Luteinizing Hormone Response Research Articles

A Phase III Extension Trial With a 1-Arm Crossover From Leuprolide to Degarelix: Comparison of Gonadotropin-Releasing Hormone Agonist and Antagonist Effect on Prostate Cancer

We investigated the efficacy and safety of degarelix treatment and the effects of switching from leuprolide to degarelix in an ongoing extension study with a median 27.5-month followup of a pivotal 1-year prostate cancer trial. Patients who completed a 1-year pivotal phase III trial continued on the same monthly degarelix maintenance dose (160 or 80 mg in 125 each), or were re-randomized from leuprolide 7.5 mg to degarelix 240/80 mg (69) or 240/160 mg (65). Data are shown on the approved degarelix 240/80 mg dose. The primary end point was safety/tolerability and the secondary end points were testosterone, prostate specific antigen, luteinizing hormone and follicle-stimulating hormone responses, and prostate specific antigen failure and progression-free survival. During followup testosterone and prostate specific antigen suppression were similar to those in the 1-year trial in patients who continued on degarelix or switched from leuprolide. The prostate specific antigen progression-free survival hazard rate was decreased significantly after the switch in the leuprolide/degarelix group while the rate in those who continued on degarelix was consistent with the rate in treatment year 1. The same hazard rate change pattern occurred in the group with baseline prostate specific antigen greater than 20 ng/ml. Adverse event frequency was similar between the groups and decreased with time. Data support the statistically significant prostate specific antigen progression-free survival benefit for degarelix over leuprolide seen during year 1 and the use of degarelix as first line androgen deprivation therapy as an alternative to a gonadotropin-releasing hormone agonist.

Genetic Dissection of Epidermal Growth Factor Receptor Signaling during Luteinizing Hormone-Induced Oocyte Maturation

Recent evidence that luteinizing hormone (LH) stimulation of ovulatory follicles causes transactivation of the epidermal growth factor receptor (EGFR) has provided insights into the mechanisms of ovulation. However, the complete array of signals that promote oocyte reentry into the meiotic cell cycle in the follicle are still incompletely understood. To elucidate the signaling downstream of EGFR involved in oocyte maturation, we have investigated the LH responses in granulosa cells with targeted ablation of EGFR. Oocyte maturation and ovulation is disrupted when EGFR expression is progressively reduced. In granulosa cells from mice with either global or granulosa cell-specific disruption of EGFR signaling, LH-induced phosphorylation of MAPK3/1, p38MAPK, and connexin-43 is impaired. Although the LH-induced decrease in cGMP is EGFR-dependent in wild type follicles, LH still induces a decrease in cGMP in Egfrdelta/f Cyp19-Cre follicles. Thus compensatory mechanisms appear activated in the mutant. Spatial propagation of the LH signal in the follicle also is dependent on the EGF network, and likely is important for the control of signaling to the oocyte. Thus, multiple signals and redundant pathways contribute to regulating oocyte reentry into the cell cycle.

LH-receptor polymorphisms and response to androgen deprivation therapy in prostate cancer.

4597 Background: Androgen deprivation therapy (ADT) is the cornerstone of treatment for advanced prostate cancer. Our recent data demonstrates an integral role of luteinizing hormone (LH) signaling in androgen synthesis in prostate cancer cells. We therefore hypothesized that genetic variation in the LH receptor may impact the efficiency of signal transduction and influence the degree of castration, the duration of response to ADT and overall course. We now report the association between LH receptor genotype and response to ADT. Methods: Fifty eligible patients had a histopathological diagnosis of prostate cancer and had received ADT for advanced prostate cancer. The blood was collected from each patient after obtaining informed consent. DNA was extracted from blood and genotypes for LHR were assayed using the TaqMan method. The time to castration resistance and level of testosterone suppression were obtained by linking to clinical records. Genotype groups were compared using ANOVA or Kruskal-Wallis tests. Results: The median age at diagnosis was 59 (range 48-69). Of the 50 patients enrolled, 29 were treated for primary metastatic disease, 18 at biochemical recurrence (BCR) and 12 with BCR accompanied by radiographic metastases. The median PSA at initiation of ADT was 109.4 ng/ml for primary metastatic disease and 9.8 ng/ml for recurrent disease. The median time to castration resistance was 12 months in the primary metastatic group and 32.4 months in the recurrent group. In the recurrent group, the presence of minor alleles in the LH receptor genotype was associated with a shorter time to castration resistance with a median of 39 months in men with no minor alleles, 23 months in men with 1 minor allele and 16 months in men with 2 minor alleles (p<.05). Median testosterone levels (T) during ADT were higher for men carrying any minor alleles. Median nadir T was 7 ng/dL for men with no minor alleles compared to 22.5 ng/dL for those with 1-2 minor alleles (p=0.07) with median peak T of 19 ng/dL vs. 43 ng/dL, respectively (p=0.01). Conclusions: Genetic variation in the LH receptor was clearly linked with time to castration resistance and depth of castration and warrants further analysis to define its role as a prognostic and predictive marker.

Differential effects of aging on estrogen negative and positive feedback

Recent studies have demonstrated an age-related decline in gonadotropins and a decrease in pituitary responsiveness to GnRH, indicating that aging influences the neuroendocrine components of the female reproductive axis independently of changes in ovarian function. To determine whether aging might also affect the luteinizing hormone (LH) negative and positive feedback responses to gonadal steroids, we administered a controlled, graded sex steroid infusion to 11 younger (45-56 yr) and nine older (70-80 yr) postmenopausal women (PMW) in whom endogenous ovarian steroids and peptides are uniformly low. The doses of estradiol (E(2)) and progesterone (P) were chosen to mimic levels across the normal follicular phase and have been shown previously to induce negative followed by positive feedback on LH. Similar E(2) and P levels were achieved in younger and older PMW (P = 0.4 and 0.3, respectively) and produced a biphasic LH response in all subjects. The early decline in LH to 53% of baseline was not different in older vs. younger PMW. However, the positive feedback effect was attenuated in older compared with younger PMW (peak LH 144.4 ± 19.5 vs. 226.8 ± 22.3 IU/l, respectively, P = 0.01). In conclusion, these studies in PMW demonstrate preservation of short-term steroid negative and positive feedback in response to exogenous E(2) and P with aging. Attenuation of positive feedback in older compared with younger PMW is consistent with previous reports of declining GnRH responsiveness with aging.

Influence of Estradiol and Fetal Stress on Luteinizing Hormone, Follicle-Stimulating Hormone, and Prolactin in Late-Gestation Fetal Sheep

Background: Hypotension and reduced cerebral blood flow secondary to brachiocephalic occlusion (BCO) stimulate various homeostatic physiological and endocrine responses. Our previous studies have also suggested a role of estradiol in augmenting the fetal stress response to BCO. Objectives: We tested the hypothesis that gonadotropins and/or prolactin (PRL) are upregulated in fetal pituitary in response to fetal stress and play a role in the response to BCO-induced stress. Methods: We performed 3 studies: one in which we measured ovine fetal pituitary PRL, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) mRNA throughout the latter half of gestation in order to better understand the ontogenetic changes upon which dynamic responses are superimposed; one in which we measured these mRNA abundances in response to BCO and/or estrogen treatment, and one in which we measured plasma LH responses to BCO in chronically catheterized late-gestation fetal sheep. Results: PRL gene expression is increased dramatically in the last 20% of gestation. LH and FSH mRNAs were unchanged except for a transient dip in the expression of LH in the last few days before the normal time of spontaneous parturition. Chronic treatment with estradiol decreased LH and FSH mRNA, but increased PRL mRNA abundance after BCO. In contrast, BCO alone increases the abundance of LH, but not FSH or PRL mRNA in fetal pituitary. Plasma LH concentrations were not increased in response to BCO. Conclusions: We conclude that the late-gestation fetal sheep responds to hypotensive stress with increases in LH mRNA but not LH secretion. LH, FSH and PRL changes are therefore unlikely to contribute to the fetal response to cerebral hypoperfusion.

Feminizing Adrenocortical Carcinoma with Selective Suppression of Follicle-Stimulating Hormone Secretion and Disorganized Steroidogenesis: A Case Report and Literature Review

We report a 61-year-old male with gynecomastia, poor libido and erectile dysfunction. Endocrinological studies showed high levels of estradiol and dehydroepiandrosterone sulfate. Although luteinizing hormone (LH) level was within the normal limit, the concentration of follicle-stimulating hormone (FSH) was under the normal limit. Delayed response of LH and poor response of FSH to gonadotropin-releasing hormone administration were detected. Magnetic resonance imaging of the abdomen revealed a left adrenal tumor. Although the surgically-resected tumor was diagnosed as a high grade ACC based on Weiss's criteria of adrenocortical malignancy, no metastasis was detected. Since estrogen levels normalized after resection, feminizing ACC was confirmed. While LH concentration increased slightly after operation, FSH level became transiently elevated over the normal limit, and finally reached the normal range. These data may suggest that FSH was suppressed selectively by hormone produced by ACC different from estrogen.

Release and bioactivity of PACA nanoparticles containing D-Lys 6-GnRH for brushtail possum fertility control

Poly(ethylcyanoacrylate) (PECA) nanoparticles containing the chemical sterilitant D-Lys 6-GnRH were prepared by an in situ interfacial polymerization technique. Their potential as a peroral delivery system for biocontrol of the brushtail possum, a major pest species in New Zealand, was evaluated. Peptide release from resulting particles was studied in vitro in artificial gastric juice (AGJ), simulated intestinal fluids (SIF) and brushtail possum plasma. The nanoparticles released a small fraction of bioactive over 6 h in AGJ and SIF (< 5%), while staying intact and retaining fractions of intact D-Lys 6-GnRH. In contrast, 60% of D-Lys 6-GnRH was released after 1 h in possum plasma. The nanoparticles were also administered in vivo into the caecum of brushtail possums. A significant biological response, measured as an increase in plasma luteinizing hormone (LH), was evident 10 min after administration. This demonstrates not only that PECA nanoparticles were able to facilitate the uptake of D-Lys 6-GnRH from the caecum into systemic circulation but also that sufficient bioactive peptide reached the pituitary to exert a significant LH response following GnRH receptor mediated endocytosis. Hence, it can be concluded that PECA nanoparticles comprise a promising formulation strategy for the peroral delivery of the chemical sterilitant D-Lys 6-GnRH to the brushtail possum in New Zealand.

Response to exogenous kisspeptin varies according to sex and reproductive condition in Siberian hamsters ( Phodopus sungorus)

Most animals experience marked changes in reproductive status across development that are regulated by changes in the hypothalamo–pituitary–gonadal (HPG) axis. The upstream mechanisms regulating this axis remain less well understood. The neuropeptide kisspeptin serves as a positive regulator of reproduction; the precise actions of kisspeptin on the HPG axis in animals of differing developmental and seasonal reproductive states, however, remain unresolved. Further, sex differences in response to kisspeptin have not been fully explored. In Experiment 1, we investigated whether sensitivity to a broad range of kisspeptin doses differed in adult male and female Siberian hamsters held on reproductively inhibitory or stimulatory photoperiods. In Experiment 2, we asked whether the response to kisspeptin differed across stages of reproductive development. Males and females displayed elevated luteinizing hormone (LH) in response to kisspeptin; however, the sexes differed in this response, with males showing greater LH responses to kisspeptin than females. Hamsters responded to kisspeptin across all stages of reproductive development, although the magnitude of this response differed between animals of differental ages and between the sexes. Males showed significant increases in LH at an earlier developmental age than females; females also showed blunted LH responses during early adulthood whereas males remained relatively constant in their response to kisspeptin. These findings suggest that reproductively active and inactive hamsters are responsive to kisspeptin, but that the sexes differ in their responsiveness. Collectively, these data provide further insight into the basic actions of kisspeptin in the regulation of reproduction and provide a potential mechanism for the regulation of differential reproductive responses between the sexes.

Estrogen Negative Feedback on Gonadotropin Secretion: Evidence for a Direct Pituitary Effect in Women

Previous animal and human studies using low-dose estrogen have demonstrated estrogen negative feedback on gonadotropin secretion through gonadotropin-releasing hormone (GnRH) release at the level of the hypothalamus in women. Whether low-dose estrogen also exerts a direct negative feedback at the level of the pituitary is unclear due to insufficient data. In a recent study, a decrease was found in pituitary responsiveness to GnRH with aging in women. Studies in human beings aimed to establish a direct pituitary site of estrogen negative feedback and investigate the interaction of estrogen, and aging in the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) feedback loop have been hampered by the inability thus far to isolate the pituitary response from endogenous hypothalamic input. This study tested the hypothesis that estrogen has a direct negative feedback effect at the pituitary and also investigated whether this effect would vary with aging. Isolation of pituitary responsiveness from hypothalamic and ovarian input was achieved through blockade of the GnRH receptor using the NAL-GLU GnRH antagonist, followed by graded doses of GnRH before and after 1 month of estrogen administration. The participants were healthy postmenopausal women aged 48 to 56 years (n = 8) or 70 to 75 years (n = 8). After estrogen administration, there was a significant decrease in the LH (P = 0.01) and FSH (P = 0.0001) responses to GnRH in all study subjects. There was also a decrease in the ratio of FSH to LH amplitudes in response to GnRH (P = 0.04). The inhibitory effect of estrogen on FSH responses was significantly diminished with aging (P = 0.02). In contrast to FSH, LH responses were not significantly affected by aging (P = 0.4). These findings demonstrate that estrogen has a direct inhibitory effect on pituitary responsiveness to GnRH in women. This estrogen negative feedback diminishes with aging. FSH but not LH responses are inhibited by estrogen.

The role of sexual steroid hormones in the direct stimulation by Kisspeptin-10 of the secretion of luteinizing hormone, follicle-stimulating hormone and prolactin from bovine anterior pituitary cells

The aims of the present study were to clarify the effect of Kisspeptin-10 (Kp10) on the secretion of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) from bovine anterior pituitary (AP) cells and evaluate the ability of sex steroids to enhance the sensitivity of gonadotropic and lactotropic cells to Kp10. AP cells prepared from 7-week-old male calves were incubated for 12 h with estradiol (E 2; 10 −8 M), progesterone (P 4; 10 −8 M), testosterone (T; 10 −8 M), or vehicle only (control), and then for 2 h with Kp10 (10 −6 M). The amounts of LH, FSH and PRL released into the culture medium after the 2-h incubation period were examined. Kp10 significantly stimulated the secretion of LH from the AP cells treated with E 2 and T ( P < 0.05), but not from the P 4-treated cells. In contrast, Kp10 had no effect on the secretion of FSH regardless of the steroid treatment. Kp10 significantly stimulated the secretion of PRL ( P < 0.05), the sexual steroid hormones having no effect. The LH- or FSH-releasing response to gonadotropin-releasing hormone (GnRH; 10 −8 M) and PRL-releasing response to thyrotropin-releasing hormone (TRH; 10 −8 M) were significantly greater than those to Kp10 ( P < 0.05). The present results suggest that E 2 and T, but not P 4, enhance the sensitivity of gonadotropic cells to the secretion of LH in response to Kp10. However, Kp10 had no stimulatory effect on the secretion of FSH regardless of the effect of sex steroids. Kp10 directly stimulates the secretion of PRL from the pituitary cells, and sex steroids do not enhance the sensitivity of lactotropic cells to Kp10. Furthermore, the LH- and FSH-releasing effect and the PRL-releasing effect of Kp10 are less potent than that of GnRH and TRH, respectively.

Potential diagnostic utility of intermittent administration of short-acting gonadotropin-releasing hormone agonist in gonadotropin deficiency

To determine if intermittent, low-dose, short-acting gonadotropin-releasing hormone agonist (GnRH-agonist) administration sufficiently up-regulates pituitary-gonadal function in gonadotropin deficiency to be of diagnostic or therapeutic value. Case-control study. General clinical research center. Normal adult volunteers and gonadotropin-deficiency patients. Low-dose leuprolide acetate administered subcutaneously at 4- to 5-day intervals up to 1 year. Levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroid responses. In normal men and women, low-dose GnRH-agonist repetitively transiently stimulated gonadotropins in a gender-dimorphic manner. In congenitally gonadotropin-deficient men (n = 6) and women (n = 1), none of whom had a normal LH response to an initial GnRH-agonist test dose, this regimen consistently stimulated LH to the normal baseline range within 2 weeks. Long-term GnRH-agonist administration to a partially gonadotropin-deficient man did not alleviate hypogonadism, however. Women with hypothalamic amenorrhea (n = 2) responded normally to a single GnRH-agonist injection; however, repeated dosing did not seem to induce the normal priming effect. The subnormal LH response to GnRH-agonist in patients with congenital gonadotropin deficiency normalized in response to repetitive intermittent GnRH-agonist administration but not sufficiently to improve hypogonadism. Hypothalamic amenorrhea patients lacked the priming response to repeated GnRH-agonist but otherwise had normal hormonal responses to GnRH-agonist. We conclude that intermittent administration of a short-acting GnRH-agonist is of potential diagnostic value in distinguishing hypothalamic from pituitary causes of gonadotropin deficiency.

Role of Prolactin in the Gonadotroph Responsiveness to Gonadotrophin‐Releasing Hormone During the Equine Annual Reproductive Cycle

A combined suppressive effect of prolactin (PRL) and dopamine on the secretion of luteinising hormone (LH) at the level of the pituitary gland has been identified in sheep, a short-day breeder. However, little is known about the role of PRL in the intra-pituitary regulation of the gonadotrophic axis in long-day breeders. In the present study, we investigated the effects of PRL on LH and follicle-stimulating hormone (FSH) secretion during the equine annual reproductive cycle. Horse pituitaries were obtained during the breeding season (BS) and nonbreeding season (NBS). Cells were dispersed, plated to monolayer cultures and assigned to one of the following specific treatments: (i) medium (Control); (ii) rat PRL (rPRL); (iii) thyrotrophin-releasing hormone (TRH); (iv) bromocriptine (Br); and (v) Br + rPRL. Gonadotrophin-releasing hormone (GnRH) dose-dependently stimulated LH release during the BS and NBS. During the BS, neither rPRL nor TRH affected the LH response to GnRH, but Br significantly (P < 0.01) enhanced both basal and GnRH-stimulated LH release through a mechanism that did not involve alterations in the concentrations of PRL. However, rPRL prevented the Br-induced increase in basal and GnRH-stimulated LH output, and suppressed LH below basal values (P < 0.05). Conversely, during the NBS, no significant effects of treatments were observed. Interestingly, at this time of year, the incidence of pituitary gap junctions within the pars distalis decreased by 50% (P < 0.01). By contrast to the effects on LH, no treatment effects were detected on the FSH response to GnRH, which was only apparent during the NBS. These results reveal no direct effects of PRL but an interaction between PRL and dopamine in the inhibitory regulation of LH, but not FSH, release at the level of the pituitary in the horse, and a modulatory role of season/photoperiod associated with alterations in folliculostellate cell-derived gap junctions.

Failure of the GnRH antagonist ganirelix to block the positive feedback effect of exogenous estrogen in normal women

This study investigated whether the GnRH antagonist ganirelix is able to block the positive-feedback effect of E2 in normal women. Ganirelix was unable to block the positive-feedback effect, suggesting that the clinical efficacy of GnRH antagonists in IVF cycles is determined by the hyperstimulation process.

Melanoma onset after estrogen, thyroid, and growth hormone replacement therapy

Background: Acute sun exposure is the main risk factor for the development of melanoma, especially if associated with a large number of benign melanocytic nevi. Although epidemiologic studies have investigated the effects of exogenous triggers, particularly hormones, our understanding of melanoma is still inadequate. Objective: The aim of this study was to report a case of melanoma that developed after hormonal therapy. Case summary: We report a case of a 26-year-old white woman (weight, 48 kg; Fitzpatrick skin phototype IV; no previous pregnancy) who was referred to the Department of Dermatology, Casa Sollievo della Sofferenza Hospital-IRCCS, San Giovanni Rotondo, Italy, with a malignant melanoma on the left thigh. At the age of 18 years (year 2000), the patient presented with amenorrhea, but no therapy was initiated until 2004. At this time, insufficiency of the gonadal, thyroid, and growth hormone (GH) axes was diagnosed without evidence of hypothalamic-pituitary anatomic damage or of congenital or acquired causes. The patient had an inadequate level of GH (base: 0.8 g/mL; peak: 1.0 ng/mL) during an insulin tolerance test, low levels of thyroid hormones, and a blunted response of luteinizing hormone (base: 0.2 mIU/mL; peak: 10 mIU/mL) and follicle-stimulating hormone (base: 2.6 mIU/mL; peak: 18.5 mIU/mL) to a gonadotrophinreleasing hormone stimulation test. Consequently, replacement therapy with ethinyl estradiol (20 μg) plus progestin (75 μg) (once daily for 21 days/month), levothyroxine (25 μg once daily), and recombinant human GH (0.8 mg SC once daily) was initiated. GH replacement therapy was discontinued after 2 years (June 2006), and thyroid and estrogen replacement therapy were discontinued after 4 years (February 2008). The patient reported first noticing the pigmented lesion 8 months after GH withdrawal, during treatment with the estrogen/progestin combination. Conclusion: We report a case of melanoma onset in a patient who had received hormonal substitutive therapy, where the role of GH therapy alone or in combination with other hormones could not be ruled out.

209 SEASONAL CHANGES IN CHARACTERISTICS OF THE ESTROUS CYCLE IN BOS TAURUS INDICUS (NELORE) HEIFERS

To evaluate the possible seasonal variation in estrous cycle characteristics, 8 heifers were synchronized with 2 prostaglandin injections and their estrous cycles were followed during different seasons of the year (autumn, n = 413; winter, n = 8; spring, n = 9; and summer, n = 9) with daily ultrasonographic exams to count and measure follicles ≥3 mm. Blood was collected every 12 h for luteinizing hormone (LH) and progesterone (P4), and every 3 h from estrus until ovulation to characterize the LH peak. Five ovariectomized heifers were injected with 17β-estradiol (2 μg/kg of liveweight) every season and blood samples were collected thereafter at 3 h intervals for LH quantification. The monthly body weight percentile difference (Δ%) did not vary among seasons. Average P4 concentration for the cycle was higher (P = 0.001) and follicle numbers lower during autumn (2.5 ± 0.2 ng mL-1; 7.8 ± 0.1) and summer (2.9 ± 0.3 ng mL-1; 6.8 ± 0.2; P = 0.001) compared with winter (1.4 ± 0.2 ng mL-1; 9.6 ± 0.3) and spring (1.6 ± 0.2 ng mL-1; 9.7 ± 0.3). During winter, there were more estrous cycles with 3 follicle waves (5/8) and during summer only there were cycles with 2 follicular waves (P = 0.009). Because LH secretion did not vary despite seasonal variation in P4 concentration and because there was a negative correlation between higher P4 values and daily percentile variation of photoperiod (A%; P = 0.0038; r = -0.4533), seasonal variation in the luteal cell sensitivity to LH needs to be evaluated. In the ovariectomized Nelore heifers, the LH circannual concentration without estradiol stimulus was significant (P = 0.02). The LH response to estradiol treatment was lower in summer (0.8 ± 0.2 ng mL-1 v. 1.3 ± 0.5 ng mL-1). We hypothesize that seasonal variation exists in hypothalamic sensitivity to estradiol. The present experiment provides evidence that seasonality in reproductive responses remains in Nelore heifers. FAPESP (07-53539-3), UNESP, and Devani Mariano Pinheiro.

Sex differences and similarities of hormonal alterations in patients with anorexia nervosa

The aim of the present study was to gain better insight into hormonal disturbances in male patients with anorexia nervosa. It included six men with anorexia nervosa aged 13–26 years, with a mean body weight of 42.83±8.03 kg, a body mass index of 15.08±1.26 and an average degree of weight loss 29.98±4.73%. The results were compared with those of 15 healthy age-matched males and 40 women with anorexia nervosa. Prolactin, growth hormone and the gonadal and thyroid axis were studied in detail. The gonadotropin basal levels and their responses to gonadotropin-releasing hormone in male patients were lower, but not significantly, in comparison with healthy men. The basal levels and the responses of luteinizing hormone in anorexic women were significantly lower in comparison with female controls, but the decreased basal level of follicle-stimulating hormone showed an exaggerated response to gonadotropin-releasing hormone. In male anorexics the testosterone levels (7.1±10.9 nmol 1−1) were significantly lower. The changes in the thyroid axis and in prolactin secretion were almost the same in male and female patients. The data of this study suggest that endocrine disturbances in males are similar to those in females with anorexia nervosa, but differences exist mainly in relation to the gonadal axis.

Alterations of the pituitary-ovarian axis in dogs with a functional granulosa cell tumor

Information on the pituitary-ovarian axis in dogs with a granulosa cell tumor (GCT) is lacking. Therefore, we investigated the plasma concentrations of luteinizing hormone (LH) and estradiol before and after gonadotropin-releasing hormone (GnRH) administration in seven bitches with a functional GCT (GCT-total), of which three were intact (GCT-intact) and four had remnant ovarian tissue (GCT-ROT). The results of the GnRH stimulation test were compared with those in six anestrous and six ovariectomized bitches. The most noteworthy results were as follows. The basal plasma LH concentrations of the GCT-ROT bitches were higher (P < 0.05) than those of the anestrous bitches. The increment in the plasma LH concentration after GnRH administration in the GCT-total bitches was lower (P < 0.001) than the increments in both the anestrous and ovariectomized bitches. The basal plasma estradiol concentrations in the GCT-total bitches were higher (P < 0.001) than those in the anestrous and ovariectomized bitches. In conclusion, the pituitary-ovarian axis is affected in bitches with a functional GCT and is characterized by relatively high plasma LH concentrations in GCT-ROT bitches and a subnormal LH response to GnRH stimulation in all GCT bitches compared with those in anestrous and ovariectomized bitches. The relatively high proportion of dogs with remnant ovarian tissue among the GCT bitches suggests a pathogenetic role for elevated gonadotropin secretion in the pathogenesis of GCT.

Effects of parathyroidectomy in pregnant rats on the luteinizing hormone and follicle-stimulating hormone response to synthetic luteinizing hormone-releasing hormone in the infantile offspring.

Effects of parathyroidectomy (PTx) in the rat at the 5th day of gestation on the functional development of gonadotrophin secretion in the infantile offspring was examined. A single subcutaneous injection of 10 micrograms/kg of luteinizing hormone-releasing hormone (LHRH) induced a significant increase in serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) in control- and PTx-F1 male and female rats already at 3 days of age. The response in female rats was greater than in males at all ages examined. In the control- and PTx-F1 rats, age-related increase in the responsiveness to LHRH was observed in both sexes for LH but only in females for FSH. However, LH and FSH release by LHRH in the PTx-F1 female rats was significantly lower than that in control females at 14 and 22 days of age. In the PTx-F1 male rats, only FSH response to LHRH showed a tendency to decrease at 22 days of age. Serum calcium levels in 3-day-old PTx-F1 male and female rats were significantly lower than those in controls but only a slight decrease was observed in the PTx-F1 rats at other ages. The present results indicated that a low serum calcium environment during fetal life in the rat affects the functional development of pituitary responsiveness to LHRH, particularly in females.

Pituitary and testicular response to luteinizing hormone releasing hormone in normal and sulpiride-induced hyperprolactinaemic men.

Pituitary and testicular response to an intravenous infusion of 480 micrograms luteinizing hormone releasing hormone (LHRH) for 8 hours (1 microgram/min) was investigated in 8 male volunteers in normal and hyperprolactinaemic state. Eight normal men were given 150 mg of sulpiride daily for 14 days. Serum prolactin (PRL) levels were elevated significantly, but basal serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) did not change following daily oral administration of sulpiride in 8 normal men. Eight men showed biphasic LH response to LHRH infusion in both normal and hyperprolactinaemic state, and there was a rather exaggerated response in serum LH concentration in hyperprolactinaemic state. Serum FSH response to LHRH was similar in normal and hyperprolactinaemic state. Although slight increase in serum testosterone concentration was observed during LHRH infusion in normal and hyperprolactinaemic state, the statistical difference was not significant. The result of the present study suggests that the function of the hypothalamic-pituitary-testicular axis, as measured by serum gonadotrophin and testosterone responses, is well reserved.

Seasonal and Cyclical Change in the Luteinizing Hormone Response to Kisspeptin in the Ewe

Background: Kisspeptins are recognized as important stimulators of gonadotropin-releasing hormone (GnRH) and gonadotropin secretion. In sheep, the nonbreeding (anestrous) period is characterized by reduced Kiss1 mRNA expression in the hypothalamus. The aim of the present study was to determine whether the response to kisspeptin treatment varies between the breeding and nonbreeding seasons. Methods: Corriedale ewes were treated intravenously with murine kisspeptin-10 (submaximal dose: 20 μg or maximal dose: 250 μg) or GnRH (250 ng) during either the anestrous period or during the breeding season at the luteal, mid-follicular, or late-follicular phase of the estrous cycle. Results: Kisspeptin treatment increased the concentration of luteinizing hormone (LH) in all animals. We found the LH response to kisspeptin (20 μg) was greater in ewes during the anestrous period, being 4-fold that seen during the luteal phase of the estrous cycle. Within the breeding season, kisspeptin (20 μg) was most effective during the late-follicular phase of the estrous cycle. Kisspeptin treatment (both 20 and 250 μg) had no effect on plasma levels of growth hormone, prolactin or cortisol. The variable effect of kisspeptin (20 μg) on LH secretion appeared to mirror that of GnRH treatment indicating that the effect may be mediated by a change in the pituitary response to GnRH. Conclusion: We conclude that the gonadotropic response to kisspeptin depends upon the reproductive status of the female.