Dominique de Ziegler

Endometriosis and infertility: pathophysiology and management

Endometriosis and infertility are associated clinically. Medical and surgical treatments for endometriosis have different effects on a womans chances of conception, either spontaneously or via assisted reproductive technologies (ART). Medical treatments for endometriosis are contraceptive. Data, mostly uncontrolled, indicate that surgery at any stage of endometriosis enhances the chances of natural conception. Criteria for non-removal of endometriomas are: bilateral cysts, history of past surgery, and altered ovarian reserve. Fears that surgery can alter ovarian function that is already compromised sparked a rule of no surgery before ART. Exceptions to this guidance are pain, hydrosalpinges, and very large endometriomas. Medical treatment-eg, 3-6 months of gonadotropin-releasing hormone analogues-improves the outcome of ART. When age, ovarian reserve, and male and tubal status permit, surgery should be considered immediately so that time is dedicated to attempts to conceive naturally. In other cases, the preference is for administration of gonadotropin-releasing hormone analogues before ART, and no surgery beforehand. The strategy of early surgery, however, seems counterintuitive because of beliefs that milder non-surgical options should be offered first and surgery last (only if initial treatment attempts fail). Weighing up the relative advantages of surgery, medical treatment and ART are the foundations for a global approach to infertility associated with endometriosis.

Premature elevation of plasma progesterone alters pregnancy rates of in vitro fertilization and embryo transfer

OBJECTIVE To determine if an increase in plasma P occurring before hCG administration might impair the outcome of IVF-ET. DESIGN Five hundred eighty-five IVF-ET cycles were prospectively studied for the occurrence of plasma P elevation before hCG administration. SETTING Tertiary institution, IVF-ET program, Hôpital A. Béclère. PATIENTS Participating patients included IVF-ET candidates 23 to 42 years of age only, excluding the couples in whom a male factor was a primary or an accessory cause of infertility. MAIN OUTCOME MEASURES To clarify the practical consequences on IVF-ET outcome of pre-hCG increases in plasma P, we studied 585 consecutive IVF-ET cycles. These were divided into two groups according to plasma P levels observed on the day of hCG administration; plasma P of 0.9 ng/mL (2.9 nmol/L) was taken as an arbitrary cutoff value. Group A included 485 IVF cycles in which plasma P was < or = 0.9 ng/mL (2.9 nmol/L); group B included the remaining 100 cycles in which plasma P was > 0.9 ng/mL (2.9 nmol/L). RESULTS The number of mature oocytes retrieved, the oocyte cleavage rate, and the number of embryos obtained were similar in groups A and B. In contrast to this apparent similarity in oocyte quality, a decrease in pregnancy rate (PR) and a trend for a decrease in embryo implantation rate were observed in group B in comparison with group A. CONCLUSIONS The similar fertilization and cleavage rates obtained in groups A and B suggest that pre-hCG elevation in plasma P does not lead to decreased oocyte quality. Yet the lower PR observed when plasma P rises prematurely suggests that the prolonged but discrete elevation in plasma P occurring in these cases might alter endometrium receptivity to embryo implantation.

Direct transport of progesterone from vagina to uterus.

Objective To compare progesterone concentrations in serum and endometrial tissue from hysterectomy specimens after vaginal or intramuscular (IM) administration of progesterone gel. Methods This was a randomized open study of 14 post-menopausal women undergoing transabdominal hysterectomies. Participants received either vaginal progesterone gel, 90 mg, or IM progesterone, 50 mg, at 8:00 AM and 8:00 PM on the day before surgery and at 6:00 AM on the day of surgery. Venous blood samples for progesterone measurement were collected at 8:00 AM on the day before surgery (baseline) and during surgery. After removal of the uterus, the endometrium was sampled from the anterior and posterior walls. Results were expressed as ratios of endometrial to serum progesterone concentrations × 100. Results Ratios of endometrial to serum progesterone concentrations were markedly higher in women who received vaginal progesterone (14.1 median, 8.5–59.4 range; 95% confidence interval [CI] 9.89, 38.79) compared with IM injections (1.2 median, 0.5–13.1 range; 95% CI −0.48, 7.39) (P < .005). Conclusion Ratios of endometrial to serum progesterone concentrations were higher after vaginal administration of progesterone than after IM injections. Our findings in endometrial tissue specimens from hysterectomies excluded the possibility of contamination by progesterone that remained in the vagina.

The antral follicle count: practical recommendations for better standardization

OBJECTIVE To provide recommendations for the standardized use of the Antral follicle count (AFC) which is used to predict ovarian response to gonadotrophin stimulation during assisted reproductive technology treatment. However, the nature of the follicles that are visualized by ultrasound and the competence of the oocytes held within are largely unknown. In addition, there is considerable variability in the clinical definitions and technical methods used to count and measure antral follicles in both published studies and clinical practice. DESIGN AND SETTING In December 2007, specialist reproductive medicine clinicians and scientists attended a workshop in an effort to address these issues. Literature concerning the physiology and measurement of ovarian antral follicles was reviewed, clinical and technical considerations regarding antral follicle measurement were discussed, and an operational definition of AFC was developed. PATIENT(S) None. INTERVENTION(S) None. OUTCOME MEASURES Simple recommendations were established for the standardization of AFC assessment in routine clinical practice. The basic clinical and technical requirements required for AFC evaluation were agreed upon, and a systematic method of measuring and counting antral follicles in routine practice was proposed. CONCLUSION(S) The use of a standardized approach according to the practical recommendations for antral follicle counting as presented is encouraged in future clinical trials and routine practice. The authors also advocate a systematic evaluation of these recommendations as standardized study data become available.

The single or dual administration of the gonadotropin-releasing hormone antagonist Cetrorelix* in an in vitro fertilization-embryo transfer program

OBJECTIVE To assess the ability of a GnRH antagonist (Cetrorelix, Asta Medica AG, Frankfurt, Germany) to prevent premature LH surges in an IVF-ET program using a simple protocol with one or two administrations. DESIGN Controlled ovarian hyperstimulation was carried out in 17 women with three ampules a day of hMG, starting on day 2 of the menstrual cycle. A dose of 5 mg of Cetrorelix was administered when plasma E2 levels were between 150 and 200 pg/mL (conversion factor to Sl unit, 3.671) per follicle of > or = 14 mm. A second injection was performed 48 hours later if the triggering of ovulation was not decided in the meantime. RESULTS Six patients received one injection and 11 patients received two administrations. Plasma LH levels showed a marked decrease and remained low after the administration of the GnRH antagonist. In six patients, the first administration of Cetrorelix was performed when a significant rise in LH plasma level was present. Even in these patients the GnRH antagonist was able to prevent an LH surge. The tolerance of the product was good. Six clinical pregnancies were obtained, of which four are ongoing (25% per ET). Two ongoing pregnancies were obtained after the transfer of a frozen-thawed embryo (35.3% per retrieval). CONCLUSIONS The GnRH antagonist Cetrorelix in a simple, unique or dual administration, protocol was able to prevent premature LH surge in all of the 17 patients studied. If these results are confirmed by larger, randomized studies, the good tolerance and efficacy that we observed suggest a bright future for this product is assisted reproductive technologies.

The role of leiomyomas in infertility

STUDY OBJECTIVE To assess the role of leiomyomas and their surgical removal on pregnancy rates. DESIGN (Canadian Task Force classification II-1). Setting. Academic center. PATIENTS Two hundred twelve women who were investigated for infertility. INTERVENTION Laparoscopic myomectomy. MEASUREMENTS AND MAIN RESULTS Patients were divided according to case control criteria as those who underwent laparoscopic removal of myomas (106) and those who did not (106); both groups were compared with 106 women with unexplained infertility without myomas. Of the 318 women, 83 (26%) became pregnant and delivered live infants. The 44 (42%) who underwent surgical removal of leiomyomas had higher delivery rates than 12 (11%) who did not undergo surgery (p <0.001) and 27 (25%) who did not have myomas (p <0.001). Patients whose myomas were not surgically treated had fewer deliveries than women who did not have myomas (12 vs 27, p <0.002). Fifteen women had spontaneous abortions before week 12: 3 (3%) who had surgery, 10 (9%) who did not have surgery, and 2 (2%) who did not have myomas. CONCLUSION Laparoscopic myomectomy improved pregnancy rates over nonsurgical management of myomas.

Transvaginal administration of progesterone.

Objective To examine the endometrial effects of three different doses of progesterone administered vaginally Methods Forty women 25–41 years old deprived of ovarian function received estradiol (E2) for 28 days. From days 15 to 27, a new mucus-like vaginal gel of progesterone was administered every other day, randomly, dosed at 45 mg (group A, n = 14), 90 mg (group B, n = 13), or 180 mg (group C, n = 13). Plasma gonadotropins, estrone, E2, and progesterone were measured. An endometrial biopsy was performed on day 20 (n = 20) or 24 (n = 20) for endometrial dating and for estrogen and progesterone receptor determinations. Results Plasma estrogen levels were in the menstrual cycle range. Mean progesterone levels were lower in group A (2.4 ± 0.2 ng/mL) than in group B (3.6 ± 0.2 ng/mL) or C (3.4 ± 0.4 ng/mL) (P < .005). Plasma FSH and LH decreased significantly during progesterone treatment. In all groups, we observed secretory transformation in the glands (day 20) and stroma (day 24) and the distribution of estrogen and progesterone receptors seen in normal menstrual cycles. Conclusion Transvaginal administration of progesterone induced normal secretory transformation of the endometrium despite low plasma levels, suggesting a direct transit into the uterus or “first uterine pass effect.”

Uterine contractility and embryo implantation.

Purpose of review The aim of this article is to assess the importance of uterine contractility in the implantation of human embryos. Recent findings Recent findings show that the receptive phase of the endometrium seems to occur in close association with the appearance of pinopodes and endometrial integrins that may be activated by the IL-1 system. Throughout the menstrual cycle wavelike activity patterns of the uterus were identified with adequate wave patterns appearing to be related to successful reproduction in spontaneous cycles and in assisted reproduction. Such patterns are controlled by steroid hormones. Embryo attachment to the predecidualized endometrium and its invasion may be determined by the expression of proteolytic enzymes that require uterine quiescence for implantation. The uterine activity was detected both in vitro and in vivo by using invasive intrauterine pressure and noninvasive ultrasound approaches. Progesterone promotes local vasodilatation and uterine musculature quiescence by inducing nitric oxide synthesis in the decidua. At present, until new evidence emerges to demonstrate otherwise, the effects of progesterone are, directly or indirectly, the only determinant of endometrial preparation for embryo nidation, with the induction of uterine quiescence being one of these effects. Summary Adequate uterine contractility may provide for gamete/embryo transportation through the utero-tubal cavities and successful embryo implantation in spontaneous or assisted reproduction. Inadequate uterine contractility may lead to ectopic pregnancies, miscarriages, retrograde bleeding with dysmenorrhea and endometriosis.

Surgery for bladder endometriosis: long-term results and concomitant management of associated posterior deep lesions

BACKGROUND Deep infiltrating endometriosis (DIE) is presented as a disease with high recurrence risk. Bladder DIE is the most frequent location in cases of urinary endometriosis. Surgical removal has been recommended for bladder DIE but long-term outcomes remains unevaluated. The objectives of this study are to evaluate the rate of recurrence after partial cystectomy for patients presenting with bladder DIE and to outline the surgical modalities for handling associated posterior DIE nodules. METHODS Seventy-five consecutive patients with histologically proved bladder DIE were enrolled at a single tertiary academic center between June 1992 and December 2007. A partial cystectomy was performed for each patient. Complete surgical exeresis of all associated symptomatic DIE lesions was carried out during the same surgical procedure. Bladder DIE patients were classified into three groups: patients with isolated bladder DIE (Group A); patients with associated symptomatic posterior DIE (Group B); patients with associated asymptomatic posterior DIE (Group C). Bladder DIE recurrence was defined as a clinical reappearance of the disease or radiological evidence that mandated a new surgical procedure. We assessed pelvic pain symptoms pre- and post-operatively using a 10-cm visual analogue scale. RESULTS In a series of 627 patients with DIE, we observed 75 patients (12%) with bladder DIE. With a 50.9 +/- 44.6 months mean follow-up after partial cystectomy no patient presented evidence of bladder DIE recurrence. Post-operatively, we observed a significant improvement with respect to pain symptoms, with only two patients (2.7%) developing major complications during follow-up. Among patients with non-operated associated asymptomatic posterior DIE lesions (n = 15), a second surgical procedure indicated for pain symptoms was necessary in only one patient (6.7%). CONCLUSIONS For patients presenting with bladder DIE, no patients required further surgery for bladder recurrence after radical surgery consisting in partial cystectomy. Exeresis of associated posterior DIE nodules is indicated only when they are symptomatic.

Characteristics of uterine contractility during menses in women with mild to moderate endometriosis

OBJECTIVE To establish the role of uterine contractions in retrograde menstruation with subsequent abdominal implantation of endometrial tissue. DESIGN Controlled prospective study. SETTING University hospital-based study. PATIENT(S) Infertile women with (n = 22) and without (n = 22) endometriosis. MAIN OUTCOME MEASURE(S) Frequency, amplitude, and basal pressure tone of uterine contractions; correlation of contractions with retrograde bleeding and presence of viable endometrial cells; and dysmenorrhea before and 3 and 24 months after surgery. RESULT(S) Compared with controls, patients with endometriosis had uterine contractions with higher frequency (22.73 +/- 5.66 osc/10 min vs. 11.09 +/- 3.26 osc/10 min), amplitude (20.83 +/- 3.94 mm Hg vs. 6.77 +/- 2.83 mm Hg), and basal pressure tone (50.14 +/- 16.30 mm Hg vs. 24.68 +/- 6.14 mm Hg). Dysmenorrhea was scored as 4.09 +/- 1.44 in patients with endometriosis and 0.86 +/- 1.42 in controls. Retrograde bleeding was found in 73% of patients with endometriosis vs. 9% of controls, and only 45% of patients with endometriosis had viable endometrial cells in the cul-de-sac. CONCLUSION(S) Endometriosis may result from abnormal myometrial contractility through tubal transportation, dissemination, and implantation of endometrial viable cells into the abdomen.