COMPASS - COpenhagen MenoPAuSe Study (COMPASS)

Copenhagen Menopause Study (COMPASS): A Randomized Clinical Trial

During menopause, estrogen levels drop while the level of another hormone - LH (luteinizing hormone) substantially increases. This hormonal shift is linked to bone Loss and other complications. Estrogen therapy can help, but some women avoid it due to the increased risk of blood clots and cancer. This project will investigate whether blocking LH could offer a safe alternative to alleviate symptoms and complications of menopause since it is known from previous research that high LH levels contribute to both bone deterioration and metabolic issues. The goal is to explore new treatment options that can improve health and quality of life for women both during and after menopause. This randomized clinical trial is a single center, sponsor-investigator-initiated single-blinded 8 weeks clinical trial with four parallel groups comparing the effect of an gonadotropin releasing hormone(GnRH)-analog with placebo, and with two additional arms given estrogen or testosterone on change on bone health in postmenopausal women with moderate-to-severe symptoms.

Study Overview

• Status: Recruiting
• Conditions: Bone Markers; Menopausal Osteoporosis
• Intervention / Treatment: Drug: Triptorelin 11.25 mg; Drug: Placebo gel; Drug: Sodium Chloride 0.9%; Drug: Estradiol (E2); Drug: Testosterone

Detailed Description

The hormonal changes occurring in perimenopause and menopause exert multiple effects on several organs and the accompanied symptoms can be very distressing and impair quality of life. Vasomotor symptoms (VMS) defined as hot flashes and sweating are the most frequent and bothersome symptoms of menopause and are experienced by up to 80% of women. Additionally, in the Western world, 66% of postmenopausal women are obese and 54% have osteoporosis. Along with obesity comes a wide variety of health issues such as type 2 diabetes, metabolic syndrome, and atherosclerosis, which can lead to cardiovascular disease. Osteoporosis is a huge economic cost for society, it impairs quality of life and vertebral and hip fractures are associated with increased mortality. Postmenopausal symptoms and complications take a large toll on both the physical and mental well-being of women and are a huge cost to society. Menopausal Hormonal Therapy (MHT) with estrogen and gestagen is used by many women as it alleviates symptoms and reduces the risk of osteoporosis and cardiovascular disease. However, due to the increased risk of breast cancer and venous thromboembolism, some women refuse MHT and there is an ongoing search for new treatments. The newly approved Veoza® (Fezolinetant) is also approved and on the marked, but only targets VMS and not menopausal complications, but can be a treatment option, if the woman can or will not have MHT.

Menopause is characterized by low circulating estrogen, but also by very high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and these hormonal changes are linked with increased bone resorption and weight gain. Despite the high LH in menopause, LH pulses occur simultaneously with hot flashes also in postmenopausal women, and LH may be involved in the events. In a clinical study 10 postmenopausal women with severe VMS were given a GnRH antagonist cetrorelix 250 μg two times a day in 6 weeks. They found a significant decrease in VMS symptoms. Postmenopausal women experience a decline in core temperature, which we suggest is due to LH actions on brown and white fat cells leading to less heat generation, beta-oxidation, and more storing of fat. Furthermore, LH appears to be a rapid and potent inducer of renal calcium excretion, which induces a secondary and persistent increase in parathyroid hormone (PTH) that mobilizes calcium from the skeleton. The LH-induced calcium excretion occurs several hours before the subsequent changes in sex steroids, particularly estrogen, which indicates a direct effect of LH that can lead to increased bone resorption and eventually osteoporosis. This may be of great importance during the perimenopause/early phase of menopause, where the decrease in bone mineral density and increase in visceral adiposity is high concurrent with serum LH increasing dramatically, while serum estrogen is still not greatly reduced. The investigators propose to investigate if lowering LH using a gonadotropin releasing hormone (GnRH) analog against placebo can improve bone markers and secondarily reduce the frequency and severity of VMS in postmenopausal women with a direct comparison to estrogen - the gold standard treatment of women in menopause, and testosterone in the same RCT.

The main aim of the study is to show that by targeting LH the investigators can change bone markers and maybe even combat hot flashes and night sweats (VMS) in postmenopausal women. For important biological knowledge purpose, the investigators also investigate the 2 additional treatment arms with estradiol and testosterone to compare the effect against the current gold standard treatment option (estradiol) and to testosterone, which is a common supplement to postmenopausal women off-label. A study by Glaser et al. effectively documents that testosterone can improve most common post-menopausal symptoms.

Sample size calculation and statistics Previous studies have shown that CTX in postmenopausal women is usually between 0.44 ng/mL with a standard diviation on SD 0.2. The sample size is calculated based on a direct comparison between GnRH analog (pamorelin) and placebo on the primary outcome 'change in bone markers' (delta CTX between pamorelin and placebo), using a power of 80% and alpha of 0.05 leads to 44 participants in each group, and the investigators would be able to detect a change in CTX on 30 %. The calculations is based on only two arms, however for comparison reasons the investigators will include two extra arms with estradiol/testosterone and patients will be allocated 1:1:1:1 leading to a total sample size of 176 participants. Our design and analysis principles rely on the intent-to-treat (ITT) approach; the investigators strive to evaluate and include all randomized participants in the primary analysis, regardless of adherence to treatment assignment or protocol requirements.

The investigators estimate to screen 250 to include 192 to be randomized and 176 to complete the study leaving 16 patients for dropout (9%). The design enables us to investigate multiple secondary outcomes where the primary comparison will be between GnRH analog treatment and placebo. The study is not powered to show significant differences between placebo and GnRH treatment for most secondary endpoints and should be considered as a pilot placebo-controlled intervention study for these outcomes. T-tests will be used for the primary endpoint, while Nonresponder imputation will be used for missing response data. Change in mean frequency and severity of VMS per 24 hours will be analyzed for each week using a mixed effect model for repeated measures, with change from baseline as the dependent variable and treatment group, visit, and smoking status as factors and baseline measurement as a covariate, as well as interaction of treatment by week and an interaction of baseline measurement by week.

Predefined subgroups: Efficacy in patients with detectable versus undetectable serum hCG, high versus low LH at baseline, low versus high BMI, low versus high BMD, low versus high fat %.

Ethics and side effects All patients will be informed of potential adverse effects, and that they can leave the trial at any point without any consequences. GnRH-analogs have been proven safe in numerous randomized clinical trials (RCT) and have for many years been involved in the treatment of several groups including children with precocious puberty, transgender hormone treatment, and as part of in vitro fertilization. MHT have been tested in previously large RCT, where an increased risk of breast cancer and thromboembolic events have been detected. It is estimated that the risk of breast cancer increases with 0.5 % after 5 years of hormonal treatment. It is therefore regarded safe for participant in this trial to be treated with estrogen in 8 weeks however women with increased risk of cancer or thromboembolic events will be excluded. All side effects will be closely monitored and reported. The study will be approved by the regional ethical committee, conducted in compliance with The Declaration of Helsinki, registered on clinicaltrial.gov, and monitored by the GCP unit of Copenhagen University Hospitals in compliance with International Conference on Harmonisation.

• Study Type: Interventional
• Enrollment (Estimated): 192
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Martin Blomberg Jensen, D.M.Sc; Phone Number: +45 38 68 63 64; Email: martin.blomberg.jensen@regionh.dk
• Study Contact Backup: Name: Nadia Poulsen, MD; Phone Number: +45 38 68 63 64; Email: nadia.nicholine.poulsen.02@regionh.dk

Study Locations

• Denmark
  • Herlev, Denmark
    • Recruiting
    • Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital Herlev.
    • Contact: Nadia Poulsen, MD; Phone Number: +45 38 68 63 64; Email: nadia.nicholine.poulsen.02@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women >40 years and ≤65 at screening visit
• A body mass index between 18-35

• Confirmed menopause

  • Method 1
  • Spontaneous amenorrhea for ≥12 consecutive months
  • Negative urine hCG test
  • Method 2
  • Spontaneous amenorrhea for ≥6 months
  • FSH >30 mIU/L
  • Negative urine hCG test

• Moderate to severe vasomotor symptoms (VMS)

  • Within the 7 days prior to randomization, participants must report ≥ 14 moderate to severe VMS per week

Exclusion Criteria:

• Current or previous hormone replacement therapy (HRT)

  • Vaginal estradiol/vaginal inserts (e.g. Vagifem®) can be used, but will have to be pause 2 weeks prior to randomization and throughout the study period
  • Menopausal Hormone Therapy (MHT) can be used by participants, but must be paused 6 weeks prior to inclusion.

• Current or previous cancer diagnosis

  • Except for basal cell carcinoma
• Known BRCA gene mutation
• Current hyperthyroid disease
• Osteoporosis
• Major psychiatric diagnosis including ongoing medication e.g. selective serotonin re-uptake inhibitors (SSRIs)
• Known prolonged QT or other known clinically significant abnormal ECG, including taking medication that can prolong QT interval (e.g. sotalol, dronedarone, amiodarone, methadone, and several antipsychotic drugs)
• Previous myocardial infarction or heart failure
• Previous thromboembolic event
• The use of opioids, anticoagulating treatment or unwilling to pause fish oil/Omega-3 supplements 3 days prior visit 1 and 3
• Current alcohol or drug abuse
• Hypertension treated with more than two drugs
• Severe history of allergy, hypersensitivity, or intolerance to drugs
• Moderate to severe liver and kidney disease (eGFR <60 mL/min)
• Diagnosed with type 1 or 2 diabetes
• Chronic diseases requiring immunomodulatory treatments such as rheumatoid arthritis, inflammatory bowel disease, and vasculitis etc.
• Known uterine fibroids, Endometriosis, Systemic lupus erythematosus (SLE), otosclerosis, severe migraine or sleep apnea
• Known Epilepsy or previous seizures or convulsive disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GnRH analog; Pamorelin 11.25 mg intramuscular injection once + Daily placebo gel	Drug: Triptorelin 11.25 mg; Pamorelin 11.25 mg intramuscular injection once; Other Names: Pamorelin; Drug: Placebo gel; Placebo gel every day or every other day
Placebo Comparator: Placebo; Saline intramuscular injection once + Daily placebo gel	Drug: Placebo gel; Placebo gel every day or every other day; Drug: Sodium Chloride 0.9%; Saline intramuscular injection once; Other Names: Saline
Active Comparator: Transdermal Estrogen; Saline intramuscular injection once + Estreva gel 1.5 mg daily	Drug: Sodium Chloride 0.9%; Saline intramuscular injection once; Other Names: Saline; Drug: Estradiol (E2); Estreva gel 1.5 mg daily; Other Names: Estreva
Active Comparator: Transdermal testosterone; Saline intramuscular injection once + Tostran gel 10 mg every other day + placebo gel every other day	Drug: Placebo gel; Placebo gel every day or every other day; Drug: Sodium Chloride 0.9%; Saline intramuscular injection once; Other Names: Saline; Drug: Testosterone; Tostran gel 10 mg every other day; Other Names: Tostran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in bone remodeling from baseline to week 8.	Change in bone remodeling defined by change in bone marker (ΔCTX) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: GnRH analog and placebo-group.After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order:; Combined analysis of all 4 arms of the RCT; GnRH analog and estradiol; GnRH analog and testosterone; Estradiol and placebo; Testosterone and placebo; Estradiol and testosterone	From baseline to week 8
Change in bone remodeling from baseline to week 8.	Change in bone remodeling defined by change in bone marker (ΔP1NP) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	From baseline to week 8
Change in bone remodeling from baseline to week 8	Change in bone remodeling defined by change in bone marker-ratios (ΔCTX/ΔP1NP, and ΔBBI) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	From baseline to week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in quality of life evaluated with MENQOL-1 from baseline to week 8	Change in quality of life evaluated with The Menopause-specific Quality of Life (MENQOL) Questionnaire from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. MENQOL is ranging from 0 (asymptomatic woman) to 232 (extremely bothered).	Baseline to week 8
Change in sexual function evaluated with female sexual function index from baseline to week 8	Change in sexual function evaluated with female sexual function index (FSFI) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. The FSFI use a 5-point Likert scale with higher scores indicating greater levels of sexual functioning on the respective item. The possible range is 2-36.	Baseline to week 8
Change in sexual function evaluated with female sexual distress scale-revised from baseline to week 8	Change in sexual function evaluated with female sexual distress scale-revised (FSDS-R) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. FSDS-R has a total score ranging from 0 to 52, with higher scores indicating more sexually related distress.	Baseline to week 8
Change in depressive symptoms evaluated by MDI from baseline to week 8	Change in depressive symptoms evaluated by Major Depression Inventory (MDI) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Total score between 0 (no depression) to 50 (maximum depressed).	Baseline to week 8
Change in depressive symptoms evaluated by CES-D from baseline to week 8	Description: Change in depressive symptoms evaluated by Center for Epidemiologic Studies Depression Scale (CES-D) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Possible range of scores is zero to 60, with the higher scores indicating the presence of more symptomatology.	Baseline to week 8
Change in anxiety symptoms evaluated by GAD-7 from baseline to week 8	Change in anxiety symptoms evaluated by General Anxiety Disorder-7 (GAD-7) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Scores ranges from 0 (No anxiety) to 21 (severe anxiety).	Baseline to week 8
Change in thyroid hormones from baseline to week 4 and 8	Change in thyroid hormones from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8.
Change in serum hCG from baseline to week 4 and 8	Change in serum hCG from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in thyroid hormone conversion (DIO2 activity) in fat cells determined by their conversion of T4 to T3 from baseline to week 8	Change in thyroid hormone conversion (DIO2 activity) in fat cells determined by their conversion of T4 to T3 from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 8
Change in adrenal hormones from baseline to week 4 and 8	Change in adrenal hormones from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in the mean frequency of moderate to severe VMS from Baseline to week 8	Change in the mean frequency of moderate to severe VMS from Baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Definition of moderate VMS: Moderate VMS is defined as a sensation of heat with sweating/dampness, but the woman is able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Definition of severe VMS: Severe VMS is defined as sensation of intense heat with sweating, caused disruption of activity. If at night	Baseline to week 8
Change in the mean frequency of moderate to severe VMS from Baseline to week 4	Change in the mean frequency of moderate to severe VMS from Baseline to week 4. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Definition of moderate VMS: Moderate VMS is defined as a sensation of heat with sweating/dampness, but the woman is able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Definition of severe VMS: Severe VMS is defined as sensation of intense heat with sweating, caused disruption of activity. If at night	Baseline to week 4
Change in the mean severity-score from Baseline to week 8	Change in the mean severity-score from Baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Definition of mean severity-score of VMS: Severity score of moderate to severe VMS per day was calculated as follows: ((number of mild hot flashes per day x 1) + (number of moderate hot flashes per day x 2) + (number of severe hot flashes per day x 3))/Total number of daily hot flashes.	Baseline to week 8
Change in the mean severity-score from Baseline to week 4	Change in the mean severity-score from Baseline to week 4. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Definition of mean severity-score of VMS: Severity score of moderate to severe VMS per day was calculated as follows: ((number of mild hot flashes per day x 1) + (number of moderate hot flashes per day x 2) + (number of severe hot flashes per day x 3))/Total number of daily hot flashes.	Baseline to week 4
Change in physical strength tests from baseline to weeks 4 and 8.	Change in physical strength test measured by 30 second Sit-To-Stand-Test (STST) from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Unit: number of stands/30 seconds.	Baseline to weeks 4 and 8.
Change in physical strength tests from baseline to weeks 4 and 8.	Change in physical strength test measured by Hand-grip strength (HGS) from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. HGS will be evaluated using a digital hand-grip dynamometer measuring the absolute (kilograms-force) and relative (kilograms/weight in kilograms) grip strength	Baseline to weeks 4 and 8.
Change in serum levels of Hypothalamic-Pituitary-Adrenal (HPA) axis from baseline to week 8	Change in serum levels of Hypothalamic-Pituitary-Adrenal (HPA) axis from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 8
Change in serum levels of Hypothalamic-Pituitary-Gonadal (HPG) axis from baseline to week 8	Change in serum levels of Hypothalamic-Pituitary-Gonadal (HPG) axis from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 8
Change in serum levels of Hypothalamic-Pituitary-Thyroid (HPT) axis from baseline to week 8	Change in serum levels of Hypothalamic-Pituitary-Thyroid (HPT) axis from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 8
Change in The Mean Patient-reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b) from baseline to week 8	Change in The Mean Patient-reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Scores ranges from 8-40. Higher scores indicate more severe sleep disturbance.	Baseline to week 8
Change in urine calcium from baseline to weeks 4 and 8	Change in urine calcium from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to weeks 4 and 8
Change in urine creatinine from baseline to weeks 4 and 8	Change in urine creatinine from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to weeks 4 and 8.
Change in urine phosphate from baseline to weeks 4 and 8	Change in urine phosphate from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to weeks 4 and 8
Change in urine magnesium from baseline to weeks 4 and 8	Change in urine magnesium from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to weeks 4 and 8
Change in urine sodium from baseline to weeks 4 and 8	Change in urine sodium from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to weeks 4 and 8
Change in urine cortisol and other hormones from baseline to weeks 4 and 8	Change in urine cortisol and other hormones from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to weeks 4 and 8.
Change in serum ionized calcium from baseline to week 4 and 8	Change in serum ionized calcium from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in serum calcium from baseline to week 4 and 8	Change in serum calcium from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in serum albumin from baseline to week 4 and 8	Change in serum albumin from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in serum PTH from baseline to week 4 and 8	Change in serum PTH from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in serum phosphate from baseline to week 4 and 8	Change in serum phosphate from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in serum vitamin D metabolites from baseline to week 4 and 8	Change in serum vitamin D metabolites from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in VMS measured by the Greene Climacteric Scale (GCS) from baseline to week 8	Change in VMS measured using the questionnaire: The Greene Climacteric Scale (GCS) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone. Ranging from 0 (when every symptom is rated as "not at all") to a maximum of 63 (when every symptom is rated as "very often")	Baseline to week 8
Change in serum LH from baseline to weeks 4 and 8	Change in serum LH from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to weeks 4 and 8
Change in serum FSH from baseline to weeks 4 and 8	Change in serum FSH from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to weeks 4 and 8
Change in serum estradiol from baseline to week 4 and 8	Change in serum estradiol from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in serum SHGB from baseline to week 4 and 8	Change in serum SHGB from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in androgens from baseline to weeks 4 and 8	Change in androgens including 11 oxygenated androgens measured by LCMS from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone.	Baseline to weeks 4 and 8.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in fasting insulin from baseline to week 8	Change in fasting insulin from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 8
Change in HbA1C from baseline to week 8	Change in HbA1C (mmol/mol) from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 8
Change in HOMA-IR from baseline to week 8	Change in HOMA-IR from baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone.	Baseline to week 8
Change in total cholesterol, cholesterol (total, HDL, LDL), and triglycerides from baseline to week 4 and 8	Change in total cholesterol, cholesterol (total, HDL, LDL), and triglycerides from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in hepatic enzymes (ALAT, ASAT, GGT, alkaline phosphatase) from baseline to week 4 and 8	Change in hepatic enzymes (ALAT, ASAT, GGT, alkaline phosphatase) from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in QTc using electrocardiogram (ECG) at baseline to week 8	Change in QTc using electrocardiogram (ECG) at baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 8
Change in weight at baseline to week 8	Change in weight at baseline to week 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 8
Change in RNA expression (RNAseq) in abdominal fat (abdominal fat biopsies) from baseline to week 8 and following in vitro stimulation with hormones and treatments such as LH/hCG	Change in RNA expression (RNAseq) in abdominal fat (abdominal fat biopsies) from baseline to week 8 and following in vitro stimulation with hormones and treatments such as LH/hCG. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 8
Change in Cerebral Spinal Fluid (CSF) hormone, mineral or neuropeptide levels between all 4 treatment arms at week 8	Change in Cerebral Spinal Fluid (CSF) hormone, mineral or neuropeptide levels between all 4 treatment arms at week 8.	between all 4 treatment arms at week 8
Change in frequency and type of reported adverse events between baseline and week 4 and 8	Change in frequency and type of reported adverse events between baseline and week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline and week 4 and 8
Change in ECG pattern from screening to week 4.	Change in ECG pattern from screening to week 4. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Screening to week 4.
Change in serum RANKL from baseline to weeks 4 and 8	Change in serum RANKL from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to weeks 4 and 8
Change in serum creatinine from baseline to week 4 and 8	Change in serum creatinine from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in serum sodium from baseline to week 4 and 8	Change in serum sodium from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in serum potassium from baseline to week 4 and 8	Change in serum potassium from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in serum urea from baseline to week 4 and 8	Change in serum urea from baseline to week 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to week 4 and 8
Change in serum FGF23 from baseline to weeks 4 and 8	Change in serum FGF23 from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to weeks 4 and 8
Change in Klotho from baseline to weeks 4 and 8	Change in Klotho from baseline to weeks 4 and 8. The following primary, secondary and exploratory endpoints will all be investigated as comparisons first and foremost between: 1) GnRH analog and placebo-group. After the first analysis between GnRH-analog group and placebo, the outcomes will be investigated between the groups in the following order: 2) Combined analysis of all 4 arms of the RCT 3) GnRH analog and estradiol 4) GnRH analog and testosterone 5) Estradiol and placebo 6) Testosterone and placebo 7) Estradiol and testosterone	Baseline to weeks 4 and 8

Collaborators and Investigators

• Sponsor: Martin Blomberg Jensen
• Investigators: Principal Investigator: Martin Blomberg Jensen, D.M.Sc., Herlev Hospital

Publications and helpful links

General Publications

• Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006 May 22;166(10):1092-7. doi: 10.1001/archinte.166.10.1092.
• Rosen R, Brown C, Heiman J, Leiblum S, Meston C, Shabsigh R, Ferguson D, D'Agostino R Jr. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther. 2000 Apr-Jun;26(2):191-208. doi: 10.1080/009262300278597.
• Yu L, Buysse DJ, Germain A, Moul DE, Stover A, Dodds NE, Johnston KL, Pilkonis PA. Development of short forms from the PROMIS sleep disturbance and Sleep-Related Impairment item banks. Behav Sleep Med. 2011 Dec 28;10(1):6-24. doi: 10.1080/15402002.2012.636266.
• Monteleone P, Mascagni G, Giannini A, Genazzani AR, Simoncini T. Symptoms of menopause - global prevalence, physiology and implications. Nat Rev Endocrinol. 2018 Apr;14(4):199-215. doi: 10.1038/nrendo.2017.180. Epub 2018 Feb 2.
• Radtke JV, Terhorst L, Cohen SM. The Menopause-Specific Quality of Life Questionnaire: psychometric evaluation among breast cancer survivors. Menopause. 2011 Mar;18(3):289-95. doi: 10.1097/gme.0b013e3181ef975a.
• Greendale GA, Sternfeld B, Huang M, Han W, Karvonen-Gutierrez C, Ruppert K, Cauley JA, Finkelstein JS, Jiang SF, Karlamangla AS. Changes in body composition and weight during the menopause transition. JCI Insight. 2019 Mar 7;4(5):e124865. doi: 10.1172/jci.insight.124865. eCollection 2019 Mar 7.
• Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen EF, Guanabens N, Obermayer-Pietsch B, Ralston SH, Eastell R, Zillikens MC. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone. 2017 Dec;105:11-17. doi: 10.1016/j.bone.2017.08.003. Epub 2017 Aug 5.
• Nelson HD. Menopause. Lancet. 2008 Mar 1;371(9614):760-70. doi: 10.1016/S0140-6736(08)60346-3.
• Greene JG. A factor analytic study of climacteric symptoms. J Psychosom Res. 1976;20(5):425-30. doi: 10.1016/0022-3999(76)90005-2. No abstract available.
• Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, Dawson-Hughes B. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 2014 Nov;29(11):2520-6. doi: 10.1002/jbmr.2269.
• Davis SR, Hirschberg AL, Wagner LK, Lodhi I, von Schoultz B. The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving systemic estrogen therapy. J Clin Endocrinol Metab. 2009 Dec;94(12):4907-13. doi: 10.1210/jc.2009-1523. Epub 2009 Oct 22.
• El-Hage G, Eden JA, Manga RZ. A double-blind, randomized, placebo-controlled trial of the effect of testosterone cream on the sexual motivation of menopausal hysterectomized women with hypoactive sexual desire disorder. Climacteric. 2007 Aug;10(4):335-43. doi: 10.1080/13697130701364644.
• Goldstat R, Briganti E, Tran J, Wolfe R, Davis SR. Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women. Menopause. 2003 Sep-Oct;10(5):390-8. doi: 10.1097/01.GME.0000060256.03945.20.
• Moller MC, Radestad AF, von Schoultz B, Bartfai A. Effect of estrogen and testosterone replacement therapy on cognitive fatigue. Gynecol Endocrinol. 2013 Feb;29(2):173-6. doi: 10.3109/09513590.2012.730568. Epub 2012 Oct 25.
• Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet. 2019 Jan 26;393(10169):364-376. doi: 10.1016/S0140-6736(18)32112-3.
• Chidi-Ogbolu N, Baar K. Effect of Estrogen on Musculoskeletal Performance and Injury Risk. Front Physiol. 2019 Jan 15;9:1834. doi: 10.3389/fphys.2018.01834. eCollection 2018.
• Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, Burki RE, Ginsburg ES, Rosen RC, Leiblum SR, Caramelli KE, Mazer NA. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 2000 Sep 7;343(10):682-8. doi: 10.1056/NEJM200009073431002.
• Derogatis LR, Rosen R, Leiblum S, Burnett A, Heiman J. The Female Sexual Distress Scale (FSDS): initial validation of a standardized scale for assessment of sexually related personal distress in women. J Sex Marital Ther. 2002 Jul-Sep;28(4):317-30. doi: 10.1080/00926230290001448.
• Hilditch JR, Lewis J, Peter A, van Maris B, Ross A, Franssen E, Guyatt GH, Norton PG, Dunn E. A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas. 1996 Jul;24(3):161-75. doi: 10.1016/s0378-5122(96)82006-8.
• Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11.
• Rosen HN, Moses AC, Garber J, Iloputaife ID, Ross DS, Lee SL, Greenspan SL. Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcif Tissue Int. 2000 Feb;66(2):100-3. doi: 10.1007/pl00005830.
• Langdahl B, Chung YS, Plebanski R, Czerwinski E, Dokoupilova E, Supronik J, Rosa J, Mydlak A, Rowinska-Osuch A, Baek KH, Urboniene A, Mordaka R, Ahn S, Rho YH, Ban J, Eastell R. Proposed Denosumab Biosimilar SB16 vs Reference Denosumab in Postmenopausal Osteoporosis: Phase 3 Results Up to Month 12. J Clin Endocrinol Metab. 2025 May 19;110(6):e1951-e1958. doi: 10.1210/clinem/dgae611.
• Kline GA, Holmes DT. Bone turnover markers for assessment of anti-resorptive effect in clinical practice: A good idea meets the problem of measurement uncertainty. Clin Biochem. 2023 Jun;116:100-104. doi: 10.1016/j.clinbiochem.2023.04.007. Epub 2023 Apr 19.
• Brown JP, Don-Wauchope A, Douville P, Albert C, Vasikaran SD. Current use of bone turnover markers in the management of osteoporosis. Clin Biochem. 2022 Nov-Dec;109-110:1-10. doi: 10.1016/j.clinbiochem.2022.09.002. Epub 2022 Sep 9.
• Migliorini F, Maffulli N, Spiezia F, Peretti GM, Tingart M, Giorgino R. Potential of biomarkers during pharmacological therapy setting for postmenopausal osteoporosis: a systematic review. J Orthop Surg Res. 2021 May 31;16(1):351. doi: 10.1186/s13018-021-02497-0.
• Everts-Graber J, Reichenbach S, Ziswiler HR, Studer U, Lehmann T. A Single Infusion of Zoledronate in Postmenopausal Women Following Denosumab Discontinuation Results in Partial Conservation of Bone Mass Gains. J Bone Miner Res. 2020 Jul;35(7):1207-1215. doi: 10.1002/jbmr.3962. Epub 2020 Feb 11.
• Shieh A, Karlamangla AS, Gossiel F, Eastell R, Burnett-Bowie SA, Greendale GA. Estimating Net Bone Formation Relative to Resorption Using Reference Bone Turnover Markers. J Clin Endocrinol Metab. 2025 Jul 15;110(8):e2544-e2552. doi: 10.1210/clinem/dgae842.
• Nathorst-Boos J, Floter A, Jarkander-Rolff M, Carlstrom K, Schoultz Bv. Treatment with percutanous testosterone gel in postmenopausal women with decreased libido--effects on sexuality and psychological general well-being. Maturitas. 2006 Jan 10;53(1):11-8. doi: 10.1016/j.maturitas.2005.01.002. Epub 2005 Sep 23.
• Donovitz G, Cotten M. Breast Cancer Incidence Reduction in Women Treated with Subcutaneous Testosterone: Testosterone Therapy and Breast Cancer Incidence Study. Eur J Breast Health. 2021 Mar 31;17(2):150-156. doi: 10.4274/ejbh.galenos.2021.6213. eCollection 2021 Apr.
• 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 Dec 30;19(1):1271. doi: 10.1186/s12885-019-6457-8.
• Simon J, Braunstein G, Nachtigall L, Utian W, Katz M, Miller S, Waldbaum A, Bouchard C, Derzko C, Buch A, Rodenberg C, Lucas J, Davis S. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab. 2005 Sep;90(9):5226-33. doi: 10.1210/jc.2004-1747. Epub 2005 Jul 12.
• Panay N, Al-Azzawi F, Bouchard C, Davis SR, Eden J, Lodhi I, Rees M, Rodenberg CA, Rymer J, Schwenkhagen A, Sturdee DW. Testosterone treatment of HSDD in naturally menopausal women: the ADORE study. Climacteric. 2010 Apr;13(2):121-31. doi: 10.3109/13697131003675922.
• Shifren JL, Davis SR, Moreau M, Waldbaum A, Bouchard C, DeRogatis L, Derzko C, Bearnson P, Kakos N, O'Neill S, Levine S, Wekselman K, Buch A, Rodenberg C, Kroll R. Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: results from the INTIMATE NM1 Study. Menopause. 2006 Sep-Oct;13(5):770-9. doi: 10.1097/01.gme.0000243567.32828.99.
• Hofling M, Lundstrom E, Azavedo E, Svane G, Hirschberg AL, von Schoultz B. Testosterone addition during menopausal hormone therapy: effects on mammographic breast density. Climacteric. 2007 Apr;10(2):155-63. doi: 10.1080/13697130701258812.
• Fooladi E, Bell RJ, Jane F, Robinson PJ, Kulkarni J, Davis SR. Testosterone improves antidepressant-emergent loss of libido in women: findings from a randomized, double-blind, placebo-controlled trial. J Sex Med. 2014 Mar;11(3):831-9. doi: 10.1111/jsm.12426. Epub 2014 Jan 16.
• Davis SR, van der Mooren MJ, van Lunsen RH, Lopes P, Ribot C, Rees M, Moufarege A, Rodenberg C, Buch A, Purdie DW. Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Menopause. 2006 May-Jun;13(3):387-96. doi: 10.1097/01.gme.0000179049.08371.c7.
• Buster JE, Kingsberg SA, Aguirre O, Brown C, Breaux JG, Buch A, Rodenberg CA, Wekselman K, Casson P. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol. 2005 May;105(5 Pt 1):944-52. doi: 10.1097/01.AOG.0000158103.27672.0d.
• Kocoska-Maras L, Hirschberg AL, Bystrom B, Schoultz BV, Radestad AF. Testosterone addition to estrogen therapy - effects on inflammatory markers for cardiovascular disease. Gynecol Endocrinol. 2009 Dec;25(12):823-7. doi: 10.3109/09513590903056134.
• Floter A, Nathorst-Boos J, Carlstrom K, Ohlsson C, Ringertz H, Schoultz Bv. Effects of combined estrogen/testosterone therapy on bone and body composition in oophorectomized women. Gynecol Endocrinol. 2005 Mar;20(3):155-60. doi: 10.1080/09513590400021193.
• Floter A, Nathorst-Boos J, Carlstrom K, von Schoultz B. Addition of testosterone to estrogen replacement therapy in oophorectomized women: effects on sexuality and well-being. Climacteric. 2002 Dec;5(4):357-65.
• Moller MC, Bartfai AB, Radestad AF. Effects of testosterone and estrogen replacement on memory function. Menopause. 2010 Sep-Oct;17(5):983-9. doi: 10.1097/gme.0b013e3181dc2e40.
• Dias RS, Kerr-Correa F, Moreno RA, Trinca LA, Pontes A, Halbe HW, Gianfaldoni A, Dalben IS. Efficacy of hormone therapy with and without methyltestosterone augmentation of venlafaxine in the treatment of postmenopausal depression: a double-blind controlled pilot study. Menopause. 2006 Mar-Apr;13(2):202-11. doi: 10.1097/01.gme.0000198491.34371.9c.
• Wisniewski AB, Nguyen TT, Dobs AS. Evaluation of high-dose estrogen and high-dose estrogen plus methyltestosterone treatment on cognitive task performance in postmenopausal women. Horm Res. 2002;58(3):150-5. doi: 10.1159/000064491.
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Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: September 30, 2025
• First Submitted That Met QC Criteria: November 19, 2025
• First Posted (Actual): November 28, 2025

Study Record Updates

• Last Update Posted (Actual): March 2, 2026
• Last Update Submitted That Met QC Criteria: February 27, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Bone Diseases, Metabolic; Osteoporosis; Nutritional and Metabolic Diseases; Osteoporosis, Postmenopausal; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Polycyclic Compounds; Inorganic Chemicals; Chlorine Compounds; Steroids; Fused-Ring Compounds; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Androstenes; Androstanes; Androstenols; Testosterone Congeners; Sodium Compounds; Gonadotropin-Releasing Hormone; Chlorides; Hydrochloric Acid; Testosterone; Triptorelin Pamoate; Estradiol; Sodium Chloride
• Other Study ID Numbers: 2025-522558-37-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No