Fig 1.
A flowchart showing the number of women participating in the RCT.
Flowchart according to Consort showing the number of women included, randomized, and followed up in a 15 week Randomized Controlled Trial (RCT) of resistance training as a treatment for vasomotor symptoms and analyzed for LH and FSH levels. * excluded due to too few hot flushes according to diary during the two weeks between the screening visit (visit 1) and the baseline visit (visit 2).
Table 1.
Inclusion and exclusion criteria for the women included in the trial.
Fig 2.
A-D: Illustrations to the possible cause of vasomotor symptoms and how Menopausal Hormone Therapy (MHT) and physical exercise may relieve them. A PREMENOPAUSAL WOMAN: The GnRH cell bodies in the preoptic area (POA) of hypothalamus constitute the central regulation of reproduction. The pulsatile GnRH secretion into the hypophyseal circulation triggers the production and release of the gonadotropins Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). Since GnRH neurons do not express steroid receptors, evidence suggests that indirect steroid feedback is mediated by Kisspeptin/Neurokinin B/Dynorphin (KNDγ) neurons. Via the neuropeptide kisspeptin, the KNDγ neurons stimulate both the GnRH pulse amplitude and frequency. Except their steroid-responsiveness and involvement in reproduction, KNDγ neurons also project to heat dissipation neurons in POA and its Median Preoptic Nucleus (MnPO), mainly via the neuropeptide Neurokinin B (NKB). The MnPO neurons constitute the primary autonomic thermoregulatory area, capable to initiate effector responses in order to stabilize the inner core temperature in a changing ambient environment. Since estrogen acts stabilizing on the thermoregulatory center by widening the thermoneutral zone, premenopausal women are less afflicted by vasomotor symptoms (VMS). B POSTMENOPAUSAL WOMAN: In postmenopausal women, the ovarian failure leads to reduced negative feedback from sex steroids, which is associated with increased KNDγ neuron activity. The gene expression of dynorphin mRNA is downregulated while the expression of both kisspeptin and NKB are simultaneously upregulated. The reduced levels of centrally produced β-endorphin further increase the KNDγ neuron activity causing hypertrophy of the nucleus. Consequently, there is an instability in the thermoregulatory center in MnPO, narrowing the thermoneutral zone, which in turn facilitates inappropriate activation of thermoregulatory effectors for heat dissipation, clinically experienced as VMS. Moreover, the increased kisspeptin expression stimulates GnRH neurons which both enhances the gonadotropin pulse frequency and amplitude from the pituitary. C POSTMENOPAUSAL WOMAN ON MHT: Endogenous estrogen and menopausal hormone therapy (MHT) modulate the thermoregulatory and reproductive functions indirectly via the hypothalamic opioid system. Both β-endorphin and dynorphin signaling lower the KNDγ neuron activity, leading to reduced levels of the stimulatory neuropeptides kisspeptin and NKB. This inhibits the pulsatile GnRH release to the portal circulation, and stabilizes the thermoregulatory center in MnPO by a widening of the thermoneutral zone, therefore decreasing VMS. D POSTMENOPAUSAL WOMAN WHO ENGAGES IN PHYSICAL ACTIVITY: Peripheral estrogen concentrations positively correlate with the central opioid tone. Thus, postmenopausal women may have a relative deficiency of hypothalamic endogenous opioids due to their ovarian failure. Moderate to intense physical activity may increase the production of hypothalamic opioids and thereby lower the KNDγ neuron activity in a similar mechanistic way as for endogenous estrogen or MHT. Therefore, physical activity could be an alternative to MHT for postmenopausal women.
Table 2.
Baseline characteristics of the original randomisation groups.
Fig 3.
Scatter dot plot of the absolute levels of change in LH and FSH between the baseline and week-15 visit.
Scatter dot plot of the absolute levels of change in LH and FSH between the baseline and week-15 visit. Separated plots are presented for each per-protocol defined group; control group (CG), intervention group (IG) and compliant intervention group (C-IG). The absolute change in LH over 15 weeks differed significantly between the compliant intervention group and the control group. A similar albeit non-significant trend was observed for FSH. * = p<0.05.