Carlo Bulletti

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.

Endometriosis and infertility

Endometriosis is a debilitating condition characterized by high recurrence rates. The etiology and pathogenesis remain unclear. Typically, endometriosis causes pain and infertility, although 20–25% of patients are asymptomatic. The principal aims of therapy include relief of symptoms, resolution of existing endometriotic implants, and prevention of new foci of ectopic endometrial tissue. Current therapeutic approaches are far from being curative; they focus on managing the clinical symptoms of the disease rather than fighting the disease. Specific combinations of medical, surgical, and psychological treatments can ameliorate the quality of life of women with endometriosis. The benefits of these treatments have not been entirely demonstrated, particularly in terms of expectations that women hold for their own lives. Although theoretically advantageous, there is no evidence that a combination medical-surgical treatment significantly enhances fertility, and it may unnecessarily delay further fertility therapy. Randomized controlled trials are required to demonstrate the efficacy of different treatments.

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.

Adhesion formation after laparoscopic myomectomy

STUDY OBJECTIVE To determine the frequency of adhesion formation after myomectomy performed by operative laparoscopy or laparotomy. DESIGN Case-control study. Setting. Academic womens hospital. PATIENTS Thirty-two premenopausal women scheduled for myomectomy by one of two techniques. INTERVENTIONS Surgical removal of myomata. MEASUREMENTS AND MAIN RESULTS Of the 32 women, 16 underwent laparotomy and 16 laparoscopy. Second-look laparoscopy was performed in 28 patients, at which time adhesions were lysed. Compared with laparotomy, laparoscopy resulted in adhesions in significantly fewer patients, and in significantly lower scores when adhesions were detected. CONCLUSION Laparoscopic removal of uterine myomata is associated with fewer adhesions than removal by laparotomy.

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.

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.

Differences in blood and semen oxidative status in fertile and infertile men, and their relationship with sperm quality.

Oxidative stress plays a fundamental role in the aetiology of male infertility by negatively affecting sperm quality and function. Assessment of blood and seminal plasma oxidative profiles might be a valuable tool to improve evaluation of sperm reproductive capacity and functional competence. This study examined the lipid-soluble antioxidant profile and levels of lipid peroxidation both in blood and seminal plasma samples of infertile and fertile males, in relation to semen parameters. Total antioxidant capacity (TAC) and vitamin E concentrations were significantly (P<0.05) lower in seminal plasma of infertile men compared with fertile subjects; concurrently, a significant accumulation of malondialdehyde was found in infertile patients (P=0.032 compared with controls), which was negatively correlated with sperm motility and morphology. In blood samples, infertile men presented lower concentrations of TAC, carotenoids and vitamin E than fertile subjects; TAC and carotenoids were positively correlated with sperm motility, morphology and concentration. Finally, blood TAC and vitamin E concentrations were positively correlated with the corresponding seminal values, confirming the close relationship between blood and semen antioxidants. All these results indicated the possibility of using not only seminal antioxidants but also blood antioxidants as biochemical markers to support sperm quality evaluation. Oxidative stress induced by reactive oxygen species (ROS) has been widely recognized as one of the major causes of male infertility; indeed, excessive ROS production can negatively impact sperm quality and function. The assessment of blood and seminal plasma oxidative profiles has been suggested as a valuable tool to improve the evaluation of sperm reproductive capacity and functional competence in infertile men. With this in mind, in the present study we examined the lipid soluble antioxidant profile (carotenoids and vitamins A and E) and the levels of lipid peroxidation (malondialdehyde; MDA) both in blood and seminal plasma samples of infertile and fertile males, in correlation with semen parameters namely motility, morphology and concentration. As a result, we obtained evidence that the total antioxidant capacity (TAC) and the concentrations of vitamin E of seminal plasma samples were significantly lower in infertile men than in fertile subjects; at the same time, a significant accumulation of MDA was found in infertile patients. MDA, in turn, negatively correlated with sperm motility and morphology, thus confirming that oxidative damage to lipids impairs sperm quality. In blood samples, infertile men presented lower TAC and lower concentrations of carotenoids and vitamin E than fertile subjects; interestingly, TAC and carotenoid concentrations were positively correlated with sperm motility, morphology, and concentration, confirming the close relationship between blood antioxidants and sperm quality. In conclusion, all these results suggested that the examination of blood and semen oxidative profiles might furnish useful information on sperm quality and function in infertile men.

The hormonal control of endometrial receptivity: estrogen (E2) and progesterone

While the number of identified substances produced by the ovary increases steadily, it remains remarkable that the sole use of exogenous estrogen (E2) and progesterone (P) can prime optimal endometrial receptivity in women whose ovaries have failed or are absent. Early work showed that a marked leeway existed in the acceptable duration of the E2-only phase of endometrial priming. Subsequently, a sequence of transformations are induced by exogenous progesterone that reproduces classical findings made in the menstrual cycle. Secretory changes in endometrial glands are best seen between the 4th and 6th day of progesterone administration (day 18-20 of an ideal cycle where progesterone exposure starts on day 15). Predecidual changes of the endometrial stroma are apparent starting on the 10th day of progesterone exposure (day 24). Contrary to earlier belief, even maximal alterations in the plasma E2 to progesterone ratio fails to alter the endometrial morphology of either glands or stroma. More recently it has been recognized that E2 and progesterone also affect uterine contractility. It has been postulated that excessively high levels of E2 may increase uterine contractility and adversely affect implantation rates in in-vitro fertilization (IVF). Exogenous progesterone has been shown to exert utero-relaxing effects and it has been hypothesised that progesterone supplementation before embryo transfer (ET) may improve receptivity in IVF.

Myomas, Pregnancy Outcome, and In Vitro Fertilization

Abstract: Uterine fibroids have been reported in 27% of infertile women, and 50% of women with unexplained infertility become pregnant after myomectomy. The age at which a first pregnancy occurs is increasing from the thirties to the forties. This increase and the recurrence rate of leiomyomas from 15 to 30% points to the effect of myomas on the infertility. Mechanisms by which myomas may cause infertility are abnormal uterine contractility, elongation of the uterine cavity, and distortion of uterine vascularization. Surgery may have beneficial or adverse effects without clear data on its effect on the assisted reproductive technology (ART) procedures. The present study was undertaken to establish the impact of surgical removal of myomas on fertility and infertility of patients undergoing ART procedures. Patients who underwent surgical removal of myomas before in vitro fertilization (Group A) had a cumulative success rate of 33% for one to three procedures (28 clinical pregnancies in 84 patients) and delivery rate of 25% (21 live births in 84 patients). Patients who underwent in vitro fertilization without previous surgery (Group B) had a 15% clinical pregnancy rate (13 pregnancies in 84 patients) (P < 0.05) and 12% delivery rate (10 deliveries in 84 pregnancies) (P < 0.05). Abortion rates were 7% (8 deliveries in 84 patients) and 4% (3 deliveries in 84 patients) in Groups A and B, respectively. This study confirms the beneficial effect of surgical removal of fibroids before undergoing ART procedures.

The First Uterine Pass Effect

The endometrial effects of vaginal progesterone have been found to be unexpectedly reliable. This has led us to suspect that a local direct vagina-to-uterus transport or first uterine pass effect was the basis of the uterine targeting of vaginal progesterone. After vaginal administration of progesterone, uterine tissue concentration has been found to exceed by more than 10-fold the levels achieved by systemic administration, despite plasma levels in the latter case that were more than seven times higher. Similar differences in systemic-to-uterine tissue level ratios have been observed between oral and vaginal administration of danazol. Originally seen as a pharmacological advantage permitting the uterine targeting of vaginally administered substances, it is possible that the first uterine pass effect plays a physiological role in the control of uterine contractile activity through the prostaglandins contained in the semen.