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PubMed1996

Incidence of spontaneous abortion in clomiphene pregnancies.

The purpose of this study was to determine whether the use of clomiphene results in a higher incidence of spontaneous abortion than occurs naturally in subfertile patients. Reproductive outcomes of 1744 clomiphene pregnancies were compared to outcomes of 3245 spontaneous pregnancies in a prospective study. Abortion was classified as clinical if a sac was seen on ultrasound or if it occurred after 6 gestational weeks, and as preclinical if a quantitative human chorionic gonadotrophin (HCG) was > or = 25 mIU and no sac was seen or abortion occurred earlier. The overall incidence of abortion was higher for clomiphene pregnancies (23.7%), compared with spontaneous pregnancies (20.4%) (P < 0.01). Preclinical abortions were increased by clomiphene for all ages (5.8 versus 3.9%, P < 0.01) and for age > or = 30 years (8.0 versus 4.9%, P < 0.001), but not for age < 30 years (3.7 versus 3.0%). Clinical abortions were increased by clomiphene for age < 30 years (15.9 versus 11.2%) (P < 0.01), but not for age > or = 30 years (20.1 versus 22.3%) or all ages (18.0 versus 16.4%). Clinical abortions occurred 22% less often following clomiphene compared with spontaneous pregnancies for patients with luteal insufficiency (18.3 versus 23.6%, P < 0.05). We conclude that the increase in abortion due to clomiphene is small and may be related to different causes for women aged < 30 and > or = 30 years, and also that clomiphene may decrease clinical abortions in patients with luteal insufficiency.

Abortion, Spontaneous↗

PubMed1987

Effect of clomiphene isomers on progestin synthesis in cultured human granulosa cells.

The effect of en-clomiphene and zu-clomiphene (10(-9)-10(-5) M) on progestin synthesis in cultured human granulosa cells was studied under basal conditions and in the presence of LH (100 ng/ml). Granulosa cells were obtained from either pre-ovulatory follicles of clomiphene-HMG-stimulated cycles or from large follicles of mid-to-late follicular phase of spontaneous cycles. The basal and LH-stimulated progesterone accumulation was dose-dependently reduced by en- and zu-clomiphene (10(-6)-10(-5) M) in cells from both groups studied, an effect similar to that of oestradiol. In contrast to oestradiol, both en- and zu-clomiphene (10(-6)-10(-5) M) reduced the basal and LH-stimulated pregnenolone accumulation in cells of stimulated cycles. The effect of clomiphene on progesterone, and pregnenolone accumulation was more pronounced in LH-stimulated cells than under basal conditions. There were no qualitative differences between the two isomers and the results were principally the same in cells from both groups of follicles studied. It is concluded that en-clomiphene and zu-clomiphene have similar inhibitory effects on progestin synthesis in human granulosa cells in vitro.

Cells, Cultured↗

PubMed1982

Effect of clomiphene citrate on preovulatory rat follicles in culture.

The effect of clomiphene citrate was tested on rat preovulatory follicles in culture. Clomiphene inhibited both basal and luteinizing hormone (LH)-stimulated steroid accumulation. The dose-dependent effect of clomiphene was much more pronounced on follicles cultured with LH; while 0.01 mM had no effect, 2 mM clomiphene decreased progesterone accumulation by 97%, estradiol-17 beta by 90% and testosterone by 65% (P less than 0.001). The inhibitory action of the drug was not prevented by addition of 8-Br-cAMP (1 mM) or pregnenolone (1 microgram/ml) to the culture medium. clomiphene (0.01 - 0.5 mM) induced the resumption of meiotic maturation even in LH-free medium in approximately 60% of follicle-enclosed oocytes. At the higher concentrations tested (0.1 - 0.5 mM) degenerative changes were noted in a high proportion of oocytes (30-40%). Follicles incubated for 24 h with clomiphene exhibited dose-dependent atretic-like changes. These effects of clomiphene on preovulatory follicles may account for the discrepancy between ovulation and pregnancy rates observed in women treated with clomiphene.

Animals↗

PubMed1983

Effects of clomiphene on luteal function in the nonpregnant cynomolgus macaque.

Although estradiol-17 beta (E2) induces premature regression of the corpus luteum (CL), its role in spontaneous luteolysis which occurs at the end of the nonfertile cycle has not been demonstrated. We compared the effects of an estrogen antagonist on E2-induced and spontaneous luteolysis by administering clomiphene (10 mg/day) to cynomolgus macaques during the luteal phase in the presence and absence of exogenous E2 (supplied by subcutaneous Silastic implants). Other animals received either vehicle or E2 implants. Luteal function was assessed by progesterone concentrations and luteal phase length. Clomiphene maintained normal luteal function in the presence of luteolytic levels of E2 in five of six monkeys. However, clomiphene alone did not prolong luteal function beyond that observed in monkeys receiving vehicle. To assess the direct effect of clomiphene on the CL, we incubated monkey luteal cells with human chorionic gonadotropin and clomiphene, E2, or clomiphene plus E2. Clomiphene (1500 ng/ml) alone and E2 (1000 ng/ml) alone significantly (P less than 0.05) inhibited progestin production. Clomiphene and E2 together depressed progestin production to an even greater extent. The data suggest that the mechanisms involved in E2-induced and spontaneous luteolysis differ.

Animals↗

PubMed1983

Pituitary responsiveness to LHRH and TRH in men: effect of bromocriptine and clomiphene treatment.

The effect of the concomitant use of bromocriptine and clomiphene on pituitary function was tested in 8 healthy men, who ingested either 100 mg of clomiphene, 5 mg of bromocriptine or 100 mg of clomiphene +5 mg of bromocriptine daily for 7 days. Plasma concentrations of FSH and LH increased similarly during clomiphene and clomiphene + bromocriptine intake. Bromocriptine decreased the plasma levels of prolactin (Prl) and this decrease was unaffected by clomiphene. The latter blunted the plasma LH response to LHRH whilst bromocriptine blunted the Prl response to TRH, but Clomiphene and bromocriptine together had no additive effects on gonadotrophin and Prl secretion. It thus seems likely that this combination offers no advantage over clomiphene alone in the treatment of normoprolactinaemic infertile men.

Adult↗

PubMed2000

Clomiphene, an ovulation-inducing agent, mobilizes intracellular Ca2+ and causes extracellular Ca2+ influx in bladder female transitional carcinoma cells.

BACKGROUND/METHODS: The effect of clomiphene, an ovulation-inducing agent, on cytosolic free Ca2+ levels ([Ca2+]i) in populations of BFTC human bladder cancer cells was explored by using fura-2 as a Ca2+ indicator. RESULTS: Clomiphene at concentrations between 10 and 75 microM increased [Ca2+]i in a concentration-dependent manner and the signal saturated at 50 microM. The [Ca2+]i signal was biphasic with an initial rise and a slow decay. Ca2+ removal inhibited the Ca2+ signal by about 40-50% in maximum [Ca2+]i. Adding 3 mM Ca2+ increased [Ca2+]i in cells pretreated with 50 microM clomiphene in Ca2+-free medium, suggesting that clomiphene induced capacitative Ca2+ entry. In Ca2+-free medium, pretreatment with 50 microM brefeldin A (to disrupt the Golgi complex Ca2+ store), 1 microM thapsigargin (to inhibit the endoplasmic reticulum Ca2+ pump), and CCCP (to uncouple mitochondria) inhibited 85% of clomiphene-induced intracellular Ca2+ release. Conversely, pretreatment with 50 microM clomiphene in Ca2+-free medium abolished the [Ca2+]i increase induced by brefeldin, thapsigargin or CCCP. The intracellular Ca2+ release was unaltered by inhibiting formation of inositol-1,4,5-trisphosphate (IP3) with 2 mM 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122; a phospholipase C inhibitor). CONCLUSION: The [Ca2+]i increase induced by 50 microM clomiphene was not affected by 10 microM of nifedipine, verapamil or diltiazem. Collectively, the results suggest that clomiphene releases intracellular Ca2+ in an IP3-independent manner and also activates extracellular Ca2+ influx.

Calcium↗

PubMed1987

Pulsatile luteinizing hormone secretion and clomiphene and bromocriptine response in amenorrheic women with normoprolactinemia and gestagen withdrawal bleeding.

This study was carried out to determine whether the ovulatory response with clomiphene citrate and bromocriptine in 20 amenorrheic women with normoprolactinemia and gestagen withdrawal bleeding is influenced by the pretreatment pattern of pulsatile luteinizing hormone (LH) secretion. Two patients who had no LH pulse for 3-5 h failed to respond to clomiphene. One of them was treated with bromocriptine, but ovulation did not occur. Eleven of 12 patients who had one or more LH pulses and LH pulse/h ratios of less than 1 for 3-5 h ovulated with clomiphene. One clomiphene nonresponsive patient ovulated with combined therapy of bromocriptine and clomiphene. All 6 patients who had LH pulse/h ratios of greater than or equal to 1 for 3-5 h failed to ovulate with clomiphene. Three of them were treated with bromocriptine. Two of 3 patients ovulated with bromocriptine alone and 1 ovulated with combined therapy of bromocriptine and clomiphene. These results suggest that the pretreatment pattern of pulsatile LH secretion may predict the clinical response to clomiphene and bromocriptine treatment in amenorrheic women with normoprolactinemia and gestagen withdrawal bleeding.

Adult↗

PubMed1986

Inhibitory effect of clomiphene citrate on the conversion of 13,14-dihydro-15-keto-prostaglandin F2 alpha to 13,14-dihydro-prostaglandin F2 alpha in rat ovary.

The effects of clomiphene citrate (clomiphene) on the in vitro conversion of 13,14-dihydro-15-keto-prostaglandin F2 alpha (15KD-PGF2 alpha) to 13,14-dihydro-prostaglandin F2 alpha (13,14H2-PGF2 alpha) in the presence of rat ovarian homogenate, and the relationship between clomiphene and gonadotropin or estrogen in the conversion were investigated. Although clomiphene inhibited the increased conversion of 15KD-PGF2 alpha to 13,14H2-PGF2 alpha by pregnant mare serum gonadotropin (PMS) in rat ovary, the drug did not inhibit the decreased conversion of 15KD-PGF2 alpha by estradiol. The 3-day administration of clomiphene reduced the conversion of 15KD-PGF2 alpha to 13,14H2-PGF2 alpha dose-dependently. A single administration of clomiphene also decreased the conversion, and this decreasing effect was similar to that of estradiol. On the other hand, the repeated administration of clomiphene decreased the ovarian and uterine weights and also inhibited the increase of the uterine weight by PMS or estradiol. These results suggest that clomiphene affects the ovarian enzyme catalyzing the conversion of 15KD-PGF2 alpha to 13,14H2-PGF2 alpha.

Animals↗

PubMed1984

Hydrocortisone elicits the effect of clomiphene citrate on luteinizing hormone-releasing hormone release in vitro.

The effect of hydrocortisone on the release of luteinizing hormone (LH) and LH-releasing hormone (LRH) in response to clomiphene citrate (clomiphene) were examined in a sequential double chamber perifusion system by perifusing the mediobasal hypothalami (MBH) and/or pituitaries excised from normal female rats in dioestrus. When the MBH and the pituitary were perifused in sequence with medium containing 5 X 10(-6) M hydrocortisone, a significant release in LH (100- 150% increase, P less than 0.01-P less than 0.05) was observed 40 min after the administration of 3 X 10(-8) mol clomiphene. Clomiphene had no effect on LH release from the pituitary when perifused in series with the MBH without basal hydrocortisone infusion. Administration of clomiphene did not cause a significant increase in LH from the pituitary perifused alone, with or without medium containing hydrocortisone. The concentration of LRH in the efflux was significantly increased 40 min after clomiphene administration when MBH was perifused with medium containing hydrocortisone, whereas clomiphene had no effect when perifused with medium only. These data indicate that hydrocortisone stimulates the effect of clomiphene on LRH release from the hypothalamus, which in turn induces LH release from the pituitary.

Animals↗

PubMedDate not supplied

Clomiphene administration for cases of nonobstructive azoospermia: a multicenter study.

Clomiphene citrate is a well-established agent that has been empirically used in cases of idiopathic oligospermia. Clomiphene increases endogenous gonadotropin-releasing hormone secretion from the hypothalamus and gonadotropin hormone secretion directly from the pituitary and, thus, increases intratesticular testosterone concentration. Using intracytoplasmic sperm injection (ICSI), very few sperm may be required for fertilization. The objective of this study was to determine if the application of clomiphene citrate in males with nonobstructive azoospermia might produce sufficient sperm for ICSI, either by resulting in sperm identified in the ejaculate or by potentially improving outcomes of surgical testicular sperm extraction. Forty-two patients with nonobstructive azoospermia (age range, 25-39 years) from 3 international centers were evaluated with routine history, physical examination, and hormonal assessment. Initial testicular biopsy demonstrated maturation arrest in 42.9% and hypospermatogenesis in 57.1% of patients. Clomiphene citrate was administered, with the dose titrated to achieve serum testosterone levels between 600 ng/dL and 800 ng/dL, and semen analyses were performed at periodic intervals. In patients remaining azoospermic on semen analysis, surgical testicular biopsy and sperm extraction were performed. After clomiphene citrate therapy, 64.3% of the patients demonstrated sperm in their semen analyses ranging from 1 to 16 million sperm/mL, with a mean sperm density of 3.8 million/mL. Sufficient sperm for ICSI was retrieved by testicular sperm extraction in all patients, even though 35.7% remained azoospermic. Additionally, clomiphene citrate administration resulted in a statistically significant increase in testis biopsy patterns associated with greater likelihood of sperm obtained by surgical extraction (P < .05). We conclude that clomiphene citrate administration may result in sperm in the ejaculate of patients with nonobstructive azoospermia or the simplification of testis sperm retrieval. Surgeons may consider a course of clomiphene citrate administration prior to surgical sperm retrieval in patients with nonobstructive azoospermia.

Adult↗

PubMed2006

Clomiphene-associated combined hyperlipidemia: a case report.

BACKGROUND: Hyperlipidemia associated with clomiphene use is an uncommon but potentiallly serious complication of this therapy. Clomiphene is structurally similar to other synthetic estrogen analogs, which are known to induce marked hypertriglyceridemia. There is a paucity of data regarding the effects of clomiphene on lipid metabolism in humans. CASE: A 33-year-old woman with obesity, polycystic ovary syndrome and a long history of amenorrhea was treated with clomiphene therapy to induce ovulation. Baseline lipids were suggestive of an underlying lipid disorder, but there was a marked deterioration in her lipid profile in association with the use of clomiphene. On cessation of the clomiphene therapy her lipid profile slowly improved, and specific lipid-lowering therapy was not used. Further investigation for the possibility of an underlying lipid disorder confirmed the diagnosis of familial dysbetalipoproteinemia. CONCLUSION: Clomiphene should be used cautiously in women known to have dyslipidemia. We recommend that patients with predisposing risk factors have their lipids measured prior to ovulation induction with clomiphene.

Adult↗

PubMed1989

Changes induced in adrenergic lipolysis by the administration of diethylstilboestrol, oestradiol and clomiphene.

The authors studied changes in adrenergic lipolysis in the epididymal adipose tissue of rats to which diethylstilboestrol and oestradiol combined with the anti-oestrogen clomiphene were administered. The maximum lipid-mobilizing effect of isoprenaline was increased not only by subcutaneously administered diethylstilboestrol, but also by the highest dose of the antioestrogen clomiphene used (p.o., 200 micrograms.kg-1 b.w.). Under the given experimental conditions, with 4 1/2 h incubation of adipose tissue, clomiphene was also effective when added in vitro. Its own oestrogenic effect probably stimulated the lipid-mobilizing action of isoprenaline. On combining the administration of increasing doses of clomiphene (p.o., 1-5 days) with a constant dose of oestradiol (200 micrograms.kg-1, s.c. on the 8th day, i.e. 24 h before the actual experiment), changes in isoprenaline lipolysis depended on the dose of clomiphene. In low doses clomiphene inhibited the stimulating effect of subsequently administered oestradiol on isoprenaline-induced lipolysis, but in large doses (100 and 200 micrograms.kg-1 daily) it potentiated, together with oestradiol, the lipid-mobilizing effect of isoprenaline. The results show that the non-steroid oestrogen diethylstilboestrol and the antioestrogen clomiphene may be included among the hormones capable of altering the response of adipose tissue to sympathomimetics (isoprenaline). We attribute the fact that clomiphene acted either as an antagonist or as an agonist of oestradiol to its combined oestrogenic and anti-oestrogenic effects.

Adipose Tissue↗

PubMed1976

The effects of clomiphene citrate on the hypothalamic-pituitary-gonadal axis in anorexia nervosa.

Serum luteinizing hormone (LH) responses to a course of clomiphene citrate were studied in eleven patients with anorexia nervosa at different stages of the illness. In malnourished patients basal levels of LH were invariably low. With the resumption of a normal weight a small but definite rise in LH levels was observed but this spontaneous response to weight gain was variable in that many patients continued to exhibit abnormally low LH levels. The response to clomiphene in terms of a rise in basal LH levels after administration of the drug, followed by a second peak of LH and subsequent menstrual bleeding, was clearly dependent in part on the patient's nutritional state. In the malnourished state the response to clomiphene was usually either absent or incomplete. After the resumption of a more normal weight, the patients invariably showed an initial rise in LH after the clomiphene, but the second LH peak and subsequent menstruation were frequently not demonstrated. Six patients maintained a normal body weight for at least six months after a course of clomiphene, but only three of them resumed cyclical menstrual bleeding. It was concluded that factors additional to the nutritional state contribute to the prolonged amenorrhoea in anorexia nervosa and that clomiphene appears to have only a limited role in the treatment and management of patients with the disorder. Some aspects of current knowledge of the endocrine mechanisms that regulate normal menstruation and of the mode of action of clomiphene are outlined. The results of the present study are discussed against this background in an attempt to elucidate further the hypothalamic disorder underlying the amenorrhoea in anorexia nervosa.

Adolescent↗

PubMed1988

Seizure control with clomiphene therapy. A case report.

Clinical seizures ceased during six months of clomiphene citrate therapy in a 36-year-old man who had hypogonadotropic hypogonadism, reproductive dysfunction, and a 16-year history of regular seizures. Seizures recurred during the month that followed the discontinuation of clomiphene therapy. This apparent antiseizure effect of clomiphene is discussed in terms of three possible mechanisms of action: (1) Clomiphene may benefit seizures by raising serum levels of antiseizure medications. (2) Clomiphene may improve seizures by normalizing serum testosterone levels. (3) Clomiphene may act at a cerebral level to lessen seizures. A controlled investigation of the effects of clomiphene on epilepsy in the setting of reproductive dysfunction is suggested.

Adult↗

PubMed1993

Preovulatory administration of clomiphene citrate to mice causes fetal growth retardation and neural tube defects (exencephaly) by an indirect maternal effect.

Clomiphene citrate was administered to female mice at different doses and different times prior to ovulation, in the preimplantation period after ovulation, and after implantation. Pregnancy outcome was determined on day 15 of gestation, when the number of implantations and resorptions were calculated relative to the number of ovulations, and fetuses were assessed for size and stage of development and morphological abnormalities. Preovulatory administration of clomiphene citrate caused decreased implantation rates and growth retardation of surviving fetuses, the degree of the effect being dependent on the dose and the time of drug injection relative to ovulation. The implantation rate was lowest, and the degree of fetal growth retardation highest, when clomiphene citrate was administered immediately before ovulation. An increased incidence of exencephaly was found in the fetuses of females injected with clomiphene citrate prior to ovulation. Transfer of blastocysts from treated mice to untreated fosters showed the effect of clomiphene citrate on implantation and fetal growth to be predominantly mediated through the female reproductive tract, rather than a direct effect on the embryo itself. Administration of clomiphene citrate in the preimplantational period resulted in complete inhibition of implantation, while the only effect when administration was after implantation was a slight reduction in fetal weight. These results indicate that preovulatory clomiphene citrate impairs uterine function, which has an indirect effect on the growth and development of the postimplantation embryo.

Animals↗

PubMed1996

Induction of ovulation in clomiphene-resistant polycystic ovary syndrome with pulsatile GnRH.

OBJECTIVE: To determine the efficacy of pulsatile GnRH alone and in combination with clomiphene citrate or gonadotropins in a stepwise approach for inducing ovulation in women with clomiphene-resistant polycystic ovary syndrome (PCOS). METHODS: Eighty women with clomiphene-resistant anovulatory infertility and PCOS were given subcutaneous pulsatile GnRH (15 micrograms every 90 minutes) using a portable infusion pump. If no follicular development was seen, clomiphene citrate (100 mg/day for 5 days) was given concurrently with the hormone in the next cycle of treatment. Those who still failed to ovulate regularly were treated with combined pulsatile GnRH with intramuscular gonadotropins (one ampule per day for 5-7 days). RESULTS. Sixty-six of 131 (50%) pulsatile GnRH cycles, 94 of 142 (66%) pulsatile GnRH with clomiphene cycles, and 48 of 69 (70%) pulsatile GnRH with gonadotropin cycles were ovulatory. Monofollicular response (one follicle at least 14 mm on the day of ovulation) occurred in 80.6, 83.9, and 53.6% of cycles, and multifollicular response occurred in 4.8, 3.1, and 21.6% of cycles in the three groups, respectively. Mild ovarian hyperstimulation occurred in one of the 342 cycles. The cumulative conception rate was 30% after three cycles, 60% after six cycles, and 73% after nine cycles. The miscarriage rate was 22% (ten of 45 pregnancies), and 35 women (78%) had live births (33 singletons and two sets of twins). CONCLUSION: The use of subcutaneous pulsatile GnRH alone and in combination with clomiphene citrate or gonadotropins for induction of ovulation in clomiphene-resistant PCOS in a stepwise approach produces a high cumulative conception rate associated with a low rate of multiple pregnancy and ovarian hyperstimulation syndrome.

Adult↗

PubMed1977

Clomiphene treatment in oligospermic infertile males.

This study of the effects of long-term clomiphene administration on semen analyses of oligospermic infertile males once again points to the potential therapeutic efficacy of clomiphene in certain subjects. Although the group of 16 subjects was small, all were men with long-standing infertility that had been refractory to previous treatments such as exogenous injections of human chorionic gonadotropin and varicocelectomy; 10 of the 16 men (62.5%) showed improvement in sperm counts within 2 to 5 months of starting clomiphene. Sperm motility improved moderately when counts improved; no effects on sperm morphology were noted. Of the 10 men classified as semen responders to clomiphene, 5 (50%) were successful in impregnating their wives within 2 to 8 months of starting treatment. These results approach the therapeutic efficacy seen with clomiphene in appropriately selected females with ovulatory disturbances. We have been unable to predict or characterize the patient who might be expected to show a semen response to clomiphene by history, physical examination response to previous treatment, or changes in blood testosterone levels while taking clomiphene.

Clomiphene↗

PubMed1982

Antiestrogenic action of high-dose clomiphene in primates pituitary augmentation but with ovarian attenuation.

Since the dominant follicle is selected by days 5 to 7 of the menstrual cycle, we assessed the differential effects of high-dose clomiphene (25 mg daily) by giving 5-day courses either before (days 1 to 5), during (days 5 to 9), or after (days 9 to 13) emergence of the selected dominant follicle in monkeys. Peripheral sera were obtained daily and assayed for follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17 beta-estradiol (E2), and progesterone (P); serial laparoscopies were performed. Rather than enhancement of gonadotropin-dependent folliculogenesis during clomiphene treatment cycles, ovulation was delayed in 18 of 18 treatment cycles. Interestingly, the interval from treatment to next ovulation lengthened when clomiphene was given in the late follicular phase. Consistently, the clomiphene treatment cycles were characterized by a marked decline of the serum E2 during the 5 days of therapy, despite concurrent elevations of pituitary gonadotropins in circulation, especially FSH. These data suggest that a direct antiestrogenic effect of clomiphene imparted ovarian refractoriness to the prevailing, even enhanced, gonadotropin levels. The vulnerability of follicular maturation to these attenuating effects of clomiphene was greatest in the late follicular phase, well after the dominant follicle had been selected. Even after this clomiphene-induced ovarian hiatus and eventual resumption of new follicle growth, the initial apparent ovulation led to latent, severe corpus luteum insufficiency.

Animals↗