An economic evaluation of laparoscopic ovarian diathermy versus gonadotrophin therapy for women with clomiphene citrate resistant polycystic ovary syndrome

BACKGROUND: Laparoscopic ovarian diathermy and gonadotrophin ovulation induction for women with clomiphene citrate resistant polycystic ovary syndrome have been shown to result in similar pregnancy rates, but their relative cost-effectiveness has not been evaluated. METHODS: A cost-minimization study was undertaken alongside a randomized controlled trial in women with anovulatory infertility secondary to clomiphene resistant polycystic ovary syndrome. Inclusion criteria were age less than 39 years, body mass index less than 35 kg/m(2), failure to ovulate with 150 mg of clomiphene citrate for 5 days in the early follicular phase, more than 12 months of infertility and no other causes of infertility. Laparoscopic ovarian diathermy was compared with three cycles of urinary or recombinant gonadotrophins. Direct and indirect costs were based on the results of a randomized trial. RESULTS: The cost of a live birth was one third lower in the group that underwent laparoscopic ovarian diathermy compared to those women who received gonadotrophins (19 640 New Zealand dollars and 29 836 New Zealand dollars, respectively). CONCLUSIONS: This economic evaluation shows that treating women with clomiphene-resistant polycystic ovarian syndrome with laparoscopic ovarian diathermy results in a significant reduction in both direct and indirect costs.     

Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene citrate treatment

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.      

Ovulation induction: a mini review

Ovulation induction is the method for treating anovulatory infertility. For patients with hypogonadotrophic hypogonadism, the treatment involves administration of both FSH and LH, while HCG is injected for follicle rupture. Pulsatile GnRH has the same effectiveness as gonadotrophins and the advantage of the low multiple pregnancy rate. In polycystic ovary syndrome (PCOS), the first treatment choice is clomiphene citrate. With this drug, in properly selected patients, the cumulative pregnancy rate approaches that of normal women. Low-dose protocols of FSH are the second line of treatment, effective in inducing monofollicular development. Laparoscopic ovarian drilling can be an alternative but not as a first choice treatment in clomiphene-resistant patients. Other treatments, such as pulsatile GnRH and GnRH agonists, are hardly used today in PCOS. However, in obese women with PCOS, weight loss and exercise should be recommended as the first line of therapy. Newer agents including aromatase inhibitors and insulin sensitizers, although promising, need further evaluation.     

Endocrinology: Two cases of ovarian tumours in women who had undergone multiple ovarian stimulation attempts

Concerns have been raised recently about the possible associationbetween superovulation and ovarian cancer. In order to contributeto the limited literature on this important issue, two casesof ovarian tumours in women who had undergone multiple ovulationinductions are presented. In the first case, the patient hadsecondary anovulatory infertility. She was treated with humanmenopausal gonadotrophin (HMG) alone and in combination withclomiphene citrate or buserelin for six cycles. She then underwentovarian stimulation with buserelin/HMG in the long protocolfor in-vitro fertilization (IVF) and embryo transfer. In preparationfor a new IVF/embryo transfer attempt, 8 months later, the screeningultrasound revealed a cystic formation of the left ovary andan enlargement of the right. During laparotomy, both ovarieswere found to bear large tumours (approximately 6x5x4 cm) whichwere removed. Histological examination showed that they wereepithelial tumours (serous-papillary cystadenomas) of borderlinemalignancy. The patient conceived spontaneously 1.5 years afterthe operation. In the second case, the patient presented withsecondary anovulatory infertility. She underwent ovulation inductionwith clomiphene/HMG and with buserelin/HMG in the long protocol,and intra-uterine insemination with husband's spermatozoa andconceived (singleton pregnancy). She was delivered by Caesareansection, during which a cystic tumour of the left ovary wasremoved. Histological examination revealed a benign mucous cystadenomaof the ovary. In conclusion, the clinical information from thesetwo cases does not support a causal association between ovarianstimulation and ovarian tumours but does potntially supporta facilitating one.     

ASRI2005-93 A new aspect of reproduction in infertility associated with polcystic ovarian syndrome

Introduction:  Polycystic ovarian syndrome (PCOS) is one of the commonest causes of anovulatory infertility presenting with menstrual abnormalities. The common treatment is to ovulate and conceive is Clomiphene citrate but 50% becomes pregnant with first trimester abortion rate high. The aim is for better judgment of efficacy of Clomiphene citrate and recombinant FSH for ovulation induction.
Method:  Patients (120) were divided in two groups: treated with Clomiphene citrate and other on recombinant FSH. Ovarian response was monitored and HCG given to trigger ovulation after appropriate follicular development. The prime out come major cumulative pregnancies after undergoing up to 4 treatment cycles. Results: The study showed that aspects of reproduction with pregnancy rate were more in recombinant FSH as compare to clomiphene citrate. Abortion rate was less in recombinant FSH then clomiphene citrate group. The incidences of OHSS were least in both. The main aspects of reproduction after 4-treatment cycle were 45.8% with recombinant FSH and only 11.2% with Clomiphene citrate.
Conclusions:  Various RCTs have been done before showing benefits of Gonadotrophins over Clomiphene citrate. Study suggests that recombinant FSH effective alternative of Clomiphene citrate in first line treatment for the reproduction of anovulatory PCOS patients.     

Uterine effects of clomiphene citrate in women with polycystic ovary syndrome: a prospective controlled study

BACKGROUND: Previous data on the efficacy of clomiphene citrate, the most commonly used drug for treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS), have shown a discrepancy between ovulation and pregnancy rates. In the present subanalysis (of a larger previously published randomized controlled trial), the effect of clomiphene citrate on several ultrasonographic markers of uterine receptivity in PCOS patients who ovulated under treatment was studied. METHODS: Thirty-three PCOS women who ovulated under 150 mg daily clomiphene citrate and 33 healthy controls were studied. Uterine, subendometrial and endometrial blood flows, endometrial thickness and pattern were assessed using serial ultrasonographic assessments. The data were analysed before and after grouping the clomiphene citrate-stimulated ovulatory cycles for reproductive outcome [unfavourable (ovulation alone or early pregnancy loss) or favourable outcome (clinical pregnancy and/or live birth)]. RESULTS: Both before and during treatment, uterine vascularity assessed at all sites was significantly lower in the PCOS group than in controls. Endometrial thickness and pattern were impaired in the PCOS group under clomiphene citrate treatment. A significant difference in all ultrasonographic parameters was observed between cycles ending in unfavourable versus those ended in favourable outcome. CONCLUSIONS: Clomiphene citrate administration alters several surrogate ultrasonographic parameters of uterine receptivity, and this effect could be crucial for its efficacy.     

Ovulation induction in perspective

It has been suggested recently that, in some quarters, IVF be offered as first-line therapy to all infertile couples, regardless of the type of infertility. Hence, the time was thought right to scrutinise the results and complications of ovulation induction for anovulatory infertile couples. In addition to examining the outcome of conventional treatment with gonadotrophins and clomiphene citrate, special attention has been paid to the suggested improvement of results by taking into account the influence of obesity and the use of a low-dose gonadotrophin protocol. The possible contribution of more recent additions to the armamentarium such as insulin sensitizers and aromatase inhibitors, although still at an infant stage, are promising. Attention has been given to the prevention and treatment of ovarian hyperstimulation syndrome. The use of intra-uterine insemination (IUI) as an adjuvant to induction of ovulation and controlled ovarian hyperstimulation (COH) is examined. The very firm conclusion has been reached that, taking into account efficiency, complication rate and cost of treatment, at this stage, women with hypogonadotrophic hypogonadism or polycystic ovary syndrome should be offered accepted methods of ovulation induction and that couples with 'unexplained' or 'multifactorial subfertility' should still be exposed to COH with IUI and only after the failure of these therapies, be offered IVF.     

Modern use of clomiphene citrate in induction of ovulation

Clomiphene citrate is the treatment of first choice in the managementof infertility in normally oestrogenized, anovulatory women(WH0 group II). The majority of women with 'pure' anovulatoryinfertility respond to treatment with clomiphene citrate. Therates of pregnancy and miscarriage are close to those expectedin a normal fertile population. Basal hormone concentrationsdo not predict outcome. An increased body mass index is theonly factor which is consistently associated with a decreasedresponse to clomiphene citrate; it follows therefore, that weightreduction should be an important part of therapy in anovulatorywomen. According to our data, only an increased luteinizinghormone value immediately post clomiphene citrate predictedan adverse pregnancy outcome in women who conceived. Clomiphenecitrate, along with other ovulation induction therapies, cancause multiple follicular development, with a risk of ovarianhyperstimulation and multiple pregnancy. Ultrasound monitoringof treatment is important in order to choose the appropriatedose of clomiphene citrate in subsequent cycles and to minimizethe risks of hyperstimulation and multiple pregnancy. When coupleswith other factors contributing to subfertility are excluded,the cumulative conception rate continues to rise after 6 monthsof treatment with clomiphene citrate, reaches a plateau by treatmentcycle 12 and approaches that of the normal population. It hasbeen reported that prolonged use of clomiphene citrate may beassociated with an increased risk of a borderline or invasiveovarian tumour. Taking into consideration these observations,we recommend that anovulatory women responsive to clomiphenecitrate should be treated for at least 6 cycles before consideringmore complex or invasive methods of ovulation induction, andthat treatment should probably be limited to a maximum of 12cycles.     

Highly purified FSH is as efficacious as recombinant FSH for ovulation induction in women with WHO Group II anovulatory infertility: a randomized controlled non-inferiority trial

BACKGROUND: The objective of this study was to demonstrate non-inferiority of a highly purified urinary follicle stimulating hormone (HP-FSH) preparation compared with a recombinant (rFSH) preparation with respect to ovulation rate (primary end-point). METHODS: This was a randomized, open-label, assessor-blind, multinational study. Women with anovulatory infertility WHO Group II and resistant to clomiphene citrate were randomized (computer-generated list) to stimulation with HP-FSH (n=73) or rFSH (n=78) using a low-dose step-up protocol. The non-inferiority limit was prespecified at -20%. RESULTS: The ovulation rate was 85.2% (51/62) with HP-FSH and 90.9% (60/66) with rFSH (per-protocol population), and non-inferiority was demonstrated [95% confidence interval: -16.9; 5.6]. No differences were noted between groups in number of follicles>or=12 mm, >or=15 mm or >or=18 mm, mono-follicular development, pregnancy rates, endometrial thickness, number of ovarian stimulation syndrome cases or frequency of injection site reactions/pain. The singleton live birth rate was 15% in both groups (11/73 with HP-FSH and 12/78 with rFSH). CONCLUSIONS: This urinary HP-FSH preparation is non-inferior compared with a rFSH preparation with respect to ovulation rate in anovulatory WHO Group II women failing to ovulate or conceive on clomiphene citrate.     

Unilateral oophorectomy in polycystic ovary syndrome: a treatment option in highly selected cases?

We performed unilateral oophorectomy (UO) in three patients with polycystic ovary syndrome (PCOS) and long-standing infertility. The indication for performing this procedure was a combination of ovarian pathology and the long-standing infertility. All three patients were resistant to clomiphene citrate and before UO all patients had been treated unsuccessfully with gonadotrophins and in-vitro fertilization. All three patients became ovulatory within the first month after UO. Two patients conceived 11 and 12 months after surgery respectively and delivered healthy babies. Testosterone concentrations decreased in two patients to upper values of the normal range and remained unchanged in one patient. We conclude that restoration of ovulation can be a beneficial side-effect of UO in clomiphene citrate resistant patients with PCOS and long-standing infertility.      

Das ovarielle Überstimulationssyndrom

The ovarian hyperstimulation syndrome (OHSS) renders a severe iatrogenic condition, which occurs in 0.3–5.0 % of stimulated cycles. The risk for OHSS can be reduced by carefully scrutinizing stimulated cycles. However, it cannot be completely avoided. It is negligent not to monitor cycles stimulated with gonadotropins or clomiphene citrate. Dosages of gonadotropins or clomiphene citrate should be as low as possible. The assumption is wrong that acceptable pregnancy rates can only be achieved with attendant OHSS. In any case, the physical health of the patients is of paramount importance.     

Intrauterine insemination treatment in subfertility: an analysis of factors affecting outcome

A total of 811 intrauterine insemination (IUI) cycles in which clomiphene citrate/human menopausal gonadotrophin (HMG) was used for ovarian stimulation were analysed retrospectively to identify prognostic factors regarding treatment outcome. The overall pregnancy rate was 12.6% per cycle, the multiple pregnancy rate 13.7%, and the miscarriage rate 23.5%. Logistic regression analysis revealed five predictive variables as regards pregnancy: number of the treatment cycle (P = 0.009), duration of infertility (P = 0.017), age (P = 0.028), number of follicles (P = 0.031) and infertility aetiology (P = 0.045). The odds ratios for age < 40 years, unexplained infertility aetiology (versus endometriosis) and duration of infertility < or = 6 years were 3.24, 2.79 and 2.33, respectively. A multifollicular ovarian response to clomiphene citrate/HMG resulted in better treatment success than a monofollicular response, and 97% of the pregnancies were obtained in the first four treatment cycles. The results indicate that clomiphene citrate/HMG/IUI is a useful and cost-effective treatment option in women < 40 years of age with infertility duration < or = 6 years, who do not suffer from endometriosis.     

A controlled study of luteinizing hormone-releasing hormone agonist (buserelin) for the induction of folliculogenesis before in vitro fertilization

Treatment with clomiphene citrate and human menopausal gonadotropin (HMG) is often used to induce folliculogenesis before in vitro fertilization, but not all women have an adequate response. It has been hypothesized that abnormally high levels of luteinizing hormone (LH) may contribute to the reduced folliculogenesis. We therefore performed a controlled, open trial in which treatment with buserelin, an agonist of luteinizing hormone-releasing hormone citrate and HMG in 44 consecutive women in whom no oocytes or only one had been produced by standard treatment with clomiphene and HMG. Twenty-nine women received buserelin with HMG, and 15 received clomiphene citrate with HMG. The median number of oocytes per patient recovered from those who received buserelin with HMG was 4 (range, 0 to 19), as compared with 0 (range, 0 to 5) in those who received clomiphene citrate with HMG. The fertilization rates of oocytes recovered from both groups of patients were similar (75.8 percent and 76.5 percent, respectively). Fifty-four percent of patients given buserelin with HMG underwent triple-embryo transfer, as compared with 13 percent of those given clomiphene citrate with HMG. Pregnancy (n = 3) occurred only among the patients receiving buserelin with HMG. In the buserelin-HMG group, significantly fewer oocytes were recovered from patients with occult ovarian failure (infertility and elevated follicular-phase levels of follicle-stimulating hormone, with regular menses) (median, 1; range, 0 to 4) than from those with other causes of infertility (median, 8; range, 0 to 19). Our data suggest that, except in women with occult ovarian failure, buserelin and HMG improve embryologic and clinical outcomes in patients with previously unsatisfactory stimulation of the ovaries for in vitro fertilization.     

Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis

BACKGROUND: Both selective estrogen receptor modulators, tamoxifen and clomiphene have been used for ovulation induction for patients with anovulatory infertility. This meta-analysis sought to compare the effectiveness of tamoxifen to clomiphene for the induction of ovulation and achievement of pregnancy. METHODS: We searched MEDLINE, BIOSIS, PreMEDLINE, CINAHL, International Pharmaceutical Abstracts, DDSR, ACP Journal Club, DARE and CCTR, along with reference lists and national experts. Inclusion criteria were prospective clinical trials, which compared tamoxifen and clomiphene for ovulation induction in infertile couples with isolated anovulatory infertility. Main outcome measures were ovulation rate and clinical pregnancy rate. Pooled odds ratios were obtained using random effects meta-analysis. RESULTS: Four trials were included. After pooling all the trials, the use of tamoxifen or clomiphene citrate resulted in similar ovulation rates [odds ratio (OR) 0.755, 95% confidence interval (CI) 0.513-1.111]. There was no benefit of tamoxifen over clomiphene citrate in achievement of pregnancy per cycle (OR 1.056, 95% CI 0.583-1.912) or per ovulatory cycle (OR 1.162, 95% CI 0.632-2.134). CONCLUSIONS: Clomiphene citrate and tamoxifen are equally effective in inducing ovulation. Although data regarding pregnancy rates and outcome are limited, there does not appear to be a significant benefit of one medication over the other.     

Successful pregnancy resulting from in-vitro matured oocytes retrieved at laparoscopic surgery in a patient with polycystic ovary syndrome: case report

Combined laparoscopic retrieval of immature oocytes and ovarian electrocautery represents a new management in patients with polycystic ovary syndrome (PCOS), one of the most prevalent endocrinopathies associated with anovulatory infertility. A 31-year-old para II presented with anovulatory, clomiphene-resistant PCOS, and a 6 year history of infertility. Conventional IVF treatment was abandoned in 1999 when she developed severe ovarian hyperstimulation syndrome (OHSS) following gonadotrophin stimulation. Sixteen oocytes were aspirated from both ovaries and collected in culture tubes containing a maturation medium. A total of three 2-cell embryos were transferred 48 h after ICSI. Two weeks after embryo transfer the urinary pregnancy test was positive and after another 2 weeks an ongoing singleton pregnancy with a fetal heartbeat was confirmed at transvaginal ultrasound examination. The combination of laparoscopy, in-vitro maturation and ICSI may open up new therapeutic strategies, even in patients without PCOS and regular menstrual cycles, undergoing laparoscopy for other causes of infertility such as tubal factors and endometriosis.     

Clinical outcome after unilateral oophorectomy in patients with polycystic ovary syndrome

The objective of this study is to report retrospectively on the clinical outcome of unilateral oophorectomy in 14 women with polycystic ovary syndrome who had undergone this treatment 14-18 years ago in our hospital for clomiphene citrate-resistant anovulation and long standing infertility or for severe hirsutism. The main outcome measures were menstrual cycle, pregnancy, hirsutism, testosterone concentrations, and premature ovarian failure. Unilateral oophorectomy restored regular menstrual cycles in 12 of the 14 patients. Thirteen years later, nine out of 12 patients still had regular menstrual cycles. Ten patients wished to become pregnant. Seven of them conceived spontaneously. Eleven patients complained of severe hirsutism. After unilateral oophorectomy, hirsutism regressed subjectively in six. Testosterone blood concentrations decreased significantly within the first year after unilateral oophorectomy in 11 patients. None of the women entered menopause within 14-18 years after surgery. Our results indicate that unilateral oophorectomy restores ovulatory function for many years in the majority of patients and does not result in premature ovarian failure. However, unilateral oophorectomy should not be recommended as a standard treatment for clomiphene citrate-resistant patients with polycystic ovary syndrome.     

Similar ovulation rates, but different follicular development with highly purified menotrophin compared with recombinant FSH in WHO Group II anovulatory infertility: a randomized controlled study

BACKGROUND: The contribution of the LH activity in menotrophin preparations for ovulation induction has been investigated in small trials conducted versus FSH preparations. The objective of this study was to demonstrate non-inferiority of highly purified urinary menotrophin (HP-HMG) versus recombinant FSH (rFSH) with respect to the primary outcome measure, ovulation rate. METHODS: This was a randomized, open-label, assessor-blind, multinational study. Women with anovulatory infertility WHO Group II and resistant to clomiphene citrate were randomized (computer-generated list) to stimulation with HP-HMG (n=91) or rFSH (n=93) using a low-dose step-up protocol. RESULTS: The ovulation rate was 85.7% with HP-HMG and 85.5% with rFSH (per-protocol population), and non-inferiority was demonstrated. Significantly fewer intermediate-sized follicles were observed in the HP-HMG group (P<0.05). The singleton live birth rate was comparable between the two groups. The frequency of ovarian hyperstimulation syndrome and/or cancellation due to excessive response was 2.2% with HP-HMG and 9.8% with rFSH (P=0.058). CONCLUSIONS: Stimulation with HP-HMG is associated with ovulation rates at least as good as a rFSH in anovulatory WHO Group II women. LH activity modifies follicular development so that fewer intermediate-sized follicles develop. This could have a positive impact on the safety of ovulation induction protocols.     

Long-term GnRH analogue treatment is equivalent to laparoscopic laser diathermy in polycystic ovarian syndrome patients with severe ovarian dysfunction

This prospective, randomized study included 18 polycystic ovarian syndrome (PCOS) patients with severe ovarian dysfunction, who were evaluated by standard clomiphene and FSH stimulation. In this group of patients, a 6 month down-regulation with gonadotrophin-releasing hormone (GnRH) analogues gave outcomes similar to laparoscopic ovarian laser diathermy with respect to stimulatory outcome and pregnancy rate. Clomiphene stimulation with 50 mg of clomiphene/day and FSH stimulation in a low-dose, step-up protocol with purified FSH did not result in oligofollicular development; thus patients were divided into two subgroups: one subgroup received laparoscopic laser drilling and the other received 6 months of therapy with GnRH analogues plus add-back therapy after diagnostic laparoscopy. Subsequently, three cycles of low-dose, step-up stimulation with recombinant FSH were started. In both groups, approximately 30% of cycles still remained anovulatory. In the down-regulated subgroup, this mainly happened in the first cycle. In each group, ovulation was achieved in 14 cycles, intrauterine insemination was performed, and five pregnancies were obtained. This resulted in a pregnancy rate of 36% per ovulatory cycle in both groups. Overall, 50% of the formerly unreactive patients in both groups overcame childlessness. In achieving this, long-term treatment with GnRH analogues was as successful as laparoscopic laser diathermy.     

Infertility: Late low-dose pure follicle stimulating hormone for ovarian stimulation in intra-uterine insemination cycles

At present, there is general agreement that ovarian stimulationimproves pregnancy rates after intra-uterine insemination (IUI).Also, ovulation induction with gonadotrophins is associatedwith higher success rates than clomiphene citrate in IUI cycles.However, the drawbacks to the use of gonadotrophin stimulationbefore IUI include the risks of ovarian hyperstimulation andmultiple gestation, and the relative cost of a treatment cyclein view of the medication costs and the need for increased monitoringby hormone assays and ultrasonographic measurements. In thepresent prospective randomized trial, the efficacy and safetyof ovarian stimulation with clomiphene citrate (50 mg/day for5 days) and IUI (clomiphene/IUI group) were compared with thoseof late low-dose pure follicle stimulating hormone (FSH, 75IU/day from day cycle 7 until the leading follicle reached >17mm in diameter) and IUI (FSH/IUI group) in ovulatory women whowere infertile because of unexplained infertility (n=40)or malesubfertility (n =60). The mean length of treatment in the FSHgroup was 6.4±2.5 days. Multiple follicular developmentwas seen in 25% of clomiphene-stimulated cycles but only in8% of those treated with FSH. Pregnancy rate per cycle in clomiphene/IUIand FSH/IUI groups was 4% (4/98) and 13% (12/94) respectively(P=0.02). All pregnancies obtained were singleton. There weretwo and one clinical abortions in the clomiphene/IUI (50%) andFSH/IUI (8%) groups respectively. No patient developed ovarianhyperstimulation syndrome. Use of our therapeutic scheme, whichproved to be efficacious, safe and economic for ovarian stimulationin IUI cycles, is advocated before the institution of in-vitrofertilization (IVF) or gamete intra-Fallopian transfer (GIFT)therapy in infertile patients with patent Fallopian tubes. Thislate low-dose technique of administering pure FSH is suitablefor use in offices without immediate access to oestradiol results.     

Reproductive features in women developing ovarian granulosa cell tumour at a fertile age

Ovarian granulosa cell tumour (GCT) is a rare malignancy, which has been linked to both infertility and infertility treatment with ovulation inducers. The reproductive features were analysed of 146 women with GCT diagnosed between 1956 and 1996. During the study period no changes were found in the mean age (53 years), menopausal status (59% postmenopausal), parity (32% nulliparous) or tumour size or stage at diagnosis. The clinical features in women with GCT at fertile age were compared with GCT diagnosed later in life and to population-based data. Nulliparity (50%) and history of infertility (22%) were more frequent if the tumour occurred at fertile age (n = 50). Of the 12 infertile cases, seven had anovulatory infertility (58%); 11 occurred during the era of ovulation inducers, but only five had used these drugs (clomiphene citrate in five patients, gonadotrophins in two, and tamoxifen in one patient) and no patient had undergone in-vitro fertilization. Endometrial hyperplasia was associated with GCT at all ages, while endometrial cancer was found solely after the age of 45 years. In conclusion, GCT at fertile age is associated with nulliparity and with a clinical presentation of anovulatory infertility, while GCT later in life is associated with a more normal average fertility pattern and with occurrence of endometrial cancer.