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PubMed1983

Dehydrogesterone treatment of endometrial luteal phase deficiency after ovulation induced by clomiphene citrate and human chorionic gonadotropin.

Twenty infertile patients being treated with clomiphene citrate (CC) and human chorionic gonadotropin (hCG) for induction of ovulation, with a defective endometrial secretory pattern despite normal plasma levels of progesterone, estradiol, and prolactin, were entered into treatment plans on a random basis involving the following: CC-hCG plus dehydrogesterone (group 1), and CC-hCG (group 2). Success rates were similar in both groups (20% and 30%, respectively), based on a corrected endometrial defect during the second treated cycle. It is concluded that progestational agents are of low therapeutic value in endometrial luteal phase deficiency induced by CC.

Adult↗
PubMed1984

Clomiphene citrate in an in vitro fertilization program: hormonal comparisons between 50- and 150-mg daily dosages.

When clomiphene citrate is used for enhanced follicular recruitment in an in vitro fertilization and embryo transfer program, the usual dosage is 150 mg/day, although we recently reported comparable follicular development (size and number) with 50 mg/day. The present report compares circulating hormone levels between groups of patients receiving the two regimens. Gonadotropin levels were higher in the 150-mg group throughout the follicular phase. Serum estradiol (E2) levels, expressed either as total E2 or E2 per follicle greater than or equal to 15 mm, were also higher throughout the follicular phase in the 150-mg group. During the luteal phase, the progesterone levels were similar in both groups. However, there were higher E2 levels in the 150-mg group during the entire luteal phase. Even though there were no significant differences between groups with regard to the degree of enhanced follicular recruitment, there were significant differences in the observed hormone levels.

Clomiphene↗
PubMed1984

A randomized study of dexamethasone in ovulation induction with clomiphene citrate.

Improved understanding of follicular dynamics has led to a reevaluation of suppression of adrenal androgens in ovulation induction. To test whether adrenal suppression during clomiphene citrate (CC) therapy would improve ovulation/pregnancy rates, 64 anovulatory patients who had not previously received CC were randomly assigned to receive either 50 mg CC on days 5 to 9 alone or with 0.5 mg dexamethasone (CC + DEX). Patients were then screened for dehydroepiandrosterone sulfate (DHEA-S) (normal range, 80 to 320 micrograms/dl), prolactin, testosterone, and semen analysis of the partner. Nine patients discontinued participation prior to completing the first treatment cycle, and ten patients were found to have either elevated prolactin (4), severe male factors (3), or tubal disease (3) and were discontinued. CC was increased 50 mg/day per cycle through 150 mg/day until ovulation occurred. Once the patient was ovulatory on therapy, a properly timed postcoital test and endometrial biopsy for luteal phase defect were performed. If anovulatory at 150 mg/day of CC or demonstrating abnormal postcoital test or endometrial biopsy at 150 mg/day of CC, patients were crossed to the other arm of the treatment protocol. The results revealed a significantly higher rate of ovulation (P less than 0.01) and conception (P less than 0.05) in the CC + DEX-treated group. When correlated with DHEA-S levels, this improvement occurred in patients with DHEA-S greater than 200 micrograms/dl (P less than 0.05).

Adrenal Glands↗
PubMed1984

Sequential use of clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin in human in vitro fertilization. II. Study of luteal phase adequacy following aspiration of the preovulatory follicles.

The 88 patients included in the in vitro fertilization program during 113 cycles were submitted to superovulation by sequential use of clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin. No correlation was found between estradiol and progesterone levels during the luteal phase and estradiol on the days preceding administration of human chorionic gonadotropin. Nineteen biopsies of the endometrium were carried out. The importance of the increase of estradiol between the day before and the day of administration of human chorionic gonadotropin is positively correlated with the quality of the endometrium.

Chorionic Gonadotropin↗
PubMed1985

Altered follicular development in clomiphene citrate versus human menopausal gonadotropin-stimulated cycles for in vitro fertilization.

The pattern of periovulatory and luteal phase serum estradiol (E2) and progesterone (P) as well as follicular fluid (FF) E2, P, androgen, gonadotropin, and prolactin concentrations of eight women undergoing clomiphene citrate (CC)/human chorionic gonadotropin (hCG) stimulation and eight women undergoing human menopausal gonadotropin (hMG)/hCG stimulation of follicular development for the purpose of in vitro fertilization were compared. Ovulation was induced with either a 5-day course of CC (100 mg/day beginning on day 5 of the cycle) or an individualized hMG regimen, and laparoscopy was performed 36 hours after hCG administration. The length of the luteal phase was significantly longer (P less than 0.05) in the CC-treated group as compared with the hMG-treated group. The pattern of serum E2 levels differed significantly (P less than 0.01) in that E2 levels were lower in the early and midluteal phase in CC-stimulated cycles; in addition, a delayed second E2 peak was observed in the late luteal phase in these women. Serum P levels, however, were lower in the hMG-stimulated group. Analysis of FF hormone concentrations revealed significantly (P less than 0.05) higher concentrations of E2 and androsterone in the FF of hMG-treated patients. It is concluded that follicular development in CC-stimulated cycles differs markedly from that in hMG-stimulated cycles. These differences may reflect either an altered follicular maturational process or may represent a direct inhibitory effect of CC on follicular steroidogenesis.

Adult↗
PubMed1985

Serum dehydroepiandrosterone sulfate and the use of clomiphene citrate in anovulatory women.

Serum dehydroepiandrosterone sulfate (DHEA-S) is frequently elevated in anovulatory women. This study was carried out to determine whether the ovulatory response with clomiphene citrate (CC) in patients with elevated levels of serum DHEA-S is influenced by the pretreatment level. Also evaluated was whether this response rate was similar to or different from that of anovulatory patients who had normal levels of DHEA-S. CC was administered to 40 anovulatory patients who had elevated levels of DHEA-S. Rankit analysis of these 40 elevated DHEA-S levels indicated that two populations existed. These patients were, therefore, divided into two groups of 29 and 11 with DHEA-S levels of less than 5 and greater than 5 micrograms/ml, respectively. Fifty-nine anovulatory patients with normal DHEA-S levels were also treated with CC. Patients with elevated and normal DHEA-S levels had similar rates of ovulation with CC (75% and 78%). Among patients with elevated levels of DHEA-S, ovulation occurred in 55% of patients with levels greater than 5 micrograms/ml and 83% with levels less than 5 micrograms/ml. The dose of CC at which ovulation occurred was unrelated to the level of DHEA-S. Pregnancies occurred in 15 of the 40 patients after at least four ovulatory cycles and were not influenced by the level of DHEA-S. It is concluded that CC is effective in inducing ovulation in patients with elevated levels of adrenal androgens. However, in patients with DHEA-S levels greater than 5 micrograms/ml, the ovulatory response rate may be decreased.

Adult↗
PubMed1985

Sequential use of clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin in human in vitro fertilization. I. Follicular growth and oocyte suitability.

Sequential treatment with clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin was successfully applied to 149 women in the framework of an in vitro fertilization and embryo transfer program and led to the birth of normal children. An average of 3.5 follicles was promoted at each cycle. Oocyte maturity was evaluated at recovery either histologically or with respect to cumulus-oocyte complexes (COC) and correlated to oocyte fertilizability. Three types of COC are described according to cell dissociation and mucification. The most expanded cumulus mass (type I) was highly fertilizable, compared with granular and poorly dissociated cumulus complexes (types II and III, respectively). No improvement in the type II and III oocyte fertilizability was obtained when type I follicular fluid was added to the incubation medium. Moreover, incubation of type III oocytes in medium containing type III follicular fluid seemed to decrease their fertilizability.

Adult↗
PubMed1985

A comprehensive dose-response study of clomiphene citrate for enhancement of the primate ovarian/menstrual cycle.

Despite the increasing use of clomiphene citrate (CC) in normally cycling women undergoing in vitro fertilization, comprehensive data on the dose-response effects of the drug are unavailable. Twenty-four adult, normally cycling monkeys were given CC on cycle days 5 through 9 in doses ranging from 1 mg/kg to 10 mg/kg. Serum estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and progesterone were measured daily. CC stimulated an early, attenuated rise in serum LH which correlated with subsequent follicle development. Concurrently, serum E2 rose to preovulatory levels. No significant increase in serum FSH concentration was seen as a result of CC therapy. No correlation was seen between CC dose and peak levels of E2, LH, or FSH. The ovulatory status of the treatment cycles was also independent of dose. The factors that modulate these hormonal changes may involve direct effects of CC, estrogen feedback, and/or ovarian factors as yet uncharacterized. The individual variation of ovarian response, however, appears to be independent of the dose of CC.

Animals↗
PubMed1985

Direct ovarian effect of clomiphene citrate in the rabbit.

The effects of clomiphene citrate (CC) on ovulation and ovum maturation were studied using the isolated perfused rabbit ovary. CC (10(-5) M) added to the perfusate with human chorionic gonadotropin (50 IU) did not affect ovulatory efficiency, ovulation time, oocyte maturation, or degeneration of ovulated ova and follicular oocytes. During perfusion without human chorionic gonadotropin, the percentage of follicular oocytes with germinal vesicle breakdown was significantly increased in response to CC (10(-5) M or 10(-7) M); a greater percentage of follicular oocytes was degenerated. Estradiol (100 ng/ml) added to the perfusate reversed the effect of CC on degeneration of follicular oocytes. Of follicular oocytes from ovaries perfused with CC, 79.3% were degenerated; in contrast, 25% were degenerated in ovaries treated with CC plus estradiol. These data suggest that CC has a direct ovarian effect and that ovum degeneration associated with CC may be related to an antiestrogenic action.

Animals↗
PubMed1985

Effect of clomiphene citrate on human spermatozoal motility and fertilizing capacity in vitro.

The effect of clomiphene citrate (CC) at various concentrations (0.005, 0.05, 0.5, 5, and 50 micrograms/ml) on the in vitro motility and fertilizing capacity of human spermatozoa was studied. Spermatozoa collected from 14 normal men were washed in modified Krebs-Ringer solution (Biggers, Whitten and Whittingham [BWW] medium) and incubated with CC for 5 hours, the period required for spermatozoal capacitation. The percent motilities of spermatozoa were recorded at 0 and 5 hours during incubation with CC. After incubation, the spermatozoa were washed with BWW medium to remove CC before insemination of the zona-free hamster ova. CC caused a significant dose-dependent decrease in the penetration of denuded hamster ova in comparison with the control (P less than 0.05). Significant depressive effect on spermatozoal motility was observed with CC at 0.05 micrograms/ml or higher concentrations (P less than 0.05). These results indicate that (1) CC decreases human spermatozoal fertilizing capacity in vitro and (2) the inhibitory effect on fertilizing capacity could be due to the sperm-immobilizing activity of CC.

Animals↗
PubMed1985

Clomiphene citrate does not improve spermatozoal fertilizing capacity in idiopathic oligospermia.

Clomiphene citrate (CC) was given to 24 men with idiopathic oligospermia at a daily dose of 25 mg (10 subjects) or 50 mg (14 subjects). Sperm concentration increased slightly after CC treatment in both groups. Sperm motility and morphology remained unchanged. Spermatozoal fertilizing capacity as assessed by the zona-free hamster ova penetration test showed no significant change throughout the treatment period. Two pregnancies occurred in the partners of the subjects treated with 50 mg CC/day, but none occurred in the other group. We conclude that oral administration of CC does not improve fertilizing capacity of sperm as measured by the zona-free hamster ova penetration test in idiopathic oligospermia.

Adult↗
PubMed1985

Ultrasonographic and clinical correlates of menotropin versus sequential clomiphene citrate: menotropin therapy for induction of ovulation.

Forty-six women remaining infertile with clomiphene citrate (CC) with or without human chorionic gonadotropin (hCG) were treated by either human menopausal gonadotropin (hMG, 44 cycles) or CC + hMG (33 cycles) and monitored by serum estradiol (E2) and ultrasonography. Ovarian hyperstimulation syndrome (OHS) and pregnancy outcome were compared in both regimens. In the presence of dominant follicles (greater than or equal to 18 mm) alone or with a single secondary follicle (14 to 16 mm) at hCG administration, OHS did not develop. A significant increase in OHS was noted when three or more secondary follicles were observed. Overall pregnancy rates were similar in both regimens but significantly higher when hCG was injected before rather than after the E2 peak. The results suggest secondary follicles rather than dominant follicles are a valuable sign of possible OHS development; and CC + hMG should be considered in CC-failure patients.

Chorionic Gonadotropin↗
PubMed1986

Different hormonal patterns in human menopausal gonadotropin-treated, clomiphene citrate-treated, and untreated conception cycles.

Serum concentrations of seven different hormones were analyzed during 189 singleton conception cycles. One hundred nine women were treated with human menopausal gonadotropin (hMG), 52 women received clomiphene citrate (CC), and 28 became pregnant spontaneously. Serum progesterone (P) levels in hMG-treated women started to increase on day 18 of the cycle and reached peak concentrations between days 28 and 32 of the cycle. Serum estradiol (E2) concentrations paralleled the P patterns. In hMG-treated women, there were significant correlations between serum E2 and P concentrations and the number of the mature follicles observed before ovulation (both P less than 0.01). CC-treated and spontaneous conception cycles revealed significantly lower serum levels of P, E2, testosterone, 17 alpha-hydroxyprogesterone, and prolactin, compared with hMG-treated cycles (P less than 0.05). Elevations of the gonadal steroids in hMG-treated women possibly reflect the multiple corpora lutea formed after multiple ovulations.

17-alpha-Hydroxyprogesterone↗
PubMed1986

Comparison of two brands of clomiphene citrate for stimulation of follicular development in a program for in vitro fertilization.

Although clomiphene citrate (CC) is used frequently to stimulate multiple follicular development in in vitro fertilization programs, comparison of the two commercially available types has been limited. Therefore, a comparison was made of Serophene (Serono Laboratories, Inc., Randolph, MA) and Clomid (Merrell Dow Pharmaceuticals, Inc., Cincinnati, OH), using the same dosage regimen of CC (150 mg/day for days 3 to 7 of the cycle). Weights and ages of the two groups were not different. Serum estradiol (E2) levels were significantly elevated in Clomid cycles, but the number of developing follicles was not different between the two brands. The percentages of patients in each group who underwent laparoscopy, oocyte recovery, oocyte fertilization, and embryo transfer were also equivalent. Among patients undergoing laparoscopy, no differences in oocyte recovery, oocyte fertilization, and embryo development were noted. Thus, despite greater elevation of serum E2 levels with Clomid, no difference in stimulation regimen outcome was observed.

Adult↗
PubMed1986

Effect of clomiphene citrate on in vitro ovulated ova.

The effect of clomiphene citrate (CC) on developmental capacity of ovulated ova was studied with isolated in vitro perfused rabbit ovaries. Fifty-two ovulated ova were recovered from ovaries perfused with human chorionic gonadotropin (hCG) in a medium containing CC and 45 ova from ovaries perfused with hCG in a CC-free medium. Ova were cultured and inseminated with capacitated sperm and observed serially for evidence of fertilization and stage of development. CC did not affect the fertilization of ovulated ova. However, the percentage of ova which had reached the morula stage by 60 hours was significantly reduced in the CC-treated (15.4%) group, compared with the control group of ovaries (48.9%). A significant percentage of inseminated ova from CC-treated ovaries (65.4%) showed evidence of degeneration, as compared with control ovaries (37.8%). Thus, a partial loss of developmental capacity may explain the discrepancy observed between the rate of successful ovulation induction and the establishment of pregnancy associated with CC administration in humans.

Animals↗
PubMed1986

Hormone excretion during early pregnancy following spontaneous and clomiphene citrate-induced ovulation.

Endocrine changes during early pregnancy have been studied in 12 patients between days 35 and 91 from the last menstrual period. Ovulation had occurred spontaneously in five patients and was induced with clomiphene citrate (CC) in the remaining seven women. All the patients collected daily samples of early morning urine throughout the period of study; on each sample, human chorionic gonadotropin (hCG), pregnanediol-3-alpha-glucuronide (PGDG) and estrone-3-glucuronide (E1G) were measured by chemiluminescence immunoassay. No significant difference was observed between the two groups of patients with respect to the concentrations of hCG and PGDG. The excretion of E1G, however, was significantly higher in patients treated with CC. These data suggest that the induction of ovulation with CC may affect estrogen production in early pregnancy.

Adult↗
PubMed1986

Single-dose pharmacokinetics of clomiphene citrate in normal volunteers.

Twenty-four healthy adult female volunteers participated in a randomized, three-phase double-blind crossover trial comparing the single-dose (50 mg) pharmacokinetics of three formulations of clomiphene citrate (CC). Plasma levels of both the Z(cis) and E(trans) isomers of CC, as well as principal metabolites, were determined at periodic intervals; and no differences between formulations were observed. The active Z isomer attained peak blood levels later than the inactive E isomer and was eliminated much more slowly, significant plasma concentrations still being detected up to 1 month after treatment. The results of this study demonstrate that three commercially available formulations of CC are bioequivalent.

Adult↗
PubMed1986

Ovulation induction with pulsatile luteinizing releasing hormone in women with clomiphene citrate-resistant polycystic ovary-like disease: clinical results.

Eighty-four treatment units were given to 11 women with clomiphene citrate-resistant polycystic ovarian disease (PCOD). PCOD was defined as oligomenorrhea elevated luteinizing hormone (LH), normal follicle-stimulating hormone (FSH), and preference-elevated androgens. Luteinizing-releasing hormone (LRH) was administered intravenously via a portable infusion pump. Doses varied between 5 and 40 micrograms/pulse given at 60-, 90-, or 120-minute intervals. In 11 women, 85 treatment units (TUs) were completed, of which 74 were ovulatory, showing no specific advantage of any particular pulse dose or pulse interval. Five pregnancies occurred in three women. Two women did not ovulate during 52 and 284 consecutive days of therapy, respectively. Oligomenorrheic patients with PCOD can be made more regular by means of LRH, not necessarily leading to a regular menstrual cycle. In general, LRH is sufficient for luteal support. No signs of hyperstimulation were observed, although two patients incidently developed unilocular cysts with a maximum diameter of 8 cm. Ovulation induction with LRH in PCOD is possible, although the disease itself does not change during therapy. This may be further evidence that altered hypothalamic LRH secretion is more the result, rather than the cause, of the phenomenon of PCOD.

17-Ketosteroids↗