Long-acting FSH Research Articles

Use of a single injection of long-acting recombinant bovine FSH to superovulate Holstein heifers: A preliminary study

Our objective was to compare several experimental preparations of a single injection of long-acting recombinant bovine FSH (rbFSH; types A and B) to a porcine pituitary-derived FSH (Folltropin) to superovulate Holstein dairy heifers. Nonlactating, nonpregnant virgin Holstein heifers (n = 56) aged 12 to 15 months were randomly assigned to one of four superstimulatory treatments. Beginning at a random stage of the estrous cycle, all follicles greater than 5 mm were aspirated. Thirty-six hours later, heifers received an intravaginal P4 device and superstimulatory treatments were initiated. Treatments were (1) 300 mg of pituitary-derived FSH (Folltropin) administered in eight decreasing doses over a period of 3.5 days; (2) a single injection of 50 μg of A-rbFSH; (3) a single injection of 100 μg of A-rbFSH; and (4) a single injection of 50 μg of B-rbFSH. All heifers received 25 mg PGF2α at 48 and 72 hours after the insertion of P4 device. At 84 hours after insertion, P4 devices were removed, and ovulation was induced 24 hours later with hCG (2500 IU). Heifers were inseminated at 12 and 24 hours after hCG treatment. The number of ovulatory follicles was greatest for heifers treated with Folltropin and B50-rbFSH, least for heifers treated with A50-rbFSH, and was intermediate for heifers treated with A100-rbFSH (25.7 ± 3.2, 18.9 ± 3.2, 5.9 ± 0.9, and 16.6 ± 3.1, respectively; P < 0.001). The number of corpora lutea was greatest for heifers treated with Folltropin, B50-rbFSH, and A100-rbFSH, and least for heifers treated with A50-rbFSH (19.1 ± 2.4, 16.1 ± 3.0, 15.9 ± 2.9, and 2.6 ± 0.9, respectively; P < 0.001). The number of good-quality embryos differed among treatments and was greatest for heifers treated with B50-rbFSH, Folltropin, and A100-rbFSH and least for heifers treated with A50-rbFSH (7.6 ± 2.4, 6.5 ± 1.7, 4.3 ± 1.5, and 0.8 ± 0.5, respectively; P < 0.001). In conclusion, a single injection of a preparation of long-acting rbFSH (either 100 μg of A-rbFSH or 50 μg of B-rbFSH but not 50 μg of A-rbFSH) produced similar superovulatory responses resulting in the production of good-quality embryos when compared with a pituitary-derived FSH preparation administered twice daily for 4 days. More studies using different types of cattle and different doses of rbFSH are needed to confirm the findings reported in this preliminary study.

Corifollitropin alfa versus daily recombinant FSH treatment for controlled ovarian stimulation in poor responders

To compare the effect of long-acting recombinant FSH (rFSH), corifollitropin alfa with daily rFSH administered during 1st 7days of controlled ovarian stimulation (COS) using GnRH antagonist multiple dose protocol (MDP) in poor responders undergoing IVF/intracytoplasmic sperm injection (ICSI).

Evaluation of the degree of satisfaction in oocyte donors using sustained-release FSH corifollitropin α

Ovarian stimulation treatment is recognized as placing a physical and psychological burden on patients and oocyte donors. The introduction of sustained follicle stimulants will reduce the number of injections and may improve the overall patient experience. This study aimed to evaluate the degree of satisfaction in oocyte donors undergoing treatment with corifollitropin α, a synthetic recombinant rFSH which replaces daily FSH injections for the first week of ovarian stimulation. The results showed no significant differences in clinical parameters between the two protocols (recombinant FSH versus corifollitropin α). Implantation rates for the corifollitropin α and daily FSH protocol groups were 39.1% and 38.4%, respectively, while ongoing pregnancy rates were 45.9% and 44.4%. There were no statistical between-group differences in the responses to the questionnaires. However, donors treated with corifollitropin α who had undergone a previous cycle with daily FSH reported greater satisfaction with the corifollitropin α protocol. In conclusion, no significant differences were found in any analysed parameters between treatments. However, when donors who had undergone both treatments chose which treatment they preferred, the results clearly showed a positive trend towards choosing corifollitropin α, confirming that this protocol may reduce treatment burden and increase donor compliance.Infertility is a stressful situation for couples trying to conceive and has both societal and personal consequences. IVF treatment offers a hopeful solution to many infertile couples; however, the stress of infertility can be increased by IVF treatment, which is a complex process that is both physically and emotionally demanding. There is a clear need for simplified treatment approaches to lessen the treatment burden of IVF. One of the improvements to shorten treatment duration and decrease the number of injections has been the introduction of corifollitropin α, a long-acting recombinant FSH. A single injection of this drug can replace daily gonadotrophin injections for 7days and can further decrease the number of injections in an ovarian stimulation cycle. In this study, we report an evaluation of the degree of satisfaction in oocyte donors undergoing treatment with corifollitropin α, compared with patients being treated with daily follitropin β. Through some questionnaires being offered to donors after oocyte retrieval, we tried to establish if there were any links between this novel treatment and a lower degree of discomfort suffered during the whole treatment.

Is there a place for corifollitropin alfa in IVF/ICSI cycles? A systematic review and meta-analysis

To evaluate the role of corifollitropin alfa, a newly developed weekly administrated long-acting recombinant FSH (rFSH), as an alternative for daily rFSH administration in women undergoing controlled ovarian stimulation in GnRH antagonist down-regulated in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment cycles. Systematic review and meta-analysis of randomized controlled trials. University and private centers. Infertile women undergoing IVF/ICSI treatment. Comparing long-acting rFSH corifollitropin alfa versus standard daily administrated rFSH in GnRH antagonist IVF/ICSI cycles. Ongoing pregnancy rate, live birth rate, clinical pregnancy rate, miscarriage rate, duration of stimulation, amount of FSH, number of retrieved oocytes, number of mature oocytes, number of embryos obtained, fertilization rate, ovarian hyperstimulation syndrome (OHSS) incidence, and adverse events. Searches (of literature through November 2011) were conducted in Medline, Embase, Science Direct, the Cochrane Library, and databases of abstracts. Four randomized trials involving 2,326 women were included. There was no evidence of a statistically significant difference in ongoing pregnancy rate for corifollitropin alfa versus rFSH. There was evidence of increased ovarian response and risk of OHSS in corifollitropin alfa. In view of its equivalence and safety profile, corifollitropin alfa in combination with daily GnRH antagonist seems to be an alternative for daily rFSH injections in normal responder patients undergoing ovarian stimulation in IVF/ICSI treatment cycles.

Corifollitropin alfa in a long GnRH agonist protocol: proof of concept trial

Fifty healthy women, aged 18-39 years with no known risk of ovarian hyperstimulation were treated with 100 or 150 μg corifollitropin alfa (dependent on body weight) in a long GnRH agonist protocol. At these doses, corifollitropin alfa initiated and supported growth of a large cohort of follicles during the first week of ovarian stimulation.

Long-acting FSH analogue: Corifollitropin-α to sustain multifollicular growth during controlled ovarian stimulation

Different gonadotropin preparations containing FSH are used for ovarian controlled stimulation prior to IVF/intracytoplasmic sperm injection (ICSI). The two most common forms used are urinary human menopausal gonadotropin (containing FSH and LH activity) and recombinant FSH (containing FSH without any LH activity). Owing to the relatively short half-life of all currently used FSH preparations (32 ± 12 h) clinical protocols for induction of multifollicular development in women stimulated for IVF require daily injections. Site-directed mutagenesis and gene transfer techniques were used to develop a longer acting gonadotrophin preparation. Corifollitropin-α (NV Organon, a part of the Schering-Plough Corporation, Oss, The Netherlands) was designed as a sustained follicle stimulant containing the α-subunit of human FSH and a hybrid subunit composed of the sequence of the α-subunit of human FSH and the C-terminal peptide part of the α-subunit of hCG. This molecular structure includes O-linked carbohydrate chain...

Single-Chain Bifunctional Vascular Endothelial Growth Factor (VEGF)-Follicle-Stimulating Hormone (FSH)-C-Terminal Peptide (CTP) Is Superior to the Combination Therapy of Recombinant VEGF plus FSH-CTP in Stimulating Angiogenesis during Ovarian Folliculogenesis

Infertility technologies often employ exogenous gonadotropin therapy to increase antral follicle production. In an effort to enhance ovarian response, several long-acting FSH therapies have been developed including an FSH-C-terminal peptide (CTP), where the FSH subunits are linked by the CTP moiety from human chorionic gonadotropin, which is responsible for the increased half-life of human chorionic gonadotropin. We found that administration of FSH-CTP for ovarian hyperstimulation in rats blunted ovarian follicle vascular development. In women, reduced ovarian vasculature has been associated with lower pregnancy rates. We were interested in determining whether vascular endothelial growth factor (VEGF) therapy could enhance ovarian angiogenesis in FSH-CTP-treated rats. Coadministration of systemic FSH-CTP plus recombinant VEGF was compared with treatment with a novel, single-chain bifunctional VEGF-FSH-CTP (VFC) analog. For VFC, the FSH portion targets the protein to the ovary and stimulates follicle growth, whereas VEGF enhances local vascular development. Both in vitro and in vivo studies confirm the dual FSH and VEGF action of the VFC protein. Evaluation of ovarian follicle development demonstrates that administration of combination therapy using VEGF and FSH-CTP failed to increase follicle vasculature above levels seen with FSH-CTP monotherapy. However, treatment with VFC significantly increased follicle vascular development while concurrently increasing the number of large antral follicles produced. In conclusion, we report the production and characterization of a long-acting, bifunctional VEGF-FSH-CTP protein that is superior to combination therapy for enhancing VEGF activity in the ovary and stimulating follicular angiogenesis in rats.

FSH and folliculogenesis: from physiology to ovarian stimulation

FSH is a glycoprotein hormone consisting of two peptide subunits. The role of FSH in folliculogenesis is well known: to stimulate the formation of a large pre-ovulatory follicle that, because of its FSH-dependent maturation, is capable of ovulation and forming a corpus luteum in response to the mid-cycle surge of LH. FSH is widely used in ovarian stimulation for assisted reproduction techniques. Ovarian stimulation protocols combine the use of human menopausal gonadotrophin, urinary FSH or recombinant FSH with gonadotrophin-releasing hormone (GnRH) agonists or antagonists in order to increase oocyte number and to avoid premature LH surge. Recently, the availability of recombinant LH has permitted new stimulation protocols, combining recombinant FSH, recombinant LH and GnRH antagonists. Due to the limitations of the new Italian law in terms of the number of oocytes that can be fertilized, protocols with a softer ovarian stimulation are now considered, reducing risk of ovarian hyperstimulation syndrome, multiple pregnancies and emotional and physical burdens on the patients. Long-acting FSH preparations are also under clinical study. Knowledge of the stereochemical three-dimensional structure of FSH and its receptor will allow the study of new non-peptide orally administered molecules that fit the FSH receptors.

Pharmacodynamics of a Single Low Dose of Long-Acting Recombinant Follicle-Stimulating Hormone (FSH-Carboxy Terminal Peptide, Corifollitropin Alfa) in Women with World Health Organization Group II Anovulatory Infertility

In a double-blind, placebo-controlled, randomized study, 55 anovulatory subjects received a single s.c. injection of placebo (n = 10) or recombinant long-acting FSH [FSH-carboxy terminal peptide (CTP), ORG 36286, corifollitropin alfa; NV Organon, The Netherlands] in doses of 7.5 (n = 13), 15 (n = 10), 30 (n = 11), or 60 microg (n = 11). The injection was given 2 or 3 d after the onset of a spontaneous or progestagen-induced withdrawal bleed. After drug administration, the induced follicular response varied widely among subjects in each dose group. The percentage of subjects with a follicular response (at least one follicle > or = 10.0 mm) increased with the dose (P < 0.01) and was 10, 31, 70, 73, and 82% in the placebo and 7.5-, 15-, 30-, and 60-microg treatment groups, respectively. In responding subjects, the average maximum number of follicles was 4.0, 7.6, 13.4, and 20.0, respectively, which was reached at 6.5, 6.9, 6.6, and 8.2 d after a single dose of 7.5, 15, 30, and 60 microg FSH-CTP, respectively. The dose-response for the number of follicles was statistically significant within the dose range tested (P < 0.01). Peak serum inhibin-B levels were significantly correlated with serum estradiol (E2) levels (r = 0.84, P < 0.01), and peak concentrations of inhibin-B and E2 correlated with the number of follicles observed at the same time point (for both hormones; r = 0.47, P < 0.01). Overall per treatment group, serum E2 and inhibin B concentrations significantly increased only in the two highest FSH-CTP dose groups, reaching peak concentrations at d 3 in the 30-microg group and at d 5 in the 60-microg group. Thereafter these hormone values declined rapidly, returning to baseline within 1 wk after FSH-CTP administration. In total, nine of the 55 treated subjects (16.4%) ovulated after drug administration: one subject in the placebo group, two subjects in the 7.5-microg group, three subjects in the 15-microg group, two in the 30-microg group, and one in the 60-microg group. Three subjects had monofollicular ovulation after placebo (n = 1) and a single dose of 15 microg FSH-CTP (n = 2). In two subjects with too many preovulatory follicles, (multiple) ovulation was prevented by GnRH antagonist administration. Thus, a single low dose of long-acting FSH-CTP was able to induce one or more follicles to grow up to ovulatory sizes, but the anovulatory status was not reversed because the incidence of subsequent (mono)ovulations was low.

Glycosylation of an N-terminal extension prolongs the half-life and increases the in vivo activity of follicle stimulating hormone.

FSH is a key component in assisted reproductive technologies. Because of rapid clearance of the hormone, patients have to be treated with daily injections. To address this problem, a long-acting FSH mutein was created by introduction of additional N-linked glycosylation into the molecule. New glycosylation sites were introduced by two different approaches: structure-aided, site-directed introduction of sites within the FSH molecule and addition of N-terminal extensions. A mutein with the extension sequence ANITVNITV at the N terminus of the alpha-chain (FSH1208) was efficiently glycosylated at both new sites. This resulted in a molecule with increased size and charge, factors known to reduce renal clearance of proteins. FSH1208 was found to have a 3- to 4-fold increased serum half-life, compared with wild-type recombinant FSH. Furthermore, in spite of a lower in vitro activity, FSH1208 had a markedly increased in vivo potency, as shown by increased ability to augment the ovarian weight and stimulate the serum estradiol levels in rats. These characteristics make FSH1208 a possible candidate for improved infertility treatment.

First live birth after ovarian stimulation using a chimeric long-acting human recombinant follicle-stimulating hormone (FSH) agonist (recFSH-CTP) for in vitro fertilization

Objective To report the first pregnancy and live birth after ovarian stimulation using a chimeric long-acting human recombinant FSH agonist (recFSH-CTP) for IVF. Design Case report. Setting Tertiary fertility center. Patient(s) A 32-year-old woman with a 7-year history of primary infertility. Intervention(s) Ovarian stimulation with a single SC injection of 180 μg recFSH-CTP on cycle day 3, followed by daily injections of 150 IU recFSH from cycle day 10 onward, combined with daily GnRH antagonist 0.25 mg SC to prevent a premature LH rise. Final oocyte maturation was induced by 10,000 IU hCG. Main outcome measure(s) First ongoing pregnancy obtained with recFSH-CTP. Result(s) Twelve oocytes were retrieved. Ten oocytes were fertilized in vitro by intracytoplasmic sperm injection, and from these 10 oocytes, two embryos were subsequently transferred after 3 days of culture. A pregnancy test 2 weeks after ET was positive, and ultrasound investigation revealed an intact, intrauterine, singleton pregnancy after 12 weeks. Conclusion(s) The first pregnancy and live birth was achieved after ovarian stimulation using recFSH-CTP for IVF.

Single dose pharmacokinetics and effects on follicular growth and serum hormones of a long-acting recombinant FSH preparation (FSH-CTP) in healthy pituitary-suppressed females.

A long-acting FSH preparation has been developed by site-directed mutagenesis and gene transfer techniques. In this open-label trial, we investigated the pharmacokinetic and pharmacodynamic properties of FSH-CTP (corifollitropin alpha, Org 36286) in healthy female volunteers. Twenty-four subjects were treated with a high-dose oral contraceptive (OC) to suppress pituitary function. A single dose of 15, 30 or 60 micro g FSH-CTP was injected (s.c., eight subjects per dose group) and seven of these 24 subjects were subsequently treated with a single dose of 120 micro g. Maximum serum FSH-CTP concentrations (0.42, 0.66, 1.49 and 3.27 ng/ml after administration of 15, 30, 60 and 120 micro g Org 36286 respectively) were reached between 36 and 48 h after injection and t(1/2) varied between 60 and 75 h. Dose proportionality was shown across the studied dose range, whereas t(max) and t(1/2) were dose independent. In most subjects follicular growth was observed; the number and maximum diameter of the follicles increased with the dose. Follicles with a diameter vertical line 8.0 mm were observed only in the 60 and 120 micro g dose groups, diameters between 12.0 and 15.9 mm occurred only in the 120 micro g group. Serum LH and 17beta-oestradiol levels remained low due to profound pituitary suppression whereas inhibin-B levels increased with dose. Maximum mean inhibin-B levels were 30.4, 322.7 and 1059.3 pg/ml in the 30, 60 and 120 micro g dose group respectively. The preparation was safe and well tolerated, and no FSH-CTP antibody formation was observed. The pharmacokinetics of FSH-CTP were shown to be proportional with the dose. The elimination half-life was approximately two times longer than that of rFSH. A single dose of FSH-CTP was shown to be safe and able to induce multiple follicular growth accompanied by a dose-dependent rise in serum inhibin-B concentrations.

Pharmacokinetics and pharmacodynamics of single-chain recombinant human follicle-stimulating hormone containing the human chorionic gonadotropin carboxyterminal peptide in the rhesus monkey

Objective: To compare the pharmacokinetics of a long-acting FSH analog containing the hCG-β carboxyterminal peptide (recombinant hFSH–CTP) with native recombinant hFSH and describe the pharmacodynamics of recombinant hFSH–CTP after SC injection in female rhesus monkeys. Design: Rhesus monkey study. Setting: Academic research environment. Animal(s): Ten female rhesus monkeys. Intervention(s): Recombinant hFSH and recombinant hFSH–CTP were administered via a single SC or IV dose to rhesus monkeys, and serial phlebotomy was performed (n = 2 and n = 4 for SC recombinant hFSH and recombinant hFSH–CTP, respectively; for IV dosing, n = 1 in each group). An additional two monkeys were pretreated with SC ganirelix and received SC recombinant hFSH–CTP after confirmation of pituitary suppression. Main Outcome Measure(s): Plasma disappearance rate of recombinant hFSH and recombinant hFSH–CTP and serum estradiol levels. Result(s): The elimination half-life of recombinant hFSH–CTP was twofold and fourfold longer than that for recombinant hFSH after SC and IV dosing, respectively. The absorption half-life was approximately threefold longer for recombinant hFSH–CTP than for recombinant hFSH after SC administration. Recombinant hFSH–CTP stimulates estradiol secretion for 5–7 days after an isolated SC dose. Conclusion(s): Addition of the hCG-β carboxyterminal peptide to hFSH-β results in an FSH analog with longer absorption and elimination half-lives compared with native hormone. This analog is capable of prolonged ovarian stimulation in rhesus monkeys after an isolated SC injection.

Follicle-stimulating hormone enhances the development of preantral follicles in juvenile rats.

The stimulatory effects of gonadotropins on antral and preovulatory follicles are well known, but conflicting results have been reported regarding the gonadotropin responsiveness and dependency of preantral follicles. Taking advantage of the relatively uniform development of the first wave of follicles in the postnatal rat ovary, we evaluated the role of endogenous and exogenous gonadotropins on preantral follicle development. Reduction of the high levels of gonadotropins present in juvenile rats by either hypophysectomy (at Day 15) or GnRH antagonist treatment (starting from Day 11 of age) resulted in decreased ovarian weight at Day 19 of age that was associated with a reduced number of developing follicles and increased atresia of remaining follicles. In contrast, treatment with FSHctp (a long-acting FSH agonist) in intact (Days 5-19 of age), hypophysectomized (Days 15-19), or GnRH antagonist-treated (Days 11-19) animals resulted in increased ovarian weight and follicle development as determined histologically and by inhibin-alpha expression. A dose-dependent stimulatory effect of hCG on ovarian weight was seen when animals were cotreated with FSHctp and the GnRH antagonist. At low doses of hCG, augmentation of antral follicle formation occurred, whereas higher doses of hCG led to morphological signs of luteinization. These findings demonstrate the important role of endogenous gonadotropins in preantral follicle development and indicate that preantral follicles are highly responsive to exogenous gonadotropins.

Erratum to “The effects of long-acting oxytocin, GnRH and FSH administration on thyroxin, triiodothyronin, oestradiol 17-β and progesterone levels as well as conception rates in post-partum ewes” [Anim. Reprod. Sci. 37 (1995) 311

Erratum to “The effects of long-acting oxytocin, GnRH and FSH administration on thyroxin, triiodothyronin, oestradiol 17-β and progesterone levels as well as conception rates in post-partum ewes” [Anim. Reprod. Sci. 37 (1995) 311

The effects of long-acting oxytocin, GnRH and FSH administration on thyroxin, triiodothyronin, oestradiol 17-β and progesterone levels as well as conception rates in post-partum ewes

Abstract This work was a first attempt to discover whether the suppression of adenopituitary gonadotropin secretion might be responsible for a decrease of systemic T4 and T3 levels in the post-partum period in ewes, and also whether the depression of T4 and T3 levels might be retroactively responsible for a depression of sexual activity in the post-partum period and in spring. T4, T3, E2 and P4 levels were observed in four groups of ewes. After parturition (lambings took place in the first 10 days of February) the animals were treated with an oxytocin-based preparation (/2-0-methyltyrosin/deamino-1-carba-oxytocinum, Depotocin injection, Leciva), synthetic LH-RH (Dirigestran injection, Spofa) or pituitary gonadotropin FSH (Folicotropin injection, Spofa). Group 1 was the control group (n = 10), and each animal received 2 ml saline. The ewes in Group 2 (experimental; n = 9) were treated with 0.14 mg Depotocin per animal, the ewes in Group 3 (experimental; n = 10) were given 200 μg Dirigestran per animal, and the ewes in Group 4 (experimental; n = 5) received 160 IU Folicotropin. All preparations were administered in two doses: an intramuscular dose at 24 h post-partum and a subcutaneous dose at 72 h post-partum. On Day 51, oestrus was induced in all animals by combined Agelin (6-chloro-6-dehydro-16 methylene-17 α-hydroxyprogesterone) and PMSG treatment. Blood samples were obtained from the jugular vein at 24 h ante-partum (a.p.) (Day -1), at 36 h post-partum and on Days 4, 7, 14, 17, 21, 25, 34, 42 and 51 post-partum. When compared with the controls, altered T4 and T3 dynamics and significantly increased levels of T3 (between Days 4 and 25, P

Hormonal control of apoptotic cell death in the testis: gonadotropins and androgens as testicular cell survival factors.

Although the requirement for pituitary gonadotropins during testicular cell differentiation is well documented, the possible role of FSH and LH in regulating testicular cell survival has not been studied. Using a quantitative autoradiographic method for the detection of internucleosomal DNA fragmentation, a hallmark feature of apoptosis, the hormonal control of apoptotic cell death was studied in testicular cells collected from immature rats after hypophysectomy. After surgery, animals were treated with daily injections of 20 IU long-acting FSH agonist (FSH-CTP) or 50 IU human CG (hCG) for 2 days. Hypophysectomy decreased testis weight by 25%, but treatment with FSH-CTP or hCG prevented the effect of hypophysectomy. Testes of intact animals contained predominantly high-mol wt DNA, whereas hypophysectomy increased DNA cleavage into low-mol wt (< 15 kilobases) ladders characteristics of apoptosis. In contrast, treatment with FSH-CTP or hCG inhibited hypophysectomy-induced apoptotic DNA cleavage by 84% and 51%, respectively. Hypophysectomy-induced DNA fragmentation was found in both interstitial cells and seminiferous tubules. Similar to whole testis, treatment with FSH-CTP suppressed hypophysectomy-induced apoptosis by over 90% in seminiferous tubules and interstitial cells. In contrast, hCG treatment was less effective in preventing hypophysectomy-induced DNA cleavage (46% suppression in tubules and 77% suppression in interstitial cells). Furthermore, testosterone replacement also suppressed hypophysectomy-induced DNA fragmentation by 75% in the whole testis tissue, 64% in tubules, and 55% in interstitial cells. To further study the role of gonadotropins, intact animals were treated with a potent GnRH antagonist (Azaline B, 10 microgram/day) to decrease serum gonadotropin levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Naltrexone effects on pituitary and gonadal hormones in male and female rhesus monkeys

The long-acting opioid antagonist, naltrexone, stimulates LH and FSH in women during the early follicular phase of the menstrual cycle and is a new provocative test of hypothalamic-pituitary function (42,63). The acute effects of naltrexone (0.25, 0.50 and 1.0 mg/kg IV) on anterior pituitary (LH, FSH, PRL) and gonadal steroid (T or E 2) hormones were studied in 7 female and 4 male rhesus monkeys ( Macaca mulatta). Integrated plasma samples were collected at 20 min intervals for 60 min before and for 300 min after intravenous infusion of naltrexone over 10 min. In females studied during the early follicular phase (cycle days 1–3), naltrexone did not stimulate LH and significantly suppressed E 2( p<0.0003-0.0001) and FSH ( p<0.006−0.0001). Naltrexone (0.50 and 1.0 mg/kg) also did not stimulate LH release in late follicular phase females (cycle days 10–12) when estradiol levels were in the peri-ovulatory range. FSH and E 2 were significantly suppressed ( p<0.01−0.05) after 1.0 mg/kg naltrexone, but not after 0.5 mg/kg naltrexone. However, in males all doses of naltrexone significantly stimulated LH ( p<0.003–0.0001) and T( p<0.001–0.0001) but not FSH. LH increased significantly above baseline within 20 to 40 min and T increased significantly within 60 min. These gender differences in naltrexone's effects on pituitary gonadotropins and gonadal steroid hormones were unanticipated. These data are not concordant with clinical studies which report significant naltrexone stimulation of LH in men and women during the early follicular phase. Only prolactin levels decreased after naltrexone infusion in both males and females and this decrease was statistically significant after a dose of 0.25 mg/kg in males ( p<0.008) and after 0.50 and 1.0 mg/kg in females ( p<0.0001).

POSTURAL ST-T WAVE CHANGES

Gonadotropin therapy plays an integral role in ovarian stimulation for infertility treatments. Efforts have been made over the last century to improve gonadotropin preparations. Undoubtedly, current gonadotropins have better quality and safety profiles as well as clinical efficacy than earlier ones. A major achievement has been introducing recombinant technology in the manufacturing processes for follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin. Recombinant gonadotropins are purer than urine-derived gonadotropins, and incorporating vial filling by mass virtually eliminated batch-to-batch variations and enabled accurate dosing. Recombinant and fill-by-mass technologies have been the driving forces for launching of prefilled pen devices for more patient-friendly ovarian stimulation. The most recent developments include the fixed combination of follitropin alfa + lutropin alfa, long-acting FSH gonadotropin, and a new family of prefilled pen injector devices for administration of recombinant gonadotropins. The next step would be the production of orally bioactive molecules with selective follicle-stimulating hormone and luteinizing hormone activity.