Treatment effect of oil-based contrast is related to experienced pain at HSG: a post-hoc analysis of the randomised H2Oil study.

STUDY QUESTION: Does pain or volume of used contrast medium impact the effectiveness of oil-based contrast during hysterosalpingography (HSG)? SUMMARY ANSWER: In women who report moderate to severe pain during HSG, the use of oil-based contrast resulted in more ongoing pregnancies compared to the use of water-based contrast, whereas in women who reported mild or no pain, no difference in ongoing pregnancies was found. WHAT IS KNOWN ALREADY: We recently showed that in infertile women undergoing HSG, the use of oil-based contrast results in more ongoing pregnancies within 6 months as compared to the use of water-based contrast. However, the underlying mechanism of this fertility-enhancing effect remains unclear. STUDY DESIGN, SIZE, DURATION: We performed a post-hoc analysis of the H2Oil study, a multicentre randomised controlled trial (RCT) evaluating the therapeutic effect of oil- and water-based contrast at HSG. Here, we evaluated the impact of pain experienced at HSG and volume of used contrast media during HSG on ongoing pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a subset of 400 participating women, pain during HSG by means of the Visual Analogue Scale (VAS) (range: 0.0-10.0 cm) was reported, while in 512 women, we registered the volume of used contrast (in millilitres). We used logistic regression analyses to assess whether pain and volume of used contrast media modified the effect of oil-based contrast on ongoing pregnancy rates. Data were analysed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: In 400 women in whom pain scores were reported, the overall median pain score was 5.0 (Interquartile range (IQR) 3.0-6.8) (oil group (n = 199) 4.8 (IQR 3.0-6.4); water group (n = 201) 5.0 (IQR 3.0-6.7); P-value 0.28). There was a significant interaction between pain (VAS ≤5 versus VAS ≥6) and the primary outcome ongoing pregnancy (P-value 0.047). In women experiencing pain (VAS ≥6), HSG with oil-based contrast resulted in better 6-month ongoing pregnancy rates compared to HSG with water-based contrast (49.4% versus 29.6%; RR 1.7; 95% CI, 1.1-2.5), while in women with a pain score ≤5, 6-month ongoing pregnancy rates were not significantly different between the use of oil- (28.8%) versus water-based contrast (29.2%) (RR 0.99; 95% CI, 0.66-1.5). In the 512 women in whom we recorded contrast, median volume was 9.0 ml (IQR 5.7-15.0) in the oil group versus 8.0 ml (IQR 5.9-13.0) in the water group, respectively (P-value 0.72). Volume of used contrast was not found to modify the effect of oil-based contrast on ongoing pregnancy (P-value for interaction 0.23). LIMITATIONS, REASONS FOR CAUTION: This was a post-hoc analysis that should be considered as hypothesis generating. The RCT was restricted to infertile ovulatory women, younger than 39 years of age and with a low risk for tubal pathology. Therefore, our results should not be generalised to infertile women who do not share these features. WIDER IMPLICATIONS OF THE FINDINGS: The underlying mechanism of the fertility-enhancing effect induced by HSG with the use of oil-based contrast remains unclear. However, these findings suggest a possible mechanistic pathway, that is increasing intrauterine pressure occurring prior to dislodging pregnancy hindering debris or mucus plugs from the proximal part of otherwise normal fallopian tubes. This information might help in the search of the underlying fertility-enhancing mechanism found by using oil-based contrast during HSG. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports consultancy for Guerbet. H.V. reports consultancy fees from Ferring. C.B.L. reports speakers' fees from Ferring and research grants from Ferring, Merck and Guerbet. V.M. reports receiving travel and speakers fees as well as research grants from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research grants from Merck KGaA and Guerbet. The other authors do not report conflict of interests. TRIAL REGISTRATION NUMBER: The H2Oil study was registered at the Netherlands Trial Registry (NTR 3270). TRIAL REGISTRATION DATE: 1 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 3 February 2012.

Endometrial scratching in women with implantation failure after a first IVF/ICSI cycle; does it lead to a higher live birth rate? The SCRaTCH study: a randomized controlled trial (NTR 5342).

BACKGROUND: Success rates of assisted reproductive techniques (ART) are approximately 30%, with the most important limiting factor being embryo implantation. Mechanical endometrial injury, also called 'scratching', has been proposed to positively affect the chance of implantation after embryo transfer, but the currently available evidence is not yet conclusive. The primary aim of this study is to determine the effect of endometrial scratching prior to a second fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle on live birth rates in women with a failed first IVF/ICSI cycle. METHOD: Multicenter randomized controlled trial in Dutch academic and non-academic hospitals. A total of 900 women will be included of whom half will undergo an endometrial scratch in the luteal phase of the cycle prior to controlled ovarian hyperstimulation using an endometrial biopsy catheter. The primary endpoint is the live birth rate after the 2nd fresh IVF/ICSI cycle. Secondary endpoints are costs, cumulative live birth rate (after the full 2nd IVF/ICSI cycle and over 12 months of follow-up); clinical and ongoing pregnancy rate; multiple pregnancy rate; miscarriage rate and endometrial tissue parameters associated with implantation failure. DISCUSSION: Multiple studies have been performed to investigate the effect of endometrial scratching on live birth rates in women undergoing IVF/ICSI cycles. Due to heterogeneity in both the method and population being scratched, it remains unclear which group of women will benefit from the procedure. The SCRaTCH trial proposed here aims to investigate the effect of endometrial scratching prior to controlled ovarian hyperstimulation in a large group of women undergoing a second IVF/ICSI cycle. TRIAL REGISTRATION: NTR 5342 , registered July 31st, 2015. PROTOCOL VERSION: Version 4.10, January 4th, 2017.

Tailored expectant management in couples with unexplained infertility does not influence their experiences with the quality of fertility care.

STUDY QUESTION: Do couples who were eligible for tailored expectant management (TEM) and did not start treatment within 6 months after the fertility work-up, have different experiences with the quality of care than couples that were also eligible for TEM but started treatment right after the fertility work-up? SUMMARY ANSWER: Tailored expectant management of at least 6 months in couples with unexplained infertility is not associated with the experiences with quality of care or trust in their physician. WHAT IS KNOWN ALREADY: In couples with unexplained infertility and a good prognosis of natural conception within 1 year, expectant management for 6-12 months does not compromise ongoing birth rates and is equally as effective as starting medically assisted reproduction immediately. Therefore, TEM is recommended by various international clinical guidelines. Implementation of TEM is still not optimal because of existing barriers on both patient and professional level. An important barrier is the hesitance of professionals to counsel their patients for TEM because they fear that patients will be dissatisfied with care. However, if and how adherence to TEM actually affects the couples' experience with care is unknown. Experiences with the quality care can be measured by evaluating the patient-centredness of care and the patients' trust in their physician. STUDY DESIGN, SIZE, DURATION: This is a retrospective cross-sectional study. A survey with written questionnaires was performed among all couples who participated in the retrospective audit of guideline adherence on TEM in 25 Dutch clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples were eligible to participate if they were diagnosed with unexplained infertility and had a good prognosis (>30%) of natural conception within 1 year based on the Hunault prediction model. We used patient's questionnaires to collect data on the couples' experience with the quality of care and possible confounders for their experiences other than having undergone TEM or not. Multilevel regression analyses were performed to investigate case-mix adjusted association of TEM with the patient-centredness of care (PCQ-Infertility) and the patients' trust in their physician (Wake Forest Trust Scale). MAIN RESULTS AND THE ROLE OF CHANCE: Couples who adhered to TEM experienced the quality of care on the same level as couples who were exposed to early treatment, i.e. started fertility treatment within 6 months after fertility work-up. There were no associations between adherence to TEM and the patient-centredness of care or the patients' trust in their physician. LIMITATIONS, REASONS FOR CAUTION: Because this study is retrospective, recall bias might occur. Furthermore, we were unable to measure the difference in experience with care over time. Therefore, our results have to be interpreted carefully. WIDER IMPLICATIONS OF THE FINDINGS: Prospective research on couples undergoing TEM have to be performed to provide more detailed insight in the patients' experiences with the decision making process and subsequently the expectant period. Tackling the barriers surrounding TEM, i.e. better counselling and more patient information material, could further improve patient experiences with the quality of care for couples who are advised TEM. STUDY FUNDING/COMPETING INTERESTS: Supported by Netherlands Organisation for Health Research and Development (ZonMW). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none. TRIAL REGISTRATION NUMBER: www.trialregister.nl NTR3405.

The postmenopausal ovary as an androgen-producing gland; hypothesis on the etiology of endometrial cancer.

Postmenopausal estrogens originate from the peripheral conversion of androgens, which are produced by the adrenal glands and the ovaries. Estrogens are considered to contribute to the neoplastic development of endometrium. Hyperplasia of ovarian stroma is associated with an increased androgen production by the ovaries and with the development of endometrial pathology. We hypothesize that, in cases of endometrial pathology, an increased production of aromatizable androgens by postmenopausal ovaries will lead to elevated prehormone availability for estrogen formation in utero. Following the conversion of ovarian androgens, a reaction catalyzed by the cytochrome p450 aromatase, estrogens may function as a local mitogenic factor eventually leading to the development of endometrial cancer. We consider the local availability of androgens and the local activity of aromatase relevant for this process. If this hypothesis proves to be right it may give rise to the introduction of aromatase inhibitors in treatment strategies of hormone dependent endometrial malignancies.

Relationship between ovarian production of estrone, estradiol, testosterone, and androstenedione and the ovarian degree of stromal hyperplasia in postmenopausal women.

OBJECTIVE: To study the relationship between ovarian production of estrone (E ), estradiol (E2), testosterone (T), and androstenedione (A) and the ovarian degree of stromal hyperplasia in postmenopausal women. DESIGN: In 18 postmenopausal women, the ovarian vein hormone levels of E1, E2, T, and A were compared with the degree of ovarian stromal hyperplasia. The degree of stromal hyperplasia was assessed by histological analysis (group 1: atrophic ovaries, n = 8; group 2: slight stromal hyperplasia, n = 8; group 3: moderate or severe stromal hyperplasia, n = 2). RESULTS: The ovarian levels of E1 and E2 did not correlate with the ovarian degree of stromal hyperplasia. The ovarian levels of A in group 3 were significantly higher than those in groups 1 and 2 (p < 0.02 and p < 0.01, respectively). The ovarian levels of T in group 3 were significantly higher than those in group 1 (p < 0.01) but did not differ significantly from those in group 2. CONCLUSIONS: The amount of stromal hyperplasia in postmenopausal ovaries is correlated with the ovarian vein levels of A and T. Morphological characteristics of the postmenopausal ovary determine the local (pelvic) endocrine status and may play a role in the etiology of hormone-dependent diseases of the internal genitals.

Endocrine activity of the postmenopausal ovary: the effects of pituitary down-regulation and oophorectomy.

The endocrine activity of the postmenopausal ovary and the effect of pituitary down-regulation were studied in a group of 35 postmenopausal women. All women underwent oophorectomy with or without hysterectomy. Fifteen women received a single dose of a depot GnRH agonist (GnRHa) 2 weeks before operation, whereas 20 women formed the control group. Peripheral venous levels of LH, FSH, estrone, 17 beta-estradiol, testosterone (T), androstenedione (A), sex hormone-binding globulin, and dehydroepiandrosterone sulfate were measured 2 weeks before, during, and 6 weeks after surgery. Ovarian venous blood was sampled during surgery. In the GnRHa and control groups, ovarian venous levels of A and T were significantly higher, and those of dehydroepiandrosterone sulfate and sex hormone-binding globulin significantly lower, compared to the peripheral levels. A significant decrease in T was found in the peripheral and ovarian vein samples during pituitary down-regulation with GnRHa. Six weeks after operation, peripheral T levels were significantly lower than those during surgery in the group that was down-regulated at the time of oophorectomy. We conclude that the postmenopausal ovary produces significant amounts of A and T, although only T contributes significantly to its peripheral serum levels. T production by the postmenopausal ovary is in part stimulated by the high levels of circulating gonadotropins, although pituitary down-regulation does not completely abolish androgenic activity.

Pituitary down-regulation with a single depot-dose of a GnRH agonist (triptorelin) in postmenopausal women.

Gonadotropin levels were determined in 17 postmenopausal women before and after administering a single depot-dose of the GnRH agonist triptorelin. E2 levels of all samples were in the normal (low) postmenopausal range and no differences were found when the patients were grouped according to chronological age, or time after menopause. Pre-GnRH agonist levels of LH and FSH were in the normal (high) postmenopausal range. Two weeks after medication, LH and FSH had decreased to premenopausal levels (P < 0.0001). Eight weeks after medication, LH levels were still low whereas FSH levels had risen significantly again (P < 0.0001). Both LH and FSH levels, however, were still significantly below the serum concentrations before the administration of triptorelin (P < 0.0001). The pre-GnRH agonist level of FSH was significantly higher in women > 67 years old (P < 0.05), as compared to women < 67 years. Two weeks after medication both LH and FSH levels were significantly higher in women more than 15 years after menopause (P < 0.05), as compared to those < 15 years. The same was found for FSH in women > 67 years old. No further significant differences were noted. This study demonstrates a significant decrease of LH and FSH serum levels in postmenopausal women within two weeks after administration of a single depot-dose of the GnRH agonist triptorelin. After eight weeks, in contrast to premenopausal women, both LH and FSH, although rising, were still significantly suppressed.

Peripheral vein, ovarian vein and ovarian tissue levels of inhibin in a postmenopausal patient with a granulosa cell tumour.

In a patient with a granulosa cell tumour, stage 1a1, peripheral and ovarian vein blood samples were drawn before, during and after bilateral oophorectomy. Before operation inhibin and follicle-stimulating hormone levels were in the premenopausal range, whereas the peripheral level of oestradiol and luteinizing hormone were in the normal postmenopausal range. In the ovarian vein at the side of the tumour, inhibin and oestradiol levels were elevated, whereas in the contralateral ovarian vein the concentrations of inhibin and oestradiol were in the same range as in the peripheral vein. Immunoreactive inhibin levels in the homogenized tumour were 23 times higher than in the contralateral ovary, whereas inhibin bioactivities in the same samples amounted to 126 and 14 U/mg protein, respectively. After removal of the tumour, peripheral serum follicle-stimulating hormone and inhibin levels were in the normal postmenopausal range again. We conclude that inhibin can have a role as a marker for granulosa cell tumours.

Utero-ovarian vein blood sampling in postmenopausal women.

A technique for the collection of utero-ovarian vein blood in postmenopausal women is described. This technique enables the study of the endocrinology of postmenopausal ovaries and of the pelvic endocrine milieu. The sampling of blood from the utero-ovarian veins was almost always adequate, and there were no complications.

Clinical history and outcome of 59 patients with idiopathic hyperprolactinemia.

OBJECTIVE: To investigate the clinical course of hyperprolactinemia without demonstrable cause. DESIGN: Prospective study of all patients with idiopathic hyperprolactinemia first seen between 1974 and 1985. SETTING: Outpatient Department of University Hospital. PATIENTS: Fifty-nine patients followed for 6 to 190 months (median 78 months). Medical treatment given only in case of anovulatory infertility or hypogonadism. OUTCOME MEASURES: Development of pituitary (micro)prolactinoma, prolactin (PRL) levels, and clinical signs of menstrual dysfunction. RESULTS: With exception of one woman in whom it probably had been missed by hypocycloidal tomography, no demonstrable prolactinoma developed. Prolactin levels rose in two patients, one using oral contraceptives and the other with prolactinoma. At the end of follow-up, 15 of 16 patients using a dopaminergic drug had a normal cycle; 13 had normal final PRL levels. From the 43 patients off medication, 28 (66%) had normal PRL levels and 23 (54%) had a normal cycle. There were no significant differences between women who had and had not been pregnant. Dopaminergic medication had no appreciable influence on the course of the disease. CONCLUSION: In idiopathic hyperprolactinemia, progression to pituitary prolactinoma seldom, if ever, occurs. There is a high tendency to spontaneous cure, and pregnancy or medication have no apparent effect. Frequent pituitary imaging was found to be not necessary in our patient population. It may best be reserved for situations in which the PRL level in symptomatic hyperprolactinemia is inconsistent with pituitary imaging results.

Clinical and pathological aspects of benign and malignant squamous epithelium of the corpus uteri; a report of two cases.

Two patients with primary squamous cell carcinoma of the uterus are described. In both patients, the disease was at an advanced stage when the diagnosis was made. Although endometrial malignancies with squamous elements account for 10-30% of endometrial carcinomas, primary squamous cell carcinoma of the uterus is extremely rare. Up to now fewer than 30 cases have been reported. The pathogenesis, morphogenesis and aetiology of squamous epithelium in the corpus uteri is discussed. Finally, some clinical aspects of the primary squamous cell carcinoma of the corpus uteri are reviewed.