Long-term testosterone pellet insertion in women with low libido shows no evidence of erythrocytosis and a minimal side effect profile
Highlight box
Key findings
• Peak testosterone levels occurred within the first 6 months.
• No significant changes were observed in hematocrit levels in either cohort.
• There were no statistically significant differences in systolic blood pressure between baseline and end-of-study measurements in either cohort.
What is known and what is new?
• Testosterone replacement for women is limited to its use in treating low libido and hypoactive sexual desire disorder.
• The pellet formulation in females effectively maintains stable hormonal levels over the long term, offering a low maintenance therapeutic option.
What is the implication, and what should change now?
• It offers patients and providers a clearer understanding of formulation options and supports the safety profile for long-term testosterone therapy in women.
Introduction
Androgens, particularly testosterone, play a crucial regulatory role in women’s health. Contrary to common misconceptions, testosterone is the most predominant hormone in the female body, produced at approximately 1,000 times the quantity of estrogen. However, due to widespread misunderstanding, the significance of testosterone in female physiology is often overlooked, particularly in relation to its role in both normal function and dysfunction.
Androgen deficiency in women can manifest as a range of symptoms, including fatigue, reduced energy, cognitive impairment, and sexual dysfunction, such as low libido (1). Low libido, while frequently discussed, is not a formal diagnosis; rather, it is a broad term used to describe the subjective experience of diminished sexual desire. In contrast, hypoactive sexual desire disorder (HSDD) is a clinical diagnosis characterized by a persistent or recurrent deficiency of sexual desire that causes significant distress or interpersonal difficulties, as defined by the DSM-V (2).
The management of low libido and HSDD typically involves a multifaceted approach, integrating both non-pharmacological interventions such as cognitive-behavioral therapy (CBT) and sexual therapy, as well as pharmacological treatments such as flibanserin and bremelanotide. Hormone replacement therapy (HRT), particularly involving estrogen and progesterone, is often the first line of treatment. However, recent evidence suggests that testosterone therapy may be particularly beneficial for menopausal women with HSDD (3). Despite these promising findings, testosterone therapy has not yet been approved for use in women, primarily due to the lack of an officially sanctioned formulation (3).
Testosterone pellets were first introduced in the 1950s as a compounded hormone replacement therapy for women, and research has since supported their efficacy and safety (3). Pellets help maintain more stable testosterone levels compared to other delivery methods. A retrospective review of over 1 million pellet implantation procedures over seven years found that complications, such as pellet extrusion, infection, or bleeding, occurred in fewer than 1% of cases. However, concerns remain regarding elevated testosterone levels exceeding physiological norms after implantation (4). While further modifications to the formulation are needed to better align with women’s specific hormonal needs, testosterone pellets remain a viable and convenient option due to their long-lasting effects and minimal required maintenance.
This study aims to expand our understanding of the biochemical effects and risk profile associated with testosterone pellet implants in women with androgen deficiency and HSDD. Conducted at Baylor College of Medicine, the retrospective chart review analyzed testosterone concentrations, dosage, and side effects in women treated with testosterone pellets for low libido. While further formulation adjustments may be needed to align with women’s specific hormonal needs, we hypothesize that testosterone pellets offer a favorable safety profile and remain a viable, long-lasting therapeutic option with minimal maintenance requirements. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-51/rc).
Methods
A Baylor College of Medicine study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its subsequent amendments. The research protocol was approved by Baylor College of Medicine Institutional Review Board with the approval number H-49807. Informed consent was not required as it was a retrospective chart review. The retrospective study was conducted in women 18 years or older, who underwent testosterone pellet insertion for the treatment of low libido between 2009 and 2022. Women who didn’t meet the follow-up criteria were excluded from the analysis. Participants were divided into two groups: (I) those who received 100 mg testosterone pellets; and (II) those who received 75 mg testosterone pellets.
This Institutional Review Board-approved (H-49807) retrospective chart review included the following data for all eligible patients: age, total serum testosterone concentration before and after implantation, number of pellets inserted, date of the first pellet insertion, interval between insertions, testosterone pellet dosage, hematocrit levels before and after treatment, and systolic blood pressure (SBP) before and after treatment.
Patient demographics, insertion details, pre-treatment hormone levels, blood parameters, and clinical data—including blood pressure and self-reported side effects—were analyzed separately for the 75 and 100 mg groups using descriptive statistics.
Statistical analysis
An analysis of variance (ANOVA) was conducted to assess statistically significant changes over the duration of the testosterone pellet’s effect.
The primary outcome measures included post-insertion total testosterone levels over the following months, as well as patient-reported clinical outcomes and side effects.
Results
Medical records from 31 female patients who underwent testosterone pellet insertion between 2009 and 2022 were analyzed in this study. Pre-insertion patient characteristics are detailed in Table 1.
Table 1
| Parameter | Value |
|---|---|
| Demographic | |
| Age (years) | 54.3±7.1 |
| Postmenopausal status | 24 (77.4) |
| Parity ≥1 birth | 19 (61.3) |
| Smoking (former) | 2 (6.5) |
| Clinical | |
| BMI (kg/m2) | 23.3±3.4 |
| Diabetes mellitus | 0 |
| Metabolic syndrome | 0 |
| Use of psychiatric medication | 6 (19.4) |
| Use of HRT: postmenopausal | 19 (61.3) |
| Use of HC: premenopausal | 2 (6.5) |
| Hormonal values pre insertion | |
| FSH (mIU/mL) | 63 [32.5–73.9] |
| LH (mIU/mL) | 34.2 [16.7–40.6] |
| Estrogen (pg/mL) | 18 [14.5–36.5] |
| Total testosterone (ng/dL) | 19 [12–66] |
| SHBG (nmol/L) | 71.9 [41.9–117.5] |
| Clinical values pre insertion | |
| HCT (L/L) | 40.5 [39.7–43] |
| SBP (mmHg) | 122 [108–149] |
Data are presented as mean ± standard deviation for normally distributed variables, median with interquartile range for non-normally distributed variables, and N with percentages for categorical variables. BMI, body mass index; FSH, follicle stimulating hormone; HC, hormonal contraception; HCT, hematocrit; HRT, hormone replacement therapy; LH, luteinizing hormone; SBP, systolic blood pressure; SHBG, sex hormone binding globulin.
Patient’s average age was 54.3 [standard deviation (SD) =7.1] years. A total of 220 pellet implantation procedures were performed, with 154 procedures (70%) utilizing 75 mg pellets and 66 procedures (30%) utilizing 100 mg pellets. The mean baseline total testosterone level for the 75 mg cohort was 64.21 ng/dL, while the 100 mg cohort exhibited a significantly lower mean baseline testosterone level of 21.81 ng/dL. This difference is attributable to the prior use of testosterone replacement in gel or cream form by the patients in the 75 mg cohort.
The mean interval between pellet insertions was 4.7 months (SE 0.1) over a 5-year period in the 75 mg cohort and 4.3 months (SE 0.1) over an 18-month period in the 100 mg cohort. In both cohorts, an average of one pellet was inserted per session (see Table 1).
Hormonal levels at various time points are illustrated in Figures 1,2. Peak testosterone levels were observed within the first 6 months in both cohorts, with mean trough values of 67.27 ng/dL for the 75 mg cohort and 68.23 ng/dL for the 100 mg cohort. These levels remained stable over the subsequent months. Notably, only the 100 mg cohort demonstrated a statistically significant increase in trough testosterone levels over the treatment period (P=0.01) further hormonal levels post insertion are illustrated in Tables 2,3 for 75 and 100 mg respectively.
Table 2
| Parameter | Value | P value |
|---|---|---|
| Hormonal values post insertion | ||
| Estrogen (pg/mL) | 17 [15–32.1] | 0.75 |
| Total testosterone (ng/dL) | 44 [20–74] | 0.51 |
| Clinical values post insertion | ||
| HCT (L/L) | 40.4 [39.2–43.5] | 0.96 |
| SBP (mmHg) | 124 [113–131.5] | 0.87 |
Data are presented as median with interquartile range for non-normally distributed variables. HCT, hematocrit; SBP, systolic blood pressure.
Table 3
| Parameter | Value | P value |
|---|---|---|
| Hormonal values post insertion | ||
| Estrogen (pg/mL) | 17 [17–23] | 0.64 |
| Total testosterone (ng/dL) | 31.5 [12–60] | 0.01 |
| Clinical values post insertion | ||
| HCT (L/L) | 39.6 [38.6–41] | 0.78 |
| SBP (mmHg) | 125 [113–136] | 0.70 |
The values for testosterone and estrogen are trough levels. Data are presented as median with interquartile range for non-normally distributed variables. HCT, hematocrit; SBP, systolic blood pressure.
For patients receiving 75 mg pellets, baseline hematocrit values averaged 41.71%, and no statistically significant variation was observed throughout the study period (P=0.96). Similarly, the 100 mg cohort exhibited a mean baseline hematocrit of 40.73%, with no significant changes over time (P=0.78). Importantly, no patients required therapeutic phlebotomies.
SBP was monitored across both cohorts throughout the study. Differences between baseline and end-of-study SBP measurements were not statistically significant, with a P value of 0.87 in the 75 mg cohort and P value of 0.70 in the 100 mg cohort.
Finally, patient-reported adverse events occurred exclusively in the 75 mg cohort. These events included mild facial hair growth 1 in 19 patients (5.3%) and vaginal bleeding reported in 2 out of 19 patients (10.5%).
Discussion
This study highlights the effects of low-dose testosterone administration in female patients experiencing low libido. Throughout the study, mean serum testosterone levels were consistently maintained, independent of the dosage administered. In the 75 mg cohort, baseline testosterone levels were elevated due to prior administration of more commonly prescribed formulations, such as gels or creams. Nevertheless, the transition to pellet therapy demonstrated a smooth continuation of stable testosterone levels.
Currently, there are no Food and Drug Administration (FDA)-approved treatments for managing low libido or HSDD in women, leaving no available formulations specifically designed for this purpose. In contrast, male testosterone replacement therapy (TRT) for hypogonadism offers various administration methods, including buccal, nasal, subdermal, intramuscular, and transdermal options. Female patients who use testosterone off-label must rely on higher-dose formulations intended for men, as women typically require only a fraction of the male dose to achieve physiological levels. Consequently, transdermal applications like gels or creams are preferred for titration, though they carry the risk of unintentional transmission to others (5). Women must take precautions to minimize this risk by thoroughly washing their hands and ensuring the application area is properly enclosed. One commonly reported side effect is localized virilization, often manifesting as increased hair growth and acne in the application area (5).
Testosterone pellets are typically administered at doses of 75–100 mg every 4 to 6 months (5). In a previous study by Buckler et al. (6), involving 30 women with a mean age of 53, administration of 100 mg pellets resulted in a peak testosterone level of 256 ng/dL at 1 month, which gradually declined to 83 ng/dL over the following 6 months. In contrast, our study demonstrated a more subtle peak of testosterone at 68.23 ng/dL at 6 months with 100 mg pellets, which remained stable through the study period. Furthermore, we observed that testosterone levels in patients receiving 75 mg pellets remained stable after transitioning from testosterone creams. These findings challenge the notion that low-dose testosterone pellets cause excessive spikes in serum testosterone levels.
One of the primary concerns regarding testosterone administration in women is its safety profile, specifically relating to cardiac risk which can manifest through hyperlipidemia, erythrocytosis, and hypertension. Although research is still inconclusive, a phase 3 study (7) published in 2012 reported a 0.72% incidence of cardiovascular events, including non-fatal stroke, non-fatal myocardial infarction, and venous thromboembolism, among 3,656 women aged 50 years or older. These women had cardiovascular risk factors such as hypertension and diabetes and were clinically diagnosed with HSDD. In addition to cardiovascular concerns, alterations in lipid profiles are another important consideration with exogenous testosterone use. A recent study by Islam et al. (8) demonstrated that non-oral testosterone formulations, such as gels, creams, and transdermal patches, maintained neutral LDL and HDL levels.
Our study also examined hematocrit levels as a marker for erythrocytosis, a commonly reported side effect in men undergoing testosterone therapy and a proposed mechanism for cardiovascular risk (9,10). Notably, neither dosage group in our study showed significant changes in hematocrit, highlighting a potential difference in testosterone’s effects between men and women. Erythrocytosis has been proposed as one mechanism contributing to cardiovascular risk in men on TRT (9,10).
The absence of this effect in women using low-dose testosterone suggests a lower risk of complications and a reduced likelihood of requiring blood donation due to elevated hematocrit levels, which is a well-established management in men (5).
Furthermore, many studies (11-13) of male TRT have shown a significant increase in SBP, prompting FDA warnings and guidelines to exclude patients with hypertension risk factors. In our female cohort, SBP remained stable across both dosage groups, showing no significant changes. This points to a key difference in how male-based data may not always translate to female patients, underscoring the need for more female-centered research. The limited available data suggests that appropriately dosed testosterone therapy in women is safe regarding blood pressure and erythrocytosis (14).
Another potential concern with testosterone therapy is androgenization. The extent of these effects can vary between individuals, influenced by their unique levels of 5-alpha reductase activity and androgen receptor (AR) density (15). A meta-analysis of testosterone transdermal patches in 3,035 participants demonstrated an increased risk of androgenic adverse events [hazard ratio 1.37; confidence interval (CI): 1.12–1.69], although the analysis combined individuals both on and off estrogen-progestin hormone therapy. In our study, 5.2% of participants in the 75 mg cohort reported mild increases in facial hair, while 10.5% experienced abnormal vaginal bleeding, with the latter group also noting concurrent systemic estrogen therapy. The potential synergistic effect of administering androgenic and estrogenic hormone replacement therapies simultaneously has not been thoroughly investigated but may explain these symptoms as well as the length of time in which treatment was administered. Nonetheless, the overall incidence of androgenization symptoms was low across both cohorts in our study.
It is well recognized that serum testosterone levels in women can vary significantly and are not commonly utilized as a primary diagnostic tool. However, measuring testosterone can serve as a valuable baseline indicator. When correlated with clinical symptoms, it offers a more holistic perspective, allowing clinicians to tailor treatment strategies more effectively. Maintaining testosterone at physiological levels minimizes the risk of adverse side effects and ensures a favorable safety profile.
A limitation of this study is its retrospective design, which led to non-standardized data collection during patient visits and variable follow-up durations for some participants. Additionally, due to its retrospective nature, we cannot accurately assess the extent of symptomatic improvement in all patients. However, the strengths of this study include its single-center design and the use of a single provider who consistently performed pellet insertions with the same technique. Additionally, most laboratory values were obtained from the same facility, reducing variability in testosterone measurements between patients or across different time points.
Despite its limitations, this cohort of 31 patients represents long-term data from a single institution, which is rare in the literature. Most studies conclude follow-up after 2 years. We hope this data provides clinicians and patients with a better understanding of testosterone replacement options for women, particularly in the context of long-term pellet therapy.
Future studies should prioritize developing guidelines for the use of testosterone therapy in female patients with low libido, HSDD, and androgen deficiency syndrome, as well as advancing the creation of a testosterone formulation specifically tailored to meet women’s needs.
Conclusions
Although testosterone is commonly prescribed off-label for treating low libido and HSDD in postmenopausal women, its therapeutic benefits extend beyond these specific conditions. Unfortunately, many women who do not meet the formal criteria yet could benefit from testosterone therapy are often overlooked. Conversely, those who do meet the criteria frequently receive off-label prescriptions, typically incurring out-of-pocket expenses. As the most bioavailable hormone in the female body, it is imperative that female-centered therapies are developed for all scenarios of hypoandrogenism encountered in female patients. This study provides further support for the safety profile of long-term testosterone therapy in women undergoing pellet insertion, whether as an initial or subsequent formulation. Additionally, it offers patients and providers a clearer understanding of formulation options, as pellets represent a low-maintenance therapeutic alternative for women.
Acknowledgments
The Abstract of this study was previously presented at SMSNA 2023.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-51/rc
Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-51/dss
Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-51/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-51/coif). M.K. is a consultant for Marius Pharmaceutical, Endo Pharmaceutical and Besins Healthcare as well as a stock own of Sprout. G.L. is the Founder and CEO of Young Medical PC, which is a for-profit medical practice. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. A Baylor College of Medicine study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its subsequent amendments. The research protocol was approved by Baylor College of Medicine Institutional Review Board with the approval number H-49807. Informed consent was not required as it was a retrospective chart review.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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