Interactions between Gonadal Steroids and the Raphe System as an Approach to the Study of Hot Flush Mechanisms

In mammals, the reproductive function is controlled by the hypothalamic-pituitary-gonadal axis. During development, mechanisms mediated by gonadal steroids exert an imprinting at the hypothalamic-pituitary level, by establishing sexual differences in the circuits that control male and female reproduction. In rodents, the testicular production of androgens increases drastically during the fetal/neonatal stage. This process is essential for the masculinization of the reproductive tract, genitals and brain. The conversion of androgens to estrogens in the brain is crucial for the male sexual differentiation and behavior. Conversely, feminization of the brain occurs in the absence of high levels of gonadal steroids during the perinatal period in females. Potential genetic contribution to the differentiation of brain cells through direct effects of genes located on sex chromosomes is also relevant. In this review, we will focus on the phenotypic alterations that occur on the hypothalamic-pituitary-gonadal axis of transgenic mice with persistently elevated expression of the human chorionic gonadotropin hormone (hCG). Excess of endogenously synthesized gonadal steroids due to a constant hCG stimulation is able to disrupt the developmental programming of the hypothalamic-pituitary axis in both transgenic males and females. Locally produced estrogens by the hypothalamic aromatase might play a key role in the phenotype of these mice. The “four core genotypes” mouse model demonstrated a potential influence of sex chromosome genes in brain masculinization before critical periods of sex differentiation. Thus, hormonal and genetic factors interact to regulate the local production of the neurosteroids necessary for the programming of the male and female reproductive function.

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Immunohistochemical localization of pituitary gonadotrophins and gonadal steroids confirms the 'two-cell, two-gonadotrophin' hypothesis of steroidogenesis in the human ovary

Journal of Endocrinology ◽

10.1677/joe.0.1260483 ◽

1990 ◽

Vol 126 (3) ◽

pp. 483-NP ◽

Cited By ~ 35

Author(s):

M. Kobayashi ◽

R. Nakano ◽

A. Ooshima

Keyword(s):

Luteal Phase ◽

Immunohistochemical Analysis ◽

Immunohistochemical Localization ◽

Follicular Phase ◽

Gonadal Steroids ◽

Immunohistochemical Method ◽

Human Ovary ◽

Luteal Cells ◽

Menstrual Cycles

ABSTRACT Ovaries from 37 women with normal menstrual cycles were analysed for localization of pituitary gonadotrophins and gonadal steroids using an immunohistochemical method. In the follicular phase, FSH and oestradiol-17β localized in the granulosa layer, and LH, progesterone and testosterone localized in the internal thecal layer. In the luteal phase, gonadotrophins and steroids localized in luteal cells. Particularly in the early luteal phase, FSH and oestradiol-17β localized in large luteal cells, and LH, progesterone and testosterone localized in small luteal cells. The results of the present immunohistochemical analysis confirm the two-cell, two-gonadotrophin hypothesis of steroidogenesis in the human ovary. Journal of Endocrinology (1990) 126, 483–488

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Gonadal steroids effect similar regulation of gonadotrophin subunit mRNA expression in both male and female rats

Journal of Endocrinology ◽

10.1677/joe.0.1320039 ◽

1992 ◽

Vol 132 (1) ◽

pp. 39-45 ◽

Cited By ~ 14

Author(s):

A. C. Dalkin ◽

S. J. Paul ◽

D. J. Haisenleder ◽

G. A. Ortolano ◽

M. Yasin ◽

...

Keyword(s):

Gene Expression ◽

Steady State ◽

Gnrh Antagonist ◽

Gonadal Steroids ◽

Female Rats ◽

Plasma Testosterone ◽

Subunit Gene ◽

Gnrh Secretion ◽

Male And Female Rats ◽

Males And Females

ABSTRACT Gonadal steroids can act both indirectly via gonadotrophin-releasing hormone (GnRH) and directly on the pituitary to regulate gonadotrophin subunit gene expression. Recent studies to assess a possible direct action at the pituitary have shown that testosterone, when given to males in the absence of endogenous GnRH action, selectively increases FSH-β mRNA concentrations. Conversely, in females, oestradiol appears to regulate gonadotrophin subunit mRNAs primarily via GnRH. The present study was designed to determine whether these differing results reflect specific actions of the gonadal steroids themselves or different responses of the pituitary gonadotroph cells in males and females. Rats which had been castrated 7 days earlier were given silicone elastomer implants (s.c.) containing oestradiol (plasma oestradiol 68 ± 4 ng/l) in males or testosterone (plasma testosterone 3·5 ± 0·3 μg/l) in females in the absence or presence of a GnRH antagonist. Seven days later pituitaries were removed and steady-state mRNA concentrations measured by dotblot hybridization. In males, oestradiol reduced LH-β and FSH-β but not α mRNA. The antagonist reduced levels of all three subunit mRNAs in males and the addition of oestradiol had no further effect, suggesting that oestradiol regulates gonadotrophin subunit gene expression in males by suppressing GnRH secretion. In females, testosterone reduced all three subunit mRNAs though FSH-β remained threefold higher than in intact animals. The GnRH antagonist was as effective as testosterone alone and reduced α and LH-β to levels found in intact animals. FSH-β mRNA was partially reduced by antagonist alone in ovariectomized females but the addition of testosterone increased FSH-β twofold versus antagonist alone (as has been observed in males). These findings, together with earlier data, suggest that testosterone increased FSH-β twofold versus antagonist alone (as has been observed in males). These findings, together with earlier data, suggest that testosterone reduces gonadotrophin subunit mRNAs by inhibiting GnRH secretion and also acts directly on the gonadotroph to increase steady-state FSH-β mRNA concentrations in both males and females. Journal of Endocrinology (1992) 132, 39–45

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ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functional Effects in the Brain after Systemic Dosing

Endocrinology ◽

10.1210/en.2008-0532 ◽

2008 ◽

Vol 149 (10) ◽

pp. 5219-5226 ◽

Cited By ~ 25

Author(s):

Peter D. Alfinito ◽

Xiaohong Chen ◽

James Atherton ◽

Scott Cosmi ◽

Darlene C. Deecher

Keyword(s):

Body Weight ◽

Skin Temperature ◽

Ethinyl Estradiol ◽

Ovariectomized Rats ◽

Ici 182,780 ◽

Hot Flush ◽

Hypothalamic Tissue ◽

Dependent Model ◽

The Brain ◽

Neuroendocrine Functions

Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. Using HPLC with mass spectrometry, ICI (1.0 mg/kg·d, 3 d) was detected in plasma and brain and hypothalamic tissues for up to 24 h with maximum concentrations of 43.1 ng/ml, and 31.6 and 38.8 ng/g, respectively. To evaluate antiestrogenic effects of ICI in the brain after systemic dosing, we tested its ability to block the effect of 17 α-ethinyl estradiol (EE) (0.3 mg/kg, 8 d) on tail-skin temperature abatement in the morphine-dependent model of hot flush and on body weight change. In the morphine-dependent model, EE abated 64% of the naloxone-induced tail-skin temperature increase. ICI pretreatment (1.0, 3.0 mg/kg·d) dose dependently inhibited this effect. ICI (3.0 mg/kg·d) alone showed estrogenic-like actions, abating 30% the naloxone-induced flush. In body weight studies, EE-treated rats weighed 58.5 g less than vehicle-treated rats after 8 d dosing. This effect was partially blocked by ICI (3.0 mg/kg·d) pretreatment. Similar to EE treatment, rats receiving 1.0 or 3.0 mg/kg·d ICI alone showed little weight gain compared with vehicle-treated controls. Thus, ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and has both antiestrogenic and estrogenic-like actions on neuroendocrine-related functions.

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