Optimizing quality of life through sex steroids by their effects on neurotransmitters

THE BRAIN - NEW INSIGHTS

OPTIMIZING QUALITY OF LIFE THROUGH SEX STEROIDS BY THEIR EFFECTS OF

NEUROSTEROIDS

Marta Caretto, Andrea Giannini, Tommaso Simoncini, Andrea R. Genazzani

1

_{Division of Obstetrics and Gynecology, Department of Experimental and Clinical Medicine, University of}

Pisa, Italy

MC: martacaretto@gmail.com

AG: andrea.giannini@unipi.it

TS: tommaso.simoncini@med.unipi.it

ARG: argenazzani@gmail.com

Tommaso Simoncini, M.D., Ph.D. Prof.

Division of Obstetrics and Gynecology

Department of Clinical and Experimental Medicine

University of Pisa

Tel:

+39.050.993523 - +39.050.553412

Fax:

+39.050.553410

ABSTRACT

Menopause-related symptoms such as hot flashes, night sweats, weight gain, and decreased sexual

functioning all have negative impacts on quality of life (QOL) and affect daily activities such as sleep, work,

and leisure activities. During the menopause transition, neurotransmitters, neuropeptides and neurosteroids

undergo important changes as a consequence of the failure of gonadal hormone production, at a time when

many Central Nervous System ( CNS ) activities deteriorate. The benefits a proper hormonal balance during

the different stages of life has in the CNS. Knowledge of steroid hormone activity in the brain will give women

and health providers an important tool for improving their health and well-being.

From the concept of neurosteroids derives another treatment strategy: the use of pharmaceutical agents that

increase the synthesis of endogenous neurosteroids within the nervous system. This approach has so far

been hampered by lack of knowledge concerning the regulation of the biosynthetic pathways of

neurosteroids and their relationship with sex steroids produced by the peripheral gland or with exogenous

steroids. The present review summarizes some of the available clinical and experimental findings supporting

the critical role of neurosteroids in postmenopausal women and their impact on QoL.

Key words: Menopause, Quality of Life, Sex steroids, Neurosteroids, Dehydroepiandrosterone,

Allopregnanolone

INTRODUCTION

Levels of sex hormones, such as estrogen and progesterone, fluctuate naturally throughout the different

ages of a woman’s life. In women, steroid hormones are mostly synthesized in peripheral glands and the

adipose tissue as well as in the brain [ CITATION Del18 \l 1040 ]. The term “neurosteroids” is applied to

those steroids that are also formed and accumulate in the nervous system from cholesterol precursors, in

part, independently of peripheral steroidogenic glands secretion. Several studies have shown that some

psychological function and symptoms such as depression, anxiety, and irritability can be related to the

fluctuation of the synthesis and the release of the neurosteroids. The major steroids that met the criteria of a

neurosteroid included DHEA and pregnenolone, their sulfated derivatives DHEA sulfate (DHEAS) and

pregnenolone sulfate, and progesterone, deoxycorticosterone and their 5 α-reduced metabolites (mainly

allopregnanolone, ALLO) [ CITATION Plu17 \l 1040 ]. The decline in the reproductive capacity of women in

the late fourth to fifth decade of life is accompanied by diverse sequelae, including vasomotor symptoms,

psychogenic disturbance, cardiovascular and cerebrovascular disease and decreased sexual functioning.

Menopause-related symptoms have negative impacts on QOL and affect daily activities.

EFFECTS OF SEXUAL STEROIDS ON CNS

Through their actions in the CNS, neurosteroids regulate different brain areas involved in the modulation of

mood, behavior, and cognition. Therefore, the endogenous sexual hormonal fluctuations during specific

reproductive stages of life are related to an increased susceptibility of women to develop mood disorders,

and also may affect different cognitive processes such as decision-making, emotion recognition,

consolidation of emotional memory (Figure 1).

The senescence of the hypothalamic and hypothalamic –pituitary – gonadal axis induces vasomotor

symptoms and hypogonadism that could trigger menopause-related mental decline in other brain areas,

before deficits in learning and cognition become evident. The epidemiological data on the neuroprotective

effects of estrogen-based therapy suggest that women who were symptomatic from the menopause have

improvement in verbal memory, vigilance, reasoning and motor speed when given Hormone therapy (HT)

[ CITATION Plu17 \l 1040 ].

Goodnick et al. [ CITATION Goo00 \l 1040 ] demonstrated that women undergoing HT exhibit a reduction in

depressive symptoms. Several studies have shown an improvement in verbal memory, attention, and

reasoning together with a reduction in the risk of dementia: estrogen’s neuroprotective capacity and its role in

synaptic systems influence memory and cognition. Estrogens also have a neurotrophic action, as

demonstrated by an increase in the number of dendritic spine formations in the amygdala, hippocampus, and

the prefrontal cortex ( PFC). HT will have pleiotropic effects that will vary according to the timing of initiation,

the form of estrogen and of progestin used, the route of administration (e.g., oral vs. transdermal) and the

therapeutic scheme used (e.g., continuous or sequential). Concerning time of initiation, window of

opportunity hypothesis has shown that neurons become insensitive to estrogens after long-term hormone

deprivation [ CITATION Wha13 \l 1040 ].

Neurosteroids have a crucial role in depression. Interestingly, the concentrations of ALLO are decreased in

the frontal cortex of animals partly due to a diminished expression of 5α-reductase, a key enzyme in the

synthesizing ALLO and other 5α-reduced neurosteroids. Indeed, major depression in humans is associated

with a dysequilibrium of endogenous neurosteroids. Also estrogens exert antidepressant effects, in part, by

modulating synthesis and uptake of Serotonin (5-hydroxytryptamine, 5-HT). Estrogens affect vasomotor tone

by increasing release of endothelium-derived vasodilatory substances and reducing platelet aggregation and

secretion. Menopausal hormone therapy (MHT) may reduce depressive symptoms directly by modulating

5-HT levels in the brain and indirectly by modulating cerebral vascular reactivity. Different studies report a

positive association between platelet 5-HT turnover and plasma estrogen levels in menopausal women, but

none have related these to cardiovascular risk and only one compared two different formulations of estrogen.

At menopause, risk increases for developing mood disturbances and cardiovascular disease. Serotonin may

contribute to both processes as a neurotransmitter in the brain and as a vasoactive amine that promotes

endothelium dependent relaxation but causes contraction of vascular smooth muscle and promotes platelet

aggregation [ CITATION Raz15 \l 1040 ]. Evidence suggests a relationship between depression and

cardiovascular disease. However, the relationship of MHT and 5-HT to both processes is controversial, in

part, due to regulation and expression of 5-HT receptor subtypes, differences in measurement of 5-HT and

differences in dose and type of estrogen treatments used in various studies [ CITATION Van86 \l 1040 ]

[ CITATION Gre11 \l 1040 ].

With regard to the form of estrogens and progestins administered, the proportion of estrogenic forms is

different during menopause compared to premenopause. Initially, the proportion of estradiol (E2) is five times

greater than that of estrone (E1) [ CITATION Gle05 \l 1040 ]. Later, in menopause or postmenopause, E1 is

the predominant form of estrogen. The transdermal use of E2 has shown a positive impact on women’s

mood during their perimenopausal stage [ CITATION Fre08 \l 1040 ]. Conversely, the administration of HT in

the form of continuous conjugated equine estrogens (CEEs) (0.625 mg/d), rich in E1, does not show positive

results with regard to mood [ CITATION Hal01 \l 1040 ].

When combined HT is indicated, it is important to consider the type of progestin utilized. Several studies

have shown negative effects on the myelination of neural cells with medroxyprogesterone acetate (MPA)

use. The large multicenter WHI (Women’s Health Initiative) randomized placebo-controlled trial has shown a

clear example of the importance of considering the timing and the type of estrogen and progestin

administered [ CITATION Shu03 \l 1040 ] [ CITATION Rap03 \l 1040 ]. However, more than 65% of the

population of this study was older than 60 years of age, meaning that many of the women included in it were

beyond the time when they could benefit from HT. After an average follow up of 4–5 years, the WHIMS

(Memory Study portion) failed to observe any improvement in measures of global cognition or rates of either

mild cognitive impairment or dementia in women taking combined HT compared with placebo. Furthermore,

WHIMS observed an increased risk of dementia with this HT [ CITATION Shu03 \l 1040 ] [ CITATION

Del18 \l 1040 ]. These results can be partly explained by the lack of positive results that could endorse the

use of CEE in postmenopausal women, the known adverse effects that MPA has upon myelination and the

negative effects of estrogen administration out of the critical window of opportunity.

In postmenopausal women, MRT is able to modify circulating levels of neurosteroids, determining an

increase in ALLO levels and a decrease in DHEA. These data indicate a main role for these compounds as

neuroendocrine mediators of the effects of estrogens on the CNS: the effect exerted by HRT on ALLO levels

might be related to the anxiolytic and antidepressive effects of HRT in symptomatic menopausal women

[ CITATION Plu17 \l 1040 ].

Menopause transition is associated with decreased ALLO levels, mainly due to reduced ovarian synthesis of

progesterone, supporting its role in the physiology of mood disorder during the climacterium. In the CNS,

ALLO has been identified as a proliferative factor for both neural stem cells and progenitor oligodendrocytes.

The proliferative action of ALLO extends to the peripheral nervous system (PNS): it promotes proliferation of

Schwann cells, recovery from spinal cord injury, and re-myelination of peripheral nerve axons. In the

hippocampus, ALLO-induced mitosis was a fortuitous discovery that was initially observed in cultures of

hippocampal neurons and was later replicated in cultures of rat and human neural stem cells.

ALLO

treatment promote regeneration in brain cells. Collectively, the regenerative processes of neurogenesis,

oligogenesis and synaptogenesis, coupled with reduction in inflammation, provide multiple lines of preclinical

and clinical studies of efficacy that support the potential for ALLO as a safe and efficacious therapeutic agent

for brain regeneration and repair [ CITATION Plu17 \l 1040 ].

Neurosteroids have been widely recognized to modulate learning and memory processes in young, aged and

in pharmacological models of amnesia. Normal aging and cognitive dysfunction is associated with decreased

levels of DHEA and DHEAS. Consequently, neurosteroids such as DHEA and DHEAS are implicated to play

a role in the manifestations of Alzheimer’s disease. There is evidence that the concentrations of DHEA and

DHEAS are decreased in patients suffering from Alzheimer’s disease [ CITATION Red10 \l 1040 ].

Estrogens were found to play a role in neuronal plasticity and spine synapse formation. Furthermore, many

studies have shown positive effects of estrogens on cognition. In Alzheimer’s disease, estrogens have been

shown to protect neurones against the toxicity of amyloid plaques. Nevertheless, more studies are necessary

[ CITATION Mor18 \l 1040 ].

Sexual dysfunction, primarily low libido, is common among women, with prevalences of 8% to 50%

previously reported. The prevalence appears to increase with age from the third decade[ CITATION Lau44 \l

1040 ] as well as after oophorectomy. Although multiple psychosocial and health factors contribute to low

sexual desire and arousal, it has been proposed that endogenous sex steroids levels are significant

independent determinants of sexual behavior in women. Most studies support a therapeutic benefit of

testosterone for women experiencing hypoactive sexual desire disorder. Davis ed al.[ CITATION SDa05 \l

1040 ] observed significant associations between low sexual desire, arousal, and responsiveness in younger

women and low responsiveness in older women and low serum DHEAS level relative to age: DHEAS, not

free testosterone, seems to be the hormone associated with low self-reported sexual function. DHEA is the

most abundant sex steroid in women and circulating DHEA and its sulfate, DHEAS, provide a large precursor

reservoir for the intracellular production of both estrogens and androgens [ CITATION Lab82 \l 1040 ]. DHEA

and DHEAS are converted in extragonadal target tissues, such as the brain, bone, and adipose, either to

androstenedione or testosterone that may then be aromatized to estrone or estradiol or converted by

5-αreductase to dihydrotestosterone in the same cells. Thus androgenic effects vary according to individual

variations in the amount and activity of the enzymes 5-αreductase and aromatase, and individual differences

in the androgen-receptor response [ CITATION SDa05 \l 1040 ]. Over the past 10 years, hormone

preparations of DHEA have been available over the counter and have been sold as the “fountain of youth”. A

growing evidence in the literature describes DHEAS as the most abundant sex steroids in plasma in humans

(more than 1000 times higher than estradiol and testosterone levels) an a low DHEAS level is negatively

correlate with domains of sexual function in pre- and postmenopausal women more than do testosterone

levels. In a cross-sectional study, higher endogenous DHEAS levels are independently and favorably

associated with several measures of cognitive function and well-being. As a consequence, DHEA

replacement may seem an attractive treatment opportunity. In the brain, DHEA is a neurosteroid that act as a

modulator of neurotransmitter receptors, such as GABA-A, N -methyl- D -aspartate, and sigma-1 receptors.

In vitro and in vivo documented effects involve neuroprotection, neurite growth, neurogenesis and neuronal

survival, apoptosis, catecholamine synthesis and secretion, as well as anti-oxidant, anti-inflammatory and

anti-glucocorticoid effects. Moreover, DHEA supplementation in postmenopausal women (6 – 12 months) is

effective in stimulating the synthesis of neuroactive steroids, in particular ALLO, and some neuropeptides

such as β-endorphin, which are crucial in the modulation of mood, memory and feeling of well-being, during

reproductive aging [ CITATION Plu17 \l 1040 ].

CONCLUSION

Synthesis of neurosteroids is critical for the brain aging process. The epidemiological data on the

neuroprotective effects of sex steroids suggest that women who were symptomatic from the menopause had

improvement in verbal memory, vigilance, cognitive and sexual function and motor speed when given HRT.

Sex steroids demonstrate neuroprotective and neuroexcitatory as well as antidepressive and memory

enhancing properties that will improve QoL in menopausal women.

REFERENCES

1. Del Río JP, Alliende MI, Molina N,Serrano FG, Molina S and Vigil P. Steroid Hormones and Their Action in

Women’s Brains: The Importance of Hormonal Balance. Front. Public Health 6:141. 2018.

2. Pluchino N, Santoro A, Casarosa E, Wenger JM, Genazzani AD, Petignat P and Genazzani AR. Advances

in neurosteroids: role in clinical practice. CLIMACTERIC. 2013, Vol. 16(Suppl 1):8–17.

3. Goodnick PJ, Chaudry T, Artadi J, Arcey S. Women' s issues in mood disorders. Expert Opin

Pharmacother. 1:903–16, 2000.

4. Wharton W, Gleason CE, Olson SR, Carlsson CM, Asthana S. Neurobiological underpinnings of the

estrogen – mood relationship. Curr Psychiatry Rev. 8:247–56, 2013.

5. Raz L, Hunte LV, Dowling NM, Wharton W, Gleason C E, Jayachandran M et al. Differential effects of

hormone therapy on serotonin, vascular function and mood in the KEEPS. Climacteric, 19(1), 49–59. 2015.

6. Vanhoutte PM, Luscher TF. Serotonin and the blood vessel wall. J Hyperten. 1986, Vol. 4:S29–S35.

7. Greendale GA, Derby CA, Maki PM. Perimenopause and cognition. Obstet Gynecol Clin North Am. 2011,

Vol. 38:519–35.

8. Gleason CE, Carlsson CM, Johnson S, Atwood C, Asthana S. Clinical pharmacology and differential

cognitive efficacy of estrogen preparations. Ann N Y Acad Sci. 115:93–115, 2005.

9. Frey BN, Lord C, Soares CN. Depression during menopausal transition: a review of treatment strategies

and pathophysiological correlates. Menopause Int. 14:123–8, 2008.

10. Halbreich U, Kahn LS. Role of estrogen in the aetiology and treatment of mood disorders. CNS Drugs .

15:797–817, 2001.

11. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. Estrogen plus progestin and the

incidence of dementia and mild cognitive impairment in postmenopausal women. JAMA . 2003.

12. Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, et al. Effect of estrogen

plus progestin on global cognitive function in postmenopausal women. JAMA . 2003, Vol. 289:2663.

13. Reddy DS. Neurosteroids: Endogenous Role in the Human Brian and Therapeutic Potentials. Progress in

Brain Research. 2010, Vol. 186: 113–137.

14. Moraga-Amaro R, van Waarde A, Doorduin J, & de Vries E FJ. Sex steroid hormones and brain function:

PET imaging as a tool for research. . Journal of Neuroendocrinology. 2018, Vol. 30(2), e12565.

15. Laumann E, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors.

JAMA. 1999;281:537-544.

16. Davis S, Davison SL, Donath S, Bell RJl. Circulating Androgen Levels and Self-reported Sexual Function in

Women. JAMA. 2005, Vol. 294, 1.

17. Labrie F, Luu-The V, Labrie C, et al. Endocrine and intracrine sources of androgens in women: inhibition

of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev. .

2003; 24:152-182.

18. Derogatis L, Rust J, Golombok S, et al. Validation of the Profile of Female Sexual Function (PFSF) in

surgically and naturally menopausal women. J Sex Marital Ther. 2004;30:25-36.

Figure 1. The figure shows areas of the brain regulated by steroid hormones and some of the effects found

when a normal or abnormal balance between estrogen and progesterone is present. PFC, prefrontal cortex