Effects of oestradiol, progesterone and androstenedione on the pulsatile secretion of luteinizing hormone in ovariectomized ewes during spring and autumn

1983 ◽  
Vol 96 (2) ◽  
pp. 181-193 ◽  
Author(s):  
G. B. Martin ◽  
R. J. Scaramuzzi ◽  
J. D. Henstridge
Keyword(s):  
Luteinizing Hormone ◽  
Breeding Season ◽  
Negative Feedback ◽  
Combined Treatment ◽  
Pulse Frequency ◽  
The Other ◽  
Ovarian Steroids ◽  
Pulsatile Secretion ◽  
Lh Secretion

The effects of oestradiol-17β, androstenedione, progesterone and time of the year on the pulsatile secretion of LH were tested in ovariectomized Merino ewes (n = 32). The steroids were administered by small subcutaneous implants, and the LH pulses were observed in samples taken at intervals of 15 min for 12 h in spring 1979, autumn 1980 and spring 1980, seasons corresponding to successive periods of anoestrus, breeding season and anoestrus. During spring, oestradiol alone was able to reduce the frequency of the LH pulses, while progesterone, either alone or in combination with oestradiol, had little effect. During autumn, on the other hand, neither oestradiol nor progesterone could significantly reduce the frequency of the pulses when administered independently, whereas the combined treatment was very effective. Androstenedione had no significant effect on pulse frequency at either time of the year, either alone or in any combination with oestradiol and progesterone. The basal levels of LH, over which the pulses are superimposed, were reduced by oestradiol alone in both seasons. Progesterone alone had no consistent effects, but interacted significantly with oestradiol and this combined treatment maintained low basal levels most effectively at all times. Androstenedione had no significant effect. The amplitude of the pulses increased throughout the course of the experiment. Within seasons, the amplitudes were significantly higher in the presence of oestradiol and progesterone, but were not significantly affected by androstenedione. It was concluded that certain of the ovarian steroids exert negative feedback on the tonic secretion of LH primarily by reducing the frequency of the pulses, and that the changes in LH secretion attributable to season and phases of the oestrous cycle can be accounted for entirely by the responses of the hypothalamus to oestradiol and progesterone. The role of the androstenedione secreted by the ovary in the ewe remains obscure.

scholarly journals Does nitric oxide act in the ventromedial preoptic area to mediate oestrogen negative feedback in the seasonally anoestrous ewe?

Reproduction ◽  
2007 ◽  
Vol 134 (1) ◽  
pp. 137-145 ◽  
Author(s):  
Christina J McManus ◽  
Miroslav Valent ◽  
Steven L Hardy ◽  
Robert L Goodman
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Breeding Season ◽  
Negative Feedback ◽  
Preoptic Area ◽  
Pulse Frequency ◽  
Nos Inhibitors ◽  
Nos Inhibitor ◽  
Lh Secretion ◽  
Important Site

Seasonal anoestrus in the ewe results from enhanced oestrogen negative feedback. Recent data have implicated the ventromedial preoptic area (vmPOA) as an important site of oestrogen action. This study addressed whether NO acts within the vmPOA to inhibit LH during seasonal anoestrus. In Experiment 1, microimplants containingNω-nitro-l-arginine methyl ester (l-NAME, NOS inhibitor),S-methyl thiocitrulline (SMTC, neural NOS (nNOS) inhibitor) or empty implants (control) were administered during mid-anoestrus to the vmPOA.l-NAME, but not SMTC, significantly increased LH pulse frequency. For Experiment 2, ewes in late anoestrus were administered 7-nitroindazole (7NI; nNOS inhibitor),l-NAME, SMTC, or empty implants. 7NI, but notl-NAME or SMTC, increased LH pulse frequency. In Experiment 3, the effects of microimplants and microinjections ofl-NAME were compared in mid-anoestrus. Microinjections ofl-NAME (300 nl at 10 μg/μl) increased LH pulse frequency, but microimplants did not. In late anoestrus, similar microinjections were ineffective. Taken together, the results of Experiments 1–3 suggested that NO inhibition may be stronger during the middle than at the end of seasonal anoestrus. To test this hypothesis, ewes in Experiment 4 received microinjection ofl-NAME or vehicle thrice during the non-breeding season; none of the treatments increased LH pulse frequency. These results indicate that NO plays a role in the vmPOA in suppressing LH secretion during seasonal anoestrus because NOS inhibitors were consistently stimulatory when LH pulse frequency was low. However, the inconsistent and modest effects of these inhibitors suggest that NO actions in this area cannot completely account for the effects of inhibitory photoperiod.

Control of luteinizing hormone secretion in ewes by endogenous opioids and the dopaminergic system during short seasonal anoestrus: rôle of plane of nutrition

1997 ◽  
Vol 65 (2) ◽  
pp. 217-224 ◽  
Author(s):  
F. Forcada ◽  
J. M. Lozano ◽  
J. A. Abecia ◽  
L. Zarazaga
Keyword(s):  
Luteinizing Hormone ◽  
Receptor Antagonist ◽  
Dopaminergic System ◽  
Hormone Secretion ◽  
Pulse Frequency ◽  
Endogenous Opioids ◽  
Endogenous Opioid ◽  
Luteinizing Hormone Secretion ◽  
Lh Secretion

AbstractThe role of endogenous opioids and the dopaminergic system on the inhibition of luteinizing hormone (LH) secretion during early and late anoestrus, together with its modulation by the plane of nutrition were investigated in ewes with a short anoestrous season. In early anoestrus (22 March; day 0), two groups of ovariectomized, oestradiol-treated adult Rasa Aragonesa ewes, maintained under natural photoperiod at 41°N, were given enough food to provide 1·4 × (high; H; no. = 6) or 0·5 × (low; L; no. = 6) energy requirements for maintenance. The effects of administration of the opiate receptor antagonist naloxone (1 mg/kg at four 1-h intervals) (day 15) and of the dopaminergic2 receptor antagonist pimozide (0·08 mg/kg) (day 21) on LH secretion were assessed. A second experiment was carried out in late anoestrus (21 June) using the same protocol. A significant increase in LH pulse frequency after naloxone treatment for both H and L groups was detected in late anoestrus. Number ofLH pulses after naloxone injections in early anoestrus also increased in H (P < 0·05) and L ewes (P = 0·08). The effect of pimozide injection on mean LH pulse frequency was greater in early than in late anoestrus, especially in ewes receiving a high plane of nutrition (P < 0·05 and P = 0·07 for H and L ewes, respectively in April and P = 0·07 for H ewes in July). A significant increase of LH pulse amplitude was also detected in early anoestrus in H ewes (P < 0·01). These results provide evidence that endogenous opioid mechanisms are involved in the inhibition ofLH pulsatile release both in early and late anoestrus in ewes with a short seasonal anoestrus. The ability of pimozide to increase LH pulse frequency in early anoestrus could be enhanced by a high plane of nutrition in the breed studied.

scholarly journals Kisspeptin Stimulates the Pulsatile Secretion of Luteinizing Hormone (LH) during Postpartum Anestrus in Ewes Undergoing Continuous and Restricted Suckling

Animals ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2656
Author(s):  
José Manuel Hernández-Hernández ◽  
Graeme B. Martin ◽  
Carlos Miguel Becerril-Pérez ◽  
Arturo Pro-Martínez ◽  
César Cortez-Romero ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Jugular Vein ◽  
Pulse Frequency ◽  
Neural Pathways ◽  
Indwelling Catheter ◽  
Pulsatile Secretion ◽  
Intravenous Application ◽  
Access To Water ◽  
Ad Libitum ◽  
Lh Secretion

This study tested whether the intravenous application of kisspeptin can stimulate the pulsatile secretion of LH in suckling ewes during postpartum anestrus. Ten days after lambing, Pelibuey ewes were allocated among two groups: (1) continuous suckling (n = 8), where the lambs remained with their mothers; and (2) restricted suckling (n = 8), where the mothers suckled their lambs twice daily for 30 min. On Day 19 postpartum, the ewes were individually penned with ad libitum access to water and feed and given an indwelling catheter in each jugular vein. On Day 20, 4 mL of blood was sampled every 15 min from 08:00 to 20:00 h to determine LH pulse frequency. At 14:00 h, four ewes in each group received 120 μg of kisspeptin diluted in 3 mL of saline as a continuous infusion for 6 h; the remaining four ewes in each group received only saline. The interaction between kisspeptin and suckling type did not affect LH pulse frequency (p > 0.05). Before kisspeptin administration, pulse frequency was similar in all groups (1.50 ± 0.40 pulses per 6 h; p > 0.05). With the application of kisspeptin, pulse frequency increased to 3.50 ± 0.43 pulses per 6 h (p ≤ 0.014), so the concentration of LH (1.11 ± 0.14 ng mL−1) was greater in kisspeptin-treated ewes than in saline-treated ewes (0.724 ± 0.07 ng mL−1; p ≤ 0.040). The frequency of LH pulses was greater with restricted suckling than with continuous suckling (2.44 ± 0.29 versus 1.69 ± 0.29 pulses per 6 h; p ≤ 0.040). We conclude that intravenous application of kisspeptin increases the pulsatile secretion of LH in suckling ewes and that suckling might reduce kisspeptin neuronal activity, perhaps explaining the suppression of ovulation. Moreover, the effects of kisspeptin and suckling on pulsatile LH secretion appear to be independent, perhaps operating through different neural pathways.

LH secretion in ovariectomized ewes: effects of morphine and ovarian steroid interactions with naloxone during the breeding season and anestrum

1991 ◽  
Vol 71 (2) ◽  
pp. 333-342 ◽  
Author(s):  
W. D. Currie ◽  
S. J. Cook ◽  
N. C. Rawlings
Keyword(s):  
Luteinizing Hormone ◽  
Breeding Season ◽  
Pulse Frequency ◽  
Endogenous Opioid Peptides ◽  
Endogenous Opioid ◽  
Ovarian Steroid ◽  
Basal Serum ◽  
Serum Lh ◽  
Lh Secretion ◽  
Higher Doses

Morphine (MOR) infusion (i.v.) was used to mimic effects of endogenous opioid peptides (EOPs) on LH secretion in ovariectomized (OVX) ewes during the breeding season and anestrum. MOR decreased luteinizing hormone (LH) pulse frequency and/or amplitude at higher doses (0.5 and 1.0 mg kg−1 h−1), and increased basal serum LH concentrations at a lower dose (0.01 mg kg−1 h−1). Simultaneous MOR and naloxone (NAL) infusion (0.5 mg kg−1 h−1, each) did not affect LH secretion, suggesting that effects of MOR were EOP receptor-specific. EOP involvement in ovarian steroid feedback was examined by NAL infusion and ovarian steroid replacement in OVX ewes. NAL infusion increased LH pulse frequency in OVX ewes during the breeding season, suggesting ovarian steroid-independent, but EOP-dependent suppression of LH secretion. NAL did not alleviate seasonal suppression of LH pulse frequency during the anestrum, suggesting ovarian steroid-independent, EOP-independent suppression of LH secretion. NAL eliminated progesterone (P4) suppression of LH pulse frequency during the breeding season, suggesting that a major portion of P4 feedback on tonic LH secretion is EOP-dependent. P4 replacement in the anestrum did not suppress LH pulse frequency. NAL infusion, following P4 replacement in the anestrum, increased LH pulse frequency to levels observed in untreated OVX ewes during the breeding season. It was concluded that EOP-dependent P4 feedback experimentally over-rode EOP-independent suppression of LH pulse frequency during the anestrum. EOP activity was not required for estradiol (E2) to suppress LH secretion from the pituitary during the breeding season. Key words: LH, morphine, naloxone, progesterone, estradiol

Estradiol Potentiates But Is Not Essential for Prolactin-Induced Suppression of Luteinizing Hormone Pulses in Female Rats

Endocrinology ◽  
2020 ◽  
Vol 161 (4) ◽  
Author(s):  
Juneo F Silva ◽  
Patricia C Henriques ◽  
Ana C Campideli-Santana ◽  
Roberta Araujo-Lopes ◽  
Nayara S S Aquino ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Pulse Amplitude ◽  
Pulse Frequency ◽  
Female Rats ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mrna Levels ◽  
Messenger Ribonucleic Acid ◽  
Ovx Rats ◽  
Lh Secretion

Abstract Hyperprolactinemia causes infertility by suppressing gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion. Because effects of prolactin (PRL) on the hypothalamus usually require estradiol (E2), we investigated the role of E2 in PRL-induced suppression of LH pulses. Ovariectomized (OVX) rats treated with oil or E2 (OVX + E2) received a subcutaneous injection of ovine PRL (oPRL) 30 minutes before serial measurement of LH in the tail blood by enzyme-linked immunosorbent assay. E2 reduced pulsatile LH secretion. oPRL at 1.5 mg/kg further reduced LH pulse frequency in OVX + E2 but had no effect in OVX rats. The higher dose of 6-mg/kg oPRL decreased LH pulse frequency in both OVX and OVX + E2 rats, whereas pulse amplitude and mean LH levels were lowered only in OVX + E2 rats. Kisspeptin immunoreactivity and Kiss1 messenger ribonucleic acid (mRNA) levels were decreased in the arcuate nucleus (ARC) of OVX + E2 rats. oPRL decreased both kisspeptin peptide and gene expression in the ARC of OVX rats but did not alter the already low levels in OVX + E2 rats. In the anteroventral periventricular nucleus, oPRL did not change kisspeptin immunoreactivity and, paradoxically, increased Kiss1 mRNA only in OVX + E2 rats. Moreover, oPRL effectively reduced Gnrh expression regardless of E2 treatment. In this study we used tail-tip blood sampling to determine the acute effect of PRL on LH pulsatility in female rats. Our findings characterize the role of E2 in the PRL modulation of hypothalamic components of the gonadal axis and LH release, demonstrating that E2 potentiates but is not essential for the suppression of pulsatile LH secretion caused by hyperprolactinemia.

EFFECT OF HYPOTHALAMIC DEAFFERENTATION ON THE CONTROL OF LUTEINIZING HORMONE SECRETION

1970 ◽  
Vol 46 (1) ◽  
pp. 1-7 ◽  
Author(s):  
S. TALEISNIK ◽  
M. E. VELASCO ◽  
J. J. ASTRADA
Keyword(s):  
Luteinizing Hormone ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Hormone Secretion ◽  
Feedback Effect ◽  
Luteinizing Hormone Secretion ◽  
Ovarian Steroids ◽  
Medial Hypothalamus ◽  
Lh Release ◽  
Positive Feedback Effect

SUMMARY The influence that the interruption of the neural afferents to the hypothalamus exerts on ovulation and on the release of luteinizing hormone (LH) was studied in the rat. Animals with retrochiasmatic sections interrupting the neural connexions between the medial hypothalamus and the preoptic area (POA) showed constant oestrus and failed to ovulate. Animals in which the dorsal neural afferents to the POA were transected had oestrous cycles and ovulated normally. The positive feedback effect of progesterone on LH release in spayed animals primed either with 20 μg. oestradiol benzoate or 2·5 mg. testosterone propionate 3 days before was studied. Transection of the dorsal afferents to the POA favoured an increase in plasma LH, but in animals with retrochiasmatic sections the response was abolished. However, the negative feedback effect of ovarian steroids operated after both types of transection because an increase in plasma LH occurred after ovariectomy. It is concluded that the negative feedback effect of ovarian steroids acts on the medial hypothalamus which can maintain a tonic release of gonadotrophins in the absence of steroids. In contrast, the POA involved in the positive feedback effect of progesterone is concerned with the phasic release of LH.

Seasonal and steroid-dependent effects on the modulation of LH secretion in the ewe by intracerebroventricularly administered β-endorphin or naloxone

1989 ◽  
Vol 122 (2) ◽  
pp. 509-517 ◽  
Author(s):  
R. J. E. Horton ◽  
H. Francis ◽  
I. J. Clarke
Keyword(s):  
Breeding Season ◽  
Luteal Phase ◽  
Pulse Frequency ◽  
Opioid Peptide ◽  
Follicular Phase ◽  
Oestrous Cycle ◽  
Opioid Antagonist ◽  
Endogenous Opioid ◽  
Endogenous Opioid Peptide ◽  
Lh Secretion

ABSTRACT The natural opioid ligand, β-endorphin, and the opioid antagonist, naloxone, were administered intracerebroventricularly (i.c.v.) to evaluate effects on LH secretion in ovariectomized ewes and in ovariectomized ewes treated with oestradiol-17β plus progesterone either during the breeding season or the anoestrous season. Ovary-intact ewes were also studied during the follicular phase of the oestrous cycle. Jugular blood samples were taken at 10-min intervals for 8 h and either saline (20–50 μl), 100 μg naloxone or 10 μg β-endorphin were injected i.c.v. after 4 h. In addition, luteal phase ewes were injected i.c.v. with 25 μg β-endorphin(1–27), a purported endogenous opioid antagonist. In ovariectomized ewes, irrespective of season, saline and naloxone did not affect LH secretion, but β-endorphin decreased the plasma LH concentrations, by reducing LH pulse frequency. The effect of β-endorphin was blocked by administering naloxone 30 min beforehand. Treating ovariectomized ewes with oestradiol-17β plus progesterone during the breeding season reduced plasma LH concentrations from 6–8 μg/l to less than 1 μg/l. In these ewes, saline did not alter LH secretion, but naloxone increased LH pulse frequency and the plasma concentrations of LH within 15–20 min. During anoestrus, the combination of oestradiol-17β plus progesterone to ovariectomized ewes reduced the plasma LH concentrations from 3–5 μg/l to undetectable levels, and neither saline nor naloxone affected LH secretion. During the follicular phase of the oestrous cycle, naloxone enhanced LH pulse frequency, which resulted in increased plasma LH concentrations; saline had no effect. In these sheep, β-endorphin decreased LH pulse frequency and the mean concentrations of LH, and this effect was prevented by the previous administration of naloxone. The i.c.v. administration of β-endorphin(1–27) to luteal phase ewes did not affect LH secretion. These data demonstrate the ability of a naturally occurring opioid peptide to inhibit LH secretion in ewes during the breeding and non-breeding seasons, irrespective of the gonadal steroid background. In contrast, whilst the gonadal steroids suppress LH secretion in ovariectomized ewes during both seasons, they only appear to activate endogenous opioid peptide (EOP)-mediated inhibition of LH secretion during the breeding season. Furthermore, these data support the notion that LH secretion in ovariectomized ewes is not normally under the control of EOP, so that naloxone has no effect. Journal of Endocrinology (1989) 122, 509–517

scholarly journals Age disrupts androgen receptor-modulated negative feedback in the gonadal axis in healthy men

2010 ◽  
Vol 299 (4) ◽  
pp. E675-E682 ◽  
Author(s):  
Johannes D. Veldhuis ◽  
Paul Y. Takahashi ◽  
Daniel M. Keenan ◽  
Peter Y. Liu ◽  
Kristi L. Mielke ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Negative Feedback ◽  
Pulse Frequency ◽  
Analysis Of Covariance ◽  
Double Blind ◽  
Healthy Men ◽  
Age Related ◽  
Lh Release ◽  
Lh Secretion ◽  
Double Blind Crossover Study

Testosterone (T) exerts negative feedback on the hypothalamo-pituitary (GnRH-LH) unit, but the relative roles of the CNS and pituitary are not established. We postulated that relatively greater LH responses to flutamide (brain-permeant antiandrogen) than bicalutamide (brain-impermeant antiandrogen) should reflect greater feedback via CNS than pituitary/peripheral androgen receptor-dependent pathways. To this end, 24 healthy men ages 20–73 yr, BMI 21–32 kg/m2, participated in a prospective, placebo-controlled, randomized, double-blind crossover study of the effects of antiandrogen control of pulsatile, basal, and entropic (pattern regularity) measurements of LH secretion. Analysis of covariance revealed that flutamide but not bicalutamide 1) increased pulsatile LH secretion ( P = 0.003), 2) potentiated the age-related abbreviation of LH secretory bursts ( P = 0.025), 3) suppressed incremental GnRH-induced LH release ( P = 0.015), and 4) decreased the regularity of GnRH-stimulated LH release ( P = 0.012). Furthermore, the effect of flutamide exceeded that of bicalutamide in 1) raising mean LH ( P = 0.002) and T ( P = 0.017) concentrations, 2) accelerating LH pulse frequency ( P = 0.013), 3) amplifying total (basal plus pulsatile) LH ( P = 0.002) and T ( P < 0.001) secretion, 4) shortening LH secretory bursts ( P = 0.032), and 5) reducing LH secretory regularity ( P < 0.001). Both flutamide and bicalutamide elevated basal (nonpulsatile) LH secretion ( P < 0.001). These data suggest the hypothesis that topographically selective androgen receptor pathways mediate brain-predominant and pituitary-dependent feedback mechanisms in healthy men.

Negative feedback effects of oestradiol-17ß on luteinizing hormone in female rhesus monkeys under different seasonal conditions

1985 ◽  
Vol 108 (1) ◽  
pp. 31-35
Author(s):  
J. G. Herndon ◽  
M. S. Blank ◽  
D. R. Mann ◽  
D. C. Collins ◽  
J.J. Turner
Keyword(s):  
Luteinizing Hormone ◽  
Breeding Season ◽  
Negative Feedback ◽  
Rhesus Monkeys ◽  
Feedback Effects ◽  
Female Rhesus ◽  
Time Of Year

Abstract. Suppression of luteinizing hormone (LH) by sc implanted oestradiol-17ß (E2) pellets was examined in 4 ovariectomized female rhesus monkeys during the breeding season, the non-breeding season and during the transition between the breeding and non-breeding season. Immunoreactive LH was suppressed to 58, 78 and 75% of untreated levels for the respective seasonal conditions. Bioactive LH was suppressed to 29, 49 and 33% of baseline. Bioactive LH (determined by testoster-one release from rat interstital cells) was significantly correlated (r = 0.84) with immunoactive LH from the same samples. It is concluded that E2 treatment of ovariectomized female rhesus monkeys results in suppressed levels of LH, regardless of the time of year.

Plasma testosterone surge and luteinizing hormone beta (LH-β) following parturition: lack of association in the male rat

1995 ◽  
Vol 133 (3) ◽  
pp. 366-374 ◽  
Author(s):  
Robert F McGivern ◽  
Ralph HM Hermans ◽  
Robert J Handa ◽  
Lawrence D Longo
Keyword(s):  
Luteinizing Hormone ◽  
Cesarean Section ◽  
Gnrh Antagonist ◽  
Male Rat ◽  
Plasma Testosterone ◽  
Treatment Groups ◽  
Natural Birth ◽  
Males And Females ◽  
Lh Secretion

McGivern RF, Hermans RHM, Handa RJ, Longo LD. Plasma testosterone surge and luteinizing hormone beta (LH-β) following parturition: lack of association in the male rat. Eur J Endocrinol 1995; 133:366–74. ISSN 0804–4643 Studies examining the role of luteinizing hormone (LH) in the initiation of the postnatal surge of testosterone in the male rat have produced ambiguous results. We examined the pattern of postnatal LH secretion in the newborn male rat, coincident with plasma testosterone levels, using a specific monoclonal antibody for LH-β. In some males, we attempted to block LH secretion and the postnatal testosterone surge by injecting males with a gonadotropin-releasing hormone (GnRH) antagonist, an LH antibody or progesterone immediately after delivery by cesarean section on day 22. Following injection, animals were immediately sacrificed (time 0) or housed in a humidified incubator maintained at 30°C until sacrifice at 60, 120, 240, 360 or 480 min after delivery. Plasma from individual animals was measured subsequently for LH-β and testosterone by radioimmunoassay. Results revealed a postnatal surge of testosterone which peaked at 2 h after delivery in males from all treatment groups. This testosterone surge was not accompanied by a postnatal rise in plasma LH-β in any group. Administration of the GnRH antagonist or the ethanol vehicle produced a transient drop of approximately 25% in LH-β levels at 60 min but did not decrease the postnatal testosterone surge in the same animals. Additional studies in untreated males and females born by cesarean section or natural birth also failed to reveal a postnatal rise in plasma LH-β during the first 3 h after birth. Plasma levels in both sexes were significantly lower in animals delivered by cesarean section compared to natural birth. Overall, these results indicate that the postnatal surge of testosterone occurs without a corresponding surge of detectable LH-β in the male rat. Robert F McGivern, 6363 Alvarado Ct, Suite 200H. San Diego, CA 92120, USA

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