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At least 19 recordsLinked to original sources
PubMed1990

Subnormal follicular-phase serum progesterone levels and elevated follicular-phase serum estradiol levels in young women with insulin-dependent diabetes.

In a search for possible hormonal reasons for the loss of protection from myocardial infarction seen in diabetic women, serum levels of estradiol, progesterone, and luteinizing hormone were compared throughout a menstrual cycle (17 points) in eight healthy nonsmoking women and five otherwise healthy nonsmoking insulin-dependent diabetic women. The total length of the menstrual cycle and the lengths of the follicular and luteal phases did not differ between the groups. During the periovulatory and luteal phases, there was no significant intergroup difference with respect to any of the three hormones. During the follicular phase, in both groups, there was a plateau in serum progesterone concentration, with the level approximately 42% lower in the diabetic group (12.0 +/- 6.6 ng/dl versus 20.7 +/- 5.7; P less than 0.0001). Follicular-phase serum estradiol showed a rising curve in both groups; day-by-day comparison (days -10 to -3 before the luteinizing hormone peak) showed consistently higher levels in the diabetic group (mean, 108 pg/ml versus 95 pg/ml; P less than 0.001). The follicular-phase serum estradiol to progesterone ratio was nearly twice as high in the diabetic group as in the normal group (8.9 versus 4.6), a difference that was highly significant. The finding of elevated serum estradiol and subnormal serum progesterone concentrations during the follicular phase is so far unique to women with insulin-dependent diabetes mellitus. The possibility that this pronounced abnormality in diabetic women may be related to coronary disease merits testing in suitable in vivo and in vitro models of atherogenesis.

Adult↗
PubMed1992

A prospective randomized comparison of luteal phase versus concurrent follicular phase initiation of gonadotropin-releasing hormone agonist for in vitro fertilization.

OBJECTIVE: To compare the effects of gonadotropin-releasing hormone agonist (GnRH-a) initiation either preceding or concurrent with controlled ovarian hyperstimulation (COH) in patients undergoing in vitro fertilization-embryo transfer (IVF-ET). DESIGN: Fifty-five patients were prospectively randomized to receive either GnRH-a on cycle day 21 before COH until ovarian suppression was achieved (group I) or GnRH-a concurrently with COH commencing on cycle day 3 (group II). MAIN OUTCOME MEASURES: Serum gonadotropin and ovarian steroid hormone levels, as well as fertilization, spontaneous abortion, and live birth rates. RESULTS: Twenty-six patients in group I and 29 patients in group II underwent COH for IVF-ET. Patients in group II had significantly higher serum luteinizing hormone, progesterone, and testosterone levels during stimulation with human menopausal gonadotropins (hMG) before oocyte retrieval (P < 0.05). Despite similar fertilization, biochemical, and clinical pregnancy rates, the spontaneous abortion rate was higher in group II (5/6) compared with group I (1/7) (P < 0.05). Thus, the live birth rate/retrieval for group I was 6 of 24 (25%) as compared with that of group II, which was 1 of 26 (3.8%) (P < 0.05). CONCLUSIONS: The initiation of GnRH-a in the follicular phase concurrently with hMG is associated with evidence of premature luteinization, hyperandrogenemia, and poorer pregnancy outcome compared with luteal phase administration of GnRH-a before hMG for IVF-ET.

Adult↗
PubMed1989

Increased human menopausal gonadotropin dose during the early follicular phase: effect on follicular recruitment and treatment outcome.

To investigate whether the provision of increased gonadotropins would enhance follicular recruitment and selection, women not responding (N = 18) to our standard clomiphene citrate (CC)-human menopausal gonadotropin (hMG) regimen were treated with increased hMG (treatment cycle II). Estradiol levels were higher in treatment cycle II and these differences were significant on days 8 and 9 (P less than or equal to 0.05 and P less than or equal to 0.03, respectively). On day 9, better follicular development was seen in cycle II (P less than or equal to 0.05). While none of the patients responded in cycle I, 10 of 18 responded in cycle II. Of the 10 responders, 2 conceived following in vitro fertilization and embryo placement. Increasing the dose of hMG improved the development of a cohort of follicles so that aspiration and possible pregnancy were achieved in women who were previously unresponsive to therapy.

Clomiphene↗
PubMed1997

Increased interleukin-1 and interleukin-1 receptor antagonist levels in cervical mucus in the ovulatory phase in comparison with the follicular phase.

Interleukin-1 (IL-1) receptor antagonist (IL-1ra) levels in the cervical mucus of women in the ovulatory phase are significantly higher than those in the follicular phase. IL-1 titers of women in the ovulatory phase are also significantly higher than those in the follicular phase. A positive correlation between IL-1ra and IL-1 levels in the cervical mucus was observed. Immunohistochemistry using an anti-IL-1ra monoclonal antibody revealed positive staining in the epithelial cells of the endocervix. These results suggest that IL-1ra from cervical epithelial cells protects the reproductive system from the toxicity of IL-1 produced in the endocervix.

Adult↗
PubMed1997

Suppression of luteal phase, but not midcycle, prolactin levels by chronic follicular phase opiate antagonism.

OBJECTIVE: To investigate whether establishment and maintenance of chronic opioid blockade throughout the follicular phase of the menstrual cycle influences midcycle and luteal phase prolactin levels. DESIGN: Randomized, double-blind, crossover study. SETTING: Academic research environment. PATIENT(S): Volunteers, aged 21-35 years, with regular menstrual cycles. INTERVENTION(S): Naltrexone (50 mg) or placebo were administered on cycle days 2-14. Blood samples were obtained in the early follicular phase and in the periovulatory and midluteal phases of the menstrual cycle. MAIN OUTCOME MEASURE(S): Serum prolactin levels. RESULT(S): In the early follicular phase, serum prolactin levels were equivalent in naltrexone (12.0 +/- 2.7 microgram/L; mean +/- SE) and placebo (12.1 +/- 2.9 micrograms/L) cycles. A statistically significant increase in serum prolactin was observed on the day of the LH surge (naltrexone: 22.6 +/- 3.7 micrograms/L; placebo: 21.7 +/- 2.7 micrograms/L; P < 0.05 versus early follicular phase), but no difference between treatments was observed. However, midluteal prolactin levels were statistically significantly lower in naltrexone cycles compared with placebo cycles (12.6 +/- 3.3 versus 15.4 +/- 3.0 micrograms/L; P < 0.05). CONCLUSION(S): Chronic blockade of opioid activities during the follicular phase does not affect midcycle prolactin increments, but withdrawal of opioid blockade may enhance opioid effects on prolactin levels in the luteal phase.

Adult↗
PubMed1987

Longitudinal evaluation of the luteal phase and its transition into the follicular phase.

The precise patterns of LH, FSH, and PRL secretion and their correlation with estradiol (E2) and progesterone (P) secretion during the entire luteal phase have not been elucidated. To analyze in detail the secretory patterns of these hormones we performed 29 consecutive studies in 5 healthy, regularly menstruating women throughout their luteal phase [days 0 (ovulation), 2, 6, 10, and 14] and subsequent early follicular phase (day 2F). During each study plasma LH, FSH, PRL, E2, and P were measured at 10-min intervals for 6 h. Both plasma LH concentrations and LH pulse frequency declined from days 0 to 10 and increased thereafter, whereas LH pulse amplitude continued to decline throughout the luteal and early follicular phases. Plasma FSH concentrations followed a pattern similar to that of LH; however, there was a larger increase in the FSH level on days 14 and 2F. Plasma PRL levels declined initially on day 2 and again on day 14. Regression analysis indicated a positive correlation between LH concentrations and LH pulse frequency (r = 0.715; P less than 0.001) and between PRL and E2 concentrations (r = 0.528; P less than 0.01). A negative correlation was found between plasma P concentrations and both LH concentrations (r = -0.521; P less than 0.01) and LH pulse frequency (r = -0.633; P less than 0.001) and between plasma E2 and FSH concentrations (r = -0.762; P less than 0.001). Thirty-six (65%) PRL pulses and only 11 (39%) FSH pulses coincided with LH pulses. There was no clear pulsatile pattern of secretion of either E2 or P. We conclude that 1) the plasma LH, FSH, PRL, E2, and P concentrations vary markedly throughout the luteal phase; 2) the plasma LH level is largely dependent on the frequency of LH pulses; 3) plasma P decreases plasma LH by reducing the frequency of LH pulses; 4) the remarkable synchrony between PRL pulses and LH pulses implies that their secretion may be regulated by a common neuroendocrine mechanism; and 5) the preferential increase in FSH during the late luteal phase may play an important role in follicular recruitment for the subsequent cycle.

Adult↗
PubMed1997

Expression of different molecular mass forms of inhibin in atretic and nonatretic follicles during the early luteal phase and altrenogest-synchronized follicular phase in pigs.

This experiment characterized changes in amounts and proportions of different molecular forms of inhibin in porcine follicular fluid as related to stage of follicular development. Thirty-seven follicles (2-4 per pig) were dissected from 12 pigs during early luteal phase of the estrous cycle on Days 5, 6, and 7 of the estrous cycle, whereas 34 follicles (2-4 per pig) were dissected from 11 pigs on Days 1, 3, 5, and 7 of a follicular phase synchronized by altrenogest. Follicles were designated atretic if incidence of apoptotic granulosa cells was > or = 10% as determined by DNA fluorescence flow cytometry. Porcine follicular fluid was fractionated on 12% SDS-PAGE gels under non-reducing conditions and electroblotted to Immobilin P membranes. Inhibin forms were detected by immunoblot analysis using a mink anti-bovine inhibin alpha C1-26 gly.tyr antiserum and quantified. Immunoblots detected seven bands corresponding to inhibin forms of 44, 49, 58, 69, 121, 227, and > 227 kDa in > 91% of porcine follicular fluid samples. Three additional forms of 27, 29, and 32 kDa were detectable in only 52%, 64%, and 48% of samples, respectively. Forms > or = 69 kDa represented 83% of total inhibin immunoblot activity. The 121-kDa form was most abundant, with 39% of the total immunoblot activity in nonatretic follicles. The proportions of individual forms and total immunoblot activity pooled over days did not differ between early luteal and follicular phase follicles. Total inhibin immunoblot activity was 59% less in atretic than in nonatretic follicles. Amounts of the 44-, 49-, 69-, 121-, and 227-kDa forms were 50-80% lower (p < or = 0.05) in atretic than in nonatretic follicles. Total inhibin immunoblot activity in nonatretic follicles decreased (p < or = 0.05) by 60% during the early luteal phase but did not change significantly during the follicular phase. In nonatretic follicles, the 121-kDa form decreased (p < 0.05) during the early luteal and follicular phases. During the early luteal phase, amounts of the other forms did not change, whereas during the follicular phase the 44-kDa form increased (p < 0.05) 10-fold. In atretic follicles, neither amount nor proportion of inhibin forms differed among days. We conclude that follicular production and/or intracellular processing of inhibin dimer and/or inhibin alpha subunits changes during different phases of follicular development, supporting the notion of physiological roles for these peptides.

Androstenedione↗
PubMed1996

Midluteal buserelin is superior to early follicular phase buserelin in combined gonadotropin-releasing hormone analog and gonadotropin stimulation in in vitro fertilization.

OBJECTIVE: To establish whether time to down-regulation and pregnancy and live birth rates were different when buserelin acetate was started in the midluteal phase or early follicular phase in IVF-ET patients. DESIGN: Prospective, controlled, randomized, parallel-group multicenter clinical study. SETTING: Women attending seven infertility clinics. PATIENTS: One hundred twenty-four women with tubal or unexplained infertility with normal menstruation and fertile partners. INTERVENTIONS: Intranasal buserelin acetate started in the midluteal or early follicular phase combined with standard hMG and hCG stimulation after achievement of down-regulation. Established IVF-ET methods. MAIN OUTCOME MEASURES: Duration of down-regulation; clinical pregnancy and live birth rates. RESULTS: Kaplan-Meier estimations of the duration of down-regulation were 15.5 days when buserelin acetate was started in the early follicular phase (127 cycles) and 14.6 days when it was started in the midluteal phase (96 cycles). This difference was statistically significant. The pregnancy rates per first treatment cycle, treatment cycle, oocyte retrieval, and ET were significantly higher when buserelin acetate was started in the midluteal phase. The live birth rates were also higher, but only significantly so for the rate per first treatment cycle. CONCLUSIONS: Clinical pregnancy and live birth rates are better when buserelin acetate is started in the midluteal phase rather than the early follicle phase before hMG and hCG stimulation in preparation for IVF-ET.

Administration, Intranasal↗
PubMed1994

CaBP9K levels during the luteal and follicular phases of the estrous cycle in the bovine uterus.

The expression of calbindin-D9K (CaBP9K) and calbindin-D28K (CaBP28K) genes in the reproductive system is well established for rodent and avian species, but not for domestic livestock. This investigation expanded the study of these proteins to include the bovine uterus and examined the levels of CaBP9K and CaBP9K mRNA in the nonpregnant bovine uterus during the estrous cycle. Immunohistochemical studies revealed that CaBP9K was present in all uterine glandular and luminal epithelial cells. In contrast, the closely related calcium binding protein CaBP28K was present in only one to two glandular cells in the samples examined. Neither protein was localized in the myometrium or in the stromal cells of the endometrium. RIA and dot blot hybridization were used to quantify the amount of CaBP9K and CaBP9K mRNA. The levels of both the protein and its mRNA were threefold higher during the luteal phase than during the follicular phase. RIA was also used to determine bovine uterine levels of 17 beta-estradiol and progesterone. Progesterone levels were higher during the luteal phase than during the follicular phase, while 17 beta-estradiol levels were higher during the follicular phase. This investigation represents the first characterization of CaBP9K gene expression in the bovine uterus. It demonstrated that the expression of CaBP9K and CaBP9K mRNA was greatest during the progesterone-dominated luteal phase of the bovine estrous cycle. These results indicated that CaBP9K may be involved in uterine glandular function during the luteal phase.

Animals↗
PubMed1985

Exogenous androgens decrease the length of the luteal phase and increase the length of the follicular phase.

This study investigated the effects of exogenous androgens on the menstrual cycle of eight transsexual females. It was found that the luteal phase decreased from 13.7 +/- 0.8 to 11.6 +/- 0.8 days, whereas the follicular phase increased in length from 13.5 +/- 0.6 to 15.3 +/- 0.6 days. With the testosterone levels attained in venous blood (+/- 4.5 nmol/l) ovulation continued, judged by the rise of basal body temperature and the increase of oestrogen and progesterone blood levels. These results relate hyperandrogenism to luteal insufficiency.

Adult↗
PubMed1982

Early follicular phase luteinizing hormone-releasing hormone agonist administration - effects on follicular maturation and corpus luteum function in women.

The potent luteinizing hormone-releasing hormone (LRH) agonist D-Ser(TBU)6-EA10-LRH was administered in a daily subcutaneous dose of 5 or 25 microgram for 1, 3 or 5 consecutive days to twelve regularly menstruating women in the early follicular phase of the menstrual cycle in an attempt to disturb follicular maturation and induce luteolysis. The treatment was monitored by clinical examinations, basal body temperature recordings, bleeding patterns and frequently taken peripheral venous blood samples for analyses of gonadotropins and ovarian steroids. The luteal phase during the LRH agonist treatment cycles did not differ in length from that of the control cycles before and after the treatment (p greater than 0.05). The maximal progesterone concentration during the luteal phase exceeded 32 nmol/l in all but one of the treatment cycles. The follicular phase of the treatment cycle was prolonged in comparison with that of the control cycles (p less than 0.01). Thus, administration of high doses of a superactive LRH agonist during the early follicular phase of the menstrual cycle prolonged the follicular phase and postponed ovulation but did not interfere with corpus luteum function in normally ovulating women.

Adult↗
PubMed1996

Gonadotrope responsiveness in orchidectomized sheep: effect of duration of a simulated follicular phase.

The effect of duration of a simulated follicular phase on gonadotrope responsiveness was assessed in orchidectomized sheep (wethers). The oestrogenic and hypothalamic inputs characteristic of the ovine follicular phase were simulated by continuous infusion of oestradiol (5 micrograms h-1 in 10% (v/v) ethanol saline) and circhoral delivery of GnRH (200 ng per hourly pulse) for 0, 6, 12, 24, 48 or 96 h (n = 6 wethers per group). Responsiveness increased (P < 0.05) with increasing duration of simulated follicular phase. In a second experiment, responsiveness was assessed 96 h after initiation of infusion of oestradiol in wethers receiving hourly pulses of GnRH or saline. Concurrent administration of GnRH reduced (P < 0.05) the magnitude of the oestradiol-induced increase in gonadotrope responsiveness. In a companion study, anterior pituitary tissue was collected 96 h after the start of infusion of oestradiol and circhoral delivery of GnRH or saline. Pituitary stores of LH and tissue concentrations of GnRH receptor and mRNA encoding the GnRH receptor were increased (P < 0.05) by oestradiol infusion. The magnitude of these oestradiol-induced responses was not affected (P > 0.05) by concurrent GnRH treatment. Tissue concentrations of FSH and mRNA encoding the FSH beta subunit were decreased (P < 0.05) by oestradiol infusion. This suppressive effect of oestradiol was not reversed by GnRH. These results indicate that oestradiol stimulation, but not concurrent delivery of GnRH, is essential for full expression of surge-like secretion of LH. In addition, the oestradiol-induced increase in gonadotrope responsiveness during the simulated follicular phase is sustained throughout the period of oestradiol delivery.

Animals↗
PubMed1986

Effects of sulpiride-induced hyperprolactinemia on human ovarian follicles during the late follicular phase.

The effect of hyperprolactinemia during the midfollicular through the late follicular phase of the menstrual cycle on follicular development and follicular fluid hormone concentrations was studied. Fourteen women underwent laparotomy in the late follicular phase for gynecologic reasons; 6 were treated with sulpiride daily from the midfollicular to the late follicular phase (sulpiride group) and 8 received no treatment (control group). Daily administration of sulpiride (150 mg orally) significantly elevated serum prolactin (PRL) levels in all six women. In the small follicles (less than or equal to 8 mm in diameter), follicular fluid 17 beta-estradiol (E2) concentration was significantly lower (P less than 0.01), and testosterone (T) concentration was higher (P less than 0.05) in the sulpiride group. In the large follicles (greater than or equal to 9 mm in diameter), however, follicular fluid E2 and T concentrations showed no significant differences between the sulpiride and control groups. In the sulpiride group, the mean diameters of the follicles were significantly smaller than in the control group (P less than 0.01). These observations suggest that PRL exerts a suppressive effect on the smaller but not the larger follicles during the late follicular phase.

Adult↗
PubMed1981

Endocrine profiles and fertility status of human menstrual cycles of varying follicular phase length.

Assessment of the relationship between ovarian endocrine function and follicular phase length was made in 48 patients (51 cycles) with spontaneous ovular cycles of varying length. On the basis of follicular phase length when measured from the first day of menstruation to, and including, the day of the luteinizing hormone (LH) peak, cycles were grouped into short (less than 21 days), medium (12 to 16 days), and long (more than 6 days). Daily serum LH, androstenedione, 17 beta-estradiol, progesterone, and 17 alpha-hydroxyprogesterone concentrations were determined in the periovular period. The overall pattern of serum steroid concentrations in medium and long cycles was similar to that previously described for normal women. However, cycles with a short follicular phase had lower mean concentrations of androstenedione and estradiol. In order to assess the fertility potential of cycles with follicular phases of varying length, the prior 265 cycles of 92 consecutive patients who conceived with artificial insemination by donor (AID) were studied. In all cases, insemination occurred on day 0 and day + 1 with respect to the LH peak, and all cycles were assumed to have equal fertility potential. Statistical analysis revealed no significant difference in fertility potential among cycles with follicular phases of differing length.

Adult↗
PubMed1987

Luteal phase dysfunction in endometriosis: elevated progesterone levels in peripheral and ovarian veins during the follicular phase.

Endometriosis has been associated with corpus luteum inadequacy and abnormalities of luteal phase progesterone (P) secretion. In this study, abnormal luteolysis, as a second factor of luteal dysfunction, was assessed in 13 women with endometriosis and 25 control patients by measurement of ovarian vein estradiol (E2) and P during the follicular phase. The results reveal that women with endometriosis have (1) significantly lower ovarian vein E2, (2) significantly higher both peripheral and ovarian vein P, and (3) threefold higher P/E2 ratios than controls during the follicular phase. These data support the concept of continued P production from an active corpus luteum well into the follicular phase of the following cycle in women with endometriosis. Failure of adequate luteolysis is a second aspect of luteal dysfunction in endometriosis and strongly supports the growing body of data confirming ovulatory asynchrony in the minimal; endometriosis infertility syndrome.

Endometriosis↗
PubMed1989

Decreased follicular phase gonadotropin secretion is associated with impaired estradiol and progesterone secretion during the follicular and luteal phases in normally menstruating women.

We tested the hypothesis that disturbed follicular development and disturbed luteal progesterone (P4) secretion are associated with reduced gonadotropin secretion in the early follicular phase by measuring pulsatile LH and FSH secretion at that time in 53 normally menstruating women. Three groups of women were identified on the basis of serum sex steroid concentrations (measured daily throughout the cycle) and luteal phase length. Group A (n = 27) had normal ovarian hormone secretion with peak serum estradiol (E2) concentrations of 440 pmol/L or more, peak serum P4 concentrations of 19 nmol/L or more, and luteal phase length of 9 days or more. Group B (n = 16) had normal peak serum E2 values, but peak serum P4 values less than 19 nmol/L and/or luteal phase length less than 9 days. Group C (n = 10) had peak serum E2 values below 440 pmol/L. Risk factors for the disturbances found in groups B and C were exercise and/or intermittent dieting. Compared to group A, both groups B and C had reduced mean serum LH concentrations (3.1 +/- 1.5 vs. 2.3 +/- 1.4 and 2.0 +/- 1.0 IU/L; P less than 0.05) and reduced LH pulse frequencies (5.2 +/- 2.1 vs. 3.5 +/- 1.8 and 3.3 +/- 2.3 pulses/12 h; P less than 0.02). LH amplitude was similar in all 3 groups. Mean serum FSH concentrations were slightly but not significantly lower in group C. We conclude that reduced gonadotropin secretion during the follicular phase may indeed affect E2 and P4 secretion at later stages of the menstrual cycle. The patterns of alteration associated with disturbed E2 and P4 secretion in normally menstruating women are similar to those that occur in women with hypothalamic amenorrhea.

Adult↗
PubMed1992

The source of pulsatile secretion of progesterone during the human follicular phase.

This study was designed to establish the normal pattern of serum progesterone and the origin of its secretion during the follicular phase of the normal menstrual cycle. In the first study, 12 normal women were studied on 3 occasions each at different times during a single follicular phase. Serum samples were collected every 10 min over 8 h, for 6 h before and 2 h after an injection of naloxone (5 mg iv). The mean serum progesterone remained constant (0.9 nmol/L) across the follicular phase until just before ovulation; individual subjects showed pulsatility of progesterone (1-6 pulses/6 h) but there was no relationship of this to LH pulsatility and no variation of progesterone pulsatility across the follicular phase. Naloxone caused an increase in the mean serum progesterone in the early follicular phase to 1.9 +/- 0.7 nmol/L and in the mid and late follicular phase to 2.1 +/- 0.7 nmol/L and 3.4 +/- 2.5 nmol/L, respectively. The second study was performed to assess the contribution of the residual corpus luteum and the developing follicle to the pulsatile secretion of progesterone. Seven anovulatory women with low levels of serum LH and absent LH pulsatility were studied before and after clomiphene (100 mg/day for 5 days) by collecting blood samples every 15 min for 6 h before GnRH (10 mg iv) and for 2 h afterwards. The anovulatory women had comparable mean serum concentration of progesterone (0.9 +/- 0.5 nmol/L) to normal women and similar frequency of progesterone pulsatility (2.1 +/- 1.1 pulses/6 h). After administration of clomiphene, there was no significant change in progesterone pulsatility (1.7 +/- 1.0 pulses/6 h) despite a substantial increase in LH pulsatility (from none to 3.0 +/- 1.0 pulses/6 h). There was no significant increase in serum progesterone after clomiphene or GnRH which both caused a substantial increase in serum LH. The third study involved eight normal women studied before and after treatment with dexamethasone (2 mg/day for 2 days) to assess the adrenal component of progesterone secretion. Blood samples were collected every 10 min for 6 h before and 2 h after naloxone (5 mg iv). Dexamethasone reduced serum progesterone to below assay sensitivity (less than 0.2 nmol/L) and obliterated progesterone pulsatility. The increase in serum progesterone and cortisol induced by naloxone was blocked by dexamethasone; the naloxone-induced rise of serum LH was not affected by dexamethasone. We conclude that neither the preceding corpus luteum nor the developing follicle are important contributors to the serum concentration of progesterone during the normal follicular phase.(ABSTRACT TRUNCATED AT 400 WORDS)

Activity Cycles↗