Neurological complications in patients with Plasmodium vivax malaria from Karachi, Pakistan.

BACKGROUND: Malaria remains an endemic disease in Pakistan with an estimated healthcare burden of 1.6 million cases annually, with Plasmodium vivax accounting for 67% of reported cases. P. vivax is the most common species causing malaria outside of Africa, with approximately 13.8 million reported cases worldwide. METHOD: We report a series of P. vivax cases with cerebral involvement that presented at Aga Khan University Hospital, Karachi, Pakistan. RESULTS: The majority of the patients presented with high-grade fever accompanied by projectile vomiting and abnormal behaviour, seizures, shock and unconsciousness. Seven of 801 patients with P. vivax monoinfection presented or developed cerebral complications. P. vivax infections were diagnosed based on peripheral smears and rapid diagnostic testing. CONCLUSION: P. vivax infection can lead to severe complications, although not with the frequency of Plasmodium falciparum infection. Current cases highlight an increasing trend of cerebral complications caused by P. vivax.

Association of Helicobacter pylori and protozoal parasites in patients with chronic diarrhoea.

Introduction An association of Helicobacter pylori and common protozoal parasites in patients with abdominal discomfort and chronic diarrhoea is unclear and may be pathological. Materials and methods One hundred and sixty-one patients with diarrhoea were compared to 114 age and sex matched controls. Stool samples were examined by microscopy and DNA extracted for PCR with specific primers for H. pylori and protozoal parasites Blastocystis sp., Entamoeba sp. (Entamoeba histolytica, Entamoeba dispar and Entamoeba moshkovskii) and Giardia duodenalis (G. duodenalis). Results There was a marked difference in the presence of parasites between patients and controls: no parasite 42/75%, one parasite 42/15%, two or more parasites 16/10%, respectively (p < 0.001). Patients with diarrhoea were more likely to be infected with Blastocystis sp (p < 0.001), E. histolytica (p = 0.027) and E moshkovskii (p = 0.003). There was no difference in the frequency of H. pylori (p = 0.528), G duodenalis (p = 0.697) or E dispar (p = 0.425). Thirty-three patients and 27 controls had H. pylori infection. Of these, 22 patients and 6 controls were infected with Blastocystis sp (p = 0.001), 6 patients and no controls were infected with E. histolytica (p = 0.02), whilst 7 patents and 9 controls were infected with E dispar (p = 0.292). Conclusion In this population, diarrhoea is linked to infection with Blastocystis sp, E. histolytica and E moshkoviskii. In H. pylori infection, diarrhoea is linked to Blastocystis sp and E. histolytica infection. These associations may be linked pathogenically.

Current situation and challenges in implementing Malaria control strategies in Pakistan.

Malaria transmission is unstable in Pakistan with the highest number of cases reported during the monsoon season. Despite its high incidence, malaria is still a poorly resourced, poorly funded and an uncontrolled disease especially in far-flung areas. Pakistan's National Malaria Control Program (NMCP), although operational since its inception in 1947, has suffered due to the unstable political, socioeconomic and financial situation prevalent in the country. In Pakistan, more than 300 000 cases of malaria are reported every year with 68% of the cases caused by Plasmodium vivax. It is estimated that about 70-80% of the population accesses the private sector for treatment. As the private sector does not routinely report data to the government, the actual malaria burden could be 4-5 times higher than reported. P. vivax now accounts for more than 85% of all cases requiring hospital admission compared to 54% in 2000. In this review, we have described the saga of poor control of malaria in Pakistan over several years in context of restructuring of the Malaria Control Program, challenges to improvement, and way forward.

The emerging threat of schistosomiasis spread in Pakistan.

Schistosomiasis is among the thirteen neglected tropical diseases of the world. While prevalent in a number of countries, it has only rarely been reported in Pakistan. Here we report a 25 year old male who acquired the infection during travel to Malawi and presented with haematuria and dysuria. He was successfully treated with praziquantel. The possibility of schistosomiasis becoming endemic in the country is discussed. A number of risk factors are present including dams, irrigation, increased travel and geographical proximity to endemic countries. The local presence of at least one snail species of potential hosts for Schistosoma mansoni is confirmed. We see that schistosomiasis endemicity is a possible threat in Pakistan. Solutions to prevent this include reducing travel to endemic areas, prompt recognition and treatment of cases, and health education.

Role of PGF2α in luteolysis based on inhibition of PGF2α synthesis in the mare.

The effects of inhibition of PGF2α synthesis on luteolysis in mares and on the incidence of prolonged luteal activity were studied in controls and in a group treated with flunixin meglumine (FM), a PGF2α inhibitor (n = 6/group). The FM was given every 8 hours (1.0 mg/kg) on each of Days 14.0 to 16.7. Concentration (pg/mL) of PGF2α metabolite averaged over 8 hours of hourly blood sampling at the beginning of each day, was lower in the FM group than in the controls on Day 14 after ovulation (6.7 ± 1.3 vs. 13.8 ± 2.9, P < 0.05), Day 15 (15.0 ± 3.9 vs. 35.2 ± 10.4, P < 0.10), and Day 16 (21.9 ± 5.7 vs. 54.7 ± 11.4, P < 0.03). Concentration (ng/mL) of progesterone (P4) was greater in the FM group than in the controls on Day 14 (10.1 ± 0.9 vs. 7.7 ± 0.9, P < 0.08), Day 15 (9.2 ± 1.0 vs. 4.3 ± 1.0, P < 0.008), and Day 16 (5.6 ± 1.6 vs. 1.2 ± 0.4, P < 0.02). The interval from ovulation to the beginning of a decrease in P4 and to the end of luteolysis (P4 < 1 ng/mL) was each delayed (P < 0.03) by ~1 day in the FM group. Intervals involving the luteal phase were long (statistical outliers, P < 0.05) in two mares in the FM group, indicating prolonged luteal activity. Results supported the hypotheses that (1) inhibition of PGF2α synthesis interferes with luteolysis in mares and (2) inhibition of PGF2α at the expected time of luteolysis may lead to prolonged luteal activity.

Endocrinology of number of follicular waves per estrous cycle and contralateral or ipsilateral relationship between corpus luteum and preovulatory follicle in heifers.

A 3-d extension of the luteal phase occurs in interovulatory intervals (IOIs) with a contralateral relationship between the corpus luteum (CL) and preovulatory follicle with 3 follicular waves (Contra-3W group). Concentrations of FSH, progesterone, LH, and estradiol-17ß for the ipsilateral versus contralateral CL and/or follicle relationship and 2 versus 3 waves per IOI were studied in 14 heifers. Follicular waves and FSH surges were designated 1, 2, or 3, according to order of occurrence in the IOI. The day (day 0 = ovulation) of the FSH peak in surge 2 occurred earlier (P < 0.02) in 3-wave IOIs (day 6.3 ± 0.5) than in 2-wave IOIs (day 8.5 ± 0.5). Mean FSH was higher in 3-wave than in 2-wave IOI on 82% of the days in the IOI. Repeatability or individuality in FSH concentration was indicated by a correlation (r = 0.54, P < 0.04) in FSH concentrations between ovulations at the beginning and at the end of the IOI. Concentrations of LH and estradiol increased (P < 0.05) near the beginning of the luteolytic period in 2-wave IOI regardless of the CL and/or follicle relationship. In the Contra-3W group, LH and estradiol remained at basal concentrations concurrently with FSH surge 3 and extension of the luteal phase. The hypotheses were supported that FSH surge 2 occurs earlier in 3-wave IOIs than in 2-wave IOIs and that the development of 3-wave IOIs occurs in individuals with greater FSH concentrations. Extension of the luteal phase in the Contra-3W group was temporally associated with lower concentrations of LH and estradiol.

Interrelationships among progesterone, LH, and luteal blood flow during a pulse of a PGF2α metabolite and functional role of LH in the progesterone rebound in heifers.

On Day 16 (Day 0 = ovulation) or before the expected transition into the luteolytic period, heifers were not treated (control group, N = 7) or were treated with a single 0.1-mg dose of estradiol (E2) (E2 group, N = 6) or E2 combined with the GnRH antagonist acyline (E2/Ac group, N = 5). Hourly blood samples were collected from hour of treatment (Hour 0) to Hour 20. Estradiol induced a pulse of PGFM, but the peak of the pulse occurred 2 hours later (P < 0.05) and mean PGFM concentrations during the descending portion of the pulse were lower (P < 0.05) in the E2/Ac group than in the E2 group. In the E2 group, concentration of progesterone (P4) decreased (P < 0.05) during the ascending portion of the PGFM pulse, and increased (rebounded; P < 0.05) along with an LH increase during the descending portion. In the E2/Ac group, a rebound in P4 and an increase in LH were not detected during the descending portion of the PGFM pulse. The percentage of CL with color Doppler signals of blood flow increased (P < 0.04) concurrently with the PGFM increase during Hours 0 to 5 and during the ascending portion of the PGFM pulse. Blood flow and PGFM decreased concurrently. The following hypotheses were supported: (1) LH has a positive effect on PGFM pulses; (2) the rebound in P4 and the increase in LH during the descending portion of a PGFM pulse are functionally related; and (3) the increase in luteal blood flow in association with a PGFM pulse represents a direct effect of PGF2α rather than an effect of P4 or LH.

Contralateral ovarian location between the future ovulatory follicle and extant corpus luteum increases the length of the luteal phase and number of follicular waves in heifers.

Location of the future ovulatory follicle and CL in the same ovary (ipsilateral) or opposite ovaries (contralateral) and number of major follicular waves (two or three) per interovulatory interval (IOI) was studied in 14 heifers. Follicle diameter and a blood sample for progesterone (P4) assay were obtained each day throughout an IOI. Heifers were partitioned into three groups: ipsilateral follicle/CL relationship and two follicular waves (Ipsi-2W, N = 5), contralateral relationship and two follicular waves (Contra-2W, N = 5), and contralateral relationship and three waves (Contra-3W, N = 4). Only one heifer had an ipsilateral relationship and three waves and was not included in the analyses. An unexpected observation was slower growth of the dominant follicle of Wave 1 in the Ipsi-2W group than in the Contra-2W and Contra-3W groups. Increased P4 production in the Contra-3W group compared with the Ipsi-2W and Contra-2W groups was indicated by significantly greater P4 concentration averaged over Days 0 to 20 (Day 0 = ovulation), longer interval from ovulation to the beginning of a decrease in P4 and to the beginning of postluteolysis (P4 <1 ng/mL), and longer IOI. The interval from the beginning of postluteolysis to ovulation was not different among groups, indicating that the prolonged IOI reflected the prolonged luteal phase. An effect of the follicle/CL relationship on length of the IOI was not detected in mares. Results supported the hypothesis that the prolonged luteal phase of the contralateral follicle/CL relationship favors the development of three follicular waves/IOI in heifers.

Follicular-phase concentrations of progesterone, estradiol-17ß, LH, FSH, and a PGF2α metabolite and daily clustering of prolactin pulses, based on hourly blood sampling and hourly detection of ovulation in heifers.

Circulating concentrations of hormones were determined each hour in 13 heifers from the end of the luteolytic period to ovulation (follicular phase, 3.5 days). Diameter of the preovulatory follicle was determined every 8 hours, and the time of ovulation was determined hourly. The diameter of the preovulatory follicle decreased 0.8 ± 0.1 mm/h in heifers when there was 1 to 3 hours between the last two diameter measurements before ovulation. The concentration of progesterone (P4) after the end of the luteolytic period (P4 < 1 ng/mL) changed (P < 0.0001), as shown by a continued decrease until Hour -57 (Hour 0 = ovulation), then was maintained at approximately 0.2 ng/mL until 2 hours before the peak of the LH surge at Hour -26, and then a decrease to 0.1 ng/mL along with a decrease in estradiol-17ß. Concentrations of LH gradually increased (P < 0.007) and concentrations of FSH gradually decreased (P < 0.0001) after the end of luteolysis until the beginning nadirs of the respective preovulatory surges. A cluster of prolactin (PRL) pulses occurred (P < 0.0001) each day with approximately 24 hours between the maximum value of successive clusters. Hourly concentrations of a PGF2α metabolite decreased (P < 0.007) until Hour -40, but did not differ among hours thereafter. Novel observations included the gradual increase in LH and decrease in FSH until the beginning of the preovulatory surges and follicle diameter decrease a few hours before ovulation. Results supported the following hypotheses: (1) change in the low circulating P4 concentrations during the follicular phase are temporally associated with change in LH concentrations; and (2) PRL pulses occur in a cluster each day during the follicular phase of the estrous cycle.

Progesterone concentration when the future ovulatory follicle and corpus luteum are located in ipsilateral or contralateral ovaries in heifers.

Three studies were done on the effects of ipsilateral location (same ovary) versus contralateral location (opposite ovaries) of the future ovulatory follicle and CL in heifers. The numbers of heifers for the ipsilateral and contralateral groups, respectively, were: experiment (Exp) 1 (N = 4 and 4), Exp 2 (N = 6 and 4), and Exp 3 (N = 5 and 10). In the Exps with available data (Exp 2 and 3), the interval between ovulation and the end of luteolysis was significantly shorter in the ipsilateral group than in the contralateral group (Exp 2: 16.8 ± 0.3 vs. 19.8 ± 1.7 days; Exp 3: 16.9 ± 0.2 vs. 19.7 ± 0.9 days). In Exp 3, the interovulatory interval was shorter (P < 0.01) in the ipsilateral group (20.1 ± 0.4 days) than in the contralateral group (22.7 ± 0.7 days), but the interval from the end of luteolysis to ovulation was not altered significantly. Circulating progesterone (P4) concentration for 33 hours normalized to the beginning of luteolysis (Exp 1) and on Days 16 to 20 (Day 0 = ovulation; Exp 3) was significantly lower in the ipsilateral group than in the contralateral group (Exp 1: 3.7 ± 0.2 vs. 4.8 ± 0.3 ng/mL; Exp 3: 1.7 ± 0.4 vs. 5.9 ± 0.4 ng/mL). Area (cm(2)) of the CL and percentage of CL with color Doppler signals of blood flow were lower and resistance index for a CL arteriole was greater in the ipsilateral group (Exp 3). The decreased P4 concentration in the ipsilateral group began by Day 16, but the decreased luteal area and vascular perfusion were not detected until Days 17 or 18. Results supported the hypothesis that the ipsilateral location of the future ovulatory follicle and CL was associated with lower P4 production and a shorter interovulatory interval.

Circadian influence on the preovulatory LH surge, ovulation, and prolactin concentrations in heifers.

A novel circadian study of the effect of clock hours on the preovulatory LH surge, ovulation, and maximal PRL concentration was done in 13 nontreated Holstein heifers. Hourly blood sampling and hourly ultrasound examinations to detect the hour of ovulation began at 8 and 48 hours, respectively, after CL area (cm(2)) had decreased 15% from the area at 15 days postovulation. The resulting experimental period began at the beginning of postluteolysis (progesterone, <1 ng/mL) and encompassed a mean of 3.5 days until ovulation. The frequency of the peak of the preovulatory LH surge for the three 8-hour periods of a 24-hour day was different (P < 0.02) between 2:00 AM to 9:00 AM (N = 9), 10:00 AM to 5:00 PM (N = 3), and 6:00 PM to 1:00 AM (N = 1). The median was 6:00 AM. The frequency of ovulations for 8-hour periods was different (P < 0.02) between 3:00 AM to 10:00 AM (N = 9), 11:00 AM to 6:00 PM (N = 3), and 7:00 PM to 2:00 AM (N = 1). The median was 7:30 AM. Two or three clusters of PRL pulses occurred during the 3.5 days. Based on all available PRL pulse clusters (N = 36), the clock hours of the maximal concentration/cluster was greater (P < 0.0001) for 9:00 AM to 2:00 PM (N = 33 clusters) than for each of the three other 6-hour periods (N = 0, 1, or 2 per period). The median was 11:30 AM. The hypothesis was supported that the peak of the preovulatory LH surge, ovulation, and maximal PRL concentration during pulse clusters occur with greater frequency during certain clock hours in heifers.

Stimulatory effect of PGF2α on PRL based on experimental inhibition of each hormone in mares.

During the luteolytic period in mares, the peak of 65% of pulses of a PGF2α metabolite (PGFM) and the peak of a pulse of PRL have been reported to occur at the same hour. It is unknown whether the synchrony reflects an effect of PGF2α on PRL or vice versa. Controls, a flunixin meglumine (FM)-treated group (to inhibit PGF2α), and a bromocriptine-treated group (to inhibit PRL), were used at 14 days postovulation in June and in September (n = 6 mares/group/mo). Blood samples were collected hourly from just before treatment (Hour 0) to Hour 10. Concentrations of PGFM in the FM group were lower (P < 0.05) at Hours 4 to 6 than in the controls in each month, but bromocriptine had no detected effects on PGFM. Concentrations of PGFM averaged over all groups and within each group did not differ between June and September. Compared to the controls, concentrations of PRL in June were lower (P < 0.05) in the FM group at Hours 4 to 8 and in the bromocriptine group at Hours 4 to 10. Concentration of PRL averaged over groups was lower (P < 0.0001) in September (0.9 ± 0.05 ng/mL, mean ± SEM) than in June (3.0 ± 0.3 ng/mL). Results supported the hypothesis that the positive association between PGFM and PRL concentrations in mares represents an effect of PGF2α on PRL rather than an effect of PRL on PGF2α.

Role of LH in the progesterone increase during the bromocriptine-induced prolactin decrease in heifers.

The luteotrophic effect of bromocriptine in heifers was studied to determine if the reported posttreatment increase in progesterone (P4) just before or at the beginning of luteolysis was attributable to loss of a luteolytic effect of prolactin (PRL) or to the stimulation of LH, a known luteotropin. Four treatment groups (n = 7) were used: control (Ct), bromocriptine (Bc; 16 mg/heifer), acyline (Ac; 3 µg/kg), and bromocriptine and acyline combined (BcAc). Bromocriptine (inhibitor of PRL) and acyline (antagonist of GnRH and therefore blocker of LH) were given at Hour 0 on Day 16 postovulation, and blood samples were taken hourly at Hours 0 to 8. Concentration of P4 was greater (P < 0.05) in the Bc group than in the Ct group at each of Hours 1 to 8. Concentration of LH increased (P < 0.05) between Hours 0 to 2 in the Bc group but not in the other three groups. The peak of the first posttreatment LH pulse occurred earlier in the Bc group than in the Ct group. Average concentration of PRL was lower (P < 0.05) and number of PRL pulses was less (P < 0.05) in the Bc group than in the Ct group. Acyline inhibited LH in the Ac and BcAc groups as indicated by a decrease (P < 0.05) in concentration between Hours 0 and 2 and a decrease (P < 0.001) in number of pulses/heifer during the 8 h. A decrease in PRL but not an increase in P4 and LH occurred in the BcAc group. Results supported the hypothesis that the P4 increase associated with PRL suppression by bromocriptine treatment is attributable to an increase in LH.

Ovarian and PGF2α responses to stimulation of endogenous PRL pulses during the estrous cycle in mares.

The effects of a PRL-stimulating substance (sulpiride) on PRL and PGF2α secretion and on luteal and ovarian follicular dynamics were studied during the estrous cycle in mares. A control group (n = 9) and a sulpiride group (Sp; n = 10) were used. Sulpiride (25 mg) was given every 8 h from Day 13 postovulation to the next ovulation. Repeated sulpiride treatment did not appear to maintain PRL concentrations at 12-h intervals beyond Day 14. Therefore, the hypothesis that a long-term increase in PRL altered luteal and follicular end points was not testable. Hourly samples were collected from the hour of a treatment (Hour 0) to Hour 8 on Day 14. Concentrations of PRL increased to maximum at Hour 4 in the Sp group. The PRL pulses were more prominent (P < 0.008) in the sulpiride group (peak, 19.4 ± 1.9 ng/mL; mean ± SEM) than in the controls (11.5 ± 1.8 ng/mL). Concentrations of a metabolite of PGF2α (PGFM), number, and characteristics of PGFM pulses, and concentrations of progesterone during Hours 0 to 8 were not affected by the increased PRL. A novel observation was that the peak of a PRL pulse occurred at the same hour or 1 h later than the peak of a PGFM pulse in 8 of 8 PGFM pulses in the controls and in 6 of 10 pulses in the Sp group (P < 0.04), indicating that sulpiride interfered with the synchrony between PGFM and PRL pulses. The hypothesis that sulpiride treatment during the equine estrous cycle increases concentrations of PRL and the prominence of PRL pulses was supported.

Stimulation of a pulse of LH and reduction in PRL concentration by a physiologic dose of GnRH before, during, and after luteolysis in heifers.

A single physiologic dose (5.0 µg) of GnRH was given to 9 heifers each day (Hour 0) beginning on Day 15 postovulation until regression of the corpus luteum. Blood samples were taken each day for Hours -3, -2, -1, 0, 0.25, 0.5, 0.75, 1, 1.25, 1.50, 1.75, 2, 3, 4, and 5. Based on daily progesterone concentrations, data were grouped into phases of before (n=4), during (n=8), and after (n=7) luteolysis. The number of LH pulses with a peak at pretreatment Hours -2 or -1 (0.35 ± 0.12 pulses/sampling session) was less (P<0.0001) than for a pulse peak at posttreatment Hours 1 or 2 (1.0 ± 0.0 pulses/session). The characteristics and effects of LH pulses on progesterone and estradiol were similar between natural (pretreatment) and primarily induced (posttreatment) LH pulses. The same dose of GnRH stimulated an LH pulse with greater (P<0.05) amplitude after luteolysis than during luteolysis. Concentrations of PRL and number and prominence of PRL pulses decreased (P<0.05) between Hours 0 and 2 within each of the phases of before, during, and after luteolysis. The hypothesis that a physiologic dose of GnRH increases the concentration of PRL was not supported; instead, GnRH reduced the concentration of PRL. Results supported the hypotheses that an appropriate dose of GnRH stimulates an LH pulse during luteolysis that is similar to a natural pulse in characteristics and in the effects on progesterone and estradiol.

Temporal interrelationships at 15-min intervals among oxytocin, LH, and progesterone during a pulse of a prostaglandin F2α metabolite in heifers.

A pulse of a PGF2α metabolite (PGFM) was induced by treatment with 0.1 mg of estradiol-17ß on Day 15 (Day 0=ovulation; n=9 heifers). Blood samples were taken every 15 min for 9h beginning at treatment (Hour 0). For PGFM and LH, an intraassay-CV method was used to detect fluctuations in the 15-min samples and pulses in the hourly samples. A mean of 6.9 ± 0.4 PGFM fluctuations/9 h were superimposed on the hourly PGFM concentrations, compared to 2.1 ± 0.5 LH fluctuations/9 h (P<0.02). An increase (P<0.02) in oxytocin began 15 min before the beginning nadir of the PGFM pulse. A transient increase in progesterone did not occur at the beginning nadir of the PGFM pulse. Progesterone decreased (P<0.02) during the ascending portion and increased (P<0.03) as a rebound during the descending portion of the PGFM pulse. The peak of an LH pulse occurred 1.5 ± 0.4 h (range, 0.25-2.75 h) after the peak of the PGFM pulse. The wide range in the interval from a PGFM peak to an LH peak obscured the contribution of increasing LH to the rebound. The results did not support the hypothesis that oxytocin and PGFM increase concurrently. Results supported the hypothesis that the immediate transient progesterone increase that has been demonstrated with exogenous PGF2α does not occur during the ascending portion of an endogenous PGFM pulse. The hypothesis that the progesterone rebound after the peak of a PGFM pulse is temporally related to an LH pulse was supported.

Inhibition of prostaglandin biosynthesis during postluteolysis and effects on CL regression, prolactin, and ovulation in heifers.

The beginning of postluteolysis (progesterone, <1 ng mL(-1)) in heifers was targeted by using 8 h after ultrasonic detection of a 25% decrease in CL area (cm2) and was designated Hour 0. Flunixin meglumine (FM; n=10) to inhibit PGF2α secretion or vehicle (n=9) were given intramuscularly at Hours 0, 4, 8, 16, 24, 32, and 40. The dose of FM was 2.5 mg/kg at each treatment. Blood sampling and measurement of the CL and dominant follicle were done every 8 h beginning 14 days postovulation in each group. Blood samples for detection of pulses of PRL and pulses of a metabolite of PGF2α (PGFM) were obtained every hour for 24 h beginning at Hour 0. Pulse concentrations of both PGFM and PRL were lower in the FM group than in the vehicle group. Concentration of PRL was greatest at the peak of a PGFM pulse. Neither CL area (cm2) nor progesterone concentration differed between groups during Hours 0 to 48 (postluteolysis). Ovulation occurred in nine of nine heifers in the vehicle group and in three of 10 heifers in the FM group. The anovulatory follicles in the FM group grew to 36.2±2.9 mm, and the wall became thickened from apparent luteinization. The hypothesis that PGF2α was involved in the continued P4 decrease and structural CL regression during postluteolysis was not supported. However, the hypotheses that pulses of PGFM and PRL were temporally related and that systemic FM treatment induced an anovulatory follicle were supported.

Direct effect of PGF2α pulses on PRL pulses, based on inhibition of PRL or PGF2α secretion in heifers.

The relationships between PRL and PGF(2α) and their effect on luteolysis were studied. Heifers were treated with a dopamine-receptor agonist (bromocriptine; Bc) and a Cox-1 and -2 inhibitor (flunixin meglumine [FM]) to inhibit PRL and PGF(2α), respectively. The Bc was given (Hour 0) when ongoing luteolysis was indicated by a 12.5% reduction in CL area (cm(2)) from the area on Day 14 postovulation, and FM was given at Hours 0, 4, and 8. Blood samples were collected every 8-h beginning on Day 14 until Hour 48 and hourly for Hours 0 to 12. Three groups of heifers in ongoing luteolysis were used: control (n = 7), Bc (n = 7), and FM (n = 4). Treatment with Bc decreased (P < 0.003) the PRL concentrations averaged over Hours 1 to 12. During the greatest decrease in PRL (Hours 2-6), LH concentrations were increased. Progesterone concentrations averaged over hours were greater (P < 0.05) in the Bc group than in the controls. In the FM group, no PGFM pulses were detected, and PRL concentrations were reduced. Concentrations of PGFM were not reduced in the Bc group, despite the reduction in PRL. Results supported the hypothesis that a decrease (12.5%) in CL area (cm(2)) is more efficient in targeting ongoing luteolysis (63%) than using any day from Days 14 to ≥ 19 (efficiency/day, 10-24%). The hypothesis that PRL has a role in luteolysis was supported but was confounded by the known positive effect of LH on progesterone. The hypothesis was supported that the synchrony of PGFM and PRL pulses represents a positive effect of PGF(2α) on PRL, rather than an effect of PRL on PGF(2α).

Dynamics of circulating progesterone concentrations before and during luteolysis: a comparison between cattle and horses.

The profile of circulating progesterone concentration is more dynamic in cattle than in horses. Greater prominence of progesterone fluctuations in cattle than in horses reflect periodic interplay in cattle between pulses of a luteotropin (luteinizing hormone; LH) and pulses of a luteolysin (prostaglandin F2alpha; PGF2alpha). A dose of PGF2alpha that induces complete regression of a mature corpus luteum with a single treatment in cattle or horses is an overdose. The overdose effects on the progesterone profile in cattle are an immediate nonphysiological increase taking place over about 30 min, a decrease to below the original concentration, a dose-dependent rebound 2 h after treatment, and a progressive decrease until the end of luteolysis. An overdose of PGF2alpha in horses results in a similar nonphysiological increase in progesterone followed by complete luteolysis; a rebound does not occur. An overdose of PGF2alpha and apparent lack of awareness of the rebound phenomenon has led to faulty interpretations on the nature of spontaneous luteolysis. A transient progesterone suppression and a transient rebound occur within the hours of a natural PGF2alpha pulse in cattle but not in horses. Progesterone rebounds are from the combined effects of an LH pulse and the descending portion of a PGF2alpha pulse. A complete transitional progesterone rebound occurs at the end of preluteolysis and the beginning of luteolysis and returns progesterone to its original concentration. It is proposed that luteolysis does not begin in cattle until after the transitional rebound. During luteolysis, rebounds are incomplete and gradually wane. A partial rebound during luteolysis in cattle is associated with a concomitant increase in luteal blood flow. A similar increase in luteal blood flow does not occur in mares.

The hour of transition into luteolysis in horses and cattle: a species comparison.

Hourly blood sampling in both horses and cattle indicate that the transition between the end of preluteolysis and the beginning of luteolysis occurs within 1 h, as manifested by a change in progesterone concentrations. Each species presents a separate temporality enigma on the relationship between pulses of a prostaglandin (PG) F2α metabolite (PGFM) and the hour of the progesterone transition. In horses, relatively small pulses of PGFM occur during preluteolysis (before transition) and at transition. Oxytocin, but not estradiol, increases and decreases concomitantly with the small PGFM pulse at transition but not with previous pulses and may account for the initiation of luteolysis during the small PGFM pulse. In cattle, the last PGFM pulse of preluteolysis occurs hours before transition (e.g., 4 h), and the next pulse occurs well after transition (e.g., 9 h); unlike in horses, a PGFM pulse does not occur at transition. During the last PGFM pulse before transition, progesterone concentration decreases during the ascending portion of the PGFM pulse. Concentration then rebounds in synchrony with an LH pulse. The rebound returns progesterone to the concentration before the PGFM pulse. During luteolysis, an LH-stimulated progesterone rebound may occur after the peak of a PGFM pulse, but progesterone does not return to the concentration before the PGFM pulse. A similar LH-stimulated progesterone rebound does not occur in horses, and therefore progesterone fluctuations are more shallow in horses than in cattle.