Brain-steroids interactions
Sex steroids exert vital organizational and activational influences within the nervous system. Organizational effects entail the permanent differentiation of neural circuitry responsible for sexual dimorphism (masculinization or feminization) during critical periods of brain development. On the other hand, the activational effects of sex hormones in the mature brain are largely reversible, essential for regulating the hypothalamic-pituitary-gonadal axis and establishing gender-appropriate patterns of sexual, aggressive, cognitive and autonomic behaviors. In both sexes, estrogen-binding neurons are concentrated in the preoptic area, medial basal hypothalamus, medial amygdala and circumventricular organs. Estrogen-binding neurons also reside, to a lesser extent, in the basal forebrain, hippocampus, several thalamic nuclei, sensory regions of the brainstem and spinal cord.
In neurons, sex steroids and their metabolites regulate the biosynthesis of enzymes and structural proteins involved in neurotransmission, cell membrane function, energy metabolism, and hormonal sensitivity. At the molecular level, progestins, estrogens, and androgens interact with specific receptor proteins within the cytoplasm or nucleus of target cells. These steroid–receptor complexes can either activate or repress the transcription of various genes. In addition to altering gene transcription profiles, sex steroids may influence neural functions through epigenetic regulation of cellular DNA methylation status. For example, estrogens influence DNA methylation and reduce promoter methylation of brain-derived neurotrophic factor (BDNF), a protein critical for neuronal maturation and synaptic plasticity.
Testosterone impacts histone acetylation and methylation through modulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs) which may impact dopaminergic signaling in Parkinson disease (PAD); and epigenetic modifications of the progesterone receptor may affect the natural history of breast cancer and endometriosis and their neurological complication. Sex hormones may also modulate neuronal discharges via rapid (nongenomic mechanisms) dependent on protein kinases and affecting surface ion channe. A significant pathway mediating the latter involves the central synthesis of neurosteroids from hormone precursors secreted by the ovaries, testes, and adrenal glands.
Neurosteroids acutely modulate neuronal firing by altering GABA-A receptor–mediated chloride conductance, either enhancing or attenuating inhibitory signaling. Positive modulators like allopregnanolone, allotetrahydro-deoxy-corticosterone and androstanediol increase GABAergic transmission thereby reducing excitability, which may ameliorate epilepsy and mood disorders. Conversely, sulfated neurosteroids such as dehydro-epiandrosterone sulfate (DHEAS) and pregnanolone sulfate increase neuronal excitability by decreasing GABAergic tone and promoting calcium influx through NMDA receptors, neurophysiological effects which may support memory in ALD and other dementing disorders.
Migraine
Migraine, the most common type of vascular headache, is approximately three times more prevalent in adult women than men and may be over-represented in persons with endometriosis and the polycystic ovarian syndrome. Depending on the stringency of diagnostic criteria applied, anywhere from 18–60% of female migraine sufferers experience a worsening of headaches around menstruation (catamenial migraine). The intensity or frequency of migraine attacks often decreases during pregnancy, especially among those with menstrual-related migraines. However, many women who experience relief during pregnancy report a relapse of symptoms at or soon after childbirth. In some cases, breastfeeding may help prevent the recurrence of migraines. Migraine may also emerge or intensify during pregnancy or the perimenopausal phase.
The reduction in plasma estradiol (but not progesterone) during the late luteal phase is thought to play an important role in the onset of catamenial migraine. In pregnancy, the lack of cyclic estrogen withdrawal may help reduce migraine activity. Estrogens can affect migraine by acting directly on vascular smooth muscle or by modulating the activity of vasoactive substances at neurovascular junctions. Perimenstrual estrogen fluctuations may influence central serotonin, prostaglandin and/or opioid metabolism, which could stimulate vasoregulatory mechanisms in the hypothalamus or brainstem leading to symptomatic changes in cerebrovascular tone. Prolactin, which exhibits pronociceptive effects, and oxytocin, which has antinociceptive properties, have recently been implicated in the expression of migraine and may contribute to sex-dependent differences in the prevalence of this disorder.
Prolactin directly sensitizes sensory neurons and increases the release of calcitonin gene-related peptide (CGRP), a neuromodulator that promotes migraine in susceptible patients and is currently a major therapeutic target (18). Additionally, the lower prevalence of migraine in adolescent and adult men relative to women of similar age may, in part, be androgen dependent in light of the antinociceptive effects of testosterone on sensory neurotransmission, CGRP release, neuroinflammation, and cerebrovascular tone. Women using oral contraceptives may experience new-onset vascular headaches or an exacerbation of pre-existent migraine. These attacks typically occur during the initial cycles, especially on placebo days when estrogen levels drop, and generally subside once the contraceptive is discontinued. Migraine sufferers who develop focal auras while on oral contraceptives may face a heightened risk of infarction in the affected brain areas.
Perimenstrual migraine is often manageable with dietary, psychological, and pharmacological approaches commonly used for migraine treatment in general. Sumatriptan and other serotonin 5-HT1D receptor agonists are effective for both noncatamenial and menstrual migraines. For severe, refractory cases of catamenial migraine, late luteal phase therapy with prostaglandin inhibitors (NSAIDs) and/or mild diuretics may provide relief. Oral contraceptives may aggravate migraine and are probably best avoided in this context. Some women have reported significant symptom relief from menstrual migraine following treatment with the testosterone derivative, danazol or the dopamine agonist, bromocriptine. To avoid risks of teratogenesis, nonpharmacological methods (such as relaxation training and biofeedback) should be prioritized when managing migraine during pregnancy.
Brain stroke
The use of oral contraceptives has been identified as a significant risk factor for thromboembolic cerebral infarction, cerebral venous thrombosis, and subarachnoid hemorrhage. Risk factors such as age over 35, hypertension, smoking, and migraine further increase stroke risk for individuals on oral contraceptives. Recent declines in thromboembolic disease rates among oral contraceptive users are likely due to reduced doses of estrogen in modern formulations (e.g., 25–35 μg compared to earlier 50–75 μg preparations). Ultra-low-dose oral contraceptives (<25 μg ethinyl estradiol) may not elevate stroke risk in normotensive, nonsmoking individuals. There is, however, conflicting evidence regarding HRT and its effects on stroke incidence, with some studies showing neutral, increased, or decreased risk.
Notably, large, randomized trials have demonstrated that HRT with 17β-estradiol or conjugated equine estrogen, with or without medroxyprogesterone acetate, may worsen outcomes for women predisposed to stroke or coronary artery disease. Conversely, HRT with transdermal low-dose estrogens, alone or combined with micronized progesterone, may be beneficial in minimizing chances of ischemic stroke. The pathophysiology of sex steroid–related stroke, in particular the multifaceted impact of gonadal hormones on circulating lipid profiles, coagulation factors, platelet function, and atherogenesis, is reviewed elsewhere. Clinically, ischemic strokes linked to oral contraceptive use are localized to both the carotid (primarily the middle cerebral artery) and vertebrobasilar systems.
Exogenous gonadal hormones should be promptly discontinued and may be unsuitable for future use in young women who present with a stroke syndrome. Management of ischemic stroke related to hormone exposure should follow general protocols, including standard pharmacotherapy (antiplatelet agents, anticoagulants, fibrinolytics), interventional neuroradiology and rehabilitation. Early implementation of intravenous thrombolysis (tissue plasminogen activators) may benefit both men and women with acute ischemic stroke, though re-canalization (reperfusion) tends to be more effective in women. Former and current users of moderate- to high-dose oral contraceptives have an estimated fourfold increased risk of subarachnoid hemorrhage compared to the general population.
However, the odds ratio for hemorrhagic stroke in current users of low-dose estrogen contraceptives (20 to 35 μg) is negligible relative to former users or nonusers. Similar to ischemic stroke, factors such as cigarette smoking and age over 35 significantly increase the occurrence of subarachnoid hemorrhage in oral contraceptive users. Gender differences in intracerebral hemorrhage due to hypertensive arteriopathy, amyloid angiopathy, vascular malformations, and Moyamoya disease have also been documented. In rare cases of periodic subarachnoid hemorrhage due to spinal canal endometriosis, treatment may include progestins, GnRH agonists/antagonists, oophorectomy, and possibly vascular endothelial growth factor receptor inhibitors (e.g., sunitinib).
Parkinson disease
Idiopathic PAD is an aging-related movement disorder characterized by degeneration of dopaminergic neurons in the substantia nigra that occurs about twice as frequently in men than women. Interestingly, female predominance has not been observed in LRRK2-associated PD, the most common monogenic form of the illness. A large-scale study comparing drug-naïve men and women with early-stage idiopathic PAD, matched for motor impairment, found notable gender differences in nonmotor symptoms: men showed more pronounced deficits in olfaction and in specific cognitive areas (global cognition, memory, and visuospatial skills), while women exhibited higher levels of trait anxiety. Initial anecdotal reports indicated that exposure to exogenous estrogen may worsen both idiopathic and neuroleptic-induced parkinsonism,
However, studies on premenopausal women with idiopathic PD disclosed perimenstrual worsening of motor symptoms when estrogen levels decline. The effects of postmenopausal HRT in women with PD are mixed, with reports suggesting HRT may be beneficial, detrimental or inconsequential. Early menopause, whether natural or surgical, has been identified as a possible risk factor for PAD, which may be mitigated by postmenopausal estrogen replacement. However, a large prospective study found no evidence that estrogen reduces the risk of developing PD. Additionally, a case-control study identified steroid contraception as a potential PD susceptibility factor. Sex differences in responses to treatment of PD have been recognized and may be driven, at least in part, by hormonal factors.
Men tend to respond better to motor symptom control with dopaminergic agents than women; the latter may be more prone to levodopa-induced dyskinesias (involuntary movements) and are more likely to experience mood-related adverse effects of DBS. Of potential therapeutic interest, cerebrospinal fluid and plasma levels of allopregnanolone are reportedly low in idiopathic Parkinson. This neurosteroid has been shown to stimulate neurogenesis in the substantia nigra, modulate dopamine release and enhance motor control in animal models of the disease.
Wilson Disease
Wilson disease is a rare genetic disorder of copper metabolism marked by low blood ceruloplasmin levels, hepatic cirrhosis, copper deposits in the cornea (Kayser–Fleischer rings) and degenerative changes in the basal ganglia. In both healthy individuals and patients with Wilson disease, serum ceruloplasmin and copper levels may rise during pregnancy and following the use of steroid contraceptives. In women with Wilson disease, diagnosis may be delayed due to the “normalization” of ceruloplasmin levels following steroid contraceptive use. This false normalization provides no therapeutic benefit and may even be linked to neurological decline (e.g., abnormal movements, seizures, psychosis) in some cases. It is unknown whether gonadal hormones similarly elevate ceruloplasmin levels in other conditions featuring abnormally low concentrations of the protein, such as acquired copper deficiency and hereditary aceruloplasminemia.
Chorea
Choreiform movements (nonrhythmic motions involving the face and extremities) may arise as complications of pregnancy (chorea gravidarum) and oral contraceptive use. Chorea associated with pregnancy and oral contraceptives is more common in individuals with a history of rheumatic fever or Sydenham’s chorea. Oral contraceptives may also induce chorea in women with a background of congenital cyanotic heart disease, the antiphospholipid antibody syndrome, systemic lupus and Henoch-Schönlein purpura. Approximately 20% of affected women may experience relapses during future pregnancies. Women with dyskinesias linked to oral contraceptive use are at increased risk of developing chorea gravidarum and the reverse is true as well. Hormonal changes associated with pregnancy and the use of steroid contraceptives can unmask latent chorea by enhancing dopaminergic neurotransmission in basal ganglia previously damaged by hypoxic or rheumatic encephalopathy.
Women with gestational or contraceptive-related chorea may also experience fever, neuropsychiatric symptoms, dysarthria (slurred speech), pendular reflexes or limb hypotonia. Chorea gravidarum and dyskinesias related to contraceptive use generally resolve following childbirth or upon discontinuation of the medication. In cases of suspected chorea gravidarum, clinical and laboratory assessments are recommended to rule out other causes, such as hyperthyroidism, rheumatic fever, Wilson disease or systemic lupus erythematosus. Since chorea gravidarum is typically self-limiting, abortion or early delivery is seldom necessary. In more severe cases, dopamine antagonists (neuroleptics) may provide symptom relief. Those with a history of chorea gravidarum or contraceptive-induced dyskinesias should likely avoid further use of estrogen-containing medications.
Epilepsy
The course of epilepsy and its management can be significantly affected by various phases of the reproductive cycle and exposure to hormonal contraceptives. Certain seizure disorders may worsen premenstrually (catamenial epilepsy), at ovulation or during pregnancy. A large study found that menstrual irregularity between ages 18 and 22 was associated with a higher risk of epilepsy. Although the menstrual cycle and oral contraceptives appear to have limited clinical effects on anticonvulsant pharmacokinetics, gestational plasma levels of phenobarbital, phenytoin and valproic acid may drop by 30–40% from pre-pregnancy levels, with smaller decreases seen for carbamazepine. Primidone levels generally remain stable, though the concentration of its metabolite, phenobarbital may be reduced during pregnancy.
Seizure disorders and their treatments can interfere with normal reproductive functions. Conditions such as hypogonadotropic hypogonadism, polycystic ovary syndrome, and hyposexuality may result from abnormal limbic discharges in patients with temporal lobe epilepsy. Curiously, left-sided temporal lobe seizures are more likely to cluster at the onset of menses, whereas right-sided temporal seizures tend to occur more randomly throughout the menstrual cycle. Estrogens and progestins exhibit opposing effects on seizure activity, with estrogens being epileptogenic and progestins having anticonvulsant properties. Estrogens and certain sulfated neurosteroids enhance glutamatergic neurotransmission while reducing GABAergic activity, thereby promoting epileptogenesis, whereas progesterone and specific pregnane and androstane neurosteroids counteract these effects.
Perimenstrual seizure activity may be triggered by an increased estrogen-to-progesterone ratio during the late luteal phase. Similarly, elevated estrogen-to-progesterone ratios typical of polycystic ovary syndrome may partly explain the frequent association of this infertility condition with temporal lobe epilepsy. Estrogen-progestin contraceptives do not appear to significantly worsen seizure control in women with epilepsy and the impact of HRT on seizure control in epileptic postmenopausal women is minimal.In gestational epilepsy, factors such as insufficient anticonvulsant levels, sleep deprivation and stress are often more critical determinants of seizure activity than direct hormonal triggers. Decreased drug compliance, lower bioavailability, increased distribution volume and enhanced metabolic clearance contribute to reduced anticonvulsant levels during pregnancy.
Management strategies for catamenial epilepsy include: (1) premenstrual or periovulatory increases in anticonvulsant doses or the addition of an adjunct antiepileptic drug, such as clobazam; (2) cyclic use of a mild diuretic, like acetazolamide, which has modest anticonvulsant properties; and (3) progesterone supplementation, administered orally or via suppository. Early-phase clinical trials have evaluated the antiepileptic properties of ganaxolone, an analog of allopregnanolone, which acts as a positive allosteric modulator of GABA-A receptors. Ganaxolone has shown promise in animal models and, in randomized, placebo-controlled trials, reduced seizure activity in adults with drug-resistant partial-onset seizures. The drug was generally safe and well tolerated, with dizziness and fatigue being the most commonly reported side effects. Ganaxolone lacks hormonal activity thereby precluding potential risks associated with progestin therapy.
Multiple sclerosis
Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system, most commonly diagnosed in men and women during their reproductive years. An earlier age at puberty may be a predisposing factor for MS in girls but not boys. While oral contraceptive use does not appear to impact the risk of developing MS, it may delay the disease’s onset (61). Contrary to previous medical assumptions, the overall effect of pregnancy on MS-related morbidity is minimal. While MS symptoms may worsen in the first 3 months postpartum, this is often balanced by an improvement in disease activity during the third trimester. The reduction in disease burden during the third trimester in MS (and other immune-mediated conditions) is likely due to a state of relative maternal immunosuppression, which helps prevent rejection of the semiallogenic fetus.
A host of circulating steroidal and protein factors has been implicated in pregnancy-related immunosuppression including α-fetoprotein, cortisol, estradiol, human chorionic gonadotropin (hCG), human placental lactogen, interleukin-10, pregnancy-associated glycoprotein, progesterone, 1,25-dihydroxyvitamin D₃, and allopregnanolone.MS attacks during pregnancy can be managed with intravenous steroids. Interferons should be discontinued at least three months before planned conception and are not recommended during pregnancy or breastfeeding. Preliminary findings suggested that oral estriol may be beneficial for women with MS, and transdermal testosterone may offer benefits for men with the condition. A recent literature review concluded that estriol may have modest anti-inflammatory, and possibly neuroprotective, effects when administered as an adjunct to first-line immunomodulatory medications in female patients with MS.
Women, especially during their reproductive years, tend to exhibit more robust responses than men to first-line disease modifying treatments such as interferon-beta and glatiramer acetate. However, women may experience more pronounced untoward effects (liver enzyme elevation, lymphopenia) of fingolimod and dimethyl fumarate, and may be at higher risk than men for infusion-related reactions and autoimmune complications accruing from monoclonal antibody (natalizumab, ocrelizumab) exposure. Commonly used immunomodulatory medications for the management of MS do not appear to diminish the effectiveness of hormonal contraception. Less is known regarding the potential impact of natalizumab, ocrelizumab, ofatumumab and other anti-MS biologics on sex steroid metabolism.
Central hypertension
Estrogen-related attenuation of the blood-brain barrier may contribute to the pathogenesis of idiopathic intracranial hypertension (pseudotumor cerebri) in humans, potentially explaining the strong female predisposition to this disorder. Estrogens increase cerebral endothelial cell permeability and post-traumatic brain edema in female rats. Progesterone, on the other hand, reduces posttraumatic cerebral edema and intracranial hypertension in rodents, an effect attributed to decreased blood-brain barrier permeability and inhibition of cerebrospinal fluid production by the choroid plexus. Gonadal steroids may impact the pathophysiology of idiopathic intracranial hypertension by their effects on the brain’s glymphatic system. The latter comprises a recently recognized network of perivascular spaces that enables the movement of interstitial fluid, solutes and waste products between the cerebral vasculature and the cerebrospinal fluid. Idiopathic intracranial hypertension may be more prevalent in women with polycystic ovary syndrome and hyperandrogenism, as well as in female-to-male transgender individuals receiving intramuscular testosterone.
Sleep disorders
In women, sleep architecture is influenced by puberty, menstruation, pregnancy, and menopause. Sleep-related complaints are generally more common in women than men. Gender differences in sleep patterns emerge after puberty and may increase susceptibility to sleep disorders. For instance, insomnia is more prevalent in women, with the gender gap widening as age advances. Restless legs syndrome also occurs more often in women, while obstructive sleep apnea and rapid eye movement (REM) sleep behavior disorder are more frequent in men. The mechanisms by which altered gonadal hormone levels and their effects on neural targets within the diencephalon and brainstem influence human sleep physiology remain poorly understood.
In women, hypogonadism may disrupt normal sleep architecture by prolonging sleep latency, reducing REM sleep periods and increasing nocturnal movement arousals. In addition to the effects of fluctuating gonadal steroid concentrations, follicle-stimulating hormone may contribute to disruption of sleep patterns during the menopausal transition. Hyperandrogenism complicating the polycystic ovarian syndrome may predispose to obstructive sleep apnea in women. The higher prevalence of obstructive sleep apnea in men may be attributed not only to differences in gonadal steroid profiles but also to sex-based variations in neuromuscular reflexes and central ventilatory control. Complex interactions between sex hormones and melatonin.
Estrogen and melatonin mutually affect each other’s metabolism and jointly regulate sleep-wake cycles and REM sleep patterns; progesterone enhances melatonin synthesis which, in turn, may promote restorative sleep in persons with sleep apnea. Testosterone instead may suppress melatonin secretion and thereby contribute to sleep disturbances in aging men. In a study of 33 postmenopausal women, estrogen-progesterone therapy reduced breathing irregularities, periodic limb movements, nocturnal arousals, hot flashes, and bruxism (teeth grinding). For patients with central sleep apnea, progestins may help reduce hypoventilation by stimulating brainstem respiratory centers. However, administration of progesterone to healthy men may decrease wakefulness and vigilance, effects potentially mediated by pregnanolone and allopregnanolone.
The porphyrias
The porphyrias are characterized by an increased production of porphyrin precursors and porphyrins due to enzymatic defects in heme biosynthesis. Common neurological manifestations of certain porphyrias include sensorimotor and autonomic neuropathies, neuropsychiatric symptoms and seizures. Estradiol and other steroid hormones can precipitate porphyric crises by stimulating the heme biosynthetic enzyme, δ-aminolevulinic acid synthase. In women with acute intermittent porphyria, episodes of neuropathy and other neurological symptoms may arise during the late luteal phase, at ovulation or during pregnancy. Long-term administration of GnRH agonists, such as leuprolide or D-His, downregulates GnRH receptors in the pituitary leading to sustained suppression of the pituitary-ovarian axis. An early study reported complete remission of catamenial acute intermittent porphyria during an 8-month course of D-His treatment. Subsequent cases of perimenstrual acute intermittent porphyriaand hereditary coproporphyria also showed positive responses to GnRH agonist therapy. However, prolonged use of GnRH analogs or antagonists may result in adverse effects such as breast tissue atrophy, hot flashes, and bone demineralization. It is advisable that asymptomatic relatives of patients with genetic porphyrias avoid exposure to oral contraceptives.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Maguire JL et al. Neuropsychopharmacology. 2024; 49(1):73–82.
Dourson AJ, Darken RS et al. Neurobiol Pain. 2024; 16:100171.
Hegen H, Berek K et al. J Neurology 2024; 271(6):3256–3267.
Wang M, Hu S et al. J Steroid Biochem Mol Biol. 2024; 239:106485.
Singhal M, Modi N, Bansal L et al. Cureus. 2024; 16(7):e65866.
Bourque M et al. Neurosci Biobehav Rev. 2024; 156:105479.
Kumar R et al. CNS Neurol Disord Drug Targets. 2023; 22(1):6–17.
Carvalho V, Colonna I et al. Eur J Neurol. 2023; 30(9):2884–98.
Maekawa K, Yamanaka K. Clin Exp Neuroimmunol. 2023;14(2):100.
