Absence Of Gonadal Hormones Research Articles

Inheritance of steroid-independent male sexual behavior in male offspring of B6D2F1 mice

The importance of gonadal steroids in modulating male sexual behavior is well established. Individual differences in male sexual behavior, independent of gonadal steroids, are prevalent across a wide range of species, including man. However, the genetic mechanisms underlying steroid-independent male sexual behavior are poorly understood. A high proportion of B6D2F1 hybrid male mice demonstrates steroid-independent male sexual behavior (identified as “maters”), providing a mouse model that opens up avenues of investigation into the mechanisms regulating male sexual behavior in the absence of gonadal hormones. Recent studies have revealed several proteins that play a significant factor in regulating steroid-independent male sexual behavior in B6D2F1 male mice, including amyloid precursor protein (APP), tau, and synaptophysin. The specific goals of our study were to determine whether steroid-independent male sexual behavior was a heritable trait by determining if it was dependent upon the behavioral phenotype of the B6D2F1 sire, and whether the differential expression of APP, tau, and synaptophysin in the medial preoptic area found in the B6D2F1 sires that did and did not mate after gonadectomy was similar to those found in their male offspring. After adult B6D2F1 male mice were bred with C57BL/6J female mice, they and their male offspring (BXB1) were orchidectomized and identified as either maters or “non-maters”. A significant proportion of the BXB1 maters was sired only from B6D2F1 maters, indicating that the steroid-independent male sexual behavior behavioral phenotype of the B6D2F1 hybrid males, when crossed with C57BL/6J female mice, is inherited by their male offspring. Additionally, APP, tau, and synaptophysin were elevated in in the medial preoptic area in both the B6D2F1 and BXB1 maters relative to the B6D2F1 and BXB1 non-maters, respectively, suggesting a potential genetic mechanism for the inheritance of steroid-independent male sexual behavior.

Sex differences in social interaction of methamphetamine-treated rats

Our previous study showed that single injection of methamphetamine decreases social interaction (SI) in a dose-dependent manner that was further affected by stressful environment conditions. The aim of this study was to examine the effect of methamphetamine and its interaction with gonadal hormones on SI. Adult male and female rats were gonadectomized and assigned to testosterone-treated and oil-treated groups in male rats and estradiol-treated and oil-treated groups in female rats, respectively. Hormones were administered 30 min before each habituation in the open field. All four hormonal groups were further divided to control (without injection), saline (1 ml/kg saline injection), and methamphetamine (1 mg/kg) groups. Injections were applied 30 min before the SI test. The total duration and the total number of SI and nonsocial behavioral patterns were assessed. This study showed that an acute methamphetamine administration in a dose of 1 mg/kg decreased different types of SI in both sexes. In contrast, the same dose of methamphetamine increased locomotion and rearing behavior in male and female rats. The frequency and/or duration of SI (especially mutual sniffing and allogrooming) was lower in adult female rats relative to gonadectomized male rats, but locomotion was increased in female relative to male rats regardless of the presence or absence of gonadal hormones. In conclusion, this study is novel especially because it examines SI in both sexes in relation to the presence or absence of gonadal hormones.

Trophic Effects of Brain-Derived Neurotrophic Factor Blockade in an Androgen-Sensitive Neuromuscular System

In adult male rats, androgens are necessary for the maintenance of the motoneurons and their target muscles of the sexually dimorphic, steroid-sensitive spinal nucleus of the bulbocavernosus (SNB) neuromuscular system, regulating motoneuron and muscle morphology, function, and expression of trophic factors. Castration of males results in somal, dendritic, and muscle atrophy as well as increases in brain-derived neurotrophic factor (BDNF) in the target musculature. Because BDNF can have either facilitative or inhibitory effects in other systems, we examined SNB neuromuscular morphology after BDNF blockade using a fusion protein (tyrosine kinase receptor type B IgG). Blockade of BDNF in gonadally intact males resulted in hypertrophy of SNB motoneuron dendrites and target musculature, suggesting that normal levels of BDNF are inhibitory in SNB neuromuscular system. BDNF blockade in castrated males prevented SNB motoneuron atrophy and attenuated target muscle weight loss. This is the first demonstration that the highly androgen-sensitive SNB motoneuron dendrites and target muscles can be maintained in the absence of gonadal hormones and, furthermore, that blocking BDNF can have trophic effects on skeletal muscle. These results suggest that whereas BDNF is involved in the signaling cascade mediating the androgenic support of SNB neuromuscular morphology, its action can be inhibitory. Furthermore, the elevations in BDNF after castration may be responsible for the castration-induced atrophy in SNB motoneurons and target muscles, and the trophic effects of androgens may be mediated in part through a suppression of BDNF. These results may have relevance to therapeutic approaches to the treatment of neurodegenerative disease or myopathies.

Direct modulation of uterine leiomyoma proliferation and fibrosis by the GnRH agonist leuprolide acetate in the absence of gonadal hormones

OBJECTIVE: Uterine leiomyomata are hormonally-regulated tumors that can impact fertility and miscarriage. Gonadotropin releasing hormone agonists (GnRHa) decrease the size of these tumors by over 30%. Hypothetically, GnRHa acts by decreasing gonadal hormone production. However, recent data demonstrates that GnRH receptors are expressed on leiomyomas, and GnRHa treatment involves systemic exposure. We therefore hypothesized that GnRHa could directly regulate leiomyoma proliferation and extracellular matrix (ECM) production.

Puberty: a finishing school for male social behavior.

The classical view of steroid-dependent organization of brain and behavior holds that gonadal steroid hormones, acting during an early critical period of development, cause permanent structural changes in neural circuits that determine behavioral responses to hormones in adulthood. This classical view has been modified to incorporate evidence that organizational effects of steroids can occur outside of the established perinatal critical period and that multiple critical periods may exist during development. Experiments in this laboratory indicate that steroid-dependent organization of neural circuits underlying male social behaviors occurs during puberty. This work shows that adult-typical reproductive and flank marking behaviors cannot be activated by gonadal steroids in male Syrian hamsters prior to puberty, suggesting that developmentally timed processes during puberty render the nervous system responsive to activating effects of gonadal steroids in adulthood. Additional experiments demonstrate that the presence or absence of gonadal hormones during puberty is a major factor in the ability of steroids to activate reproductive and flank marking behavior in adult male hamsters and in androgen receptor expression within the neural circuit underlying these behaviors. Thus, gonadal hormones during puberty appear to exert long-lasting changes in neural circuits that are responsible for the programming of activational responses to steroids later in adulthood. A two-stage model for maturation of male social behaviors is proposed: a perinatal critical period for sexual differentiation of neural circuits, followed by the pubertal period, during which gonadal steroids further organize the circuits to enhance behavioral responsiveness to hormones in adulthood. Whether puberty is a critical period for the proposed second wave of steroid-dependent organization of behavioral circuits remains to be determined.

Modeling of bone formation and resorption mediated by parathyroid hormone: response to estrogen/PTH therapy

Bone, a major reservoir of body calcium, is under the hormonal control of the parathyroid hormone (PTH). Several aspects of its growth, turnover, and mechanism, occur in the absence of gonadal hormones. Sex steroids such as estrogen, nonetheless, play an important role in bone physiology, and are extremely essential to maintain bone balance in adults. In order to provide a basis for understanding the underlying mechanisms of bone remodeling as it is mediated by PTH, we propose here a mathematical model of the process. The nonlinear system model is then utilized to study the temporal effect of PTH as well as the action of estrogen replacement therapy on bone turnover. Analysis of the model is done on the assumption, supported by reported clinical evidence, that the process is characterized by highly diversified dynamics, which warrants the use of singular perturbation arguments. The model is shown to exhibit limit cycle behavior, which can develop into chaotic dynamics for certain ranges of the system’s parametric values. Effects of estrogen and PTH administrations are then investigated by extending on the core model. Analysis of the model seems to indicate that the paradoxical observation that intermittent PTH administration causes net bone deposition while continuous administration causes net bone loss, and certain other reported phenomena may be attributed to the highly diversified dynamics which characterizes this nonlinear remodeling process.

Permanence of brain sex differences and structural plasticity of the adult brain.

Sex differences in brain structure have been widely recognized since the pioneering studies of Raisman and Field (1). For the most part, brain sex differences are thought to arise in perinatal development through the actions of testosterone secreted by the developing testes, and these sex differences are believed to persist in the absence of gonadal hormones in adult life, very much like the basic plan of the male and female reproductive tracts, which are also developmentally determined. As shown in Fig. 1, the basic plan of brain and body sex differences is the result of a cascade of events beginning with the role of the sex-determining genes in sexual differentiation and continuing with the actions of hormones in embryonic, neonatal, peripubertal, and adult life. The emphasis on early developmental programming of brain structural sex differences was reinforced over several decades by the long-standing view that the brain is not capable of significant structural changes in adulthood. However, this view is changing, and in this issue of the Proceedings, Cooke et al. (2) describe a brain sex difference controlled entirely by circulating androgens. The postereodorsal nucleus of the medial amygdala is larger in male rats and females, but castration of adult males causes the volume of the nucleus to decrease to female levels within 4 weeks, whereas testosterone treatment of adult females for 4 weeks enlarges volume of this nucleus to male levels. Not only is the volume of the anatomical nucleus affected, but the individual cell soma areas are also increased in size by androgen, irrespective of genetic sex of the animal. These interesting findings are not as heretical as they might have seemed a few years ago, and they should be interpreted in light of new evidence for the structural plasticity of the adult brain at different …

Familiarity and gender influence social preferences in prairie voles (Microtus ochrogaster)

The physiological mechanisms influencing group cohesion and social preferences are largely unstudied in prairie voles (Microtus ochrogaster). In nature, prairie vole family groups usually consist of an adult male and female breeding pair, one or more litters of their offspring, and occasionally unrelated adults. Pair bonds, defined by heterosexual preferences, develop in male and female prairie voles following cohabitation or mating. However, social preferences between members of the same sex also may be important to the maintenance of communal groups. In the present study we compared the development of social preferences for conspecific strangers of the same sex versus preferences for the opposite sex, and examined the effect of the gonadal status of the stimulus animal on initial social preference. The present study revealed that reproductively naive males, but not females, showed initial preferences for partners of the opposite sex. In both sexes preferences for the opposite sex were not influenced by the presence or absence of gonadal hormones. Heterosexual and same-sex preferences for a familiar individual formed following 24 h of nonsexual cohabitation in both males and females. Male and female same-sex preferences, however, were no longer stable when the stranger in the preference test was of the opposite sex to the experimental animal. The development of same-sex preferences may help to maintain group cohesion, but same-sex preferences formed by cohabitation do not withstand the challenge of an opposite-sex stranger.

Skeletal Effects of Estrogen*

BONE differs from reproductive tissues in that many aspects of skeletal growth, turnover, and function occur in the absence of gonadal hormones. Nevertheless, sex steroids have an important impact on bone physiology: they participate in the sexual dimorphism of the skeleton, play a role in maintenance of mineral homeostasis during reproduction, and are essential to maintaining bone balance in adults. Insufficient levels of certain sex steroids predispose the human skeleton to bone loss and to osteoporotic fractures. Estrogen appears to be the most important sex steroid in preventing osteoporosis in women and is the subject of this review. Serious difficulties must be overcome to understand the action of estrogen on mineralized tissues. The skeleton is heterogeneous and contains many cell types. The cells that synthesize (osteoblasts), lie within (osteocytes), and degrade (osteoclasts) bone matrix are present in small numbers, are difficult to isolate as pure populations, and probably do not proliferate.

Gonadectomy does not prevent novelty or drug-induced motor hyperresponsiveness in rats with neonatal hippocampal damage

To explore the possibility that gonadal hormones are required for triggering the postpubertal emergence of enhanced dopamine-related behaviors in rats with neonatal excitotoxic lesions of the ventral hippocampus (VH), we assessed behavioral changes in castrated VH lesioned rats. The VH of rat pups was lesioned with ibotenic acid on day 7 after birth (PD7). Rats were castrated on PD21. Novelty- and amphetamine-induced locomotor activity were tested on PD56, and apomorphine-induced stereotypic behaviors and locomotion were evaluated on PD98. As demonstrated previously, the VH lesioned rats expressed enhanced novelty-, amphetamine- and apomorphine-induced hyperlocomotion (PD56) as well as potentiated apomorphine-induced stereotypic behaviors (PD98) in young adulthood as compared with sham-lesioned counterparts. Castration had no significant effect on novelty-induced locomotion or apomorphine-induced stereotypies but potentiated amphetamine- and apomorphine-induced hyperactivity in lesioned rats. These results indicate that the absence of gonadal hormones not only does not prevent the appearance in adulthood of behavioral disturbances linked to increased DA transmission in rats with neonatal lesions of the VH but even exaggerates those linked primarily to the mesolimbic DA system.

Sex differences in anxiety behavior in rats: Role of gonadal hormones

These experiments examined the role of gonadal hormones at both the organizational and activational time periods on sex differences in plus-maze behavior. In the first experiment, adult female Long-Evans rats were found to spend more time on the open arms of the plus maze than adult males, indicating less anxious behavior. In the second experiment, male and female subjects received a neonatal treatment (chemical castration with flutamide or tamoxifen, vehicle injection, or no injection) and a prepubertal treatment (gonadectomy, sham surgery, or no surgery). Adult females receiving either neonatal tamoxifen or prepubertal ovariectomy spent less time on the open arms than control females, but females who received both treatments were the most defeminized subjects. Males were not affected by the absence of gonadal hormones at either time period. These experiment indicate that female gonadal hormones play an important role both organizationally and activationally in plus-maze behavior. The role of the GABA receptor complex in mediating this effect is discussed. Knowledge of sex differences in plus-maze behavior may help to make this maze a more useful tool in investigating anxiety behavior in rats.

Influence of photoperiod and gonadal steroids on hibernation in the European hamster.

Torpor was monitored daily in adult male and female European hamsters (Cricetus cricetus) induced to hibernate by exposure to a cold environment (6 degrees C). The effect of photoperiodic manipulations or administration of exogenous gonadal steroids was examined in gonadectomized or intact hamsters. 1. Gonadal regression occurred in all short day, but only in some long day, cold-exposed hamsters. Entry into hibernation was not observed until reproductive regression had occurred. Thus, gonadal atrophy appears to be a necessary precondition for hibernation. 2. Castrated hamsters in the short day cold condition showed a significantly greater incidence of torpor than those in the long day cold condition. Hence, photoperiod affected torpor independently of its effect on the gonadal cycle. 3. Testosterone, when administered via silastic capsules at near physiological levels, completely inhibited torpor in gonadectomized male and female hamsters hibernating in the short day cold condition. 4. In ovariectomized females, torpor was unaffected by progesterone treatment, but partially inhibited by estradiol. A greater inhibition of torpor was observed when estradiol-primed females were administered both estradiol and progesterone simultaneously. Thus, the effect of both hormones may be functionally comparable to that of the single testicular hormone. 5. Estradiol inhibited torpor to a greater extent in intact and ovariectomized female hamsters hibernating in long days than those in short days, suggesting an effect of photoperiod on responsiveness to estradiol. These results indicate an inverse relationship between the gonadal and hibernation cycles, and a probable role for gonadal steroids to influence the timing of the hibernation season. However, non-gonadal factors must also be involved in controlling hibernation, since photoperiod affected the incidence of torpor in gonadectomized animals and because hamsters were able to terminate hibernation in the absence of gonadal hormones.

Hormonal differentiation of sexual behavior in Japanese quail

The effect of hormones on the development of Japanese quail during the postembryonic period was examined. First, subcutaneous implants of estradiol monobenzoate (EB) and testosterone propionate (TP) were implanted 6–12 hr after hatching. EB and TP had no effect on the differentiation of sexual behavior in genetic males or females. However, EB had marked feminizing effects on plumage in genetic males. Second, the role of gonadal hormones during development was examined by gonadectomizing males and females 6–12 hr after hatching and treating them intramuscularly with EB or TP as adults. EB-treated adult females displayed sexual behavior typical of the genetic female and developed female plumage. A significant proportion of TP-treated females (57%) displayed male sexual behavior patterns. Cloacal gland development and male-type vocalizations were induced. EB-treated males displayed either male or female sexual patterns depending on the stimulus conditions. Third, to test whether bisexuality in gonadectomized males and females is maintained despite steroid treatment and expression of sexual behavior in adulthood, gonadectomized quail which were originally treated with EB received TP and vice versa. The results indicate that in the absence of gonadal hormones after hatching female quail remain bisexual until exposed to estrogen, whereas gonadectomized male quail retain behavioral bisexuality irrespective of prior estrogen or androgen exposure.

Sexual behavior patterns in the prepubertally castrate rat.

AbstractPrepubertally castrate female rats are capable of showing the lordosis response when given replacement therapy with female sex steroids, regardeless of age at which the ovaries are removed post birth, or when replacement therapy is commenced after adulthood. Estrogen alone is reraly a sufficient stimulus for behavioral estrus. Therefore the natural physiological trigger for estrous behavior in the rat is likely estrogen plus progesterone. Prepubertally castrate male or female rats never showed any male or female behavior following androgen implant in the brain. All rats castrated on day three or ealier, and given implants of estrogen plus progesterone in the preoptic hypothalamic area displayed the lordosis response. Thus the female sex response pattern is present in both sexes in the absence of gonadal hormones from birth. Brain development in the male castrate at birth does not appear to be identical to brain development in the female castrate at birth because a number of males showed the complete male sexual response pattern plus the female response pattern following neural implant of estrogen plus progesteron. The genotypic male thus appears to possess the information necessary to produce the neural connections for male and female sexual response patterns. Androgen acting at birth disrupts the development of the feminine response pattern so that the adult male ordinarily displays only the copulatory pattern.