https://orcid.org/0000-0002-9952-4888
Abstract
Testosterone therapy (TTh) is recommended for postmenopausal women with hypoactive sexual desire disorder (HSDD); however, there remain insufficient data to support use of TTh in premenopausal women with sexual dysfunction.
In this study, we used a large national database to evaluate prescribing trends of TTh for women with HSDD.
We conducted a cohort analysis of information from electronic health records acquired from the data network TriNetX Diamond. The study cohort consisted of women 18-70 years of age with a diagnosis of HSDD. We analyzed trends of testosterone prescriptions, routes of testosterone administration, and coadministration of testosterone with estrogen.
Despite an increase in rates of testosterone prescriptions for HSDD, there remains a high degree of variability in the duration of treatment, route of administration, and coadministration of estrogen with significant underprescription of testosterone.
Our query of the TriNetX database led to the identification of 33 418 women diagnosed with HSDD at a mean age of 44.2 ± 10.8 years, among whom 850 (2.54%) women received a testosterone prescription. The testosterone prescriptions were highly variable with regard to duration and route of administration and coadministration with estrogen. For all patients until 2015, the prevalence of testosterone prescriptions for HSDD showed a positive quadratic relation was observed. Since 2015 a linear increase in prevalence was observed, with the highest rate of increase for patients aged 41-55 years.
The findings of this study reveal a significant need for further research investigating the optimal use of TTh to enhance the sexual health of women with HSDD, and further studies on the long-term effects of testosterone use must be undertaken to ensure that patients have access to safe and effective treatment.
Limitations to this study include patient de-identification and lack of availability of testosterone dosage data. However, this study also has many strengths, including being the first, to our knowledge, to characterize the prescribing trends of testosterone for women with HSDD.
Testosterone therapy should be considered as a potential therapy for premenopausal female patients with HSDD. Further studies on the long-term effects of testosterone use must be undertaken to address disparities in the management of HSDD and to ensure patients can access treatment.
Introduction
Hypoactive sexual desire disorder (HSDD) is the most common sexual health condition affecting women.1 This condition, which is present in close to 10% of all women, with prevalence increasing with age,2 was previously defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-4) as a persistent deficiency or absence of libido that causes marked distress without other identified causes or relationship difficulties. In the updated DSM-5, HSDD has been combined with the condition previously defined as “female sexual arousal disorder,” and this combination is now termed “female sexual interest/arousal disorder,”3 which is a condition with a physiological basis, not a purely psychosociological cause. It is well established that low levels of testosterone are associated with low libido in men, and that testosterone therapy (TTh) is both an effective monotherapy and a recommended treatment for bothersome low libido in these patients.4,5
Despite the known hypogonadal basis for sexual dysfunction in male patients and the clear rationale for TTh in male and female patients, nonpharmacologic options such as mental health counselors, sex therapists, and/or pelvic physical therapists are typically offered as initial treatment for patients. However, there are several available pharmacologic options, including androgen therapy. The use of TTh is currently recommended for postmenopausal women in the 2019 Global Consensus Position Statement on the Use of Testosterone Therapy for Women (2019 Global Concensus Statement)6–9 and supported by the International Society for the Study of Women’s Sexual Health in their Process of Care for the Management of HSDD.10 The Endocrine Society and American Congress of Obstetricians and Gynaecologists support the use of TTh in women only for the treatment of HSDD.11,12 Current level I, grade A evidence supports use of TTh to treat HSDD in postmenopausal women, with data showing meaningful improvements in female sexual function, including domains of sexual satisfaction, sexual desire, arousal, orgasm, and pleasure, with a decrease in sexual distress and minor adverse effects.13–16 Three placebo-controlled randomized clinical trials have also demonstrated positive outcomes of transdermal TTh in premenopausal women experiencing low libido, who showed improvements in sexual satisfaction, sexual function, overall well-being, and mood with TTh compared to placebo.17–19 However, it is important to note that these trials had limited sample sizes, leaving a gap in our understanding of the efficacy of TTh in a broader population of premenopausal women with sexual dysfunction.20
A large variation of formulations (testosterone, methyltestosterone) and delivery systems (oral, transdermal patch, topical gel, injectable) remain understudied.20 As such, testosterone use in women is not approved by the United States Food and Drug Administration, and there is no approved formulation for use in female patients.
The lack of an established treatment paradigm and of an approved and available female-specific formulation, in addition to the complexity and multifactorial nature of sexual dysfunction, may contribute to the scarcity of available data to guide interventions for female sexual function disorders. Further, physicians also report infrequently addressing female sexual dysfunction, citing factors such as a lack of confidence in guiding interventions, time constraints, and lack of available treatments as barriers to care.2 As such, we hypothesized that prescription availability and likelihood of compliance with TTh for HSDD faces several barriers in the United States. Research into current prescribing patterns will elucidate practice and management of this highly prevalent and distressing condition, which remains understudied. In the present study, we evaluated prescribing trends of TTh for women with HSDD by using a large national claims database.
Methods
Study design
We conducted a cohort analysis utilizing electronic health records (EHRs) acquired from the real-world data research network TriNetX Diamond (Cambridge, MA, United States). TriNetX provides access to electronic medical records supplemented with medical and pharmaceutical insurance claims for approximately 220 million patients from 92 healthcare organizations. Data used in this study were collected and analyzed as of December 2022. Information regarding demographics, diagnoses from International Classification of Disease (ICD-10) codes, and procedures from Current Procedural Terminology (CPT) codes were recorded and used for analysis.
TriNetX adheres to the Health Insurance Potability and Accountability Act (HIPAA) and has received a waiver from Western IRB as all patient data is de-identified as per the standard defined in Section § 164.514(a) of the HIPAA Privacy Rule. Any patient counts less than 10 have been obfuscated to ensure patient anonymity. Additionally, only aggregate patient counts and statistical summaries are provided to protect all patient health information and maintain de-identification.
Study participants
The TriNetX database was queried from 2009 through 2022. Selection criteria were based on ICD-10 codes. A patient was considered to have a diagnosis if the corresponding ICD code was linked to the patient’s EHR in the database. Our cohort consisted of women aged 18-70 years with a diagnosis of HSDD (ICD-10 F52.0), with exclusion of individuals with a diagnosis of intersex surgery female to male (CPT 55980), personal history of sex reassignment (Z87.890), or gender identity disorders (F64), and those with a prescription for testosterone (VA 10379) prior to the first HSDD diagnosis.
We analyzed trends of testosterone prescriptions, routes of testosterone administration, and coadministration of testosterone with estrogen. A patient was considered to have received a testosterone prescription if the first instance of testosterone prescription occurred after any instance of being diagnosed with HSDD. Coadministration with estrogen was defined as receiving a concurrent prescription of estrogen (HS300, GU500, or 4099) along with testosterone during the same clinic visit.
The significance of incidence over time, the incidence rate (prescriptions/person-day), was calculated by dividing the given incidence proportion numerator by the product of the given incidence proportion denominator and the number of days within the specific time interval. Incidence was calculated as the number of patients with new testosterone prescriptions during the time window, divided by the total number of patients with HSDD by the end of the time interval who had not received testosterone prescriptions prior to the time window of the analysis. Prevalence was calculated as the number of patients with testosterone prescriptions during the time window, divided by the total number of patients with HSDD by the end of the given time interval. All time analysis was conducted for time intervals of one-half year (365/2 days) from March 4, 2012, until September 1, 2020. Although the dataset was queried through 2022, no new HSDD diagnoses are reflected in the database after September 1, 2020. Sub/group analyses were conducted with the following defined age groups: 18-40 years for premenopausal, 41-55 years for perimenopausal, and 56-70 years for postmenopausal women. Pearson’s chi-square test was used to analyse significance of linear trends; P values less than .05 were considered significant.
Results
Our query of the TriNetX database identified 33 418 women (0.14% of those aged 18-70 years in the database) diagnosed with HSDD at a mean age of 44.2 ± 10.8 years; 573 (1.71%) of these females received their first testosterone prescription within 6 months after their initial diagnosis of HSDD, at a mean age of 47.8 ± 8.7 years.
Over a 3-year period after an initial HSDD diagnosis, a total of 761 female patients (2.28%) received an initial testosterone prescription, with a total of 850 (2.54%) receiving their first testosterone prescription at any point after their initial HSDD diagnosis. Of these 850 female patients, 378 received just 1 prescription for testosterone, 195 received 2-3 prescriptions, 161 received 4-9 prescriptions, and 116 received more than 10 prescriptions. Prescriptions for injectable testosterone were received by 54.24% (461) women, for topical testosterone by 30.24% (257), and for testosterone pellets by 14.00% (119), and 1.53% (13) women received prescriptions for testosterone with an unknown route of administration. Testosterone was coprescribed with estrogen in 162 female patients, with 159 women having a prescription for vaginal estrogen and 142 having a prescription for systemic estrogen.
The age groups of the 850 women who received their first testosterone prescription at any point after their initial HSDD diagnosis were as follows: 18-40 years (premenopausal, 66 women), 41-55 years (menopausal, 347 women), and 56-70 years (postmenopausal, 437 women).
Across all age groups, the incidence of testosterone prescriptions for HSDD exhibited considerable variability (Figure 1). Premenopausal patients were observed to have the lowest prescription rates. A substantial decrease in incidence of testosterone prescriptions, particularly for the postmenopausal age group, was observable in late 2015.
Incidence rate of testosterone prescriptions for HSDD across age groups.
Among all age groups, postmenopausal HSDD patients consistently exhibited the highest prevalence of testosterone prescriptions over the entire analysis period. Conversely, premenopausal patients consistently showed the lowest prevalence. A positive quadratic trend in the prevalence of testosterone prescriptions for HSDD was observed across all age groups until September 1, 2015, after which there was an observable decrease in prevalence compared to the expected forecast based on the polynomial trend line for all age groups. A positive linear trend in prevalence emerged from this point onward (Figure 2). Specifically, the slope of this linear trend was 0.0005 for the overall population (P < .0001), 0.0004 for both the premenopausal (P = .0002) and postmenopausal (P = .011) age groups, and 0.0009 for the perimenopausal (P < .0001) age group. R-squared values for all trendlines were upwards of 0.8 (values listed in Figure 2).
Prevalence of testosterone prescriptions for HSDD across age groups.
Discussion
For our analysis of prescribing trends for TTh in women with HSDD using a large national claims data, the initial findings demonstrated that 2.5% of this population was prescribed systemic testosterone, with highly variable patterns regarding duration, route, and coadministration with estrogen that likely resulted from a lack of guidelines.2 Moreover, long-term adherence to TTh remained low despite an increase in prevalence since 2015. These findings suggest that patients either find therapy unsatisfactory on an individual basis or discontinue it before experiencing noticeable benefits. Given the current lack of high-quality evidence concerning the ideal duration of TTh, patients are often left without clear guidance for their treatment. Consequently, the initiation of additional research efforts to ascertain the optimal duration of TTh is crucial.
Owing to a dearth of research, we attempted to elucidate patterns in testosterone prescriptions to better understand the complex and critical issue of therapy utilization. Intriguingly, the prevalence of TTh appeared to reach its zenith in the early 2010s, potentially aligning with the heightened interest in TTh for men that occurred between 2001 and 2011.21 Following this peak, the prevalence of TTh prescriptions declined in subsequent years, reaching its nadir in 2014-2015. Although the approval of Addyi® (flibanserin) for premenopausal patients with HSDD in 2015 may have initially sparked renewed interest in the diagnosis and treatment of HSDD, we observed a drop in TTh prescriptions from late 2015 to early 2016, accompanied by a decrease in TTh incidence.22 This drop coincided with emerging information about cardiovascular risks and FDA cautionary recommendations against TTh.23 Although research undertaken by the International Society for the Study of Women’s Sexual Health has since demonstrated that TTh is an effective method for managing HSDD in postmenopausal women and that TTh has a moderate therapeutic benefit for premenopausal women with HSDD, few data have been collected on the long-term effects of TTh.10 As such, broader implementation of TTh has remained elusive.
In this study, a linear increase in TTh prevalence since 2015 was observed, with the most significant rise occurring in the perimenopausal group. Surprisingly, the increases were similar in both the postmenopausal and premenopausal groups, even though most studies of TTh for HSDD have primarily involved the postmenopausal population. This finding might be attributable to potential underdiagnosis of HSDD in the postmenopausal group, possibly due to limited discussions regarding sexual function and increasing recognition of HSDD and its treatment options in the premenopausal group. Interestingly, the 2019 Global Consensus Statement did not appear to have a significant impact on the prevalence of TTh, but a slight increase in TTh incidence was observed shortly thereafter.6 More extensive data are necessary for comprehensive evaluation of the effect of the 2019 Global Consensus Statement on TTh prescriptions.
We postulate that the limited use of TTh may be attributable to conflicting evidence in the literature regarding safety, as well as no availability of an approve testosterone formulation for female patients. The UK Biobank Study revealed an association between endogenous testosterone levels and breast cancer.24 However, these findings were heterogeneous by menopausal status and their validity was questioned because an inaccurate test was used to measure female testosterone levels, indicating that further research is merited. In another study, Davis et al. (2008) assessed the efficacy and safety of testosterone for postmenopausal women with HSDD and reported incidences of breast cancer diagnosis after commencing TTh.14 While these findings have complicated the use of testosterone as an established therapy for HSDD, in a phase 3 randomized controlled trial of women who had undergone oophorectomy and were taking transdermal testosterone a lower-than-expected number of cardiovascular events and an expected incidence of breast cancer given the participants’ ages were found.25 The results of this study were published as a press release, rather than as a peer-reviewed publication, which limits the extent to which robust statements can be drawn from the findings.10,25 However, due to concerns pertaining to adverse effects associated with TTh, the US Food and Drug Administration has remained hesitant in approving testosterone as a treatment for HSDD in women. As a result, clinicians continue to face limited prescription options. Thus, longitudinal studies—observational or randomized control trials—are necessary to elucidate whether TTh is an effective means for treating HSDD.
In addition to the paucity of data, there are barriers to the implementation of testosterone from the patient’s perspective. As testosterone has not been approved for use in women with HSDD, it is not covered by insurance. This makes treatment options far more restrictive for patients seeking support. Our findings also indicate that long-term compliance with prescribed testosterone is low, suggesting that sustained testosterone use for HSDD may also be determined by patients’ willingness to adhere to therapy. The most common side effects of testosterone use include mild hirsutism and acne, which raises questions about whether latent messages are being promoted in clinical spaces that discourage women with HSDD from using testosterone.26
The lack of clarity about the efficacy and effectiveness of testosterone for women with HSDD, along with a lack of formal training surrounding HSDD and insufficient understanding of treatment, have led to a reality where women’s sexual health is given decreased prioritization. As few therapeutic treatments for women with HSDD exist, clinicians utilize off-label formulations of testosterone approved for men without a clear standard of care formulation.10 While the 2019 Global Consensus Statement advises against the use of pellets, injections, compounded preparations, or other formulations that could result in supraphysiological testosterone levels, our study revealed a diverse range of testosterone administration routes.6 These variations in administration may stem from the fact that the Global Consensus Statement was issued in 2019, whereas our cohort began earlier, or they could be attributable to the necessity of employing off-label formulations due to limited insurance coverage options for patients.
Along with increasing understanding the impact of HSDD on female sexual function through ongoing research, it is crucial that women with HSDD have greater access to treatment options. Testosterone and other androgens mediate various pathophysiological pathways which are crucial in secondary sex characteristic development and sexual maturation.10 Androgen receptors are widely expressed in the female central nervous system and reproductive tissues, suggesting that androgens may be prominent and critical regulatory molecules. While robust clinical data on the role of testosterone in moderating sexual function in women have not been collected, preliminary data have demonstrated that testosterone, but not estrogen, regulates brain activity linked to sexual motivation and reward behaviors.27 Estrogen alone has been shown to improve sexual function but not libido, while a combination therapy of estradiol and testosterone gel in postmenopausal women improved both sexual satisfaction and general mood.28 Further research is needed to obtain data on the efficacy, safety, and dosing of TTh in women with HSDD.
Clinical data collection has led to the development of preliminary guidelines for treatment of HSDD in women. In 2014, the Endocrine Society concluded that a 3- to 6-month trial of TTh with appropriate monitoring may be implemented for women with HSDD.11 Testosterone levels should be measured at baseline and after 3-6 weeks to determine endogenous levels; excess androgen levels would require cessation of TTh. If the patient has not responded to treatment after 6 months, TTh should be stopped. However, it should be noted that the Endocrine Society explicitly stated that limited longitudinal data restricted their suggested treatment duration to 24 months of use. Testosterone formulations for men are also discouraged for use in women with HSDD due to a lack of efficacy and effectiveness; however, these formulations are recommended by the 2019 Global Consensus Statement.6,11 Questions remain, therefore, regarding accessibility of treatment given that few options exist and these options are dependent on the patient’s sex, age, and menopausal status.
As such, testosterone should be prioritized as a potential therapy for women with HSDD, and further studies on the long-term effects of testosterone use must be undertaken to ensure that patients can access treatment. Without these data, clinicians and patients remain in a therapeutic conundrum where established testosterone treatment is unavailable but further studies to validate its use are rarely undertaken because of a concern for its efficacy. In particular, as HSDD is the most common sexual health issue affecting women, it is imperative that effective treatment methods are developed to assess the long-term safety and efficacy of TTh.1 If pharmacological treatments that have proven effective in treating HSDD in postmenopausal women are available, then studies to determine their efficacy in premenopausal women with HSDD should be developed.
The TriNetX database presented inherent limitations to this study, including de-identification for patient anonymity, which does not allow for investigation of individual factors that may have an impact on patient ability to obtain TTh, such as insurance coverage; reliable transportation; menopausal status; procurement of TTh not captured by the database, such as that received from compounding pharmacies; and dosage of testosterone. However, this study also has many strengths, including being, to our knowledge, the first to describe prescribing trends of testosterone in women with HSDD. The TriNetX Diamond Network also allows for significant generalizability on a national level by encompassing over 1.8 million providers who cover 99% of US healthcare plans. Further, the database can capture complete health information by linking patient identifiers from participating healthcare organizations to pharmaceutical data, insurance claims, and EHRs. We limited selection bias and increased the data generalizability by categorizing our cohorts via CPT and ICD-10 codes. While data about testosterone’s efficacy is limited, these analytics provide a robust framework for considering the next steps to address disparities in management of HSDD.
Conclusion
The study reported here presents evidence that reveals a dire need for further research in the field of women’s sexual health. As the number of prescriptions of testosterone for managing HSDD have increased, there must be further research into the mechanisms of action, efficacy, and long-term effectiveness of treatment. This demand is not new but is urgently needed more than ever. Thus, collaboration among researchers, clinicians, the US Food and Drug Administration, and advocacy organizations is imperative to ensure the health and well-being of many women with HSDD who currently do not have access to guaranteed therapy.
Funding
None declared.
Conflict of interest
None declared.
Data availability
None.
References
ACOG Practice Bulletin No. 119: Female sexual dysfunction.
