Hypothalamic-pituitary-gonadal Axis Activity Research Articles

The roles of kisspeptin and gonadotropin inhibitory hormone in stress-induced reproductive disorders.

Several kinds of stress suppress the hypothalamic-pituitary-gonadal (HPG) axis and reproductive behavior in humans and animals. These changes can eventually cause diseases and disorders, such as amenorrhea and infertility. In previous studies, it has been shown that stress-related factors, e.g., corticotropin-releasing hormone, cortisol, and pro-inflammatory cytokines, promote the stress-induced suppression of the HPG axis. However, these mechanisms are not sufficient to explain how stress suppresses HPG axis activity, and it has been suggested that some other factors might also be involved. In the early 21st century, novel neuroendocrine peptides, kisspeptin and gonadotropin inhibitory hormone (GnIH)/RFamide-related peptide 3 (RFRP-3), which directly regulate GnRH/gonadotropin synthesis and secretion, were newly discovered. Growing evidence indicates that kisspeptin and GnIH/RFRP-3 play pivotal roles in the stress-induced disruption of the HPG axis and reproductive behavior in addition to their physiological functions. This review summarizes what is currently known about the roles of kisspeptin and GnIH/RFRP-3 in stress-induced reproductive disorders.

Sex-Specific Effects of Chronic Administration of Relaxin-3 on Food Intake, Body Weight and the Hypothalamic-Pituitary-Gonadal Axis in Rats.

The present study examined the effects of chronic central administration of relaxin-3 (RLN3) on food intake, body weight and fat mass in intact and sterilised male and female rats, as well as on hypothalamic-pituitary-gonadal (HPG) axis activity in intact male and female rats that received i.c.v. infusions of RLN3 (400pmol/day) or vehicle during a 14-day period. The intact RLN3-injected rats displayed a higher body weight than the vehicle-treated groups, and this increase was statistically significantly stronger in female rats compared to male rats. In addition, feed efficiency and gonadal white adipose tissue weight were higher in female RLN3-injected rats. Chronic i.c.v. administration of RLN3 activated the HPG axis in intact male rats, whereas inhibition of the HPG axis was observed in intact female rats. RLN3 significantly increased the plasma levels of luteinising hormone and follicular-stimulating hormone in male rats but not in female rats. Conversely, hypothalamic expression of gonadotrophin-releasing hormone mRNA was decreased by RLN3 in female rats but not in male rats. In addition, the plasma levels of oestradiol were significantly decreased by RLN3 administration in female rats. Consequently, intact RLN3-injected female rats failed to display phasic inhibition of eating during oestrus. Sex-specific effects of RLN3 on food intake and body weight were also observed in ovariectomised female and orchidectomised male rats, suggesting that the sex-specific effects of RLN3 on energy metabolism are independent on the differential effects of RLN3 on HPG axis activity in male and female rats.

Gonadotropin and Estradiol Levels after Leuprolide Stimulation Tests in Brazilian Girls with Precocious Puberty

Study ObjectiveTo determine the best cutoff value on the leuprolide stimulation test for the diagnosis of central precocious puberty (CPP) in a Brazilian population. Design, Setting, and ParticipantsThis observational study included 60 girls with CPP, as shown on the basis of serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) before and 3 hours after subcutaneous administration of 500 μg leuprolide acetate and by measuring serum estradiol concentrations 24 hours later. Six months later, each subject was clinically evaluated to determine whether she had experienced progressive or nonprogressive puberty. Main Outcome MeasuresAnalyzing the best cutoff for LH after subcutaneous administration of 500 μg leuprolide acetate. ResultsThe best cutoff was a 3-hour LH level of greater than 4.0 mIU/mL, providing the highest sensitivity (73%) and specificity (83.1%), whereas a 3-hour LH level greater than 8.4 mIU/mL had a specificity of 100%. A 24-hour E2 concentration greater than 52.9 pg/mL had a sensitivity of 68% and a specificity of 74%. There was no association between pubertal development and disease progression. Signs such as thelarche and pubarche did not determine the evolution of the disease (P = .17). Clinical condition was associated with bone age/chronological age (P = .01), basal LH (P < .01), 3-hour LH (P = .02), baseline LH/FSH indices (P < .01) and after 3 hours (P < .01), and E2 at 24 hours (P = .02). ConclusionThe optimal parameter indicating hypothalamic–pituitary–gonadal axis activation in our sample was a 3-hour LH level greater than 4.0 mIU/mL. A diagnosis of CPP, however, should be based on a set of criteria and not on an isolated measurement, because typical laboratory findings associated with CPP may not be present in all patients.

Testosterone production in non-breeding Northern Cardinals (Cardinalis cardinalis): is temperature influential?

Abstract In seasonally breeding birds annual changes occur in hormone production by the hypothalamic-pituitary-gonadal (HPG) axis as individuals transition between breeding and non-breeding condition. Typically, some external environmental cue induces the observed changes; changes in day length, corresponding to change of seasons, are a strong cue for HPG axis activity in many species. Some species use cues other than day length as their primary initiator of breeding, and a number of light-sensitive species incorporate other cues to initiate breeding. Northern Cardinals (Cardinalis cardinalis) exhibit individual variation in when breeding begins and circulating testosterone is present throughout the year. Chemical tests of HPG axis responsiveness indicate that many individuals have an activated HPG axis as early as December. Here we use GnRH injections to assess whether individuals with active HPG axes prior to the winter solstice and increasing day lengths, may be influenced to initiate breeding by low t...

Increased Activity of the Hypothalamic-Pituitary-Testicular Axis in Infancy Results in Increased Androgen Action in Premature Boys

Transient activation of the hypothalamic-pituitary-gonadal (HPG) axis is observed in boys during the first months of life. Previous research suggests increased HPG axis activation in premature infants, but the physiological significance of this has not been studied. The objective of this study was to evaluate the differences in reproductive hormone levels and their biological effects between full-term (FT) and preterm (PT) infant boys. Twenty-five FT and 25 PT (gestational age 24.7-36.6 wk) boys were recruited at birth and followed up monthly from 1 wk to 6 months of age (d 7, months 1-6). Nineteen FT and 20 PT boys were reexamined at 14 months of age. Urinary gonadotropins and testosterone were measured in serial urine samples and compared with testicular and penile growth. Urinary prostate-specific antigen was measured as an androgen biomarker. LH and testosterone levels were higher in PT boys (P < 0.001 for both) than FT boys. Compared with FT boys, FSH levels were lower at d 7 (P = 0.002) but higher from month 1 to month 3 (P = 0.002-0.030) in PT boys. This was associated with significantly faster testicular and penile growth in PT boys compared with FT boys. Transient increase in the prostate-specific antigen levels in both groups indicated androgen action in the prostate. Postnatal HPG axis activation in infancy is increased in PT boys and associated with faster testicular and penile growth compared with FT boys. Possible long-term consequences of hyperandrogenism in PT infant boys warrant further research.

Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats.

The subjective experience of stress leads to reproductive dysfunction in many species, including rodents and humans. Stress effects on reproduction result from multilevel interactions between the hormonal stress response system, i.e., the hypothalamic-pituitary-adrenal (HPA) axis, and the hormonal reproductive system, i.e., the hypothalamic-pituitary-gonadal (HPG) axis. A novel negative regulator of the HPG axis known as gonadotropin-inhibitory hormone (GnIH) was recently discovered in quail, and orthologous neuropeptides known as RFamide-related peptides (RFRPs) have also been identified in rodents and primates. It is currently unknown, however, whether GnIH/RFRPs influence HPG axis activity in response to stress. We show here that both acute and chronic immobilization stress lead to an up-regulation of RFRP expression in the dorsomedial hypothalamus (DMH) of adult male rats and that this increase in RFRP is associated with inhibition of downstream HPG activity. We also show that adrenalectomy blocks the stress-induced increase in RFRP expression. Immunohistochemistry revealed that 53% of RFRP cells express receptors for glucocorticoids (GCs), indicating that adrenal GCs can mediate the stress effect through direct action on RFRP cells. It is thought that stress effects on central control of reproduction are largely mediated by direct or indirect effects on GnRH-secreting neurons. Our data show that stress-induced increases in adrenal GCs cause an increase in RFRP that contributes to hypothalamic suppression of reproductive function. This novel insight into HPA-HPG interaction provides a paradigm shift for work on stress-related reproductive dysfunction and infertility, and indicates that future work on stress and reproductive system interactions must include investigation of the role of GnIH/RFRP.

Activity of the hypothalamic–pituitary–gonadal axis differs between behavioral phenotypes in female white-throated sparrows (Zonotrichia albicollis)

The white-throated sparrow (Zonotrichia albicollis) lends itself particularly well to investigations of neuroendocrine mechanisms of social behavior because of a behavioral polymorphism that correlates with a plumage phenotype. Roughly half of the individuals of this species exhibit a white stripe (WS) on the crown and engage in a more aggressive strategy, whereas the other half exhibit a tan stripe (TS) and assume a more parental strategy. These behavioral differences are mirrored by hormonal and neuroendocrine differences; for example, males of the WS morph have higher plasma testosterone than do TS males, and females of the TS morph have higher plasma luteinizing hormone than females of the WS morph. These differences suggest that the regulation of the hypothalamic–pituitary–gonadal (HPG) axis may differ according to morph. In this study, we compared HPG axis activity at each level by measuring (1) the number, size, and staining intensity of GnRH immunoreactive (ir) neurons; (2) plasma LH; and (3) plasma estradiol (E2) in females. We found that TS females had more GnRH-ir neurons in the septo-preoptic area of the hypothalamus than did WS females, and GnRH-ir neuronal cell bodies were larger in the WS than the TS females. There was no morph difference in the intensity of GnRH labeling. TS females had higher plasma LH, which is consistent with a previous report, and higher plasma E2. We hypothesize that the differences in GnRH-ir cell number and size are related to differences in LH and E2 secretion, and may be relevant to polymorphic social behavior.

The reproductive system at the neuroendocrine-immune interface: focus on LHRH, estrogens and growth factors in LHRH neuron–glial interactions

Bidirectional communication between the neuroendocrine and immune systems plays a pivotal role in health and disease. Signals generated by the hypothalamic–pituitary–gonadal (HPG) axis (i.e. luteinizing hormone-releasing hormone, LHRH, and sex steroids) are major players coordinating the development immune system function. Conversely, products generated by immune system activation exert powerful and longlasting effects on HPG axis activity. In the central nervous system (CNS), one chief neuroendocrine-immune (NIE) compartment is represented by the astroglial cell population and its mediators. Of special interest, the major supporting cells of the brain and the thymus, astrocytes and thymic epithelial cells, share a similar origin and a similar set of peptides, transmitters, hormones and cytokines functioning as paracrine/autocrine regulators. This may explain some fundamental analogies in LHRH regulation of both cell types during ontogeny and in adult life. Hence, the neuropeptide LHRH significantly modulates astrocyte and thymic cell development and function. Here we focus this work on LHRH neuron–glial signaling cascades which dictate major changes during LHRH neuronal differentiation and growth as well as in response to hormonal manipulations and pro-inflammatory challenges. The interplay between LHRH, growth factors, estrogens and pro-inflammatory mediators will be discussed, and the potential physiopathological implications of these findings summarized. The overall study highlights the plasticity of this intersystem cross-talk and emphasize neuron–glial interactions as a key regulatory level of neuroendocrine axes activity.