Effectiveness and safety of gonadotropins used in female infertility: a population-based study in the Lazio region, Italy.

PURPOSE: Infertility is a topic of growing interest, and female infertility is often treated with gonadotropins. Evidence regarding comparative safety and efficacy of different gonadotropin formulations is available from clinical studies, while real-world data are missing. The present study aims to investigate effectiveness and safety of treatment with different gonadotropin formulations in women undergoing medically assisted procreation treatments in Latium, a region in central Italy, through a real-world data approach. METHODS: A retrospective population-based cohort study in women between the ages of 18 and 45 years who were prescribed with at least one gonadotropin between 2007 and 2019 was conducted. Women were enrolled from the regional drug dispense registry, and data on their clinical history, exposure to therapeutic cycles (based on recombinant "REC" or extractives "EXT" gonadotropin, or combined protocol "CMD" (REC + EXT)), and maternal/infantile outcomes were linked from the regional healthcare administrative databases. Multivariate logistic regression models were applied to estimate the association between exposure and outcomes. RESULTS: Overall, 90,292 therapeutic cycles prescribed to 35,899 women were linked to pregnancies. Overall, 15.8% of cycles successfully led to pregnancy. Compared to extractives, recombinant and combined treatments showed a stronger association with conception rate (RRREC adj = 1.06, 95% CI: 1.01-1.12; RRCBD adj = 1.17, 95% CI: 1.11-1.24). Maternal outcomes occurred in less than 5% of deliveries, and no significant differences between treatments were observed (REC vs EXT, pre-eclampsia: RR adj = 1.24, 95% CI: 0.86-1.79, ovarian hyperstimulation syndrome: RR adj = 1.25, 95% CI: 0.59-2.65, gestational diabetes: RR adj = 1.06, 95% CI: 0.84-1.35). Regarding infantile outcomes, similar results were obtained for different gonadotropin formulations (REC vs EXT: low birth weight: RR adj = 0.98, 95% CI: 0.83-1.26, multiple births: RR adj = 1.06, 95% CI: 0.92-1.23, preterm birth: RR adj = 1.03, 95% CI: 0.92-1.26). CONCLUSIONS: Efficacy and safety profiles of REC proved to be similar to those of EXT. Regarding the efficacy in terms of conception rate and birth rate, protocols using the combined approach performed slightly better. Outcomes related to maternal and infantile safety were generally very rare, and safety features were overlapping between gonadotropin formulations.

Distal Corporal Anchoring Stitch: A Technique to Address Distal Corporal Crossovers and Impending Lateral Extrusions of a Penile Prosthesis.

BACKGROUND: Unidentified distal crossovers, delayed distal crossovers, and impending lateral extrusion are complications of penile prosthesis implant insertion but are not as common as prosthesis infection or mechanical failure. AIM: To evaluate results of a surgical technique, the distal corporal anchoring stitch, that addresses fixation of the penile prosthesis in patients with these complications. METHODS: A lateral sub-coronal incision is used on the side where the crossover or laterally extruding cylinder should be positioned. Dissection is carried through the Buck fascia, followed by a transverse incision of the tunica albuginea, where the distal aspect of the affected cylinder is delivered. A 4-0 PDS suture is threaded through the distal cylinder ring of the implant. A new, properly positioned intracorporal channel is created and the suture is passed through the distal end of the channel. Once the suture is through the glans and the cylinder is in the correct position, a small cruciate incision is made on the glans at the location of the anchor stitch. The suture is tied with the knot buried in the glans tissue. OUTCOMES: Fifty-three patients underwent treatment of their distal penile implant crossover with a distal corporoplasty using this method and their anatomic and functional outcomes and overall satisfaction were evaluated. RESULTS: This technique ensured that the cylinder remained in the newly created, appropriately positioned channel. No patients developed infections, wound-healing defect, glandular hypoesthesia, anesthesia, or altered sensation or pain in the glans related to the suture and only two reported recurrence of a lateral herniation that did not require further treatment. CLINICAL IMPLICATIONS: Distal fixation of the penile prosthesis is a useful surgical adjunct to treating patients with prosthetic lateral extrusions or crossovers that can be applied in almost all cases. STRENGTHS AND LIMITATIONS: Considering these rare complications, our experience is based on a relatively large number of patients and showed a low incidence of complications and a high satisfaction rate. The main limitation of this study is the retrospective nature of the data and the series included patients from two high-volume surgeons that might not be generalizable to all practices. CONCLUSION: The distal corporal anchoring stitch is safe and effective in securing distal fixation of the extruding inflatable penile prosthesis. Antonini G, Busetto GM, Del Giudice F, et al. Distal Corporal Anchoring Stitch: A Technique to Address Distal Corporal Crossovers and Impending Lateral Extrusions of a Penile Prosthesis. J Sex Med 2017;14:767-773.

Three-component hydraulic penile prosthesis malfunction due to penile fibrolipoma secondary to augmentative phalloplasty: A case report.

Fibrolipomas are an infrequent type of lipomas. We describe a case of a man suffering from subcutaneous penile fibrolipoma, who twelve months earlier has been submitted to augmentative phalloplasty due to aesthetic dysmorphophobia. The same patient three years earlier has been submitted to three-component hydraulic penile prostheses implantation due to erectile dysfunction. After six months from removing of the mass, the penile elongation and penile enlargement were stable, the prostheses were correctly functioning and the patient was satisfied with his sexual intercourse and life. The diagnostics and surgical characteristics of this case are reported.

Ovarian Stimulation Protocol in IVF: An Up-to-Date Review of the Literature.

The Assisted Reproductive Technology (ART) was born in order to help couples with infertility issues in having a baby. The first treatments of IVF used the spontaneous cycle of the women, with the retrieval of only one oocyte. Further studies have shown that it is possible to induce ovulation by administrating gonadotropins during the menstrual cycle, in order to obtain a higher number of oocytes. Many stimulation protocols have been introduced for controlled ovarian hyperstimulation of patients undergoing in vitro fertilization treatment. This review describe the different stimulation protocols using follicle-stimulating hormone (FSH) in combination with Gonadotropin releasing hormone (GnRH) either agonist or antagonist, oral supplementations and ovarian triggering. Using GnRH antagonist protocols have been demonstrated to improve significantly the clinical pregnancy rates for expected poor and high-responders, and in those women at high risk of developing ovarian hyperstimulation syndrome (OHSS). Two meta-analyses showed a better outcome in terms of the live birth rate when highly purified human menopausal gonadotropin (HMG) was used for ovarian stimulation compared with recombinant follicle stimulating hormone (rFSH) in the GnRH agonist long protocol. One of the most efficient stimulation protocol is the use of a combined protocol of human derived urinary FSH (uFSH) and rFSH. Combined protocol has resulted in a significant increase in the proportion of mature metaphase II oocytes and grade 1 embryos when compared to either rFSH or uFSH alone. A significantly higher delivery rate was achieved in rFSH+uFSH compared to the other protocols in poor and normal responders. Studying the combination of melatonin with myo-inositol and folic acid has also showed a higher percentage of mature oocytes in the melatonin group and a higher percentage of G1 embryos as well. However, It remains a crucial step to confirm the efficacy of such protocols for clinical application and it is still needs to comparison studies on larger scale with more focused on the differences in patients' response criteria and additional confounding variables, in order to draw more defined conclusions.

Effect of myo-inositol and melatonin versus myo-inositol, in a randomized controlled trial, for improving in vitro fertilization of patients with polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) induces anovulation in women of reproductive age, and is one of the pathological factors involved in the failure of in vitro fertilization (IVF). Indeed, PCOS women are characterized by poor quality oocytes. Therefore, a treatment for enhancing oocyte quality becomes crucial for these patients. Myo-Inositol and melatonin proved to be efficient predictors for positive IVF outcomes, correlating with high oocyte quality. We tested the synergistic effect of myo-inositol and melatonin in IVF protocols with PCOS patients in a randomized, controlled, double-blind trial. Five-hundred twenty-six PCOS women were divided into three groups: Controls (only folic acid: 400 mcg), Group A (Inofolic® plus, a daily dose of myo-inositol: 4000 mg, folic acid: 400 mcg, and melatonin: 3 mg), and Group B (Inofolic®, a daily dose of myo-inositol: 4000 mg, and folic acid: 400 mcg). The main outcome measures were oocyte and embryo quality, clinical pregnancy and implantation rates. The treatment lasted from the first day of the cycle until 14 days after embryo transfer. Myo-inositol and melatonin have shown to enhance, synergistically, oocyte and embryo quality. In consideration of the beneficial effect observed in our trial and on the bases of previous studies, we decided to integrate routinely MI and M supplementation in the IVF protocols. The same treatment should be taken carefully in consideration in all procedures of this kind.

Fas and Fas-Ligand in Eutopic and Ectopic Endometrium of Women With Endometriosis: The Possible Immune Privilege of Ectopic Endometrium.

The Fas/Fas-Ligand system is an important mediator of apoptosis. We analyzed their expression in tissue specimens obtained from 33 women with severe endometriosis and 18 women without endometriosis. Immunostaining for Fas-Ligand in the eutopic endometrium was stronger in the epithelial cells of secretory phase, while the epithelial cells of endometriotic lesions showed a significantly stronger staining for Fas-Ligand independently from the menstrual phase (P < 0.01). Immunostaining for Fas in the eutopic endometrium showed a reduced staining during the proliferative phase, whereas it was strong in the secretory phase. The epithelial cells of the ectopic endometrium showed a reduced staining for Fas independently from the menstrual phase with respect to the eutopic tissue (P < 0.01). The reduced expression of Fas in the ectopic endometrium with the contemporary higher expression of Fas-Ligand in the corresponding cells suggests a possible immune privilege of this tissue.

Surrogate motherhood: Where Italy is now and where Europe is going. Can the genetic mother be considered the legal mother?

This paper explores a recent case, which has reawakened the debate in Italy over the opportunities offered by technological progress in the field of Assisted Reproduction. On 17 January 2013, the Juvenile Court of Brescia ordered the removal and adoption of a newborn baby whose parents had turned to surrogate motherhood and heterologous insemination in Ukraine, thus expressly violating the Italian and Ukrainian laws. The authors provide a critical analysis of the legal reasoning given by the Court in order to balance the best interests of the unborn child and the needs of certain parents suffering from sterility/infertility problems. In establishing the legal status of parent, the guiding principle must be the child's right not to be objectified or exploited by the adult. Therefore, it is necessary to provide appropriate tools to balance, on the one hand, the defence of the desire to become parents, if legitimate, and on the other the preservation of the legal and harmonious development of the child. Thus, the professionals have the burden of adapting the legal rules to a variety of individual cases, always taking into account the need to comply with the principles of both Constitutional and European Union law.

A survey of Italian physicians' opinion about stem cells research: what doctors prefer and what the law requires.

To evaluate the Italian physicians' knowledge/information level about the therapeutic potential of stem cells, the research choice between embryonic and cordonal stem cells, and the preference between autologous and heterologous storage of cordonal stem cells, we performed a national survey. The questionnaire--distributed to 3361 physicians--involved physicians of different religious orientations and of different medical specialities. Most of the physicians involved (67%) were Catholics, and the majority were gynaecologists and paediatricians (43%) who are mainly in charge to inform future mothers about the possibility of cordonal stem cells conservation. The majority of the physicians interviewed do not have specific knowledge about stem cells (59%), most of them having only generic information (92%). The largest part of physicians prefer to use umbilical cord blood cells rather than embryonic stem cells. Nevertheless, a large percentage of physicians were in favour of embryo research, especially when embryos are supernumerary (44% versus 34%). Eighty-seven % of the physicians interviewed proved to have a general knowledge about stem cells and believe in their therapeutic potential. They prefer research on cordonal stem cells rather than on embryo stem cells. Although they are in favour of heterologous stem cells donation, they still prefer cryopreservation for personal use.

Not only a clinical nightmare: amniotic fluid embolism in court.

Amniotic fluid embolism (AFE) is an uncommon obstetric condition involving usually women in labour or in the early post-partum period. Clinical consequences of this unpredictable and unpreventable pathology may be extremely serious with high morbidity and mortality rates. Data obtained from the US Amniotic Fluid Embolism Registry show that the process is more similar to anaphylaxis than to embolism, and the term anaphylactoid syndrome of pregnancy has been suggested because foetal tissue or amniotic fluid components are not universally found in women who present signs and symptoms related to AFE. The first aim of this paper has been to focus on the medico-legal aspects concerning the misdiagnosis and the treatment of the AFE and the Authors, with this purpose in mind, reviewed the main national law cases on medical malpractice claims involving both physicians and hospitals. The second aim has been to highlight the need to introduce a National register as a useful tool to raise the awareness of this disease among physicians and to improve the quality of care, which can be achieved through a proper identification and reporting of AFE cases. The application of a national register may limit the number of medico-legal litigations, which according to the national and foreign Jurisprudence are not currently based in favour of the predictability of AFE, but they focus their discussion on the importance of a prompt medical assistance when the effects of this disorder occur.

Ovarian stripping versus cystectomy: recurrence of endometriosis and pregnancy rate.

PURPOSE: To compare two different surgical techniques, stripping or cystectomy, in patients treated with the same post-operative medical therapy in terms of recurrence of endometrioma, recurrence of pain and spontaneous pregnancy rate within 2 years from surgery. METHODS: The inclusion criteria of this study were: (1) 25-40 years old; (2) ovarian endometrioma more than 3 cm of diameter detected by transvaginal ultrasonography (3) regular menstrual cycle (4) post-operative treatment with GnRH analogs, (5) tubal patency assessed by laparoscopic chromopertubation (6) normal human semen characteristics. Exclusion criteria were uterine myoma, previous medical treatment for endometriosis, presence of adenomyosis, previous surgery of ovarian endometrioma, multiple cysts, bilateral involvement, co-existence of deep endometriosis. Patients were assigned to two study groups: group A (N = 45) patients undergoing stripping technique and group B (N = 64) patients undergoing cystectomy technique for ovarian endometrioma. RESULTS: In group B the percentage of ultrasonographic recurrence (15.4 %, N = 15) is much lower than in group A (55.6 %, N = 25). (p value 0.001). In group B the percentage of symptomatic recurrence (21.8 %, N = 14) is much lower than in group A (53.3 %, N = 24) (p value 0.001). Spontaneous pregnancy rate in group A patients was of 4.4 % (N = 2) and in group B 22.3 % (N = 21), (p value 0.0072). However, the percentage of specimen with adjacent healthy ovarian tissue was lower in group A (26.6 %) than in group B (50 %) (p value 0.01). CONCLUSIONS: Among the different treatment options for surgical treatment of ovarian endometrioma, in our experience cystectomy appears to be the most appropriate treatment, both in terms of recurrence and pregnancy rate.

Evaluation of serum anti-Mullerian hormone levels to assess the ovarian reserve in women with severe endometriosis.

OBJECTIVE: The aim of this study was to measure anti-Mullerian hormone (AMH) serum levels in women with severe endometriosis, in order to demonstrate the effect of the disease on ovarian reserve. STUDY DESIGN: Prospective case-control study. One hundred and ninety-five patients were enrolled: 130 fertile patients (group A) and 65 patients with stage III and IV endometriosis, diagnosed by laparoscopy and histological examination (group B). AMH serum levels were measured in both groups and were compared using Student's t-test. RESULTS: The two groups were homogenous for main demographic data. Group B had statistically significantly lower mean AMH serum levels (0.97±0.59ng/ml) than group A (1.72±0.63ng/ml) (p=0.001). CONCLUSIONS: This study is a demonstration of the damage of endometriosis on ovarian reserve, leading to a form of incipient ovarian failure, which is considered as an early sign of advanced ovarian depletion in young women. These findings suggest that AMH could be used in the follow-up of patients with endometriosis, in order to assess promptly the decrease of ovarian reserve.

Pregnancy outcome after loop electrosurgical excision procedure for cervical intraepithelial neoplasia.

OBJECTIVE: To determine pregnancy outcomes among women who underwent loop electrosurgical excision procedure (LEEP). METHODS: In a case-control study in Italy, 475 pregnant women who underwent LEEP and 441 untreated pregnant women were enrolled between January 2003 and January 2007. Outcome measures were spontaneous abortion, preterm delivery, and at-term delivery rates. Continuous and discrete variables were analyzed via t, χ(2), and Fisher exact tests. Groups were compared by analysis of variance and Tukey HSD test. RESULTS: The spontaneous abortion rate was 14.5% and 14.1% in the LEEP and untreated groups, respectively. The preterm delivery rate was 6.4% and 5.0% in the LEEP and untreated groups, respectively. The number of women with a cervical length of less than 30mm was higher in the LEEP group, but this did not influence preterm delivery rate (odds ratio [OR], 1.01; 95% confidence interval [CI], 0.53-1.95). Among women with a cervical length of less than 15mm, those treated with a wider removal of cervical tissue showed increased risk of preterm delivery (OR, 5.31; 95% CI, 1.01-28.07). CONCLUSION: The preterm delivery rate was not higher among women who underwent LEEP than among untreated women. Preterm delivery was associated with cone size and cervical length in the second trimester.

Pain in the upper anterior-lateral part of the thigh in women affected by endometriosis: study of sensitive neuropathy.

OBJECTIVE: To assess whether pain in the anterior-lateral part of the thigh in women affected by endometriosis is due to femoral nerve invasion by endometriotic implants. DESIGN: Case-control study. SETTING: Hospital. PATIENT(S): We enrolled 30 patients with endometriosis and leg pain in the anterior-lateral part of the thigh and 30 healthy women. INTERVENTION(S): Skin biopsy and neurologic examination for detection of neuropathy. MAIN OUTCOME MEASURE(S): Intraepidermal small fiber density reduction and positive neurologic examination agree with sensitive neuropathy. RESULT(S): Biopsy results showed no statistically significant difference between the case group and the control group. At neurologic examination nine patients in the study group (30%) showed positive results, none in the control group showed signs. These nine patients had reduced intraepidermal small fiber density, compared to the lower cutoff values of the control group, suggesting a sensitive neuropathy. CONCLUSION(S): When there is leg pain in women with endometriosis it is important to distinguish neuropathic from referred pain. Skin biopsy and neurologic examination should be introduced in the management of leg pain in endometriosis, due to their low invasiveness to diagnose a sensitive neuropathy. As a result early detection of nerve injury and planning for a prompt specific treatment would be possible.

Is age the limit for human-assisted reproduction techniques? 'Yes', said an Italian judge.

Although use of assisted reproduction techniques was examined by an ad hoc act in 2004 in Italy, there are many opposing views about ethical and economic implications of the technologies dealing with infertility and sterility problems. In this paper, the authors examine a recent judge's decision that ordered the removal and subsequent adoption of a 1-year-old child because her parents were considered too old to be parents. The couple had had recourse to heterologous artificial insemination abroad and decided to give birth in Italy. The judgement deals with and discusses the complex issue of the right to procreate in order to balance the opportunities offered by scientific progress with the unborn child's condition.

First case of transformation for breast fibroadenoma to high-grade malignant cystosarcoma in an in vitro fertilization patient.

OBJECTIVE: To evaluate the possible malignant transformation of fibroadenoma of the breast in patients undergoing an IVF cycle. DESIGN: Case report. SETTING: Assisted reproduction center. PATIENT(S): A 41-year-old female patient undergoing assisted fertilization treatment. INTERVENTION(S): The patient underwent fine needle aspiration biopsy that confirmed fibroadenoma before the IVF attempt. She started a short stimulation protocol with triptorelin and recombinant FSH. After the first unsuccessful IVF attempt, she underwent a second short ovarian stimulation protocol with triptorelin and urinary FSH and she become pregnant. At 17 weeks, due to an increase in volume of the fibroadenoma, an excisional biopsy was performed that showed a malignant phyllode tumor. Then she underwent quadrantectomy. MAIN OUTCOME MEASURE(S): Malignant transformation of breast fibroadenoma. RESULT(S): Cytologic examination of the first fine needle aspiration biopsy specimen showed a fibroadenoma of the breast; excisional biopsy showed a high-grade malignant cystosarcoma. CONCLUSION(S): Fibroadenoma was transformed into high-grade malignant cystosarcoma after ovarian stimulation in an IVF patient.

The re-infection rate of high-risk HPV and the recurrence rate of vulvar intraepithelial neoplasia (VIN) usual type after surgical treatment.

BACKGROUND: VIN usual type appears to be related to the HPV's oncogenic types. The aim of this prospective multicenter study was to evaluate the re-infection rate of high-risk HPV and the recurrence rate of VIN usual type after surgical treatment. MATERIAL/METHODS: The study enrolled 103 women affected by VIN usual type. They underwent wide local excision by CO2 laser. The patients were investigated by clinical evaluation and HPV DNA test 6 months after surgical treatment, and then were followed-up at 12, 18, 24, and 36 months. The recurrences were treated with re-excision. RESULTS: The rate of HPV infection after surgical treatment was 34% at 6 months, 36.9% at 12 months, 40% at 18 months, 41.7% at 24 months and 44.7% at 36 months. The mean time from HPV infection to the development of VIN was 18.8 months. CONCLUSIONS: HPV testing in the follow-up of VIN usual type patients might be useful for identifying those patients with a higher risk of recurrence after surgical treatment, although more studies are needed. These preliminary data suggest that the test, in addition to clinical examination, can improve the efficacy of the follow-up.

Impact of human papillomavirus infection on the neovaginal and vulval tissues of women who underwent surgical treatment for Mayer-Rokitansky-Kuster-Hauser syndrome.

OBJECTIVE: To evaluate the impact of human papillomavirus (HPV) infections on the neovaginal and vulval tissues of women who underwent surgical treatment for Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. DESIGN: Multicenter observational study. SETTING: University and community hospitals. PATIENT(S): Thirty-three women who had previously undergone neovagina reconstruction due to MRKH and who were referred to our centers for the evaluation and treatment of HPV neovaginal/vulval-related lesions. INTERVENTION(S): HPV infections were confirmed by polymerase chain reaction analysis or hybrid capture 2 tests; the patients underwent vaginoscopy, pap smear, and biopsy of the lesion and were treated by laser vaporization. Follow-up was conducted for 5 years. MAIN OUTCOME MEASURE(S): HPV-related neovaginal/vulval lesions, HPV testing, follow-up, recurrence rate. RESULT(S): Seventeen patients showed vulval lesions, and 16 patients neovaginal lesions. HPV testing results were positive for low-risk HPVs in 27 patients and high-risk HPVs in six patients. All the vulval lesions were condylomata, whereas 10 neovaginal lesions were condylomata, three were vaginal intraepithelial neoplasia (VAIN) degree 1, two were VAIN degree 2, and one was an adenocarcinoma. Eight patients were lost to follow-up. Twenty patients tested positive for an HPV infection, and seven patients (28%) had a recurrence of the lesion in the follow-up time. CONCLUSION(S): Patients who underwent neovagina reconstruction have sexual relationships and are HPV exposed. These patients should be evaluated after surgery for HPV infections to prevent HPV-related diseases and cancers.

Expression of oct-4 and c-kit antigens in endometriosis.

The objective of this study was to test the expression of the oct-4 and c-kit, both markers of stem cells, in the ectopic endometrial tissue of endometriotic lesions of women with severe endometriosis. Our findings show that ectopic epithelial cells express oct-4 and c-kit and this suggests that the ectopic endometrium in endometriosis has a stem cell origin and could explain the possible progression to ovarian cancer.

Pregnancies and deliveries after injection of vitrified-warmed oocytes with cryopreserved testicular sperm.

The purpose of this study is to report successful pregnancies and deliveries from embryos derived from vitrified-warmed oocytes injected with frozen-thawed testicular sperm. After the vitrification-warming procedure, surviving oocytes from 11 patients were microinjected with thawed testicular spermatozoa, and subsequent viable cleaving embryos were transferred, resulting in four clinical pregnancies.