Follicular phase treatment of luteal phase dysfunction

Previously, we demonstrated that selective suppression of serum follicle-stimulating hormone (FSH) in monkeys treated with charcoal-extracted porcine follicular fluid (pFF) in the early follicular phase induced luteal defects resembling those which occur spontaneously in women and monkeys. Here, we assessed whether luteal phase defects arising in association with induced FSH deficiencies during the early follicular phase can be treated by early FSH therapy. Rhesus monkeys were treated with pFF and human menopausal gonadotropin (hMG) (FSH:luteinizing hormone [LH], 3:1) on cycle days 1 to 3 or day 4, respectively. Daily femoral blood samples were analyzed for LH, FSH, and estradiol by radioimmunoassay. In the monkeys treated with the pFF-hMG combination, a single ovulation was uniformly noted at laparoscopy, and initial luteal phase elevations in serum progesterone levels were nearer those of normal ovulatory cycles than after pFF alone. These results suggest that FSH/LH treatment in the early follicular phase compensated, in part, for the pFF-induced deficiency in endogenous FSH levels.     

Premature ovulation after ovarian ultrasonography

Summary. Whereas follicle rupture never occurred before the 37th hour after an ovulatory stimulus (either the onset of the LH surge or hCG administration) in control patients, ovulation was observed at 26 to 36 h in women submitted to ultrasonography during the late follicular phase. Premature ovulation was observed in 5 out of 23 and 8 out of 19 cycles when ultrasonography occurred during the 3 days preceding or in the 36 h following ovulatory stimulus. This as yet unexplained observation leads us to reconsider the advisability of ovarian scan during the late follicular phase of the menstrual cycle.     

Regulation of ovarian follicular and luteal function during treatment with exogenous gonadotropins in anovulatory infertility

The dosage, duration of treatment, and plasma hormone levels were analyzed statistically between and within groups of treatment cycles with (n = 46) and without (n = 10) ovulation. A significant difference was observed in the dosage of human menopausal gonadotropins (hMG) over various days of treatment, but not in the mean dosage of hMG and human chorionic gonadotropin (hCG) administered per cycle. Follicle-stimulating hormone (FSH):luteinizing hormone (LH) ratios, prolactin (PRL) levels, and the magnitude and the duration of the estradiol response were greater in the ovulatory cycles. Additionally, in the ovulatory cycles, the dose of hMG correlated with the plasma levels of estradiol, FSH, and LH, while in the anovulatory cycles, hMG dosage correlated only with the LH concentrations. After administration of hCG, the mean plasma concentrations of its beta subunit peaked within 1 day and remained detectable for up to 10 days thereafter. In the ovulatory cycles, the mean progesterone level was maximal 6 days following hCG administration. In these cycles, luteal phase progesterone levels correlated positively with the preovulatory estradiol and inversely with concentrations of the beta subunit of hCG. The data demonstrate that, in contrast to anovulatory follicles, ovulatory follicles were exposed to a relative "dominance" of FSH over LH, with higher concentrations of estradiol and PRL for several days before hCG was administered. Apart from hMG dosage, the endogenous discharge of LH appeared to be an important determinant of the ovarian response. A single 10,000 IU dose of hCG was adequate for inducing ovulation and maintaining luteal function.     

Luteal phase deficiency after completely normal follicular and periovulatory phases

Luteal phase defect (LPD) accounts for a significant proportion of reproductive disorders, however its etiology is still debated. A prospective study was performed on 37 ovulatory women to determine whether LPD can occur in cycles characterized by completely normal folliculogenesis. Criteria for normal folliculogenesis included: a gradual rise of serum estradiol, a luteinizing hormone (LH) surge, the presence of a dominant follicle that disappeared, an increase of serum progesterone, and normal serum levels of prolactin, testosterone, dehydroepiandrosterone sulfate, follicle-stimulating hormone, and LH. Thirty of 37 women fulfilled the above mentioned strict criteria and underwent endometrial biopsy in the late luteal phase. Seven of 30 (23%) demonstrated a delay in endometrial development and all had normal hormonal and ultrasonographic parameters of folliculogenesis and ovulation. Women with delayed endometrial development demonstrated slightly longer follicular phases (17.0 +/- 1.1 versus 14.5 +/- 0.3 days). Perfectly normal follicular and periovulatory events may be followed by deficient luteal phases.     

The use of gonadotropins for the induction of ovulation in women with polycystic ovarian disease

Ten infertile patients with polycystic ovarian disease were treated with 18 cycles of "pure" human pituitary follicle-stimulating hormone (HP-FSH) and 10 cycles of human menopausal gonadotropin (HMG) consisting of FSH and luteinizing hormone (LH) in a 1:1 ratio. Human chorionic gonadotropin was used to trigger ovulation when optimal follicular development was achieved as judged by urinary estrogen determinations. Of the 18 cycles utilizing HP-FSH, 14 were presumptively ovulatory, 2 were conceptual, and in 5 cycles ovarian enlargement was noted. Of the 10 HMG cycles, none was ovulatory, no conceptions resulted, and 6 instances of hyperstimulation were noted. Pretreatment serum LH levels were significantly higher than normal follicular phase values. These observations suggest that endogenous LH levels in patients with polycystic ovaries are quite adequate for follicular development so that the administration of exogenous LH is unwarranted. Furthermore, the data suggest that HP-FSH or low-LH-containing HMG may prove to be an additional safe and effective nonsurgical treatment modality for patients who are anovulatory because of polycystic ovaries.     

宫颈粘液过氧化物酶在月经周期中的变化规律

本文对29例月经周期正常妇女的宫颈粘液过氧化物酶进行了30个周期的研究。在月经周期不同时间测定宫颈粘液过氧化物酶(CMPx)活性及血清促黄体生成素(LH)、雌二醇(E_2)和孕酮(P)。结果表明:在排卵前三天酶活性明显下降,至排卵后一天开始上升。卵泡期,酶活性与E_2呈负相关(r=-0.67);黄体期,酶活性与P呈正相关(r=0.79)。本研究提示:1.CMPx在排卵周期具有特定的变化规律,其变化受体内激素水平影响,可作为预告排卵的指标。2.如简化测定方法,可为自然避孕提供新途径。     

Accuracy of basal body temperature for ovulation detection.

In 30 normally menstruating women, ages 19 to 41 (mean 24), gravida 0 to 5 (mean 0.7), basal body temperature (BBT) was correlated with serum luteinizing hormone (LH), progesterone, and estradiol or urinary estrogen levels assayed serially during one menstrual cycle. In 21 subjects (70%), a biphasic BBT correlated with an ovulatory hormonal pattern. Six women (20%) had a monophasic BBT but demonstrated a preovulatory estrogen peak, a midcycle LH surge, and a significant rise in serum progesterone levels during the luteal phase. The remaining three women (10%) showed anovulatory cycles (two women) or a deficient luteal phase (one woman) as determined by BBT and hormonal assays. The results indicate that in approximately 20% of ovulatory cycles the BBT failed to demonstrate ovulation.     

Interference in follicular maturation following acute intranasal LH-RH agonist administration during mid and late follicular phase

A dose of 300 micrograms of Buserelin was insufflated into the nose twice on a single day between days 5 and 14 in 23 regularly ovulating volunteers, for a total of 25 cycles. The acute gonadotropin response to the first dosing at 8 A.M. was maximal on treatment days 9 to 14 and was followed by a 2- to 10-fold increase in serum estradiol at 10 A.M. and 2 P.M. The response to the second dosing 10 hours later (6 P.M.) was preserved on treatment days 5 to 8, but was diminished on treatment days 9 to 14. Daily endocrine determinations of serum LH, FSH, estradiol, and progesterone revealed three different situations, according to the time of treatment: In 6 cycles (24%), LH-RH agonist treatment on days 5 to 8 was associated with a delayed LH surge, followed by a normal or short luteal phase; when Buserelin was administered between days 7 and 11 in 16 cycles (64%), there was not subsequent LH surge--progesterone remained in the follicular phase range in 9 cycles, and inadequate secretion of serum progesterone was found along with a luteinized follicle in 5 cycles, being in the luteal phase range in only 2 cycles; in three cycles (12%), the treatment coincided with a presumptive LH surge, and the luteal phase was deficient in two cases. There were no clinical side effects of treatment. Immediate posttreatment cycles were normal. Acute intranasal LH-RH agonist administration predominantly delayed ovulation when administered at midfollicular phase, and interfered with final follicular maturation when given in the late follicular phase.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Reliability of ovulation tests in infertile women

OBJECTIVE: To assess the reliability of the most widely used clinical methods for predicting or confirming ovulation. METHODS: We monitored spontaneous cycles in 101 infertile women using basal body temperature (BBT), transvaginal ultrasound, a urinary stick system for LH surge, and three serum progesterone measurements in the midluteal phase. Transvaginal ultrasound monitoring was standard for ovulation detection and sensitivity. We calculated specificity and accuracy of each method compared with that standard. RESULTS: Follicular development and ultrasound evidence of ovulation were confirmed in 97 of 101 cycles (96%). Urinary LH surge preceded follicular rupture assessed by ultrasonography in all cycles and showed concordance with ultrasound-evidenced ovulation in 98 of 101 cases. The timing of BBT nadir had wide variability, and BBT and ultrasonography agreed in a similar percentage of cases (74%). Midluteal serum progesterone assessments showed ovulatory values in 93 subjects, and ovulation was concordant with ultrasonography in 90 subjects. CONCLUSION: Urinary LH was accurate in predicting ovulation with ultrasonography as the standard for detection, but time varied widely. The nadir of BBT predicted ovulation poorly. The BBT chart was less accurate for confirming ovulation, whereas a single serum progesterone assessment in midluteal phase seemed as effective as repeated serum progesterone measures.     

Ovulation induction using "pure" follicle-stimulating hormone in monkeys

Recently we have demonstrated that administration of a "pure" follicle-stimulating hormone (FSH) preparation (Urofollitropin, Serono Laboratories, Inc., Randolph, MA) to normally cycling monkeys induces multiple follicular development. In these earlier studies, a spontaneous luteinizing hormone (LH) surge was uncommon; no attempt was made to induce ovulation with exogenous human chorionic gonadotropin (hCG). In this study, multiple follicular development and ovulation were induced in normally cycling monkeys by daily follicular phase administration of "pure" FSH followed by hCG. Short-term administration of "pure" FSH during the early or late follicular phase also induced multiple follicular development; however, multiple ovulations subsequent to a spontaneous LH surge never occurred. One monkey treated in the late follicular phase did demonstrate a spontaneous LH surge and single ovulation following late follicular phase FSH treatment. These findings suggest that administration of "pure" FSH alone, to enhance the natural ovarian cycle, may be useful for inducing multiple follicular development, but that ovulatory competence is usually dependent on exogenous LH/hCG.     

Inadequate luteal phase usually indicates ovulatory dysfunction: observations from serial hormone and ultrasound monitoring of 115 cycles

We have studied 100 women with regular menstrual cycles and infertility and tried to assess how frequently an 'inadequate' luteal phase (defined by low-peak progesterone levels) follows 'normal' ovulation. Normal follicular growth on serial ultrasound scan and follicular disappearance or collapse within 48 hours of the recorded LH peak were taken together as convincing evidence of ovulation. Eighty-three of 115 cycles were judged to be ovulatory and 32 to be anovulatory. A peak mid-luteal phase maximum serum progesterone (Po) level of 32 nmol/L (10 ng/ml) was taken arbitrarily as the cut-off level of discrimination between 'adequate' and 'inadequate' corpus luteum function. Serum progesterone was undetectable (less than 2.5 nmol/L) throughout in 2 cycles while the maximum was above 32 nmol/L in 102 and detectable but less than 32 nmol/L in 11. Of the latter only 1 was ovulatory. We conclude that cycles with low luteal phase Po levels represent luteinization without ovulation.     

Human gonadotropin therapy. II. Serum estradiol and progesterone patterns during nonconceptual cycles

Hormone patterns during 113 nonconceptual gonadotropin-induced cycles of 65 infertile anovulatory women were analyzed. All but one women ovulated, i.e., the ovulation rate was 98%. Signs of defective corpus luteum function were observed during 8 cycles, and anovulation occurred in 11 treatment cycles. The duration of the active phase of the follicular stimulation was shorter during cycles with defective luteal phases and anovulatory cycles. The mean estradiol level at induction of ovulation by human chorionic gonadotropin did not differ between the groups. Premature ovulation was observed in six treatment cycles. No case of severe hyperstimulation was encountered. The hormone pattern during gonadotropin-induced conceptual cycles did not differ in comparison with gonadotropin-induced nonconceptual ovulatory cycles.     

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.     

Cervicovaginal peroxidases: sex hormone control and potential clinical uses

Thirty-one normal women were studied daily in 41 cycles. Venous blood samples were taken for measurements of luteinizing hormone (LH), estradiol (E2), and progesterone (P), and vaginal examinations were done to obtain cervical mucus and vaginal fluid. The specific activity of guaiacol peroxidase (GP), extracted from cervicovaginal secretions with 0.5 M CaCl2, was determined in the vaginal samples. In the follicular phase, from day -7 to day 0 (the LH +1 day, when ovulation presumably occurred), there was a strong negative correlation between GP and the rising E2 (r = -0.94). On days 1 to 10 after ovulation, there was a strong positive correlation between GP and P (r = 0.84). In nine ovulatory cycles in which P levels did not exceed 8 ng/ml on any day, indicating possible luteal phase inadequacy, there were significantly lower GP levels than in another 32 ovulatory cycles with higher P (P = 0.04). These results suggest that (1) at midcycle, E2 seems to "down-regulate" the GP specific activity; and (2) in the luteal phase, serum P levels parallel those of GP activity, even in the presence of high luteal E2. GP activity profiles during the menstrual cycle can be used to define the fertile period, may prove useful in diagnosing pregnancy, and may be a simple, convenient test for an inadequate corpus luteum.     

Induction of ovulation with pulsatile LHRH in anovulatory women

Nine anovulatory patients were treated by administering pulsatile LHRH (2-20 micrograms, i.v. at 90 min intervals) for 15-58 days. These patients consisted of 4 women with hypothalamic amenorrhea, one women with oligomenorrhea, 2 women with polycystic ovarian disease (PCOD) and 2 women with hyperprolactinemic amenorrhea. Four of them were involuntarily infertile. The pulsatile LHRH therapy induced follicular maturation and ovulation, as evidenced by increased plasma estradiol levels followed by a midcycle LH surge and subsequent rise in plasma progesterone (P) levels, in 8 of the 9 patients. One patient with PCOD failed to ovulate. All of 11 treatment cycles were ovulatory in the 8 patients. A maximal P level of below 10 ng/ml was seen in 3 of the 11 induced ovulatory cycles, indicating corpus luteum insufficiency. Luteolysis occurred soon after discontinuing the pulsatile LHRH administration at the mid to late luteal phase in 3 ovulatory cycles. One of the 4 infertile women became pregnant. The results indicate that chronic pulsatile administration of LHRH is useful in inducing ovulation not only in hypothalamic amenorrhea, but also in PCOD and hyperprolactinemic amenorrhea. They also suggest that although a possible augmentation of the hypothalamic LHRH release at the preovulatory phase cannot be denied, a series of endocrine events during the human menstrual cycle may be regulated by the feedback action of the ovarian signals on the pituitary under a fixed input of the hypothalamic LHRH.     

A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women

OBJECTIVE: To evaluate the ovarian follicular dynamics of cycle modification with the aromatase inhibitor letrozole compared with clomiphene citrate in normal ovulatory women. DESIGN: Randomized double-blind controlled trial. SETTING: Tertiary care hospital. PATIENT(S): Nineteen ovulatory female volunteers, ages 18-35 years. INTERVENTION(S): Subjects were monitored in one control cycle. Subjects then received either letrozole 2.5 mg daily or clomiphene citrate 50 mg daily on days 5-9 after menses. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness and endometrial pattern at ovulation, and follicular profiles of LH, FSH, and E(2). RESULT(S): The number of mature follicles at the LH surge in natural cycles was 1.0 with an exaggerated response seen for treatment both with clomiphene and letrozole. There was no difference in the endometrial thickness at midcycle during either the natural cycles or the medicated cycles. LH surges and spontaneous ovulation were documented in all natural and medicated cycles. When measured daily, follicular profiles of LH and FSH are similar between the groups in both the natural and medicated cycles. In the medicated cycles, clomiphene results in a significant increase in E(2) levels, while E(2) levels in letrozole-stimulated cycles appeared lower than in natural cycles. CONCLUSION(S): Transient inhibition of aromatase activity in the early follicular phase with the aromatase inhibitor letrozole results in stimulation of ovarian folliculogenesis similar to that seen with clomiphene citrate with no apparent adverse effect on endometrial thickness or pattern at midcycle.     

Quantitative and qualitative tests for urinary luteinizing hormone. Comparison in spontaneous and clomiphene-citrate-treated cycles

A study was performed to evaluate conditions in which false-positive and -negative predictions of ovulation occur with qualitative urinary luteinizing hormone (LH) tests. Three urine specimens and a serum sample were collected daily for LH determination from five anovulatory women treated with clomiphene citrate and from six spontaneously cycling women. The urinary LH was determined with one quantitative and three qualitative tests, and the serum LH was determined with a quantitative assay. Ovulation was determined with transvaginal ultrasound and a serum progesterone level on day 22 of the menstrual cycle. There were six ovulatory and five anovulatory cycles. In those 11 cycles the qualitative urinary LH tests were falsely positive twice and falsely negative thrice. All the false-positive and -negative tests except for one occurred when the quantitative urinary LH was 24-28 mIU/mL. Two false-positive tests occurred one to two days after clomiphene administration. Two false-negative tests occurred in a cycle in which follicular development appeared suboptimal, and one occurred in a cycle with a brief urinary LH surge.     

Vaginal progesterone administration in physiological doses normalizes raised luteinizing hormone levels in patients with polycystic ovarian syndrome.

A raised luteinizing hormone (LH) level is a typical finding in the polycystic ovarian syndrome (PCOS). This inappropriate elevation of LH is thought to interfere with normal follicular development and ovulation. The resulting chronic anovulation is associated with the absence of the luteal phase increase in secretion of progesterone and inhibin. Progesterone can exert both a positive and negative feedback action on LH secretion, but inhibition is thought to occur following prolonged exposure to progesterone. Therefore, the aim of this study was to see if exogenously administered progesterone in physiological doses would normalize circulating LH concentrations in patients with PCOS. Vaginal progesterone was administered twice daily in a dose of 100 mg, at 12 h intervals, to ten women with PCOS. Serum samples were taken on alternate days for radioimmunoassay of follicle stimulating hormone (FSH), LH, estradiol, progesterone and inhibin. To determine the effect of progesterone on LH secretory dynamics in PCOS, LH pulse studies were carried out prior to treatment, and on day 10 of progesterone administration in four of the ten subjects. Mean serum progesterone concentrations reached 51 nmol/l by 4 days after exogenous progesterone treatment, and remained in the mid-luteal phase range, as established in 12 normal cycles, during the use of the vaginal suppository. The mean serum LH concentration had fallen significantly (p < or = 0.01) after 8 days of treatment, and continued to fall progressively until the end of progesterone administration. Serum LH concentrations had fallen into the normal follicular phase range by 14 days (mean 5.5, range 3.4-10.9 IU/l; normal follicular phase range 1.8-10.0 IU/l).(ABSTRACT TRUNCATED AT 250 WORDS)     

Monitoring induction of ovulation with human menopausal gonadotropin by a rapid estrogen radioimmunoassay

A study of human menopausal gonadotropin (HMG) in the induction of ovulation in 14 infertile, anovulatory women is presented. All of the women had failed to ovulate following clomiphene therapy. The dose of HMG administered in each of the 43 treatment cycles was determined by measuring the estrogen levels by either fluorimetric tests of total urinary estrogen, radioimmunoassay of serum estradiol, or a rapid 4-hour radioimmunoassay of immunoreactive serum estrogen. A significant correlation among the methods in establishing estrogen production obtained (r=.935; p less than .001). 38 of the 43 treatment cycles were presumed to be ovulatory, based on serum progesterone levels and basal body temperature. 7 of the 14 patients became pregnant (11 of the 38 ovulatory cycles). There were 5 instances of mild ovarian hyperstimulation during the study. The results demonstrate that the rapid radioimmunoassay technique for measuring serum estrogens, without chromatography, is capable of determining the extent of follicular maturation during HMG therapy.