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Induction of ovulation by prolonged pulsatile administration of luteinizing hormone releasing hormone (LRH) in patients with clomiphene resistant polycystic ovary-like disease.

Induction of ovulation with pulsatile administration of LRH by automatic portable infusion pump for 74 and 147 consecutive days in 2 patients with clomiphene resistant PCO-like disease is described. The patients exhibited 6 ovulatory cycles. One patient conceived during the fourth cycle. During the treatment a unilocular cyst, probably a lutein cyst, developed in one patient, but subsequently disappeared spontaneously under uninterrupted therapy. No chemical hyperstimulation was observed. Follicular phases lasted for 32 and 13 days in patient I and for 19, 25, 14 and 22 days in patient II. Luteal phases lasted for 16 and 15 days in patient I and for 17, 18 and 15 days, respectively in patient II. Total urinary oestrogen and pregnanediol excretion did not differ from that seen in normal cycles. LH baseline and peak values and LH responses declined to normal levels accompanied by a normalization of the LH/FSH ratio during pulsatile LRH treatment in both patients. The first pre-ovulatory episode occurred already after partial normalization of the LH/FSH ratio. The endocrinology of the second LRH induced cycles of patients I and II was not different from cycles similarly induced in hypogonadotrophic patients. We conclude that ovulation induction with pulsatile LRH administration in patients with clomiphene resistant PCO-like disease is possible. Our findings give hope that this mode of treatment may not only be effective, but may prove to be safer than ovulation induction with menopausal gonadotrophins in patients with clomiphene resistant PCO-like disease.

Adult↗

Ovulation induction with a single-blind treatment regimen comparing naltrexone, placebo and clomiphene citrate in women with secondary amenorrhea.

Secondary amenorrhea is often associated with emotional stress, weight loss, eating disorders or polycystic ovary-like disease. Involvement of the endogenous opioids in the pathophysiology of hypothalamic amenorrhea, by inhibition of hypothalamic GnRH secretion, has been demonstrated in some cases. Chronic blockade of the endogenous opioids with the long-acting opioid antagonist naltrexone could result in increased gonadotropin secretion and ovulation induction in these cases. A single-blind ovulation induction protocol comparing naltrexone, placebo and clomiphene citrate was evaluated in eight patients with secondary amenorrhea. Naltrexone proved not to be more effective than placebo in our study. Only one patient ovulated on naltrexone, one on placebo and four on clomiphene citrate. The latter therapy caused a better endocrine response. In conclusion, although ovulation could be incidentally induced by naltrexone, this drug did not appear to be more successful than placebo and clomiphene citrate for ovulation induction in this population of patients.

Amenorrhea↗

Effects of clomiphene citrate on early pregnancy in guinea-pigs.

Clomiphene citrate (2 mg/kg body wt) given on the day of mating can block or interrupt pregnancy in guinea-pigs. Corpus luteum function, uterine histology, implantation and embryo development were studied in clomiphene-treated and control animals on Days 5, 9 and 20 of pregnancy. Following treatment, only 25% of the females were regularly pregnant, presenting large and healthy foetuses. The other females examined showed either pregnancy with embryos undergoing resorption or no sign of pregnancy. In these females, corpus luteum size was reduced, progesterone concentrations were very low and the endometrial glands and the epithelium were often altered. It is concluded that clomiphene causes a reduction in fertility by altering the uterus and, by directly or indirectly inducing luteolysis, causes later pregnancy loss.

Animals↗

Addition of exogenous estrogens to improve cervical mucus following clomiphene citrate medication. Patient selection.

Medication with Clomiphene Citrate and its effects on the quality of cervical mucus and the addition of exogenous estrogens in order to suppress abnormal mucus secretion are controversial issues. We have prospectively studied a group of 19 anovulatory women who were treated with clomiphene citrate in order to characterize those patients most likely to respond to the addition of exogenous estrogens. On day 14 of the cycle, 17 beta estradiol and cervical score were measured and 1 mg estradiol benzoate was injected intramuscularly. Cervical scores were below 7 in 12 out of the 19 patients before estradiol benzoate administration. In these patients, 17 beta estradiol rose from 751 +/- 541 to 1321 +/- 648 pg/ml (p less than 0.03), and cervical scores rose from 3.75 +/- 2.1 to 7.1 +/- 3.7 (p less than 0.01), after estradiol benzoate administration. Patients with cervical scores of 8-12 did not improve significantly. In the 12 patients with cervical scores below 7, those (n = 6) with 17 beta estradiol below 600 pg/ml experienced a significant improvement in cervical score, in contrast to those (n = 6) with 17 beta estradiol above 600 pg/ml who had no improvement. The reduction in cervical mucus accomplished with clomiphene citrate can be further improved by adding exogenous estrogens, mainly in patients who have low 17 beta estradiol levels concomitant with low cervical score.

Anovulation↗

Synergism of pulsatile LHRH therapy with oral clomiphene treatment.

Eighteen anovulatory patients who were resistant to induction of ovulation with clomiphene and with subcutaneous pulsatile LHRH were treated with these two agents given simultaneously. Twelve of the 14 patients with polycystic ovary syndrome, 1 patient with weight-related amenorrhea and 1 of 3 patients with intrinsic pituitary disease responded to the combined treatment. Serial determinations of serum gonadotropin concentrations showed that these remained unchanged by clomiphene treatment, suggesting a direct action on the ovary. For induction of ovulation for in vivo fertilization, the combination of oral clomiphene with subcutaneous pulsatile LHRH is worth trying before proceeding to intravenous LHRH or hMG therapy.

Administration, Oral↗

[Therapeutic evaluation of male infertility--the increase of seminal transferrin level and the improvement in sperm concentration following administration of clomiphene citrate].

This study was designed to evaluate the functional changes of Sertoli cells following the administration of clomiphene citrate for male infertility. Sperm count and seminal transferrin level were measured before and after the treatment in 22 cases of oligozoospermia (sperm count: less than 20 X 10(6)/ml) and 14 cases of subnormal sperm count group (sperm count: 20-30 X 10(6)/ml). Clomiphene citrate was administered per os for more than 3 months consecutively in a dose of 25 mg/day. Seminal transferrin concentration increased more than 1.5 times compared with pre-treatment level in 6 cases (16.7%). Among these patients, sperm count markedly increased (20 X 10(6)/ml or more than the pre-treatment level) in 3 cases (50%) and slightly increased (10 X 10(6)/ml or more than pre-treatment) in 1 case (16.7%). In 30 cases, in which seminal transferrin level did not increase, sperm count markedly increased in 6 cases (20%) and slightly increased in 6 cases (20%). Thus, sperm count was improved more frequently in the cases in which seminal transferrin level remained elevated than the cases with no elevation of serum transferrin level. Serum FSH level of patients whose seminal transferrin level remained elevated after the treatment was significantly higher than that of patients with no elevation of serum transferrin level (mean +/- SD = 32.8 +/- 18.0 mIU/ml v.s. 14.4 +/- 11.7 mIU/ml, respectively). These data suggested that the activation of Sertoli cells may contribute to the increase of sperm count following the administration of clomiphene citrate and the elevated seminal transferrin secretion may be related to the increase of serum FSH level following this treatment.

Clomiphene↗

Clomiphene-responsive hypogonadism in sickle cell anemia.

Two 19-year-old men with sickle cell anemia and hypogonadism had hypothalamic dysfunction that responded to oral clomiphene therapy. The patients had no nutritional deficiencies or anatomic lesions known to result in the hypogonadism associated with sickle cell anemia. Their sickle cell disease was characterized by infrequent crises, severe hemolytic anemia, urinary iron loss, and iron deficiency. Partial hypothalamic hypogonadism was shown by low levels of testosterone, low to low-normal levels of luteinizing hormone and follicle-stimulating hormone, and a nearly normal rise in gonadotropin levels in response to exogenous gonadotropin releasing hormone. Treatment with oral clomiphene raised luteinizing hormone, follicle-stimulating hormone, and testosterone levels to normal, and induced puberty in both patients. Treatment was discontinued in one patient because of the onset of priapism, but was continued for 10 months without side effects in the other. Severe hypogonadism in patients with sickle cell anemia should be thoroughly evaluated and clomiphene therapy considered in patients with hypothalamic dysfunction.

Adult↗

Effects of clomiphene citrate on neonatal rat skin.

BACKGROUND: Clomiphene citrate is chemically related to non-steroidal estrogens, and has antiestrogenic properties. It is used in the treatment of anovulatory female infertility and its therapeutic effect mainly depends on inhibiting the negative feedback effects of endogenous estrogen by stimulating the gonadotropin releasing hormone. Today, it is also used in the treatment of male infertility. OBJECTIVES: In this study the effects of clomiphene citrate on skin maturation in neonatal rats were investigated. METHODS: Forty Spraque-Dawley female newborn rats were separated into two control and two experimental groups (n = 10). One day after birth. experimental newborn rats were given clomphene citrate subcutaneously in a dosage of 100 mg/kg/day for five days. The first experimental group of rats were anesthetised at 21 days whereas the second experimental group of rats were then anestetised on day 28. Biopsies were taken immediately from the perineal skin. Histopathological assessments were made and compared with their control groups. RESULTS: In both the experimental groups of newborn rats, increased keratinization and irregular hypertrophy were observed in the epidermal cells. Disorganization of the basal layer cells and hyperplasia were found to be more prominent in the first experimental group and dermal fibrosis and lymphohistiocytic inflammatory cell infiltration were especially prominent around the sebaceous glands in the second experimental group. CONCLUSION: The administration of clomiphene citrate in newborn rats showed impaired skin maturation.

Animals↗

[Biophysical characteristics of cervical mucus after stimulation of ovulation by clomiphene citrate and HMG].

OBJECTIVES: Characteristics of cervical mucus during monofollicular stimulation of ovulation by clomiphene citrate and by clomiphene citrate with HMG was evaluated. MATERIALS AND METHODS: 226 women of couples treated for male factor infertility or idiopathic infertility were studied. Favourable parameters of cervical mucus in women treated by clomiphene citrate with HMG were found although they were worse than observed in spontaneous ovulatory cycle. RESULTS AND CONCLUSIONS: The E2/follicle index was used for evaluating efficiency of stimulation. It was the highest during cycles were CC and HMG were used, although they did not reflect the risk of hyperstimulation. Authors discuss the importance of their findings in cases when techniques of ART can not be applied.

Adult↗

Correction of the luteal phase defect with clomiphene citrate.

Among the various strategies proposed for the therapy of the luteal phase defects (L.P.D.), the administration of clomiphene citrate during the early follicular phase has proved to be very effective even though it is not one of the most used. Nevertheless, very soon has been risen the question if such drug acts by an overphysiological increase of the hormonal levels or instead by a re-balance of the altered latter ones. In order to answer this question a clinical study was carried out during 265 cycles on 63 normally ovulating and menstruating women, whose 27 with a luteal phase defect (L.P.D.), detected by clinical, echographic, endocrine, and morphological criteria. Each of these latter patients were given clomiphene citrate, 100 mg per day from the 2nd to the 6th day of the cycle, for a total of 108 cycles. The other 36 women without any luteal abnormality, were used during 156 cycles, as a control group. At the end of our study there were no significant differences in all parameters between two studied groups. This suggest that early follicular phase administration of clomiphene citrate in these pathologies can act by gradually improving the luteal function.

Clomiphene↗

Endocrine changes after laparoscopic ovarian drilling in clomiphene citrate-resistant women with polycystic ovarian syndrome.

OBJECTIVE: To study the effects of laparoscopic ovarian drilling on the serum hormone levels in clomiphene citrate resistant women with polycystic ovarian syndrome (PCOS) and to determine the criteria which influenced their clinical response. METHODS: A prospective study that was carried out at Salmaniya Medical Complex in Bahrain. One hundred and eighty-one women with clomiphene citrate-resistant PCOS were treated with laparoscopic ovarian drilling, all procedures were performed over a 4-year period between June 1996 and June 2000. Fasting blood samples for determination of the serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), LH-FSH ratio, testosterone and prolactin were taken during the follicular phase before and one month after laparoscopic ovarian drilling. RESULTS: Responders who ovulated spontaneously after the drilling were obese and had higher preoperative LH levels and the LH-FSH ratio. Both responders and non-responders showed a significant decline in LH, LH-FSH ratio and testosterone with a significant increase in FSH but no significant change in prolactin mean values compared with pretreatment levels. The magnitude of change was significantly higher for LH and the LH-FSH ratio (p<0.05) in responders, while there were no significant differences in the corresponding values of the other hormones between the 2 groups. Moreover, the decrease in LH (p<0.01) and the LH-FSH ratio (p<0.05) was significantly greater in obese than non-obese women and this was only observed in the responders group. CONCLUSION: Laparoscopic ovarian drilling is an effective procedure in women with clomiphene citrate resistant PCOS. It produces significant endocrine changes with better results in obese patients with higher preoperative LH values and LH-FSH ratio. The magnitude of these changes was the highest in obese responders.

Adult↗

Presentation of polycystic ovary syndrome and its management with clomiphene alone and in combination with metformin.

BACKGROUND: This study was carried out to determine the pattern of presentation of Polycystic ovary syndrome (PCOS) in patients presenting at our unit and to compare effects of clomiphene alone and in combination with metformin in management of PCOS. METHODS: This study was conducted from Jan 2001-2003 at Military Hospital, Rawalpindi. All patients presenting with infertility were evaluated with a view to select 100 patients of PCOS with the help of history of oligomenorrhoea, hirsuitism and acne. Diagnosis was confirmed by ultrasonography and hormone analysis (LH, FSH, prolactin, testosterone along with LH:FSH>2). The 100 selected patients were divided into two equal groups. One was given combined clomiphene citrate (CC) and metformin for ovulation induction and the other CC alone. These patients were followed for six cycles for ovulation and conception. Follicle tracking on ultrasonography and day-21 serum progesterone level were used to detect ovulation while conception was confirmed by urine pregnancy test, serum B-HCG level and ultrasonography for gestational sac. RESULTS: Hirsuitism and oligomenorrhoea were the two most common clinical features of PCOS. In the first group 34 patients (68%) ovulated as compared with 18 (36%) in the second group. In the first group 18 out of 34 women (52.9%) conceived as compared with only 8 out of 18 (44%) in the second group. The difference was significant at >0.05 when ovulatory and pregnancy responses were compared among two groups. All patients tolerated metformin well and no teratogenic effects were observed in patients who conceived after treatment with metformin. CONCLUSION: A combination of metformin and clomiphene citrate significantly increases the ovulation and conception rates in these patients.

Adult↗

[Reduced ovarian function in infertile women. Experiences with the clomiphene test].

The authors briefly describe the current understanding of follicular maturation, the influence of FSH on follicular maturation and the regulation of FSH secretion. They discuss the complex mechanisms of the impacts of clomiphene citrate, and how clomiphene citrate can be used in a test of ovarian reserve based on the FSH response. The article reports of the clomiphene citrate challenge test in patients referred to in vitro fertilization.

Adult↗

[Ovulation induction using clomiphene conversion].

20 anovulatory and clomiphene resistant patients had been treated by the so called clomiphene conversion. Pregnancies could be achieved in 6 women. 7 further patients reacted by ovulation. In selected cases the clomiphene conversion may be an alternative of therapy with gonadotrophins and GnRH pulsatile.

Adolescent↗

The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume.

Fifteen ovulating women had serial ultrasound scans to measure follicular, endometrial, and uterine growth, as well as biochemical indices including estradiol (E2) and the free androgen index, throughout a natural and a clomiphene-citrate-induced cycle. Despite higher E2 levels in the 5 days preceding ovulation, the clomiphene cycles were characterized by absence of the normal increase in uterine volume and an inhibition of endometrial thickening. It is proposed that the anti-estrogen effect of clomiphene inhibits the normal cyclical growth of the uterus and endometrium.

Adult↗

Effects of clomiphene citrate on cervical mucus: analysis of some influencing factors.

A multicenter study was performed to investigate the effects of a standard dose of clomiphene citrate (100 mg/day from day 5 of the cycle for five days) on the quality of cervical mucus. A total of 82 cervical mucus samples from 60 infertile patients (15 with secondary amenorrhea, 16 with delayed ovulation, 15 with anovulatory cycles, 14 with oligomenorrhea) was examined on the day of maximum follicular diameter. As a control we studied 54 cervical mucus samples from 47 patients with documented tubal sterility or infertile partners, who had spontaneous cycles with normal rhythm. Cervical mucus was unfavorable in 59% of the treatment cycles compared with 11% of the control cycles. Clomiphene citrate's antiestrogenic effect on cervical mucus was found to be related to the length of time between the last drug administration and the day of maximum follicular diameter (delta days), since cervical mucus was favorable in 64% of the cycles with a delta days more than 6 and in only 16% of the cycles with a delta days of 6 or less. Clomiphene citrate thus seems able to decrease cervical mucus quality. This could be one of the causes of the discrepancy between the rates of ovulation and pregnancy reported in patients treated with this drug.

Adult↗

Synchronous intrauterine and ectopic pregnancy associated with clomiphene citrate.

Although synchronous intrauterine and ectopic pregnancies associated with the use of clomiphene citrate for infertility are rare, the actual incidence might, in fact, be considerably higher than previously thought. The cornerstone for ruling out an extrauterine gestation is the presence of sonographic evidence of an intrauterine pregnancy, as the possibility of concomitant intrauterine and extrauterine gestation is perceived to be statistically rare. This has resulted in an unacceptably high incidence of negative ultrasound interpretations. During a recent 12 month period, four women treated with clomiphene citrate for infertility were diagnosed as having concomitant intrauterine and ectopic pregnancies. Three had pelvic sonograms that were erroneous for the extrauterine component. However, successful evacuation of the products of ectopic gestation was performed in each, despite an immediate preoperative false-negative ultrasound report. Three of the women delivered healthy normal infants at full term, and the fourth woman spontaneously aborted the products of the concomitant intrauterine gestation. All four did well postoperatively, and no gross complications were encountered. Reassessment of ultrasound diagnostic criteria and the use of more sensitive methods, such as endovaginal ultrasound in high risk patients, are indicated for any symptomatic patient using clomiphene citrate for infertility. Awareness of the prevalence of this entity and the limitations of ultrasound will lead to prompt intervention and improved survival rates.

Clomiphene↗

Acute effects of low doses of clomiphene upon LH release in ovariectomized estrogen-progesterone treated rats.

The acute effects of low doses of clomiphene citrate upon serum LH within the first two hours after the intravenous injection into ovariectomized, estrogen-progesterone blocked rats were investigated. There was a short-lasting elevation of LH release 45--60 min after injection of 2.5 microng clomiphene. A second LH releasing effect occurred within 60 min when 50 microng clomiphene or more were injected. Doses between these two dose levels were not effective. It is concluded that these effects may probably be due to a partial reduction of distinct estrogen receptor sites both in the hypothalamus and in the pituitary which causes a short-lasting decrease of the negative feedback of the circulating estrogens.

Animals↗