Use of gonadotropins in infertile patients.

A new era in the history of gonadotropins.

History and challenges surrounding ovarian stimulation in the treatment of infertility.

OBJECTIVE: To examine the history of superovulation for ovulation induction, its contributions to reproductive medicine, and its impact on multiple births. DESIGN: A search of the relevant literature using PubMed and other online tools. RESULT(S): Infertility has been a condition known and studied for thousands of years. However, it was not until this past century that effective treatments were developed. With the advancement of our knowledge of the hypothalamic-pituitary axis, therapies utilizing gonadotropins were developed to stimulate ovulation. Not only could we now treat anovulatory infertility but also induce superovulation for IVF. With these successes came consequences, including increased multiple pregnancies. Several countries recognized the high costs associated with multiple births and implemented regulations on the infertility industry. The rate of triplet and higher-order multiples has declined over the past decade. This is largely attributed to a decreased number of embryos transferred. Nonetheless, the twin rate has remained consistently high. CONCLUSION(S): Superovulation has become a routine medical therapy used for ovulation induction and IVF. With the development of this technology have come effective therapies for infertility and new ethical and medical challenges. Since the advent of gonadotropin therapy we have already developed technologies to improve monitoring and decrease hyperstimulation and high-order multiple pregnancies. In the future we anticipate new tools devised to optimize one embryo for one singleton live birth.

Gonadotropin therapy: a 20th century relic.

Gonadotropin therapy has been a cornerstone of infertility therapy for half a century. From the very beginning, its use has been associated with a high rate of multiple births, particularly high order multiples, and ovarian hyperstimulation syndrome. Initially, success rates seemed acceptable when used for superovulation (SO)/IUI therapy. However, as data from RCTs have emerged, reported outcomes suggest that we question the use of injectible gonadotropins. This manuscript examines the studies that have challenged gonadotropin use for SO/IUI and other research that supports reduced doses of gonadotropins for IVF. We examine the challenges for its continued use for SO/IUI and for moving to lower doses worldwide for IVF. We propose a future that views gonadotropins as a relic of the twentieth century.

¿Hay diferencias entre las gonadotropinas disponibles para la estimulación ovárica en técnicas de reproducción asistida? / Are there any differences in the gonadotrophins available for ovarian stimulation in assisted reproduction techniques?

En el mercado español se dispone de diversas gonadotropinas utilizadas en los programas de reproducción asistida. El objetivo de esta revisión es determinar las diferencias entre ellas y establecer las ventajas y los inconvenientes de cada una en base a su origen, seguridad y eficacia clínica. Desde el punto de vista técnico, las gonadotropinas recombinantes presentan ventajas técnicas y mayor pureza, actividad específica y homogeneidad entre lotes. Desde el punto de vista de la seguridad, aunque hay diferencias claras en el origen, y por tanto en los riesgos de transmisión de enfermedad infecciosa, todas las gonadotropinas disponibles han mostrado ser seguras. Es desde el punto de vista de la eficacia donde es más difícil establecer diferencias. Muchos de los estudios disponibles son pequeños y no siempre los parámetros de evaluación han sido comparables. La mayoría de los estudios no han podido establecer diferencias, por lo que existen en la literatura científica diversos metaanálisis que tratan de responder básicamente a dos aproximaciones: saber si las FSH recombinantes (FSHr) son mejores que las urinarias y si la hormona recombinante es mejor que la gonadotropina menopáusica humana. Los datos no permiten demostrar que las urinarias o la hMG, solas o en combinación, sean más eficaces que la FSHr, mientras que, por el contrario, las recombinantes han mostrado ser más eficaces que las urinarias purificadas agrupadas (AU)

In Spain, several different gonadotrophins are available for assisted reproductive techniques. The present review aims to determine the differences between these gonadotrophins and to establish the advantages and limitations of each in terms of their origin, safety, and efficacy. From the technical point of view, recombinant gonadotrophins have enhanced purity, specific activity and greater consistency. From the safety point of view, there are clear differences in the origin and manufacturing process and consequently in the risk of infectious diseases; however, to date, all gonadotropins have been demonstrated to be safe. Differences in efficacy are more difficult to establish. Many trials have compared preparations but, because of their small size and variations in study design, the results have been variable. Most of the studies have failed to detect any differences and consequently several meta-analyses have aimed to determine whether recombinant follicle- stimulating hormone (FSH) gonadotrophins are preferable to urinary-derived FSH and whether recombinant hormone is superior to human menopausal gonadotropin (hMG). The published results do not demonstrate that urinary-derived FSH or hMG, alone or when data are pooled, are more effective than recombinant FSH. In contrast, recombinant gonadotrophins have been shown to be more effective than urinary- derived gonadotrophins as a whole (AU)

Historical perspectives in gonadotrophin therapy.

The 20th century witnessed the steady development of knowledge about the reproductive process in animals and humans. These advances led to the identification of higher centres governing the dynamics of ovarian function and to the discovery of gonadotrophic hormones. As the mechanisms of action of these hormones became increasingly understood, they began to be used in the management of infertility during the early 1930s. Hormone extracts were originally prepared from animal pituitaries and pregnant mare serum, as well as from human pituitaries, placenta and urine, with pregnancies reported following their use in the late 1930s. This review traces the constant quest to reduce risks and improve safety and efficacy of hormone preparations for patients. It describes the complex path and perils leading to the pure hormone preparations that are available today, concluding with an optimistic glimpse towards the future. Small molecules that are orally active and specific are currently being investigated, some with the capacity to bypass many parts of the receptor conformation. Here lies the immediate future of this field, utilizing low-cost, small, defined molecules to stimulate follicle growth, ovulation and corpus luteum formation. Perhaps one day the classical gonadotrophins will no longer be required in clinical treatment.

Ovarian stimulation: from basic science to clinical application.

Treatment for infertility, including ovarian stimulation, was first introduced almost 100 years ago. At this time, radiation therapy became an established treatment, and it was only some decades later that the problem of radiation-induced cancer emerged. Non-human gonadotrophins, such as pregnant mare serum gonadotrophin (PMSG), and human pituitary gonadotrophins (HPG), were commonly used for hormonal stimulation procedures. However, use of PMSG led to antibody formation, and it was therefore only useful for the first treatment cycle. HPG produced good results, but its use came to an end in the late 1980s when it was linked to the development of Creutzfeldt-Jakob disease. The first hormonal product from human menopausal urine to be used was human menopausal gonadotrophin (HMG), followed later by purified preparations of this product. All of these preparations contained a high percentage of unknown urinary proteins, which interfered with batch-to-batch consistency. This changed with the introduction of recombinant gonadotrophins, produced from an immortalized/standardized mammalian cell line (CHO). More recent developments include the introduction of long-acting gonadotrophin formulations. The development of gonadotrophin-releasing hormone (GnRH) analogues and more recently the use of GnRH antagonists has helped to improve ovarian stimulation protocols by optimizing their efficacy, and making them easier to administer.