The benefits of testosterone therapy for menopausal symptoms

Abstract

Objectives

This study will address the effects of testosterone pellet therapy in menopausal women treated over a ten-year period.

Study design

A retrospective review of a single gynecologic practice was performed to evaluate patients treated with subcutaneous testosterone pellet therapy for androgen deficiency. Consent was obtained from all patients before pellet placement. Women completed a menopause rating scale (MRS) questionnaire prior to starting therapy and before the third pellet placement. Patients were treated every 3 months. Blood work was obtained prior to treatment, before the third pellet insertion and then yearly. Non-parametric analysis was performed using the Wilcoxon signed-rank test and the Bonferroni test was used to correct for comparisons across multiple domains. A p value of less than 0.05 was considered significant.

Main outcome measures

Scores on the MRS were calculated as medians and compared from the initial MRS to the subsequent MRS questionnaire. Patient’s age and peak testosterone levels were used to evaluate the effect of therapy on menopausal symptoms. Side effects from therapy were noted at follow-up visits.

Results

There were 78 patients who completed both MRS questionnaires. A comparison of results from the initial and subsequent MRS questionnaire showed that median scores were significantly reduced in all eleven categories of symptoms. Scores improved in all categories of patient age and peak testosterone levels. The most common side effects were acne and facial hair. These were treated with dose reduction and or spironolactone therapy.

Conclusions

The use of testosterone pellet therapy in women with androgen deficiency results in rapid and sustained relief of menopausal symptoms in all age groups and at all testosterone levels. Further studies are needed to optimize the use of testosterone in women with menopausal symptoms.

Highlights

• •Testosterone therapy relieves androgen deficiency symptoms.
• •Symptomatic relief of symptoms is independent of patient age and peak testosterone levels.
• •Symptomatic relief of symptoms is rapid and maintained for up to 10 years.
• •Testosterone therapy should be a front-line therapy for androgen deficiency in women.

Introduction

One of the most challenging, misunderstood, and undertreated conditions in medicine today is hormonal changes in menopausal women. Prior to the publication of the Women’s Health Initiative (WHI) study, menopausal symptoms were treated primarily with oral estrogen with or without medroxyprogesterone [1]. In the WHI study, women on estrogen or combined therapy did show significant improvement in their hormonal issues [1]. However, the WHI study showed a significant increase in the risk of developing breast cancer on combined hormonal therapy, dementia, deep venous thrombosis and cardiovascular events [1]. After the publication of the WHI study, there was a dramatic decrease in the prescribing of estrogen with or without progestins for menopausal symptoms in women due to these risks [2], [3].

For menopausal women using hormonal therapy, a recent study showed a significant benefit in reduced biological aging and decreased mortality from cardiovascular events while improving patient’s hormonal symptoms [4]. Hormonal therapy comes in many different forms and can be taken orally, applied topically, injected intramuscularly, placed subcutaneously or any combination of these. Testosterone therapy has been used to treat androgen deficiency symptoms in women for decades [5]. Symptoms of androgen deficiency include sexual dysfunction, dysphoric mood, physical fatigue, changes in cognition, memory loss, insomnia, hot flashes, rheumatoid complaints, vaginal dryness, and urinary complaints. Testosterone is found in women of all ages and does not decrease at menopause as abruptly as other female hormones [6]. Testosterone acts via the androgen receptor that is found in almost every major organ system in the body [7]. Testosterone has been shown to improve vasomotor symptoms and sleep disorders that can be treated with estrogen and/or progesterone but it also addresses the genitourinary symptoms, sexual dysfunction, and mood disorders associated with menopause [6], [8], [9]. Testosterone therapy has also been shown to decrease the risk for breast cancer in women in observational studies [10], [11]. Despite all this evidence, most consensus statements do not recommend the use of testosterone for the management of menopausal symptoms [12], [13]. The most common reasons for this are the lack of an FDA approved product for women and the lack of long-term safety data. This study will evaluate the risks and benefits of using subcutaneous testosterone pellet therapy for menopausal women in the setting of a community gynecologic practice.

Methods

This is a retrospective review of patients from a single gynecologic practice who were given subcutaneous testosterone therapy to treat hormonal imbalance. Patients were deemed eligible for hormonal therapy if their menopausal symptoms impacted their daily quality of life. Eligibility criteria are outlined in Table 1. Patients with only hot flashes and/or sleep disorders were treated with estrogen therapy. Patients with symptoms related to androgen deficiency were offered therapy with testosterone. These symptoms included low libido, sleep disturbance, loss of energy, muscle weakness and joint pain, hot flashes, vaginal dryness, bladder issues as well as psychosocial complaints of anxiety, irritability, and depression. From October of 2014 to December of 2024, 100 patients were identified who had been treated with subcutaneous testosterone pellet therapy for symptoms primarily related to androgen deficiency. After a thorough discussion and joint decision making concerning hormonal options, patients were consented for testosterone pellet therapy. Patients actively being treated for breast cancer, with unexplained vaginal bleeding, cardiovascular risks or with a known clotting disorder were excluded from treatment. Exclusion criteria are seen in Table 1.

Table 1.

Eligibility criteria for testosterone therapy.

Inclusion Criteria	Exclusion Criteria
1.Peri-menopausal or menopausal status 2.Vaso-motor symptoms 3.Androgen deficiency symptoms 4.Persistent or worsening menopausal symptoms on oral/topical hormones	1.Unexplained vaginal bleeding 2.Active breast cancer treatment 3.History of clotting 4.Liver dysfunction 5.Cardiovascular risks

Clinical charts were reviewed to obtain patient demographics including the patient’s age at the start of treatment, menopausal status, and previous use of hormonal therapy. Pretreatment evaluation included a full history and physical exam, CBC, Chem 12, total testosterone, and estradiol. Mammograms and PAP smears were reviewed in all patients. Patient dosing for testosterone pellet therapy was calculated using a standard formula based on ideal body weight (IBW). The initial dose is calculated in pounds by the formula: IBW (pounds) = 100 + 5(number of inches over 5 feet). The initial dose used is 1 mg/pound (or 2.2 mg/Kg).

Pellets were placed by the physician or physician assistant at regular intervals (12 weeks +/- 3 weeks). After the placement of adequate local anesthesia, pellets were placed under sterile conditions by trocar insertion in the subcutaneous tissue of the patient’s upper outer quadrant of the buttock. The incision was closed with steri-strips and a non-occlusive bandage. The number of times testosterone pellets were placed, the dose of pellets used, and the interval between pellet placement was recorded for each patient.

Severity of hormonal symptoms was quantified using the 11-category Menopausal Rating Scale (MRS). The MRS questionnaire was completed by patients before their initial pellet insertion and again prior to placement of the third dose of pellets. Patients rated their symptoms in each category on a scale with 0 being no symptoms, 1- being mild symptoms, 2 -being moderate symptoms, 3- being severe symptoms and 4- being extremely severe symptoms (Appendix 1). Patient’s scores in each category were recorded and compared to their subsequent scores following treatment. Patients were divided into three groups based on age and four groups based on peak testosterone levels to evaluate the effect these factors have on symptomatic relief by using the MRS scoring system.

Serum blood values were obtained 4 weeks after the initial dosing. Blood work included total testosterone, estradiol, complete metabolic panel, and a complete blood count. Blood work was then followed every 6–12 months based on the patient’s clinical course.

Side effects were recorded at each clinical visit and treated based on the patient’s history and condition. Testosterone doses were adjusted in small increments to address side effects or improve symptom relief when necessary. Spironolactone was used for patients with persistent facial hair and/or acne who did not respond completely to dosing changes.

Statistical analysis of comparative MRS scores was done using the non-parametric Wilcoxon signed-rank test. The Bonferri test was used to analyze data across multiple domains. The Spearman correlation was used for independence testing. Statistical significance was determined by a p value of less than 0.05.

Results

One hundred patients were identified who received subcutaneous testosterone pellet therapy. Patient demographics and pellet data are shown in Table 2. The median age was 52 years and the range was 38–68 years. Most patients (77 %) were menopausal while the remaining were peri-menopausal. There were 78/100 patients who had completed an initial and follow-up menopausal rating scale (MRS) evaluation. A follow-up MRS questionnaire could not be found in twenty patient’s charts and two patients had not done an initial questionnaire. Overall, 71/78 (91 %) patients showed an improvement in median MRS scores from a baseline of 17.0 to the second questionnaire of 7.0 (p < 0.0001). The median score for each category on the initial and subsequent evaluation is shown in Table 3. There were statistically significant changes from pretreatment values to post-treatment values in all 11 categories (p < 0.0001). The most significant changes were seen in women with sexual problems, anxiety, vaginal dryness, irritability, and physical and mental exhaustion.

Table 2.

Patient demographics.

Age (years)
Median Range Distribution < 50 50–59 60–68	52 38–68 n (%) 24 (24 %) 63 (63 %) 13 (13 %)
Menopausal Status Peri-menopausal Post-menopausal	n (%) 23 (23 %) 77 (77 %)
Number of Pellets Inserted
Median Range Distribution < 10 11–19 20–29 30 or more	14 2–46 n (%) 40 (40 %) 20 (20 %) 12 (12 %) 28 (28 %)
Interval between pellet insertions (weeks) Average	Weeks 15

Table 3.

Results from the Menopausal Rating Scale (MRS).

Symptom Category	Initial MRS Score (median)	Second MRS Score (median)	Significance (p value)*
Sexual Problems	2.5	0	< 0.0001
Depressive Mood	2	0	< 0.0001
Vaginal Dryness	2	0	< 0.0001
Physical/Emotional Exhaustion	2	1	< 0.0001
Hot Flashes Sweating	2	1	< 0.0001
Anxiety	2	1	< 0.0001
Irritability	2	1	< 0.0001
Sleep Problems	2	1	< 0.0001
Joint/Muscular Discomfort	1.5	1	< 0.0002
Heart Discomfort	1	0	< 0.0001
Bladder Problems	1	0	< 0.0001

^*All categories showed statistically significant improvement after Bonferroni correction for multiple domains.

The MRS scoring system was used to determine the effect of age and peak testosterone levels on symptomatic relief. Patients in all age groups showed significant improvement in overall MRS scoring (Table 4). The patients in the age group 50–59 had the most significant change. The Spearman correlation between age groups did not show significant differences in symptomatic outcomes between age groups (p = 0.16). Patients were divided into quartiles based on their peak testosterone levels. MRS scoring showed significant symptomatic relief in all four groups (Table 5). There was no correlation between testosterone levels and symptomatic relief based on the Spearman analysis (p = 0.37).

Table 4.

Age Related Response to Therapy Based On Total Score of MRS Questionnaire.

Age Group (yrs)	n	Median Improvement*
< 50	21	9
50–59	49	11
60–68	8	5

^*Spearman correlation did not show a significant association between symptom improvement and age category (p = 0.16).

Table 5.

Testosterone Related Response to Therapy Based on Total Score of MRS Questionnaire.

Quartile	Testosterone Range (mg/dl)	n	Median Improvement*
1	85.9–115.0	20	9
2	115.1–137.1	19	8
3	137.2–189.6	19	11
4	> 189.6	20	9

^*Spearman correlation did not show a significant association between peak testosterone levels and symptom improvement (p = 0.37)

Side effects related to testosterone therapy were seen in 58 patients (Table 6) with 28 patients reporting more than one side effect. The most common side effect was facial hair (43 patients) followed by acne (16 patients). The treatment for side effects was a reduction in testosterone dose. Patients were placed on spironolactone if side effects persisted after dose reduction. Laboratory results revealed 2 women who exceeded a hemoglobin of 15 mg/dl. Testosterone doses were reduced and both women were able to continue pellet therapy while monitoring hemoglobin levels. No patient required phlebotomy. Liver function tests (ALT, AST) were elevated in one patient. The patient was diagnosed with active hepatitis. Testosterone therapy was stopped and the patient elected not to continue therapy after resolution of her hepatitis. There were 14 patients who stopped pellet therapy before their sixth dose. The two most common reasons were geographic relocation (10 patients) and persistent side effects (4 patients).

Table 6.

Side Effects.

Side Effect	n	Percentage
Facial Hair	43	74.1
Acne	16	27.6
Hair Loss	5	8.6
Other	3	5.1

Mammograms were followed regularly in all patients and two patients developed breast cancer while on testosterone therapy. One patient developed Stage 1 breast cancer after 23 pellet placements and the other developed Stage 0 breast cancer after 18 pellet placements.

Discussion

Following the publication of the World Health Initiative (WHI) study in 2001 on the management of menopausal symptoms, there was a significant reduction in health care providers who were willing to prescribe hormones for symptomatic women in menopause [2], [3]. Recently, the Food and Drug administration initiated the removal of the black box warning for the use of hormonal therapy for women with menopausal symptoms that arose from the WHI study. After two decades of fear and trepidation, health care providers can now prescribe hormonal therapy for one of the most undertreated conditions in health care. Options for treatment vary among health care providers but the use of testosterone has gained popularity. Testosterone has been shown to be effective and safe in the treatment of androgen deficiency and it has been recognized to play a major part in relieving menopausal symptoms [5], [6], [8], [9].

There are two limitations in this observational study that may prevent it from being generalizable. The first is that the data came from a single gynecologic practitioner. The second limitation is the lack of strict objective criteria for eligibility for testosterone therapy. Historically, consensus statements for the treatment of menopausal symptoms with hormones have lacked strict inclusion criteria. In this study, the Menopausal Rating Scale [8] to assess symptom severity and to determine treatment outcomes should make this study more generalizable to all providers and address the subjective criteria used in consensus statements.

The onset of menopausal symptoms occurs in patients during their late forties and early fifties. Our data shows that women as young as 38 years may develop hormonal imbalance. Almost a quarter of the patients treated in this study were under the age of 50 years. It is important for physicians to realize the onset of menopausal symptoms may start earlier than expected and patients should be offered treatment if they so desire. Health care providers must not down play symptoms of androgen deficiency that persist or occur later in life as these can be debilitating. Our study showed 13 % of the patients did not start pellet therapy until the age of sixty.

Pellet insertion is recommended every 3 months for symptomatic relief. In this study, most women became aware of the diminishing effects of their pellet therapy as they approached their next pellet insertion. The median number of pellet insertions was 14 in this study and 28 % of patients had more than 30 pellet insertions. Most patients have been on therapy over 5 years. Therefore, testosterone therapy offers a durable treatment option for this population of patients.

The menopausal rating scale (MRS) has been used and validated in determining the outcome of testosterone therapy for women with androgen deficiency [8]. The MRS consists of 11 categories of menopausal complaints (Appendix 1). Potential patients use a score of 0–4 to define the severity of their symptoms. In our study, patients completed a MRS questionnaire before starting therapy and before the insertion of the third pellet. Median scores fell at least one full point in 10/11 categories from the first to the second questionnaire (Table 3). This difference was statistically significant in all 11 categories and persisted after correcting for multiple comparisons across categories. This confirms that testosterone had a rapid and profound impact on symptomatic relief in our patient population. The use of topical estrogens only addresses the issues of vaginal dryness and atrophy which makes testosterone a strong treatment choice for these patients.

The MRS scoring system was used to determine the effect testosterone had on patient’s symptoms based on age. Testosterone improved the overall median MRS score in all age groups (Table 4). The largest improvement in MRS scoring was seen in women aged 50–59 years and a significant difference was also seen in women over 60 years of age. Testosterone therapy is effective in symptomatic relief in all age groups for patients with androgen deficiency.

An additional variable that was investigated to determine the effect on symptom relief was peak testosterone levels. Patients were divided into four groups based on their levels. The total MRS score improved significantly in all quartiles (Table 5), suggesting that testosterone levels are not indicative of patient response to therapy. Our data confirms other studies which have shown that following testosterone levels is unnecessary and the management of patient’s symptoms should be based on clinical findings [6], [8], [9].

Side effects of therapy in this study occurred in slightly more than half of the patients. The most common side effect was facial hair accounting for over half of patient complaints (Table 6). Acne accounted for almost all the other patients with side effects. Initially, these patients were treated by decreasing testosterone dosing. Patients in both groups that did not improve were placed on spironolactone. Although most patients responded to management of their side effects, there were four patients who discontinued therapy due to persistent side effects.

Two patients developed breast cancer while on testosterone therapy. One patient was diagnosed with Stage 0 breast cancer and the other with Stage 1. Both patients have been treated and are in remission. It would be difficult to estimate the number of women who would be expected to develop breast cancer in this study but two patients do not seem excessive. Observational studies have shown that the use of testosterone pellets may decrease a women’s risk of developing breast cancer [10], [11].

This study’s findings suggest that testosterone pellet therapy is associated with meaningful improvements in menopausal symptoms across multiple domains. However, given the observational nature and limitations of this study, these results need to be interpreted cautiously. Further studies are needed to establish efficacy, determine optimal dosing strategies, to compare results to other treatment options and evaluate long term safety before testosterone can be recommended as a first line therapy for androgen deficiency.

CRediT authorship contribution statement

Catherine Cunningham: Writing – review & editing, Methodology, Formal analysis, Data curation, Conceptualization. John Cunningham: Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Data curation, Conceptualization. Colin Cunningham: Formal analysis, Data curation. Jillian Chan: Writing – review & editing, Methodology, Formal analysis, Data curation. Cunningham Julia E: Writing – review & editing, Data curation.

Declaration of Competing Interest

No author has a financial or personal relationship with any organization or persons that could inappropriately influence this work.

Appendix A. : Menopausal Rating Scale

Symptoms Score	None 0	Mild 1	Moderate 2	Severe 3	Extremely Severe 4
Hot flashes, sweating, episodes of sweating
Heart discomfort (unusual awareness of heartbeat, heart skipping, heart racing, tightness)
Sleep problems (difficulty falling asleep, difficulty in sleeping through the night, waking up early)
Depressive mood (feeling down, sad, on the verge of tears, lack of drive, mood swings)
Irritability (feeling nervous, inner tension, feeling aggressive)
Anxiety (inner restlessness, feeling panicky)
Physical and mental exhaustion (general decrease in performance, impaired memory, decrease in concentration, forgetfulness)
Sexual problems (change in sexual desire, in sexual activity and satisfaction)
Bladder problems (difficulty in urinating, increased need to urinate, bladder incontinence)
Dryness of vagina (sensation of dryness or burning in the vagina, difficulty with sexual intercourse)
Joint and muscular discomfort (pain in the joints rheumatoid complaints