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.     

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.     

The importance of human chorionic gonadotropin support of the corpus luteum during human gonadotropin therapy in women with anovulatory infertility

One hundred ten women with anovulatory infertility (World Health Organization [WHO] group I n = 50, WHO group II n = 60) were given 341 treatment courses with human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG). Additional hCG was given as single or repeated injections during the luteal phase in 205 ovulatory cycles. In WHO group I, the incidence of luteal phase defects was lower and the pregnancy rate higher in cycles with extra hCG administration during the luteal phase than in cycles with no extra hCG. In WHO group II, there was no such difference after supplemental hCG. The abortion rate was the same after cycles with or without extra hCG administration. It is suggested that during ovulation induction with hMG/hCG in anovulatory women with no evidence of endogenous estrogen activity, the luteal phase should be supplemented with additional 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.     

Detrimental effect of endometrial biopsies on pregnancy rate following human menopausal gonadotropin/human chorionic gonadotropin-induced ovulation

The effect of luteal phase endometrial biopsy was studied in 33 anovulatory women treated with human menopausal gonadotropins (hMG) to induce ovulation and pregnancy. Over-all, 33 of 85 ovulatory cycles resulted in pregnancy (39%). Of 50 nonbiopsied cycles, 26 resulted in pregnancy (52%) whereas only 7 of 35 biopsied cycles resulted in pregnancy (20() (P less than 0.01). Four pregnancies terminated in spontaneous first-trimester abortions, 12% in the nonbiopsied group and 14% in the biopsied group. Luteal phase endometrial biopsy significantly lowers pregnancy rates in hMG-induced ovulatory cycles, but does not change abortion rates.     

Serum levels of placental protein 14 reflect ovulation in nonconceptional menstrual cycles

Placental protein 14 (PP14), originally isolated from the human placenta and its adjacent membranes, was detected in the serum of nonpregnant women. The levels were measured by radioimmunoassay in 218 serum samples from 19 women throughout the menstrual cycle. In 13 women with a normal ovulatory cycle, the levels showed consistent variation. They were highest (up to 172 ng/ml) in the late secretory phase and remained high for the first days of the next cycle. Low concentrations were found from the midproliferative to the early luteal phase of the cycle. No similar variation was seen in anovulatory cycles of six other women. Compared with ovulatory cycles, anovulatory cycles exhibited lower PP14 levels in the latter part of the cycle (P less than 0.001) and in the beginning of the next cycle (P less than 0.01). In ovulatory cycles, the sustained elevation of serum PP14 concentration over the following period may be explained by the fairly long half-life (42 hours) of PP14 in serum: once the level has increased, it declines slowly. These results suggest that PP14 measurement may become a novel means to distinguish between ovulatory and anovulatory cycles even after the onset of the next period.     

Clinical and endocrinological studies on anovulatory women treated with two-step administration of clomiphene citrate

The two step clomiphene citrate (CL) administration therapy was performed in 89 patients with first grade amenorrhea during 1980 through 1983, and clinical data in 89 patients and daily serum hormone levels in 20 patients were investigated. Out of the 89 women, ovulation occurred in 71 (79.8%). As to the treatment cycles, ovulation occurred in 158 cycles (53.4%) out of the total 296 cycles. Pregnancy was achieved in 16 women, among whom 2 women ended in spontaneous abortion and one had a multiple pregnancy. (1) As for 9 women in whom ovulation was induced by this treatment, the serum level of LH in the follicular phase and that of estradiol in the late follicular phase and luteal phase were higher than those of women who had normal ovulatory cycles. (2) No significant differences were observed between the serum levels of FSH and progesterone of the 9 women and those of women with normal ovulatory cycles. (3) As for 11 women in whom ovulation was not induced by this treatment, a transient increase in serum levels of LH and estradiol were observed after the first step administration of CL. This change also appeared soon after completion of the second step administration of CL and became more significant as additional stepwise administration of CL was performed. In view of observations, it was concluded that CL two step administration is effective for anovulatory women who did not respond to one step use of CL. As previously reported, CL exerts its action on the central nervous system to promote ovulation, but it is also strongly suggested that CL has its direct action on the ovary too.     

Induction of luteal phase defect with clomiphene citrate

The effect of clomiphene citrate and progesterone on luteal function in infertile women was studied. Endometrial biopsies were performed in 103 women immediately prior to menstruation. Group 1 (n = 62) had secretory endometrium with a histologic lag time of ≥48 hours with respect to the subsequent menses, that is, luteal phase defect. Group 2 (n = 10) had normal histologic characteristics of the secretory phase. Group 3 (n = 31) had anovulatory endometrium. The last group was subdivided into those with polycystic ovary syndrome (n = 9) and those without the characteristic gonadotropin pattern of polycystic ovary syndrome (n = 22). Clomiphene citrate at doses of 50 to 250 mg daily for 5 days was administered for induction of ovulation, timing of ovulation, or treatment of luteal phase defect. An endometrial biopsy was obtained after three ovulatory treatment cycles. Only one fourth of the women with prior luteal phase defect had normalization of the biopsy specimen with clomiphene citrate, while one half of those treated with progesterone had normal specimens. Half of the normally ovulating women had induction of a luteal phase defect with clomiphene citrate. Only women with polycystic ovary syndrome had consistently well-timed endometrial histologic features with clomiphene citrate therapy. Despite successful induction of ovulation, 16 of the other 22 previously anovulatory women had endometrial histologic findings compatible with luteal phase defect. Increasing the clomiphene citrate dosage was unsuccessful in improving endometrial maturation. These results suggest that the use of clomiphene citrate may be associated with a high rate of luteal phase defect induction, except among women with polycystic ovary syndrome. Clomiphene citrate, even at high doses, appears to be ineffective therapy for luteal phase defect.     

Endometrial biopsy during induction of ovulation with clomiphene citrate in polycystic ovary syndrome.

BACKGROUND: The dichotomy between ovulation rates and pregnancy rates for women with polycystic ovary syndrome (PCOS) treated with clomiphene citrate (CC) prompted the present study to determine the effect of CC on endometrial maturity. METHODS: Retrospective case-control study of anovulatory women with PCOS (n = 119) on their third ovulatory cycle of CC and controls, 238 healthy regularly ovulating women whose partners had abnormal sperm, all of whom had an endometrial biopsy in the late luteal phase. RESULTS: Endometrial histology classified according to the classical Noyes criteria revealed out-of-phase endometrium in 19/119 (16%) of the CC group compared with 7/238 (3%) in controls (p < 0.0001). Duration of the luteal phase was not influenced by histological age of the endometrium. Endometrial biopsy performed during 138 conception cycles extracted from the database did not increase the miscarriage rate significantly (23.9%). CONCLUSIONS: CC treatment significantly increases the prevalence of out-of-phase endometrium and this could explain, in part, the large difference between ovulation and pregnancy rates. There was no correlation between the results of the endometrial biopsy and the duration of the luteal phase. Performing an endometrial biopsy during a conception cycle does not seem to have a significant negative effect on the outcome of pregnancy.     

Intermittent bromocriptine treatment for the induction of ovulation in hyperprolactinemic patients

Postovulatory treatment with bromocriptine bears a potential teratogenic risk. Therefore, after restoration of the menstrual cycle in 20 infertile hyperprolactinemic anovulatory patients, treatment was restricted to the follicular phase and the periovulatory period. The resulting intermittent treatment regimen using a dose of 5 mg of bromocriptine/day yielded ovulatory cycles in all 20 patients. Fifteen pregnancies were achieved in thirteen patients, two women becoming pregnant twice. Discontinuation of treatment after ovulation caused hyperprolactinemia during the luteal phase. This did not seem to interfere with the establishment and maintenance of pregnancy. Hyperprolactinemia during the follicular phase may be related to luteal insufficiency.     

Prolactinemia during the menstrual cycle. A possible role for prolactin in the regulation of ovarian function

We measured the concentration of circulating prolactin (PRL) in the serum during ovulatory and anovulatory cycles of normoprolactinemic menstruating women. The results demonstrate that during the luteal phase of ovulatory cycles a significant increase of PRL is observed together with that of progesterone. On the contrary, in menstruating women with anovulatory cycles we could not detect these increases. These data, analyzed together with the concomitant changes of gonadotrophins secretion, suggest a possible luteotrophic action of PRL in humans during the menstrual cycle.     

Induction of ovulation with pulsatile subcutaneous administration of human menopausal gonadotropin in anovulatory infertile women

Pulsatile administration of human menopausal gonadotropin (hMG) via the subcutaneous route was evaluated in 15 patients with various ovulatory disorders. Administration of hMG was started at a dose of 4.6875 IU (75 IU/day) or 9.375 IU (150 IU/day) per pulse every 90 minutes. Ovulation was observed in 26 (92.9%) of 28 treatment cycles, and two singleton pregnancies were confirmed. Ovarian hyperstimulation was observed in 1 to 26 ovulatory cycles; however, no other side effects were observed during treatment. A regimen of 75 IU/day resulted in a significant increase (P less than 0.0001) of the total dose and prolongation of the treatment period for induction of ovulation, as compared with that of 150 IU/day. Shortened luteal phases occurred in ovulatory cycles induced by pulsatile subcutaneous treatment. Human chorionic gonadotropin administration given every other day until the midluteal phase significantly prolonged the duration of the luteal phase (P less than 0.05). This treatment in patients with the polycystic ovary syndrome was followed by a normalization of luteinizing hormone/follicle-stimulating hormone ratio and resulted in a successful induction of ovulation in 8 to 10 cycles. The present data demonstrated that pulsatile subcutaneous administration of hMG was effective in inducing follicular maturation and ovulation in patients with various types of anovulatory infertility.     

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.     

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.     

Endometrial biopsy during induction of ovulation with clomiphene citrate in polycystic ovary syndrome

Background.?The dichotomy between ovulation rates and pregnancy rates for women with polycystic ovary syndrome (PCOS) treated with clomiphene citrate (CC) prompted the present study to determine the effect of CC on endometrial maturity.

Methods.?Retrospective case–control study of anovulatory women with PCOS (n = 119) on their third ovulatory cycle of CC and controls, 238 healthy regularly ovulating women whose partners had abnormal sperm, all of whom had an endometrial biopsy in the late luteal phase.

Results.?Endometrial histology classified according to the classical Noyes criteria revealed out-of-phase endometrium in 19/119 (16%) of the CC group compared with 7/238 (3%) in controls (p < 0.0001). Duration of the luteal phase was not influenced by histological age of the endometrium. Endometrial biopsy performed during 138 conception cycles extracted from the database did not increase the miscarriage rate significantly (23.9%).

Conclusions.?CC treatment significantly increases the prevalence of out-of-phase endometrium and this could explain, in part, the large difference between ovulation and pregnancy rates. There was no correlation between the results of the endometrial biopsy and the duration of the luteal phase. Performing an endometrial biopsy during a conception cycle does not seem to have a significant negative effect on the outcome of pregnancy.     

Induction of ovulation with pulsatile gonadotropin releasing hormone (GnRH) in anovulatory women

In this study we employed pulsatile GnRH therapy in different anovulatory disorders to test its real efficacy on ovulation induction. Ten adult women, 25-35 years old with primary or secondary infertility, underwent our study; all women showed anovulatory disorders such as Secondary Amenorrhea (n. 4), PCOD (n. 3) or Oligomenorrhea resistant to Clomiphene Citrate (n. 3). Pulsatile gonadotropin releasing hormone (GnRH) was given intravenously via automatic micropump, with a pulse interval of 90' and a pulse dose of 5 mcg/day. Ovulation was achieved in 7 cases (70%), whereas the failure of therapy was observed in 3 patients (30%), all affected by PCOD. The mean duration of follicular phase was 15 days and the ovulatory cycles did not need the luteal phase support. The maximum length of infusional therapy was 20 days with a low incidence of adverse side effects such as phlebitis; only in one patient a mild ovarian hyperstimulation was observed. Our results confirm that infusional pulsatile GnRH therapy is a very important tool to ovulation induction and it is more successful in primary or secondary amenorrhea and in hypothalamic disorders than in PCOD.     

Endometrial blood flow measured by xenon 133 clearance in women with normal menstrual cycles and dysfunctional uterine bleeding

Endometrial blood flow was measured through the menstrual cycle in nonpregnant women (28 studies of 17 women with normal menstrual cycles and 32 studies of 20 women with dysfunctional uterine bleeding) with use of a clearance technique in which 100 to 400 microCi of the gamma-emitting isotope, xenon 133 in saline solution was instilled into the uterine cavity. The mean (+/- SEM) endometrial blood flow in normal cycles was 27.7 +/- 2.6 ml/100 gm/min, with a significant elevation in the middle to late follicular phase, followed by a substantial fall and a secondary slow luteal phase rise that was maintained until the onset of menstruation. There was a significant correlation between plasma estradiol levels and endometrial blood flow in the follicular but not the luteal phase. Blood flow patterns in women with ovulatory dysfunctional bleeding were similar to normal, except for a significantly lower middle follicular rate. Women with anovulatory dysfunctional bleeding exhibited exceedingly variable flow rates.     

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.     

Dieting influences the menstrual cycle: vegetarian versus nonvegetarian diet

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

Luteal phase hyperprolactinemia during ovulation induction with human menopausal gonadotropins: incidence, recurrence, and effect on pregnancy rates

Hyperprolactinemia may develop during ovulation induction with human menopausal gonadotropins and hCG (hMG/hCG). Because elevated serum prolactin (PRL) has several adverse effects on female reproductive function, this event has been implicated as a factor to explain the difference between ovulation and pregnancy rates in hMG/hCG treatment cycles. The incidence and severity of hyperprolactinemia in the luteal phase of hMG/hCG-stimulated cycles was investigated in a large series of patients. We analyzed 240 consecutive, ovulatory hMG/hCG cycles in 96 women from July 1984 to January 1986. All women had failed to conceive with clomiphene citrate, and had normal luteal phase PRL levels during unstimulated cycles. Daily serum total estrogens were determined during hMG administration. Serum progesterone and PRL were determined in the mid-luteal phase (7 days post-hCG administration). In 7.5% of the cycles, luteal phase PRL elevations were greater than 25 ng/mL. Only 2.5% of cycles had levels of PRL greater than 35 ng/mL. Hyperprolactinemia infrequently recurred in different cycles of the same patient (two of 16 patients, 12.5%). Cycles with hyperprolactinemia were found to have significantly higher preovulatory estrogen levels. Serum progesterone levels were not significantly decreased in cycles with elevated PRL. Pregnancy rates in cycles with and without hyperprolactinemia were similar (7.7 versus 11.1%, respectively; P greater than .05). We conclude that the development of luteal phase hyperprolactinemia during ovulation induction with hMG/hCG is an isolated event. High preovulatory estrogen levels may predispose to its development. Because hyperprolactinemia is uncommon and is usually mild, other factors must be responsible for the difference between ovulation and pregnancy rates using hMG/hCG.