Mid-luteal Progesterone Research Articles

Hormonal and ultrasound characteristics of menstrual function during chronic hemodialysis and after successful renal transplantation

The cycles of 11 renal transplant recipients (RTR), at least 24 months after stabilization of graft function and four hemodialyzed (HD) patients, menstruating regularly, were evaluated by concurrent and systematic determinations throughout the cycle of LH, FSH, estradiol, progesterone, testosterone, prolactin and SHBG and in the case of RTR also by ultrasound follow-up. Biphasic estradiol secretion, midcycle LH and FSH surge, duration of luteal phase, midluteal progesterone values and in the case of RTR, ultrasonic parameters were consistent with: (1) normal ovulatory cycles in five RTR; (2) ovulatory cycles with luteal phase deficiency in five RTR and two HD patients; (3) anovulatory cycles in one RTR and two HD patients. Thus, in HD patients only abnormal cycles of central etiology were found, while in RTR, luteal phase deficiency was a very common syndrome, in equal percentage with normal ovulatory cycles.

Assessment of luteal function after surgical tubal sterilization

To evaluate ovarian luteal function after tubal occlusion, a group of women who underwent Pomeroy sterilization were studied. A prospective group I (n = 16) were followed for one year and scheduled for blood sampling every other day during their luteal phase before surgical procedure and at 3 and 12 months thereafter. Group II (n = 15) included women who were studied during their luteal phase at 1 or 5 years post-surgery. Mid-luteal progesterone and estradiol serum levels were calculated by estimating the average of at least 3 values of serum samples obtained in days 20-25 of a menstrual cycle. The data suggest that no major changes occur in ovarian function after surgical tubal occlusion, as assessed by the mid-luteal hormone serum levels, and underscore the safety of this procedure.

Rationelle hormonale Diagnostik der normozyklischen funktionellen Sterilität*

Functional infertility in women with a normal menstrual cycle is the first symptom of a pathophysiological sequence of multiple different endocrinopathies. It usually progresses and leads to secondary amenorrhoea which is the most severe symptom of ovarian insufficiency. The percentage of abnormal hormonal parameters will increase with the duration and extent of the endocrinological aberration. The aim of this study is to examine the frequency of the different potential changes in hormone levels of an unselected group of female patients in a fertility clinic. 307 patients suffering from functional sterility (menstrual cycle 25-34 days) were investigated via basal hormone laboratory tests (including TRH test) under standardised conditions. 73 patients had pathological changes of the Fallopian tubes and in 116 patients their husbands had severe andrological problems. Excluded from this study were patients with bilateral occlusion of the Fallopian tubes and patients whose partners had a sperm count of less than 1 million/ml. The percentage of abnormal hormone levels (greater than mean + standard deviation + grey area) was 32.2% for prolactin (PRL), 7.8% for TSH, 20.9% for Delta-TSH, 18.4% for DHEA-sulfate (DS), 9.8% for testosterone (T), 18.9% for LH, and 11.5% for FSH (LH and FSH were specifically calculated only in 87 patients). In 65.5% of the patients the midluteal oestradiol (E2) and progesterone (P) levels were below normal, as sign of a corpus luteum insufficiency (CLI). A step- by-step diagnostic procedure would have yielded the following cumulative abnormal hormone levels retrospectively: (1) PRL (n = 99) = 32.2% (2) +TSH/delta TSH (n = 85) = 48.9% (3) +DS (n = 56) = 58.0% (4) +T (n = 30) = 59.3% (5) +LH/FSH (n = 28) = 62.2% [(6) +E2/P (n = 201) = 82.7%.] Only in 37.8% (116 patients) all hormone levels were within normal limits during the early follicular phase (FP); if the patients with signs of CLI are added, the percentage would be only 17.8% (n = 53). Case analysis demonstrated that functional sterility was accompanied by hyperprolactaemia in 32.4% of all patients, by abnormalities of the thyroid function (hypothyroidism 16.0%, hyperthyroidism 7.8%) in 23.8%, by hypothalamic and/or pituitary dysfunction in 28.7%, and by hyperandrogenaemia in 22.5%. Primary ovarian insufficiency was diagnosed in 4.6%. 31.3% of all patients (n = 307) had a combination of different hormonal abnormalities. The average duration of infertility among this group of patients was 6.3 years.(ABSTRACT TRUNCATED AT 400 WORDS)

Characteristics of ovarian follicular development in Norplant users

Daily transvaginal ultrasound (US) scanning of the ovaries to assess follicular development and daily blood sampling were performed on 19 Norplant (Leiras, Turku, Finland) subdermal contraceptive implant users who had regular menstrual cycles and on 10 normally cycling women. Three groups were identified in the implant users based on US finding. Six (31.6%) of the implant users had US findings that were consistent with a normal ovulatory pattern. However, their mean peak luteinizing hormone levels and peak midluteal phase progesterone (P) levels were significantly lower than control values. Eleven (57.9%) users had persistent follicles, and 2 users (10.5%) had no follicular development. These data suggest that after 2 to 4 years of use, about one third of Norplant users with regular bleeding patterns may ovulate but most have deficient luteal P levels. In this small study, the presence of persistent follicular enlargement in implant users was common.

Value of endometrial biopsies and serum hormone determinations in women with infertility

Premenstrual endometrial biopsies were performed in 324 infertile women. Their hormonal status was established in the early follicular phase of the same cycle (FSH, LH, oestradiol-17 beta, testosterone, DHEAS, TSH and prolactin, the latter two both basally and following TRH stimulation). In the luteal phase, oestradiol-17 beta and progesterone concentrations were determined three times between the fifth and tenth hyperthermic days, as was prolactin, both basally and following metoclopramide stimulation. All pregnancies occurring before January 1986 were recorded. Seventy-five per cent of the biopsies were evaluated on the expected ovulation date from the basal temperature charts, 77% according to the next onset of menstruation. Twenty-six per cent of the biopsies were out of phase, and 7% displayed abortive secretion. A significant correlation existed between endometrial profiles and the characteristics of the cycle, stimulated TSH and prolactin levels, and with testosterone and FSH concentrations. No correlation of the endometrial status with midluteal oestradiol or progesterone concentrations was found. While various hormones of both the follicular and luteal phases correlated significantly with the pregnancy rate, the same was not demonstrated for the state of endometrial biopsy. Therefore, following exclusion of organic explanations of infertility in women with biphasic cycles, the determination of progesterone and oestradiol-17 beta in the luteal phase was considered. In women with reduced concentrations of these hormones, androgens, gonadotrophins, prolactin and TSH should be determined. Endometrial biopsy is valuable only if pregnancy fails to occur, despite therapeutically normalized hormone concentrations.

Clomiphene treatment for women with unexplained infertility: placebo-controlled study of hormonal responses and conception rates

One hundred and eighteen patients with unexplained infertility were treated with clomiphene (Clomid, Merrell) in a randomized placebo-controlled cross-over study lasting up to 3 months with each preparation. Compared with placebo, clomiphene led overall to a 66% increase in mid-luteal serum progesterone levels (from mean 43 nmol/l to 71 nmol/l, p less than 0.001) and a 53% rise in the 3-month cumulative conception rate (from 14.6% to 22.33%, p less than 0.05). The greatest relative increase in conception rates with clomiphene was in women with infertility lasting more than 3 years (3-month rates from 2.9% to 14.4%, p less than 0.05). Differences in conception rates were not related to the rises in progesterone, and there was no carryover effect of clomiphene into the following placebo cycles in terms of progesterone levels or conceptions. The findings suggest that couples with unexplained infertility of less than 3 years duration are essentially normal, but with more than 3 years duration there is often a subtle disorder of ovulation that is corrected by clomiphene therapy.

The effect of therapy initiation day on clomiphene citrate therapy

Eighty-seven anovulatory patients were treated with clomiphene citrate (CC) to induce ovulation in 414 cycles. Clomiphene citrate was initiated randomly on the 2nd, 3rd, 4th, or 5th day of the menstrual cycle to evaluate the effectiveness of therapy. The results of therapy were assessed in terms of ovarian response and pregnancy outcome. Ovarian response was evaluated employing basal body temperature (BBT) to define follicular, luteal, and cycle lengths, and a midluteal serum progesterone (P) level and the integrated luteal P to define luteal adequacy. Pregnancy outcome was evaluated in the categories of total pregnancy, live birth, first trimester abortion, and fecundity rates. There were no significant differences noted between the groups who started CC on the 2nd, 3rd, 4th, or 5th day of cycle in terms of anovulation rates (12% to 21%), luteal dysfunction (28% to 39%), and normal ovulation rates (42% to 57%). Pregnancy was achieved in 31% (n = 27/87) of patients with a spontaneous abortion rate of 19% (n = 5/27). The fecundity rates ranged between 5.7% and 9.4%. Pregnancy outcomes also were not significantly different between the groups. Significantly shorter luteal phase length and longer follicular phase length were observed in the cycles with luteal dysfunction. The luteal progesterone parameters, including midluteal serum P concentration, the integrated luteal P, and the luteal P amplitude were significantly lower in the cycles with luteal dysfunction.

Twenty-four-hour progesterone and luteinizing hormone profiles in the midluteal phase of the infertile patient: correlation with other indicators of luteal phase insufficiency

AbstractThe authors have further analyzed women diagnosed as having luteal phase insufficiency in hope of determining the value of specific screening tests as well as determining the degree of heterogeneity of pathophysiologic mechanisms involved in the disorder. Twelve women with the disorder were identified, 6 with two consecutive midluteal serum progesterone (P) levels <10 ng/ml (group 1) and 6 with two consecutive late luteal phase endometrial biopsies out of phase (group 2); 4 infertile women with normal serum P and late luteal biopsies also were studied (group 3). All underwent serum sampling for P and luteinizing hormone (LH) at 20-minute intervals for 24 hours, beginning at 9:00 A.M. of day 7 post-LH surge. No significant differences were noted among the three groups for LH area under the curve, pulse frequency, or pulse amplitude. Furthermore, no differences were ascertained for P area under the curve. However, individuals were identified who had one or more hormonal abnormalities but no abnormal biopsy, as well as patients with normal hormonal profiles but having abnormal endometrial development. Receiver Operating Characteristic curves demonstrated that pooled morning serum P levels provided optimal predictive ability of biopsy results. The authors conclude that luteal phase insufficiency is a heterogeneous disorder, and that neither endometrial biopsy nor serum hormonal analysis obviates the need for the other.

Follicular growth and corpus luteum function in women with unexplained infertility, monitored by ultrasonography and measurement of daily salivary progesterone.

Ovarian function was evaluated over a minimum of 3 consecutive menstrual cycles from each of 41 women with unexplained infertility. Follicular development and ovulation were monitored using real time ultrasonography and luteal function was evaluated by daily salivary progesterone measurement. In 129 spontaneous cycles, normal single ovulations were detected in 121 (93.8%). Luteal phase insufficiency was identified in 21 (17.4%) of these 121 cycles and this was a recurrent phenomenon in the cycles of 5 of the 41 women (12.2%). A successful pregnancy was seen only in association with consistently normal salivary progesterone profiles or where the empirical use of clomiphene citrate therapy had corrected previously diagnosed luteal phase insufficiency. Basal body temperature records or mid-luteal serum progesterone measurements were less satisfactory indices of luteal function than a salivary progesterone profile.

LH surge induction by GnRH agonist at the time of ovulation

Eight women were treated for 1 cycle at the time of ovulation with GnRH agonist (3 injections of 0.2 mg buserelin s.c. at 12-hour intervals) to obtain follicular rupture. Clomiphene citrate was administered to 1 patient and pure FSH to 2 patients, whilst in the case of a woman with hypothalamic amenorrhea a pulsatile GnRH regimen was used. Four patients had an untreated follicular phase. When the maximal follicular diameter was 20-22 mm all treatments were withheld and GnRH-A was administered. Plasma LH, FSH, progesterone and estradiol were determined 24 hours before, at the time of and 12, 24 and 48 hours after the 1st injection of buserelin. Ovulation was detected in all cycles. LH levels increased dramatically from baseline levels of 14.4 +/- 4.1 to 155 +/- 48 IU/l 12 hours after the beginning of treatment, then returned to preovulatory values 48 hours later (13.0 +/- 3.9 IU/l). The duration of the luteal phase was 13.2 days and normal mid-luteal progesterone plasma levels were detected (39.8 +/- 9.3 nmol/l). These data suggest that the GnRH agonist can be successfully used at the time of ovulation to induce an endogenous ovulatory LH peak and that it can be used in conjunction with different medical treatments to induce follicular maturation.

Midluteal Progesterone/Estradiol Ratio as an Indicator of Pregnancy Potential

In an effort to determine the reliability of the midluteal progesterone(P)/estradiol(E2) ratio as an index of the potential for conception, we measured the midluteal P and E2 levels in 76 infertile women who had been treated at our infertility clinic. This parameter in conception cycles was compared with that in non-conception cycles. Eighty cycles of the 76 women were classified into two groups, depending upon whether pregnancy occurred or not. Group 1 and group 2 were composed of 31 conception cycles and 49 drug-induced cycles, respectively. Midluteal concentrations of P and E2 did not show any significant differences between the two groups. The P/E2 ratios were 106.4 +/- 71.3 (mean +/- SD) and 71.5 +/- 44.16, respectively. This difference was statistically significant (p less than 0.05). Discriminant function analysis showed that the smallest probability of misclassification between the two groups decreased from 44% when using P only to 36% when using the combined P and E2. The following equation: Y = 0.0727X1 - 0.00456X2 - 0.130 was obtained (when X1 = P, X2 = E2). These results suggest that the midluteal P/E2 ratio gives clinicians the best indication of luteal function for the achievement of pregnancy.

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.

Luteal deficiency not a persistent cause of infertility.

A mid-luteal serum progesterone measurement was made in 579 cycles from 159 infertile women with unexplained infertility and the results compared with those in 267 cycles from 58 normal controls. There were no significant differences between the two groups in terms of mean progesterone values (41 versus 44 nmol/l); incidence of defective cycles (progesterone less than 28 nmol/l: 17 versus 15%) or severely defective cycles (progesterone less than 14 nmol/l: 4 versus 3%); incidence of a clinical diagnosis of luteal deficiency (LD) (at least two out of three cycles defective: 13 versus 12%); or incidence of persistent LD (continuing into a second series of two to three cycles: 1.7 versus 4.9%). There were no differences related to age, previous pregnancy or duration of infertility. These findings suggest that defective cycles occur as a random phenomenon in infertility and no more often than in normal women, and a diagnosis of LD implying a persistent condition to explain prolonged infertility in women with normal menstrual cycles must be a rare entity and requires at least six cycles of investigation (or none!) before treatment is considered.

Monitoring of ovulation in the assessent of reproductive hazards in the workplace

If women are exposed to reproductive hazards in the workplace, some disturbances of ovulation are expected. Assessment of ovulation requires monitoring to distinguish normal and abnormal ovarian cycles. Menstrual interval and basal body temperature charts are inadequate for identifying many abnormal cycles. A late-luteal endometrial biopsy or a single mid-luteal morning progesterone level each appears to be only 80% accurate in distinguishing normal and abnormal cycles. The complete “cycle profile” of daily ovarian ultrasonic scans and daily serum levels of reproductive hormones appears to be a definitive approach to characterizing ovarian cycles, but this demanding regimen would not be applicable to monitoring large populations in the workplace. An ovarian cycle monitoring protocol consisting of daily measurement of salivary or vaginal electrical resistance, mid-cycle urine testing for the luteinizing hormone surge, and daily luteal phase salivary progesterone levels would provide a practical comprehensive corroborative assessment of ovarian cycles in such populations of women. This monitoring of ovarian cycles would aid in the early detection of reproductive hazards and medical conditions that might present as an ovulatory disturbance.

Corpus luteum insufficiency and fertility: a matter of controversy.

This paper analyses different controversial aspects of luteal phase deficiency (LPD) on the basis of our own data and current clinical experience. Conceptual and diagnostic concerns include: (i) the lack of predictive value of mid-luteal plasma progesterone determinations regarding the progestational transformation of the endometrium, and (ii) the need for a minimum of two, or even three, endometrial biopsies for diagnosis of LPD. From an aetiologic point of view follicular phase determinants of LPD are emphasized and conflicting data on claimed predisposing factors of LPD are analysed. Primary therapeutic approaches to LPD and the effectiveness and significance of such therapy on fertility are discussed.

Prolactin measurement in the investigation of infertility in women with a normal menstrual cycle.

Basal serum prolactin concentrations were compared with mid-luteal serum progesterone concentrations and prospectively studied conception rates up to 12 months in women with otherwise unexplained infertility including a normal menstrual cycle. There were altogether 188 women with mean prolactin levels up to 3075 mU/l: 47 with prolactin up to 200 mU/l, 100 with prolactin 201-400 mU/l, 18 up to 600 mU/l, 16 up to 800 mU/l, and 7 greater than 800 mU/l. There were no significant differences in the mean progesterone values or chance of conception between any of the groups. The findings indicate that prolactin measurement is generally of no value in normally menstruating women, except possibly in the unusual event of evidence of persistent distinct luteal deficiency (not found in the present study).

Disparate effects of endogenous and exogenous oestradiol on luteal phase function in women.

Five normally ovulating women were induced to superovulate with pulsatile 'pure' FSH (28 i.u. every 3 h by a s.c. pump), and another 5 women were given an i.m. injection of 10 mg oestradiol benzoate in the late follicular phase. Serum oestradiol concentrations in the luteal phase were similar in both groups and significantly higher than in corresponding control cycles. The luteal phase was of shorter duration in the FSH (11.2 +/- 0.7 days) than in the control (13.4 +/- 0.2 days) and the oestrogen-treatment cycles (13.4 +/- 0.7 days) (P less than 0.05, mean +/- s.e.m.). FSH cycles had significantly lower early luteal serum LH (Day 1: 5.3 +/- 1.5 mi.u./ml) and mid-luteal serum progesterone values (35.4 +/- 3.5 nmol/l) compared with the control (27.8 +/- 5.8 mi.u./ml and 65.4 +/- 5.7 nmol/l, respectively) and oestrogen treatment cycles (25.3 +/- 8.3 mi.u./ml and 59.1 +/- 8.4 nmol/l, respectively) (P less than 0.05, mean +/- s.e.m.). These results suggest that, in hyperstimulated cycles, the luteal phase can be disrupted even without follicle aspiration, and that suppression of endogenous LH secretion may be responsible.

Periovulatory 17β-estradiol pattern in conceptional and nonconceptional cycles during menotropin treatment of anovulatory infertility

The value of multiple parameters in the prediction of fertile cycles was prospectively evaluated in 52 menotropin-induced cycles. The periovulatory pattern of estradiol (E2) was found to correlate with conceptional cycles. E2 levels greater than 500 pg/ml on the day of human chorionic gonadotropin administration (day 0) with a further increase on day +1 (high ascending pattern--A1) were found to have a 51% predictive value for fertile cycles. Twelve of the 17 fertile cycles had an A1, type of response (71%), whereas the overall incidence of an A1 pattern was 42% (22 of 52). No pregnancies have occurred with preovulatory follicles less than or equal to 14 mm in diameter. The number of preovulatory follicles, E2 level on day 0, and midluteal progesterone had no predictive value for fertile cycles.

Ovulatory disturbances in patients with luteal insufficiency.

In order to study ovulatory disturbances in patients with luteal insufficiency we evaluated 210 cycles of 170 women from infertile couples by ultrasonographic follicle measurements and hormonal determinations. Only cycles with evidence of luteinization were included into the study. Mid-luteal progesterone (P) levels were determined in relation to the ultrasonographic ovulation time or, where the follicle failed to rupture, in relation to the LH peak. In spontaneous cycles with a mid-luteal P level below 32 nmol/l (10 ng/ml) a luteinized unruptured follicle (LUF) was found in 71.1% of cycles, whereas in spontaneous cycles with a mid-luteal P level above 32 nmol/l only 7.9% cycles exhibited a failure of the follicle to rupture. The same phenomenon was encountered in cycles in which agents had been given to induce ovulation. The incidence of LUF cycles in an average infertility population could be calculated to be as high as 50% if the mid-luteal P level is below 32 nmol/l and as low as 4% if the mid-luteal P level is above 32 nmol/l. The geometric mean mid-luteal P level in spontaneous LUF cycles was 32.5 nmol/l, compared to 55.2 nmol/l in spontaneous ovulatory cycles (P less than 0.001). We conclude that in patients with luteal insufficiency a high incidence is found of a failure of the follicle to rupture. The entrapment of the oocyte in the unruptured follicle constitutes an important cause of infertility in these patients.

Diurnal variations in midluteal serum progesterone measurements

The utility of a single midluteal phase progesterone (P) value has been questioned by studies that document pulsatile P secretion. In this study, fluctuations of P values during clinical sampling times were investigated. Significant differences were found between morning and afternoon mean P values and in the timed occurrence of clinically relevant P values. Despite reported pulsatile secretion, the impact of clinically significant fluctuations may be minimized by the use of timed sampling.