madman
Super Moderator
The first commercially available gonadotropin product was a human chorionic gonadotropin (hCG) extract, followed by animal pituitary gonadotropin extracts. These extracts were effective, leading to the introduction of the two-step protocol, which involved ovarian stimulation using animal gonadotropins followed by ovulation triggering using hCG. However, ovarian response to animal gonadotropins was maintained for only a short period of time due to immune recognition. This prompted the development of human pituitary gonadotropins; however, supply problems, the risk for Creutzfeld–Jakob disease, and the advent of recombinant technology eventually led to the withdrawal of human pituitary gonadotropin from the market. Urinary human menopausal gonadotropin (hMG) preparations were also produced, with subsequent improvements in purification techniques enabling the development of products with standardized proportions of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) activity. In 1962 the first reported pregnancy following ovulation stimulation with hMG and ovulation induction with hCG was described, and this product was later established as part of the standard protocol for ART. Improvements in immunopurification techniques enabled the removal of LH from hMG preparations; however, unidentified urinary protein contaminants remained a problem. Subsequently, monoclonal FSH antibodies were used to produce a highly purified FSH preparation containing <0.1 IU of LH activity and <5% unidentified urinary proteins, enabling the formulation of smaller injection volumes that could be administered subcutaneously rather than intramuscularly. Ongoing issues with gonadotropins derived from urine donations, including batch-to-batch variability and a finite donor supply, were overcome by the development of recombinant gonadotropin products. The first recombinant human FSH molecules received marketing approvals in 1995 (follitropin alfa) and 1996 (follitropin beta). These had superior purity and a more homogenous glycosylation pattern compared with urinary or pituitary FSH. Subsequently, recombinant versions of LH and hCG have been developed, and biosimilar versions of follitropin alfa have received marketing authorization. More recent developments include a recombinant FSH produced using a human cell line, and a long-acting FSH preparation. These state-of-the-art products are administered subcutaneously via pen injection devices.
Introduction
It was observed in 1927, by Ascheim and Zondek, that the blood and urine of pregnant women contained a gonad-stimulating substance, human chorionic gonadotropin (hCG) (1, 2). Seegar-Jones and colleagues demonstrated in the 1940s that hCG was produced by the placenta (3). In 1929, Zondek proposed, based on his experiments and those of Smith, that two hormones were produced by the pituitary gland, both of which stimulated the gonads (4–6). These hormones were described as gonadotropins and subsequently named follicle-stimulating hormone (FSH) and luteinizing hormone (LH), according to their specific actions. The biological activity of gonadotropins suggested that they might be useful for the treatment of patients who were infertile. These observations eventually led to the development of pure gonadotropin products that have enabled the birth of millions of children to people affected by infertility.
This review provides an overview of the major milestones in the development of gonadotropin products (Figure 1), as well as issues that may have affected decision making during the development processes, and summarizes the available evidence supporting the use of recombinant gonadotropin products for the treatment of infertility
Human Chorionic Gonadotropin
The first commercially available gonadotropin was an hCG extract launched by Organon in 1931 (4). However, the original product was of limited use owing to a lack of reproducibility, in part due to the use of animal units (mouse or rat) to measure bioactivity (7). Reproducibility was greatly improved in 1939 when the League of Nations developed the international standard for hCG; one International Unit (IU) of hCG was defined as the activity contained in 0.1 mg of the reference hCG preparation which was pooled from six sources (8). Following the introduction of this standard, purified hCG preparations extracted from the urine of women during the first half of pregnancy, with bioactivity up to 8,500 IU/mL, became available (9, 10).
Clinical Use
In women, hCG is used during infertility treatment to trigger final follicular maturation and ovulation, as well as for luteal phase support. In men, it is used to stimulate the production of testosterone by the Leydig cells in cases of hormone deficiency as well as in male hypogonadism.
*Animal Pituitary Gonadotropins
*Cadaveric Human Pituitary Gonadotropins
*Human Menopausal Gonadotropin
-Clinical Use
*Recombinant Gonadotropins
-Follicle-Stimulating Hormone
-Follitropin Alfa and Follitropin Beta
-Follitropin Delta
-Follitropin Epsilon
-Corifollitropin Alfa
-Differences Between Recombinant and Urinary Follicle-Stimulating Hormone Preparations
*r-hFSH for the Treatment of Male Infertility
FSH plays an important role in spermatogenesis, stimulating the Sertoli cells to facilitate germ cell differentiation. Follitropin alfa and follitropin beta are approved for clinical use in males who have congenital or acquired hypogonadotropic hypogonadism, for the stimulation of spermatogenesis with concomitant hCG therapy (42, 46). In a small study (N = 8), r-hFSH (follitropin alfa) was observed to induce testicular growth, spermatogenesis, and fertility, with acceptable tolerability, in men with gonadotropin deficiency; the magnitude of the effect was considered to be similar to that achieved historically with u-FSH when used to restore normal fertility in men with gonadotropin deficiency (105). In a second larger study, 15 of 19 men treated with r-hFSH and hCG achieved spermatogenesis (106). A Cochrane review evaluating gonadotropins for idiopathic male factor subfertility identified six RCTs including 456 patients and observed a higher spontaneous pregnancy rate per couple with gonadotropin treatment compared with placebo/no treatment (five studies [412 patients]; OR 4.94, 95% CI 2.13, 11.44) (107). This review noted that reporting of adverse event data was sparse. However, the risk/benefit balance in males is considered positive (40).
*Human Chorionic Gonadotropin
Recombinant hCG (r-hCG) is produced in a CHO cell line in a similar manner to r-hFSH (55, 108) and is suitable for subcutaneous injection and self-administration (109). In healthy subjects, the PK (Table 2) and PD profiles of r-hCG are consistent with endogenous hCG physiology and similar to those seen with urinary hCG (u-hCG) (111). The elimination half-lives of r-hCG and u-hCG are comparable (29–30 h for r-hCG 250 μg vs. 35 h for u-hCG 5000 IU) as are the areas under the concentration-time curve; however, u-hCG tends to be distributed and eliminated slightly slower than r-hCG (111).
*Luteinizing Hormone
*Oral Gonadotropins
All gonadotropin preparations have to be injected, which increases the treatment burden for patients. There has therefore been interest in producing a product that can be dosed orally. It is not possible to dose gonadotropins orally because they are proteins and will not be absorbed, rather they are digested by enzymes. As a result of this, attempts to produce an oral drug for ovarian stimulation have focussed on FSH agonists. One oral FSH agonist has been evaluated in healthy females but no effect on follicular development was observed, which was eventually attributed to the low doses used (141). Non-conclusive data is available for this option nowadays.
*Injection Devices
Animal-derived and urinary gonadotropin products had to be injected intramuscularly using a syringe and vial, with reconstitution required before injection. Owing to the increased purity of recombinant products, a smaller injection volume is required and these can be injected subcutaneously using smaller gauge needles. In addition, these products have greater stability and liquid formulations of recombinant products have been produced, removing the need for reconstitution before injection. This in turn has enabled the development of pen injection devices, which are designed to improve ease-of-use and patient convenience, including the ability to both select the starting dose with greater precision (in increments as low as 12.5 IU) and adapt the dose during treatment, based on treatment response in small increments (12.5 IU) (142–144).
Conclusions
ART has come a long way since 1927 when gonadotropins were first identified, and currently, available gonadotropin preparations better enable treatment individualization as part of patient-centered care. Patient-centeredness should be an aspect of all consultations and treatment decisions relating to medically assisted reproduction treatment. This should include discussions of whether treatment is appropriate, and if it is appropriate, which treatment would be most favorable. This treatment should be individualized according to the characteristics of the patient(s) and monitored to ensure that effectiveness is optimal, based on treatment response and safety, with treatment adjusted during treatment if it is not. The availability of recombinant products, which provide a pure form of gonadotropin and can be accurately dosed, has improved the ability of medical practitioners to individualize treatment in this manner. Currently, available products can be injected subcutaneously rather than intramuscularly, and pen injection devices are available, improving ease-of-use and more precise dose selection and adaption (in 12.5 IU dose increments). Work to develop new preparations is continuing, and a goal must remain the development of orally active FSH agonists and antagonists.
Introduction
It was observed in 1927, by Ascheim and Zondek, that the blood and urine of pregnant women contained a gonad-stimulating substance, human chorionic gonadotropin (hCG) (1, 2). Seegar-Jones and colleagues demonstrated in the 1940s that hCG was produced by the placenta (3). In 1929, Zondek proposed, based on his experiments and those of Smith, that two hormones were produced by the pituitary gland, both of which stimulated the gonads (4–6). These hormones were described as gonadotropins and subsequently named follicle-stimulating hormone (FSH) and luteinizing hormone (LH), according to their specific actions. The biological activity of gonadotropins suggested that they might be useful for the treatment of patients who were infertile. These observations eventually led to the development of pure gonadotropin products that have enabled the birth of millions of children to people affected by infertility.
This review provides an overview of the major milestones in the development of gonadotropin products (Figure 1), as well as issues that may have affected decision making during the development processes, and summarizes the available evidence supporting the use of recombinant gonadotropin products for the treatment of infertility
Human Chorionic Gonadotropin
The first commercially available gonadotropin was an hCG extract launched by Organon in 1931 (4). However, the original product was of limited use owing to a lack of reproducibility, in part due to the use of animal units (mouse or rat) to measure bioactivity (7). Reproducibility was greatly improved in 1939 when the League of Nations developed the international standard for hCG; one International Unit (IU) of hCG was defined as the activity contained in 0.1 mg of the reference hCG preparation which was pooled from six sources (8). Following the introduction of this standard, purified hCG preparations extracted from the urine of women during the first half of pregnancy, with bioactivity up to 8,500 IU/mL, became available (9, 10).
Clinical Use
In women, hCG is used during infertility treatment to trigger final follicular maturation and ovulation, as well as for luteal phase support. In men, it is used to stimulate the production of testosterone by the Leydig cells in cases of hormone deficiency as well as in male hypogonadism.
*Animal Pituitary Gonadotropins
*Cadaveric Human Pituitary Gonadotropins
*Human Menopausal Gonadotropin
-Clinical Use
*Recombinant Gonadotropins
-Follicle-Stimulating Hormone
-Follitropin Alfa and Follitropin Beta
-Follitropin Delta
-Follitropin Epsilon
-Corifollitropin Alfa
-Differences Between Recombinant and Urinary Follicle-Stimulating Hormone Preparations
*r-hFSH for the Treatment of Male Infertility
FSH plays an important role in spermatogenesis, stimulating the Sertoli cells to facilitate germ cell differentiation. Follitropin alfa and follitropin beta are approved for clinical use in males who have congenital or acquired hypogonadotropic hypogonadism, for the stimulation of spermatogenesis with concomitant hCG therapy (42, 46). In a small study (N = 8), r-hFSH (follitropin alfa) was observed to induce testicular growth, spermatogenesis, and fertility, with acceptable tolerability, in men with gonadotropin deficiency; the magnitude of the effect was considered to be similar to that achieved historically with u-FSH when used to restore normal fertility in men with gonadotropin deficiency (105). In a second larger study, 15 of 19 men treated with r-hFSH and hCG achieved spermatogenesis (106). A Cochrane review evaluating gonadotropins for idiopathic male factor subfertility identified six RCTs including 456 patients and observed a higher spontaneous pregnancy rate per couple with gonadotropin treatment compared with placebo/no treatment (five studies [412 patients]; OR 4.94, 95% CI 2.13, 11.44) (107). This review noted that reporting of adverse event data was sparse. However, the risk/benefit balance in males is considered positive (40).
*Human Chorionic Gonadotropin
Recombinant hCG (r-hCG) is produced in a CHO cell line in a similar manner to r-hFSH (55, 108) and is suitable for subcutaneous injection and self-administration (109). In healthy subjects, the PK (Table 2) and PD profiles of r-hCG are consistent with endogenous hCG physiology and similar to those seen with urinary hCG (u-hCG) (111). The elimination half-lives of r-hCG and u-hCG are comparable (29–30 h for r-hCG 250 μg vs. 35 h for u-hCG 5000 IU) as are the areas under the concentration-time curve; however, u-hCG tends to be distributed and eliminated slightly slower than r-hCG (111).
*Luteinizing Hormone
*Oral Gonadotropins
All gonadotropin preparations have to be injected, which increases the treatment burden for patients. There has therefore been interest in producing a product that can be dosed orally. It is not possible to dose gonadotropins orally because they are proteins and will not be absorbed, rather they are digested by enzymes. As a result of this, attempts to produce an oral drug for ovarian stimulation have focussed on FSH agonists. One oral FSH agonist has been evaluated in healthy females but no effect on follicular development was observed, which was eventually attributed to the low doses used (141). Non-conclusive data is available for this option nowadays.
*Injection Devices
Animal-derived and urinary gonadotropin products had to be injected intramuscularly using a syringe and vial, with reconstitution required before injection. Owing to the increased purity of recombinant products, a smaller injection volume is required and these can be injected subcutaneously using smaller gauge needles. In addition, these products have greater stability and liquid formulations of recombinant products have been produced, removing the need for reconstitution before injection. This in turn has enabled the development of pen injection devices, which are designed to improve ease-of-use and patient convenience, including the ability to both select the starting dose with greater precision (in increments as low as 12.5 IU) and adapt the dose during treatment, based on treatment response in small increments (12.5 IU) (142–144).
Conclusions
ART has come a long way since 1927 when gonadotropins were first identified, and currently, available gonadotropin preparations better enable treatment individualization as part of patient-centered care. Patient-centeredness should be an aspect of all consultations and treatment decisions relating to medically assisted reproduction treatment. This should include discussions of whether treatment is appropriate, and if it is appropriate, which treatment would be most favorable. This treatment should be individualized according to the characteristics of the patient(s) and monitored to ensure that effectiveness is optimal, based on treatment response and safety, with treatment adjusted during treatment if it is not. The availability of recombinant products, which provide a pure form of gonadotropin and can be accurately dosed, has improved the ability of medical practitioners to individualize treatment in this manner. Currently, available products can be injected subcutaneously rather than intramuscularly, and pen injection devices are available, improving ease-of-use and more precise dose selection and adaption (in 12.5 IU dose increments). Work to develop new preparations is continuing, and a goal must remain the development of orally active FSH agonists and antagonists.
