Clomiphene Citrate Therapy Research Articles

Effect of clomiphene citrate therapy on postcoital tests in successive treatment cycles including response to supplemental estrogen therapy.

Debate continues as to whether clomiphene citrate (CC) has an adverse effect on cervical mucus. Some researchers conclude that adverse effects maybe related to hormonal abnormalities, e.g., premature luteinization or improper timing. This study evaluated the initial and accumulative effects of CC on postcoital testing (PCT) and attempted to determine if supplemental estrogen (E) improves PCT and/or inhibits follicular maturation. The majority of patients taking CC had poor PCT tests even on the first treatment cycle. Good initial PCTs tended to remain so in subsequent cycles or at least to respond to subsequent supplemental E. Poor PCTs responding to E tended to continue to respond to the combination. PCTs not responding to E therapy continued this pattern in subsequent cycles. Supplemental E did not suppress follicular maturation.

Alternate‐day GnRH therapy for ovarian hypofunction induced by weight loss: treatment of six patients who remained amenorrhoeic after weight gain

Body weight loss has an adverse effect on the pituitary-ovarian function, and no restoration of the function occurs in 20-30% of patients even after the recovery of body weight. In the present study, the efficacy of alternate-day GnRH therapy was investigated in six patients whose pituitary-ovarian function had not recovered at 15 months to 6 years after the recovery of body weight. Synthetic GnRH (100 micrograms) was injected intramuscularly on alternate days for a total of 12 doses. On the completion of GnRH administration the efficacy of clomiphene-human chorionic gonadotrophin (hCG) therapy was evaluated. A GnRH loading test and evaluation of LH secretion patterns were also performed to investigate the changes in hypothalamic-pituitary-ovarian function secondary to GnRH treatment. All six patients ovulated in response to clomiphene-hCG therapy after 1-3 courses of GnRH treatment. The ovulatory response to clomiphene-hCG continued during follow-up periods of 5 months to 5 years. The initial hormonal change induced by GnRH treatment was a rise in the basal serum FSH level and a return of the FSH response to GnRH loading. This was followed by an increase in serum LH and the return of LH response to GnRH loading. In all six patients, pulsatile LH secretion was absent before starting GnRH treatment. GnRH treatment produced LH pulses in five of the six patients, although the pulse frequency was less than that in normally cycling women. A further increase in the pulse frequency was observed during clomiphene therapy. Alternate-day GnRH administration is effective in inducing responsiveness to clomiphene in patients with anovulation secondary to weight loss.

Adhesion formation after laparoscopic ovarian cautery for polycystic ovarian syndrome: lack of correlation with pregnancy rate

ObjectiveTo assess adhesion formation after laparoscopic ovarian cautery in women with polycystic ovarian syndrome (PCOS) and the efficacy of Interceed Adhesion Barrier (Ethicon, Summerville, NJ) in their prevention. DesignProspective, randomized, blinded, clinical study of laparoscopic ovarian cautery with application of Interceed to one ovary, followed by short interval second-look laparoscopy, scoring of adhesions, and clinical follow-up. SettingTertiary care clinic at a University teaching hospital. PatientsEight infertile women with PCOS who failed to conceive with previous clomiphene citrate (CC) therapy. ResultsPeriovarian adhesions of varying severity developed in all women after laparoscopic ovarian cautery. Interceed showed no protective effect. Despite this finding, all women initiated regular menses after laparoscopic ovarian cautery and seven of eight women spontaneously conceived eight singleton pregnancies without any further therapy. ConclusionLaparoscopic ovarian cautery should be considered in infertile women with PCOS who fail to respond to CC therapy. These women must be counseled with respect to the possible complication of postoperative adhesion formation.

9 Surgical options in polycystic ovary syndrome patients who do not respond to medical ovulation induction

Women with PCOS often present with anovulatory infertility. In these women, attempts at ovulation induction should be initiated with clomiphene citrate. However, 10 to 15% of women will not ovulate in response to clomiphene citrate, and in those who do, half will not conceive. Ovulation induction in these patients may involve the administration of hMG or pure FSH, with or without prior pituitary desensitization by GnRH agonists. However, gonadotrophin therapy is expensive, requires extensive monitoring, is not available at all centres and is associated with a significant incidence of ovarian hyperstimulation syndrome, multiple pregnancy and pregnancy loss. Furthermore, the chance of conception is limited to the treatment cycle. For women who fail to respond to clomiphene citrate therapy, and for whom gonadotrophin therapy is unsuccessful or unavailable, surgical therapy should be considered. There is a very limited role, if any, for OWR in the treatment of anovulation due to PCOS. Although effective in inducing ovulation in approximately 80% of women, with pregnancy rates approximating 60%, OWR requires major surgery and is associated with significant adhesion formation. Newer, less invasive techniques are emerging for the anovulatory woman who fails medical management. These include laparoscopic ovarian cautery and laparoscopic ovarian laser vaporization. These surgical techniques can be performed as outpatient procedures and may be combined with a diagnostic laparoscopy. Knowledge of the long-term effects of these techniques is still limited, but results appear promising, with spontaneous ovulation being initiated in 70 to 90% of women. Of the patients who remain anovulatory or oligo-ovulatory after these procedures, most will have been rendered sensitive to clomiphene citrate. Conception rates approximate 60%. The mechanism of action remains uncertain, but is likely to involve alteration of the intraovarian steroid environment and, in turn, the feedback to the hypothalamic-pituitary axis. The overall result is normalization of gonadotrophin drive and follicular microenvironment, allowing follicular recruitment and development to proceed to ovulation. Future clinical studies with long-term follow-up will be required to determine relapse rate and fecundity rates following these procedures. The risk of postoperative adhesion formation and the role of second-look laparoscopy in the prevention of this undesirable complication remains uncertain. Until more complete, long-term information is known, caution must be exercised and complete information provided to the patient with respect to the possible adverse affects.

Effect of clomiphene citrate on hormonal profile in male hemodialysis and kidney transplant patients.

The aim of this study was to evaluate the role of clomiphene citrate (CC) therapy in the hypothalamus-pituitary-gonadal axis of male uremic subjects. Thirty-four patients on hemodialysis (HD) and 8 successful kidney transplant subjects (RT) were evaluated. Nine healthy males were used as controls (C). At baseline, zinc, testosterone (TEST), prolactin (PRL), FSH, LH and estradiol plasma concentrations were measured. All subjects were treated with CC (100 mg/day) for a week. The aforementioned parameters were determined again on the seventh day of CC therapy, and 3 days after drug withdrawal. Following CC, there was a rise in FSH, LH and TEST levels in all subjects (p < 0.05); it is interesting to stress that TEST became normal in HD. In addition, we observed a decrease of PRL after CC only in HD patients (p < 0.01). In summary, CC was able to partially correct most of the hormonal disturbances of the gonadal axis in uremic patients.

A role for thyroid hormone in the induction of ovulation and corpus luteum function.

We have previously demonstrated that thyroid hormone synergizes with follicle-stimulating hormone (FSH) to exert stimulatory effects on granulosa cell differentiation and function, suggesting that it plays a physiological role in amplifying FSH-mediated differentiation of granulosa cells. The adequate differentiation of these cells, followed by normal follicle development, is indispensable for ovulation and subsequent corpus luteum formation. Thus, in the present studies, the clinical implications of thyroid hormone in the induction of ovulation and corpus luteum function were investigated. Serum levels of total 3,5,3'-triiodothyronine (T3) and total thyroxine (T4) as well as free T3 and T4 were significantly lower in patients with weight loss amenorrhea compared to normal cycling women. Although no ovulation was induced by clomiphene therapy when the serum T3 levels were less than 80 ng/dl, the rate of ovulation induced by clomiphene increased in parallel with the augmentation of serum T3 levels. This suggests that an adequate circulating level of thyroid hormone is one of the factors responsible for successful induction of ovulation by clomiphene citrate. Furthermore, the short luteal phase and insufficient progesterone secretion observed in patients with subclinical hypothyroxinemia were not improved by clomiphene therapy alone, but were improved markedly by combined treatment with thyroid hormone replacement and clomiphene citrate. These data imply that concomitant clomiphene treatment with thyroid hormone replacement therapy is of a great value not only for ovulation induction, but also for the treatment of luteal-phase defect in patients with subclinical hypothyroxinemia.

Multiple follicles in an unstimulated cycle despite elevated gonadotropins in a perimenopausal female.

The presence of estrogen deficiency associated with elevated gonadotropins usually signifies menopause. However, there have been a few case reports of ovulation and pregnancy despite hypergonadotropic hypogonadism. Described herein is a case of a perimenopausal woman who not only failed to ovulate in response to clomiphene citrate therapy but also failed to generate a level of serum estradiol (E2) over 30 pg/ml. Following pharmacologic suppression of her elevated gonadotropins with ethinyl estradiol, she spontaneously formed 3 mature follicles, and her serum E2 climbed to 868 pg/ml. This case suggests that some perimenopausal women may respond to their own endogenous elevated gonadotropins as if they are taking ovulation-inducing drugs and may, as a consequence, form multiple follicles.

妊孕性を考慮した婦人科腹腔鏡下レーザー治療

The feasibility and efficacy of laparoscopic laser surgery for the treatment of polycystic ovarian disease (PCOD) and ectopic pregnancy were evaluated in 9 PCOD patients (treated with CO2 laser) and 5 tubal pregnancy patients (treated with KTP/YAG laser). Seven of 9 patients with PCOD resistant to standard clomiphene citrate therapy ovulated after laparoscopic laser vaporization. Serum LH concentrations declined, while FSH levels did not change following laser treatment. Decline of serum testosterone concentration was noted in these patients. Four out of 5 patients with unruptured tubal pregnancy were successfully removed the ectopic chorionic tissues by laparoscopic laser treatment. Postoperative hysterosalpingography revealed the patency of the operated tubes. These results suggest that endoscopic laser surgery is useful method for the treatment of both PCOD and ectopic pregnancy patients.

CASE REPORT

A case of bilateral adnexal torsion after clomiphene citrate therapy is reported. Although this is rare, there is an increased risk after ovulation induction. Laparoscopic aspiration was successfully performed.

Exogenous estrogen therapy for treatment of clomiphene citrate-induced cervical mucus abnormalities: Is it effective?

Clomiphene citrate (CC) may have an adverse effect on cervical mucus (CM) quality and quantity. A placebo-controlled study was performed to assess the effect of exogenous follicular phase estrogen (E) on CM. Subjects qualified for inclusion by repeated demonstration of poor CM while on CC therapy as judged by spinnbarkeit, quantity, and viscosity. Subjects were treated by a randomized, placebo-controlled format using: (1) oral micronized estradiol (E2), 2 mg; (2) conjugated Es, 5 mg, or (3) placebo administered on cycle days 9 to 14. Cervical mucus was scored blindly during therapy within 48 hours before ovulation. Twelve subjects were observed through 36 treatment cycles with mean (+/- SD) CM scores: micronized E2, 4.2 +/- 1.8; conjugated Es, 4.3 +/- 1.7; and placebo, 4.7 +/- 2.9. There was no significant difference in mean values (P = 0.96, analysis of variance) or frequency of CM score greater than 4 (P = 0.85, Fisher exact test). We conclude that therapy with the E preparations tested did not improve the quality or quantity of CM in CC-treated patients.

The impact of luteal phase inadequacy in an infertile population

A retrospective analysis of patients evaluated and treated for infertility was performed. Luteal phase inadequacy was diagnosed when the late luteal endometrial biopsy pattern was greater than 2 days out of phase in two cycles; in patients treated with clomiphene citrate therapy was changed if one biopsy was out of phase. One hundred ninety-seven patients underwent 242 biopsies. Among 137 women not treated with clomiphene citrate, 24 (17.5%) had out-of-phase biopsy specimens; 7 of 24 (29.2%) repeat biopsies were out of phase, with luteal phase inadequacy in 7 of 137 (5.1%) women. The probability of an out-of-phase biopsy occurring by chance alone was 4.2 of 137 or 3.1 %. No woman was diagnosed to have luteal phase inadequacy as the single infertility factor. Fifty-three pregnancies (41%) occurred in 130 women without luteal phase inadequacy and in 2 of 7 (28.6%) diagnosed to have luteal phase inadequacy with other infertility factors. In clomiphene citrate-treated patients, pregnancy occurred in 15 of 26 (57.7%) with corrected luteal phase inadequacy and in 21 of 34 (61.8%) without luteal phase inadequacy. In this population the diagnosis of luteal phase inadequacy was not made more frequently than by chance alone. Moreover, fecundity in patients with treated luteal phase inadequacy is comparable to that in patients without this diagnosis. (AM J OBSTET GYNECOL1990;162:937-45.)

Screening infertile women for the assessment of corpus luteal function and their response to therapy by ELISA of pregnanediol glucuronide

Corpus luteal function was assessed by estimating pregnanediol 3-α-glucuronide (PdG) in three midluteal-phase urine samples collected from 85 women attending the infertility clinic. The previously established cut off limits based on PdG estimations were useful in detecting anovulation in 23 cases, corups luteal adequacy in 42 cases and corpus luteum deficiency (CLD) in 20 cases. In 8 women CLD could be corrected with 50 mg of clomiphene citrate (CC) therapy whereas 6 women required 100 mg of CC and 3 pregnancies were achieved. This rapid screening method is thus useful in segregating a large number of women according to their ovulatory status and in the subsequent treatment of CLD.

Pure FSH for ovulation induction in patients with polycystic ovary syndrome and resistant to clomiphene citrate therapy

Twenty-nine infertile women with polycystic ovary disease which was resistant to therapy with clomiphene citrate underwent a combined treatment for follicle recruitment consisting of pure FSH during the first days of the cycle and HMG during the last days of the follicular phase. Sixty cycles were stimulated of which 83% were ovulatory. Eighteen pregnancies were achieved (36% of cycles, 62% of patients). The multiple pregnancy rate was 39%. Twelve cycles (20%) showed the ovarian hyperstimulation syndrome (OHS) although seven of these resulted in full term deliveries. There were no miscarriages among the patients studied.

Luteinizing hormone bioactivity and variable responses to clomiphene citrate in chronic anovulation

In 18 women with infertility and chronic anovulation with normal gonadotropins, three different responses were observed to increasing doses (250 to 750 mg) of clomiphene citrate (CC). Follicle development and ovulation in 8, follicle development but no ovulation without human chorionic gonadotropin (hCG) in 6, and no response to CC in 4. Serum concentrations of bioactive luteinizing hormone (bioactive-LH), immunoactive (immunoactive-LH), follicle-stimulating hormone, and estradiol (E2) were measured and follicle growth was assessed by daily ultrasound. Findings were compared with 8 normal ovulatory controls. Folliculogenesis on CC therapy, based on our data, was 78%; however, only 44% ovulated spontaneously, 34% required hCG for follicle rupture. There were no apparent hormonal indicators to predict responders from nonresponders. The absence of an LH surge in the presence of follicles and sustained high E2 concentrations in 34% of patients may be associated with a decreased E2 sensitivity at the hypothalamic-pituitary level. Ultrasound easily identified patients who responded to CC with folliculogenesis but did not initiate an LH surge. Follicle rupture was achieved promptly by hCG administration.

OVARIAN ELECTROCAUTERY VERSUS HUMAN MENOPAUSAL GONADOTROPHINS AND PURE FOLLICLE STIMULATING HORMONE THERAPY IN THE TREATMENT OF PATIENTS WITH POLYCYSTIC OVARIAN DISEASE

Eighty-eight clomiphene citrate-resistant infertile patients with oligomenorrhoea or amenorrhoea attributable to polycystic ovarian disease were divided at random into three groups. Twenty-nine patients were treated with ovarian electrocautery, 30 with human menopausal gonadotrophins (hMG) and 29 with pure follicle stimulating hormone (FSH). Successful ovulation was induced in 71.4, 70.6 and 66.7% of the cycles in the groups respectively. Ten patients conceived after electrocautery and pure FSH therapy while 15 conceived after hMG medication (chi-squared = 1.6464, P = 0.439). The six-cycle cumulative pregnancy rate in the three consecutive groups was 52.1, 55.4, and 38.3%. Four further pregnancies were achieved after treating 10 patients in the electrocautery group with clomiphene citrate (100 mg/day for 5 days) for 25 cycles. The rate of pregnancy wastage in the corresponding groups was 21.4, 53.3 and 40% (chi-squared = 3.127, P = 0.2039). Ovarian electrocautery is equally effective as hMG and pure FSH in the treatment of PCO patients resistant to clomiphene citrate therapy.

Exogenous estrogen therapy for treatment of clomiphene citrate-induced cervical mucus abnormalities: is it effective?

Clomiphene citrate (CC) may have an adverse effect on cervical mucus (CM) quality and quantity. A placebo-controlled study was performed to assess the effect of exogenous follicular phase estrogen (E) on CM. Subjects qualified for inclusion by repeated demonstration of poor CM while on CC therapy as judged by spinnbarkeit, quantity, and viscosity. Subjects were treated by a randomized, placebo-controlled format using: (1) oral micronized estradiol (E2), 2 mg; (2) conjugated Es, 5 mg, or (3) placebo administered on cycle days 9 to 14. Cervical mucus was scored blindly during therapy within 48 hours before ovulation. Twelve subjects were observed through 36 treatment cycles with mean (+/- SD) CM scores: micronized E2, 4.2 +/- 1.8; conjugated Es, 4.3 +/- 1.7; and placebo, 4.7 +/- 2.9. There was no significant difference in mean values (P = 0.96, analysis of variance) or frequency of CM score greater than 4 (P = 0.85, Fisher exact test). We conclude that therapy with the E preparations tested did not improve the quality or quantity of CM in CC-treated patients.

HORMONAL PROFILES FOLLOWING CLOMIPHENE CITRATE THERAPY IN CONCEPTION AND NONCONCEPTION CYCLES

The hormonal profiles following clomiphene citrate (CC) administration during a single cycle were compared in infertile women who conceived and in those who did not. Of 41 treated patients, ovulation was assumed to have occurred in 28 and was confirmed by clinical pregnancy in five. In the 28 women who presumably ovulated, two distinct patterns of hormonal secretion were observed. A normal response was exhibited by 17 patients (including the five who became pregnant). The other 11 patients exhibited an abnormal response, characterized by significantly higher luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratios than in the normal response group from day 9 until the occurrence of the LH peak (days 9 and 10, P less than 0.05; days 11 and 12, P less than 0.001), and significantly higher oestradiol (E2) levels throughout the cycle (P less than 0.01). In addition, in comparison with the normal response group their LH levels during the follicular phase were significantly higher (P less than 0.05) but their LH peaks at ovulation were significantly lower (P less than 0.02). Moreover, their progesterone levels, in contrast to those in the normal response group, began to increase prior to the LH peak and remained high during the early and mid-luteal phases. None of the women who exhibited this abnormal gonadotrophin response to CC therapy achieved a clinical pregnancy. Exposure to high LH levels in the follicular phase following CC therapy seems to reduce the rate of fertilization and/or to contribute to early embryonic loss.

Post-molar trophoblastic disease following coexisting molar pregnancy and living fetus subsequent to clomiphene citrate therapy

A case of the cominbation of a complete hydatidiform mole and a coexisting, living fetus arising from a twin pregnancy, subsequent to clomiphene citrate therapy for ovulation induction, is presented. The diagnostic problems of this combination as well as the incidence of molar pregnancy following the use of ovulation inducers are discussed.

Bilateral virilizing sclerosing stromal tumours of the ovary in a pregnant woman with Gorlin's syndrome: implications for pathogenesis of ovarian stromal neoplasms

A woman with Gorlin's syndrome who had become pregnant following clomiphene therapy presented in early pregnancy with bilateral ovarian sclerosing stromal tumours which were associated with profound virilization. Pre- and post-operative hormone profiles indicated androgen production by the tumours. Ovarian sclerosing stromal tumours have not previously been reported as occurring bilaterally or in association with Gorlin's syndrome. We discuss the questions raised by this unusual case regarding the pathogenesis of ovarian stromal neoplasms.

The impact of luteal phase inadequacy in an infertile population

A retrospective analysis of patients evaluated and treated for infertility was performed. Luteal phase inadequacy was diagnosed when the late luteal endometrial biopsy pattern was greater than 2 days out of phase in two cycles; in patients treated with clomiphene citrate therapy was changed if one biopsy was out of phase. One hundred ninety-seven patients underwent 242 biopsies. Among 137 women no treated with clomiphene citrate, 24 (17.5%) had out-of-phase biopsy specimens; 7 of 24 (29.2%) repeat biopsies were out of phase, with luteal phase inadequacy in 7 of 137 (5.1%) women. The probability of an out-of-phase biopsy occurring by chance alone was 4.2 of 137 or 3.1%. No woman was diagnosed to have luteal phase inadequacy as the single infertility factor. Fifty-three pregnancies (41%) occurred in 130 women without luteal phase inadequacy and in 2 of 7 (28.6%) diagnosed to have luteal phase inadequacy with other infertility factors. In clomiphene citrate-treated patients, pregnancy occurred in 15 of 26 (57.7%) with corrected luteal phase inadequacy and in 21 of 34 (61.8%) without luteal phase inadequacy. In this population the diagnosis of luteal phase inadequacy was not made more frequently than by chance alone. Moreover, fecundity in patients with treated luteal phase inadequacy is comparable to that in patients without this diagnosis.