Effect of menstrual cycle variation in female sex hormones on cellular immunity and regulation

Ovarian steroid hormones reduce cell-mediated immunity (CMI), perhaps by increasing regulatory T cells. We examined the relationship of estrogen and progesterone plasma concentrations during the menstrual cycle with circulating regulatory T cells (Treg cells) and with varicella-zoster virus (VZV)-specific lymphocyte proliferation (VZV-LPA). Twenty healthy and 20 HIV-infected women were tested at 1-4, 10-14, and 20-24days of the menstrual cycle. HIV-infected women experienced significant increases in the frequency of peripheral blood CD4+IL10+ and CD8+FoxP3+ Treg cells from the early and late follicular phases to the luteal phase of their cycles. Healthy women experienced significant increases only in CD4+IL10+ Treg cells. The increase in CD4+IL10+ Treg cells between the late follicular and the luteal phases of HIV-infected and uninfected women significantly correlated with the corresponding increases in progesterone plasma concentrations. VZV-LPA results decreased from the early and late follicular phases to the luteal phase in both groups. The decrease in VZV-LPA results significantly correlated with the increase in CD4+IL10+ Treg cells underscoring the potential immunosuppressive effect of the progesterone-stimulated Treg cells. In conclusion, the increase in progesterone levels during the menstrual cycle was associated with higher Treg frequencies and lower CMI.     

Association between hormonal and haemorheological changes during the menstrual cycle in healthy women

Summary. Blood rheology was studied in 15 healthy women throughout a normal menstrual cycle. Significant increases in fibrinogen, blood and plasma viscosity, and a reduction of erythrocyte filtrability were demonstrated during the follicular and ovulatory phase in comparison with mid- and late luteal phase of the menstrual cycle. Positive correlations were found between oestradiol levels and the haemorheological variables. Our data suggest that ovarian hormonal activity influences haemorheology and blood flow in healthy women.     

The immune response during the luteal phase of the ovarian cycle: increasing sensitivity of human monocytes to endotoxin

OBJECTIVE: To test the hypothesis that during the luteal phase of the human ovarian cycle, as compared with the follicular phase, the percentage of cytokines producing peripheral monocytes after in vitro stimulation with endotoxin is increased. DESIGN: Prospective study. SETTING: Academic research institution. PATIENT(S): Women with regular menstrual cycles. INTERVENTION(S): Blood samples were collected between days 6 and 9 of the menstrual cycle (follicular phase) and between days 6 and 9 of the menstrual cycle following the LH surge (luteal phase). MAIN OUTCOME MEASURE(S): Percentages of tumor necrosis factor (TNF)-alpha-, interleukin (IL)-1 beta-, and IL-12-producing monocytes as well as total white blood cell (WBC) count, differential WBC counts, and plasma 17 beta-estradiol and progesterone concentrations. RESULT(S): Mean plasma 17 beta-estradiol and progesterone concentrations, percentage of TNF-alpha- and IL-1 beta-producing monocytes, WBC counts, and granulocyte cell count were significantly increased in the luteal phase as compared with the follicular phase of the ovarian cycle. The percentage of IL-12-producing monocytes, monocyte count and lymphocyte count did not vary between the 2 phases of the ovarian cycle. CONCLUSION(S): Together with an increase in progesterone and 17 beta-estradiol during the luteal phase, there is an increase in percentage TNF-alpha- and IL-1 beta-producing peripheral monocytes after in vitro stimulation with endotoxin as compared with the follicular phase of the ovarian cycle. Whether this increased sensitivity of monocytes for proinflammatory stimuli during the luteal phase is due to increased plasma levels of progesterone or 17 beta-estradiol needs further investigation.     

Association between hormonal and haemorheological changes during the menstrual cycle in healthy women

Blood rheology was studied in 15 healthy women throughout a normal menstrual cycle. Significant increases in fibrinogen, blood and plasma viscosity, and a reduction of erythrocyte filtrability were demonstrated during the follicular and ovulatory phase in comparison with mid- and late luteal phase of the menstrual cycle. Positive correlations were found between oestradiol levels and the haemorheological variables. Our data suggest that ovarian hormonal activity influences haemorheology and blood flow in healthy women.     

Erythrocyte concentrations and transmembrane fluxes of sodium and potassium and biochemical measurements during the menstrual cycle in normal women

The erythrocyte concentrations and the transmembrane fluxes of sodium and potassium were investigated in 20 normal women during the two stages of the menstrual cycle. Half of the women were using oral contraceptives and the other half were not. In women with a normal menstrual cycle the erythrocyte sodium concentration and the ouabain-insensitive total potassium efflux were lower in the luteal than in the follicular phase. Intracellular potassium concentration, ouabain-sensitive rubidium 86 uptake and the furosemide-sensitive sodium and potassium efflux did not differ significantly between the two periods of the cycle. No cycle-related variation in sodium or potassium intracellular concentration was observed in women using oral contraceptives. In these women, however, the ouabain-sensitive 86Rb uptake was increased in the second part of the menstrual cycle. In each woman with a normal menstrual cycle the plasma progesterone, renin activity, angiotensin II, plasma aldosterone concentration, and urinary aldosterone excretion increased during the luteal phase. The increment in the plasma renin activity, plasma angiotensin II, and plasma and urinary aldosterone indicate a stimulation of the renin-aldosterone axis in this menstrual period. During the same phase, serum cholesterol was decreased significantly. When the women using oral contraceptives were compared to those not using them, the renin-aldosterone axis was already stimulated during the first part of the cycle; no further stimulation occurred during the second part.     

Prolactin response to secretin during the spontaneous menstrual cycle in women.

The effect of an intravenous infusion of secretin (2.0 CU/kg/h) on serum prolactin (PRL) and estradiol levels and plasma levels of vasoactive intestinal polypeptide and somatostatin (SRIH) was studied in 8 healthy and normally cycling women during the midfollicular phase (cycle day 7), at midcycle (day 14), and during the midluteal phase (day 21) of the menstrual cycle. When compared to basal preinfusion levels, a significant decrease in serum PRL levels was observed at steady state concentrations of plasma secretion (+30 to +60 min) both during the follicular (p less than 0.03) and the luteal (p less than 0.0001) phases. At midcycle a nonsignificant decrease was observed. A significant and negative correlation existed between serum PRL and plasma secretin levels in the follicular phase (r = -0.33; p less than 0.05) and in the luteal phase (r = 0.73; p less than 0.0001). The plasma concentrations of SRIH increased significantly at steady state conditions of secretin at midcycle (p less than 0.02) and in the luteal phase (p less than 0.04), while no effect was found during the follicular phase. A significant and positive correlation between plasma levels of SRIH and secretin was observed at midcycle (r = 0.63; p less than 0.002) and in the luteal phase (r = 0.46; p less than 0.02). No effect of secretin on plasma vasoactive intestinal polypeptide and serum estradiol concentrations was demonstrated. These results suggest that the suppression of PRL in the follicular phase of the spontaneous menstrual cycle can be ascribed to an effect of secretin alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated plasma levels of oxytocin in women taking low-dose oral contraceptives. Identification of the plasma oxytocin with high performance liquid chromatography

The aim of the present study was to investigate whether low-dose oral contraceptives affect oxytocin concentrations in plasma. Twenty women participated in an open cross-over study. Six consecutive blood samples were drawn twice, with a 4-week interval, in the luteal phase of the menstrual cycle when the women were/were not taking oral contraceptives. Plasma levels of oxytocin were analysed with a radio-immunoassay specific for oxytocin. A significant increase in oxytocin concentrations was observed following ingestion of oral contraceptives (p less than 0.02). Women with the highest oxytocin levels during a normal menstrual cycle increased their levels the most when on oral contraceptives. Analysis with high performance liquid chromatography demonstrated that immunoreactive oxytocin found in plasma, whether with or without oral contraceptives, co-eluted with synthetic oxytocin standard. An interesting possibility could be that the mental side effects and effects on glucose metabolism occurring after treatment with oral contraceptives might be related to elevated oxytocin levels, since metabolic and CNS effects of oxytocin are known.     

Physiological changes of Fas expression in peripheral lymphocyte subsets during the menstrual cycle

We have examined changes in peripheral lymphocyte subsets, and Fas expression in these subsets, during the menstrual cycle. Measurements were made by three-color flow cytometry in the follicular and luteal phases of the menstrual cycle in ten healthy women. The numbers of leukocytes, granulocytes and monocytes were significantly higher in the luteal phase than the follicular phase. The percentage of CD8⁺ cells was greater in the luteal phase than the follicular phase. The percentages of Fas⁺ cells among T cells and NK cells were higher in the luteal phase than the follicular phase. These findings suggest that the menstrual cycle affects leukocytes, lymphocyte subsets, and Fas expression in these subsets, and that changes in the luteal phase of the menstrual cycle are similar to those in pregnancy.     

Opioid control of luteinizing hormone secretion in patients with hirsutism and hyperandrogenemia

The present study was designed to evaluate the influence of hyperandrogenemia on the activity of the opioid system regulating LH secretion in menstruating women. Ten subjects presenting with hirsutism and hyperandrogenemia and 9 healthy normally cyclic subjects participated in the study. Naloxone or saline was administered on 2 different days both during the follicular (6-8 days after menstrual bleeding) and during the luteal phase of the menstrual cycle. Naloxone significantly increased plasma LH levels in the luteal, but not during the follicular phase of the cycle in both subject groups. It may be inferred from these observations that opioid-mediated inhibition of LH secretion is not altered in menstruating hyperandrogenic patients, suggesting that the circulating androgens are not an important determinant of the functional neuroendocrine activity of the opioid system.     

The relation between plasma testosterone levels and the lengths of phases of the menstrual cycle.

Plasma testosterone levels were measured in 331 women of reproductive age. The incidence of clinical signs of hyperandrogenism (hirsutism, acne) was recorded. Ovulatory activity was evaluated clinically by basal body temperature and frequent observation of changes in the appearance of the cervical os and cervical mucus. Plasma testosterone levels were abnormally elevated in patients with clinical signs of hyperandrogenism. The highest mean testosterone levels were noted in the group of hyperandrogenic women with amenorrhea. Significant prolongation of the follicular phase and shortening of the luteal phase were demonstrated to be associated with clinical signs of hyperandrogenism and elevated plasma testosterone levels. Statistically significant correlations between plasma testosterone levels and duration of phases of the menstrual cycle were observed. Testosterone levels were directly related to the length of the follicular phase and inversely related to the length of the luteal phase. A significant inverse correlation between the lengths of the two phases of the menstrual cycle was also demonstrated. These results suggest an association between hyperandrogenism and prolongation of the follicular phase and shortening of the luteal phase of the menstrual cycle, possibly related to the high incidence of infertility and menstrual irregularity reported for hyperandrogenic women.     

Increased tumor necrosis factor-alpha in whole blood during the luteal phase of ovulatory cycles

OBJECTIVE: To evaluate whether the fact that blood from premenopausal, ovulatory women shows a significant fluctuation in tumor necrosis factor-alpha (TNF-alpha) levels when tested randomly over time is related to the hormonal cycle. STUDY DESIGN: In this pilot study, whole blood was collected from 8 women during the follicular, ovulatory and midluteal phases of the menstrual cycle. Ovulation was confirmed by luteinizing hormone surge and mid-luteal progesterone levels. For each subject at each phase of the menstrual cycle, TNF-alpha levels were measured at baseline and after stimulation of whole blood with 10 microg/mL of lipopolysaccharide (LPS). Supernatant was collected and assayed by enzyme-linked immunosorbent assay. TNF-alpha levels were compared with the Wilcoxon matched pairs signed rank sum test. RESULTS: Whole blood unstimulated by LPS showed increasing TNF-alpha levels over the hormonal cycle, with significantly increased median levels during the luteal phase (903 pg/mL; range, 0-3707) as compared with the follicular phase (162 pg/mL; range, 0-656) (P = .03). Blood stimulated with LPS showed increased TNF-alpha levels overall but no association with cycle timing. CONCLUSION: TNF-alpha levels in unstimulated whole blood appear to be associated with menstrual cycle timing, with highest levels during the luteal phase. However, the lack of variation in TNF-alpha production after LPS stimulation suggests that experiments do not need to be timed with the menstrual cycle.     

Gonadotropin-releasing hormone-stimulated gonadotropin levels in women with premenstrual dysphoria.

Despite consistent evidence that premenstrual dysphoria (PMD) is not characterized by abnormalities in basal ovarian hormone secretion, the possibility remains that PMD is associated with an abnormality in the regulation of the hypothalamic-pituitary-ovarian (HPO) axis. We studied HPO axis regulation in 11 women with prospectively confirmed PMD and 20 asymptomatic controls, during both the follicular and luteal phases of the menstrual cycle. Plasma levels of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), were obtained before and after stimulation with gonadotropin-releasing hormone (GnRH) (100 microg intravenously). Potential diagnostic- and menstrual cycle phase-related diferences in basal and plasma hormone levels were analyzed by repeated-measures analysis of variance. No significant differences were observed between women with PMD and controls in either basal or stimulated levels of FSH and LH. Stimulated FSH was significantly increased and stimulated LH was significantly decreased during the follicular compared with the luteal phase in both women with PMD and controls. These data are consistent with prior findings of normal basal reproductive hormone levels in women with PMD. Our data suggest the absence in women with PMD of an abnormality of dynamic ovarian function as measured by GnRH stimulation.     

Effect of prednisone on plasma testosterone levels and on duration of phases of the menstrual cycle in hyperandrogenic women.

A group of 106 women of reproductive age with laboratory and clinical evidence of hyperandrogenism was treated with prednisone. The daily dosage varied between 7.5 and 10 mg. Ovulatory activity was assessed prior to and during therapy by basal body temperature and observation of changes in the cervical os and cervical mucus. Plasma testosterone levels were significantly suppressed by prednisone therapy. This was associated with initiation of ovulatory activity in 5 of 14 (35.7%) amenorrheic patients and 10 of 11 (90.9%) anovulatory patients. In 81 ovulatory patients, prednisone therapy resulted in statistically significant shortening of the follicular phase and lengthening of the luteal phase of the menstrual cycle. The mean length of the menstrual cycle was unchanged. Significant correlations between percentage suppression of plasma testosterone and shortening of the follicular phase or lengthening of the luteal phase were observed. Suppression of plasma testosterone by prednisone was maximal after 2 months of treatment, while the effect on the phases of the menstrual cycle was progressive with duration of treatment. The effects of prednisone at daily dosages of 7.5 or 10 mg were not significantly different. These results suggest that prednisone therapy in hyperandrogenic women exerts an effect on both phases of the menstrual cycle, possibly related to suppression of plasma testosterone levels.     

Influence of menstrual cycle on NK activity

Natural killer (NK) cells are CD3⁻ CD56⁺ and/or CD16⁺ cytotoxic lymphocytes that mediate first-line defense against various types of target cells without prior immunization. To assess the effect of the menstrual cycle and gender on NK activity we evaluated 30 healthy women (mean age 28.1 years, range 21–39) in follicular and luteal phases, 29 postmenopausal women (mean age 58.8 years, range 42–72) and 48 healthy men (mean age 31.6 years, range 21–40). In a flow cytometric test of NK activity, peripheral blood mononuclear effector cells were mixed with K562 targets cells labeled with DiO (3,3′-dioctadecyloxacarbocyanine perchlorate) at effector:target cell ratios of 40, 20, 10 and 5:1. Dead cells were stained with propidium iodide and results were expressed as lytic units per 10⁷ cells. In addition, progesterone levels were determined in the luteal phase of the menstrual cycle of healthy women by a chemiluminescence assay. Our results showed that (1) NK cytotoxicity was higher in the follicular than in the luteal phase of the menstrual cycle (P<0.0001); (2) postmenopausal women and men showed NK activity similar to women in the folicular phase but higher than women in the luteal phase of the menstrual cycle (P<0.05); and (3) there was no correlation between NK activity and levels of progesterone. The data suggest that progesterone does not influence NK activity directly and that other factors may explain the reduction of NK activity in the luteal phase of the menstrual cycle.     

Bleeding after loop electrosurgical excision procedure performed in either the follicular or luteal phase of the menstrual cycle: a randomized trial

OBJECTIVE: To estimate the perioperative or postoperative bleeding rates after treatment of cervical intraepithelial neoplasia by loop electrosurgical excision procedure in either the follicular or luteal phase of the menstrual cycle. METHODS: A randomized controlled trial was carried out to compare the outcomes in terms of primary and secondary hemorrhage between patients treated by loop electrosurgical excision procedure during either the follicular (30 women) or luteal phase (30 women) of the menstrual cycle. The two groups did not differ in terms of mean age, grade of cervical intraepithelial neoplasia, depth of excision, parity, and duration of menses. Primary outcome measures included the objective and subjective assessment of intraoperative and postoperative bleeding. RESULTS: Women treated during the luteal phase of the menstrual cycle experienced significantly more postoperative bleeding than women treated during the follicular phase, as assessed by the fall in hematocrit levels (P <.001) and subjective reports. Intraoperative bleeding was judged to be more severe in women treated during the luteal phase of the cycle by a single, blinded colposcopist (P =.02). These women also experienced higher levels of anxiety postoperatively, which resulted in more consultations with medical staff (P =.007). CONCLUSION: The use of loop electrosurgical excision procedure to treat cervical intraepithelial neoplasia results in less bleeding if performed during the follicular phase of the menstrual cycle.     

Dieting influences the menstrual cycle: vegetarian versus nonvegetarian diet

Eighteen healthy, normal-weight women aged 19 to 27 years who had regular ovulatory menstrual cycles volunteered for the study. Blood was drawn on Mondays, Wednesdays, and Fridays throughout the control cycle and during a 6-week diet period that began with commencement of a new cycle. Nine women followed a vegetarian diet and nine a nonvegetarian diet. Both groups lost an average of 1 kg body weight/week. Seven of nine women in the vegetarian group became anovulatory. During the vegetarian diet the average luteinizing hormone (LH) values were significantly decreased during the midcycle and the luteal phase. Estradiol (E2) and progesterone (P) values were significantly lower during the luteal phase. In contrast, the nonvegetarian group did not show significant reduction of LH, E2, and P values during any part of the menstrual cycle. Seven of nine women in the nonvegetarian diet group maintained ovulatory cycles with no changes in cycle length or in the length of the follicular phase. In one woman who became anovulatory, E2 values did not increase during the follicular phase.     

Effect of bromocriptine on menstrual cycle length

Forty-seven women with regular ovulatory menstrual cycles and normal plasma prolactin levels were treated with different doses of bromocriptine, and changes in follicular and luteal phase length determined by daily estimation of plasma gonadotrophin concentration. Follicular phase length was highly significantly reduced from a median duration of 12.7 days in the basal cycle to 11.7 days in the first treatment cycle, and to 10.7 days during the second treatment cycles. The length of the luteal phase was unaltered by treatment with bromocriptine. Reduction of follicular phase length was not influenced by the dose of bromocriptine used, and it is concluded that this effect is a consequence of the reduction of plasma prolactin concentration.     

The effects of superovulatory doses of clomiphene citrate on spontaneous luteinizing hormone peaks in regularly ovulating women

The effects of superovulatory doses of clomiphene citrate (150 mg orally every day for 5 days) on normal spontaneous menstrual cycles were studied in 16 women. Eight-eight percent of treatment cycles had clearly defined, timely luteinizing hormone (LH) peaks indistinguishable from those observed in normal cycles. Eight percent of treatment cycles did not have clearly defined LH peaks but were ovulatory. One cycle (4%) was anovulatory. Treated cycles were 2.1 days longer than previous control cycles (p less than 0.005). The follicular phase was significantly longer than control cycles (p less than 0.025) whereas the luteal phase was not (p greater than 0.05). There was a direct positive correlation between previous menstrual cycle length and follicular phase length in the treated cycle (r = 0.730, 0.01 less than p less than 0.05). The conclusion was that 96% of menstrual cycles of normally ovulating women remained ovulatory when the women were given superovulatory doses of clomiphene and that 88% of the cycles had clearly defined LH peaks.     

Uterine tissue development in healthy women during the normal menstrual cycle and investigations with magnetic resonance imaging

OBJECTIVE: High-resolution magnetic resonance imaging (MRI) was used to monitor both uterine endometrial and junctional zone morphometry during the normal menstrual cycle. STUDY DESIGN: Twenty-four healthy, ovulating women were studied during a single menstrual cycle. Three scans were performed to prospectively coincide with the follicular, periovulatory, and luteal phases of the cycle. RESULTS: MRI data showed a significant increase in endometrial and junctional zone volume, between the follicular and periovulatory phases, with a significant decrease in endometrial volume observed from the periovulatory to luteal phases. The regularity index, which is a novel subjective assessment of junctional zone structure, varied significantly and demonstrated a less regular junctional zone in the luteal phase. CONCLUSION: This study has quantified the normal developmental changes of uterine tissue during the menstrual cycle with MRI. Junctional zone data from MRI may play a major role in future studies that investigate menstrual disorders, subfertility, and pathologic changes.     

Menstrual cyclicity of CA-125 in patients with endometriosis.

OBJECTIVE: To examine the serum levels of CA-125 in the menstrual, follicular, and luteal phases of the menstrual cycle in women with endometriosis and to determine if serum CA-125 levels drawn during menses improve the clinical utility of the test in diagnosing endometriosis. DESIGN: Serum CA-125 was measured in the menstrual, follicular, and luteal phases of the cycle preceding surgery. CA-125 levels for each phase were categorized by postoperative diagnosis and endometriosis stage. SETTING: The reproductive endocrine unit of a tertiary care university-affiliated hospital. PATIENTS: A total of 65 patients were recruited from the Fertility and Endocrine Unit and the Gynecology Service of Brigham and Women's Hospital. MAIN OUTCOME MEASURE: Serum CA-125 levels were measured by an immunoradiometric assay and were stratified by menstrual cycle phase, diagnosis, and stage of endometriosis. The menstrual cycle phase was confirmed by serum estradiol and progesterone measurements. RESULTS: Serum CA-125 levels in patients with stages II to IV endometriosis were significantly elevated in the menstrual phase compared with levels drawn in the nonmenstrual follicular and luteal phases. The sensitivity and specificity of CA-125 for the diagnosis of endometriosis were not significantly better in the menstrual than in the follicular or luteal phases. CONCLUSIONS: Despite menstrual cyclicity of CA-125, measurement of serum CA-125 during menses does not improve the clinical utility of the test in the diagnosis of endometriosis.