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.     

Ovulation defects despite regular menses: Part III

OBJECTIVE: To describe subtle ovulatory defects that can contribute to infertility and/or miscarriage despite regular menses with apparent ovulation. METHODS: By using follicular maturation studies and measurement of serum estradiol, progesterone, and LH certain imperfections in the ovulatory process can be ascertained. RESULTS: Careful evaluation of follicular maturation was able to determine infertility factors, e.g., premature luteinization, luteinized unruptured follicle syndrome, and luteal phase defects. Effective treatment agents include follicular maturing drugs and gonadotropin releasing hormone antagonists in the follicular phase, human chorionic gonadotropins and leuprolide acetate at time of peak follicular maturation and progesterone in the luteal phase. CONCLUSIONS: Progesterone supplementation alone is more effective than follicle maturing drugs in women with luteal phase defects with mature follicles. Small doses of follicle stimulating hormone in the late follicular phase is most effective for luteal phase deficiency associated with immature follicles. Sometimes leuprolide acetate can allow egg release when hCG has failed.     

Plasma concentrations of 11-deoxycorticosterone in women during the menstrual cycle

As plasma 11-deoxycorticosterone (DOC) can arise from adrenal secretion and from 21-hydroxylation of plasma progesterone in extraadrenal tissues, alterations in plasma progesterone concentrations might alter significantly the plasma DOC levels in humans. Therefore, the authors measured DOC in plasma of 6 normal, ovulatory women daily throughout their menstrual cycles and in plasma of normal men. The plasma DOC concentrations in women during the follicular phase, when plasma progesterone levels are low, were also low (42 +/- 1.7 pg/ml, mean +/- SE). An increase in the plasma levels of DOC and progesterone occurred at midcycle. The plasma DOC levels remained elevated (P less than .001, as compared with levels during the follicular phase) throughout most of the luteal phase (119 +/- 7.9 pg/ml), declining prior to the onset of menses. However, the plasma levels of cortisol and dehydroepiandrosterone sulfate did not fluctuate during the cycle. The plasma DOC levels in men were 57 +/- 4.3 pg/ml (N = 10). The authors conclude that, during the ovarian cycle of women, significant changes in the plasma levels of DOC occur that are coupled to fluctuations in plasma progesterone concentrations.     

The corpus luteum: determinants of progesterone secretion in the normal menstrual cycle

Fourteen normal volunteers were studied during one menstrual cycle. Follicular development, the luteinizing hormone (LH) surge, and the relationship between LH and progesterone secretion in the luteal phase were studied to determine the factors that control corpus luteum function. Follicular development was assessed by measuring follicle size and daily estradiol (E2) levels; the LH surge was quantified by determining the area under the curve. Although there was a significant positive correlation between mean follicle diameter and E2, these same parameters did not correlate with postovulatory progesterone secretion; nor did the LH surge correlate with progesterone secretion. A decrease in LH pulse frequency occurred in moving from the follicular to the luteal phase. There was a trend toward an increase in the late luteal LH pulse frequency compared with the midluteal phase, but this was not significant. Progesterone was secreted in an intermittent (pulsatile) fashion in the midluteal and late luteal phases. The general decrease in progesterone in the latter days of the menstrual cycle appears to be due to a decrease in the progesterone pulse amplitude. A significant correlation between LH and progesterone was present when the data were "smoothed"; however, there was not a significant synchrony for LH and progesterone pulses for most of the subjects when the initial data were analyzed by objective criteria. Progesterone secretion in the luteal phase is quite complex and leads to highly variable serum levels of progesterone when samples are obtained at random from normal women.     

Effect of clomiphene citrate administration during the early luteal phase on the luteal function and pregnancy rate of women

To study the effect of clomiphene citrate (clomiphene) administration during the early luteal phase of the menstrual cycle on the luteal function and the pregnancy rate in women, 75 infertile women who ovulated but did not conceive after clomiphene treatment during the early follicular phase and 6 normal cycling women were chosen. Clomiphene was administered orally to 35 of the 75 infertile women at a dose of 50 mg per day for 5 days from the second day of the rise in the basal body temperature (BBT) as well as during the follicular phase, while 40 control patients received clomiphene only during the follicular phase. In the test patients, the rate of pregnancy (25.7%) was significantly (p less than 0.05) higher than that of control patients (10.0%). On the 7th of the rise of BBT, the mean serum progesterone levels of the test patients and normal cycling women treated with clomiphene were significantly (p less than 0.05) higher than those of the control patients. However, the levels of serum estradiol, LH and FSH, the gonadotropin pulsatilities, and the pituitary responses to LH-RH in the test women were not significantly different from those of the control. These data suggest that, when administered during the early luteal phase, clomiphene may act directly on the ovary, enhancing the secretion of progesterone from the corpus luteum, and thereby increasing the rate of pregnancy in infertile women with clomiphene-induced ovulation.     

The induction of premature luteolysis in normal women--follicular phase luteinizing hormone secretion and corpus luteum function in the subsequent cycle

Women with luteal phase deficiency have been shown to have an increased frequency of luteinizing hormone pulses in the early follicular phase of the menstrual cycle. Because progesterone is known to modulate luteinizing hormone secretion, it has been hypothesized that the decreased progesterone secretion in a previous luteal phase deficiency cycle could lead to the abnormal luteinizing hormone secretory pattern in the ensuing early follicular phase. With the possibility that the higher luteinizing hormone pulse frequency might lead to another deficient luteal phase, it becomes conceivable that luteal phase deficiency could be self-perpetuating. To test this hypothesis, luteal phase deficiency was induced in six normal women by decreasing luteinizing hormone support of the corpus luteum with a gonadotropin-releasing hormone antagonist Nal-Glu, administered twice daily beginning in the midluteal phase after a control cycle. During the antagonist-treated luteal phase, each subject met the predetermined criteria for induced luteal phase deficiency: a 33% or greater decrease in integrated progesterone from the control cycle and an integrated progesterone level less than 100 ng/ml per day. Luteinizing hormone secretion patterns were determined by frequent blood sampling performed every 10 minutes for 12 hours in the early follicular phase of the control cycle and the cycle after antagonist administration. Daily luteal progesterone levels were measured in the control, treatment, and posttreatment cycles. Each volunteer served as her own control. Standard parameters were compared between the control and posttreatment pulse studies in the early follicular phase: (1) luteinizing hormone pulse frequency was 9.5 +/- 1.0 vs 10.0 +/- 0.9 pulses/12 hours, control vs posttreatment, respectively, p = 0.5; (2) luteinizing hormone pulse amplitude was 11.0 +/- 1.3 vs 12.0 +/- 2.2 ng/ml, p = 0.6; and (3) luteinizing hormone mean level was 19.4 +/- 2.3 vs 22.2 +/- 3.3 ng/ml, p = 0.1. Corpus luteum function was also compared between the control and posttreatment cycles. Luteal phase length was 13.7 +/- 0.6 vs 12.7 +/- 0.6 days, p = 0.08. Integrated progesterone values were 136.9 +/- 12.9 vs 130.5 +/- 11.3 ng/ml per day, p = 0.5. Therefore no discernible abnormalities in early follicular luteinizing hormone secretions or corpus luteum secretion of progesterone occurred after an induced luteal phase deficiency cycle.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pituitary and ovarian response to luteinizing hormone releasing factor in normal and sulpiride-induced hyperprolactinemic women

Five Japanese women with regular menstrual cycles (control group) and 5 sulpiride-induced hyperprolactinemic women (sulpiride group) were given a 100-microgram synthetic luteinizing hormone releasing factor (LRF) intravenously, on the 20th day of the menstrual cycle and on the 10th day of the next cycle. The mean responses of luteinizing hormone and follicle-stimulating hormone to LRF in the sulpiride group were higher than those in the controls. Despite enhancement of the gonadotropin levels, the mean response of estradiol was suppressed significantly in the sulpiride group in the luteal and follicular phase of the menstrual cycle. However, the mean response of progesterone was not statistically different, in either group, in the luteal phase. The results suggest that sulpiride-induced hyperprolactinemia exerts an inhibitory effect on steroidogenic activity in estradiol but not in progesterone in the ovary.     

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.     

Differences in hormonal patterns during the first postabortion menstrual cycle after two techniques of termination of pregnancy

Fifteen patients underwent first-trimester abortion by one of two techniques. In group P, seven patients received prostaglandin vaginal suppositories during the 12 hours prior to vacuum aspiration, whereas eight patients in group V were aborted by aspiration alone. During the first postabortion menstrual cycle, daily peripheral blood levels of several hormones, including follicle-stimulating hormone (FSH), luteinizing hormone, human chorionic gonadotropin, estradiol, and progesterone, were determined. Patients in group P demonstrated a more rapid fall in progesterone levels following pregnancy termination (P less than 0.01). They also experienced a more physiologic first postabortion cycle as evidenced by a larger preovulatory estradiol peak (P less than 0.05) and a more normal luteal phase as judged by both the duration and elevation of progesterone levels. Certain endocrine changes common to both groups but different from those of normally menstruating women were also observed. These consisted of short-term spurts of progesterone secretion in many patients (10 of 15) prior to ovulation and exaggerated levels of FSH during the early follicular phase.     

Inhibition of the primate ovarian cycle by a porcine follicular fluid protein(s)

Monkeys received twice daily intramuscular injections of 3 mg of purified porcine follicular fluid protein(s) for the first 14.5 days of the menstrual cycle. Two of five treated monkeys had anovulatory menstrual cycles. Three monkeys had cycles characterized by long follicular phases, low follicular and luteal phase serum estradiol concentrations, and subnormal luteal progesterone production. Serum gonadotropin concentrations were not affected by the follicular fluid protein(s). The data demonstrate in the nonhuman primate that porcine follicular fluid contains a protein(s) that acts at the ovarian level to inhibit gonadotropin action.     

Abnormal patterns of pulsatile luteinizing hormone in women with luteal phase deficiency

Luteal phase deficiency is usually a problem of inadequate progesterone production associated with inadequate ovarian follicular development. The hypothesis that luteal phase deficiency results from an abnormal secretion pattern of luteinizing hormone (LH) was tested in these women. To this end, the early follicular LH secretion pattern in four women with luteal phase deficiency was characterized and compared with patterns in normal women. Blood samples were obtained through indwelling catheters every ten minutes for eight hours (10 AM to 6 PM), and plasma levels of LH and FSH were measured. Luteinizing hormone and FSH secretion profiles were analyzed for pulse frequency, amplitude, and mean plasma level. A significantly greater LH pulse frequency in women with luteal phase deficiency was observed when compared with the frequency in normal controls (luteal phase deficiency, 10.5 pulses/eight hours; normal, 5.2 pulses/eight hours; P less than or equal to .05). The mean FSH concentration was less in the women with luteal phase deficiency, but the level was not significant. These data suggest that the abnormal LH secretion pattern observed in women with luteal phase deficiency is responsible for their inadequate luteal phase progesterone secretion and their infertility.     

Pharmacological options in resistent ovary syndrome and premature ovarian failure

PURPOSE: To present methods of treating women in apparent ovarian failure to allow them to ovulate and conceive. METHODS: Ethinyl estradiol was used to lower elevated serum follicle stimulating hormone (FSH) levels to restore down-regulated FSH receptors on the follicle. Ovulation and pregnancy rates were then determined. Aggressive progesterone (P) therapy in the luteal phase was also used. Lowering elevated serum FSH with gonadotropin releasing hormone agonists was also successful in inducing ovulation in these patients. RESULTS: Several anecdotal studies have demonstrated that ethinyl estradiol therapy can induce ovulation in women in apparent menopause and achieve live births. CONCLUSIONS: The advantage of ethinyl estradiol over other estrogens to induce ovulation in hypergonadotropic women is that it does not cross-react in the assay for serum estradiol and can allow detection of estradiol secretion by the follicle. Thus estrogen therapy is by far the most effective treatment.     

Effects of tamoxifen on corpus luteum function and luteal phase length in cynomolgus monkeys

Previous data in nonhuman primates have demonstrated that tamoxifen prolongs the luteal phase without altering reproductive hormone levels. A small study in humans found no effect on menstrual cycle length, but an increase in luteal ovarian steroid levels. In view of these conflicting results, we studied the effect of tamoxifen on corpus luteum (CL) function in monkeys (n = 20). Blood was obtained daily beginning cycle day 8, and sera assayed for estradiol (E2), progesterone (P), luteinizing hormone, and follicle-stimulating hormone. Four days after the midcycle E2 peak, laparoscopy confirmed CL formation, and the animals were administered (1) lactose (n = 7), (2) tamoxifen, 0.5 mg.kg-1.d-1 (n = 6), or (3) tamoxifen, 3.0 mg.kg-1.d-1 (n = 7) for 12 consecutive days. Serum collection continued until cycle day 50 or menses, whichever came first. Results indicate a biphasic response among tamoxifen-treated animals, with 7 of 13 developing prolonged luteal phases. There was, however, no significant difference in luteal phase length among the three groups, although when the two groups given tamoxifen were combined, the difference in luteal phase length versus controls approached significance. No differences were found among peak P levels, mean luteal phase P levels, or mean luteal phase gonadotropin levels. No variables were found to correlate significantly with luteal phase length. These results suggest that luteal phase administration of the antiestrogen tamoxifen does not alter pituitary gonadotropin secretion or CL function. However, tamoxifen does prolong luteal phase length in a subset of monkeys, perhaps via a direct effect on the endometrium.     

Follicular growth in relation to serum hormonal patterns in adolescent compared with adult menstrual cycles

The purpose of this study was to clarify the endocrine regulation of the adolescent menstrual cycle, especially the relationships between ovarian follicular development, luteal phase progesterone secretion, and function of the hypothalamic-pituitary unit. One menstrual cycle of each of 17 women who were 15 and 16 years of age and 12 women who were 25 to 35 years of age was characterized by ultrasonography and hormone measurements. In both groups there was a close correlation between follicle size and serum estradiol concentrations. In the adolescents, follicle development was slower, and an eventual ovulation took place from a smaller follicle than in the older group. The immediate preovulatory follicle size correlated with the maximal serum progesterone concentration during the luteal phase. Late follicular development in adolescents may be related to the slow increase of serum follicle-stimulating hormone concentrations early in the cycle.     

The effect of thyrotropin-releasing hormone stimulation on serum levels of gonadotropins in women during the follicular and luteal phases of the menstrual cycle

Thyrotropin-releasing hormone (TRH) can stimulate the secretion of adenohypophyseal thyroid-stimulating hormone and prolactin (PRL). The effect of TRH on gonadotropin secretion has not been well defined. This study investigated the effect of TRH administration on the peripheral levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during the early follicular and midluteal phases of the menstrual cycle in five ovulatory, euthyroid, and normoprolactinemic women. Two hundred micrograms of TRH were administered intravenously on days 3 to 5 and on days 21 to 23 of the same cycle. LH and FSH were measured prior to and every 30 minutes for 2 hours following TRH injection. Ovulation was confirmed in all cycles by midluteal progesterone. All women had normal thyroid-stimulating hormone (TSH) and PRL responses to TRH stimulation in both cycle phases. Baseline and stimulated gonadotropin levels were analyzed by analysis of variance. Thirty minutes following TRH infusion, follicular and luteal levels of LH (mIU/ml, mean +/- standard error of the mean) significantly increased from 6.0 +/- 0.8 to 8.0 +/- 1.1 (P less than 0.005), and from 4.8 +/- 0.6 to 7.6 +/- 0.7 (P less than 0.005), respectively. Levels of FSH increased during both phases of the cycle, but the elevation was not statistically significant. These results suggest that TRH can stimulate gonadotrope secretion of LH, but not of FSH, in both the follicular and luteal phases of the cycle.     

Serum immunoreactive beta-endorphin in the human ovulatory cycle

Daily serum immunoreactive beta-endorphin (IR-beta-EP) levels, in conjunction with luteinizing hormone, follicle-stimulating hormone, 17 beta-oestradiol, progesterone, and prolactin, were measured during the ovulatory cycle in five healthy Chinese women. Standardization of raw data by conversion to the statistical "Z scores" and composite plot of the five cycles showed that serum IR-beta-EP levels fluctuated during the follicular, late luteal, and menstrual phases. A preovulatory rise occurred two to three days prior to the luteinizing hormone surge, followed by a postovulatory dip for two to three days. The concentrations of IR-beta-EP were (mean +/- S.E.M.): 85.5 +/- 10.5 pg/mL (n = 36) in the follicular phase; 92.4 +/- 36.5 pg/mL (n = 5) in the ovulatory phase; 72.3 +/- 16.6 pg/mL (n = 7) in the early luteal phase; 100.0 +/- 10.7 pg/mL (n = 38) in the late luteal phase. The values in the luteal phase were the highest of any in the ovulatory cycle. The findings suggest that the fluctuation of endogenous beta-EP is under the influence of, among other factors, ovarian sex steroids. The significance of beta-EP in the regulation of gonadotropin release during normal menstrual cycles is discussed.     

Lower esophageal sphincter pressure during the normal menstrual cycle.

Lower esophageal sphincter pressure (LESP), basal gastric pH, and plasma levels of gastrin, estradiol, and progesterone were determined in ten women known to have normal menstrual cycles. All determinations were performed both during the follicular phase (Days 2 to 8) and during the luteal phase (Days 20 to 30). In addition, an intraluminal pH probe placed 5 cm. above the lower esophageal sphincter was used to test for the presence of acid reflux in response to three provocative procedures. LESP during the follicular phase was 19.0 +/- 1.5 mm. Hg (mean +/- S.E.M.) and during the luteal phase 16.5 +/- 1.3 mm. Hg (p less than 0.01). Basal gastric pH and plasma gastrin levels were similar at both times. Plasma estradiol in the follicular phase (76.1 +/- 7.0 pg. per milliliter) increased twofold during the luteal phase (159.0 +/- 6.0) (p less than 0.01). Plasma progesterone increased from a level of 1.5 +/- 0.8 ng. per milliliter during the follicular phase to 19.2 +/- 4.2 during the luteal phase. Coincident with these changes in LESP and increases in steroid levels, acid reflux was detected in five women during the luteal phase but was present in only one during the follicular phase.     

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.     

Effect of postovulatory treatment with a luteinizing hormone-releasing hormone analog on the plasma level of progesterone in women.

(des-Gly-NH2(10),Pro-ethylamide9) luteinizing hormone-releasing hormone (LH-RH) (100 microgram) was administered subcutaneously once daily for 5 days during the postovulatory period in six women with regular menstrual cycles. Plasma levels of luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone were measured daily by radioimmunoassay from the ovulatory stage to menses. Suppression of plasma progesterone occurred during the treated luteal phase as compared with that of the control luteal phase. This finding suggests that repetitive, massive, endogenous luteinizing hormone or massive, exogenous, LH-RH itself during the early luteal phase of the cycle may induce functional luteolysis.     

Midcycle administration of single-dose GnRHa for luteal phase failure in women with ovarian hyperstimulation. A report of five cases

BACKGROUND: Exogenous administration of gonadotropin-releasing hormone agonist (GnRHa) induces an endogenous midcycle gonadotropin surge. However, its use to induce ovulation and maintain luteal function in non-in vitro fertilization patients who receive ovarian stimulation is unknown. CASES: Five infertile women who underwent controlled ovarian hyperstimulation with human menotropin developed multiple ovarian follicles. In an attempt to circumvent the potential ovarian hyperstimulation syndrome, 1 mg of leuprolide acetate was administered subcutaneously to three patients in an attempt to induce the endogenous luteinizing hormone surge. All three patients began menstruation six to seven days after GnRHa administration with serum progesterone levels between 0.2 and 0.5 ng/mL. Similar ovarian stimulation cycles with ovulation induced by human chorionic gonadotropin in these individuals revealed a normal luteal phase length and midluteal progesterone levels. When double doses of leuprolide acetate were used on two patients, normal luteal length and midluteal serum progesterone levels occurred. CONCLUSION: A single bolus of GnRHa during the late follicular phase may be inadequate to initiate normal luteal function in cycles with ovarian hyperstimulation.