Testosterone is a vital hormone that is produced by the ovaries, adrenal glands, and peripheral conversion of other hormones in the tissues (e.g. fat and skin) in women. After menopause the adrenal glands produce most of the body’s androgens and their precursors, but the ovaries still play an important role at all stages of life. 

Testosterone is involved in many important processes throughout the body including musculoskeletal health, mood, energy, cognitive function, cardiovascular health, glucose metabolism, sexual function, and libido. 

Naturally as women age, there is an overall decline in ovarian and adrenal function, leading to a gradual decrease in androgen production.  However, what may be shocking news to some is learning that there is a steady decline in testosterone production beginning in the early reproductive years, starting in her late 20s. By the time a woman goes through menopause she will have been experiencing this decline for 20 years or more.  

Natural ovarian menopause has been shown to have no effect on androgen levels, with age being the major cause of decline. However, when the ovaries are removed or damaged, such as in surgical or iatrogenic menopause (e.g. radiation or chemotherapy induced), testosterone can decline by up to 50% in some studies, highlighting the significance of postmenopausal ovarian androgen production. 

Why is this important?  Testosterone is an abundant hormone in women and is a significant source of hormonal activity. Testosterone can convert downstream to other biologically active metabolites to 5a-DHT, 5a-Adrostendione, Androsterone, Estrone, and Estradiol aiding in other processes in the body.  You can check out the enzymes involved in this conversion process by reviewing the Steroid Pathway Chart for more details.  

Although it is normal for testosterone levels to decline with age, low levels of testosterone in women can manifest in a variety of symptoms, including fatigue, decreased libido, sexual dysfunction, vaginal dryness, mood changes, brain fog, muscle weakness, decreased bone density, infertility, and complaints of overall decrease in sense of well-being.

What do the major associations say regarding testosterone therapy in premenopausal women?

A Global consensus position statement by Davis et al. in 2019 determined there is insufficient data to make any recommendations regarding the use of testosterone in premenopausal women for treatment of sexual function or any other outcome (Davis et al, 2019).

Current research of Testosterone (T) therapy use in pre/perimenopause is scarce.  Women with low T do not always have bothersome symptoms.  And women who are symptomatic with low T do not consistently see improvements with T therapy.  More research is necessary to determine safety, route of administration guidelines, dosing, and length of use with T therapy amongst all age groups.  Because there is a lack of data, major associations in the United States (US) cannot make recommendations. The use of T therapy in women remains “off-label” in the US.

Still, some women do see noticeable improvements in symptoms when using T therapy. In addition, the available studies have shown no adverse outcomes with the use of T therapy in pre/peri/postmenopause, when using doses that approximate physiological testosterone concentrations for premenopausal women. Keep in mind that no long-term safety studies have been conducted.

Total Testosterone Serum LC-MS/MS Reference Range:
Premenopausal adult females: 15-70ng/dL (Lab ranges may vary)

What do the major associations say regarding testosterone therapy in postmenopausal women?

The Global consensus concluded the only evidence-based indication for T therapy for postmenopausal women is for the treatment of Hypoactive Sexual Desire Disorder (HSDD) or generalized Female Sexual Dysfunction (FSD).  There is no testosterone level for diagnosis of HSDD or FSD or for the use as treatment target. Although research has shown benefits of T therapy, in doses that approximate physiological testosterone concentrations for premenopausal women, exert beneficial effects on sexual function (Davis et al, 2019). 

Other off-label use of T therapy has been reported for complaints outside of sexual dysfunction conditions such as, decreased sense of well-being, mood, cognitive decline, and musculoskeletal benefits resulted with insufficient data to show consistent results with symptom improvements or outcomes.  Improving serum levels to physiologically normal ranges for premenopausal women did not predict resolution of symptoms. 

There are no FDA-approved female formulations available for T therapy in the US. Although providers have used male-approved products at much lower doses – typically a dose adjustment of 1/10th of the recommended starting dose for men.  Compounding pharmacies are commonly used to provide female specific doses. Transdermal routes of administration are the preferred route for women.  Informed consent before prescribing T therapy for women should be obtained including risk to benefits due to the off-label use.

Due to different absorption rates and pharmacokinetics of testosterone formulations, regular monitoring is key for safe and efficacious treatment.  Testosterone levels and its effects on the body should be regularly monitored (Uloko et al, 2022).  Testosterone can impact liver function, hemoglobin/hematocrit, and lipid profiles.  It is beyond the scope of this blog to review all the contraindications for T use. Individualized care is suggested.

What is the best test to use for assessing testosterone levels in women experiencing low T symptoms?

Immunoassay testing is not sensitive enough to accurately capture the low concentration of testosterone in females. 

Rosner et al (2007), noted a task force by the Endocrine Society published a statement highlighting that testosterone values change with age and disease status as well as time of day and concluded that current normative values for women by direct immunoassays across the lifespan are not accurate and unreliable.

Many research studies have used the less accurate immunoassays, possibly contributing to the confusion about use of testosterone in females. Using the validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) serum assays have been shown to be the gold standard for testosterone testing in women.  Many researchers, including Rothman et al (2011), found that serum hormone levels (T, DHT, E2, and E1) measured by LC-MS/MS were lower than previously reported with the standard immunoassays commonly used by many laboratories.  

The LC-MS/MS high-sensitivity/specificity testing helps to capture low levels of hormones with better accuracy and less interference from other molecules than standard immunoassays. 

DUTCH urine testing uses LS-MS/MS testing for a comprehensive look at hormones and metabolites. Women in any life stage – pre, peri, postmenopause, can use DUTCH testing for hormone evaluation and be ensured of accuracy of results.

The DUTCH 4-spot urine test will reflect an average of circulating levels over 24 hours as well as metabolism patterns. DUTCH reports include 5a-androstanediol, a marker of androgen status in women, which is a direct metabolite of the most potent androgen 5a-DHT. You can read more about this important androgen metabolite here for more information.

The metabolism patterns showing the 5a-activation of testosterone can give insights into hormone activity at the tissue level and detoxification which relates to symptoms.  The unique metabolism pattern that each patient has can aid in identifying how sensitive a patient is to testosterone. For example, patients with high 5a-reductase activity may find lower doses more helpful to optimize levels while avoiding high androgen symptoms. A patient sensitive to androgens and favoring 5a-metabolism may experience higher rates of androgen excess symptoms (acne, facial hair, scalp hair loss, etc.).

For most, DUTCH results can provide androgen levels and metabolism, aiding in identifying androgen deficiency and metabolism. While the DUTCH test is an excellent complement to conventional labs, if urinary testosterone is low, it should always be confirmed with serum LC-MS/MS testing. Some people can have very low testosterone in urine but normal in serum. While this is by far the minority of cases, it is important to confirm low testosterone before initiating testosterone therapy. 

How can the DUTCH test be useful when monitoring T therapy in women?

Providers use the DUTCH test to help monitor:

1. Is testosterone level in the premenopausal range?
2. Is tissue androgen activity (5a-Androstanediol) normal?
3. Is there a preference for the more potent 5a-metabolism?
4. Is testosterone aromatization to estrogen appropriate?

Scenario 1: A common case is a patient using testosterone therapy for complaints of moodiness, depression, fatigue, weight gain, low libido, and/or vaginal dryness. She is still complaining of low androgen symptoms despite starting T therapy, and serum and urine levels are at the top of the premenopausal range. Many Associations suggest optimizing estrogen and progesterone levels before initiating T therapy as testosterone alone has not been shown to get consistent results with symptom relief.  This may help guide the provider to re-evaluate other parameters before increasing T dosages.

Scenario 2: A patient has been on T therapy for more than 6 months; serum and urine levels were within the premenopausal range.  However, she complains of androgen excess symptoms (acne, facial hair growth).  She shows a preference for 5a-metabolism pathways and has an elevated 5a-Androstanediol – indicating high androgen activity at the tissue level. The provider may not want to continue to raise T dosages as it may exacerbate symptoms and may even need to decrease dosages to prevent worsening symptoms if the patient continues to be sensitive to T therapy.  

Final thoughts

Testosterone therapy in women remains a nuanced area of clinical practice, requiring careful patient selection, individualized dosing, and close monitoring.  While not universally indicated, it may provide significant benefits for women with low testosterone related symptoms.  Continued research, evidence-based guidelines, and individualized care are essential to ensure safe and effective treatment.

Summary

• Testosterone levels begin to decline in the early reproductive years in women.
• Research for T therapy use in premenopausal women is lacking and therefore major associations cannot make recommendations regarding use in this population.
• Primary evidence for use of T therapy in postmenopausal women showed positive effects related to sexual dysfunction conditions such as HSDD or FSD.  
• Total Testosterone level should not be used to diagnose HSDD or FSD. However, baseline levels should be used for monitoring.
• Some data shows improvements in other areas such as wellbeing, mood, cognition, musculoskeletal effects, etc. Monitor symptom improvement and outcomes regularly.
• Informed consent should be obtained reviewing risks and benefits prior to T therapy.
• Serum total testosterone, using LC-MS/MS methods, is the gold standard for baseline and monitoring, while a urine androgen panel can complement serum by tracking androgen metabolism. 
• It is recommended to keep serum levels within premenopausal ranges when using T therapy.
• Total Testosterone Serum LC-MS/MS Reference Range: Premenopausal adult females: 15-70ng/dl (labs may vary).

References

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