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Published in final edited form as: Harv Rev Psychiatry. 2023 May-Jun;31(3):114–123. doi: 10.1097/HRP.0000000000000366

The Impact of Sex Hormones on Transcranial Magnetic Stimulation Measures of Cortical Excitability: A Systematic Review and Considerations for Clinical Practice

Ana Maria Rivas-Grajales 1, Tracy Barbour 2, Joan Camprodon 2,3, Michael D Kritzer 2,3
PMCID: PMC10264142  NIHMSID: NIHMS1889097  PMID: 37171472

Abstract

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative for the treatment of major depressive disorder (MDD), although its clinical effectiveness varies substantially. The effects of sex hormone fluctuations on cortical excitability have been identified as potential factors that can explain this variability. However, data on how sex hormone changes affect clinical response to rTMS is limited. To address this gap, we reviewed the literature examining the effects of sex hormones and hormonal treatments on transcranial magnetic stimulation (TMS) measures of cortical excitability. Results show that variations of endogenous estrogen, testosterone, and progesterone have modulatory effects on TMS-derived measures of cortical excitability. Specifically, higher levels of estrogen and testosterone were associated with greater cortical excitability, while higher progesterone was associated with lower cortical excitability. This highlights the importance of additional investigation into the effects of hormonal changes on rTMS outcomes and circuit-specific physiological variables. These results call for TMS clinicians to consider performing more frequent motor threshold (MT) assessments in patients receiving high doses of estrogen, testosterone, and progesterone in the cases such as in vitro fertilization, hormone replacement therapy, and gender-affirming hormonal treatments. It may also be important to consider physiological hormonal fluctuations and their impact on depressive symptoms and the MT when treating female patients with rTMS.

Keywords: transcranial magnetic stimulation, cortical excitability, estrogen, progesterone, testosterone, sex hormones

INTRODUCTION

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a safe and effective treatment option for patients with major depressive disorder (MDD). Approximately 50% to 60% of people with MDD who have failed pharmacological interventions experience a clinically meaningful response with rTMS, and among these, about 30% of patients may achieve remission of symptoms.1 However, the clinical response to rTMS varies substantially, with some patients showing improvement and others showing little to no improvement throughout the treatment course.2 This variability has been attributed to patient characteristics and considered to be independent of the rTMS protocol.2

Women have higher rates of depression than men, and transgender individuals have higher rates of depression than the general population.3–5 Sex hormones have been identified as a potential factor affecting rTMS response by affecting cortical excitability and possibly clinical outcomes. The sex hormones that have been most widely studied have been estrogen and progesterone. Estrogen has been shown to increase cortical excitability by enhancing glutamate neurotransmission and reducing GABAergic responses.6,7 In contrast, progesterone exhibits an inhibitory action by binding to a steroid-specific site on the GABA-A receptor, facilitating chloride channel opening and elevating the seizure threshold.8,9 Administration of estrogen has been shown to increase the expression of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of rodents, a protein that plays an important role in neuronal plasticity.10,11 In addition, estradiol-to-progesterone ratios are positively associated with improvements in depression score in premenopausal women following rTMS, which supports the potential role of sex hormones in the antidepressant response to rTMS.12While several studies have assessed the impact of sex hormones on transcranial magnetic stimulation (TMS)-derived measures of motor cortex physiology, very few have assessed clinical targets such as the dorsolateral prefrontal cortex (DLPFC), the pre-supplementary motor area, and the ventromedial prefrontal cortex. These are targets of great therapeutic importance for the treatment of MDD and obsessive-compulsive disorder,13,14 and understanding the impact of sex hormones on treatment outcomes could inform the development of new rTMS protocols. Only one study has evaluated how hormonal changes affect the neuroplastic effects of rTMS to the left dorsolateral prefrontal cortex (DLPFC).15 In this study it was found that estrogen contributed to the magnitude and the variance of EEG-derived measures of cortical excitability following rTMS, and this was reflected in variability in clinical outcomes.15

Overall, addressing the facilitatory or inhibitory effects of sex hormones in rTMS outcomes for the treatment of MDD can have mechanistic and therapeutic implications. To address this gap in knowledge, we carried out a systematic review to investigate the potential role of sex hormones and hormonal treatments on cortical excitability.

METHODS

We conducted a review of the available literature on the effect of sex hormones and hormonal treatments in TMS-derived measures of cortical excitability. PubMed, EMBASE, and PsycINFO databases were searched independently by 2 of the authors (AMRG and MDK) using the following query: “(luteinizing hormone) OR (follicle stimulating hormone) OR (gonadotropin-releasing hormone) OR (sex hormones) OR (estrogen) OR (progesterone) OR (testosterone) OR (spironolactone) OR (finasteride) AND (transcranial magnetic stimulation).” The search was performed in April 2022 and included studies from inception to April 2022.

Our search strategy yielded a total of 74 articles. Supplemental Figure 1, http://links.lww.com/HRP/A212, shows our PRISMA diagram and selection process, which ultimately yielded a total of 18 articles that met criteria for review: full-text, written in English. Reviews, abstracts, and conference articles were excluded.

The studies included described the effects of sex hormones on cortical excitability as reflected in changes TMS- and EEG-derived measures: we included studies using single-pulse TMS, paired-pulse TMS, rTMS, and paired-associative stimulation (PAS). Details extracted from each study included: year, number of subjects, sex hormone, TMS protocol, measure of cortical excitability, adjustment for menstrual cycle, outcome measures (if applicable), and findings.

TMS Protocols

Single-pulse TMS is used to evaluate the integrity of the corticospinal motor pathway. It consists of the application of one pulse over the motor cortex and recording the response in the muscle (i.e., the motor-evoked potential [MEP]) using electromyography. This is also used to determine the motor threshold (MT), which is a measure of cortical excitability. The resting motor threshold (RMT) is defined as the minimum intensity needed to induce a MEP larger than 50mV in at least 50% of trials. The active motor threshold (AMT) is typically defined as the lowest TMS stimulation intensity that produces a MEP greater than 0.1mV in at least 50% of trials when the subjects maintained a constant muscle contraction, typically of the hand.16* Single-pulse TMS can also be used to determine the cortical silent period (SP) duration. The SP consist of a period of electromyographic suppression after a pulse of TMS during active contraction of the contralateral muscle. The SP reflects cortical inhibition which is mediated by GABAB receptors.17

Paired-pulse TMS protocols are used to study various physiological processes, such as intracortical inhibition and facilitation. They consist of the application of two separate stimuli of different strengths (between 80% to 120% of the MT) and interstimulus interval. The two most studied protocols are short-interval cortical inhibition (SICI) and intracortical facilitation (ICF). SICI consists of the application of a first subthreshold (conditioned) stimuli (at 80% of the MT but unable to elicit an MEP), followed by a second suprathreshold (test) stimulus (at approximately 120% of the MT), with an interstimulus interval of 1 to 5 milliseconds. These responses are explained by the recruitment of distinct populations of interneurons and pathways, which result in inhibitory and excitatory effects (for a detailed description see Wagle-Shukla and colleagues18).

rTMS modulates cortical activity by inducing neuroplastic changes resembling long-term depression and long-term potentiation that last beyond the period of stimulation that has therapeutic implications. The effects depend on the parameters used: low frequency stimulation (i.e 1Hz) usually leads to suppression of activity in the target region, while high-frequency stimulation (i.e > 5Hz) usually leads to excitatory effects.17

Paired associative stimulation (PAS) is a protocol that has been also used as a model of long-term depression and potentiation. It involves repeated pairing of electrical stimulation to a peripheral nerve with single pulses of TMS over the contralateral motor cortex. When the two stimuli arrive in synchrony, or just prior to the TMS stimuli, there is an increase in MEP amplitudes. This is defined as facilitatory PAS. When the peripheral stimuli is applied after the TMS stimuli, there is a decreased in MEP amplitudes, and defined as inhibitory PAS.19

RESULTS

The 18 studies that met review criteria included a total of 393 subjects (244 females). Four studies included clinical outcome measures. Seven studies included healthy men as the control group. Three articles included female patients with epilepsy, one included patients with premenstrual dysphoric syndrome, and one included men with disorders of consciousness. Only one study included subjects on oral contraceptives. Twelve of these studies used paired-pulse TMS, six studies used rTMS, and one used PAS to obtain measures of cortical excitability. Among the studies reviewed here, 15 stimulated the motor cortex to study motor physiology and three stimulated the left DLPFC. Measures of cortical excitability included: short-interval cortical inhibition (SICI), intracortical facilitation (ICF), silent period duration (SP), motor evoked potential (MEP) amplitude, motor threshold (MT), and paired associative stimulation (PAS). One study used EEG-derived measures of cortical excitability: P60, N45, N100, and P180 EEG amplitudes evoked by single-pulse TMS over the left DLPFC. The participants, TMS characteristics, and the main findings of each study are outlined in Tables 1 and 2. Table 2 summarizes the studies that included outcome measures.

Table 1.

Summary of Studies Examining the Impact of Sex Hormones in Measures of Cortical Excitability

Author Year Subjects (N/Sex) Sex hormone TMS Protocol Measure of Cortical Excitability Adjustment for Menstrual Cycle Findings
Smith et al. 1999 13 HF Estradiol, Progesterone Paired-pulse TMS SICI, ICF Measures obtained during mid-follicular and mid-luteal phases ICI was higher during mid-lutheal phase (high progesterone)
Herzog et al. 2001 1F with epilepsy Progesterone Paired-pulse TMS MT, SP, MEP None. Progesterone supplementation was given during the luteal phase No changes in MT, SP, and MEP. Trend towards decreased excitability during progesterone suplementation
Smith et al. 2002 14 HF Estradiol, Progesterone Paired-pulse TMS SICI, ICF Measures obtained during early follicular, late follicular, and mid-luteal phases Higher ICF during late follicular phase (high estrogen). ICI was high and similar in early folicular (low estrogen) and mid-luteal phases (high progesterone)
Smith et al. 2003 14 HF/9F with PMS Estradiol, Progesterone Paired-pulse TMS SICI, ICF Measures obtained during mid-follicular and mid-luteal phases Increased ICI during lutheal phase (high progesterone) in HF. Increased ICF in luteal phase in PMS.
Inghirelli et al. 2004 8 HF/8 HM Estradiol, Progesterone 5Hz rTMS to the MC MT, MEP, SP Measures obtained at day 1 and 14 of the menstrual cycle Larger MEP size in females during day 14 of menstrual cycle (high estrogen). No change in MT and SP
Bonifazi et al. 2004 6 HM Estradiol, Testosterone Single-pulse TMS (5–10 stimuli delivered at 10–15 second intervals) MT Not applicable MT reduction was associated with increase in testosterone and estradiol
Haussman et al. 2006 13 HF Estradiol, Progesterone Paired-pulse TMS ipsilateral SP (iSP) and contralateral SP (cSP) Measures obtained during early follicular, late follicular, and mid-luteal phases iSP duration was shorter during both the late follicular phase (high estrogen) and mid follicular phase (high progesterone)
Hattemer et al. 2006 6 F with epilepsy Not obtained Paired-pulse TMS MT, SP, SICI, ICF Measures obtained on days 8, −14, −7 and 2 of the cycle SP duration was shorter during luteal phase
Hattemer et al. 2007 8 HF with anovulatory cycles / 12 HF with ovulatory cycles Estradiol, Progesterone Paired-pulse TMS MT, SP, SICI, ICF Measures obtained on days 8, −14, −7 and 2 of the cycle ICI was higher at day −14 and 2 in anovulatory females
Badawy et al. 2013 11 HF/9F with epilepsy Estradiol, Progesterone Paired-pulse TMS MT, MEP, SICI, ICF Measures obtained during late follicular and mid luteal phase Increased ICF during late follicular phase (high estrogen) in HF. Increased ICF in luteal phase in epilepsy
Polimanti et al. 2016 20HF/15HM Estradiol, Progesterone, Testosterone Paired-Asssociative Stimulation (PAS) (150 pairs at 0.2 Hz for 12 minutes) PAS-induced Plasticity (ratio of the average across 20 peak-to-peak MEP amplitudes before and after TMS None PAS-induced plasticity was higher in younger females, and positively correlated with testosterone levels
Rogers et al. 2017 6 HF / 4HM Estradiol, Progesterone 1Hz rTMS over the MC Change in MEP recruitment curve pre-post rTMS Measures obtained on days corresponding to a range of progesterone-to-estradiol concentrations Increased MEP size resulting in greater rTMS-induced inhibition during high estrogen phase
Chung et al. 2019 14HF/15HM Estradiol 10Hz rTMS over left DLPFC P60, N45, N100, P180 EEG amplitudes, evoked with TMS Measures obtained 2–5 days after onset of menses and 6–9 days before onset of menses Increase in P60 and decrease in N45, N100, and P180 during high estrogen phase
El-Sayes et al. 2019 17HF / 17HM Estradiol, Progesterone, Testosterone Paired-pulse TMS Change in MEP recruitment curve pre-post rTMS Measures obtained during mid-follicular and mid-luteal phases No changes in MEPs during follicular versus lutheal phase
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Abbreviations: HF: Healthy females, SICI: short intracortical inhibition, ICF: intracortical facilitation, F: females, TMS: transcranial magnetic stimulation, MT: motor threshold, SP: silent period, MEP: motor evoked potential amplitude, PMS: premenstrual syndrome, rTMS: repetitive transcranial magnetic stimulation, MC: motor cortex

Table 2.

Summary of Studies Examining the Impact of Sex Hormones in Measures of Cortical Excitability and Clinical Outcomes

Author Subjects Design Outcomes Measures Sex hormone TMS Protocol Measure of Cortical Excitability Adjustment for Mentrual Cycle Findings
Huang et al. (2008)9 31HF (17 pre-menopausal 14 post-menopausal) 16 HM Observational 50% HAMD reduction Estradiol, Progesterone 5Hz TMS over the left DLPFC Not applicable Not applicable Higher E/P ratio associated with a greater improvement in HAMD scores in premenopausal women
Zogui et al. (2015)28 10 HF/10 HM Observational Manual Dexterity Performance Estradiol, Progesterone Paired-pulse TMS ICI, ICF Hormone levels were meausured during follicular and mid-luteal phases ICI and ICF remained unchanged during the menstrual cycle. Manual dexterity was lower during mid-luteal phase.
Ansdell et al. (2019)32 15 HF on OCPs and 14 HF w/o OCPs Observational Motor performance of knee extensors Estradiol, Progesterone Single and Paired-pulse TMS MT, MEP, SP, ICI Measures obtained at day 2, 14 and 21 of the menstrual cycle Increase progesterone concentrations was associated with increased ICI during day 21 in HF w/o OCPs
He et al. (2021)33 57 M with severe TBI and disorders of consciousness Placebo Controlled RTC Improvement in LOC Estradiol 10Hz rTMS over left DLPFC None Not applicable Improvement in LOC in patients receiving rTMS. Higher estradiol levels correlated with clinical response.
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Abbreviations: DLPFC: dorsolateral prefrontal cortex, E/P: estrogen-progesterone, HAM-D: Hamilton depression rating scale, HF: healthy females, HM: healthy males, ICF: intracortical facilitation, ICI: intracortical inhibition, LOC: level of consciousness, M: males, MEP: motor evoked potential, MT: motor threshold, OCPs: oral contraceptive pills, RCT: randomized control trial, rTMS: repetitive transcranial magnetic stimulation, SICI: short interval cortical inhibition, SP: silent period, TBI, traumatic brain injury, TMS: transcranial magnetic stimulation

The Effects of Estrogen in Cortical Excitability

The female menstrual cycle is typically 28 days and begins with the onset of menses (menstruation). Menses is followed by the follicular phase, during which estrogen gradually increases and then surges along with follicle stimulating hormone and luteinizing hormone, at ovulation on day 14. The cycle then enters the luteal phase, where progesterone gradually increases and prepares the uterine lining for implantation pregnancy.20 Estrogen has been associated with greater cortical excitability across studies. Smith and colleagues21,22 observed higher ICF during the late follicular phase, which is when estrogen levels are higher and under the opposed effects of progesterone. Using a low frequency rTMS protocol, Inghilleri and colleagues23 showed that MEP did not increase during menses (cycle day 1), but more than doubled during ovulation at day 14. The finding of increased MEP size during ovulation was replicated by Rogers and colleagues24 using a similar rTMS protocol. MT was not affected by estrogen variations across the menstrual cycle in women.23,25–27 However, a single-pulse TMS in men showed that higher estrogen was associated with a reduction in MT.28

Chung and colleagues15 investigated the influence of endogenous estrogen in the cortical response to high frequency rTMS over the left DLPFC using EEG and TMS-evoked potentials (TEPs). They studied a group of 29 healthy volunteers. Males attended one session and females attended two sessions: 2–3 days after the onset of menses and 6–9 days before the onset of menses. EEG measures included N45, P60, N100, and P180, which reliably represent components of cortical excitation or inhibition. More specifically, P60 relates to excitation in motor and prefrontal cortex, whereas N45 and N100 relate to cortical inhibition. While mechanisms mediating the P180 amplitude are unknown, neuromodulation studies have interpreted changes in this measure as a marker of cortical reactivity.29,30 Chung and colleagues29 found that only females in the high estrogen phase had significant TEPs changes following rTMS. Between-group comparisons comparing men and women during the high estrogen phase revealed changes at baseline (or session 1 in women) in N100 and P180. Females during the high estrogen phase had more consistency and less variance after rTMS, suggesting that estrogen plays a role in the magnitude and variance in the neuroplastic effects of rTMS. In three out of the 18 studies reviewed, cortical excitability measures remained unchanged throughout the menstrual cycle.31–33 Polimanti and colleagues32 reported changes in PAS-plasticity in females, but they did not perform any adjustments for hormonal changes throughout the menstrual cycle to be able to distinguish the differential effects of estrogen and progesterone. These studies indicate that while estrogen may have influence on cortical excitability, it may not overtly affect the MT and its impact may not be consistent. The clinical implications of this for the treatment of depression and other neuropsychiatric illnesses are not known. Additionally, there have not been trials during pregnancy—a physiological state with gradually increasing levels of progesterone over months.

The Effects of Progesterone in Cortical Excitability

Progesterone was associated with a reduction in cortical excitability across studies as reflected by a higher SICI and longer SP duration. Smith and colleagues21 studied 13 healthy females during the midfollicular and luteal phases of the menstrual cycle using paired-pulse TMS. They observed an increase in SICI and decreased ICF during the luteal phase compared to the midfollicular phase of the menstrual cycle. In a similar study, Smith, Adams and colleagues22 obtained two measures during the follicular phase (i.e., early, when both estrogen and progesterone are low, and late, when estrogen is high but progesterone is low) in addition to the luteal phase. They found that SICI was higher when circulating levels of both estrogen and progesterone are low. Under the opposed influence of estrogen during the late follicular phase, there was greater ICF. During the luteal phase, in the presence of high progesterone and estrogen SICI levels returned to those observed during the early follicular phase. Hattemer and colleagues26 investigated eight women with anovulatory cycles and 12 women with ovulatory cycles using paired-pulse TMS. They similarly observed that SICI was significantly more pronounced during the luteal phase, which they attributed to the withdrawal of the excitatory effects of estrogen in anovulatory cycles.

Hausmann and colleagues34 studied changes in transcallosal transfer during the menstrual cycle in a group of 13 healthy females using paired-pulse TMS over the left motor cortex and by measuring activity of the ipsilateral first dorsal interosseus muscle. They specifically evaluated the ipsilateral silent period (iSP), which relates to a short period of suppression of voluntary muscle activity ipsilateral to the area of stimulation. Based on the assumption that this measure is mediated by cortical excitatory transcallosal fibers targeting inhibitory interneurons to reduce ipsilateral motor activity, the iSP should be shorter when progesterone levels are high and prolonged when estrogen levels are high. Consistent with this idea, they found that only progesterone levels were significantly related to a reduction of iSP during the mid-luteal phase. Contrary to their hypotheses, they also found that high estrogen levels during the follicular phase were also related to a reduced iSP. They attributed this unexpected finding to a potential role of estrogen on GABA receptors leading to a prolonged inhibitory response, although more experimental data is needed.

The opposite pattern was reported in patients with epilepsy and premenstrual syndrome (PMS), in which higher cortical excitability was observed with higher progesterone in the luteal phase. Hattemer and colleagues27 found that SP duration was shorter during the luteal in a group of six patients with epilepsy. Similarly, Badawy and colleagues35 and Smith, Adams and colleagues36 reported an increase in ICF during the luteal phase in 11 patients with epilepsy and in nine females with PMS, respectively, although only the latter included healthy controls. In one study by Herzog and colleagues,25 there was a trend toward reduction in cortical excitability during the luteal phase in one patient with epilepsy who received progesterone supplementation. These findings illustrate that there are contrasting data on the effects of progesterone on cortical excitability and that timing throughout the menstrual cycle may be an important factor. The effects of low progesterone combined with a dramatic increase in estrogen, as is typically observed prior to ovulation, on the MT and subsequent treatment outcomes is not known but potentially clinically relevant.

The Effects of Testosterone in Cortical Excitability

Two studies evaluated the effects of testosterone in cortical excitability.28,32 Bonifazi and colleagues28 showed that testosterone was associated with a MT reduction in six healthy men. Similarly, Polimanti and colleagues32 showed that higher testosterone levels were correlated with greater PAS-induced plasticity. It is not known whether exogenous testosterone taken for gender-affirming care or if misuse or abuse of anabolic steroids affect clinical outcomes of rTMS therapy.

Studies That Included Outcome Measures

Three studies included clinical outcome measures.12,33,38 Zoghi and colleagues.33 and Ansdell and colleagues37 studied the impact of hormonal changes on motor performance using paired-pulse TMS. The former found that performance was lower during the mid-luteal phase, but SICI and ICF remained unchanged during the menstrual cycle. 33 37 However, although the latter found no changes in performance across the menstrual cycle, they observed that progesterone was associated with increased ICI. 33 12,38Two studies assessed the association between hormonal changes and response to rTMS, but they did not look at the association with measures of cortical excitability. Huang and colleagues12 included 31 women (17 pre-menopausal and 14 post-menopausal) and 16 men with treatment resistant MDD. Menopause was defined as amenorrhea for 12 months or more and level of estradiol < 20pg/mL. Patients received a total of 10 sessions of rTMS at 5Hz over the left DLPFC. They found that women in the premenopausal group who had a higher estrogen-to-progesterone ratio had greater improvement in depression scores. Finally, He and colleagues38 found that higher estradiol levels correlated with improvement in level of consciousness in a group of 57 men with severe traumatic brain injury (TBI) after 10 sessions of 10Hz rTMS over the left DLPFC. These limited studies provide some evidence that higher levels of estrogen may lead to better clinical outcomes in patients with MDD and TBI. Studies such as these should be replicated on a larger scale, and investigators may consider comparing post-menopausal women receiving systemic estrogen supplementation to those without to determine clinical relevance.

DISCUSSION

In summary, the results of this literature review suggest that variations in endogenous estrogen, testosterone, and progesterone have modulatory effects on TMS-derived measures of cortical excitability. Specifically, higher estrogen and testosterone were associated with greater cortical excitability, while higher progesterone was associated with lower cortical excitability. The opposite pattern was seen in patients with epilepsy and PMS, in which higher cortical excitability was observed during the high progesterone or mid-luteal phase, which can be attributed to the alterations in GABA neurotransmission that has been observed in these populations.39–41 Exogenous neuroactive steroids have been shown to augment cortical excitability and have variable effects on motor threshold. Consequently, this may affect the seizure threshold and/or clinical outcomes. Neuroactive steroids, particularly iatrogenic exogenous steroids in the form of hormonal treatment (e.g., gender-affirming, menopausal, IVF, etc), are delivered in higher than physiologic doses and, therefore, may more dramatically affect neurophysiology. Effects of endogenous menstrual cycle variation have also been shown to augment cortical excitability, though to a lesser extent. It is currently unknown whether adjusting the dose of rTMS stimulation would have a significant impact on clinical outcomes. These findings highlight the potential importance of considering sex hormone variations when using rTMS for the treatment of MDD.

Sex Hormones, MDD, and Cortical Physiology

Significant clinical evidence demonstrates that fluctuations in sex hormones are associated with increased risk of depressive states. Women experience depression at nearly twice the rate of men, a significant gender imbalance that first emerges during adolescence.42 Discrete periods of mood and hormonal fluctuations (e.g., premenstrual, postpartum, menopause) may further complicate the course of depressive illness. The menopause transition is a particularly vulnerable period for the development of MDD and the exacerbation of depressive symptoms. These findings are supported by preclinical studies showing enhanced depressive-like behaviors in the low-estrogen phase of the menstrual cycle43 and increased behavioral despair in ovariectomized rats that can be diminished with the administration of estrogen.44

There is recent interest in neuroactive steroid therapeutics, exemplified by the advent of GABA-A modulator brexanolone, so attention to the physiological and neuropsychiatric effects of hormonal variation is warranted. The most potent endogenous allosteric modulator of the GABA-A receptor is allopregnanolone, for which progesterone is a precursor and its synthesis rate is limited by 5-alpha-reductase. Interestingly, the novel antidepressant brexanolone is an allopregnanolone analog used to treat postpartum depression. At this time, brexanolone is a continuous intravenous infusion over two and a half days and not used for ongoing treatment.45 Other neuroactive steroids under investigation for roles in neuropsychiatric illness are pregnenolone, pregnenolone sulfate, Dehydroepiandrosterone (DHEA), and DHEA-sulfate; however, none have been evaluated in the context of neuromodulation with TMS. If combined with a TMS protocol, for example, one would be advised to monitor the motor threshold frequently.46

Sex hormones not only contribute to the pathophysiology of MDD but may be also predictors of response to rTMS for the treatment of MDD. As reported by Huang and colleagues,12 menopausal status and estradiol levels relative to progesterone were important predictors of antidepressant response to rTMS treatment. These effects may be mediated by the influence of sex hormones on glutamate and GABA function in the cerebral cortex. As mentioned earlier, estrogen is known to increase neuronal excitability by the activation of the NMDA receptor and to attenuate GABAA and GABAB mediated responses.6 rTMS induces a complex mechanism of synaptic potentiation, and estrogen may influence the glutamatergic mediated-synaptic potentiation activated by this therapeutic modality.7,47 In the studies reviewed here, estrogen and testosterone were associated with measures of increased cortical excitability (i.e., greater ICF, MEP size, MT and MT reduction), suggesting that these hormones promote synaptic potentiation in the motor cortex. Progesterone, on the other hand, decreases neural firing by prolonging the inhibitory effects of GABA.8,9 This is consistent with the findings of an increase in SP duration and SICI, which are variables that reflect the activity of inhibitory circuits in the motor cortex.

The Implications of Sex Hormone Variations in TMS Clinical Practice

This review highlights the need for more thorough and clinically relevant investigation to better understand the impact of sex hormone variations on the effectiveness of rTMS. Only two studies investigated the impact of sex hormones in rTMS response in patients with MDD. These showed that higher levels of endogenous estrogen, specifically, are associated with better outcomes, and this may play a role in the variability of response to rTMS for the treatment of MDD. As such, these findings justify trials in tailoring rTMS protocols around periods of hormonal flux and performing more frequent MT assessments in patients undergoing hormonal treatment and in females of reproductive age. Given that a standard rTMS course is 36 sessions over 7–8 weeks, this allows the opportunity for changes in MT as a woman would experience up to two menstrual cycles. Additionally, any woman on monthly contraceptives may experience a week of dramatic change in sex hormones when they menstruate. There is also a need to incorporate measures of pathology and treatment response with tools such as functional MRI and EEG to evaluate the physiology of non-motor cortical areas, such as the DLPFC, the pre-supplementary motor area, and the ventromedial prefrontal cortex, which have been identified as therapeutic targets for various psychiatric conditions.

This review also raises the question how to deliver rTMS in patients undergoing hormonal changes and treatments, which is not an uncommon occurrence. In vitro fertilization currently accounts for millions of births worldwide and 1–3% of all births every year in the U.S. and Europe.48 The number of individuals seeking gender-affirming hormonal treatment is also increasing.49 Meanwhile, pregnant and postpartum lactating women are typically encouraged to seek nonpharmacological treatment for depression.

Lastly, the menopause transition is a particularly vulnerable period for the development of MDD and exacerbation of depressive symptoms for which rTMS usually is presented as a more attractive option given its low side effect profile. As such, we would like to propose that the TMS clinician:

  1. Consider inquiring about association between exacerbation of depressive symptoms and the menstrual cycle in all women undergoing rTMS.

  2. Consider assessing the MT prior to ovulation (cycle day 10) and in the mid-luteal phase (cycle day 20) of the menstrual cycle in all women of reproductive age who are not on systemic oral contraceptive pills.

  3. In pregnant women, consider assessing the MT at least biweekly during the course of rTMS.

  4. Consider performing MT assessments at weekly in patients receiving changes in the dose of estrogen and/or progesterone, such as in the case of in vitro fertilization, hormone replacement therapy, and gender-affirming hormonal treatments.

  5. Consider delaying the rTMS course until the hormone treatment is stable.

CONCLUSION

In summary, the results from this review show that variations in progesterone, estrogen, and testosterone have modulatory effects on TMS-derived measures of cortical excitability. These findings justify the need for clinical trials evaluating the role of neuroactive steroids and hormonal changes on rTMS protocols, clinical outcomes, and circuit-specific physiological variables.

Supplementary Material

Supplemental Figure 1

Source of Funding:

MDK is receiving funding from the National Institutes of Health (NIH) Translational Neuroscience Training for Clinicians (Grant Number: T32 MH112485). JAC was partially funded by the National Institutes of Health (R01MH12737). JAC is a member of the scientific advisory board of Hyka Therapeutics and Feelmore Labs, and has been a consultant for Neuronetics.

Supported in part by the National Institutes of Health (NIH) Translational Neuroscience Training for Clinicians (Grant Number: T32 MH112485)(Dr. Kritzer); the National Institutes of Health (R01MH12737)(Dr. Camprodon).

Footnotes

*

For purposes of this review, RMT and MT will be interchangeably throughout.

Declaration of Interest

The rest of the authors report no conflicts of interest.

Dr. Camprodon is a member of the scientific advisory board of Hyka Therapeutics and Feelmore Labs and has been a consultant for Neuronetics. Drs. Rivas-Grajales, Barbour, and Kritzer report no conflicts of interest.

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