Hormone Replacement Therapy, Menopause
Conditions
Keywords
cortico-reticular, central nervous system, physical performance, strength
Brief summary
Post-menopausal women who request to begin hormone-replacement therapy (HRT) are directed to the research team. The participants are tested before beginning HRT, after two months of HRT, and five months of HRT. Tests include strength performance, central nervous system functioning, body composition, resting metabolic rate, and vascular screening. The participants are provided a 12-week training intervention (2 x strength, 2 x endurance per week) that can be voluntarily followed between tests at month 2 and 5. Compliance with the training program is recorded. A minimum of 15 participants are needed a priori, but the investigators aim to recruit and test 20 women.
Detailed description
Study aim: To determine cortico-reticular functioning during low and high female sex hormone, estrogen and progesterone, concentrations. Hypothesis: Greater functioning/response during neurophysiological tests will occur in the presence of high compared to low estrogen concentrations accompanying greater force production capacity. In addition, pathways reliant on a greater number of synapses, i.e. cortico-reticulospinal, will demonstrate the greatest difference between hormone concentrations. Justification: Several studies in monkeys and humans suggest that the methodology employed is sensitive to distinguish between high and low force production capacity. Estrogen is a neurotransmitter agonist exerting its influence at least via glutamate and GABA interneuron functioning, respectively. The MENSA study is a locally administered trial where volunteers who request to be put on combined hormone replacement therapy will be recruited through cooperation with gynaecologists in the Jyväskylä area. Participants visit the University of Jyväskylä laboratories 1-5 days before beginning treatment (baseline), 2 months after beginning treatment and 5 months after beginning treatment having completed a 12-week non-supervised exercise intervention. The experimental sessions will be conducted in the morning (beginning at approximately 7 am) following an overnight fast, and the time of the day kept constant for each individual participant (± 1 h). The posteriori measurement of serum follicular-stimulating hormone, estradiol and progesterone concentrations will be used to verify the hormonal status of the participants. A recent study showed that a sample of 12-15 participants would be expected to lead to moderate-to-large (0.2-0.9) effect sizes in the tests of cortico-cortico and cortico-reticular functioning. The target muscle is the biceps brachii performing voluntary unilateral isometric elbow flexion actions. MENSA aims to recruit 20 females; this attempts to overcome potential reduced sample size through drop-out or measurement/technical error, as well as sufficiency for detection of possible changes in secondary outcome measures.
Interventions
BEHAVIORALPhysical training
A 12-week, 4 x per week (2 x strength and 2 x endurance) training program to be performed voluntarily by the participants after tests at month 2.
Sponsors
University of Jyvaskyla
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
50 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
* at least 6 months since their last period but no more than being 5 years post-menopausal * basal follicular-stimulating hormone concentration \> 30 IU/L (confirmed post-recruitment) * willing to start combined hormonal treatment * womb and ovaries intact with normal functioning throughout reproductive age * willing to provide informed consent * does not have any of the
Exclusion criteria
for TMS measurements according to Rossi et al. (2021 Clin Neurophysiol. 132(1):269-306.) (i.e. arterial hypertension, heart attack/seizure history, migraine, pacemaker or cochlear implant or other implanted metal/electronic device)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Short-interval intracortical inhibition (SICI) | Change from baseline to month 2 and change from baseline to month 5 | Ten double-pulse transcranial magnetic stimulations delivered with 3 ms inter-stimulus interval. The conditioning pulse delivered at 80% of active motor threshold and the test pulse delivered at 120% of active motor threshold. Motor-evoked potential amplitude compared to single-pulse responses at 120% of active motor threshold. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Motor-evoked potential recruitment curve | Change from baseline to month 2 and change from baseline to month 5 | Ten transcranial magentic stimulations (single-pulse) at 100%, 120%, 140%, 160%, 180% and 200% of active motor threshold. Calculations of I50 and area-under-the-recruitment-curve to be performed offline. |
| StartleTMS | Change from baseline to month 2 and change from baseline to month 5 | Twenty single-pulse transcranial magnetic stimulations delivered using 120% of active motor threshold. Ten stimulations without sound and ten stimulations conditioned by a loud sound (120 dB, 50 Hz) delivered 50 ms prior to TMS discharge. |
| Intra-cortical facilitation (ICF) | Change from baseline to month 2 and change from baseline to month 5 | Ten double-pulse transcranial magnetic stimulations delivered with 15 ms inter-stimulus interval. The conditioning pulse delivered at 80% of active motor threshold and the test pulse delivered at 120% of active motor threshold. Motor-evoked potential amplitude compared to single-pulse responses at 120% of active motor threshold. |
| Long-interval intracortical inhibition (LICI) | Change from baseline to month 2 and change from baseline to month 5 | Ten double-pulse transcranial magnetic stimulations delivered with 50 ms inter-stimulus interval. The conditioning pulse delivered at 120% of active motor threshold and the test pulse delivered at 120% of active motor threshold. Motor-evoked potential amplitude of the test pulse compared to the amplitude of the conditioning pulse. |
| Motor-evoked potential to anterior-posterior current | Change from baseline to month 2 and change from baseline to month 5 | The TMS coil is rotated 180 degrees to induce the opposite direction current within the cortex. A new active motor threshold for this coil orientation is first attained and then ten stimulations with 120% and 140% of active motor threshold are delivered. Motor-evoked potential amplitude is analysed offline. |
| StartReact | Change from baseline to month 2 and change from baseline to month 5 | Reaction test where the participant contracts the biceps brachii upon seeing a flashing white LED light 1 m in front. Ten flashes occur without accompanying sound. Ten flashes occur accompanied by a quiet sound (80 dB, 50 Hz). Ten flashes occur accompanied by a loud sound (120 dB, 50 Hz). The order of the conditions presented is randomized and separated by approximately 8 s. Reaction time is analysed from the presentations of the flash to the beginning (7 SD above baseline) of the voluntary electromyogram burst. The difference in the reactions times between conditions are calculated. Further analyses regarding rate of force development and voluntary EMG amplitude over 0-50 ms from each contraction are assessed. |
| Maximum isometric voluntary contraction (MVC) | Change from baseline to month 2 and change from baseline to month 5 | Testing is performed under controlled pre-test conditions (10-12 h fast, no vigorous physical activity in the prior 24 h), seated in a thermoneutral room. The participant performs 3-5 isometric elbow flexion actions by maximally contracting the biceps brachii muscle while seated in an electromechanical dynamometer. Force and electromyography (EMG) activity are recorded during the contractions. |
| Resting energy expenditure (i.e. resting metabolic rate) | Change from baseline to month 2 and change from baseline to month 5 | Measured by Indirect Calorimetry Resting energy expenditure (REE) is measured by indirect calorimetry (ventilated hood; overnight fast 10-12 h; supine, thermoneutral room). After stabilization, VO2 and VCO2 are recorded for ≥20-30 min; a steady-state segment (e.g., ≥5 min with CV \<10% and physiologic RQ) is used to compute REE (kcal/day) via the Weir equation, higher values = higher energy expenditure. Outcome is change from baseline to follow-up (follow-up - baseline); higher positive values = higher increase in energy expenditure. Procedures/quality criteria follow the device manual and the Statistical Analysis Plan (SAP). Per SAP, supportive analyses may adjust for body composition (FFM/FM) or express REE relative to FFM; these do not replace the prespecified analysis of this primary outcome. |
| Total fat mass | Change from baseline to month 2 and change from baseline to month 5 | Total fat mass (FM) will be measured by bioelectrical impedance analysis (BIA; InBody) under standardized conditions, including a 10-12 h fast before assessment. FM is reported in kg; higher values indicate higher fat mass. The outcome is the change from baseline to the specified follow-up (follow-up - baseline). |
| Fat-free mass | Change from baseline to month 2 and change from baseline to month 5 | Fat-free mass (FFM) will be measured by bioelectrical impedance analysis (BIA; InBody) under standardized conditions, including a 10-12 h fast before assessment. FFM is reported in kg; higher values indicate higher fat-free mass. |
| Aotic pulse wave velocity | Change from baseline to month 2 and change from baseline to month 5 | Aortic pulse wave velocity (PWV) will be measured using an oscillometric Arteriograph device under standardized resting conditions, including a 10-12 h fast and avoidance of vigorous physical activity during the previous 24 h. Measurements are taken supine in a quiet, thermoneutral room. PWV is reported in m/s; higher values indicate greater arterial stiffness. |
| Arterial wave reflection | Change from baseline to month 2 and change from baseline to month 5 | Augmentation Index (AIx) will be measured using the Arteriograph under the same standardized resting conditions, including a 10-12 h fast and avoidance of vigorous physical activity during the preceding 24 h. AIx is expressed in %; higher values indicate greater arterial wave reflection. |
| Reflection time | Change from baseline to month 2 and change from baseline to month 5 | Reflection time measured by Arteriograph in standardized rest (as above). ms; shorter RT = faster wave return. |
| Microvascular perfusion | Change from baseline to month 2 and baseline to month 5 | Resting cutaneous microvascular perfusion measured at the forearm using Laser Doppler under standardized resting conditions (10-12 h fast, no vigorous physical activity in prior 24 h, supine, thermoneutral). Perfusion units (PU); higher = higher resting microvascular flow. |
| Endothelium-Dependent Vasodilation (Laser Doppler, %) | Change from baseline to month 2 and change from baseline to month 5 | Endothelium-dependent vasodilatory response measured at the forearm using Laser Doppler during standardized forearm occlusion to induce a controlled ischemic stimulus under resting conditions (as above). % change from baseline; higher = better endothelial function. |
| Post-Occlusive Reactive Hyperemia (PORH, %) | Change from baseline to month 2 and change from baseline to month 5 | Post-occlusive reactive hyperemia measured at the forearm with Laser Doppler under standardized rest (as above). % increase; higher = better microvascular reactivity. |
| Resting Near-Infrared Spectroscopy (NIRS) Tissue Oxygen Saturation (StO2, %) | Change from baseline to month 2 and change from baseline to month 5 | Near-Infrared Spectroscopy (NIRS)-derived quadriceps StO2 at rest under standardized conditions (10-12 h fast, no vigorous PA in prior 24 h, supine, thermoneutral). %; higher = higher oxygenation. |
| Near-Infrared Spectroscopy (NIRS) Total Hemoglobin (tHb, au) | Change from baseline to month 2 and change from baseline to month 5 | NIRS-derived tHb signal (during rest). Arbitrary units; marker of local microvascular blood volume. |
Countries
Finland
Contacts
CONTACTSimon Walker Dr (Dos.), PhD
PRINCIPAL_INVESTIGATORSimon Walker, PhD
Universirty of Jyväskylä, Finland
Outcome results
None listed