Oral anti-oestrogens and medical adjuncts for subfertility associated with anovulation.
Topic: Hormone Therapy

Infertility due to anovulation is a common problem in women. The first line oral treatment is with anti-oestrogens, such as clomiphene citrate. Unfortunately there may be resistance and alternative and adjunctive treatments have been developed. These include tamoxifen, dexamethasone, bromocriptine and aromatase inhibitors (AIs).

PICO
Population: Women with infertility due to anovulation
Intervention: Oral anti-oestrogens and medical adjuncts (clomiphene citrate, tamoxifen, dexamethasone, bromocriptine, aromatase inhibitors)
Comparison: Standard treatment with clomiphene citrate
Outcomes: Improvement in subfertility associated with anovulation

Included studies:
title: A clomiphene citrate and tamoxifen citrate combination therapy: a novel therapy for ovulation induction.
abstract: To assess the efficacy of a clomiphene citrate (CC) and tamoxifen citrate (CC/tamoxifen) combination therapy in ovulation induction by comparing with a CC alone therapy.
title: Recurrent spontaneous abortion and polycystic ovarian disease: comparison of two regimens to induce ovulation.
abstract: To determine whether pituitary suppression before induction of ovulation reduces the rate of spontaneous abortion in women with polycystic ovarian disease and primary recurrent spontaneous abortions.
title: Antiestrogens as treatment of female and male infertilities.
abstract: Antiestrogens are widely used to treat eugonadal anovulation, luteal phase deficiency (LPD) and oligospermia. This paper reviews the rationales, endocrine effects, profertility effects and side effects of these treatments. Furthermore, we present our own experience of the use of antiestrogens in this field. We have compared the results of clomiphene citrate (CC) to those of tamoxifen (TAM) in a randomized study including 66 infertile women presenting eugonadal anovulation (n = 26) or LPD (n = 40). Both drugs obtained the same pregnancy rate of 80% at 9 months in the anovulatory patients. Conversely, CC was superior to TAM in the LPD cases (pregnancy rates at 6 months of respectively 40 and 11%). The abortion rates were of 11% on CC versus 36% on TAM. Both drugs significantly increased the luteal phase length and plasma progesterone level to the same extent. The results of endometrial biopsies suggest that the difference in their effects on female fertility could result from a detrimental effect of TAM on endometrium. The rates of the side effects proved to be almost identical on both drugs. Thus the use of TAM is not justified as a first-step treatment in ovulation disturbances. TAM should be reserved for patients who experience severe visual side effects on CC. We have also tested TAM in 100 subfertile males. In the 92 oligospermic males, TAM significantly increased the mean sperm count only in the normogonadotropic patients, but as much whether oligospermia was idiopathic or not. Sperm improvement was not significantly related to any hormone criterion except basal serum FSH. The cumulative pregnancy rate was of 41.2% at 1 year. Whether TAM actually improves male fertility, and is superior to CC in this indication, remains to be confirmed in controlled studies.
title: Improved responsiveness of PCOS patients to clomiphene after CYP17a inhibitor.
abstract: To study the effect of CYP17a inhibitor, "ketoconazole," on clomiphene responsiveness in PCOS patients.
title: Induction of ovulation in clomiphene-resistant polycystic ovary syndrome with pulsatile GnRH.
abstract: 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).
title: Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.
abstract: To use aromatase inhibition for induction of ovulation in women in whom clomiphene citrate (CC) treatment was unsuccessful.
title: A randomized study of dexamethasone in ovulation induction with clomiphene citrate.
abstract: 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).
title: A double-blind, randomized, placebo-controlled study to assess the efficacy of ketoconazole for reducing the risk of ovarian hyperstimulation syndrome.
abstract: To evaluate the role of ketoconazole in prevention of ovarian hyperstimulation syndrome (OHSS) in women with the polycystic ovary syndrome (PCOS) undergoing ovarian stimulation with gonadotropins.
title: Induction of ovulation with clomiphene citrate in combination with metoclopramide in patients with amenorrhea of hypothalamic origin.
abstract: Literature data have demonstrated that the chronic use of metoclopramide (MCP), a dopamine antagonist, causes increased gonadotropin secretion in patients with hypothalamic amenorrhea but without triggering ovulation. It has also been observed that women with hypothalamic amenorrhea respond poorly to ovulation induction with clomiphene citrate (CC). On this basis, the objective of the present study was to determine the effect of MCP on the response to CC in patients with hypothalamic amenorrhea in order to evaluate the validity of the simultaneous use of these drugs as ovulation inducers in this type of chronic anovulation. Twenty-two patients with amenorrhea of hypothalamic origin were submitted to a randomized double blind study in which one tablet of 5 mg MCP or placebo was administered every 8 hours for 2 months. After the 30th day of medication (MCP or placebo), CC, 100 mg orally, was additionally administered to both groups for 5 days. Blood samples were collected on days 1, 15 and 30 during the first month of the study and on days 7, 14 and 21 after the last CC tablet during the second month, for later measurement of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol and progesterone by radioimmunoassay. The group that received MCP showed a significant increase in LH and FSH during the first month of the study, as well as a slighter increase in estradiol. Prolactin increased only during the second stage of treatment. No significant increases in gonadotropins, prolactin or estradiol occurred in the placebo group. In the group treated with MCP, 40% of the patients ovulated after CC, with menstruation occurring in 60% of them. In the placebo group, 33.3% of the women ovulated after CC and 44.4% menstruated at the end of the study. We conclude that MCP increases the circulating levels of LH, FSH, estradiol and prolactin in patients with hypothalamic amenorrhea and low estrogen levels, supporting the hypothesis that an increase in hypothalamic dopaminergic tonus occurs in these patients. On the other hand, the combination of MCP and CC does not improve the rate of ovulation compared to placebo.
title: A prospective randomized trial comparing clomiphene citrate with tamoxifen citrate for ovulation induction.
abstract: To compare the rates of ovulation and pregnancy after tamoxifen citrate (TMX) or clomiphene citrate (CC) among anovulatory women with infertility.
title: A comparsion of the effects of clomiphene and tamoxifen treatment on the concentrations of oestradiol and progesterone in the peripheral plasma of infertile women.
title: A prospective, double-blind, randomized, placebo-controlled clinical trial of bromocriptin in clomiphene-resistant patients with polycystic ovary syndrome and normal prolactin level.
abstract: The purpose of this study was to examine the effects of of bromocriptin combined with clomiphene citrate in clomiphene-resistant patients with polycystic ovary syndrome and normal prolactin level.
title: Common statistical errors in the design and analysis of subfertility trials.
abstract: The quality of clinical trials has received increasing attention with the growth of evidence-based medicine and systematic reviews. We aimed to identify whether errors and omissions commonly encountered when undertaking Cochrane reviews in this field are still passing peer review.
title: A randomized clinical trial of treatment of clomiphene citrate-resistant anovulation with the use of oral contraceptive pill suppression and repeat clomiphene citrate treatment.
abstract: The purpose of this study was to evaluate the effectiveness and endocrine response of oral contraceptive ovarian suppression followed by clomiphene citrate in patients who previously were clomiphene citrate resistant.
title: Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene citrate treatment.
abstract: Patients suffering from normogonadotrophic anovulation and infertility are initially treated with clomiphene citrate. Those who do not respond to clomiphene citrate usually receive gonadotrophin treatment which is labour-intensive, expensive, and associated with an increased risk of multiple pregnancies and ovarian hyperstimulation syndrome. We treated 22 patients with clomiphene resistant normogonadotrophic anovulation with naltrexone (an opioid receptor blocker) alone or naltrexone in combination with an antioestrogen. In 19 patients ovulation and resumption of a regular menstrual cycle was achieved and in 12 out of 19 a singleton pregnancy was observed. In conclusion, ovulation can be induced successfully using naltrexone alone or naltrexone in combination with an anti-oestrogen in clomiphene citrate resistant anovulatory patients. Compared to gonadotrophin induction of ovulation, this method is safe, simple and inexpensive.
title: Ovulation induction with a single-blind treatment regimen comparing naltrexone, placebo and clomiphene citrate in women with secondary amenorrhea.
abstract: 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.
title: Use of ethinyl estradiol to reverse the antiestrogenic effects of clomiphene citrate in patients undergoing intrauterine insemination: a comparative, randomized study.
abstract: To compare the effectiveness of clomiphene citrate used alone and in combination with ethinyl E2 for the induction of ovulation in patients undergoing IUI.
title: Behavioral and emotional factors and treatment responses in a study of anovulatory infertile women.
abstract: In a controlled treatment study of 49 anovulatory infertile women, responses to clomiphene citrate (CC) and placebo treatments were compared and associations of behavioral and emotional factors with treatment responses were investigated. In the first treatment series, ovulation occurred in 20 of 24 women in the CC group and 8 of 22 women in the placebo group. Pregnancy was achieved by 11 women during CC treatment and 3 women during placebo treatment. Overall, 28 women completed the protocol and 21 withdrew. Those who achieved pregnancy (n = 14) did not differ significantly from the ovulation-only group (n = 22) on pretreatment measures of emotional, behavioral, and personality factors including the Hopkins Symptom Checklist (HSCL-90), Eysenck Personality Inventory, Langner Screening Scale, Mood Analog Scale, Social Adjustment Scale, Mooney Problem Checklist, and the Minnesota Multiphasic Personality Inventory (MMPI). Conclusions were that a placebo response was observed in both ovulation and pregnancy, but psychologic factors as measured in this sample were not associated with these treatment outcomes.
title: Use of dexamethasone and clomiphene citrate in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome and normal dehydroepiandrosterone sulfate levels: a prospective, double-blind, placebo-controlled trial.
abstract: To evaluate the effects of short-course administration of dexamethasone (DEX) combined with clomiphene citrate (CC) in CC-resistant patients with polycystic ovary syndrome (PCOS) and normal DHEAS levels.
title: Ovulation induction in clomiphene-resistant anovulatory women with normal dehydroepiandrosterone sulfate levels: beneficial effects of the addition of dexamethasone during the follicular phase.
abstract: To evaluate the effect on ovulation of a 10-day course of dexamethasone (DEX) initiated concurrently with a 5-day course of clomiphene citrate (CC) in CC-resistant patients with normal DHEAS levels.
title: A study on follicle stimulation and ovulation induction in polycystic ovary syndrome (PCOS).
abstract: The present study was undertaken to verify the efficacy of preparations for inducing follicular maturation and ovulation in patients with polycystic ovary syndrome (PCOS). Successful induction of ovulation in patients with PCOS was observed in treatment cycles with daily injections or pulsatile subcutaneous administration of human menopausal gonadotropin (hMG), the combination of clomiphene citrate and bromocriptine, or the combination of clomiphene citrate and hMG. The incidence of ovarian hyperstimulation syndrome varied with the different clinical conditions in which ovulation was induced, the types of preparations administered, and the doses and schedules administered.
title: The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials.
abstract: To comprehend the results of a randomised controlled trial (RCT), readers must understand its design, conduct, analysis, and interpretation. That goal can be achieved only through total transparency from authors. Despite several decades of educational efforts, the reporting of RCTs needs improvement. Investigators and editors developed the original CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by use of a checklist and flow diagram. The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement. The checklist items pertain to the content of the Title, Abstract, Introduction, Methods, Results, and Discussion. The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect, or because the information is essential to judge the reliability or relevance of the findings. We intended the flow diagram to depict the passage of participants through an RCT. The revised flow diagram depicts information from four stages of a trial (enrollment, intervention allocation, follow- up, and analysis). The diagram explicitly shows the number of participants, for each intervention group, included in the primary data analysis. Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis. In sum, the CONSORT statement is intended to improve the reporting of an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results.