Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort.

BACKGROUND: Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown. METHODS: We identified a nationwide historic cohort of 19,146 women who received IVF treatment in the Netherlands between 1983 and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997-1999, data on reproductive risk factors were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group. RESULTS: After a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared with the general population [standardized incidence ratio (SIR) = 1.76; 95% confidence interval (CI) = 1.16-2.56]. The overall SIR for invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P = 0.02); the SIR was 3.54 (95% CI = 1.62-6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group were significantly increased compared with risks in the subfertile comparison group (hazard ratios = 4.23; 95% CI = 1.25-14.33 and 2.14; 95% CI = 1.07-4.25, respectively, adjusted for age, parity and subfertility cause). CONCLUSIONS: Ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.

Birth weight and age at menarche in patients with polycystic ovary syndrome or diminished ovarian reserve, in a retrospective cohort.

BACKGROUND: Few studies have investigated the association between subfertility in women and factors in early life such as birth weight and age at menarche, and most have produced contradictory results. In the present study, this association was investigated among women undergoing artificial reproductive techniques (ART), including IVF for reason of polycystic ovary syndrome (PCOS) or diminished ovarian reserve. Herein, PCOS included oligomenorrhoea and at least one additional symptom such as hyperandrogenism, hirsutism or polycystic ovaries on ultrasound. In most patients this was concomitant with elevated serum LH levels. Diminished ovarian reserve was defined as receiving a donated oocyte or having a low response to ovarian hyperstimulation. METHODS: Among a retrospective cohort of 26 428 women diagnosed with subfertility between 1980 and 1995, three study groups and one reference group were defined using data from medical records. Women were included in the first group if diagnosed as having PCOS (n = 265). In order to define diminished ovarian reserve capacity, two groups were selected: (i) women receiving a donated oocyte (n = 98); and (ii) women having a low response (three follicles or less) to ovarian hyperstimulation in both their first and second IVF cycles (n = 351). Women with tubal obstruction formed the reference group (n = 957). In a logistic regression model, the effect of birth weight and age at menarche was examined. Information on both variables was obtained from mailed questionnaires. RESULTS: Birth weight did not differ significantly between the study groups and the reference group. However, PCOS patients were significantly older at menarche [OR 3.31 (2.18-5.04)]. Women receiving a donated oocyte and low responders were significantly younger at menarche [OR 2.67 (1.35-5.29) and OR 2.01 (1.26-3.20) respectively]. CONCLUSION: The fetal origins hypothesis, the association between intrauterine growth retardation and disease in adult life, could not be confirmed, though a relationship between timing of menarche and PCOS and a diminished ovarian reserve was identified. Further investigation of the effect of birth weight on fertility outcome in a prospective setting is strongly advised.

[Fibroids and fertility]. / Myomen en vruchtbaarheid.

Fibroids are the most common benign uterine tumours. A relation between fibroids and infertility is suggested. Successful implantation depends on a normal, receptive endometrium. Fibroids can change the normal appearance of the uterine cavity and can adversely affect the endometrium. It seems that treatment of fibroids in infertility patients is useful but this is not yet proven scientifically. It is advised to refrain from extirpation of fibroids in patients with fertility problems.

Obstetric outcome of twin pregnancies after in-vitro fertilization: a matched control study in four Dutch university hospitals.

In singleton pregnancies after in-vitro fertilization (IVF), increased rates of obstetric and perinatal complications have been reported. Studies that compared IVF twin pregnancies with spontaneously conceived twins have yielded conflicting results. We compared 96 IVF twin pregnancies to 96 controls after elaborate matching. The design of our study precluded matching by zygosity. The monozygosity rate was higher in the control group and this implies that beforehand the risk for a less favourable outcome in the control group was higher than in the IVF group. However, the average birthweight of the IVF children was less than that of children in the control group (P = 0.04). This was not due to more intrauterine growth retardation in the IVF group. The mean gestational age at birth was 5 days shorter in IVF than control pregnancies, and although this difference was not significant it might explain the lower birthweight in the IVF group. The discordance rate in the IVF group was significantly increased. We found no difference in perinatal mortality and morbidity. We conclude that this study provides further evidence for a different outcome of IVF twin pregnancies in comparison with spontaneously conceived twin pregnancies.

Leiomyomatosis peritonealis disseminata: does malignant transformation occur? A literature review.

Leiomyomatosis peritonealis disseminata (LPD) is a rare smooth muscle tumor. In the literature more than 100 cases have been described. LPD is characterized by multiple small nodules on the peritoneal surface, mimicking a malignant process with metastases, but generally demonstrates benign histologic features. Exposure to estrogen seems to play an etiologic role. Many patients have uterine leiomyomas as well. The diagnosis of LPD is easily made on biopsy. Reduction of estrogen exposure is generally sufficient to cause regression of LPD. Surgical castration or gonadotrophin releasing hormone agonists seem good alternatives in the case of progression or recurrence of LPD. In six patients a malignant leiomyosarcoma has been described shortly after the diagnosis of LPD was made. Five of these patients did not have uterine leiomyomas or exposure to exogenous or increased endogenous estrogen. The relationship with pregnancy in the sixth patient may be coincidental. Whether malignant transformation of LPD occurs remains uncertain. Characteristics of these patients differ from those of LPD patients and may indicate a high malignant potential, necessitating a different approach.

Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist Cetrorelix in healthy female volunteers.

The gonadotrophin-releasing hormone antagonist Cetrorelix is in advanced clinical development for the control of endogenous gonadotrophin secretion during the course of a fertility programme. The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of Cetrorelix following single and multiple s.c. administration of different doses. Thirty-six healthy female volunteers received either 0.25, 0.50 or 1.00 mg Cetrorelix, in a first menstrual cycle as single dose and in a second cycle as multiple dose (daily between cycle days 3 and 16). Frequent blood samples were collected for determination of Cetrorelix, follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and progesterone concentrations. Follicular growth was measured by transvaginal ultrasonography. After single administration of each dose, maximum Cetrorelix concentrations (Cmax) were reached after 1 h, and Cmax and area under curve (AUC) increased linearly with the dose. The median terminal half-life ranged from 5 to 10 h in the three different dose groups. FSH, LH, oestradiol and progesterone concentrations were suppressed, with a nadir at 6-12 h after Cetrorelix administration. During multiple administration, Cmax and AUC also showed dose-linearity. The median terminal half-life of Cetrorelix varied between 20 and 80 h. A dose-dependent suppression of FSH, LH and oestradiol concentrations was observed during treatment. After multiple administration, ovulation was delayed for 5, 10 and 13 days in the 0.25, 0.50 and 1.00 mg dose groups, respectively. In conclusion, Cetrorelix showed linear pharmacokinetics, and effectively delayed the LH surge.

Follicular fluid hormone concentrations after ovarian stimulation using gonadotropin preparations with different FSH/LH ratios. I. Comparison of an FSH-dominant and a purified FSH preparation.

OBJECTIVE: A small amount of LH is necessary for 17beta-estradiol production in the ovarian follicle. Human menopausal gonadotropin (hMG) contains equal amounts of FSH and LH activity, whereas recombinant FSH is a gonadotropin preparation without LH. The aim of the present randomized study was to investigate whether ovarian stimulation treatment with recombinant FSH or hMG resulted in different steroidal composition of follicular fluid. METHODS: Antral fluid from mature follicles was collected in in vitro fertilization cycles and concentrations of testosterone, androstenedione, estrone, estradiol, progesterone, FSH, and LH were determined. Seven patients (27 samples) were treated with hMG, 6 patients (22 samples) with recombinant FSH. RESULTS: Androgen, estrogen, progesterone, and FSH concentrations in follicular fluid tended to be lower in the group treated with recombinant FSH, but the variation was large and differences were statistically not significant. CONCLUSION: Treatment with a gonadotropin preparation containing no LH resulted in adequate androgen and estrogen levels in antral fluid of the ovarian follicle in women with normal endocrine profiles, even during pituitary suppression by a GnRH agonist. Apparently, the amount of endogenous LH was sufficient for steroid production within the follicle.

Glutathione S-transferases in human ovarian follicular fluid.

OBJECTIVE: To study the levels of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 in human preovulatory ovarian follicular fluid (FF) and pooled granulosa and cumulus cells. DESIGN: The relation of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 with P and 17 beta-E2 concentrations were studied. SETTING: The Department of Obstetrics and Gynecology, the Department of Gastroenterology, and the Laboratory of Endocrinology and Reproduction of the University Hospital Nijmegen in Nijmegen, the Netherlands. PATIENT(S): Infertile women participating in an IVF program. RESULT(S): Detectable amounts of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 were found in ovarian FF and pooled cumulus and granulosa cells. Concentrations of glutathione S-transferase Alpha 1-1 were always much higher than those of glutathione S-transferase Pi 1-1. Both ovarian FF concentrations of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 did not correlate with ovarian FF concentrations of 17 beta-E2 and P. CONCLUSION(S): The high FF concentrations of glutathione S-transferase Pi 1-1 and especially of glutathione S-transferase Alpha 1-1 suggest that these enzymes may play an important role in the detoxification processes in the follicles. The lack of correlation between follicular P and 17 beta-E2 and glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 indicates that both enzymes presumably are not present as a result of the high steroid levels.

Conditions at conception and risk of menstrual disorders.

In a case-control study, we evaluated the association of the risk of menstrual disorders with four periconceptional factors: short preceding interpregnancy interval (< 6 months), low (< or = 19 years) or high (> or = 40 years) maternal age at conception, and month of conception. We divided 919 women who had visited a fertility clinic between 1991 and 1995 into three categories: cases (with mean menstrual cycle length > or = 42 or < or = 21 days, or a variation of > or = 14 days between cycles, or amenorrhea, N = 294), controls (with cycles within a range of 25-35 days and variation < or = 7 days, N = 520), and intermediates (N = 105). A self-administrable questionnaire was mailed, asking for information about maternal reproductive history and age, and potential confounders such as smoking, exercise, and level of education. Response (77%) differed little among cases, intermediates, and controls. We found elevated risks for short pregnancy intervals [adjusted odds ratio (OR) = 2.04; 95% confidence interval (CI) = 1.04-4.02] and advanced maternal age (OR = 3.24; 95% CI = 1.27-8.30) but not for low maternal age (OR = 0.58; 95% CI = 0.11-3.14) (cases vs controls). We found similar effects for intermediates vs controls. The distribution of month of conception did not differ much from controls for both cases and intermediates. The results indicate that conception after short pregnancy intervals or at advanced maternal age increases the risk of menstrual disorders in daughters. The precise etiology is unclear, but it may lie in the quality of the oocyte at conception.

Follicular fluid hormone concentrations during controlled ovarian hyperstimulation using gonadotropin preparations with different FSH/LH ratios. I. Comparison of an FSH-dominant and a purified FSH preparation.

OBJECTIVE: The aim of the present randomized study was to investigate whether ovarian stimulation treatment with gonadotropin preparations containing different amounts of LH activity resulted in variations of steroidal composition of follicular fluid. A different endocrine milieu within the follicle might influence oocyte quality. METHODS: Antral fluid from mature follicles was collected in in vitro fertilization cycles and concentrations of testosterone, androstenedione, estrone, estradiol, progesterone, FSH, and LH were determined. A comparison was made between treatment with a purified FSH preparation (nine patients, 35 follicular fluid samples) and a FSH-dominant human menopausal gonadotropin (hMG) preparation (nine patients, 34 samples). RESULTS: No differences in any of the hormone levels could be detected between the two groups. CONCLUSION: Treatment with gonadotropin preparations containing different FSH/LH ratios did not result in different androgen, estrogen and progesterone levels in follicular fluid.

Follicular fluid hormone concentrations after ovarian stimulation using gonadotropin preparations with different FSH/LH ratios. II. Comparison of hMG and recombinant FSH.

OBJECTIVE: A small amount of LH is necessary for 17 beta-estradiol production in the ovarian follicle. Human menopausal gonadotropin (hMG) contains equal amounts of FSH and LH activity, whereas recombinant FSH is a gonadotropin preparation without LH. The aim of the present randomized study was to investigate whether ovarian stimulation treatment with recombinant FSH or hMG resulted in different steroidal composition of follicular fluid. METHODS: Antral fluid from mature follicles was collected in in vitro fertilization cycles and concentrations of testosterone, androstenedione, estrone, estradiol, progesterone, FSH, and LH were determined. Seven patients (27 samples) were treated with hMG, 6 patients (22 samples) with recombinant FSH. RESULTS: Androgen, estrogen, progesterone, and FSH concentrations in follicular fluid tended to be lower in the group treated with recombinant FSH, but the variation was large and differences were statistically not significant. CONCLUSION: Treatment with a gonadotropin preparation containing no LH resulted in adequate androgen and estrogen levels in antral fluid of the ovarian follicle in women with normal endocrine profiles, even during pituitary suppression by a GnRH agonist. Apparently, the amount of endogenous LH was sufficient for steroid production within the follicle.

Surgical treatment of symptomatic rectosigmoid endometriosis.

OBJECTIVE: To assess the results of surgical treatment of symptomatic intestinal endometriosis. DESIGN: Retrospective study. SETTING: University hospital, The Netherlands. SUBJECTS: 14 patients in whom medical treatment had failed. INTERVENTIONS: Hysterectomy (n = 5), salpingo-oophorectomy (n = 8, bilateral in 5), posterior vaginal wall excision (n = 14), and partial resection (n = 6) or anterior wedge excision (n = 8) of the rectum. MAIN OUTCOME MEASURES: Blood loss, operating time, morbidity, and relief of symptoms. RESULTS: 9 patients became symptom free (64%), 5 of whom developed postmenopausal symptoms later on. 2 had unrelated vague abdominal symptoms and 3 more could not be assessed because they underwent in vitro fertilisation and developed stimulation-related abdominal symptoms. All were content with the operative results. CONCLUSIONS: Operations for rectosigmoid endometriosis are technically difficult with a long operating time and considerable blood loss, but they are successful in relieving symptoms when conservative treatment has failed.

Hormonal serum profiles and follicular development after intramuscular and pulsatile intravenous administration of human menopausal gonadotrophin.

A study was performed to compare, in a randomized way, the effect of pulsatile intravenous (i.v.) and intramuscular (im) human menopausal gonadotrophin (hMG) administration on hormonal serum profiles and follicular development in in vitro fertilization (IVF). Fourteen IVF patients participated in the study, aged between 20 and 40 years, with a normal endocrine profile, no hormonal medication used for at least 3 months previously, no endometriosis, both ovaries present and a normal male factor. Seven patients were treated with im hMG at a daily dose of 150 IU and seven patients with pulsatile i.v. hMG at a daily dose of 112.5 IU, in both cases in combination with buserelin. Ultrasonography was performed every other day during the stimulation phase and blood samples were collected once daily up to five times a day during the entire IVF cycle. Serum concentrations of follicle-stimulating hormone, luteinizing hormone, 17 beta-oestradiol, progesterone and human chorionic gonadotrophin were determined. There were no differences in hormonal profiles between the two groups. The numbers of retrieved oocytes, fertilization rates and mean embryo quality were identical in this study, as was follicular growth. In conclusion, in the present randomized study no differences were observed in hormonal levels or follicular development after im and pulsatile i.v. hMG treatment.

Stapedial ankylosis in the Mayer-Rokitansky-Küster-Hauser syndrome.

We describe a 21-year-old woman with congenital unilateral conductive hearing loss and an atypical form of the Mayer-Rokitansky-Küster-Hauser syndrome. To our knowledge, this is the first reported case of this syndrome in which surgery for congenital stapedial ankylosis was successful. Besides aplasia of the vagina and uterus, the patient also had various other anomalies, such as the Klippel-Feil syndrome, Sprengel's deformity, and congenital stapedial ankylosis. Congenital hearing loss is an associated characteristic of the Mayer-Rokitansky-Küster-Hauser syndrome (10% to 20% of cases), particularly in the atypical form. Against the background of the favorable results of surgery for isolated unilateral congenital stapedial ankylosis and other unilateral congenital anomalies of the middle ear that have been described in the literature and the significant advantages of bilateral hearing, we used stapedectomy to successfully treat this case of Mayer-Rokitansky-Küster-Hauser syndrome with unilateral congenital stapedial ankylosis.

Patterns of serum FSH, LH and hCG after i.m. or i.v. administration of hMG during pituitary suppression.

OBJECTIVE -- The study was undertaken to investigate the effects of a commonly used ovarian stimulation regimen on gonadotropin levels. METHODS -- The behavior of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and human chorionic gonadotropin (hCG) was studied after intramuscular (i.m.) and intravenous (i.v.) human menopausal gonadotropin (hMG) administration. Six female volunteers participated in the study. During pituitary suppression with a gonadotropin-releasing hormone (GnRH) agonist (Buserelin), a single dose of hMG (150 IU) was injected i.m. or i.v., in a cross-over design with an interval of 2 weeks. Blood samples were collected frequently after the injection. Serum concentrations of FSH, specific LH and hCG were determined. RESULTS -- After i.m. administration of hMG, a peak FSH concentration of 7.4 +/- 1.3 U/L was reached after 8 (6-24) hours, with a subsequent decrease. At 0.5 hour after i.v. administration, peak FSH values of 30.5 +/- 5.6 U/L were obtained, followed by a decrease to baseline levels within 48 hours. Exogenous LH and hCG were hardly detectable after i.m. administration of hMG. One-half hour after i.v. injection of hMG, a small increase in specific LH levels to 6.7 +/- 2.6 U/L was shown, followed by a decline. hCG concentrations increased after i.v. hMG administration to 7.6 +/- 1.6 U/L.

Human leukocyte antigen typing and associated abnormalities in premature ovarian failure.

A case-controlled study was designed to assess the distribution of human leukocyte antigens (HLA) A, B, Cw, DR and DQ, and associated abnormalities in patients with premature ovarian failure (POF). A total of 37 patients in a tertiary care centre were diagnosed as having POF; all were < 37 years old. A subset was HLA-typed. The occurrence of associated diseases in patients with POF was recorded. A comparison of HLA typing was made between patients with POF and 100 organ donors from the same population. No statistically significant difference in the distribution of A, B, Cw, DR and DQ antigens was found between the study and control groups when corrected for the number of antigens tested. The commonest associated abnormality was positive autoimmune screen (43.3%). Abnormal thyroid function tests were detected in 23.3% of the patients. The observed high frequency of associated autoimmune phenomena in patients with POF points to an underlying autoimmune disorder in POF and warrants further studies to unravel the pathology of this condition.

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome without and with associated features: two separate entities?

A multidisciplinary study was conducted on a total of 100 women with congenital absence of vagina and uterus, the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. It was possible to analyse whether the MRKH syndrome can be considered as a single clinical entity or whether two or more syndromes lie behind the title 'the MRKH syndrome'. Complete gynaecological and laparoscopic data were available on all of the patients. The patients were divided into two groups on the basis of the laparoscopic data: a typical and an atypical form of the MRKH syndrome. We performed various diagnostic investigations to establish whether there were any associated congenital anomalies. These tests included general physical examination, radiographs of the vertebral column, the upper extremities and intravenous urography (IVU), and general otorhinolaryngological and ossicular chain examinations. Associated anomalies were most common in the group with the atypical form of the MRKH syndrome. These findings suggest that there might be two different syndromes in this patient group, namely an isolated form of congenital agenesis of the vagina and uterus and a more generalized condition, in which agenesis of the vagina and uterus is a major and perhaps even obligatory characteristic. The term MRKH syndrome should no longer be used for the atypical group. A suggestion has been made to call this type the GRES [genital (G), renal (R), ear (E), skeletal (S)] syndrome.

Hearing loss and the Mayer-Rokitansky-Küster-Hauser syndrome.

The hearing of 51 female patients with the Mayer-Rokitansky-Küster-Hauser syndrome was examined using otoscopy and standard audiometry. A unilateral or bilateral hearing loss of more than 15 dB Fletcher index was found in 13 of 51 (25.5%). Four of these 13 patients had a hearing loss of less than 20 dB in the worst ear. The remainder had a hearing loss of at least 30 dB in the worst ear. Five of the 13 patients had pure conductive hearing loss; in four of these five, a congenital origin was accepted. Two of the 13 had mixed hearing loss that was a residual symptom from previous otitis media; six had sensorineural hearing loss. A congenital cause was found in one of these six, based on the fact that she had been deaf and dumb since birth. In one other patient, noise-related deafness was likely (i.e., an acquired cause). In the other four cases in this group, the cause was unknown. The results of this study show that hearing loss is a characteristic associated with the Mayer-Rokitansky-Küster-Hauser syndrome.

Different follicle stimulating hormone/luteinizing hormone ratios for ovarian stimulation.

The aim of the present study was to investigate whether reducing the amount of luteinizing hormone (LH) in gonadotrophic preparations impairs follicular growth in in-vitro fertilization (IVF) cycles during suppression of endogenous LH levels. A selected group of 20 IVF patients was randomly divided into two groups. One group was treated with Org 31338 [follicle stimulating hormone (FSH)/LH 3:1], the other group with Metrodin (purified FSH), both during pituitary down-regulation with buserelin. A fixed daily dose of 150 IU FSH i.m. was given. Serum concentrations of FSH, LH, oestradiol and progesterone were determined frequently and serial ultrasound examinations were performed. Multiple follicular growth with concomitant rise of oestradiol levels was observed in all cycles. The duration of the stimulation phase was shorter in the group treated with Org 31338 than in the group treated with Metrodin. The number of follicles and oocytes and the fertilization rate was larger and the mean embryo quality was higher in the Org 31338 group, but the differences did not reach statistical significance. No significant differences were found in hormonal values. In women with normal endocrine profiles, lowering of the LH activity in gonadotrophic preparations during gonadotrophin-releasing hormone agonist treatment results in adequate ovarian stimulation. However, a preparation with some LH needed a shorter stimulation than a purified FSH preparation. Whether the other beneficial effects of Org 31338 also occur in a larger population needs further investigation.