Purpose - The purpose of the present study is to compare intrauterine msemination (IUI) pregnancy rates (PR) as a function of diagnosis and ovulation protocol utilizing an extended semen transport time. This allowed clients to conveniently collect IUI specimens in the comfort and privacy of their home. A single IUI per treatment cycle was performed. Basic Procedures - Three-hundred-ten consecutive infertilty couples having unexplained, male factor, ovulatory dysfunction, endometriosis, tubal factor or combined diagnostic factors receiving a total of 584 cycles of IUI were included. Ovulation protocols included LH surge, clomiphene citrate (CC)-hCG, CC-gonadotropins(Gn)-hCG, Gn-hCG or leuprolide acetate (L)-Gn-hCG followed 36-42 hours by a single IUI. Pregnancy rates per cycle (fecundity) and per couple (fertility) as a function of diagnosis, ovulation protocol and cycle number were evaluated. In each cycle the couples processed the specimen by adding sperm washing medium at room temperature to the specimen 30 min following collection and allowed it to incubate for two hours prior to IUI during transport. Main Findings - Overall, fecundity was 11.8% (69/584) and fertility was 22.3% (69/310); respectively by diagnosis was: unexplained 22.6%,38.8%; male factor 18.8%,42.9%; ovulatory dysfunction 12.4,22.6%; endometriosis 5.3%,11.1%; tubal factor 7.6%,13.3%; and combined factors 9.7%, 20.0%. Unexplained vs endometriosis (P < 0.0001, P < 0.005), tubal factor (fecundity P < 0.008) and ovulatory dysfunction (fecundity P < 0.027) was statistically different. Male factor vs endometriosis (P < 0.011, P < 0.036) was significantly different. Ovulatory dysfunction vs endometriosis was significantly different (fecundity P < 0.027). Pregnancies by ovulation protocol: LH surge 4.5%,10.5%; CC-hCG 9.4%,14.9%; CC-Gn-hCG 13.7%,23.7%; Gn-hCG 17.5%,45.3%; L-Gn-hCG 3.5%,6.7%. For Gn-hCG vs L-Gn-hCG (P < 0.009, P < 0.030) and LH surge (fecundity P < 0.033). CC-Gn-hCG vs CC-hCG (fertility P < 0.050) and L-Gn-hCG (P < 0.033, P < 0.034). Gn-hCG vs CC-hCG (fecundity P < 0.043). Conclusions - We conclude that IUI is effective when utilizing an extended transport time allowing most couples to collect the specimen at home and is most effective when utilizing Gn-hCG therapy. Based on our analysis, endometriosis, tubal factor and combined diagnostic categories should proceed earlier to higher level assisted reproductive technologies.

Faculty of Science School of Anatomical Sciences 9901061h karrenthomson@yahoo.co.uk / Clomiphene citrate (CC), a synthetic estrogen, is an efficient superovulator used in infertility treatment. However pregnancy rates resulting from CC treatment are low. Research has suggested that this may be due to an aberrant effect on implantation; CC binds to estrogen receptors (ER) and may affect estrogen responsive gene expression and thus implantation. This study investigates the effect of CC on ERa, 90kDa heat shock protein (Hsp90) and Hoxa10 expression in the rat uterus. Hsp90 binds to ERa in the absence of ligand and is involved in inducing a high affinity ligand binding conformation in the ER and in transactivation of the ER. Hoxa10 has been shown to be essential for uterine receptivity to implantation. CC (0.25mg) was given to ovariectomized rats, either alone or prior to a hormonal regime known to induce uterine receptivity for implantation. Expression of ERa, Hsp90 and Hoxa10 was determined by Western blotting, fluorescence immunocytochemistry and reverse transcription polymerase chain reaction. The single dose CC treated rats were compared to the controls as well as to ovariectomized rats treated with 0.5mg 17b estradiol (E2). The CC treated pseudopregnant rats (CCPPPE treated) were compared to 5½ day pregnant and pseudopregnant rats without CC (PPPE treated), to determine CCs effect at implantation. E2 upregulated ERa and Hsp90 expression in the rat uterus compared to controls (p<0.05). The finding for ERa was unexpected as other studies have shown that E2 decreases ERa levels a few hours after administration in the uterus. The present study therefore suggests a biphasic effect of E2 on ERa expression in the rat uterus. The effect of E2 on Hsp90 and ERa also proposes a balance between the levels of these two proteins in the uterus, to keep ERa in its optimal state and suggests that too high and too low a concentration of Hsp90 may both be inhibitory to ERa functioning. No significant difference was found in ERa and Hsp90 expression between the non-receptive (vehicle treated) and the receptive (PPPE treated) rat uteri, suggesting that these two genes are not markers for receptivity. However E2 is known to induce implantation of donor blastocysts in progesterone (P4) primed uteri. Therefore it is still essential for ERa to be present at implantation. It is of interest that CC downregulated ERa levels both in ii the absence of ovarian hormones and at implantation in the rat uterus. It is therefore proposed that this antiestrogenic effect would render the uterus less sensitive to the E2 required to induce implantation, thus accounting for low pregnancy rates with CC use. Although CC did not alter the expression of Hsp90 in this study, the reduction in ERa levels in response to CC may also upset the balance in the expression of these two genes, which may affect the transcriptional activity of ERa, and further prevent implantation. No clear results were obtained for Hoxa10 expression with the Western blots. However based on the ICC results, CC did not appear to affect Hoxa10 expression. Since P4 and not E2 is known to have the predominant effect on Hoxa10 expression, it is likely that E2 analogs, such as CC, would also not affect Hoxa10 expression to a significant degree. Future work will aim to separate the different uterine compartments and to determine the effects of CC on the expression of other implantation specific genes in the uterus.

Abstract The effectiveness of intrauterine insemination (IUI) combined with controlled ovarian hyperstimulation (COH) in the treatment of subfertility was investigated in the present study. For this purpose the prognostic factors associated with success of clomiphene citrate (CC)/human menopausal gonadotrophin (HMG)/IUI were identified in 811 treatment cycles. Furthermore, a long gonadotrophin-releasing hormone agonist (GnRHa)/HMG stimulation protocol was compared with a standard CC/HMG protocol. In addition, the usefulness of alternative insemination techniques including fallopian tube sperm perfusion (FSP) and intrafollicular insemination (IFI) was investigated. Finally, the obstetric and perinatal outcome of pregnancies after COH/IUI was examined and compared with those of matched spontaneous and in vitro fertilization(IVF) pregnancies. Female age, duration of infertility, aetiology of infertility, number of large preovulatory follicles and number of the treatment cycle were predictive as regards pregnancy after CC/HMG/IUI. The highest pregnancy rate (PR) was obtained in women of &lt; 40 years of age with infertility duration ≤ 6 years, who did not suffer from endometriosis. A multifollicular ovarian response to CC/HMG resulted in better treatment success than a monofollicular response, indicating the necessity of COH combined with IUI. A significantly higher PR was achieved in the first treatment cycles compared with the others, and 97% of the pregnancies were obtained in the first four treatment cycles. The PR per cycle did not differ significantly between a long GnRHa/HMG and a standard CC/HMG protocol, but the average medication expense of GnRHa/HMG stimulation was four times the cost of CC/HMG stimulation. Therefore, the routine use of a long GnRHa/HMG protocol in IUI treatment remains questionable. The FSP procedure was easy to perform by using a paediatric Foley catheter. The success rate in couples with either FSP or standard IUI did not differ significantly, although there was a trend towards a lower PR in the FSP group. The FSP technique should not replace the simpler and less time-consuming IUI technique in routine use. The IFI technique was also simple to perform and convenient for patients. However, only one normal singleton intrauterine pregnancy resulted in 50 IFI-treated women, indicating that IFI is inefficacious for treating subfertility. The IUI parturients differed from average Finnish parturients in respect to higher maternal age, more frequent primiparity and a higher incidence of multiple pregnancies. The use of antenatal care services was significantly lower in IUI singleton pregnancies compared with IVF singletons, although there were no more complications in IVF pregnancies. The hospitalization and Caesarean section rates were generally high in all pregnancies. The mean birthweight of IUI singletons was significantly lower than that in spontaneous pregnancies, but comparable to that in IVF pregnancies. However, the incidence of preterm birth, low birth weight and other variables describing the outcome of infants were similar in IUI, IVF and spontaneous pregnancies. In summary, the IUI procedure itself does not seem to affect adversely the obstetric and perinatal outcome of pregnancy, and patient characteristics and multiplicity may be more important in this respect.

Clomiphene citrate (CC) is the leading treatment for women with anovulatory infertility. The precise mechanism of action of the drug on the hypothalamic-pituitary-gonadal (HPG) axis has yet to be determined. Neurons expressing kisspeptin, neurokinin B (NKB) and dynorphin A (Dyn), collectively called KNDy neurons, in the arcuate nucleus (ARC) of the hypothalamus have been shown to play an integral role in the estradiol (E2) feedback pathways of the reproductive system in mammals. KNDy neurons are found in the ARC and the anteroventral periventricular nucleus (AVPV) in humans but have been predominantly reported to not express NKB and Dyn in rodents. The axons of these neurons project to the medial eminence (ME) in the region where the gonadotropin-releasing hormone (GnRH) terminals and fibres are located. It was hypothesised that CC upregulates the gene expression of kisspeptin and neurokinin B while down-regulating the gene expression of dynorphin A which results in a leutenizing hormone surge and an increase in oestradiol which causes ovulation. This was a randomized experiment which included 18 female Sprague-Dawley rats in which the aim was to analyse the expression of kisspeptin, NKB and Dyn in the ARC and the AVPV as well as blood plasma levels of oestradiol and leutinizing hormone (LH) in female rats after CC administration. Six of the rats constituted the control group that received a vehicle solution. The second group of 6 rats received the intervention in the form of CC and the third group of six rats received CC as well as p234-penetratin, a kisspeptin antagonist (KpA). The mRNA expression of the KNDy genes were analysed using real-time quantitative polymerase chain reaction (qPCR) and the plasma levels of E2 and LH were analysed by enzyme-linked immunosorbant assays (ELISA). ELISA results show that the E2 concentration in the group that received CC plus KpA was found to be marginally lower than that of the control group but there was no significant difference between the E2 concentrations of the control group and the group that received only CC. The LH concentration in the group that received CC plus KpA was significantly higher than both other groups but again, there was no significant difference between the LH concentration control group and the group that only received CC. The qPCR showed that in the AVPV, the kisspeptin expression of the CC group and the CC plus KpA groups are marginally higher than that of the control group. Conversely, the Dyn expression of the CC group and the CC plus KpA groups are marginally lower than that of the control group in the AVPV. There were no significant differences in NKB expression across the three groups. In the ARC, there were no significant differences in kisspeptin or Dyn expression across the groups. The NKB expression of the CC group was marginally lower than that of the control and there was no significant difference between the CC plus KpA group and the control group. In summary, CC appears to have a marginal effect on the kisspeptin and Dyn mRNA via the positive feedback systems in the rat AVPV as well as a significant decrease of NKB mRNA via the negative feedback systems in the ARC. To increase the validity of similar future studies, higher sample sizes, different drug administration doses, possibly more precise surgical techniques and more accurate age determination methods or ovariectomised rats could be used. / Dissertation (MSc)--University of Pretoria, 2016. / Physiology / MSc / Unrestricted

OBJECTIVE: To evaluate the effectiveness of offering double intrauterine insemination (IUI) to clients in our fertility program. STUDY DESIGN: In this prospective, nonrandomized study, 595 couples with ovulatory dysfunction, endometriosis, male factor, unexplained, tubal factor and combined diagnoses utilizing clomiphene citrate-hCG (CC-hCG), CC-gonadotropin-hCG (CC-Gn-hCG), Gn-hCG, lupron-Gn-hCG (L-Gn-hCG) or luteinizing hormone (LH) surge monitoring of natural cycles were offered single or double IUI in a total of 1,276 cycles. Single IUIs were performed at 36 hours following hCG or the day following LH surge; double IUIs were performed 18 and 36 hours following hCG or the day of and day following LH surge. Single versus double IUI clinical pregnancy outcomes were compared between ovarian stimulation protocols and diagnostic categories. RESULTS: One hundred ten clinical pregnancies occurred for 508 couples in 999 single IUI cycles (fecundity, 11.0%); 45 clinical pregnancies for 174 couples occurred in 277 double IUI cycles (16.2%, p < 0.004). The single IUI group was younger than the double IUI group (32.8 vs 33.7, p < 0.004). Differences for fecundity were noted regarding diagnostic categories between single and double IUI groups (ovulation dysfunction, 12.9% vs 19.5%, p < 0.048, and male factor, 7.9% vs 17.5%, p < 0.030) and ovulation protocols (CC-Gn-hCG, 13.0% vs 21.3%, p < 0.031, and L-Gn-hCG, 4.2% vs 25.0%, p < 0.002). CONCLUSION: Double IUI is superior to single IUI overall, especially when comparing Gn-containing ovarian stimulation protocols or within the ovulatory dysfunction and malefactor diagnostic categories.

A diferenciação sexual cerebral é um fenômeno importante que ocorre no período perinatal essencial para definir alguns padrões comportamentais na orientação sexual na fase adulta. Este evento ocorre após uma descarga abrupta da testosterona testicular no recém-nascido que é convertido em estrógeno E2 pela aromatase no hipotálamo do neonato e, juntamente com aquela de origem materna promove as alterações no cérebro que determinam a orientação sexual masculina do neonato. Em fêmeas, o E organiza o cérebro feminino e a orientação sexual. Assim, investigou-se o efeito do Citrato de Clomifeno, um inibidor da aromatase em ratos machos e fêmeas tratados perinatalmente. Os resultados mostraram alterações comportamentais e bioquímicas compatíveis com a desmasculinização, alteração do comportamento sexual de ambos os sexos, comportamento homossexual, ciclo estral, alteração dos níveis de testosterona, estrógeno, FSH e LH e do peso dos órgãos na fase adulta. Os resultados são explicados pelo bloqueio da aromatase, no período da diferenciação sexual cerebral. / Sexual differentiation of the brain is an important phenomenon that occurs perinatally essential to define some behavioral patterns of sexual orientation in adulthood. This event occurs after an abrupt discharge of testicular testosterone in newborns that E2 is converted into estrogen by aromatase in the hypothalamus of the newborn and, along with that of maternal origin promotes changes in the brain that determine sexual orientation male neonate. In females, the E organizes the female brain and sexual orientation. Thus, we investigated the effect of clomiphene citrate, aromatase inhibitor in male and female rats treated perinatally. The results showed behavioral and biochemical changes consistent with demasculinization, altered sexual behavior of both sexes, homosexual behavior, estrous cycle, changing levels of testosterone, estrogen, FSH and LH and organ weight in adulthood. The results are explained by blocking the aromatase during the period of sexual differentiation of the brain.

A diferenciação sexual cerebral é um fenômeno importante que ocorre no período perinatal essencial para definir alguns padrões comportamentais na orientação sexual na fase adulta. Este evento ocorre após uma descarga abrupta da testosterona testicular no recém-nascido que é convertido em estrógeno E2 pela aromatase no hipotálamo do neonato e, juntamente com aquela de origem materna promove as alterações no cérebro que determinam a orientação sexual masculina do neonato. Em fêmeas, o E organiza o cérebro feminino e a orientação sexual. Assim, investigou-se o efeito do Citrato de Clomifeno, um inibidor da aromatase em ratos machos e fêmeas tratados perinatalmente. Os resultados mostraram alterações comportamentais e bioquímicas compatíveis com a desmasculinização, alteração do comportamento sexual de ambos os sexos, comportamento homossexual, ciclo estral, alteração dos níveis de testosterona, estrógeno, FSH e LH e do peso dos órgãos na fase adulta. Os resultados são explicados pelo bloqueio da aromatase, no período da diferenciação sexual cerebral. / Sexual differentiation of the brain is an important phenomenon that occurs perinatally essential to define some behavioral patterns of sexual orientation in adulthood. This event occurs after an abrupt discharge of testicular testosterone in newborns that E2 is converted into estrogen by aromatase in the hypothalamus of the newborn and, along with that of maternal origin promotes changes in the brain that determine sexual orientation male neonate. In females, the E organizes the female brain and sexual orientation. Thus, we investigated the effect of clomiphene citrate, aromatase inhibitor in male and female rats treated perinatally. The results showed behavioral and biochemical changes consistent with demasculinization, altered sexual behavior of both sexes, homosexual behavior, estrous cycle, changing levels of testosterone, estrogen, FSH and LH and organ weight in adulthood. The results are explained by blocking the aromatase during the period of sexual differentiation of the brain.

To investigate the in vitro antioxidant properties of the ovulation induction drug, Citrate clomiphene (CC), and to access whether its effects are influenced by the Ala16Val polymorphism in the SOD2 gene, which encodes mitochondrial manganese superoxide dismutase (SOD), an in vitro experimental study testing the effect of different concentrations of CC on antioxidant capacity, reactive oxygen species (ROS) production and peripheral blood mononuclear cells (PBMC) culture viability was performed. A total of 58 healthy adult women were genotyped for the Ala16Val SOD2 polymorphism, and blood samples were collected to perform in vitro experiments analyzing the biological antioxidant effects of CC. Free radical production and cytotoxicity assays were performed on blood and peripheral blood mononuclear cells (PBMCs) with different Ala16Val SOD2 genotypes. According to the observations described here, CC exhibited antioxidant effects. Additionally, the CC treatments led to a decrease in ROS production, with blood samples from the AA genotype displaying a more responsive antioxidant effect from CC than other genotypes. AA and AV PBMCs showed an increase in viability following treatment with 10 μM CC when compared with PMBCs from control groups. In the VV PBMC group, only the 5 μM and 10 μM CC treatments presented a significant positive viability effect. The CC exhibits antioxidant activity, similar to that observed with other Selective Estrogen Receptor Modulators (SERMs), in the presence of the Ala16Val-SOD2 polymorphism suggesting pharmacogenetic effect. / Para investigar in vitro as propriedades antioxidantes de drogas que induzem a ovulação, como citrato de clomifeno (CC) e verificar se os efeitos são influenciados pelo polimorfismo Ala16Val do gene da SOD2, o qual codifica a superóxido dismutase (SOD) mitocondrial dependente de manganês. Um estudo experimental in vitro foi conduzido testando o efeito de diferentes concentrações de CC sobre a capacidade antioxidante, produção de espécies reativas de oxigênio (EROs) e na viabilidade de células mononucleadas de sangue periférico (CMSP) em cultura celular. Um total de 58 mulheres adultas saudáveis foram genotipadas para o polimorfismo Ala16Val do gene da SOD2, e sangue foi coletado para realizar os experimentos in vitro e analisar os efeitos antioxidantes biológicos do CC. A produção de radicais livres e análise de citotoxicidade foram conduzidas em sangue e CMSP com diferentes genótipos do Ala16Val SOD2. De acordo com as observações descritas aqui, o CC exibiu um efeito antioxidante. Adicionalmente, os tratamentos com CC levaram a um decréscimo na produção de EROs, com amostras de sangue o genótipo AA desenvolveu um efeito antioxidante mais responsivo para o CC do que os outros genótipos. A cultura de CMSP dos genótipos AA e AV mostraram um aumento na viabilidade seguida do tratamento com 10μM CC quando comparada com as culturas CMSP do grupo controle. No grupo de cultura CMSP do genótipo VV, somente os tratamentos com 5μM e 10μM de CC apresentaram efeito positivo na viabilidade. O CC apresentou uma atividade antioxidante similar à observada com outros moduladores seletivos dos receptores de estrogênio (SERMs). Entretanto, essa atividade foi influenciada pelos diferentes genótipos do polimorfismo Ala16Val SOD2 sugerindo efeito farmacogenético.

L’infertilité touche environ 11 à 15 % des couples au Canada. Les modalités de la procréation médicalement assistée (PMA) incluent la stimulation ovarienne (SO), l’insémination intra-utérine (IIU) et les techniques de la reproduction assistée (TRA). Les grossesses multiples sont parmi les effets indésirables les plus communs de l’utilisation des TRA. Toutefois, il n’y a pas de consensus sur l’ampleur du risque de grossesses multiples associé à l’utilisation des modalités de la PMA. De plus, il n’est pas clair si les modalités de la PMA sont associées à un risque élevé de malformations congénitales majeures (MCM) d’un ou plusieurs systèmes et organes du corps humain. Un projet de recherche en trois volets a été développé afin de répondre à ces questions. Dans un premier volet, une étude cas-témoin a été conduite afin de quantifier le risque de naissances multiples associé à l’utilisation des modalités de la PMA. Comparativement à une conception spontanée (CS), le recours à la SO seule, l’IIU, et les TRA étaient associés à une augmentation significative de plus de quatre, neuf et 31 fois du risque de naissances multiples, respectivement. Les femmes ayant fait appel à une IIU+SO ou aux TRA avaient un risque accru de naissances multiples (odds ratio (OR)ajusté, 1,98; IC95%, 1,12-3,49; ORajusté, 6,81; IC95%, 3,72-12,49, respectivement) comparativement à l’utilisation de la SO seule. Dans un deuxième volet, une analyse cas-témoin a été conduite afin de quantifier le risque de MCM associés à l’utilisation des modalités de la PMA. Comparée à une CS, l'utilisation des TRA était associée à une augmentation du risque des malformations du système urogénitale (ORajusté, 3,11; IC95%, 1,33–7,27) et l'utilisation de l'IIU était associée à un risque accru des malformations du système musculosquelettique (ORajusté, 2,02; IC95%, 1,10–3,71). L'utilisation des TRA était associée à une augmentation du risque des malformations du système urogénitale (ORajusté, 7,18; IC95%, 1,59-32,53) par rapport à l’utilisation de la SO seule. Dans un troisième volet, les résultats de la revue systématique et méta-analyse ont démontré que l'utilisation de la SO seule et l’IIU±SO étaient associée à une augmentation significative de presque 9 fois du risque de grossesses multiples par rapport à une CS. Des augmentations similaires ont été observées suite à l’utilisation du citrate de clomifène seul. Par rapport à une CS, l'utilisation de la SO seule était associée à une augmentation significative de 48% du risque des malformations du système musculosquelettique, de 73% le risque des malformations du système nerveux, de 76% le risque de malformations congénitales du système digestif, de 68% le risque de malformations des yeux, des oreilles, du visage et du cou, et plus de deux fois le risque de malformations congénitales du système respiratoire. L'utilisation de l'IIU était associée à une augmentation significative de 52% du risque de malformations du système urogénitales et de 54% du risque de malformations musculosquelettiques par rapport à une CS. Bien que le risque de grossesses multiples associées aux TRA puisse être contrôlé par le transfert d'un embryon unique, un suivi particulier devrait être accordée au risque de grossesses multiples associé à l’utilisation des traitements n’impliquant pas un transfert d’embryons. L’effet tératogène potentiel associé à l’utilisation des modalités de la PMA doit être considéré dans la prise des décisions thérapeutiques. La mise en place d’un registre de la PMA pour la surveillance des effets périnataux indésirables devient nécessaire / Infertility affects 11 to 15% of couples in Canada. The modalities of medically assisted reproduction (MAR) include ovarian stimulation (OS), intrauterine insemination (IUI) and assisted reproduction techniques (ART). Multiple pregnancies are among the most common side effects of using ART. However, there is no consensus on the magnitude of the risk of multiple pregnancies associated with the use of MAR modalities. In addition, it is unclear whether the modalities of MAR are associated with a high risk of major congenital malformations (MCM) affecting one or more specific organ system. A three-part research project was developed to answer these questions. In the first part, a case-control study was conducted to quantify the risk of multiple births associated with the use of the three MAR modalities. Compared to spontaneous conception (SC), the use of OS alone, IUI, and ART was associated with a significant increase of more than four, nine, and 31 times the risk of multiple births, respectively. Women who used IUI with OS or ART had an increased risk of multiple births (adjusted odds ratio (OR), 1.98; 95%CI, 1.12-3.49; adjusted OR, 6.81; 95%CI, 3.72-12.49, respectively) compared to the use of OS alone. In a second part, a case-control analysis was conducted in order to quantify the risk of MCM associated with the use of MAR modalities. Compared to SC, the use of ART was associated with an increased risk of urogenital malformations (adjusted OR, 3.11; 95%CI, 1.33–7.27) and the use of IUI was associated with increased risk of musculoskeletal malformations (adjusted OR, 2.02; 95% CI, 1.10–3.71). The use of ART was associated with an increased risk of urogenital malformations (adjusted OR, 7.18; 95% CI 1.59-32.53) compared to the use of OS alone. In a third part, results of the systematic review and meta-analysis demonstrated that the use of OS alone and IUI ± OS were associated with a significant increase of nine times the risk of multiple pregnancies compared to a SC. Similar increases have been found following the use of clomiphene citrate alone. Compared to SC, the use of OS alone was associated with a significant 48% increased risk of musculoskeletal malformations, 73% increased risk of malformations of the nervous system, 76% increased risk of digestive system malformations, 68% increased risk of malformations of the eye, ear, face and neck, and more than twice the risk of congenital respiratory system malformations. The use of IUI was associated with a significant 52% increased risk of urogenital malformations and 54% increased risk of musculoskeletal malformations compared to SC. Although the risk of multiple pregnancies associated with ART can be controlled using a single embryo transfer in IVF cycles, monitoring the risk of multiple pregnancies associated with the use of treatments that do not involve embryo transfer is essential. The potential teratogenic effect associated with the use of MAR modalities should be considered when making therapeutic decisions. The establishment of a registry for the surveillance of MAR adverse perinatal outcomes becomes necessary.

Introduction: Male idiopathic infertility is a rising problem globally and a significant challenge in clinical practice. Clomiphene citrate emerges as a promising therapy. Our objective is to synthesize available primary evidence about the efficacy and safety of clomiphene citrate treatment for male idiopathic infertility. Materials and Methods: We carried out a Systematic Review. We performed the primary search in PubMed/MEDLINE, Embase, WoS, Medline, Scopus, Cochrane and Trip Database until December 2020 for RCTs evaluating the effect of clomiphene citrate therapy compared to placebo and other therapies on adult males from any age group with idiopathic infertility diagnosis according to WHO 2010 criteria and ICD-10. The outcomes we studied were divided between efficacy: pregnancy and spermogram changes; and security: adverse effects. We evaluated the risk of bias using the Cochrane® Risk of Bias tool. Results: From 1010 registries, we selected 11 RCTs. Sample sizes varied between 23 and 141 participants. Five studies compared clomiphene citrate versus placebo and the remaining six compared clomiphene versus other therapies. The clomiphene doses used in the intervention group were 25mg and 50mg. For the main outcome, pregnancy, nine studies presented results, only one had a positive effect with unclear results (Ghanem et al. RR 3,00; 95% CI; 1,09 –8,25; p<0,05). Seven trials reported a significant increase in sperm concentration, three reported increased motility and one in morphology. However, these changes did not reflect on the increase in pregnancies. Six studies reported adverse effects out of 291 patients that received clomiphene citrate. 12 participants (4.12%) reported adverse effects, including headache and visual symptoms, no serious adverse effects were presented. Conclusion: Due to the variability and heterogeneity of the studies, a qualitative synthesis could not be realized. Nevertheless, evidence suggests pregnancy would not be achieved and so, their use in male idiopathic infertility could not be recommended. Furthermore, better quality randomized controlled trials with a larger sample size are required to measure its effect more validly and reliably. / Introducción: La infertilidad idiopática masculina es un problema creciente a escala global y un desafío importante en la práctica clínica. El citrato de clomifeno se presenta como una terapia prometedora. El objetivo de nuestro estudio fue sintetizar la evidencia primaria disponible respecto a la eficacia y seguridad del tratamiento con citrato de clomifeno en la infertilidad idiopática masculina. Métodos: Llevamos a cabo una revisión sistemática de ensayos clínicos aleatorizados (ECA). Realizamos la búsqueda primaria en PubMed/Medline, Embase, WOS, Medline, Scopus, Cochrane y Trip Database hasta diciembre de 2020 para estudios que evalúan el efecto del tratamiento con citrato de clomifeno en comparación con placebo u otras terapias en pacientes adultos de cualquier grupo etario con diagnóstico de infertilidad idiopática masculina según los criterios de la OMS 2010 y el CIE-10. Los desenlaces que evaluamos fueron de eficacia: embarazo y cambios en el espermograma, y de seguridad: Eventos adversos (EA) totales, EA serios y que conllevan a EA descontinuar la terapia. Evaluamos el riesgo de sesgo mediante la herramienta Cochrane®. Resultados: De un total de 1010 registros, seleccionamos 11 estudios. Los tamaños de muestra variaron entre 23 a 141 pacientes. Cinco estudios comparan clomifeno frente a placebo y los seis restantes clomifeno frente a otras terapias. Las dosis de clomifeno usadas en el grupo intervención fueron de 25mg y 50mg. Para el desenlace principal en nuestra revisión, embarazo, nueve de los once ensayos presentaron resultados. Solo uno de ellos presentó efecto positivo para el embarazo, aunque con resultados imprecisos (Ghanem et al. RR 3,00; IC 95%; 1,09 –8,25; p<0,05). Siete ensayos reportaron aumento significativo de la concentración espermática, tres reportaron aumento en la motilidad y uno en morfología. Sin embargo, estas mejoras laboratoriales no se reflejaron en el aumento del número de embarazos. Por el lado de seguridad, de los seis estudios que reportaron este desenlace, de un total de 291 pacientes que recibieron Clomifeno, 12 personas (4,12%) reportaron EA, de los cuales tres descontinuaron la terapia por cefalea y molestias visuales, no se reportó EA serios. Conclusión: Dada la variabilidad y heterogeneidad de los estudios no se pudo realizar una síntesis cualitativa. No obstante, la evidencia apunta a que no habría efecto en el logro del embarazo, siendo este la finalidad principal de la terapia. Por, ende basados en la evidencia analizada no se podría recomendar su uso en el tratamiento de infertilidad idiopática. Se requieren estudios aleatorizados controlados de mejor calidad y con mayor tamaño de muestra, para medir de manera más válida y confiable su efecto. / Tesis