Table 1

Hormonal effects on neurotransmitters and mood

Hormone; study	Model	Study design	Effect
Estrogen
Robichaud et al.7	A	Male and female rats received ICV 17 β-estradiol for 7 d.	Increased activity of 5-HT neurons v. controls.
Bethea et al.8	A	Ovariectomized monkeys treated with estradiol for 28 d or	Increased expression of enzyme involved in the synthesis of 5-HT
Pecins-Thompson et al.9		estradiol and progesterone for the last 14 d.	(i.e., TPH) in the dorsal raphe v. controls.
Smith et al.10	A	Ovariectomized monkeys treated with estrogen, estrogen + progesterone or raloxifene for 5 mo.	All 3 treatment arms increased TPH in the dorsal raphe v. controls.
Mize et al.11	A	Hippocampal and frontal cortex cells of ovariectomized rats incubated with 17 β-estradiol, BSA-estradiol or tamoxifen.	All 3 treatment arms desensitized 5-HT_1A autoreceptors.
Sumner et al.12	A	Castrated male and ovariectomized female rats treated with estradiol benzoate.	Castration significantly reduced 5-HT_2A receptor binding in the frontal, cingulate and piriform cortices, olfactory tubercle and nucleus accumbens. Estradiol increased receptor density in both sexes.
Raap et al.13	A	Recently ovariectomized rats treated with estradiol benzoate or vehicle for 2, 4 or 14 d.	Estradiol was found to desensitize 5-HT_1A autoreceptors.
Pau et al.14	A	Ovariectomized monkeys treated with intravenous estrogen.	Stimulated noradrenaline activity in the hypothalamus v. controls.
Panek and Dixon15	A	Female ovariectomized rats treated with 17 β-estradiol or saline for 7 d.	Estradiol exposure increased availability and synthesis of norepinephrine in the hypothalamus and cerebral cortex.
Petitti et al.16	A	Ovariectomized rats treated with estradiol benzoate at 24 and 48 h before death.	Estradiol effects α1- and β-adrenoreceptor activity in the hypothalamus.
Karkanias et al.17	A	Ovariectomized rats treated with estradiol benzoate at 24 and 48 h before death.	Estrogen controls norepinephrine activity in the hypothalamus through α2-adrenoreceptors.
Ansonoff et al.18	A	Ovariectomized rats treated with oestradiol benzoate or vehicle.	Estrogen treatment reduced β-adrenoreceptor activity in the hypothalamus and preoptic area.
Karkanias et al.19	A	Ovariectomized rats treated with estradiol benzoate (24 or 24 and 48 h) and untreated controls.	Estradiol exposure for 24 and 48 h produced increases in α1b-adrenoreceptor mRNA in the preoptic areas of the hypothalamus.
Clarke et al.20	A	Ovariectomized ewes treated with estradiol benzoate.	An estradiol-related release of norepinephrine in the preoptic area was observed that coincided with luteinizing hormone secretion.
Velisek et al.21	A	Ovariectomized rats treated with 17 β-estradiol or vehicle for 6 d had a seizure induced then continued treatment.	Estrogen treatment impacted GABA_B receptor–mediated inhibition in the dentate gyrus, protecting them from seizure related damage.
Schumacher et al.22	A	Ovariectomized and adrenalectomized rats were treated with estradiol benzoate alone or concomitantly with progesterone or vehicle.	Estrogen increased GABA_A receptor binding in hippocampal structures rich in ERs.
Jussofie et al.23	A	Rats ovariectomized or ovariectomized and adrenalectomized to assess the effect of a decline in estrogen and progesterone on GABA_A receptors.	Ovariectomy alone and ovariectomy + adrenalectomy had region-specific effects on the affinity of GABA_A receptor binding that coincided with decreases in estradiol and progesterone.
OConnor et al.24	A	Ovariectomized rats treated with 17 β-estradiol or vehicle.	No effect of estradiol on glutamic acid decarboxylase but significant effect on GABA_A receptor binding in brain areas rich/deficient in ERs.
Murphy et al.25	A	Hippocampal cells from rat embryos treated with 17 β-estradiol.	Estradiol was found to indirectly decrease inhibition of GABAergic activity and branching in the hippocampus.
Bazzett et al.26	A	Castrated male and ovariectomized female rats treated with estradiol benzoate (d 1–3) and progesterone (d 4), vehicle (d 1–3) and progesterone (d 4), or vehicle (d 1–4).	Estrogen’s effect on dopamine receptor activity is regional- and sex-specific. Females experienced an increase in D₂ activity in the caudal striatum, and males experienced a decrease in the rostral striatum.
Tinkler et al.27	A	Ovariectomized monkeys treated with estrogen for 24 mo or were untreated controls.	Ovariectomy associated with decrease in cholinergic fibre length and density in prefrontal cortex; estrogen prevented those changes.
Shughrue et al.28	A	Ovariectomized rats subcutaneously injected with colchicine followed by estrogen.	Active ERs were found in forebrain cholinergic neurons.
Nilsen et al.29	A	Hippocampal neurons collected from rat fetuses treated with conjugated equine estrogen.	Estrogen’s regulation of NMDA receptor activity associated with toxic levels of glutamate occurs via intracellular calcium. These results may indicate the ways in which estrogen provides neuroprotection.
Wihlback et al.30	H	Symptomatic postmenopausal women received continuous treatment with estradiol valerate then during 3–28 d periods either MPA, norethindrone acetate or placebo.	Significant improvements in depressed mood, irritability and tension in postmenopausal women during estrogen treatment.
Gregoire et al.31	H	Women with postnatal depression received double-blind treatment with transdermal 17 β-estradiol or placebo for 12 wk; cyclical dydrogesterone (12 d/mo) was added for 12 wk.	Estradiol treatment improved depressive symptoms to a greater degree than placebo.
Hlatky et al.32	H	Postmenopausal women with history of CAD received double-blind equine estrogen + MPA or placebo for 36 mo.	Among patients experiencing hot flushes, hormone treatment was associated with improvements in depressive symptoms.
Halbreich et al.33	H	Postmenopausal women given 30 d transdermal estradiol.	Treatment with estradiol increased serotonergic responsivity.
Soares et al.34	H	Depressed perimenopausal women randomized to double-blind transdermal 17 β-estradiol or placebo for 12 wk.	Significantly greater improvements in depressive symptoms were seen in the active treatment group v. placebo.
Morrison et al.35	H	Depressed postmenopausal women randomized to transdermal estradiol or placebo for 8 wk. Estradiol patients also received 2 wk of medroxyprogesterone treatment.	Similar changes in depressive symptom improvement with estradiol and placebo. Added progesterone produced a significantly greater decrease in positive affect compared with estradiol monotherapy.
Schmidt et al.36	H	Perimenopausal women with depression randomized to 6 wk of treatment with 17 β-estradiol or 3 wk of placebo lead-in phase followed by 3 wk active 17 β-estradiol treatment.	Significant improvements in depressive symptoms after 3 and 6 wk of continuous 17 β-estradiol treatment v. placebo. Patients who crossed over from placebo to 17 β-estradiol also saw improvements in depressive symptoms after 3 wk of active treatment.
Kugaya et al.37	H	Postmenopausal women receiving transdermal 17 β-estradiol were observed for 10 wk.	5-HT_2A receptor binding increased in the right prefrontal cortex.

Progesterone
Gundlah et al.38	A	Ovariectomized monkeys treated with progesterone for 28 d.	Decreased levels of monoamine oxidase-A in dorsal raphe v. controls.
Kaura et al.39	A	5-HT neurons collected from the dorsal raphe nucleus of rats were treated with allopregnanolone.	Allopregnanolone attenuates the response of serotonin neurons to GABA_A activation.
Karkanias et al.40	A	Ovariectomized rats treated with estradiol benzoate and progesterone or vehicle.	Progesterone suppressed activity of α1-adrenoreceptors in the hypothalamus and preoptic area.
Bitran et al.41	A	Ovariectomized rats participated in 2 animal models of anxiety while being treated with progesterone.	Treatment with progesterone produced an anxiolytic effect, which was related to its effect on GABA_A receptors.
Weiland et al.42	A	Ovariectomized and adrenalectomized rats were treated with estrogen and progesterone or either treatment alone.	Progesterone alone and with the addition of estradiol had an effect on the activity of GABA_A receptors.
Rapkin et al.43 Monteleone et al.44	H	Women with PMS and control women were compared during the luteal phases of their menstrual cycles.	Lower allopregnanolone levels were observed in patients with PMS when compared with control women.
Bicikova et al.45	H	Several hormones known to be GABA_A modulators were assessed in women with mixed anxiety-depressive disorder and healthy control women.	During the follicular and luteal phases significantly higher levels of pregnelone-sulfate were observed when compared with healthy control women.
Baker et al.46	H	Women with PMS received double-blind treatment with vaginal progesterone suppository or placebo.	Progesterone treatment had no effect on depressive symptoms.
Freeman et al.47	H	Healthy women administered oral progesterone in a double-blind, placebo-controlled manner.	Progesterone and allopregnanolone levels correlated with improvements in anxiety symptoms.

Testosterone
Robichaud et al.7	A	Male and female rats received ICV testosterone for 7 d.	An increased activity of 5-HT neurons was observed.
Zhang et al.48	A	Male rats that were controls, vehicle controls, castrated, castrated and treated with testosterone, and sham castrated rats were assessed on expression of 5-HT_1A and 5-HT_2A receptor mRNA expression.	Castrated rats had significantly higher activity of 5-HT_1A mRNA than controls, which was prevented by administration of testosterone.
Sumner et al.12	A	Castrated male rats treated with testosterone or 5-α dihydrotestosterone.	Castration significantly reduced 5-HT_2A receptor binding in the frontal, cingulate, and piriform cortices, olfactory tubercle and nucleus accumbens, which was reversed by testosterone treatment.
Shifren et al.49	H	Oopherectomized women aged 31–56 y currently receiving orally administered estrogen were administered 150 or 300 μg of transdermal testosterone.	An improvement in depressive symptoms was seen with the higher dose of testosterone.
Barret-Connor et al.50	H	Community-dwelling men aged 50–89 y and suffering from depression were assessed.	Decreases in bioavailable testosterone levels were associated with increases in depressed mood.
Weber et al.51	H	Pre- and postmenopausal women with severe depression and elevated cortisol levels and nondepressed control women not receiving hormonal therapy were enrolled.	Levels of circulating androstenedione, testosterone and dihydrotestosterone were significantly elevated in women with depression, compared with nondepressed women.
Santoro et al.52	H	Community-dwelling women aged 40–55 y.	Decreases in circulating testosterone levels were associated with higher depressive symptom levels.

DHEA/S
Robichaud et al.7	A	Male rats received ICV administration of DHEA for 7 d.	No effect on 5-HT firing.
Robichaud et al.53	A	Female rats were administered ICV DHEA for 21 d.	Greater increases in 5-HT firing in DHEA-treated rats v. controls on days 7, 14 and 21.
Majewska et al.54	A	Assessed DHEAS binding using nerve cells from rat brains and barbiturates as a biochemical assay.	DHEAS acts as a GABA_A allosteric antagonist.
Demirgoren et al.55	A	The forebrain of rats treated with DHEAS.	DHEAS served as a negative modulator of GABA_A activity.
Yaffe et al.56	H	Community-dwelling women aged ≥ 65 y assessed with a depression ratings scale and circulating hormone levels.	Women with DHEAS levels > 2.0 μg/dL had higher depression ratings than women with detectable DHEAS levels.
Wolkowitz et al.57	H	Depression patients randomly assigned to double-blind treatment with DHEA or placebo for 6 wk.	DHEA-treated patients had a significantly greater antidepressant response than those receiving placebo.
Bloch et al.58	H	Double-blind, randomized clinical trial comparing DHEA and placebo for the treatment of midlife dysthymia.	6 wk of DHEA treatment improved depression ratings to a significantly greater degree than placebo.
Barrett-Connor et al.59	H	Postmenopausal women with depression not taking estrogen provided plasma to assess hormone assays.	DHEAS levels were significantly and inversely related to depressive symptoms.
Wolkowitz et al.60	H	Men and women aged 51–72 y with depression and low plasma DHEA and DHEAS levels treated with DHEA for 4 wk	Significant improvements in mood related to increases in DHEA and DHEAS.

5-HT = serotonin; A = animal; BSA = bovine serum albumin; CAD = coronary artery disease; DHEA = dehydroepiandrosterone; DHEA/S = dehydroepiandrosterone sulfate; ER = estrogen receptor; GABA = γ-aminobutyric acid; H = human; ICV = intracerebroventricular; MPA = medroxyprogesterone acetate; mRNA = messenger ribonucleic acid; NMDA = N-methyl-d-aspartic acid; PMS = premenstrual syndrome; TPH = tryptophan hydroxylase.