Recombinant gonadotropin therapy to improve spermatogenesis in nonobstructive azoospermic patients - A proof of concept study

ABSTRACT Purpose: Nonobstructive azoospermia (NOA) associated with primary spermatogenic failure is a common cause of male infertility usually considered untreatable; however, some reports have suggested that hormonal stimulation to boost the intra-testicular testosterone level and spermatogenesis might increase the chance of achieving pregnancy using homologous sperm. Materials and Methods: We report a series of eight NOA males who received long-term treatment with recombinant human chorionic gonadotropin twice a week for spermatogenesis stimulation. Six males received additional recombinant follicle-stimulating hormone (FSH) supplementation 150-225 IU twice weekly. Results: After recombinant gonadotropin therapy, viable spermatozoa were retrieved from the ejaculate in two patients and by testicular sperm aspiration (TESA) in another two subjects. Singleton spermatozoon retrieved from testes were frozen by vitrification on Cell-Sleeper devices. Two live births were obtained after intracytoplasmic sperm injection with ejaculated spermatozoa and one live birth and an ongoing pregnancy using thawed spermatozoa from TESA. Conclusion: Our proof-of-concept study indicates that hormonal therapy with recombinant gonadotropins could be considered in infertile men with NOA as an alternative to sperm donation. Large-scale studies are needed to substantiate hormone stimulation therapy with recombinant gonadotropins in routine clinical practice for this severe form of male infertility.

The combined effect of lifestyle intervention and antioxidant therapy on sperm DNA fragmentation and seminal oxidative stress in IVF patients: a pilot study

ABSTRACT Purpose: Sperm DNA fragmentation (SDF) and seminal oxidative stress are emerging measurable factors in male factor infertility, which interventions could potentially reduce. We evaluated (i) the impact of lifestyle changes combined with oral antioxidant intake on sperm DNA fragmentation index (DFI) and static oxidation-reduction potential (sORP), and (ii) the correlation between DFI and sORP. Materials and Methods: We conducted a prospective study involving 93 infertile males with a history of failed IVF/ICSI. Ten healthy male volunteers served as controls. Semen analysis was carried out according to 2010 WHO manual, whereas seminal sORP was measured using the MiOXSYS platform. SDF was assessed by sperm chromatin structure assay. Participants with DFI >15% underwent a three-month lifestyle intervention program, primarily based on diet and exercise, combined with oral antioxidant therapy using multivitamins, coenzyme Q10, omega-3, and oligo-elements. We assessed changes in semen parameters, DFI, and sORP, and compared DFI results to those of volunteers obtained two weeks apart. Spearman rank correlation tests were computed for sORP and DFI results. Results: Thirty-eight (40.8%) patients had DFI >15%, of whom 31 participated in the intervention program. A significant decrease in median DFI from 25.8% to 18.0% was seen after the intervention (P <0.0001). The mean DFI decrease was 7.2% (95% CI: 4.8-9.5%; P <0.0001), whereas it was 0.42% (95%CI; -4.8 to 5.6%) in volunteers (P <0.00001). No differences were observed in sperm parameters and sORP. Based on paired sORP and DFI data from 86 patients, no correlation was observed between sORP and DFI values (rho=0.03). Conclusion: A 3-month lifestyle intervention program combined with antioxidant therapy reduced DFI in infertile men with elevated SDF and a history of failed IVF/ICSI. A personalized lifestyle and antioxidant intervention could improve fertility of subfertile couples through a reduction in DFI, albeit controlled trials evaluating reproductive outcomes are needed before firm conclusions can be made. Trial registration number and date: clinicaltrials.gov NCT03898752, April 2, 2019.

Are specialized sperm function tests clinically useful in planning assisted reproductive technology?

CASE STUDY 40-year-old male patient and 32-year-old female partner, with a history of primary infertility of two years duration. The workup revealed idiopathic mild oligoasthenotheratozoospermia, and no apparent female infertility factors. The couple has failed three intrauterine insemination (IUI) cycles, planning more IUI cycles but also considering in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI).

Persistent Mullerian Duct Syndrome: a rare entity with a rare presentation in need of multidisciplinary management

ABSTRACT Main findings: A typical male looking adolescent with a legal female gender assignment presented with haematuria. Investigations led to the diagnosis of Persistent Mullerian Duct Syndrome. The condition is indeed a rare entity that needs a multidisciplinary team management. Case hypothesis: A case of Persistent Mullerian Duct Syndrome undiagnosed at birth because karyotyping was defaulted, thus resulting in a significant impact on the legal gender assignment and psychosocial aspects. Promising future implications: The reporting of this case is important to create awareness due to its rarity coupled with the rare presentation with hematuria as a possible masquerade to menstruation. There were not only medical implications, but also psychosocial and legal connotations requiring a holistic multidisciplinary management.

Establishing a quality management system in a fertility center: experience with ISO 9001 / SISTEMA DE GESTÃO DE QUALIDADE NA CLÍNICA DE REPRODUÇÃO HUMANA: EXPERIÊNCIA COM A NORMA ISO 9001

In Fertility Centers, quality should be measured by how well the organization complies with pre-defined requirements, and by how quality policies are implemented and quality objectives achieved. Having a quality management system (QMS) is a mandatory requirement for IVF centers established in most countries with regulatory guidelines, including Brazil. Nevertheless, none of the regulatory directives specify what a QMS must have in detail or how it should be implemented and/or maintained. ISO 9001 is the most important and widespread international requirement for quality management. ISO 9001 standards are generic and applicable to all organizations in any economic sector, including IVF centers. In this review, we discuss how we implemented QMS according to ISO 9001 and what we achieved 5 years later. In brief, with ISO we defined our structure, policies, procedures, processes and resources needed to implement quality management. In addition, we determined the quality orientation of our center and the quality objectives and indicators used to guarantee that a high-quality service is provided. Once measuring progress became part of our daily routine, quantifying and evaluating the organization's success and how much improvement has been achieved was an inevitable result of our well-established QMS. Several lessons were learned throughout our quality journey, but foremost among them was the creation of an internal environment with unity of purpose and direction; this has in fact been the key to achieving the organization's goals.

Na clínica de reprodução humana, a qualidade deve ser medida pela maneira como a organização cumpre os requisitos pré-definidos, e pela forma como as políticas de qualidade são implementadas e os objetivos de qualidade alcançados. Ter um sistema de gestão da qualidade (SGQ) é um requisito obrigatório para centros de fertilização in vitro estabelecidos na maioria dos países com diretrizes regulatórias, incluindo o Brasil. No entanto, nenhuma das diretivas regulamentares especifica o que um SGQ deve ter em detalhe ou como ele deve ser implementado e/ou mantido. A norma ISO 9001 é a exigência internacional mais importante e adotada mundialmente para a gestão da qualidade. Os conceitos da norma ISO 9001 são genéricos e aplicáveis a todas as organizações em qualquer setor económico, incluindo as clínicas de fertilização in vitro (ou bancos de células e tecidos germinativos tipo 2, como denominados no Brasil pela Agência Nacional de Vigilância Sanitária). Neste artigo, discutimos como implementamos um SGQ de acordo com a norma ISO 9001 e o que conseguimos 5 anos mais tarde. Em suma, com a norma ISO definimos nossa estrutura, políticas, procedimentos, processos e recursos necessários para implementar a gestão da qualidade. Além disso, determinamos a orientação da qualidade do nosso centro além dos objetivos de qualidade e indicadores utilizados para garantir que um serviço de alta qualidade seja fornecido para nossos clientes. A partir do momento que a mensuração do progresso tornou-se parte da nossa rotina diária, quantificar e avaliar o sucesso da organização e os resultados atingidos passou a ser uma consequência inevitável de um SGQ bem estabelecido. Várias lições foram aprendidas ao longo de nossa jornada de qualidade, mas o mais importante foi a criação de um ambiente interno com unidade de propósito e direção, que se tornou peça chave para alcançar os objetivos da organização.

Pregnancy and birth after intracytoplasmic sperm injection with normal testicular spermatozoa in a patient with azoospermia and tail stump epididymal sperm

Main findings: An intriguing yet perplexing case report of a successful pregnancy and live birth with intracytoplasmic sperm injection using normal testicular sperm, after the finding of azoospermia in the semen analysis and discovering only tail stump abnormal sperm in the epididymis. Case hypothesis: A tail stump sperm defect of genetic origin was suspected. However, after obtaining normal testicular sperm we concluded that obstructive azoospermia, either idiopathic or secondary to multiple minor genital trauma was the plausible scenario. This has rendered the search of previous reports on a similar condition, but none was found. However, it has raised scientific thoughts for future research. Promising future implications: The importance of reporting this case is to alert urologists performing sperm retrieval that healthy and morphologically normal sperm may be found in the testis of azoospermic men with 100% tail stump epididymal sperm. Retrieval of normal testicular sperm obviates the need of a more complex investigation, including sperm electron microscopy. It also offers the possibility of utilizing such gametes for sperm injections rather than abnormal tail stump sperm that may be associated with a poor reproductive outcome.

Efficacy, efficiency and effectiveness of gonadotropin therapy for infertility treatment / Eficácia, eficiência e efetividade da terapia gonadotrófica para o tratamento da infertilidade

Gonadotropin therapy is an essential element in infertility treatments involving assisted reproductive technology. In recent years there have been outstanding advances in the development of new gonadotropins, particularly with the production of gonadotropins using biotechnological resources. Recombinant gonadotropins have higher specific activity compared with urinary counterparts, thus allowing subcutaneous administration of minimal amounts of glycoprotein. As a result, recombinant formulations have a better safety profile despite an overall similarity in terms of efficacy for pregnancy, as reported in many randomized controlled trials and meta-analyses. Gonadotropins stimulate the ovaries to develop follicles and oocytes, which are the raw material for fertilization and embryo production. The resulting embryos are transferred (fresh or frozen-thawed) to achieve pregnancy. The efficiency of a gonadotropin should therefore measured by the amount of drug used, the number of oocytes/embryos produced, and the number of pregnancies achieved by transferring fresh and/or frozen-thawed embryos to the uterus (cumulative pregnancy). Comparisons between different gonadotropin preparations should also take into account other important quality indicators in reproductive medicine, such as safety and patient-centeredeness. Altogether, the aforementioned quality indicators favor biotech gonadotropins over biologic products in infertility therapy.

RESUMO A terapia gonadotrófica é elemento essencial nos tratamentos de infertilidade que envolvem tecnologia de reprodução assistida. Nos últimos anos houve avanços notáveis no desenvolvimento de novas gonadotrofinas, principalmente com a produção de gonadotrofinas via recursos biotecnológicos. As gonadotrofinas recombinantes têm maior actividade específica em comparação com os suas homólogas urinárias, permitindo, assim, a administração subcutânea de quantidades mínimas de glicoproteína. Como resultado, as formulações recombinantes tem um melhor perfil de segurança, apesar de semelhança em termos de eficácia para a gravidez, como relatado em diversos ensaios clínicos randomizados e meta-análises. As gonadotrofinas estimulam os ovários a desenvolver folículos e ovócitos, que são a matéria-prima para a fertilização e produção de embriões. Os embriões resultantes são transferidos (frescos ou congelados/descongelados) para produzir gravidez. Comparações entre as gonadotrofinas devem, portanto, ser medidas não somente pela eficácia clínica de produzir gravidezes pela transferência de embriões a fresco, mas sobremaneira pela eficiência na produção de ovócitos e embriões em relação à quantidade de droga administrada, e efetividade na obtenção de gravidezes pela transferência de embriões frescos e congelados/descongelados (taxa de gravidez cumulativa). As comparações entre diferentes preparações de gonadotrofinas também devem levar em conta outros indicadores importantes de qualidade em medicina reprodutiva, como a segurança e o interesse do paciente. Estes indicadores de qualidade favorecem as gonadotrofinas biotecnológicas em relação aos produtos biológicos na terapia da infertilidade.

Insights into the role of cervical mucus and vaginal pH in unexplained infertility / Sobre o papel do muco cervical e do PH vaginal na gênese da infertilidade inexplicada

Unexplained infertility diagnosis is made in the presence of a normal semen analysis when tubal patency and normal ovulatory function are established. Among several potential causes, unexplained infertility could be attributed to vaginal pH and cervical mucus abnormalities. Although the vaginal canal and the cervix generally function as effective barriers to sperm, and although the production of mucus is essential to transport them from the vagina to the uterine cavity, these factors receive little attention in the investigation of couples with unexplained infertility. A substantial reduction in sperm number occurs as they transverse the cervix. From an average of 200 to 300 million sperm deposited in the vagina, only a few hundred achieve proximity to the oocyte. Given this expected high spermatozoa loss, a slight modification in cervical mucus may rapidly transform the cervix into a "hostile" environment, which, together with changes in vaginal environment and cervix structure, may prevent natural conception and be a cause of infertility. In this review, we discuss the physiological role of the vaginal pH and cervical mucus in fertility, and describe several conditions that can render the cervical mucus hostile to sperm and therefore be implicated in the pathophysiology of unexplained infertility.

RESUMO O diagnóstico de infertilidade inexplicada baseia-se na presença de espermograma normal, constatadas também permeabilidade tubária e função ovulatória normais. Entre as várias causas potenciais de infertilidade inexplicada, a presença de muco cervical e pH vaginal anormais devem ser consideradas. Embora a produção adequada de muco cervical seja essencial para o transporte dos espermatozóides da vagina para a cavidade uterina, e tanto o canal vaginal quanto o colo do útero desempenham função importante como barreira à passagem dos espermatozóides, estes fatores recebem pouca atenção na investigação de casais com infertilidade inexplicada. Uma redução substancial do número de espermatozoides ocorre à medida que estes percorrem o trato reprodutivo feminino. Partindo de cerca de 200 a 300 milhões de espermatozoides depositados na vagina, apenas algumas centenas alcançam a proximidade do oócito. Alteracões do muco cervical podem rapidamente transformar o colo do útero num ambiente hostil, que em conjunto com alterações no ambiente vaginal e da estrutura de colo do útero, podem apresentar-se condicões impedientes para a concepção natural; desse modo, convertem-se em causa de infertilidade. Nesta revisão, discutimos o papel fisiológico do pH vaginal e do muco cervical na fertilidade, descrever várias condicões que podem tornar o muco cervical hostil aos espermatozoides e, por fim analisamos como estes fatores interferem na fisiopatologia da infertilidade inexplicada.