Hypothalamus-pituitary-ovary Research Articles

Animal models of polycystic ovary syndrome: A review of hormone-induced rodent models focused on hypothalamus-pituitary-ovary axis and neuropeptides.

BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age and a major cause of infertility; however, the pathophysiology of this syndrome is not fully understood. This can be addressed using appropriate animal models of PCOS. In this review, we describe rodent models of hormone‐induced PCOS that focus on the perturbation of the hypothalamic‐pituitary‐ovary (HPO) axis and abnormalities in neuropeptide levels.MethodsComparison of rodent models of hormone‐induced PCOS.Main findingsThe main method used to generate rodent models of PCOS was subcutaneous injection or implantation of androgens, estrogens, antiprogestin, or aromatase inhibitor. Androgens were administered to animals pre‐ or postnatally. Alterations in the levels of kisspeptin and related molecules have been reported in these models.ConclusionThe most appropriate model for the research objective and hypothesis should be established. Dysregulation of the HPO axis followed by elevated serum luteinizing hormone levels, hyperandrogenism, and metabolic disturbance contribute to the complex etiology of PCOS. These phenotypes of the human disease are recapitulated in hormone‐induced PCOS models. Thus, evidence from animal models can help to clarify the pathophysiology of PCOS.

Fuel Fine Particulate Matter Induces Ovary Dysfunction via Metal Elements Imbalance and Steroid Biosynthesis Signaling Pathway Inhibition

Fuel fine particulate matter (FPM) is an important component of ambient pollution, has wide biological activity, and can cause a variety of diseases. Epidemiological studies have reported that FPM can decrease human fertility rates, retard embryonic growth, cause adverse effects on pregnancy outcomes, and result in male reproductive damage. However, the effects of FPM on female ovary function and associated mechanisms are still unclear. In this research, different concentrations of gasoline and diesel FPM were chosen to treat female mice in vivo. Fuel FPM can significantly inhibit ovarian function and follicle maturation. The hypothalamus–pituitary–ovary axis was inhibited significantly, with an increase in follicle-stimulating hormone and luteinizing hormone levels and a decrease in estradiol levels, as well as ovary weight loss, which was similar to the symptoms of premature ovarian failure in humans. Fuel FPM can induce the accumulation of copper and lead in the ovary and decrease the levels of zinc, m...

Crocetin attenuates DHT-induced polycystic ovary syndrome in mice via revising kisspeptin neurons

Polycystic ovarian syndrome (PCOS), the most common endocrine disorder of women in reproductive age, is typical with hyperandrogenism and disturbance of the hypothalamus–pituitary–ovary (HPO) axis, i.e. abnormal expression of hypothalamic gonadotropin-releasing hormone (GnRH) followed by the elevated ratio of serum luteinizing hormone (LH) level to follicle-stimulating hormone (FSH) level. This derangement might have a close relationship with hypothalamic kisspeptin expression that is thought to be a key regulator of GnRH. Crocetin, one of the main components of Saffron clinically used as traditional medicine in gynecology diseases, was evaluated for its therapeutic effects on PCOS induced by prenatally exposure to dihydrotestosterone (DHT) in mice. Herein, we found that DHT-treated mice showed a similar phenotype to human PCOS such as heavier ovary, prolonged diestrus, multiple enlarged follicles with fewer corpus luteum, and higher LH and testosterone levels. Kisspeptin expression was lower in anteroventral periventricular nucleus (AVPV) but higher in arcuate nucleus (ARC). Treatment of crocetin prevented the prolongation of diestrus and reduction in corpora luteum, recover the levels of GnRH, FSH, LH, progesterone (P4), estradiol (E2) and testosterone (T), and increase the kisspeptin level in AVPV but reduce that in ARC. The present study provides in vivo evidence that crocetin improved the PCOS in mice via increasing AVPV-kisspeptin and reducing ARC-kisspeptin expression.

Roles of Hypothalamic-Pituitary-Adrenal Axis and Hypothalamus-Pituitary-Ovary Axis in the Abnormal Endocrine Functions in Patients with Polycystic Ovary Syndrome.

Polycystic ovary syndrome(PCOS) is a common reproductive endocrine disease in women of childbearing age. While it can be affected by a variety of factors,its pathophysiology remains unclear. Its clinical features mainly include anovulation,hyperandrogenism,and hyperinsulinemia,which are closely related with abnormal neuroendocrine system. Hypothalamic-pituitary-gonadal axis(HPG) plays a crucial regulatory role in various life activities in mammals. In particular,hypothalamic-pituitary-adrenal(HPA) axis and hypothalamus-pituitary-ovary(HPO) axis can be abnormal in PCOS patients. The corresponding abnormalities include abnormal gonadotropin releasing hormone pulse frequency,increased luteinizing hormone/follicle-stimulating hormone ratio,and excessive excretion of adrenal and ovarian androgens. Meanwhile,insulin and leptin also play key roles in endocrine dysfunction in PCOS patients. This article systematically reviews the role of HPA axis and HPO axis in the neuroendocrine dysfunction in PCOS patients.

Genome-wide DNA methylation analysis of the porcine hypothalamus-pituitary-ovary axis

Previous studies have suggested that DNA methylation in both CpG and CpH (where H = C, T or A) contexts plays a critical role in biological functions of different tissues. However, the genome-wide DNA methylation patterns of porcine hypothalamus-pituitary-ovary (HPO) tissues remain virtually unexplored. In this study, methylomes of HPO tissues were profiled to investigate their differences and similarities. We found that HPO methylomes displayed tissue-specific methylation patterns in both CpG and CpH contexts. At gene locations, the methylation and density of CpGs was negatively linked at transcription start sites but positively linked at transcription end sites. The densities of CpGs and CpHs at CpG island (CGI) locations were negatively correlated with their methylation. Moreover, the methylation interactions between CGIs and genes showed similar pattern in the CpG context but tissue-specific pattern in the CpH context. CpGs located in CGIs, upstream regions and exons were protected from methylation dynamics, whereas CGI shores, CGI shelves and intergenic regions were more likely to be targets of methylation changes. The methylation dynamics enriching in a tissue-specific manner appeared to maintain and establish the biological functions of HPO tissues. Our analyses provided valuable insights into the tissue-specific methylomes of porcine HPO tissues.

Effects of electroacupuncture at Guanyuan (CV 4) or Sanyinjiao (SP 6) on hypothalamus-pituitary-ovary axis and spatial learning and memory in female SAMP8 mice

OBJECTIVETo investigate the effects of electroacupuncture (EA) at the Guanyuan (CV 4) or Sanyinjiao (SP 6) acupoints on the hypothalamus-pituitary-ovary (HPO) axis and spatial learning and memory in female mice. METHODSNine-month-old female mice with senescence-accelerated mouse prone 8 (SAMP8) were divided into three groups: the disease model, EA-Guanyuan and EA-Sanyinjiao groups. Concurrently, 9-month old female mice with senescence-accelerated mouse resistance 1 (SAMR1) were set as the control model group. The two treatment groups were given the same pattern of EA stimulation. Gonadotropin-releasing hormone, luteinizing hormone, follicle-stimulating hormone (FSH) and Serum estradiol levels in the Hypothalamus-pituitary-ovary axis were assessed by enzyme-linked immunosorbent assay to determine the HPO axis function level. Spatial learning and memory were assessed by the Morris Water Maze (MWM) test. RESULTS(a) HPO axis: compared with the control model group, the disease model group displayed a decrease in E2 levels (P < 0.01), and an increase in GnRH, LH and FSH levels (P < 0.01). E2 levels were increased in EA treatment groups compared with the disease model group (P < 0.05). In contrast, GnRH and LH and FSH levels were reduced (P < 0.05). EA-Sanyinjiao group was superior than EA-Guanyuan group on increasing E2 and declining GnRH levels (P < 0.01). (b) The MWM test demonstrated that the response latency in the EA-Sanyinjiao treatment group declined from day 2 to day 5 compared with the disease model group (P < 0.05), whereas the EA-Guanyuan treatment group showed no significant difference. CONCLUSIONEA can regulate hormone (E2, FSH, LH, GnRH) levels in the HPO axis and the spatial learning and memory ability in female SAMP8 mice. Moreover, this effect may have been more pronounced in the EA-Sanyinjiao group than the EA-Guanyuan group. The underlying mechanism of the EA-induced changes may be related to gonadal hormone shifts in the HPO axis, followed by an improvement in spatial learning and memory.

Invited

To investigate the effects of electroacupuncture (EA) at the Guanyuan (CV 4) or Sanyinjiao (SP 6) acupoints on the hypothalamus-pituitary-ovary (HPO) axis and spatial learning and memory in female mice.Nine-month-old female mice with senescence-accelerated mouse prone 8 (SAMP8) were divided into three groups: the disease model, EA-Guanyuan and EA-Sanyinjiao groups. Concurrently, 9-month old female mice with senescence-accelerated mouse resistance 1 (SAMR1) were set as the control model group. The two treatment groups were given the same pattern of EA stimulation. Gonadotropin-releasing hormone, luteinizing hormone, follicle-stimulating hormone (FSH) and Serum estradiol levels in the Hypothalamus-pituitary-ovary axis were assessed by enzyme-linked immunosorbent assay to determine the HPO axis function level. Spatial learning and memory were assessed by the Morris Water Maze (MWM) test.(a) HPO axis: compared with the control model group, the disease model group displayed a decrease in E2 levels (P < 0.01), and an increase in GnRH, LH and FSH levels (P < 0.01). E2 levels were increased in EA treatment groups compared with the disease model group (P < 0.05). In contrast, GnRH and LH and FSH levels were reduced (P < 0.05). EA-Sanyinjiao group was superior than EA-Guanyuan group on increasing E2 and declining GnRH levels (P < 0.01). (b) The MWM test demonstrated that the response latency in the EA-Sanyinjiao treatment group declined from day 2 to day 5 compared with the disease model group (P < 0.05), whereas the EA-Guanyuan treatment group showed no significant difference.EA can regulate hormone (E2, FSH, LH, GnRH) levels in the HPO axis and the spatial learning and memory ability in female SAMP8 mice. Moreover, this effect may have been more pronounced in the EA-Sanyinjiao group than the EA-Guanyuan group. The underlying mechanism of the EA-induced changes may be related to gonadal hormone shifts in the HPO axis, followed by an improvement in spatial learning and memory.

Impact of Food Restriction on the Expression of the Adiponectin System and Genes in the Hypothalamic-Pituitary-Ovarian Axis of Pre-Pubertal Ewes.

Adiponectin, a cytokine secreted typically by adipocytes, has been implicated as a molecular switch between female reproduction and energy balance. The present study was undertaken to investigate the expression of adiponectin system and patterns of genes in the hypothalamic-pituitary-ovary (HPO) axis of food-restricted pre-pubertal ewes. Eighteen 2-month-old female ewes were assigned to 3 groups after a pre-feeding adlibitum for 10days (six in each group): the control group (C), the low-food-restricted group (LR) and the high-food-restricted group (HR), which were fed with 100%, 70% and 50% of adlibitum food intake, respectively. The hypothalamus, pituitary, ovary and serum were collected after food restriction for 2months. Results by ELISA showed that food restriction increased serum adiponectin concentrations. Quantitative real-time PCR showed that the gene transcriptions for adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2) were enhanced in the hypothalamic-pituitary-ovarian (HPO) axis, while KISS-1/GPR-54 and gonadotropin-releasing hormone (GnRH) in the hypothalamus and luteinizing hormone β-subunit (LHβ) and follicle-stimulating hormone β-subunit (FSHβ) in the pituitary were reduced after food restriction. Immunohistochemistry results demonstrated that AdipoR1 localized in the oocytes of follicles in the ovary. These results suggest that the alterations in the expression of adiponectin and its receptors in response to food restriction might negatively influence the HPO axis.

Molecular cloning and tissue expression of the CCNG1 gene in sheep

The CCNG1 gene encodes cyclin G1, which is an important cell cycle regulator and has been reported to be involved in reproductive biological processes, such as oocyte maturation and granule cell proliferation in mammals. But the study of CCNG1 in sheep has been rarely reported. To examine the effects of CCNG1 on estrous control and seasonal breeding in sheep, we first cloned and characterized the expression level of the sheep CCNG1 gene. Then by Real-time PCR, we detected and analyzed the expressions of CCNG1 gene at mRNA levels in the hypothalamus-pituitary-ovary (HPO) axis in different stages of an estrous cycle in Duo Lang sheep (non-seasonal breeding) and Merino sheep (seasonal breeding). The results showed that the open reading frame of the sheep CCNG1 gene is 885 bp in length and encodes 294 amino acids. Bioinformatic analysis indicated that the secondary structure of the sheep CCNG1 protein contained multiple phosphorylation sites and some Protein Kinase C phosphorylation sites. CCNG1 mRNA was identified in all tissues tested, with the levels in ovary and kidney higher than others. The expression profiles of CCNG1 in the HPO axis in different stages of an estrous cycle were similar in different sheep breeds: the expression levels of CCNG1 in the ovary, uterus, pineal gland and pituitary gland all peaked in the estrus phase. But there were significant differences for expression change extent of CCNG1 in ovaries in the oestrus and metestrus phase between different sheep breeds. The results suggested that CCNG1 probably participated in the regulation of estrous behavior and seasonal reproduction through controling the growth and development of follicles in sheep.

Progesterone and 17β-estradiol regulate expression of nesfatin-1/NUCB2 in mouse pituitary gland

Nesfatin-1 was first shown to be involved in the control of appetite and energy metabolism in the hypothalamus. Many recent reports have shown nesfatin-1 expression in various tissues including the pituitary gland, but its expression and regulation mechanisms in the pituitary gland are unclear. Therefore, first, we investigated the mRNA and protein expression of nesfatin-1 in the pituitary using qRT-PCR and Western blotting, respectively. Expression of NUCB2 mRNA and nesfatin-1 protein was higher in the pituitary gland than in other organs, and nesfatin-1 protein was localized in many cells in the anterior pituitary gland. Next, we investigated whether NUCB2 mRNA expression in the pituitary gland was regulated by sex steroid hormones secreted by the ovary. Mice were ovariectomized and injected with progesterone (P4) and 17β-estradiol (E2). The expression of NUCB2 in the pituitary gland was dramatically decreased after ovariectomy and increased with injection of P4 and E2, respectively. The in vitro experiment to elucidate the direct effect of P4 and E2 on NUCB2 mRNA expression showed NUCB2 mRNA expression was significantly increased with E2 and decreased with P4 alone and P4 plus E2 in cultured pituitary tissue. The present study demonstrated that nesfatin-1/NUCB2 was highly expressed in the mouse pituitary and was regulated by P4 and E2. These data suggest that reproductive-endocrine regulation through hypothalamus–pituitary–ovary axis may contribute to nesfatin-1/NUCB2 expression in the pituitary gland.

Effects of carbohydrate supplements on exercise-induced menstrual dysfunction and ovarian subcellular structural changes in rats

BackgroundExercise-associated menstrual dysfunction (EAMD) is a common health problem in female athletes as a part of female athlete triad (FAT), a condition related to low energy availability. In this study, we explored the possibility that carbohydrate supplements can improve the status of EAMD and prevent exercise-induced ovarian injury in a FAT rat model. This research aimed to provide experimental evidence with regard to the relationship of energy intervention and EAMD. MethodsForty-five female Sprague–Dawley rats (2 months old) were randomly divided into five experimental groups: control group (C), 9-week exercise as model for EAMD (E), post-EAMD recovery group (R), oligosaccharide intervention group (O), and glucose intervention group (G). All rats were sacrificed at the end of 9 weeks. Serum samples were collected for measuring gonadotropin releasing hormone, follicle stimulating hormone, luteinizing hormone, 17β-estradiol and progesterone levels. The ovaries were taken for investigation of exercise- and carbohydrate-induced follicular subcellular structure changes. ResultsExercise induced irregular menstrual cycles and ovary subcellular structural damages, such as swollenness of mitochondria in rats from groups E and R. Both glucose and oligosaccharide supplements restored well-differentiated mitochondria in the ovarian follicular cells, and a significant improvement of endoplasmic reticulum and Golgi in swollenness in theca cells in groups O and G compared to groups C, E, and R. There was no difference in mitochondria subcellular structural changes between groups O and G. Group E showed attenuation of serum levels of 17β-estradiol and progesterone compared to C. There were no differences of 17β-estradiol serum levels among groups O, G, and R, while group G showed a lower level of progesterone than C. ConclusionFemale adult rats with 9-week continuous exercise can cause menstrual dysregulation as a model for EAMD. Post-EAMD intervention with glucose and oligosaccharide intake can normalize the menstrual cycle, restore the follicular subcellular structure, and reverse the exercise-induced reduction of ovary sex hormones. It suggests a positive feedback of hypothalamus–pituitary–ovary axis might be involved in the molecular mechanisms of energy intake in treating EAMD.

Elevated estrogen receptor expression in hypothalamic preoptic area decreased by electroacupuncture in ovariectomized rats

In the present study, effects of electroacupuncture (EA) on estrogen receptor alpha (ERα) and beta (ERβ) mRNA and protein expression in the hypothalamus of ovariectomized (OVX) rats were detected by quantitative real-time reverse transcription PCR (qRT-PCR) and western blot analysis. Gonadotropin-releasing hormone (GnRH) release and GnRH mRNA level in hypothalamic preoptic area (POA) were evaluated by push–pull perfusion and qRT-PCR. Our results showed that elevated mRNA and protein expression of ERα and ERβ in hypothalamus were restrained following EA treatment in OVX rats. EA treatment also inhibited GnRH release and GnRH mRNA levels in OVX rats. These results provide novel evidence that EA treatment down regulates the expression of hypothalamic estrogen receptors (ERs), thus restores the response of GnRH neurons to estrogen depression, and partially resets the negative feedback of estrogen to hypothalamus–pituitary–ovary axis (HPOA) in OVX rats, which may be a critical mechanism for EA on female reproductive disorders.

Serum adiponectin and resistin in relation to insulin resistance and markers of hyperandrogenism in lean and obese women with polycystic ovary syndrome

Objectives It seems that adipokines participate in disturbances of the function of the hypothalamus–pituitary–ovary axis. The aim of the study was to assess the relationship between plasma adiponectin and resistin levels and insulin resistance and markers of hyperandrogenism in lean and obese PCOS women. Study design Forty-one women with PCOS (22 lean and 19 obese) and 16 healthy lean women were enrolled. Body mass and height were measured and body mass index was calculated. In addition to serum glucose, lipids, androgens and insulin, adiponectin and resistin concentration were assessed in the fasting state. The insulin resistance was calculated based on the HOMA-IR. Results Similar serum resistin concentrations were found in both PCOS subgroups and controls. The obese PCOS subgroup was characterized by the lowest serum adiponectin level (10.8 ± 8.3, compared with 21.0 ± 15.1 in the normal weight PCOS subgroup and 26.7 ± 12.5 μg/ml in controls). There were no correlations between resistin and adiponectin levels and HOMA-IR values and serum androgen concentrations. Significant positive correlations between adiponectin to resistin ratio and plasma FSH ( r = 0.49; p = 0.001) and LH ( r = 0.45; p = 0.003) concentrations, and a negative correlation with free androgen index ( r = −0.34; p = 0.03) in PCOS group were found. Conclusions Obese but not normal weight PCOS women have lower adiponectin levels whereas resistin concentration did not differ in normal weight and obese PCOS compared to control subjects. We hypothesize that changes of the relative proportion of adiponectin to resistin, but not circulating adiponectin and resistin levels themselves, may play a role in hormonal disturbances but not in insulin resistance in PCOS.

Effect of Wujijing Oral Liquid on menstrual disturbance of women

Objective Wujijing Oral Liquid (WJJ) contained principally the flesh essence of the black-boned chicken. As a kind of food and medicine in China, it was used to treat the menstrual disturbance traditionally, but the exact mechanism of the action was not yet clear. The clinical effects of the WJJ on the symptoms of the menstrual disturbance and the reproductive hormones were studied in this paper. Materials and methods The 53 women with the menstrual disturbance were selected as the study object, and then they were randomly divided to receive either WJJ 10 mL twice daily ( n = 28) or the placebo ( n = 25) from the 1st day after menstrual flow for 2 menstrual cycles. On the 1st day after the discontinuation of the medication but before the treatment, the scores for the menstrual pattern and the related symptoms were obtained and the blood samples were collected to test the reproductive hormones. The serum levels of the follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) and estradiol (E2) were examined by enzyme-linked immunosorbent assay (ELISA). The levels of progesterone (P) and testosterone (T) in serum were measured by the radioimmunoassay. Results The score for the primary and related symptoms of the menstruation was increased significantly among patients treated with the WJJ. The differences on the FSH, PRL, and E2 levels of patients were significant before and after the treatment with WJJ. Comparing the WJJ group and the placebo group, the levels of P and T differed significantly after treatment. The oral liquid of WJJ was found to be safe, as it did not cause any change in the hepatic and renal functional parameters. Conclusion The oral liquid of Wujijing could improve the menstrual disturbance and were generally safe and well tolerated. The possible mechanism could be associated with its effects in reinforcing the kidney and regulating the hypothalamus–pituitary–ovary axis (HPOA).

Expression of NMS and NMU2R in the pig reproductive axis during the estrus cycle and the effect of NMS on the reproductive axis in vitro

Evidence has revealed that neuromedin S (NMS) and neuromedin U-receptor type-2 (NMU2R) mRNAs are expressed in the central nervous system and reproductive organs. Previous data indicated that variation of NMS and NMU2R was due to the phases of the adult rat hypothalamus estrus cycle. However, the expression and function of NMS in the pig reproductive axis remains unexplored. In this study, 16 virginal gilts were classified into four groups: proestrus, estrus, diestrus 1, and diestrus 2; the expression of NMS and NMU2R in the cyclic pig hypothalamus–pituitary–ovary axis was studied by reverse transcriptaion-polymerase chain reaction (RT-PCR), and the effect of NMS on the reproductive axis in vitro was detected by radioimmunoassay (RIA). The cloned pig NMS and NMU2R sequences were 82% and 90.2% identical to those of the corresponding human homologues, respectively. RT-PCR showed that NMS and NMU2R mRNA expression in the hypothalamus and pituitary changed with the estrus cycle, i.e., with the highest level in the proestrus group and the lowest in the estrus group. In the ovary, NMS and NMU2R expression was highest in the diestrus 2 group and the lowest in the proestrus group. In the in vitro study, different concentrations of NMS induced the release of gonadotropin-releasing hormone, luteinizing hormone, and estradiol at different levels of the reproductive axis. Taken together, the expression pattern of NMS during the estrus cycle and its role in reproductive hormones in vitro provide novel evidences of the potential roles of NMS in the regulation of pig reproduction.

Erratum to: Age-related changes in the oestrous cycle and reproductive hormones in senescence-accelerated mouse

To investigate age-related changes in the oestrous cycle and reproductive hormone levels in senescence-accelerated mouse (SAM), we examined these parameters in 3-, 5-, 7-, 9- and 11-month-old female SAM-prone/8 (SAMP8) and SAM-resistant/1 (SAMR1) strains. Levels of �-endorphin (�-EP) and substance P (SP) in the hypothalamus were also measured. The oestrous cycle and dioestrus of 9-month-old SAMP8 mice were significantly prolonged compared with age-matched SAMR1 mice. Furthermore, the concentration of serum oestradiol was lower and the level of pituitary luteinising hormone was higher in SAMP8 mice compared with SAMR1 mice. This characterises the hypothalamus.pituitary.ovary (HPO) axis of the SAMP8 strain as hypergonadotropic.hypogonad. The levels of �-EP and SP in the SAMP8 hypothalamus were lower than in the SAMR1 hypothalamus. These results indicate that the function of the HPO axis in SAMP8 mice declines early and this may be attributed, in part, to the decline in �-EP and SP concentrations in the hypothalamus.

The hypothalamus–pituitary–ovary axis and type 1 diabetes mellitus: a mini review

A high prevalence of menstrual cycle and fertility disturbances has long been associated with diabetes mellitus. However, rationalization of the intrinsic mechanisms of these alterations is controversial and even contradictory. This review considers (i) the relationship between diabetes mellitus, especially type 1 diabetes mellitus (T1DM), and the hypothalamus-pituitary-ovary (HPO) axis, (ii) the state of our knowledge concerning neuroendocrine control and its relationship with dopaminergic and opioid tonus, and (iii) the influence of the hypothalamus-pituitary-adrenal axis on ovarian function. Functional disturbances that occur as a consequence of diabetes are also discussed, but some T1DM-related diseases of autoimmune origin, such as oophoritis, are not further analysed. Although there are clear indications of a relationship between menstrual and fertility alterations and glycaemic control, in many instances the improvement of the latter is not sufficient to reverse such alterations. It appears that the oligoamenorrhoea and amenorrhoea associated with T1DM is mainly of hypothalamic origin (i.e. failure of the GnRH pulse generator) and may be reversible. The importance of the evaluation of the HPO axis in T1DM women with menstrual irregularities, even in the presence of adequate metabolic control, is emphasized.

Electroacupuncture stimulates hypothalamic aromatization

We have previously reported that the repeated electroacupuncture (EA) stimulation significantly increased the concentrations of circulating estradiol and restored the depressed function of the hypothalamus–pituitary–ovary axis (HPOA) in ovariectomized (OVX) rats. We hypothesize that extragonadal aromatization in specific brain areas might be responsible for these changes. Thus, various assays, including radiometric assay, Western blot, and reverse transcriptase polymerase chain reaction (RT-PCR), were employed to determine the aromatization in the hypothalamus of rats that received both OVX and electroacupuncture (OVX + EA). The results showed that EA significantly increased the aromatase activity as well as the expressions of its mRNA and protein ( P < 0.05) in the OVX rats. These results suggest that EA enhances brain aromatization, which might contribute to influence the function of gonadotropin-releasing hormone (GnRH) neurons and promote the hypofunction of the HPOA in the ovariectomized rats.

Age-related changes in the oestrous cycle and reproductive hormones in senescence-accelerated mouse

To investigate age-related changes in the oestrous cycle and reproductive hormone levels in senescence-accelerated mouse (SAM), we examined these parameters in 3-, 5-, 7-, 9- and 11-month-old female SAM-prone/8 (SAMP8) and SAM-resistant/1 (SAMR1) strains. Levels of beta-endorphin (beta-EP) and substance P (SP) in the hypothalamus were also measured. The oestrous cycle and dioestrus of 9-month-old SAMP8 mice were significantly prolonged compared with age-matched SAMR1 mice. Furthermore, the concentration of serum oestradiol was lower and the level of pituitary luteinising hormone was higher in SAMP8 mice compared with SAMR1 mice. This characterises the hypothalamus-pituitary-ovary (HPO) axis of the SAMP8 strain as hypergonadotropic-hypogonad. The levels of beta-EP and SP in the SAMP8 hypothalamus were lower than in the SAMR1 hypothalamus. These results indicate that the function of the HPO axis in SAMP8 mice declines early and this may be attributed, in part, to the decline in beta-EP and SP concentrations in the hypothalamus.

Specific enkephalin-degrading aminopeptidase activity in the HPT and HPO axes of rats with breast cancer induced by N-methyl nitrosourea

State and function of breast depend on an endocrinological balance, the upsetting of which can be a factor favorable to the development of cancer. Enkephalins (ENK) have been considered as a particular form of adaptation to defense to the organism against neoplastic processes. However, ENK may modify the endocrine functions of glands such as the ovary or the thyroid through the hypothalamus–pituitary axis, acting direct or indirectly as endocrine, paracrine or autocrine stimulatory growth factors. The present work analyses enkephalin-degrading tyrosyl aminopeptidase (EDA) activity in the hypothalamus–pituitary–thyroid (HPT) and hypothalamus–pituitary–ovary (HPO) axes in a rat model of breast cancer induced by N-methyl-nitrosourea (NMU) to state the relationship between ENK levels modification through EDA activity at different neuroendocrine levels and breast cancer. Results obtained show a decrease in EDA activity in hypothalamus, anterior and posterior pituitary, thyroid and ovary, suggesting increased levels of ENK in all these locations. These ENK may induce breast cancer cell growth and progression not only at breast level, but also acting at several neuroendocrine levels such as the HPT and HPO axes, inducing an unbalance of several other hormones, which could also facilitate the progression of cancer as an undesirable concomitant effect.