Luteinizing Hormone Ovulation Research Articles

Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats

Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active when administered orally. The aim was to study the effectiveness of TP4/2 (orally, 40 mg/kg) as an ovulation inducer in FSH-stimulated immature female rats, compared with hCG (s.c., 15 IU/rat). TP4/2 stimulated progesterone production and corpus luteum formation; time-dependently increased the ovarian expression of steroidogenic genes (Star, Cyp11a1, Cyp17a1) and genes involved in ovulation regulation (Adamts-1, Cox-2, Egr-1, Mt-1); and increased the content of metalloproteinase ADAMTS-1 in the ovaries. These effects were similar to those of hCG, although in some cases they were less pronounced. TP4/2, in contrast to hCG, maintained normal LH levels and increased the ovarian expression of the LH/hCG receptor gene, indicating preservation of ovarian sensitivity to LH, and did not cause a sustained increase in expression of vascular endothelial growth factor-A involved in OHSS. Thus, TP4/2 is an effective ovulation inducer that, unlike hCG, has a lower risk of OHSS and ovarian LH resistance due to its moderate stimulating effect on steroidogenesis.

Effects of whole-body vibration on reproductive physiology in a rat model of whole-body vibration

ABSTRACT Findings from epidemiological studies suggest that occupational exposure to whole-body vibration (WBV) may increase the risk of miscarriage and contribute to a reduction in fertility rates in both men and women. However, workers exposed to WBV may also be exposed to other risk factors that contribute to reproductive dysfunction. The goal of this experiment was to examine the effects of WBV on reproductive physiology in a rat model. Male and female rats were exposed to WBV at the resonant frequency of the torso (31.5 Hz, 0.3 g amplitude) for 4 hr/day for 10 days. WBV exposure resulted in a significant reduction in number of developing follicles, and decrease in circulating estradiol concentrations, ovarian luteinizing hormone receptor protein levels, and marked changes in transcript levels for several factors involved in follicular development, cell cycle, and steroidogenesis. In males, WBV resulted in a significant reduction in spermatids and circulating prolactin levels, elevation in number of males having higher circulating testosterone concentrations, and marked alterations in levels of transcripts associated with oxidative stress, inflammation, and factors involved in regulating the cell cycle. Based upon these findings data indicate that occupational exposure to WBV contributes to adverse alterations in reproductive physiology in both genders that may lead to reduction in fertility.

Lifetime changes of the oocyte pool: Contributing factors with a focus on ovulatory inflammation.

In mammalian species, females are born with a number of oocytes exceeding what they release via ovulation. In humans, an average girl is born with over a thousand times more oocytes than she will ovulate in her lifetime. The reason for having such an excessive number of oocytes in a neonatal female ovary is currently unknown. However, it is well established that the oocyte number decreases throughout the entire lifetime until the ovary loses them all. In this review, data published in the past 80 years were used to assess the current knowledge regarding the changing number of oocytes in humans and mice, as well as the reported factors that contribute to the decline of oocyte numbers. Briefly, a collective estimation indicates that an average girl is born with approximately 600,000 oocytes, which is 2,000 times more than the number of oocytes that she will ovulate in her lifetime. The oocyte number begins to decrease immediately after birth and is reduced to half of the initial number by puberty and almost zero by age 50 years. Multiple factors that are either intrinsic or extrinsic to the ovary contribute to the decline of the oocyte number. The inflammation caused by the ovulatory luteinizing hormone surge is discussed as a potential contributing factor to the decline of the oocyte pool during the reproductive lifespan.

Testosterone level correlates significantly with luteinizing hormone to follicle-stimulating hormone ratio among women with polycystic ovary syndrome: A cross sectional study

Background: Polycystic ovary syndrome (PCOS), an endocrinological problem among women in the reproductive age, is characterized by chronic ovulatory dysfunction, hyperandrogenism, and elevated luteinizing hormone: follicle stimulating hormone (LH-FSH) ratio. The goal of this study was to examine if the blood LH-FSH ratio and total testosterone (TT) levels in Sudanese women with PCOS were linked. Methods: This cross-sectional study included 300 women with confirmed PCOS based on Rotterdam criteria. PCOS women mean (standard deviation): age 29.1(5.8) years; body mass index (BMI) 27.9±4.6 kg/m2. Each participant underwent a clinical history, physical examination, and ovaries ultrasonogram. ASYS Expert Plus Microplate was used to quantify serum LH, FSH, and TT levels in fasting blood specimen drawn during the follicular phase of the menstrual cycle of women with PCOS. Results: More than two-thirds of the participants (71.0%) had an aberrant LH-FSH ratio (cut-off>1.0), and 58.3% had hyperandrogenemia (TT>109.5 ng/dL). Hyperandrogenemic women had significantly increased LH-FSH ratio (P= 0.000). The LH-FSH ratio and serum TT were significantly positive correlated (r= 0.329, P= 0.000). Overall, 52.0% of women with PCOS exhibited menstrual cycle irregularity, and 59.0 % had a positive family history of PCOS. On logistic regression analysis, the LH-FSH ratio (odds ratio (OR) (95% confidence interval (CI)): 2.308 (1.698- 3.139, P= 0.000) was found to be positively related to hyperandrogenemia independently. Furthermore, when the LH-FSH ratio is greater than one, hyperandrogenemia can be distinguished from normoandrogenemia, area under the curve (AUC) = 0.726, P= 0.000, 95% CI: (0.668-0.785) with a serum TT threshold of 109.5 ng/dL (sensitivity 70.0%, specificity 77.1%). Conclusions: In women with PCOS, the serum LH-FSH ratio and TT have a strong relationship. Furthermore, LH-FSH ratio of greater than one can be used to distinguish between hyperandrogenic and non-hyperandrogenic PCOS women.

Pelvic and breast ultrasound abnormalities and associated metabolic disturbances in girls with premature pubarche due to adrenarche.

Premature adrenarche (PA) has been suggested as a risk factor for future health problems, such as metabolic syndrome and early menarche. However, not all girls with PA have these features and it is not certain who will develop them. We propose that these abnormalities might be identified earlier, even before they are visible. Case-control study. Tertiary care hospital. Forty-eight girls with premature pubarche due to PA and age (mean age 7.6 ± 1.0 years), weight, body mass index (BMI), birth weight and gestational age-matched 49 girls with no palpable breast tissue. Early pubertal pelvic and breast ultrasonographic changes and their associations with obesity and metabolic parameters were evaluated. Blood samples were collected, breast and pelvic ultrasound examinations were performed and bone ages were assessed. Girls with PA were taller and their bone ages were higher (p = .049 and p = .005). Fasting blood glucose, insulin, triglycerides, high-density lipoprotein and low-density lipoprotein cholesterol were not different between the groups. Luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol were not different either. Ultrasonography revealed breast gland tissue in 30% of girls with PA and 5% of controls (p = .006). Uterine volume and endometrial thickness were higher in girls with PA (p = .03 and p = .04). Endometrial thickness was positively associated with serum insulin levels in the whole study group and after adjusting for age, diagnosis, BMI, mean ovarian volume and LH, FSH, estradiol levels, this association remained with a borderline p-value (R2 = 0.486, p = .050). We found early changes in uterus and breast glands of girls with PA and endometrial thickness was positively associated with insulin levels.

Integrated Analysis of Transcriptome and Histone Modifications in Granulosa Cells During Ovulation in Female Mice.

The ovulatory luteinizing hormone (LH) surge induces rapid changes of gene expression and cellular functions in granulosa cells (GCs) undergoing luteinization. However, it remains unclear how the changes in genome-wide gene expression are regulated. H3K4me3 histone modifications are involved in the rapid alteration of gene expression. In this study, we investigated genome-wide changes of transcriptome and H3K4me3 status in mouse GCs undergoing luteinization. GCs were obtained from mice treated with equine chorionic gonadotropin (hCG) before, 4 hours, and 12 hours after human chorionic gonadotropin injection. RNA-sequencing identified a number of upregulated and downregulated genes, which could be classified into 8 patterns according to the time-course changes of gene expression. Many genes were transiently upregulated or downregulated at 4 hours after hCG stimulation. Gene Ontology terms associated with these genes included steroidogenesis, ovulation, cumulus-oocyte complex (COC) expansion, angiogenesis, immune system, reactive oxygen species (ROS) metabolism, inflammatory response, metabolism, and autophagy. The cellular functions of DNA repair and cell growth were newly identified as being activated during ovulation. Chromatin immunoprecipitation-sequencing revealed a genome-wide and rapid change in H3K4me3 during ovulation. Integration of transcriptome and H3K4me3 data identified many H3K4me3-associated genes that are involved in steroidogenesis, ovulation, COC expansion, angiogenesis, inflammatory response, immune system, ROS metabolism, lipid and glucose metabolism, autophagy, and regulation of cell size. The present results suggest that genome-wide changes in H3K4me3 after the LH surge are associated with rapid changes in gene expression in GCs, which enables GCs to acquire a lot of cellular functions within a short time that are required for ovulation and luteinization.

Interactions of Cortisol and Prolactin with Other Selected Menstrual Cycle Hormones Affecting the Chances of Conception in Infertile Women.

One of the major problems of success in infertility treatment could depend on the understanding how the potential factors may affect the conception. The aim of this study was to evaluate present understanding of such factors or hormonal causes that may induce infertility. We studied the interactions between the two menstrual cycle hormones i.e., cortisol (COR) and prolactin (PRL), along with the ultrasonographic ovulation parameters in a group of N = 205 women with diagnosed infertility. The control group consisted of N = 100 women with confirmed fertility. In both groups, follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), thyroid stimulating hormone (TSH), PRL, COR were examined on the third day of the cycle, and estradiol (E2), progesterone (P), and COR were examined during ovulation and 7-days afterwards. In the infertile group, higher levels of PRL and COR were observed than that of in the control group. Cortisol levels at all phases of the menstrual cycle and PRL negatively correlated with E2 secretion during and after ovulation, thus contributed to the attenuation of the ovulatory LH surge. Infertile women who conceived presented with higher levels of E2 during and after ovulation, higher P after ovulation, and thicker endometrium than that of the women who failed to conceive. In conclusion, elevated secretion of COR and PRL in infertile women impairs the menstrual cycle by decreasing the pre-ovulatory LH peak and E2 and postovulatory E2 levels that affect the endometrial growth, and consequently reduce the chances to conceive.

Efficacy of Vitamin D Combined with Metformin and Clomiphene in the Treatment of Patients with Polycystic Ovary Syndrome Combined with Infertility

We aimed to explore the clinical efficacy of vitamin D combined with metformin and clomiphene in the treatment of patients with polycystic ovary syndrome combined with infertility. Overall, 396 cases of polycystic ovarian syndrome combined with infertility in Yantai Yuhuangding Hospital, Yantai, China were prospectively analyzed. Among them, 204 cases treated with vitamin D combined with metformin and clomiphene were set as the study group; 192 cases treated with only metformin and clomiphene were set as the control group. The ovarian volume and thickness of uterine wall before and after treatment were recorded. Levels of fasting insulin (FINS), luteinizing hormone (LH), testosterone (T), follicle-stimulating hormone (FSH), and estradiol (E2) before and after treatment were recorded. There was no difference in body weight, BMI, ovarian volume, thickness of ovarian wall, FINS, LH, T, FSH and E2 between the study group and the control group; there was no significant difference in FSH, E2 and the thickness of uterine wall between the two groups. After treatment, the BMI, FINS, LH, and T in the study group were significantly lower than those in the control group (P<0.05); the incidence rates of oligomenorrhea, facial acne and hairy symptoms in the study group were significantly lower than those in the control group (P<0.05); after treatment, the ovulation rate and pregnancy rate in 36 cycles in the observation group were significantly higher than those of the control group (P<0.05). Our challenge could significantly improve clinical symptoms and endocrine conditions, and greatly enhance the ovulation rate and pregnancy rate.

Evaluation of Ovaries in Patients with Polycystic Ovary Syndrome using Shear Wave Elastography

Shear wave electrography (SWE) is a novel non-invasive imaging technique which demonstrate tissue elasticity. Recent research evaluating the elasticity properties of normal and pathological tissues emphasize the diagnostic importance of this technique. Polycystic ovarian syndrome (PCOS), which is characterized by menstrual irregularity, hyperandrogenism, and polycystic overgrowth, may cause infertility. The aim of this study was to evaluate the elasticity of ovaries in patients with PCOS using SWE. 66 patients diagnosed with PCOS according to the Rotterdam criteria (PCOS = group I) and 72 patients with non-PCOS (Control = group II), were included in the study. Demographic and clinical characteristics of the participants were recorded. Ovarian elasticity was assessed in all patients with SWE, and speed values were obtained from the ovaries. The elasticity of the ovaries was compared between the two groups. While there were statistically significant differences between the groups in body mass index (BMI), right and left ovarian volumes, luteinizing hormone and testosterone levels (p<0.05), no significant differences were found between groups I and II in the velocity (for the right ovary 3.89±1.81 vs. 2.93±0.72, p=0.301; for the left ovary 2.88±0.65 vs. 2.95±0.80, p=0.577) and elastography (for the right ovary 36.62±17.78 vs. 36.79±14.32, p=0.3952; for the left ovary 36.56±14.15 vs. 36.26±15.10, p=0.903) values, respectively. We could not obtain different velocity and elastography values from the ovaries of the patients with PCOS using SWE. Therefore, further large-scale studies are needed to elucidate this issue.

Follicle rupture during ovulation with an emphasis on recent progress in fish models.

Ovulation, which is induced by the ovulatory luteinizing hormone (LH) surge, is a dynamic process that results in a discharge of one or more fertilizable oocytes from the ovarian follicle into the ovarian cavity or into the abdominal cavity. Follicle rupture is a core event of the ovulatory process and has been the subject of intensive investigation. Many studies have been performed in various vertebrate animals that focused on proteolysis during ovulation. Despite much effort, the proteases responsible for follicle rupture in ovulation have not yet been identified for mammalian species. However, studies conducted using the teleost medaka have recently provided valuable information about the follicle rupture process. Follicle rupture during medaka ovulation is accomplished by a two-step extracellular matrix (ECM) hydrolysis mechanism involving two distinct protease systems, the urokinase-type plasminogen activator-1 /plasmin and the matrix metalloproteinase system. In the 24-h spawning cycle of the fish, the former protease system is activated first, and the latter subsequently becomes active. Proteolytic activities of these systems are regulated by their intrinsic inhibitors. The endocrine regulation of the rupture was examined by investigating the expression of matrix metalloproteinase 15 (Mmp15), which is the only LH-inducible protease among those involved in the rupture process. At least two transcription factors, classical nuclear progestin receptor and CCAAT/enhancer-binding protein β, play critical roles in the expression of the protease transcript. This review also summarizes studies addressing follicle rupture during ovulation conducted using other teleost models to understand the current status of teleost ovulation studies.

GnRH-agonist implants suppress reproductive function and affects ovarian LHR and FSHR expression in prepubertal female cats

Effect of a GnRH-agonist (deslorelin) was studied on reproductive function and ovarian luteinizing hormone receptor (LHR) and follicle stimulating hormone receptor (FSHR) expression in prepubertal female cats that were either implanted with 4.7-mg deslorelin (implanted: n = 6) or not (controls: n = 18) or ovariohysterectomized at prepubertal age (prepubertal OVH: n = 6). Body weights, fecal estradiol, and sexual behavior of implanted and control cats were monitored for 48 weeks followed by collection of ovaries and uteri. Ovaries and uteri were collected from control cats at follicular, luteal, and inactive stage (n = 6/group) and from prepubertal OVH cats at prepubertal age. Ovaries and uteri were analyzed for anatomical/histological characteristics. Ovaries were also analyzed for LHR and FSHR expression. Statistical analysis showed higher (P ≤ 0.05) body weight in control than implanted cats only during 22nd to 26th weeks of the study. Estrus was observed in control cats only. Deslorelin reduced (P ≤ 0.05) ovarian weight and number of antral follicles but did not affect endometrial thickness and gland diameter. However, myometrial thickness of implanted cats was significantly lower than control cats at follicular and luteal stage. Ovarian LHR mRNA expression was lower (P ≤ 0.05) in implanted cats than control cats at follicular stage. FSHR mRNA and LHR protein expression did not differ among the three groups. FSHR protein expression was lower (P ≤ 0.05) in prepubertal OVH cats and was not affected by deslorelin. In conclusion, deslorelin suppresses reproductive function in prepubertal female cats for at least 48 weeks possibly through a change in the ovarian mRNA expression of LHR.

Concentración de hormona luteinizante en el suero de la mujer normal

Se ha determinado lo concentración de hormona luteinizante (LH) en el suero sanguíneo de 20 mujeres en edad reproductiva, con ciclos menstruales normales, sin tratamiento hormonal alguno, únicamente a 6 se había implantado un D. l. U. Con este objeto se empleó una técnica radioinmunológica. En tres ciclos no se pudo demostrar una elevación significativa de LH en la mitad del mismo. En los 17 ciclos, considerados bifásicos, ovulatorios, se encontró una concentración mayor de LH en la fase folicular (8 .93 mU/ml, expresados en unidades del 2nd. IRP-HMG) que en la fase luteal (7.43 mU/ml), p = 0.025. Para una duración promedio de 30 días, el pico ovulatorio de LH se presentó alrededor del 17° día del ciclo, con amplias variaciones entre el 11° y el 25° día. La fase luteal duró como término medio 14 días. Lo concentración promedio de LH del pico mesocíclico fue de 79.97 mU/ml, lo cual representó un incremento mayor de nueve veces la concentración de LH hallado durante lo fase folicular.

The Ovarian Antral Follicle: Living on the Edge of Hypoxia or Not?

Oocytes within antral follicles are thought to have restricted access to O2, as follicle vascularity is not adjacent and both granulosa and cumulus cells are metabolically active. Indeed, measured follicular antrum partial pressure (pO2) is regarded as low, but accurate and direct measurement represents a technical challenge that has yet to be overcome. The oocyte itself is highly dependent on oxidative phosphorylation for survival and competence for further development following fertilization, and it has been suggested that follicular pO2 levels are correlated with this capacity for further development. It is clear that gonadotropins are involved in regulating antrum formation, follicle vascularization, cellular differentiation, and the hypoxia-inducible factors (HIF), which are mainly regulated by dissolved O2 concentration. A newly discovered player in this story is the intracellular production of hemoglobin by both granulosa and cumulus cells, as well as the oocyte. Furthermore, cellular hemoglobin levels are dynamic, responding to the ovulatory luteinizing hormone (LH) surge. We hypothesize that this gas transport and antioxidant molecule is involved in the prevention of hypoxic response signaling by HIFs within the preovulatory antral follicle; and the transition of granulosa cells to luteal tissue by facilitating the stabilization of HIFs, enabling induction of luteinization signaling. Another possible role is by sequestering nitric oxide (NO) during the ovulatory period, which may facilitate the resumption of meiosis in the oocyte. Testing these hypotheses will be challenging but important if the regulation of ovarian function is to be fully understood.

Hindbrain lactate regulates preoptic gonadotropin-releasing hormone (GnRH) neuron GnRH-I protein but not AMPK responses to hypoglycemia in the steroid-primed ovariectomized female rat

Steroid positive-feedback activation of the gonadotropin-releasing hormone (GnRH)–pituitary luteinizing hormone (LH) neuroendocrine axis propagates the pre ovulatory LH surge, a crucial component of female reproduction. Our work shows that this key event is restrained by inhibitory metabolic input from hindbrain A2 noradrenergic neurons. GnRH neurons express the ultra-sensitive energy sensor adenosine 5′-monophosphate-activated protein kinase (AMPK); here, we investigated the hypothesis that GnRH nerve cell AMPK and peptide neurotransmitter responses to insulin-induced hypoglycemia are controlled by hindbrain lack of the oxidizable glycolytic end-product l-lactate. Data show that hypoglycemic inhibition of LH release in steroid-primed ovariectomized female rats was reversed by coincident caudal hindbrain lactate infusion. Western blot analyses of laser-microdissected A2 neurons demonstrate hypoglycemic augmentation [Fos, estrogen receptor-beta (ER-β), phosphoAMPK (pAMPK)] and inhibition (dopamine-beta-hydroxylase, GLUT3, MCT2) of protein expression in these cells, responses that were normalized by insulin plus lactate treatment. Hypoglycemia diminished rostral preoptic GnRH nerve cell GnRH-I protein and pAMPK content; the former, but not the latter response was reversed by lactate. Results implicate caudal hindbrain lactoprivic signaling in hypoglycemia-induced suppression of the LH surge, demonstrating that lactate repletion of that site reverses decrements in A2 catecholamine biosynthetic enzyme and GnRH neuropeptide precursor protein expression. Lack of effect of lactate on hypoglycemic patterns of GnRH AMPK activity suggests that this sensor is uninvolved in metabolic-inhibition of positive-feedback-stimulated hypophysiotropic signaling to pituitary gonadotropes.

The Effects of Unpredictable Stress on the LHR Expression and Reproductive Functions in Mouse Models

Sung-Young Choi, Jin-Heum Park, Yuxia Zhu, Young-Jong kim, Jae-Ok Park, Changjong Moon, Taekyun Shin, Meejung Ahn, Suk-Soo Kim, Young-Sik Park, Hyung-Bok Chae, Tae-Kyun Kim and Seung-Joon Kim. J Vet Clin 2014;31:394-402. https://doi.org/10.17555/ksvc.2014.10.31.5.394

Serum leptin levels and reproductive function during the menstrual cycle

The purpose of this study was to investigate the role of leptin on reproductive hormones and ovulation. The BioCycle Study (2005-2007) followed 259 healthy premenopausal women not using hormonal contraceptives for ≤2 menstrual cycles (n = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone, and testosterone were measured ≤8 times per cycle. The association of time-varying leptin and reproductive hormones over the cycle was estimated with the use of linear mixed models that were adjusted for percent body fat and age with inverse probability weighting for time-varying physical activity, caloric intake, and other reproductive hormones. The odds ratio for sporadic anovulation (n = 42 cycles) was estimated with the use of generalized linear models that were adjusted for percent body fat and age. Geometric mean serum leptin levels increased from menses to the late luteal phase (16.7-20.4 ng/mL; P < .01), with a mid-cycle peak (21.7 ng/mL) at the time of the LH surge (P < .01). A 10% higher leptin level across the menstrual cycle was associated with higher estradiol levels (2.2%; 95% CI, 1.5-3.0), luteal progesterone levels (2.1%; 95% CI, 0.5-3.7), ovulatory LH levels (1.2%; 95% CI, 0-2.3), testosterone levels (0.6%; 95% CI, 0.3-0.9), and lower follicle-stimulating hormone levels (-0.7%; 95% CI, -1.1 to -0.4). Leptin at the time of the expected LH surge was moderately inversely associated with sporadic anovulation (per log increase in leptin; adjusted odds ratio, 0.58; 95% CI, 0.28-1.22). The association that was observed between leptin level and reproductive function points to a possible relationship between serum leptin level and enhanced fertility.

The effects of 11-ketotestosterone on ovarian physiology of previtellogenic captive hapuku (Polyprion oxygeneios)

The present study investigated, for the first time in a perciform teleost, the effects of in vivo 11-ketotestosterone (11-KT) treatment using slow-release implants on ovarian development and gonadotropin receptor mRNA levels in captive previtellogenic females of hapuku (Polyprion oxygeneios). At the cellular/functional level, ovarian development and ovarian and hepatic total lipid levels were examined. At the molecular level, transcript abundance of ovarian follicle-stimulating hormone receptor (FSH-R) and luteinizing hormone receptor (LH-R) was measured. Additionally, cyclic adenosine monophosphate (cAMP) levels in ovarian fragments from placebo and 11-KT implanted fish incubated with or without human chorionic gonadotropin (hCG) in vitro were compared between groups. There were no significant differences between treatments with regard to oocyte size and lipid contents of liver and ovary. Messenger RNA levels of FSH-R and LH-R were significantly lower in the treated females. Similarly, cAMP levels were significantly lower in the ovarian fragments of the 11-KT implanted females. These results suggest that 11-KT specifically, but possibly androgens in general, may not have an important function in regulating gonadal development of previtellogenic female hapuku; indeed, if anything, 11-KT appeared to have a detrimental effect and its use will not be beneficial in advancing sexual maturity of hapuku in aquaculture.

The permissive role of prolactin as a regulator of luteinizing hormone action in the female mouse ovary and extragonadal tumorigenesis

Transgenic female mice overexpressing the hCGβ subunit (hCGβ(+)) and producing elevated levels of luteinizing hormone (LH)/hCG bioactivity present as young adults with enhanced ovarian steroidogenesis, precocious puberty, and infertility. They subsequently develop pituitary prolactinomas, high circulating prolactin (PRL) levels, and marked mammary gland lobuloalveolar development followed by adenocarcinomas. None of these phenotypes appear in gonadectomized mice, indicating that the hCG-induced aberrations of ovarian function are responsible for the extragonadal phenotypes. PRL receptor-deficient (PRLR(-/-)) female mice are sterile, despite ovulating, due to a failure of embryo implantation, as a consequence of decreased ovarian LH receptor (Lhcgr) expression and inadequate corpus luteum formation and progesterone production. To study further the presumed permissive role of PRL in the maintenance of gonadal responsiveness to LH/hCG stimulation, we crossed the hCGβ(+) and PRLR(-/-) mice. The double-mutant hCGβ(+)/PRLR(-/-) females remained sterile with an ovarian phenotype similar to PRLR(-/-) mice, indicating that LH action, Lhcgr expression, and consequent luteinization are not possible without simultaneous PRL signaling. The high frequency of pituitary prolactinomas in PRLR(-/-) mice was not affected by transgenic hCGβ expression. In contrast, none of the hCGβ(+)/PRLR(-/-) females showed either mammary gland lobuloalveolar development or tumors, and the increased mammary gland Wnt-5b expression, possibly responsible for the tumorigenesis in hCGβ(+) mice, was absent in double-mutant mice. Hence, high LH/hCG stimulation is unable to compensate for missing PRL signaling in the maintenance of luteal function. PRL thus appears to be a major permissive regulator of LH action in the ovary and of its secondary extragonadal effects.

Characterizing the neuroendocrine and ovarian defects of androgen receptor-knockout female mice

Homozygous androgen receptor (AR)-knockout (ARKO) female mice are subfertile due to both intra- and extraovarian (neuroendocrine) defects as defined by ovary transplantation. Using ARKO mice, this study set out to reveal the precise AR-regulated pathways required for optimal androgen-regulated ovulation and fertility. ARKO females exhibit deficient neuroendocrine negative feedback, with a reduced serum luteinizing hormone (LH) response to ovariectomy (OVX) (P < 0.01). Positive feedback is also altered as intact ARKO females, at late proestrus, exhibit an often mistimed endogenous ovulatory LH surge. Furthermore, at late proestrus, intact ARKO females display diminished preovulatory serum estradiol (E2; P < 0.01) and LH (P < 0.05) surge levels and reduced Kiss1 mRNA expression in the anteroventral periventricular nucleus (P < 0.01) compared with controls. However, this reduced ovulatory LH response in intact ARKO females can be rescued by OVX and E2 priming or treatment with endogenous GnRH. These findings reveal that AR regulates the negative feedback response to E2, E2-positive feedback is compromised in ARKO mice, and AR-regulated negative and positive steroidal feedback pathways impact on intrahypothalamic control of the kisspeptin/GnRH/LH cascade. In addition, intraovarian AR-regulated pathways controlling antral to preovulatory follicle dynamics are disrupted because adult ARKO ovaries collected at proestrus have small antral follicles with reduced oocyte/follicle diameter ratios (P < 0.01) and increased proportions of unhealthy large antral follicles (P < 0.05) compared with controls. As a consequence of aberrant follicular growth patterns, proestrus ARKO ovaries also exhibit fewer preovulatory follicle (P < 0.05) and corpora lutea numbers (P < 0.01). However, embryo development to the blastocyst stage is unchanged in ARKO females, and hence, the subfertility is a consequence of reduced ovulations and not altered embryo quality. These findings reveal that the AR has a functional role in neuroendocrine regulation and timing of the ovulatory LH surge as well as antral/preovulatory follicle development.

Dietary lipid and cholesterol induce ovarian dysfunction and abnormal LH response to stimulation in rabbits.

Background/AimExcess of fat intake is dramatically increasing in women of childbearing age and results in numerous health complications, including reproductive disorders. Using rabbit does as a biomedical model, the aim of this study was to evaluate onset of puberty, endocrine responses to stimulation and ovarian follicular maturation in females fed a high fat high cholesterol diet (HH diet) from 10 weeks of age (i.e., 2 weeks before normal onset of puberty) or a control diet (C diet).Methodology/Principal FindingsThree experiments were performed, each including 8 treated (HH group) and 8 control (C group) does. In experiment 1, the endocrine response to Gonadotropin releasing hormone (GnRH) was evaluated at 13, 18 and 22 weeks of age. In experiment 2, the follicular population was counted in ovaries of adult females (18 weeks of age). In experiment 3, the LH response to mating and steroid profiles throughout gestation were evaluated at 18 weeks of age. Fetal growth was monitored by ultrasound and offspring birth weight was recorded. Data showed a significantly higher Luteinizing hormone (LH) response after induction of ovulation at 13 weeks of age in the HH group. There was no difference at 18 weeks, but at 22 weeks, the LH response to GnRH was significantly reduced in the HH group. The number of atretic follicles was significantly increased and the number of antral follicles significantly reduced in HH does vs. controls. During gestation, the HH diet induced intra-uterine growth retardation (IUGR).ConclusionThe HH diet administered from before puberty onwards affected onset of puberty, follicular growth, hormonal responses to breeding and GnRH stimulation in relation to age and lead to fetal IUGR.