacement.

    • https://www.liebertpub.com/doi/10.1089/andro.2021.0003

  • Reduced or lack of libido is very common in menopausal women. The National Institute for Health and Care Excellence (NICE) guidelines state that testosterone supplementation can be considered for menopausal women with low sexual desire if hormone replacement therapy (HRT) alone is not effective.2The British Menopause Society (BMS) 2016 recommendations advise that this indication could be extended to include menopausal women with low sexual desire and tiredness.

    • Should we be prescribing testosterone to perimenopausal and menopausal women? A guide to prescribing testosterone for women in primary care Br J Gen Pract. 2020 Apr; 70(693): 203–204.

Measuring T levels

  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182226/

The Future

  • It has been demonstrated that women may have symptoms of androgen insufficiency

  • Testosterone can help women with physical and mental health

  • Testosterone can be delivered in a safe manner

  • Additional high quality studies are required to further define the safety and efficacy of testosterone replacement