Pharmacological non-hormonal treatment options for male infertility: a systematic review and network meta-analysis.

BACKGROUND: Male factor infertility affect up to 50% of couples unable to conceive spontaneously. Several non-hormonal pharmacological treatments have been proposed to boost spermatogenesis and increase chances of conception in men with infertility. Still, no clear evidence exists on the most effective treatment strategy. OBJECTIVE: We aimed to compare the effectiveness of non-hormonal pharmacological treatment options for men with infertility using a systematic review and network meta-analysis. METHODS: We searched MEDLINE, EMBASE, and CENTRAL until October 2023 for randomised/quasi-randomised trials that evaluated any non-hormonal pharmacological treatment options for men with idiopathic semen abnormalities or those with hypogonadism. We performed pairwise and network meta-analyses using a random effect model. We assessed risk of bias, heterogeneity, and network inconsistency. We calculated the mean rank and the surface under the cumulative ranking curve (SUCRA) for each intervention the maximum likelihood to achieve each of reported outcomes. We reported primarily on sperm concentration and other important semen and biochemical outcomes using standardised mean difference (SMD) and 95% confidence-intervals(CI). RESULTS: We included 14 randomised trials evaluating four treatments (Clomiphene citrate, Tamoxifen, Aromatase inhibitors, anti-oxidants) and their combinations in 1342 men. The overall quality of included trials was low. Sperm concentration improved with clomiphene compared to anti-oxidants (SMD 2.15, 95%CI 0.78-3.52), aromatase inhibitor (SMD 2.93, 95%CI 1.23-4.62), tamoxifen (SMD - 1.96, 95%CI -3.57; -0.36) but not compared to placebo (SMD - 1.53, 95%CI -3.52- 0.47). Clomiphene had the highest likelihood to achieve the maximum change in sperm concentration (SUCRA 97.4). All treatments showed similar effect for sperm motility, semen volume, and normal sperm morphology. FSH levels showed significant improvement with clomiphene vs.anti-oxidant (SMD 1.48, 95%CI 0.44-2.51) but not compared to placebo. The evidence networks for LH and testosterone suffered from significant inconsistency (p = 0.01) with similar trend of improvement with clomiphene compared to other treatments but not compared to placebo. CONCLUSION: There is insufficient evidence to support the routine use of Clomiphene, tamoxifen, and aromatase inhibitors to optimise semen parameters in men with infertility. Future randomised trials are needed to confirm the efficacy of clomiphene in improving fertility outcomes in men. PROSPERO: CRD42023430179.

Surgical options for the retrieval of a migrated intrauterine contraceptive device.

The intrauterine contraceptive device is a popular form of contraception for women; however, it does carry a rare but serious risk of migration into the myometrium and then into the peritoneal cavity. We report an unusual case of an intrauterine contraceptive device (IUCD) migrating through the uterus into the peritoneal cavity and subsequently into the sigmoid colon, which was finally retrieved laparoscopically. We also discuss three different methods for the retrieval of a migrated IUCD: colonoscopy, hysteroscopy and laparoscopy and compare and contrast each method.

Serial estimation of Th1:th2 cytokines profile in women undergoing in-vitro fertilization-embryo transfer.

PROBLEM: To investigate changes in the ratio of T-cell subpopulations expressing intracellular T helper1 (Th1) and T helper 2 (Th2) cytokines in women with a history of recurrent failed implantation under going in-vitro fertilization (IVF)-embryo transfer. METHOD OF STUDY: Twenty-eight peripheral blood samples were obtained at two time points, from 14 women undergoing IVF treatment; eight women with a history of recurrent failed implantation, who did not get pregnant in the index IVF cycle and six who had one or more previous successful IVF pregnancy and who became pregnant in the index IVF cycle. The proportion of lymphocytes expressing interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), and interleukin 4 (IL-4) and the Th1:Th2 ratios of IFN-gamma:IL-4, and TNF-alpha:IL-4 in T helper cells was measured by flow cytometry, in samples obtained before commencing IVF treatment and in samples obtained after ovarian stimulation (on the day of oocyte retrieval). RESULTS: In samples collected during oocyte retrieval, women with a history of recurrent failed implantation had a higher IFN-gamma:IL-4 and TNF-alpha:IL-4 ratio than the control group, (18.6+/-9.3 versus 6.47+/-1.68, P=0.009) and (39.1+/-15.7 versus 11.53+/-3.76, P=0.001) respectively. In women with a history of recurrent failed implantation the ratio of IFN-gamma:IL-4 and TNF-alpha:IL-4 at oocyte retrieval was higher than pre-treatment ratios (18.6+/-9.3 versus 12.01+/-9.8, P=0.018) and 39.10+/-15.7 versus 18.66+/-11.42, P=0.010) respectively, showing a Th1 bias. In women with a successful IVF the converse was true; the ratio at oocyte retrieval was significantly lower than pre-treatment ratios (6.47+/-1.68 versus 9.37+/-6.8, P=0.035) and 11.53+/-3.76 versus 18.60+/-12.9, P=0.027) respectively, representing a Th2 bias. CONCLUSION: Women with a history of unexplained recurrent failed IVF treatment have a Th1 bias and this polarization is more enhanced following hormonal manipulations during IVF treatment. Comparing pre-treatment ratios of IFN-gamma:IL-4 and TNF-alpha:IL-4 to ratios obtained at oocyte retrieval may be clinically useful. Women with recurrent failed IVF have increasing ratios.

Cytokine profiles in serum and peritoneal fluid from infertile women with and without endometriosis.

OBJECTIVE: To study the serum and peritoneal fluid cytokine profiles in infertile women with minimal/mild active endometriosis. METHODS: Fifty-seven consecutive infertile women undergoing laparoscopy for unexplained infertility had peritoneal fluid and serum samples obtained at the time of laparoscopy. The levels of interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-1 beta (IL-1 beta), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-alpha), monocyte chemotatic protein-1 (MCP-1), RANTES, platelet derived growth factor (PDGF), soluble Fas (sFas), and soluble Fas Ligand (sFasL) in peritoneal fluid and serum were measured to compare the concentration in both biological fluids, in women who have minimal/mild red endometriosis using women with no endometriosis as controls. RESULTS: Peritoneal fluid levels of MCP-1, IL-8 and IL-6 were significantly higher in the endometriosis group (P < 0.012, P = 0.003, and P = 0.015, respectively). There was no significant difference in the peritoneal fluid levels of IL-1 beta, TNF-alpha, RANTES, VEGF, PDGF, sFas and sFasL in the two groups. Although serum levels of IL-8 were higher in women with endometriosis, the difference was not significant (P = 0.07). Serum levels of PDGF, IL-6, RANTES, IL-1 beta, TNF-alpha, and sFas, were not significantly different in the two groups. CONCLUSION: The elevated levels of MCP-1, IL-6, and IL-8 in peritoneal fluid but not serum may indicate the importance of local macrophage activating factors in the pathogenesis of endometriosis.

Pregnancy following oocyte donation in a woman with Noonan's syndrome and a balanced Robertsonian translocation a case report.

Successful pregnancy in Noonan's syndrome and balanced Robertsonian translocation women is extremely rare. This is because pregnancies in these women usually end in spontaneous miscarriage or termination before 24 weeks gestation due to severe congenital anomaly. In this article, we report the case of a 41-years-old woman with Noonan's syndrome and balanced Robertsonian translocation. She was delivered by an elective caesarean section at 38 weeks of a live male infant following a second attempt of in vitro fertilisation (IVF) and embryo transfer from donor oocytes. The use of donor eggs and IVF in these women means more of them will achieve successful term pregnancy as in this case. It is therefore important that Obstetricians understand this rare condition and optimise care. This case highlights some of the medical problems encountered by Obstetricians in managing patients in this high risk group.

Initial investigation of the infertile couple. Pre-clinic request of investigations to facilitate diagnosis: utilising the waiting time to minimise delay.

OBJECTIVE: To evaluate the effectiveness of pre-clinic request of investigations to facilitate diagnosis in couples referred to the infertility clinic and to assess patient satisfaction of the concept. STUDY DESIGN: Prospective cohort study with analysis of patient satisfaction questionnaire. Investigation packs were sent to patients in advance of their clinic appointment. These contained written explanation about various fertility tests to enable patients to have investigations before their first clinic appointment. The results should then be available at the time of consultation enabling a diagnosis to be made at their first clinic visit. RESULTS: Eighty percent (43/54) of couples had completed all the investigations requested by the time of their clinic appointment. The full investigation results of 41 couples were available at the time of consultation. From the available results, a diagnosis could be reached in 76% of couples at the first clinic visit. Twenty-three percent of couples were not happy with the concept of pre-clinic investigation and would prefer to come to clinic first to discuss these tests, even if that meant a delay in diagnosis. There appears to be a trend in age, with those who were satisfied with the concept of pre-clinic investigation being older. Older women seem to have an increasing sense of urgency with advancing age. CONCLUSION: While the concept of pre-clinic request of investigations may not be suitable for every couple it does allow for early initiation of treatment in selected patients.

IVF/ICSI in a woman with active acromegaly: successful outcome following treatment with pegvisomant.

A 29 year old woman with difficult to control acromegaly and a pituitary macroadenoma responded to pegvisomant therapy and subsequently conceived with her first cycle of in-vitro fertilization and intra-cytoplasmic sperm injection. Pregnancy was complicated by gestational diabetes, pituitary gland enlargement and deteriorating visual fields. Conservative management with elective cesarean section was performed at 32 weeks gestation. A healthy boy was delivered who remains developmentally normal at 1 year. This complex case required intricate care by a multi-disciplinary team and is likely to represent the first in many cases of assisted conception on pegvisomant therapy for active acromegaly.

Follicle tracking of women receiving clomiphene citrate for ovulation induction.

Forty-five cycles of forty subfertile women were monitored with follicle tracking. Thirty women were anovulatory and 10 had unexplained infertility. Thirty women responded to the initial dose of Clomiphene Citrate (CC) and 10 remained anovulatory. Of those who ovulated with the first dose of CC, 25 developed one follicle, 2 developed 2 follicles and 3 developed three follicles. All the women that produced three follicles belonged in the unexplained infertility group. Eight women from the anovulatory group developed 1 follicle, two developed 2 follicles and 8 failed to respond. Provision of universal follicle tracking proved to be time consuming and required significant resources. Our results indicate that if there is a place for selective monitoring that should include women with unexplained infertility. We should also offer the first scan at around day 12 of the cycle as this could detect multiple follicle development. Patients with Polycystic Ovaries that start on 50 mgs of CC may not necessarily need follicle tracking as they usually do not respond to that dose.

Appendiceal mucocele: a rare differential diagnosis of a cystic right adnexal mass.

CASE REPORT: We present the case of a 42-year-old woman with an incidental finding of a large right adnexal mass during pelvic ultrasound scan for a spontaneous miscarriage. Ultrasound suggested the mass was ovarian in origin and serum Ca125 was normal. Laparotomy, however, revealed normal ovaries with no ovarian pathology. The right adnexal mass was appendiceal in origin and was delivered intact with no spillage. Histology confirmed a diagnosis of mucinous cystoadenoma of the appendix. DISCUSSION: Pre-operative diagnosis of this condition is difficult. Various radiological tools including CT scans, MRI, and ultrasound scans have been used with poor results. Pre-operative diagnosis would be useful, as extra measures could be taken to avoid intra-peritoneal rupture during surgery with the consequent development of pseudomyxoma peritonei. For a similar reason, needle aspiration should be avoided. In malignant cases co-existing ovarian neoplasm must be excluded as this will be present in 2-24% of cases. Simple appendicectomy is curative in uncomplicated, unruptured cases. CONCLUSION: Although relatively rare, appendiceal tumours should be considered in women who present to gynaecologists with a right adnexal mass.

Audit of primary care and initial secondary care investigations set against RCOG guidelines as standard in cases of subfertility.

Subfertility affects one in seven couples in the United Kingdom and is associated with considerable patient stress and anxiety. The RCOG, with the publication of the evidence-based guidelines, gives us clear recommendations on the initial investigation of the infertile couple. Against these guidelines we audited patient care over a period of 5 months in a dedicated consultant-led infertility clinic. Our results show that a considerable number of patients failed to have the correct advice clearly documented, and the initial primary care investigations of mid-luteal progesterone and semen analysis were performed correctly with results available in only 33% and 2% of occasions, respectively. There were, however, areas where the guidelines were adhered to very efficiently. To improve care we recommend the use of an infertility referral form for use in primary care upon which the practitioners can fill in the appropriate details and be guided on the necessary investigations.