Luteinizing Hormone Response Research Articles

Obesity Alters POMC and Kisspeptin Neuron Cross Talk Leading to Reduced Luteinizing Hormone in Male Mice.

Obesity is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms. Herein, we used mice fed chronic high-fat diet, which mimics human obesity, to determine mechanisms of impairment at the level of the hypothalamus, in particular gonadotropin-releasing hormone (GnRH) neurons that regulate luteinizing hormone (LH), which then regulates testosterone. Consistent with obese humans, we demonstrated lower LH, and lower pulse frequency of LH secretion, but unchanged pituitary responsiveness to GnRH. LH pulse frequency is regulated by pulsatile GnRH secretion, which is controlled by kisspeptin. Peripheral and central kisspeptin injections, and DREADD-mediated activation of kisspeptin neurons, demonstrated that kisspeptin neurons were suppressed in obese mice. Thus, we investigated regulators of kisspeptin secretion. We determined that the LH response to NMDA was lower in obese mice, corresponding to fewer glutamate receptors in kisspeptin neurons, which may be critical for kisspeptin synchronization. Given that kisspeptin neurons also interact with anorexigenic POMC neurons, which are affected by obesity, we examined their cross talk, and determined that the LH response to either DREADD-mediated activation of POMC neurons or central injection of αMSH, a product of POMC, is abolished in obese mice. This was accompanied by diminished levels of αMSH receptor, MC4R, in kisspeptin neurons. Together, our studies determined that obesity leads to the downregulation of receptors that regulate kisspeptin neurons, which is associated with lower LH pulse frequency, leading to lower LH and hypogonadism.

Modulatory Effects of Ethinyl Estradiol Plus Drospirenone Contraceptive Pill on Spontaneous and GnRH-Induced LH Secretion

Background: Combined oral contraceptives (COCs) work mostly by preventing the pre-ovulatory gonadotropin surge, but the action of COCs on spontaneous episodic and GnRH (gonadotropin-releasing hormone)-induced LH (luteinizing hormone) release has been poorly evaluated. Oral contraceptives are known to act on the spontaneous hypothalamic–pituitary functions reducing both GnRH and gonadotropin release and blocking ovulation. Aim: To evaluate spontaneous and GnRH-induced LH release during both phases of the menstrual cycle or under the use of the contraceptive pill. Methods: A group of 12 women, subdivided into two groups, volunteered for the study. Group A (n = 6, controls) received no treatments, while Group B (n = 6) received a 21 + 7 combination of ethinyl-estradiol (EE) 30 µg + drospirenone (DRSP) 3 mg. Both groups were evaluated twice: Group A during follicular and luteal phases, Group B during pill assumption and during the suspension interval, performing a pulsatility test, GnRH stimulation test, and hormonal parameters evaluation. Spontaneous and GnRH-induced secretory pulses were evaluated, as well as the instantaneous secretory rate (ISR). Results: COC treatment lowered LH and FSH (follicle stimulating hormone) levels significantly if compared to the follicular phase of spontaneous cycles. During the suspension interval, hormone levels rapidly rose and became comparable to those of the follicular phase of the control group. The LH pulse frequency under COC administration during the suspension interval was similar to that observed during the follicular phase (2.6 ± 0.3 pulses/180 min and 2.3 ± 0.2 pulses/180 min, respectively). The GnRH-induced LH peaks were greater in amplitude and duration than those observed after ISR computation in both groups. The GnRH-induced LH release during the luteal phase of the control subjects was higher than in the follicular phase (51.2 ± 12.3 mIU/mL and 14.9 ± 1.8 mIU/mL, respectively). Conversely, subjects under COC showed a GnRH-induced LH response similar during COC and during the suspension interval. Conclusions: Our data support that the EE + DRSP preparation acts on both spontaneous pulsatile release and GnRH-induced LH release during the withdrawal period of the treatment, and that after 5–7 days from the treatment suspension, steroidal secretion from the ovary is resumed, such as that of androgens. This suggests that in hyperandrogenic patients, a suspension interval as short as 4 days might be clinically better.

EFFECT OF GONADOTROPHIN RELEASING HORMONE ON FOLLICULAR DYNAMICS, LUTEINISING HORMONE, AND PROGESTERONE LEVELS IN BUNAJI COWS

This study evaluated the ovarian and hormonal responses of Bunaji cows to ovsynch protocol initiated at random oestrus cycle stages. Fifteen animals were arranged into three groups and treated as follows: control (n=5), 2mL normal saline; group A (n=5), 50mg Gonadotrophin releasing hormone (GnRH) on day 0 and day 9 followed by 500mg of Prostaglandin F2 alpha (PGF2a) on day 7; and group B (n=5) 100mg of GnRH on day 0 and day 9 followed by 500mg PGF2a on day 7. Ultrasound examination of the ovaries was carried out daily from d 1 to d 9 and, thereafter every 12h until ovulation was detected. Blood sampling was carried out at 30 min intervals for 6 h following the GnRH administration for determination of serum luteinizing hormone (LH) and once daily for 12 days after the injection of the first GnRH to determine plasma progesterone concentration. The ovarian response of the treated groups showed no significant difference between the two dosages of ovsynch protocol but differed significantly between the treated and the control groups. Peak values of serum LH obtained on day 0 and day 9 of GnRH administration differed significantly (P<0.05). Plasma progesterone increased among treated groups following injection of GnRH reaching a peak on day 7 compared to control, but did not differ among treated groups. In conclusion, GnRH at 50 mg and 100 mg was able to elicit adequate LH and progesterone responses that caused the disappearance of dominant follicles and, subsequent ovulation thereby increasing the reproductive efficiency of Bunaji cows.

A high-fat eucaloric diet induces reprometabolic syndrome of obesity in normal weight women.

We examined the effects of 1 month of a eucaloric, high-fat (48% of calories) diet (HFD) on gonadotropin secretion in normal-weight women to interrogate the role of free fatty acids and insulin in mediating the relative hypogonadotropic hypogonadism of obesity. Eighteen eumenorrheic women (body mass index [BMI] 18-25 kg/m2) were studied in the early follicular phase of the menstrual cycle before and after exposure to an HFD with frequent blood sampling for luteinizing hormone (LH) and follicle-stimulating hormone (FSH), followed by an assessment of pituitary sensitivity to gonadotropin-releasing hormone (GnRH). Mass spectrometry-based plasma metabolomic analysis was also performed. Paired testing and time-series analysis were performed as appropriate. Mean endogenous LH (unstimulated) was significantly decreased after the HFD (4.3 ± 1.0 vs. 3.8 ± 1.0, P < 0.01); mean unstimulated FSH was not changed. Both LH (10.1 ± 1.0 vs. 7.2 ± 1.0, P < 0.01) and FSH (9.5 ± 1.0 vs. 8.8 ± 1.0, P < 0.01) responses to 75 ng/kg of GnRH were reduced after the HFD. Mean LH pulse amplitude and LH interpulse interval were unaffected by the dietary exposure. Eucaloric HFD exposure did not cause weight change. Plasma metabolomics confirmed adherence with elevation of fasting free fatty acids (especially long-chain mono-, poly-, and highly unsaturated fatty acids) by the last day of the HFD. One-month exposure to an HFD successfully induced key reproductive and metabolic features of reprometabolic syndrome in normal-weight women. These data suggest that dietary factors may underlie the gonadotrope compromise seen in obesity-related subfertility and therapeutic dietary interventions, independent of weight loss, may be possible.

Use of the Subcutaneous Triptorelin Stimulation Test for Diagnosis of Central Precocious Puberty.

The gold standard gonadotropin-releasing hormone (GnRH) stimulation test uses the response to intravenously injected gonadorelin to diagnose central precocious puberty (CPP). However, gonadorelin is not always readily available. This study investigated the diagnostic efficacy of the subcutaneous triptorelin test and the optimal blood sampling time for diagnosis of CPP. This study retrospectively examined the medical records of 220 girls who had undergone either the triptorelin or gonadorelin test and compared their clinical characteristics. We retrospectively compared clinical parameters between girls diagnosed with CPP (n = 111) and idiopathic premature thelarche (IPT) (n = 109) using three different diagnostic methods: the gonadorelin, triptorelin 120 min, and triptorelin 180 min tests. The diagnostic ability of the stimulated luteinizing hormone (LH) concentration in the triptorelin test for CPP was evaluated using receiver operating characteristic (ROC) analysis. The CPP group exhibited higher basal and peak gonadotropin levels, more advanced bone age, and a lower body mass index standard deviation score than the IPT group. In the gonadorelin test group, all girls with CPP exhibited a peak LH response 30-60 min after intravenous gonadorelin injection. In the triptorelin test group, most girls with CPP exhibited a peak LH response 60-180 min after subcutaneous triptorelin injection (n = 68). On the ROC curve, a peak LH concentration of ≥ 4.52 IU/L at 120 min had the highest CPP diagnostic accuracy, with sensitivity and specificity of 100% and 95.83%, respectively.

PSIV-17 Postnatal Obesity Amplifies Gnrh-Induced Lh Release in Prenatal Testosterone-Treated Female Sheep

Abstract Polycystic ovary syndrome (PCOS) is the most common hormonal disorder in females of reproductive age. Hypersecretion of luteinizing hormone (LH), partly due to increased pituitary sensitivity to gonadotrophin-releasing hormone (GnRH), is a significant cause of infertility in women with PCOS. Moreover, obesity amplifies the severity of reproductive dysfunction in PCOS. In sheep, testosterone (T) excess during gestational days (GD) 30 to 90 results in GnRH-mediated LH hypersecretion and recapitulates the PCOS phenotype. This study investigated 1) if mid-gestation (GD 60 to 90) is the susceptibility window for programming pituitary hypersensitivity to GnRH, and 2) the contribution of postnatal obesity in modulating LH responsiveness to GnRH. Suffolk ewes received T propionate (T; 100 mg i.m.) or corn oil (C; vehicle) twice weekly from GD 60 to 90 (term = 147 d). At 5 mo of age, T lambs were assigned randomly to either a maintenance (100% of NRC requirements) or overfed diet (130% of NRC requirements), and Control lambs were fed the maintenance diet. During the anestrous period (late summer), ewes (n = 8/group; ~17 mo of age) received a GnRH bolus injection (2 ng/kg) intravenously every 1.5 h and blood samples were collected at 15-min intervals for a 6-h period. Despite animals being in seasonal anestrous, few endogenous LH pulses were evident during the 6 h-sampling period. To avoid confounding, only clear responses to GnRH challenge that occurred within 15 to 45 min after each GnRH injection were considered for further analyses. Mean number of exogenous GnRH-induced LH responses that met these criteria did not differ between groups and averaged 1.81 ± 0.27 pulses/animal. The parameters of these GnRH-induced responses were analyzed as one-way ANOVA with Tukey’s HSD post-hoc analysis. Mean LH pulse peak was greater (P &amp;lt; 0.05) in T overfed ewes (4.59 ± 0.49 ng/mL) compared with T maintenance (2.19 ± 0.61 ng/mL) and Control ewes (2.58 ± 0.53 ng/mL). Additionally, amplitude of LH pulses was greater (P &amp;lt; 0.05) in T overfed ewes (2.66 ± 0.39 ng/mL) compared with T maintenance (1.03 ± 0.48 ng/mL) and tended (P = 0.089) to be greater in T overfed compared with Control ewes (1.41 ± 0.42 ng/mL). LH pulse peak and amplitude in T maintenance did not differ from Control ewes. In conclusion, failure of GD 60 to 90 T treatment to increase GnRH responsiveness as opposed to our earlier finding of increased responsiveness in GD 30 to 90 T-treaded sheep indicates that the susceptibility window for programming pituitary hypersensitivity to GnRH lies between GD 30 to 60. Postnatal obesity may act as an independent activational signal in amplifying the pituitary sensitivity to GnRH in female sheep. This premise is supported by observations that obesity exacerbates pituitary-mediated LH hypersecretion in women with PCOS. Research support: NIH-NICHD (R01HD099096).

The effect of NK3-Saporin injection within the arcuate nucleus on puberty, the LH surge, and the response to Senktide in female sheep†.

The timing of puberty onset is reliant on increased gonadotropin-releasing hormone (GnRH). This elicits a corresponding increase in luteinizing hormone (LH) due to a lessening of sensitivity to the inhibitory actions of estradiol (E2). The mechanisms underlying the increase in GnRH release likely involve a subset of neurons within the arcuate (ARC) nucleus of the hypothalamus that contain kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons). We aimed to determine if KNDy neurons in female sheep are critical for: timely puberty onset; the LH surge; and the response to an intravenous injection of the neurokinin-3 receptor (NK3R) agonist, senktide. Prepubertal ewes received injections aimed at the ARC containing blank-saporin (control, n = 5) or NK3-saporin (NK3-SAP, n = 6) to ablate neurons expressing NK3R. Blood samples taken 3/week for 65days following surgery were assessed for progesterone to determine onset of puberty. Control ewes exhibited onset of puberty at 33.2 ± 3.9days post sampling initiation, whereas 5/6 NK3-SAP treated ewes didn't display an increase in progesterone. After an artificial LH surge protocol, surge amplitude was lower in NK3-SAP ewes. Finally, ewes were treated with senktide to determine if an LH response was elicited. LH pulses were evident in both groups in the absence of injections, but the response to senktide vs saline was similar between groups. These results show that KNDy cells are necessary for timely puberty onset and for full expresson of the LH surge. The occurrence of LH pulses in NK3-SAP treated ewes may indicate a recovery from an apulsatile state.

SAT606 Comparison Of Psychosocial And Immune/Inflammatory Stress On Luteinizing Hormone Pulsatile Secretion

Abstract Disclosure: J. Jang: None. M.J. Kreisman: None. K.M. Breen Church: None. Stress induces a physiological response in the body to return to the homeostatic state. It is recognized that many stress types impair reproduction, but the mechanisms conveying inhibition may be distinct and stressor-dependent. Our research aims to understand how stress inhibits the neuroendocrine mechanisms controlling the pulsatile release of luteinizing hormone (LH). This is especially important because pulsatile LH is pivotal to reproductive health in males and females. Immune/inflammatory stressors such as lipopolysaccharides (LPS) cause an inflammatory response, producing peripheral cytokines that can signal to the brain in distinct ways compared to the neural mechanisms employed in response to psychosocial stress. However, how LPS disrupts the neural mechanisms involved in gonadotropin pulsatility is still unknown. Here, we compared the alteration in LH pulses in response to psychosocial restraint stress or immune/inflammatory LPS stress and sought to understand stress-specific regulation of the upstream targets controlling LH synthesis and secretion. Our initial observations demonstrated, in ovariectomized (OVX) female mice, that restraint stress elicited suppression rapidly, within 30 minutes; yet, the response to LPS was delayed, occurring approximately 90 minutes from injection. Therefore, we investigated the prolonged response of the stressors on LH pulses, observing LH pulse profiles 90 minutes to 180 minutes after the initiation of stress. Restraint stress significantly suppressed mean LH, resulting from a suppression of pulse frequency. LPS injected intraperitoneal (IP, 1.5 ug/g) also significantly suppressed mean LH. In contrast to restraint stress, LPS induced a reduction in both frequency as well as LH pulse amplitude. We conducted two follow-up experiments to investigate the lowered LH pulse amplitude during immune/inflammatory stress. The first study assessed hypothalamic kisspeptin gene expression and pituitary LHβ and GnRH receptor expression, in LPS versus restraint animals, to test whether altered gene transcription in LPS animals resulted in lowered LH secretion. The results of this experiment are still pending. The second study tested the LH response to a single bolus of GnRH or kisspeptin. Interestingly, we found equivalent LH increases, to either agonist, in saline versus LPS-treated animals. Collectively, these data indicate that both restraint and immune/inflammatory stress inhibit LH pulse frequency. However, the endogenous LH pulse profiles suggest an additional stressor-specific mechanism that lowers pulsatile LH during immune/inflammatory stress via LPS. Identification of stress pathways that alter endocrine hormones is critical as it allows for the development of therapeutics and medications to treat endocrine disorders. Presentation: Saturday, June 17, 2023

Mechanisms and predictors of menses resumption once normal weight is reached in anorexia nervosa

BackgroundIn cases of Anorexia Nervosa (AN), achieving weight gain recovery beyond the lower limits set by the World Health Organization and normalizing classical nutritional markers appears to be essential for most patients. However, this is not always adequate to restore menstrual cycles. This discrepancy can cause concern for both patients and healthcare providers, and can impact the medical management of these individuals. Thus, the purpose of this study was to assess the ability of anthropometric and hormonal factors to predict the resumption of menstrual cycles in individuals with anorexia nervosa upon reaching a normal body weight.MethodPatients with AN who had achieved a normal Body Mass Index but had not yet resumed their menstrual cycles (referred to as ANRec) were evaluated on two occasions: first at visit 1 and then again 6 months later, provided their body weight remained stable over this period (visit 2). Among the 46 ANRec patients who reached visit 2, they were categorized into two groups: 20 with persistent amenorrhea (PA-ANRec) and 26 who had regained their menstrual cycles (RM-ANRec). Anthropometric measurements, several hormone levels, Luteinizing Hormone (LH) pulsatility over a 4-h period, and LH response to gonadotropin-releasing hormone injection (LH/GnRH) were then compared between the two groups at visit 1.ResultsPatients in the RM-ANRec group exhibited higher levels of follicular stimulating hormone, estradiol, inhibin B, LH/GnRH, and lower levels of ghrelin compared to those in the PA-ANRec group. Analysis of Receiver Operating Characteristic curves indicated that having ≥ 2 LH pulses over a 4-h period, LH/GnRH levels ≥ 33 IU/l, and inhibin B levels > 63 pg/ml predicted the resumption of menstrual cycles with a high degree of specificity (87%, 100%, and 100%, respectively) and sensitivity (82%, 80%, and 79%, respectively).ConclusionsThese three hormonal tests, of which two are straightforward to perform, demonstrated a high predictive accuracy for the resumption of menstrual cycles. They could offer valuable support for the management of individuals with AN upon achieving normalized weight. Negative results from these tests could assist clinicians and patients in maintaining their efforts to attain individualized metabolic targets.Trial registrationIORG0004981.

The GLP-1 agonist, Exendin-4, stimulates LH secretion in female sheep.

Our previous studies showed that microinjection into the median eminence of the sheep of glucagon-like peptide- 1 (GLP-1) or its receptor agonist Exendin-4 stimulates luteinizing hormone (LH) secretion but it is unknown whether the same effect may be obtained by systemic administration of the same. The present study measured the response in terms of plasma LH concentrations, to intravenous (iv) infusion of Exendin-4. A preliminary study showed that infusion of 2mg Exendin-4 into ewes produced a greater LH response in the follicular phase of the oestrous cycle than the luteal phase. Accordingly, the main study monitored plasma LH levels in response to either 0.5mg or 2mg Exendin-4 or vehicle (normal saline) delivered by jugular infusion for 1h in the follicular phase of the oestrous cycle. Blood samples were collected at 10 min intervals before, during and after infusion. Both doses of Exendin-4 increased mean plasma LH concentrations and increased LH peripheral pulse amplitude. There was no effect on inter-pulse interval or timing of the preovulatory LH surge. These doses of Exendin-4 did not alter plasma insulin or glucose concentrations. Quantitative PCR of the gastrointestinal tract samples from a population of ewes confirmed expression of the preproglucagon gene (GCG). Expression increased aborally and was greatest in the rectum. It is concluded that endogenous GLP-1, most likely derived from the hind-gut may act systemically to stimulate LH secretion. The present data suggest that this effect may be obtained with levels of agonist that are lower than those functioning as an incretin.

An automated system for cattle reproductive management under the IoT framework. Part II: Induction of luteinizing hormone release after gonadotropin releasing hormone analogue delivery with e-Synch

Technologies for automating animal management and monitoring tasks can improve efficiency and productivity of livestock production. We developed the e-Synch system for automated control and monitoring the estrous cycle of cattle through intravaginal hormone delivery and sensing. Thus, our objective was to evaluate luteinizing hormone (LH) concentrations after intravaginal instillation of the Gonadotropin-releasing hormone (GnRH) analogue Gonadorelin with the e-Synch system. This system consists of an intravaginal electronically controlled automated hormone delivery and sensing device integrated with an IoT platform. Lactating Holstein cows with their estrous cycle synchronized were used in two experiments (Exp). In Exp 1, at 48 h after induction of luteolysis, cows (n=5-6 per group) were randomized to receive 100 µg of Gonadorelin through intramuscular (i.m.) injection, 100 µg of Gonadorelin in a 2 mL solution delivered with e-Synch, and an empty e-Synch device. In Exp 2, at 48 h after induction of luteolysis cows (n=6-7 per group) were randomized to receive 100 µg of Gonadorelin i.m., or an intravaginal treatment with e-Synch consisting of 100 or 1,000 µg of Gonadorelin in 2 or 10 mL of solution containing 10% citric acid as absorption enhancer. Circulating concentrations of LH were analyzed with linear mixed models with or without repeated measurements. In Exp 1, cows in the i.m. Gonadorelin treatment had a surge of LH whereas cows in the other two treatments did not have a surge of LH for up to 8 h after treatment. In Exp 2, the 1,000 µg dose of Gonadorelin elicited more LH release than the 100 µg dose, regardless of solution quantity. The overall LH response as determined by area under the curve, mean, and maximum LH concentrations was similar between cows receiving 1,000 µg of Gonadorelin delivered with e-Synch and 100 μg of Gonadorelin i.m. Increasing volume of solution for delivering the same dose of Gonadorelin partially increased LH release only for the 100 µg dose. We conclude that the e-Synch system could be used to automatically release Gonadorelin in a dose and volume that induces a surge of LH of similar magnitude than after i.m. injection of 100 μg of Gonadorelin. Also, the dose of Gonadorelin delivered by e-Synch is more critical than the volume of solution used.

Is seminal nerve growth factor-induced luteinizing hormone release in camelids mediated at the hypothalamus?

Seminal nerve growth factor induces ovulation in camelids by influencing the secretion of gonadotrophin-releasing hormone (GnRH) into the portal vessels of the pituitary gland. We show that the nerve growth factor-induced release of GnRH is not mediated directly through interaction with hypothalamic neurons. Ovulation in camelids is triggered by seminal nerve growth factor (NGF). The mechanism of action of NGF appears to occur via the central nervous system. In this study, we tested the hypothesis that NGF acts in the hypothalamus to induce GnRH release. To determine if NGF-induced ovulation is associated with a rise in NGF concentrations in the cerebrospinal fluid (CSF), llamas were i) mated with an urethrostomized male, ii) mated with intact male, or given intrauterine iii) seminal plasma or i.v.) saline (Experiment 1). To characterize the luteinizing hormone (LH) response after central vs peripheral administration, llamas were treated with saline (negative control) or NGF either by i.v. or intracerebroventricular (ICV) administration (Experiment 2). To determine the role of kisspeptin, the effect of ICV infusion of a kisspeptin receptor antagonist on NGF-induced LH secretion and ovulation was tested in llamas (Experiment 3). In Experiment 1, a surge in circulating concentrations of LH was detected only in llamas mated with an intact male and those given intrauterine seminal plasma, but no changes in CSF concentrations of NGF were detected. In Experiment 2, peripheral administration (i.v.) of NGF induced an LH surge and ovulation, whereas no response was detected after central (ICV) administration. In Experiment 3, the kisspeptin receptor antagonist had no effect on the LH response to NGF. In conclusion, results did not support the hypothesis that NGF-induced ovulation is mediated via a trans-synaptic pathway within the hypothalamus, but rather through a releasing effect on tanycytes at the median eminence.

The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure.

The etiopathogenesis of fibromyalgia (FM) and chronic fatigue syndrome (CFS) is not yet elucidated. Hypothalamo-pituitary-adrenal (HPA) axis dysfunction is reflected in the hormonal disturbances found in FM and CFS. Some study groups have introduced a novel hypothesis that moderate or intermittent intracranial hypertension may be involved in the etiopathogenesis of FM and CFS. In these conditions, hormonal disturbances may be caused by the mechanical effect of increased cerebrospinal fluid pressure, which hampers blood flow in the pituitary gland. Severe intracranial pressure may compress the pituitary gland, resulting in primary empty sella (ES), potentially leading to pituitary hormone deficiencies. The aim of this narrative review was to explore whether similar hormonal changes and symptoms exist between primary ES and FM or CFS and to link them to cerebrospinal fluid pressure dysregulation. A thorough search of the PubMed and Web of Science databases and the reference lists of the included studies revealed that several clinical characteristics were more prevalent in primary ES, FM or CFS patients than in controls, including increased cerebrospinal fluid pressure, obesity, female sex, headaches and migraine, fatigue, visual disturbances (visual acuity and eye motility abnormalities), vestibulocochlear disturbances (vertigo and neurosensorial hearing loss), and bodily pain (radicular pain and small-fiber neuropathy). Furthermore, challenge tests of the pituitary gland showed similar abnormalities in all three conditions: blunted adrenocorticotropic hormone, cortisol, growth hormone, luteinizing hormone, and thyroid stimulating hormone responses and an increased prolactin response. The findings of this narrative review provide further support for the hypothesis that moderately or intermittently increased cerebrospinal fluid pressure is involved in the pathogenesis of FM and CFS and should stimulate further research into the etiopathogenesis of these conditions.

Canine splenic hemangiosarcoma cells express and activate luteinizing hormone receptors in vitro.

To determine luteinizing hormone receptor (LHR) expression and response to LHR activation in isolated canine splenic hemangiosarcoma cell lines in vitro. In vitro cultures of commercially available canine splenic hemangiosarcoma cell lines (EFS, GRACE-HSA, and DAL-4). The percentage of each cell line expressing LHR was determined by immunocytochemistry. Cells were then treated with increasing doses (7.5 ng/mL, 75 ng/mL) of recombinant canine luteinizing hormone (cLH) for 48 hours and evaluated using a cell proliferation assay. The percentage of cells expressing LHR was 17.2 ± 4.5%, 11.8 ± 3.1%, and 6.9 ± 2.5% in EFS, GRACE-HSA, and DAL-4, respectively. There was significant increase in cell count in the DAL-4 and EFS cell lines following a 48-hour incubation at the highest cLH concentration (P = .028 and P = .019, respectively). There was not a significant increase in cell count in the GRACE-HSA cell line at either cLH concentration. Activation of LHR results in cell proliferation in some canine splenic hemangiosarcoma cell lines. These results may explain why spayed and castrated dogs with high circulating LH concentrations may develop hemangiosarcoma more frequently than intact dogs.

Ovarian functions and polycystic ovary syndrome in adult women with type 1 diabetes mellitus in a Turkish population.

The effect of gonadotropin-releasing hormone agonist (GnRHa) stimulation has not been studied in adult women with type 1 diabetes mellitus (DM). We investigated the baseline and stimulated hormone levels after GnRHa and the frequency and relationship between polycystic ovary syndrome (PCOS) and type 1 DM in adult women with type 1 DM. We included 55 adult women (age, 17-35years) with type 1 DM and 15 healthy women (age, 20-29years). Hormones including total testosterone, androstenedione, dehydroepiandrosterone sulphate (DHEAS), follicle-stimulating hormone (FSH), luteinising hormone (LH), estradiol, prolactin, and thyroid-stimulating hormone were measured in the early follicular phase of the menstrual cycle. All participants underwent GnRHa stimulation test, and FSH, LH, estradiol and 17-OHP response levels were measured every 6h for 24h. PCOS was diagnosed according to ESHRE/ASRM (Rotterdam) criteria. Between patients with type 1 DM and healthy controls, no significant differences were noted in mean age and body mass index (BMI) as well as baseline and stimulated hormone levels after buserelin stimulation, except for baseline serum 17-OHP levels, which was higher in patients with type 1 DM. Polycystic ovary morphology (PCOM) was detected in 14 (25%) patients, clinical hyperandrogenism in 16 (29%), hyperandrogenemia in 25 (45%), anovulatory cycle in 72%, and PCOS in 20 (36%). All parameters representing androgen excess disorders, except 17-OHP level, of both groups were similar, and frequencies of PCOS and anovulatory cycle in adult women with type 1 DM were 36% and 72%, respectively.

Serum Gonadotropin Levels Predict Post-Trigger Luteinizing Hormone Response in Antagonist Controlled Ovarian Hyperstimulation Cycles.

The objective of this study was to investigate the utility of using serum gonadotropin levels to predict optimal luteinizing hormone (LH) response to gonadotropin releasing hormone agonist (GnRHa) trigger. A retrospective cohort study was performed of all GnRH-antagonist controlled ovarian hyperstimulation (COH) cycles at an academic fertility center from 2017-2020. Cycles that utilized GnRHa alone or in combination with human chorionic gonadotropin (hCG) for trigger were included. Patient and cycle characteristics were collected from the electronic medical record. Optimal LH response was defined as a serum LH ≥ 40 mIU/mL on the morning after trigger. Total sample size was 3865 antagonist COH cycles, of which 91% had an optimal response to GnRHa trigger. Baseline FSH (B-FSH) and earliest in-cycle LH (EIC-LH) were significantly higher in those with optimal response. Multivariable logistic regression affirmed association of optimal response with EIC-LH, total gonadotropin dosage, age, BMI and Asian race. There was no difference in the number of oocytes retrieved (p = 0.14), maturity rate (p = 0.40) or fertilization rates (p = 0.49) based on LH response. There was no difference in LH response based on use of combination vs. GnRHa alone trigger (p = 0.21) or GnRHa trigger dose (p = 0.46). The EIC-LH was more predictive of LH trigger response than B-FSH (p < 0.005).The optimal B-FSH and EIC-LH values to yield an optimal LH response was ≥ 5.5 mIU/mL and ≥ 1.62 mIU/mL, respectively. In an era of personalized medicine, utilizing cycle and patient characteristics, such as early gonadotropin levels, may improve cycle outcomes and provide further individualized care.

Changes in levels of testosterone, insulin sensitivity and metabolic profiles during GnRH therapy: Reciprocity between insulin sensitivity and pituitary responsiveness to GnRH in teenage and young male patients with congenital hypogonadotropic hypogonadism.

A direct evaluation of insulin sensitivity on pituitary response to gonadotropin relasing hormone (GnRH) has not been shown in congenital hypogonadotropic hypogonadism (CHH), despite a growing body of evidence in the association of testosterone concentrations with insulin sensitiviy. The objective of the study was to explore whether increased testosterone concentrations in men with CHH improve insulin sensitivity, or vice versa. A retrospective study at a tertiary centre. Series of male CHH patients were included from Jannuary 2014 to December 2019. Insulin sensitivity indices calculated from oral glucose tolerance test and steroid hormone levels were examined in 52 patients with newly diagnosed CHH and 22 healthy controls. Thirty-two of the 52 CHH patients received pulsatile GnRH therapy with follow-up every 3-6 months. Compared to healthy controls, CHH patients had elevated 2 hpost-load glucose, HbA1c, fasting insulin, HOMA of insulin resistance(HOMA-IR)and decreased Matsuda index and testosterone (p ≤ .01). The median follow-up for patients (n = 32) who received pulsatile GnRH therapy was 13.5 (11.3-24) months (432 person-months in total). GnRH therapy increased testosterone and Matsuda index (p ≤ .0001), whilst decreased platelet count (p = .04), leptin (p = .04), fasting glucose (p = .01)and HOMA-IR (p &lt; .0001) compared with baseline. The median treatment duration first time to reach the lower limit of normal testosterone concentrations of patients with high and low baseline insulin sensitivity was 15 (95% CI:8.1-21.9) and 30 months (21.2-38.8), respectively. Correspondingly, after GnRH therapy, luteinizing hormone responsiveness to GnRH provocative test was more vigorous in patients with high insulin sensitivity than those with low insulin sensitivity [17.0 (9.5-25.9)vs. 8.2 (3.3-13.0), p = .01]. Pulsatile GnRH therapy elevated testosterone levels in male CHH patients, ameliorated impaired insulin sensitivity and attenuated subclinical inflammatory response, increased insulin sensitivity, in turn, may benefit the efficacy of pulsatile GnRH therapy.

Provocative tests with Kisspeptin-10 and GnRH set the scene for determining social status and environmental impacts on reproductive capacity in male African lions (Panthera leo)

Understanding the hypothalamic factors regulating reproduction facilitates maximising the reproductive success of breeding programmes and in the management and conservation of threatened species, including African lions. To provide insight into the physiology and pathophysiology of the hypothalamic-pituitary–gonadal reproductive axis in lions, we studied the luteinising hormone (LH) and steroid hormone responses to gonadotropin-releasing hormone (GnRH) and its upstream regulator, kisspeptin. Six young (13.3 ± 1.7 months, 56.2 ± 4.3 kg) and four adult (40.2 ± 1.4 months, 174 ± 6 kg) male lions (Ukutula Conservation Centre, South Africa) were used in this study. Lions were immobilised with a combination of medetomidine and ketamine and an intravenous catheter was placed in a jugular, cephalic or medial saphenous vein for blood sampling at 10-min intervals for 220 min. The ten-amino acid kisspeptin which has full intrinsic activity (KP-10, 1 µg/kg) and GnRH (1 µg/kg) were administered intravenously to study their effects on LH and steroid hormone plasma concentrations, measured subsequently by ELISA and liquid chromatography tandem mass spectrometry (LC-MS/MS), respectively. Basal LH levels were similarly low between the age groups, but testosterone and its precursor levels were higher in the adult animals. Adult lions showed a significant LH response to KP-10 (10-fold) and GnRH (11-fold) administration (p < 0.05 and P < 0.001, respectively) whereas in young lions LH increased significantly only in response to GnRH. In adults alone, testosterone and its precursors steadily increased in response to KP-10, with no significant further increase in response to GnRH. Plasma levels of glucocorticoids in response to KP-10 remained unchanged. We suggest that provocative testing of LH and steroid stimulation with kisspeptin provides a new and sensitive tool for determining reproductive status and possibly an index of exposure to stress, environmental insults such as disease, endocrine disruptors and nutritional status.272 words.

Benchmark dose approach in investigating the relationship between blood metal levels and reproductive hormones: Data set from human study.

The main objective of this research was to conduct a dose-response modeling between the internal dose of measured blood Cd, As, Hg, Ni, and Cr and hormonal response of serum testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The study included 207 male participants from subjects of 5 different cohorts (patients with prostate, testicular, and pancreatic cancer, patients suffering from various thyroid and metabolic disorders, as well as healthy volunteers), enrolled from January 2019 to May 2021 at the Clinical Centre of Serbia in Belgrade, Serbia. Benchmark dose-response modeling analysis was performed with the PROAST software version 70.1, showing the hormone levels as quantal data. The averaging technique was applied to compute the Benchmark dose (BMD) interval (BMDI), with benchmark response set at 10%. Dose-response relationships between metal/metalloid blood concentration and serum hormone levels were confirmed for all the investigated metals/metalloid and hormones. The narrowest BMDI was found for Cd-testosterone and Hg-LH pairs, indicative of high confidence in these estimates. Although further research is needed, the observed findings demonstrate that the BMD approach may prove to be significant in the dose-response modeling of human data.

Integrity of hypothalamic-pituitary-testicular axis in exceptional longevity.

Hypothalamic integrity increasingly is being recognized as a marker of healthy longevity in rodent models. Insight into hypothalamic function in humans with exceptional longevity can be gained via investigation of the hypothalamic–pituitary‐testicular (HPT) axis in men with exceptional longevity. This study aimed to characterize the HPT axis function, defined by levels of testosterone (T) and luteinizing hormone (LH), in 84 Ashkenazi Jewish men aged 90–106 years. We found that 94% of men exhibited preserved hypothalamic–pituitary function, as evidenced by either normal testosterone and LH levels (25%) or an appropriate rise in LH in response to aging‐related primary testicular dysfunction (69%), a hormone pattern mirroring female menopause. Total T level was not associated with metabolic parameters or survival. These results demonstrate a high prevalence of testicular dysfunction with preserved hypothalamic–pituitary function in men with exceptional longevity. Thus, the role of hypothalamic integrity and HPT axis in healthy aging warrants further investigation.