ABSTRACT Title of Dissertation: GONADAL AND STEROID FEEDBACK REGULATION OF THE HYPOTHALAMUS-PITUITARY AXIS IN STRIPED BASS (Morone saxatilis) Ulrike Klenke, Doctor of Philosophy, Dissertation directed by: Professor Yonathan Zohar Center of Marine Biotechnology, University of Maryland Biotechnology Institute. gonadal steroid hormones: Behavioral, endocrine, and fMRI investigations in humans by Steven J. Stanton A dissertation submitted in partial fulfillment of the requirements for the degree of. Continued research is needed to understand how the gonadal steroids, such as oestrogen, progesterone, and testosterone, affect neural development during adolescence and subsequently influence adult behaviour. The present thesis focuses on the influence of estrogen (particularly estradiol) and progesterone on cerebral lateralisation, functional connectivity, and cognition in naturally cycling women. Young, naturally cycling women, free of hormonal contraceptives, were tested. Cellular and Molecular Characterisation of Pelvic Ligaments Fibroblasts: Effects of Gonadal Steroids Thesis submitted for the degree of Doctor of Medicine Department of Cancer Studies and Molecular Medicine Leicester and Warwick Medical School University of Leicester By Ayman A. A. Ewies MBChB, MSc, MRCOG.
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Language: English Spanish French. The nature and extent of the impact of gender and reproductive function on mood has been the subject of speculation and controversy for centuries. Over the past 50 years, however, it has become increasingly clear that not only is the brain a major target of reproductive steroid hormones, but additionally, the steroid hormones, as neuroregulators, create a context thai influences a broad range of brain activities; ie, neural actions and resultant behaviors are markedly different in the presence and absence of gonadal steroids.
In turn, the actions of gonadal steroids are themselves context-dependent.
Thus, even where it can be demonstrated thai gonadal steroids trigger mood disorders, the triggers are normal levels of gonadal steroids to be contrasted with the mood disturbances accompanying endocrinopathies , and the mood disorders appear only in a subset of susceptible individuals. The context specificity and differential susceptibility to affective dysregulation seen in women with reproductive endocrine-related mood disorders are undoubtedly important underlying characteristics of a wide range of psychiatric disorders in which the triggers have not yet been identified.
Consequently, reproductive endocrine-related mood disorders offer unparalleled promise for the identification of those contextual variables that permit biological stimuli to differentially translate into depression in individuals at risk. Por ejemplo, las acciones neural es y las conductas resultantes son marcadamente diferentes en presencia o ausencia de esferoides gonadales.
This issue of Dialogues in Clinical Neuroscience focuses on depression and senescence in women for several reasons. First, mood disorders linked to reproductive endocrine change in women eg, premenstrual syndrome [PMS], postpartum depression [PPD], and perimenopausal depression [PMD] are clinically significant: they are prevalent and attended to by considerable morbidity.
Simply put, these steroids create a context such that the brain functions differently in their presence and absence. Third, political objections notwithstanding, it is now clear that reproductive steroids play a critical role in triggering reproductive endocrine-related mood disorders, thus compromising arguments that these disorders do not exist or that the ostensible link to reproductive endocrine change is illusory. Fourth, it is equally clear that reproductive steroids do not, by themselves, cause reproductive endocrine-related mood disorders; ie, women with these disorders are differentially sensitive to levels or changes in reproductive steroids that are without effect on mood in women lacking these disorders.
This differential sensitivity, the fact that people respond differently to the same reproductive endocrine stimulus, is important for three reasons.
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First, the failure to consider this phenomenon has been the keystone of the argument that reproductive endocrine-related mood disorders do not exist.
The syllogism is as follows: The effects of reproductive hormones should be similar across individuals; not all individuals have the same behavioral concomitants of changes in reproductive endocrine function; therefore, reproductive hormones have nothing to do with behavior. In other words, if changes in reproductive steroids do not precipitate mood disorders in everyone, they must do so in no one.
As will be shown below, this argument is fallacious and serves to obscure rather than clarify. Second, the principle that the response to a biologic stimulus depends upon the context in which the stimulus is administered is gcneralizablc and underlies much of our physiology. The observed links between reproductive function and behavior date back at least several millennia to Aristotle, who noted that castration of immature male birds prevented the development of characteristic male singing and sexual behavior.
In this fashion, reproductive steroids were found to regulate the expression of a variety of proteins of relevance for neural function eg, neurotransmitter synthetic and metabolic enzymes, neuropeptides, receptors, etc.
More recently, advances in neuroscience reviewed in the accompanying article by McHwen8 have demonstrated vastly more complex, broad-ranging, and powerful mechanisms for neural control by reproductive steroids, and have further uncovered several regulatory principles that help explain how a given steroid signal may elicit diverse behavioral responses. One inescapable, overarching principle is that the molecular and behavioral effects of steroids are highly context-dependent.
Data overwhelmingly suggest that the cell is a context that determines the response to a stimulus.
First, steroidactivated receptors influence transcription not as solitary agents, but by forming combinations with other intracellular proteins. Other proteins, the cointegrators, permit activated receptors to regulate genomic expression through sites eg, activator protein, API other than the classical DNA hormone response elements, thus expanding the range of genes influenced by steroids.
Once again, the effect observed depends upon the type of cell examined: estradiol activates the second messenger, mitogen-activated protein kinase MAPK , in neurons, but decreases MAPK activation in cortical glia. As steroid hormones are highly homologous and serve as precursors for one another, the manner in which steroids are metabolized can markedly change the amplitude or nature of the steroid signal.
Steroid metabolic enzymes, then, can contribute to the variance in a steroid signal in several ways. Perinatal reproductive steroids create a context that influences organizes brain development and the adult behavioral repertoire. Phoenix et al 23 and Gorski et al 24 showed that prenatal exposure of female guinea pigs or perinatal exposure of rats to androgens resulted in enhanced behavioral sensitivity eg, increased sexual and aggressive behaviors to androgens administered during adulthood.
Thus, differences in early exposure to reproductive steroids created the capacity in adults for different behavioral responses to the same stimulus. The effects of reproductive steroids are also developmental stage-specific. Estradiol, for example, stimulates its own receptor early in development inhibits it during adulthood, and stimulates it again in the context of brain injury.
Gonadal steroids, brain, and behavior: role of context
For example, spine density in the dentate gyrus is modulated by estradiol in old but not young female rats. These age-dependent effects are particularly of interest given a burgeoning literature describing the ability of reproductive steroids to regulate cell death and survival through effects on cell survival proteins eg, Bcl-2, Bax , signal transduction eg, MAPK, Akt , amyloid precursor protein metabolism, and free radical species generation.
Early effects influence pruning 31 and the shaping of brain circuitry. Modulation of neural and glial survival during aging provides yet another means by which reproductive steroids may influence the susceptibility to neuropsychiatrie illness, given the putative role of neurodegeneration in depression 32 - 34 and its demonstrated role in Alzheimer's disease.
The brain is a nonlinear transform system, in which the response to a stimulus can be altered as a function of past history or present environment. Multiple demonstrations of this process can be found in the animal literature. For example, behavioral sensitization refers to an amplified behavioral response eg, aggression to repeated exposure to a pharmacologic stimulus.
First, Antelman has suggested that even without repeated administration, exposure to certain drugs may yield an amplified response upon readministration, simply by virtue of the passage of time. Second, Post and coworkers have demonstrated that expression of behavioral sensitization may be context dependent, in that the exaggerated response elicited to cocaine in the test cage will not be manifest if, after sensitization is achieved, the cocaine is administered in the home cage.
One of the most impressive demonstrations of experience and development -related alterations in context is provided by the work of Meaney and coworkers. These authors 38 expanded the work of Levine 39 and showed that the separation and handling of rat pups elicited licking and grooming behavior from mothers that differentially and permanently determined the nature of the offspring's response to stressors.
Several studies also demonstrate the exquisite sensitivity of reproductive physiology and behavior to environmental alterations during development. Ward and Weisz 41 , 42 demonstrated that male offspring of a rat dam stressed during gestation were demasculinized, with lower testosterone levels on critical gestational days and deficient adult male mating behavior. Finally, reproductive hormones interact with environmental factors during development to determine the adult behavioral repertoire.
Adult aggressive behavior in mice can be attenuated by prepubertal castration; the attenuation, however, is blunted to the extent to which the mouse has already been exposed to aggressive encounters. Early hypotheses that the brain displays sex-related differences in structure and function were confirmed by the demonstrations by Pfaff 46 of sexual dimorphisms in rat brain morphology and by Raisman and Field 47 of sexrelated differences in the synaptic density of the preoptic area in the rat.
There is now an impressive literature detailing sexual dimorphisms at all levels of the neuroaxis, including differences in the following: nuclear volume; neuron number, size, density, morphology, and gene expression; signal transduction; neuronal neuritic branching patterns; synapse formation; and physiological and behavioral response.
Nonetheless, the source and significance of many of the dimorphisms are far from clear. For example, while exposure to reproductive steroids is believed to organize perinatally or activate adulthood most dimorphisms, Reiscrt and Pilgrim 50 showed that dimorphisms in the course of development of embryonic mesencephalic and diencephalic neurons appear under genetic control ie, they are determined well before the appearance of any differences in reproductive steroid levels.
Similarly, both the morphologic eg, neuritic extension and functional eg, signal transduction responses of cultured neurons and glia to reproductive steroids have been shown to display dramatic sexual dimorphisms despite exposure to identical levels of steroid, 17 , 51 , 52 ie, the dimorphic response cannot be attributed to differences in the steroid milieu of males and females. Additionally, the existence of brain sexual dimorphisms often is not translatable into gender-related differences in behavior.
Depression differs in women and men in a number of respects. Studies consistently demonstrate a twofold increased prevalence of depression in women compared with men, 56 - 59 and this increased prevalence has been observed in a variety of countries. Prepubertal depression prevalence rates are not higher in girls, 65 , 66 possibly reflecting ascertainment bias depressed boys may be more likely to come to the attention of health care providers or the possibility that prepubertal major depression is premonitory of bipolar illness.
Women are more likely to present with anxiety, atypical symptoms, or somatic symptoms 60 , 68 , 72 , 81 , 83 , 85 are more likely to report symptoms particularly in selfratings , 60 , 68 , 85 are more likely to report antecedent stressful events, 86 , 87 and manifest a more robust effect of stress on the likelihood of developing depression during adolescence.
Finally, while the prevalence of bipolar disorder is comparable in men and women, women are more likely to develop rapid cycling 64 and may be more susceptible to antideprcssantinduced rapid cycling.
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It is one matter to identify sex-related differences in depression and quite another to interpret their meaning. Specifically, one cannot infer that the observed differences are a product or a reflection of sex-specific biology. Sex-related differences in the prevalence of depression, for example, could occur consequent to increased number and severity of stressors experienced by women eg, greater demands to manage both home and vocational responsibilities; societal encouragement of conciliatory behavior and discouragement of expression of anger; a lack of social empowerment or to social stigmatization of endorsement of depressive symptoms in men.
Nonetheless, the potential for sex-dependent biology to play a significant role in affective and cognitive disorders is suggested by the following described below : i sexual dimorphisms in brain structure and physiology have been identified in humans; ii reproductive steroids regulate brain function in humans in vivo; and iii reproductive steroids play a role in the precipitation and treatment of mood disorders that are linked to periods of reproductive endocrine change.
Berman et al demonstrated that the normal pattern of cognitive task-activated cerebral blood flow was eliminated by induced hypogonadism and restored by replacement with estradiol or progesterone, findings supported by Shaywitz et al, who demonstrated estrogen enhancement of cognitive task-stimulated brain regional activation functional magnetic resonance imaging [fMRl] in postmenopausal women.
Wong et a! Further, in two recent studies using paired-pulse transcranial magnetic stimulation, Smith et al , showed that cortical facilitation was enhanced in the late follicular phase, while cortical inhibition was enhanced during the luteal phase, consistent with putative central excitatory effects of estradiol and inhibitory effects of progesterone metabolites. Despite gender-related and reproductive steroid-related differences in brain physiology, it is the investigation of mood disorders linked to reproductive endocrine change that offers the greatest potential insight into the role of reproductive steroids in the regulation and dysregulation of affect.
For example, in , Dr Ernst G. Despite the appeal of this hormone excess or deficiency hypothesis, however, early studies of the putative hormonal etiologies of PMS were inconsistent in their conclusions. A major source of study inconsistency was identified in the s, namely that samples of women with PMS were selected diagnosed with highly unreliable techniques ie, unconfirmed history.
Without prospective demonstration of luteal phase-restricted symptom expression, samples selected were certain to contain a large number of false positives, thus rendering the data obtained ungeneralizable to the population with PMS. Indeed, more recent studies have, if anything, largely preserved the formerly observed inconsistency.
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For example, Wang et al observed increased estradiol and decreased progesterone levels in women with PMS, Redei and Freeman reported nonsignificant increases in both estradiol and progesterone, while Facchinetti et al found no differences from controls in integrated progesterone levels.
Results from studies of androgen levels have been similarly inconsistent demonstrating both normal and decreased testosterone levels - and elevated and decreased free testosterone levels. Several studies do, however, suggest that levels of estradiol, progesterone, or neurosteroids eg, pregnenolone sulfate may be correlated with symptom severity in women with PMS.
If PMS is not due to a deficiency or excess of reproductive steroids or of any other hormone studied to date , do these steroids play any role at all in the precipitation of the syndrome? We attempted to answer this question by posing four questions.
If there was no obvious abnormality in the activity of the reproductive axis, was PMS in fact dependent on the menstrual cycle for its expression, or could it be dissociated from the luteal phase?
We blinded women to their position in the menstrual cycle by administering the progesterone receptor antagonist RU which both precipitates menses and ends corpus luteum activity , alone or with human chorionic gonadotropin hCG which preserves corpus luteum activity. Subjects in all three groups a placebo-only group was included experienced highly comparable symptoms that were significantly greater than those seen in the follicular phase; ie, women receiving RU alone developed characteristic symptoms of PMS in the experimentally produced follicular phase of the next cycle.
S, therefore, was not dependent on reproductive endocrine changes occurring in the mid-late luteal phase, as we were able to eliminate those changes without influencing subsequent symptom development. This left open the question of whether events occurring earlier than the mid-late luteal phase might, nonetheless, be influencing subsequent symptom development.
As the RU study eliminated only the mid-late luteal phase, PMS symptoms might have appeared consequent to reproductive endocrine events occurring earlier in the menstrual cycle.
Eighteen women whose PMS symptoms were significantly attenuated or eliminated by leuprolide-induced ovarian suppression were then continued on leuprolide and received in addition in a double-blind, crossover fashion estradiol 4 weeks followed by a fifth week in combination with progesterone to promote endometrial shedding and progesterone 4 weeks.
Finally, the same regimen of leuprolideinduced hypogonadism followed by sequential hormone replacement was performed in 15 control women, in whom the absence of menstrual cycle-related mood disturbances was confirmed with longitudinal ratings prior to study entry. The women with PMS whose symptoms were successfully eliminated or attenuated by leuprolide-induced hypogonadism experienced significant return of symptoms on either estradiol or progesterone, but not on placebo.
Characteristically, symptoms returned within 2 weeks of initiating hormone replacement and remitted by the fourth week of administration. In the control women lacking a history of PMS, however, neither the hypogonadal nor the hormone replacement conditions were associated with any perturbation of mood.
This study, then, raised a fundamental question: Why do similar changes in or levels of gonadal steroids trigger mood deterioration in women with PMS, while showing no apparent effect on mood in women lacking this history? While mood disorders may be seen in association with the pathological function of certain endocrine organs eg, adrenal, thyroid , mood disturbances precipitated by gonadal steroids in PMS appear in the context of normal ovarian function.
There are several possible means by which otherwise normal steroid signals might elicit a change in behavioral state. The serotonin systems are appealing candidates for conferring vulnerability to gonadal steroid-precipitated mood changes : gonadal steroids and serotonin display numerous reciprocal regulatory effects in the central nervous system CNS ; aggression against intruders by female rats resident intruder model varies with the estrous cycle, is ovarian steroid dependent, and is prevented by serotonin agonist antidepressants ; serotonin has a role in behaviors eg, appetite, impulsivity, mood, sleep, and sexual interest that vary with the menstrual cycle in PMS; blunted endocrine responses to serotonergic agonists eg, L-tryptophan, meta -chlorophenyl-piperazine have been described in PMS although not confined to the luteal phase , ; serotonergic agonists are efficacious in the treatment of PMS, and the therapeutic efficacy of serotonin agonists can be reversed by tryptophan depletion or serotonin receptor blockade.
PMS offers an ideal opportunity to identify genetic contributions to the vulnerability for affective disturbance, since the offending stimuli steroid triggers are known. Several polymorphisms in gonadal steroid receptors have been shown to alter receptor transcriptional efficacy eg, CAG repeat in exon 1 of the androgen receptor; progins insertion in intron 7 of the progesterone receptor and to be associated with differential illness risk ie, prostate cancer or breast cancer.
In genetic studies that we have performed to date in women with PMS and controls C. Roca and B. A significant difference has been identified, however, for the SLC6A4 promoter polymorphism of the serotonin transporter, with a higher frequency of the L long allele associated with increased transport and increased response to SSRIs , in the women with P. Roca et al, unpublished data.