Variability in the hormonally estimated fertile phase of the menstrual cycle

The purpose of this study was to determine the variability in length of the fertile phase of the menstrual cycle with 140 participants who produced 1,060 cycles with an electronic hormonal fertility monitor. The length of the fertile phase, as defined by the first day with a threshold level of urinary E3G and ending with a second day above a threshold of LH, varied from <1 to >7 days, with the most frequent length being 3 days.     

New approaches to fertility awareness-based methods: incorporating the Standard Days and TwoDay Methods into practice

Helping clients select and use appropriate family planning methods is a basic component of midwifery care. Many women prefer nonhormonal, nondevice methods, and may be interested in methods that involve understanding their natural fertility. Two new fertility awareness-based methods, the Standard Days Method and the TwoDay Method, meet the need for effective, easy-to-provide, easy-to-use approaches. The Standard Days Method is appropriate for women with most menstrual cycles between 26 and 32 days long. Women using this method are taught to avoid unprotected intercourse on potentially fertile days 8 through 19 of their cycles to prevent pregnancy. They use CycleBeads, a color-coded string of beads representing the menstrual cycle, to monitor their cycle days and cycle lengths. The Standard Days Method is more than 95% effective with correct use. The TwoDay Method is based on the presence or absence of cervical secretions to identify fertile days. To use this method, women are taught to note everyday whether they have secretions. If they had secretions on the current day or the previous day, they consider themselves fertile. The TwoDay Method is 96% effective with correct use. Both methods fit well into midwifery practice.     

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.     

Characterization of subendometrial myometrial contractions throughout the menstrual cycle in normal fertile women

The objective was to study the characteristics of ultrasonographically detected subendometrial myometrial contractions. The contractions were evaluated by 328 ultrasound scans throughout the menstrual cycle. Reproducibility of these findings were studied in consecutive cycles. Eighteen healthy ovulatory volunteers with proven fertility were evaluated for at least one complete menstrual cycle in the follicular, periovulatory, and luteal phases. Multiple cycles were studied in 10 volunteers. The results showed that the contractions increase in frequency, amplitude, and percentage toward the fundus throughout the follicular and periovulatory phases. The pattern is essentially reversed in the luteal phase. There is reproducibility of these patterns from cycle to cycle. We conclude that there is a definite identifiable pattern of subendometrial myometrial contractility that varies with the phases of the normal menstrual cycle and recurs in a similar fashion from cycle to cycle.     

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.     

An estrogen test to determine the times of potential fertility in women

Defined changes in the concentration of estrone glucuronide in daily samples of early morning urine have been used to locate the limits of the fertile period and the time of maximum conception probability during 118 cycles (106 menstrual, 12 conceptional) in 73 women. The peak day of urinary luteinizing hormone was used as an index of ovulation. Follicular growth was monitored daily by ultrasonography throughout 38 cycles, and the time of maximum follicular diameter was used as an alternative reference point to define the times of potential fertility according to the life spans of the gametes. With optimized algorithms and the best index of ovulation, the estrogen test delineated the limits of the fertile period in 89% of the tests (mean length, 10.8 days; range, 5 to 17 days) and the time of maximum conception probability in 82% of the cycles, with a mean time to the maximum follicular diameter of 0.42 days (range, -4 to +4 days).     

Length and variation in the menstrual cycle--a cross-sectional study from a Danish county.

OBJECTIVE: To investigate the current epidemiology of menstrual patterns among women of fertile age. DESIGN: Cross-sectional postal questionnaire study. SETTING: County of Copenhagen, Denmark. SUBJECTS: 3743 women, aged 15-44, selected at random from a Danish county, who were asked to provide information on menstrual pattern during the preceding year, 1981. The response rate was 78%. Information from non-responders was obtained via telephone interviews. RESULTS: In women with regular menstrual cycles, the 5th-95th centile range of usual cycle length decreased from 23-35 days in the 15-19 years age group to 23-30 days in the 40-44 years age group. Only 0.5% of regular menstruating women had a usual cycle length of less than 21 days and 0.9% had a usual cycle length of greater than 35 days. At least one cycle length of less than 21 days was experienced by 18.6%, whereas 29.5% had at least one cycle of greater than 35 days. Menstrual cycle variation of greater than 14 days was present in 29.3% of all women. Cycle length variation of greater than 14 days was 2.7 times more frequent in women from lower social groups (controlled by age). CONCLUSION: The study confirmed the normally used definitions of polymenorrhoea (cycle length less than 21 days) and oligomenorrhoea (cycle length between 36 and 90 days), as these very short or long menstrual cycle lengths were very seldom recorded for a longer period. However, the high frequency in a normal population of large menstrual cycle length variation challenges the view that an intra-individual variation of greater than 5 days should be regarded as a sign of disease in the woman.     

Effects of the antiprogesterone RU486 in the early follicular phase of the menstrual cycle

To investigate the role of progesterone (P) in the early follicular phase, the antiprogesterone effect of RU486 was examined in five normally cycling women monitored by daily hormonal levels during three consecutive cycles (control, treatment, and recovery). In addition, luteinizing hormone (LH) pulse characteristics were assessed by frequent blood sampling (10 minutes for 10 hours) on day 3 of the control and the corresponding day of treatment cycles. Administration of RU486 (3 mg/kg, orally) for the first 3 days of the menstrual cycle did not significantly alter the length of the follicular phase (13.4 +/- 1.7 to 15.2 +/- 1.3 days), the LH surge, or the luteal phase length (12.2 +/- 0.5 to 12.6 +/- 0.7 days). The intermenstrual length of the treatment cycle (29.8 +/- 1.9 days) did not differ from the control (27.6 +/- 1.8 days) or recovery cycles (29.6 +/- 2.5 days). Integrated secretion of P and estradiol (E2) did not vary during the luteal phase of the control, treatment, or recovery cycles. During RU486 treatment, LH pulse frequency, pulse amplitude, and mean LH were not altered. Whereas mean E2 levels were significantly decreased from 150.5 +/- 15.1 to 110.1 +/- 7.0 pmol/L, follicle-stimulating hormone, P, adrenocorticotropin hormone, and cortisol were not significantly altered. Thus, in spite of the transient decrement in E2 secretion during RU486 treatment, the integrity of the ovulatory menstrual cycle was maintained. We conclude that administration of the antiprogesterone RU486 at the dose used during the first 3 days of the follicular phase does not perturb menstrual cyclicity.     

Serum müllerian-inhibiting substance levels during normal menstrual cycles

OBJECTIVE: To measure serum levels of müllerian-inhibiting substance (MIS) during the normal menstrual cycle. DESIGN: Serum was collected from women during ovulation and the mid-luteal and early follicular phases of the menstrual cycles. It was stored frozen at -80 degrees C until assayed. SETTING: University of Louisville Departments of Obstetrics and Gynecology and Surgery. PATIENT(s): Twenty healthy women 22-35 years of age with normal menstrual cycles. Intervention(s): Blood samples were collected on menstrual cycle day two or three and on the day of LH surge plus one and plus seven or eight. MAIN OUTCOME MEASURE(s): Serum MIS levels were measured by using an enzyme-linked immunosorbent assay. RESULT(s): Serum MIS levels ranged from a low of 1.4 +/- 0.9 ng/mL (mean [+/-SD]) in the early follicular phase, peaked mid-cycle at 1.7 +/- 1.1 ng/mL, and decreased to 1.4 +/- 0.9 ng/mL in the mid-luteal phase of the normal menstrual cycle. CONCLUSION(s): Fluctuations in serum MIS levels during the menstrual cycle suggest that MIS may have a regulatory role in folliculogenesis.     

Fertility awareness-based methods of family planning

Fertility awareness-based methods (FABMs) of family planning involve monitoring various signs and symptoms of fertility during the menstrual cycle to identify the “fertile window,” or the days of the cycle when unprotected intercourse is most likely to result in pregnancy. Signs and symptoms include menstrual cycle length, basal body temperature, urinary hormone measurements, and/or cervical fluid and may be used alone or in combination. Fertility signs reflect both physiological changes during the menstrual cycle and the life cycle of the ovum and sperm. Women learn to observe or measure and interpret these signs according to the instructions of their chosen FABM and avoid unprotected intercourse on fertile days. FABMs are appropriate for those who choose to use them, are able and willing to observe one or more fertility signs, and are in relationships that support the use of a coitus-related method such as a condom or abstaining from intercourse on fertile days.     

Influence of human menopausal gonadotropin on the recruitment of human ovarian follicles

Human menopausal gonadotropin (hMG) was administered once (225 IU) to 16 women during different phases of the menstrual cycle: either late-luteal, early-follicular, midfollicular, or late-follicular phases before surgical ovarian resection or ablation. The mitotic index (MI) of follicular granulosa cells and the proportion of recruitable healthy follicles were analyzed 4 to 5 days after hMG injection, the findings being compared with those in unstimulated ovaries from 22 normally cycling patients. The percentages of healthy recruitable follicles greater than or equal to 2 mm in diameter was not altered by hMG as compared with controls. The granulosa cell MI was highly stimulated by hMG when administered in late-luteal or early-follicular phases; however, no granulosa cell MI stimulation was noted when hMG was administered in the midfollicular or late-follicular phases. The progressive abolition of the ability of hMG to stimulate follicular growth as ovulation approaches supports the existence of an inhibitory activity (possibly ovarian) designed to suppress the selection and the maturation of the less developed antral follicles from the midfollicular phase of the spontaneous human menstrual cycle.     

Effects of subchronic infusion of dehydroepiandrosterone sulfate on serum gonadotropin levels and ovarian function in the cynomolgus monkey.

OBJECTIVE: To assess the impact of elevated adrenal androgen levels on ovarian function in a nonhuman primate using a repeated measures experimental design. DESIGN: Osmotic pumps that released dehydroepiandrosterone sulfate (DHEAS) were implanted subcutaneously in five cynomolgus monkeys (Macaca fascicularis) for one menstrual cycle. The pumps were filled with saline for the two control cycles, one preceding and the other following DHEAS infusion. RESULTS: Administration of DHEAS elevated its levels in serum fourfold and in urine sevenfold, which returned to pretreatment values in the next cycle. Serum concentrations of estradiol (E2) were reduced by 55% during DHEAS administration in both follicular and luteal phases and were still decreased in the following cycle by 69% in follicular phase and 48% in luteal phase (P less than 0.01). Luteal serum progesterone (P) levels were diminished by 52% during treatment and were accompanied by 56% reduction in immunoreactive pregnanediol excretion in urine (P less than 0.05). Serum luteinizing hormone (LH) levels were decreased during DHEAS infusion by 51% in follicular phase and 58% in luteal phase (P less than 0.01) but returned to baseline in the next cycle. Conversely, serum follicle-stimulating hormone (FSH) concentrations were increased during treatment by 70% in follicular phase and 101% in luteal phase and remained increased by 58% in follicular phase of the next cycle (P less than 0.05). Estrone excretion in urine was higher during DHEAS infusion (1.5-fold increase) but was below pretreatment values in the following cycle by 57% in follicular phase and 51% in luteal phase (P less than 0.001). Administration of DHEAS did not change significantly serum levels of sex hormone-binding globulin. The length of menstrual cycles was not affected by increased levels of adrenal androgens either. However, in the cycles that followed DHEAS infusion, follicular phase was prolonged by an average of 9 days, and luteal phase was shortened by an average of 5 days (P less than 0.01). CONCLUSIONS: These data document that subchronically elevated adrenal androgen levels in primates: (1) suppress E2 and P levels, which may affect fertility; (2) differentially affect gonadotropin secretion, decreasing LH and increasing FSH serum concentrations; and (3) result in disturbances of ovarian function that persist for at least one menstrual cycle after normalization of androgen levels.     

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.     

Subnormal 24-hour mean plasma LH concentration and elevated plasma FSH/LH ratio in obese premenopausal women. A possible human counterpart of the slow-GnRH-pulsing model in primates

The 24-hour mean plasma concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured during the follicular phase of the menstrual cycle in 15 healthy, regularly cycling obese women (59-218% above desirable weight) and 9 healthy, regularly cycling nonobese women (14% below to 14% above desirable weight). The obese women showed slightly but not significantly higher FSH values (12.5 vs. 9.6 mIU/ml), definitely and significantly lower LH values (11 vs. 17 mIU/ml; p less than 0.005) and markedly and very significantly higher FSH/LH ratios (1.2 vs. 0.62; p less than 0.0005). These abnormalities may represent a human counterpart of the slow-GnRH-pulsing model of primates: monkeys in which the GnRH secretory centers have been ablated and that receive GnRH infusions at subnormal pulsing rates show slightly elevated FSH levels, markedly decreased LH levels, greatly elevated FSH/LH ratios and anovulation.     

Changes in endometrial wave-like movements in accordance with the phases of menstrual cycle

OBJECTIVE: To investigate whether endometrial wave-like movements change with phases of the menstrual cycle. METHODS: Endometrial wave-like movements were observed by transvaginal sonographic tomography during 50 menstrual cycles of 20 regularly menstruating women. RESULTS: Endometrial wave-like movements were not observed during the early follicular phase. These movements proceeded perpendicularly to the longitudinal uterine axis and appeared at the midfollicular phase. In the periovulatory phase, waves reached a peak and moved from cervix to fundus. In the postovulatory phase, endometrial wave-like movements became parallel to the longitudinal uterine axis. In the midluteal phase, most of these waves disappeared. Immediately before menstruation, the waves reappeared moving from fundus to cervix. These movements continued until day 1 of the subsequent menstrual phase. CONCLUSION: Endometrial wave-like movements change with the passage of menstrual cycle. They appear to play an important role in the transport of sperm and cervical mucus and the excretion of menstrual flow.     

Women with regular menstrual cycles and a poor response to ovarian hyperstimulation for in vitro fertilization exhibit follicular phase characteristics suggestive of ovarian aging

OBJECTIVE: To investigate whether follicular phase characteristics associated with ovarian aging can be observed in women of normal reproductive age, who had previously shown a poor response to ovarian hyperstimulation for IVF. DESIGN: Observational, prospective study. SETTING: Tertiary fertility center. PATIENT(S): Eleven regularly cycling, ovulatory women, aged 29-40 years who previously presented with fewer than four dominant follicles after ovarian hyperstimulation for IVF. INTERVENTION(S): Frequent serum hormone assessments and transvaginal ultrasound during the follicular phase of a spontaneous, unstimulated cycle. MAIN OUTCOME MEASURE(S): Duration of the follicular phase; serum LH, FSH, E(2), P, inhibin A, and inhibin B levels; and number of antral follicles observed by ultrasound. Results were compared with the cycle characteristics of a reference population of 38 healthy normo-ovulatory women aged 20-36 years (as published elsewhere). RESULT(S): Poor responders had significantly fewer antral follicles than controls. Median FSH concentrations were significantly higher compared with controls, but the majority had FSH levels within the normal range. Follicular phase P levels were significantly higher in poor responders. Duration of the follicular phase, E(2), and inhibin A and inhibin B serum levels did not differ between poor responders and controls. CONCLUSION(S): Normo-ovulatory regularly cycling women with a previous poor response to ovarian hyperstimulation for IVF show follicular phase characteristics suggestive of ovarian aging.     

Effect of short-term cyclic administration of cyproterone acetate on pituitary-ovarian function in the human

Short courses of cyproterone acetate, a compound with progestational and antiandrogenic activities, were administered to normally menstruating women during different phases of the menstrual cycle to suppress growth and maturation of the follicles and corpus luteum function. Postovulatory administration of 20 mg of the drug daily for 8 days to two women delayed menstruation by 4 to 6 days, followed by prolonged bleeding and short post-treatment cycles. Plasma levels of progesterone were suppressed temporarily during therapy, but increased immediately after cessation of treatment. Administration of 10 mg of the drug for 8 days during the early follicular phase to two women resulted in irregular bleeding, short cycles, and decreased plasma levels of progesterone throughout the cycle. Reduction of the dose to 2.5 mg during the early follicular phase in two other women also resulted in irregular cycles. When the 2.5-mg dose was administered to three women from the 8th to the 15th days of the cycle, vaginal bleeding and cycle length were normal. Plasma levels of luteinizing hormone and progesterone were suppressed during therapy. In one subject, cervical mucus was found to be hostile to sperm penetration in all three treatment cycles. The results indicate that, with cyclic administration of low doses of cyproterone acetate to women during the late follicular phase, it may be possible to interrupt pituitary-ovarian function, as well as sperm transport through the cervical mucus.     

Cyclic changes in the concentration of glucose and fructose in human cervical mucus.

OBJECTIVE: To determine a possible cyclic change in the concentration of glucose and fructose in the aqueous phase of human cervical mucus (CM). DESIGN: Concentrations of glucose and fructose were longitudinally determined in the aqueous phase of CM of normal cycling women using enzymatic techniques, modified for small quantities. SETTING: Patients visiting a fertility clinic were selected. PATIENTS: Nine healthy women with regular menstrual cycles of 28 +/- 3 days that appeared to be ovulatory, demonstrated by sonographic follicle immaging and serum progesterone (P) measurements. INTERVENTIONS: Cervical mucus samples were longitudinally collected preovulatory, postovulatory, and premenstrual in ovulatory cycles, monitored by ultrasound and blood estradiol and P measurements. MAIN OUTCOME MEASURES: The study was designed to measure glucose and fructose longitudinally on three different points during one cycle. RESULTS: The preovulatory glucose concentrations in CM were lower than postovulatory and premenstrual. The preovulatory fructose concentrations were lower than premenstrual. The glucose concentration correlated with the blood P level. CONCLUSION: There is a consistent change in the glucose concentration measured in human CM in three phases of the menstrual cycle. The preovulatory and premenstrual fructose concentrations differ significantly. Knowledge of the carbohydrate metabolism in human cervical mucus may contribute in illuminating the possible role of the carbohydrate metabolism in sperm migration at midcycle and implantation in the luteal phase.     

Antral follicle counts by transvaginal ultrasonography are related to age in women with proven natural fertility

OBJECTIVE: To investigate the relation between reproductive age and ultrasound (US)-based follicle counts and the reproducibility of follicle counts in regularly cycling women with proven fertility. DESIGN: Prospective observational study. SETTING: Tertiary fertility center. PATIENT(S): Healthy female volunteers with proven fertility, recruited by advertisement in local newspapers. INTERVENTION(S): The number of antral follicles sized 2-10 mm and ovarian volume were estimated by transvaginal US in the early follicular phase of the menstrual cycle in 162 women. A subgroup of 81 women underwent transvaginal US at several times in three subsequent cycles. MAIN OUTCOME MEASURE(S): Antral follicle count and total ovarian volume. RESULT(S): Women aged 25-46 years (n = 162) were studied. The relation of age with the US indices was computed after natural log transformation. Antral follicle count showed the clearest correlation with age (R = -0.67). A biphasic linear model gave the best fit to the data. Before the age of 37 years, the antral follicle count showed a mean yearly decline of 4.8%, compared with 11.7% thereafter. The reproducibility of the antral follicle count in two subsequent cycles was moderate. CONCLUSION(S): The number of small antral follicles in both ovaries as measured by US is clearly related to reproductive age and could well reflect the size of the remaining primordial follicle pool.     

Vascular reactivity in men and women of reproductive age

OBJECTIVE: This study was undertaken to document vascular reactivity in both phases of normal menstrual cycles and anovulatory cycles of women receiving oral contraceptives and to compare vascular reactivity of women in the follicular phase of the normal menstrual cycle with that of men of a similar age group. STUDY DESIGN: Forearm blood flow was measured with plethysmography in 15 women with ovulatory cycles during the follicular and luteal phases of the normal cycle, at equivalent times in 14 women receiving oral contraceptives, and in 15 age-matched men. Changes in forearm blood flow, an index of vascular reactivity, were measured during a randomly ordered brachial artery infusion schedule of norepinephrine, sodium nitroprusside, angiotensin II, and Nomega-monomethyl-L -arginine and were analyzed with repeated measures analysis of variance. RESULTS: Forearm blood flow responses were similar in the two phases of the normal cycle. Responses were similar between women with ovulatory cycles and users of oral contraceptives, apart from a significantly greater response to angiotensin II in the oral contraceptive group during the medication phase than during the withdrawal phase (P =.027). Basal forearm blood flow was higher in men than in women (7 +/- 1.6 vs 5 +/- 1.4 mL/100 mL per minute; P =.015), and men demonstrated a significantly greater vasoconstrictor response to norepinephrine (P <.05) than did women. CONCLUSION: Vascular reactivity is similar in the two phases of the normal menstrual cycle, but women who use oral contraceptives have an exaggerated response to angiotensin II during the medication phase. Men demonstrate greater vascular reactivity to norepinephrine than do women, perhaps because of the lack of estrogen-mediated protective effects and increased adrenergic activity.