Follitropin Research Articles

Dose-response endocrine profiles for a novel recombinant FSH preparation (FE 999049) derived from a human cell-line

To investigate the endocrine responses to five different doses of FE 999049, a novel recombinant FSH derived from a human cell-line (PER.C6) during controlled ovarian stimulation in a GnRH antagonist cycle, and to characterize them according to serum AMH. Exploratory analysis of 222 IVF/ICSI patients undergoing controlled ovarian stimulation with FE 999049 (Ferring Pharmaceuticals) in a randomized, assessor-blind, multicentre, dose-response trial (NCT01426386). Patients were randomized to fixed doses of 5.2, 6.9, 8.6, 10.3 or 12.1 μg/day FE 999049. Randomization was stratified by serum AMH (low: 5.0-14.9 pmol/L, high: 15.0-44.9 pmol/L; Beckmann-Coulter Gen 2 ELISA). Stimulation was carried out in a GnRH antagonist cycle (ganirelix 0.25 mg/day from day 6). Blood was sampled at stimulation days 1, 4 and 6 and end-of-stimulation for central analysis. Ongoing pregnancy was determined 10-11 weeks after compulsory single blastocyst transfer. Serum estradiol, inhibin B and inhibin A on days 4, 6 and end-of-stimulation were positively associated with FE 999049 dose in both AMH strata (p<0.05). Serum progesterone on day 6 and end-of-stimulation was positively correlated with FE 999049 dose only in the high AMH stratum (p<0.01). Progesterone levels ≥1 ng/mL during stimulation were associated with a reduced ongoing pregnancy rate in the low AMH stratum (p<0.01), but had no impact in the high AMH stratum. The percentage of patients with premature LH rise (≥10 IU/L) increased with FE 999049 dose (p<0.01), and was associated with a reduced ongoing pregnancy rate (p<0.05) independent of AMH. Serum estradiol, progesterone, inhibin A and inhibin B are significantly correlated with the dose of FE 999049. Both premature LH rise and elevation of progesterone seem to be associated with a reduced ongoing pregnancy rate. The negative impact of elevated progesterone on treatment outcome is observed in patients with low AMH levels.

A randomized, assessor-blind, dose-response trial in patients undergoing controlled ovarian stimulation for IVF/ICSI with a novel recombinant FSH preparation (FE 999049) derived from a human cell-line

To establish the relationship between the dose of FE 999049, a novel recombinant FSH derived from a human cell-line (PER.C6) and the number of oocytes retrieved, and to characterize it according to serum AMH. Randomized, controlled, assessor-blind, multicentre, dose-response trial in 265 IVF/ICSI patients undergoing controlled ovarian stimulation with one of five doses of FE 999049 (Ferring Pharmaceuticals) or one dose of follitropin alfa (GONAL-F, EMD Serono) (NCT01426386). Patients were randomized to fixed doses of 5.2, 6.9, 8.6, 10.3 or 12.1 μg/day FE 999049 (N=222) or follitropin alfa 11 μg/day (150 IU/day) (N=43). Randomization was stratified by serum AMH (low: 5.0-14.9 pmol/L, high: 15.0-44.9 pmol/L; Beckmann-Coulter Gen 2 ELISA). Stimulation was carried out in a GnRH antagonist cycle (ganirelix 0.25 mg/day from day 6). Triggering was done when ≥3 follicles ≥17 mm. Ongoing pregnancy was determined 10-11 weeks after compulsory single blastocyst transfer. There was a significant (p<0.001) dose-response relationship for FE 999049 with respect to number of oocytes retrieved; overall and for each AMH strata. Increasing the FE 999049 dose with 10% led to an increase of 1 oocyte (95% CI: 0.65-1.30) in the high AMH stratum and 0.5 oocyte (95% CI: 0.22-0.72) in the low AMH stratum. The dose-response curves were significantly (p<0.05) different for the two strata, with 31-97% more oocytes in the high AMH stratum across FE 999049 doses. The percentage of FE 999049 patients with extreme responses (i.e. <4 or ≥20 oocytes) followed a U-shaped dose-response curve. No linear relationship was observed between FE 999049 dose and number of blastocysts, but rather a threshold relationship. The ongoing pregnancy rate was 35% for FE 999049 and unrelated to dose. A significant dose-response relationship was established between FE 999049 and number of oocytes retrieved with significantly different slopes for the low and high AMH strata.

Effects of Urinary and Recombinant Gonadotropins on In Vitro Maturation Outcomes of Mouse Preantral Follicles

Gonadotropins including follicle-stimulating hormone (FSH) and luteinizing hormone (LH) play a crucial role in human-assisted reproduction techniques. Despite wide use of recombinant gonadotropins in clinical practice, the efficacy of urinary gonadotropins and the dosage of LH component have not yet been elucidated. This study was designed to investigate the difference of follicle culture outcomes according to various compositions of gonadotropins during in vitro culture of mouse preantral follicles. Ovaries were obtained from the 14-day-old C57BL/6 mice, and preantral follicles were isolated and cultured in culture media supplemented with human menopausal gonadotropin (hMG) 200 mIU/mL (group 1), recombinant FSH and LH (rFSH + rLH) 200 mIU/mL each (group 2), rFSH 200 mIU/mL + rLH 100 mIU/mL (group 3), or rFSH 200 mIU/mL + rLH 20 mIU/mL (group 4). Follicle survival rate was significantly lower in group 4. Antral follicles in lower doses of LH (groups 3, 4) showed a statistically significant larger diameter and tended to have a higher antral formation rate. However, follicles in group 1 tended to have a higher oocyte maturation rate. Estradiol concentration from conditioned media from 2:1 FSH/LH (group 3) was significantly higher than those from 1:1 FSH/LH (group 2) or 10:1 FSH/LH (group 4). Half dose of rLH to rFSH facilitated upregulation of growth differentiation factor 9 (Gdf9) expression in granulosa cells when compared to 1:1 FSH/LH or 10:1 FSH/LH. Conclusively, recombinant gonadotropins provided a comparable condition to hMG, and half dose of rLH to rFSH seems to be more suitable for follicular development during in vitro culture.

Evaluation of the oligosaccharide composition of commercial follicle stimulating hormone preparations

Glycosylation is an important PTM in proteins, and it is of paramount importance for the manufacture and efficacy of therapeutic glycoproteins. The elucidation of the glycosylation patterns is greatly hampered by the structural heterogeneity, which involves the oligosaccharide moieties, and sometimes also the protein chain. Several strategies are used to map the glycosylation state of glycoproteins: they generally involve analysis of the glycopeptides obtained upon glycoprotein proteolytic digestion, and/or analysis of the glycans, enzymatic or chemically released from the glycoproteins. These approaches are efficient in determining the total glycan content, as well as the glycan structures; nevertheless, information regarding the whole protein is lost. Recent advances in MS allowed us to directly analyze human follicle stimulating hormone (hFSH). RP-HPLC/IT-TOF MS, coupled to bioinformatic algorithms, was used to determine the glycan content of intact hFSH preparations, either urinary-derived or recombinant. More traditional and complementary analytical methods (oligosaccharide profiling, IEF, and peptide mapping analyses) were employed to compare the obtained results. Our analysis shows a predominance of highly sialylated, highly branched glycans in a urinary hFSH preparation as compared to recombinant hFSH expressed in rodent cell lines. Noteworthy, high-resolution mass spectra may allow to evaluate the glycosylation profile during the manufacturing process of different preparations.

A prospective, randomised, investigator-blind, controlled, clinical study on the clinical efficacy and tolerability of two highly purified hMG preparations administered subcutaneously in women undergoing IVF

The aim of this multicentre, prospective, randomised, investigator blind, controlled clinical trial was to evaluate the clinical efficacy and tolerability of a highly purified human menopausal gonadotrophin (hMG) preparation (Merional-HG) when administered to patients undergoing controlled ovarian stimulation (COS) for in-vitro fertilisation (IVF) procedure enrolled in hospital departments.One hundred fifty-seven patients were randomised in two parallel groups: 78 started COS with Merional-HG and 79 with Menopur. Results of the study showed that both highly purified hMG preparations were equivalent in terms of number of oocytes retrieved (primary endpoint: 8.8 ± 3.9 versus 8.4 ± 3.8, p = 0.54). In the patients treated with Merional-HG, we observed a higher occurrence of mature oocytes (78.3% versus 71.4%, p = 0.005) and a reduced quantity of gonadotrophins administered per cycle (2.556 ± 636 IU versus 2.969 ± 855 IU, p < 0.001). Fertilisation, cleavage, implantation rates and the number of positive β-human chorionic gonadotrophin (hCG; pregnancy) tests and the clinical pregnancy rate were comparable in the two groups. Both treatments were well tolerated. In conclusion, the results of this study support the efficacy and safety of Merional-HG administered subcutaneously for assisted reproduction techniques. Efficiency of Merional-HG appears to be higher due to reduced quantity of drug used and the higher yield of mature oocytes retrieved.

Advantages of recombinant follicle-stimulating hormone over human menopausal gonadotropin for ovarian stimulation in intrauterine insemination: a randomized clinical trial in unexplained infertility

ObjectiveTo compare two different gonadotropin preparations, human menopausal gonadotropin (hMG) and recombinant follicle-stimulating hormone (rFSH), combined with clomiphene citrate (CC) in women with unexplained infertility undergoing intrauterine insemination (IUI). Study designIn this prospective clinical trial, couples prepared for IUI cycles were randomly allocated to two groups either to receive CC and hMG (group A, n=127) or CC and rFSH (group B, n=132) for ovarian stimulation. Outcomes including rates of clinical pregnancy, miscarriage, OHSS, multiple pregnancy, cancelation, and live birth were compared between groups. ResultsDuration of gonadotropin therapy was significantly shorter in group B (5.1±0.84 vs. 4.7±0.8 days, CI=95%, P<0.001). The total dose of administered gonadotropin was also significantly lower in group B (386.9±68.2 vs. 348.2±56.3IU, CI=95%, P<0.001). Dominant follicle number (>17mm), mean follicular diameter, and endometrial thickness on the day of hCG injection were similar. Clinical pregnancy, multiple pregnancies, abortion, live birth, ovarian hyperstimulation syndrome (OHSS), and cancelation rates were not statistically different between the groups. ConclusionIUI cycles in which rFSH had been administered may require shorter duration and a lower total gonadotropin dose.

Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles: prediction of ovarian response and cumulative treatment outcome in good-prognosis patients

To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol. Secondary analysis of data prospectively collected in a randomized, assessor-blind trial comparing two different gonadotropin preparations with respect to ongoing pregnancy rate. Twenty-five centers in seven countries. 749 women, aged 21 to 34 years, with primary diagnosis of infertility being unexplained infertility or mild male factor infertility and with serum follicle-stimulating hormone (FSH) level 1-12 IU/L and antral follicle count (AFC) ≥10. Controlled ovarian stimulation with highly purified human menopausal gonadotropin (hphMG) or recombinant FSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer and potential subsequent 1-year cryopreserved blastocyst replacement in natural cycles. Relationships between AMH at start of stimulation and ovarian response and treatment outcome. Serum AMH concentration was strongly correlated with oocyte yield: AMH accounted for 85%, FSH for 14%, and inhibin B and AFC for <1% each of the explained variation in oocyte yield. Also, AMH showed a high accuracy for the prediction of poor (≤3 oocytes) and high response (≥15 oocytes), which was statistically significantly better than basal FSH, AFC, or inhibin B. AMH was statistically significantly positively associated with ongoing pregnancy rate in the fresh cycle as well as with the 1-year cumulative ongoing pregnancy and live-birth rates. There is a positive relationship between AMH and oocyte yield in GnRH antagonist cycles, and AMH is the best predictor for identifying patients with poor and high ovarian response. The positive association between AMH and cumulative live-birth rates after fresh and cryopreserved cycles reflects the availability of more oocytes/blastocysts, not higher quality. NCT00884221.

A questionnaire-based survey to assess patient satisfaction, ease-of-learning, ease-of-use, injection site pain and overall patient satisfaction of the follitropin-alpha (Gonal-f) filled-by-mass (FbM) prefilled pen compared with other systems of gonadotrophin administration

BackgroundGonadotrophins are used routinely for follicular stimulation during ovarian induction and assisted reproduction techniques. Developments in recombinant follicle-stimulating hormone preparations and their injection devices have improved patient quality of life by enabling patients to self-administer treatment at home. The objective of this study was to investigate patient experiences of learning to use and overall satisfaction with the follitropin-alpha (Gonal-f) filled-by-mass (FbM) prefilled pen.MethodsThis questionnaire-based survey study was conducted in 23 fertility centres in Japan over a period of 14 months. Patients who were receiving fertility treatment with the follitropin-alpha (FbM) prefilled pen were asked to complete a questionnaire to assess their satisfaction, ease of learning and use, and injection site pain following treatment.ResultsA total of 663 women participated in the study. The majority of patients found the instructions for administering follitropin-alpha with the prefilled pen easy to understand (83.0%; n = 546/658) and patients found that a hands-on demonstration by a nurse or doctor was the most useful tool for learning to use the follitropin-alpha (FbM) prefilled pen (80.0%; n = 497/621). Forty-eight percent (n = 318) of patients in the study had previous experience with different types of fertility medications and the majority of these patients found the follitropin-alpha (FbM) prefilled pen easier to use (75.1%; n = 232/309) and less painful (89.0%; n = 347/390) than their previous medication. The majority (80.2%; n = 521/650) of patients reported overall satisfaction with the follitropin-alpha (FbM) prefilled pen.ConclusionsThe follitropin-alpha (FbM) prefilled pen is an easy-to-use injection device according to this questionnaire-based survey. Patients who had experience of different types of fertility medication preferred the follitropin-alpha (FbM) prefilled pen to other injection devices.

The Anti-Epileptic Drug Valproic Acid (VPA) Inhibits Steroidogenesis in Bovine Theca and Granulosa Cells In Vitro

Valproic acid (VPA) is used widely to treat epilepsy and bipolar disorder. Women undergoing VPA treatment reportedly have an increased incidence of polycystic ovarian syndrome (PCOS)-like symptoms including hyperandrogenism and oligo- or amenorrhoea. To investigate potential direct effects of VPA on ovarian steroidogenesis we used primary bovine theca (TC) and granulosa (GC) cells maintained under conditions that preserve their ‘follicular’ phenotype. Effects of VPA (7.8–500 µg/ml) on TC were tested with/without LH. Effects of VPA on GC were tested with/without FSH or IGF analogue. VPA reduced (P<0.0001) both basal (70% suppression; IC50 67±10 µg/ml) and LH-induced (93% suppression; IC50 58±10 µg/ml) androstenedione secretion by TC. VPA reduced CYP17A1 mRNA abundance (>99% decrease; P<0.0001) with lesser effects on LHR, STAR, CYP11A1 and HSD3B1 mRNA (<90% decrease; P<0.05). VPA only reduced TC progesterone secretion induced by the highest (luteinizing) LH dose tested; TC number was unaffected by VPA. At higher concentrations (125–500 µg/ml) VPA inhibited basal, FSH- and IGF-stimulated estradiol secretion (P<0.0001) by GC without affecting progesterone secretion or cell number. VPA reversed FSH-induced upregulation of CYP19A1 and HSD17B1 mRNA abundance (P<0.001). The potent histone deacetylase (HDAC) inhibitors trichostatin A and scriptaid also suppressed TC androstenedione secretion and granulosal cell oestrogen secretion suggesting that the action of VPA reflects its HDAC inhibitory properties. In conclusion, these findings refute the hypothesis that VPA has a direct stimulatory action on TC androgen output. On the contrary, VPA inhibits both LH-dependent androgen production and FSH/IGF-dependent estradiol production in this in vitro bovine model, likely by inhibition of HDAC.

Urine gonadotropin and estradiol levels in female very-low-birth-weight infants

BackgroundThe postnatal activation of the hypothalamic–pituitary–gonadal axis is more exaggerated in preterm than in full-term born infants and may be important for future reproductive function. AimThe objective of this study was to investigate the postnatal activation of the hypothalamic–pituitary–gonadal axis in female very-low-birth-weight infants. Study designWe performed serial measurements of gonadotropin and estradiol levels in urine samples of female very-low-birth-weight infants collected at 1 and 4weeks postnatal age, at 32weeks postmenstrual age, at expected date of delivery and at the corrected age of three and six months. SubjectsTwenty-two very-low-birth-weight infants (gestational age 25.4–30.1weeks), participating in the Neonatal Insulin Replacement Therapy in Europe trial, were included in this study. Outcome measuresGonadotropin and estradiol levels were measured in serial urine samples. ResultsLongitudinal analysis shows that after birth FSH and LH levels increase until 32weeks postmenstrual age (4weeks postnatal age) and then decrease until 3months corrected age (26weeks postnatal age). Estradiol levels decrease from 28weeks postmenstrual age (1week postnatal age) until 6months corrected age (39weeks postnatal age). ConclusionsSerial urine sampling for measurement of gonadotropin and estradiol levels provides an accurate description of the postnatal activation of the hypothalamic–pituitary–gonadal axis in very-low-birth-weight girls. Levels of FSH and LH peak at a mean postmenstrual age of 32weeks (postnatal age of 4weeks) whereas estradiol levels are highest shortly after birth.

Urine Gonadotropin and Testosterone Levels in Male Very-Low-Birthweight Infants

Background/Aims: The postnatal activation of the hypothalamic-pituitary-gonadal axis is more exaggerated in preterm than in full-term-born infants, and may be important for reproductive function. Our objective was to investigate this activation of the hypothalamic-pituitary-gonadal axis in male very-low-birthweight (VLBW) infants. Methods: Twenty-one VLBW boys (gestational age 26.0–30.0 weeks), participating in the NIRTURE trial, were included. Gonadotropin and testosterone levels were measured in serial urine samples collected at 1 and 4 weeks’ postnatal age, at 32 weeks’ postmenstrual age, at expected date of delivery and at the corrected age of 3 and 6 months. Results: Longitudinal analysis shows that after birth LH and FSH levels peak at a mean postnatal age of 1–4 weeks (mean postmenstrual age of 30–32 weeks) and decrease until 38 weeks’ postnatal age (corrected age of 6 months). Testosterone levels decrease with increasing age, and this decrease is faster in infants receiving early insulin therapy. Conclusions: Serial urine sampling for measurement of gonadotropin and testosterone levels provides accurate information about the postnatal activation of the hypothalamic-pituitary-gonadal axis in VLBW boys. FSH and LH levels peak at 1–4 weeks of age. Insulin treatment causes faster decrease in testosterone levels.

Iatrogenic prion diseases in humans: an update

Although Creutzfeldt-Jakob disease (CJD) was first identified in 1920, prevention of transmission raised particular concern all over the world when a new variant of the disease was first described in 1996. There is good evidence of iatrogenic transmission of this new variant among human beings through blood, blood components, tissues and growth hormone. Furthermore, four cases of iatrogenic transmission of CJD through fertility treatment with human pituitary-derived gonadotrophins have been reported. It is important to distinguish the categories of infectivity and categories of risk, which require consideration not only of the level of infectivity of a given tissue or fluid, but also the amount of tissue/fluid to which a person is exposed, the duration of exposure and the route by which infection is transmitted. The potential presence and infectivity of prion proteins in human urinary gonadotrophin preparations is a matter of debate. Differences in the sensitivity of bioassay methods are of paramount importance when considering the infectivity of a tissue. Some new methods might detect small amounts of agent in some tissues currently thought to be free of infectivity. No cases of human prion disease due to the use of urinary gonadotrophins have been recognized to date. However, the detection of prions in the urine of experimental animals and in some urine-based preparations, and the young age of fertility drug recipients, require the application of the precautionary principle to urinary preparations.

Management of anovulatory infertility

Anovulatory subfertility is a heterogeneous condition with various underlying causes, which should be identified with appropriate history taking, physical examination and relevant investigations. Optimisation of body weight is essential in either underweight, overweight or obese individuals. Women with hypogonadotrophic anovulation can be treated with pulsatile gonadotrophin-releasing hormone therapy or a gonadotrophin preparation containing both follicle-stimulating hormone or luteinising hormone activities. For normogonadotrophic anovulation, clomiphene citrate should be used as first-line medical treatment. Metformin co-treatment with clomiphene citrate may be considered in a subgroup of women with polycystic ovary syndrome who are obese or clomiphene-resistant. Ovulation induction with gonadotrophin or laparoscopic ovarian drilling is the next option. Dopamine agonist is indicated for anovulation as a result of hyperprolactinaemia.

The impact of dose of FSH (Folltropin) containing LH (Lutropin) on follicular development, estrus and ovulation responses in prepubertal gilts

FSH is favored over chorionic gonadotropins for induction of estrus in various species, yet little data are available for its effects on follicle development and fertility for use in pigs. For Experiment 1, prepubertal gilts (n=36) received saline, 100mg FSH, or FSH with 0.5mg LH. Treatments were divided into six injections given every 8h on Days 0 and 1. Proportions of gilts developing medium follicles were increased for FSH and FSH–LH (P<0.05) compared to saline, but follicles were not sustained and fewer hormone-treated gilts developed large follicles (P<0.05). No gilts expressed estrus and few ovulated. Experiment 2 tested FSH preparations with greater LH content. Prepubertal gilts (n=56) received saline, FSH–hCG (100mg FSH with 200IU hCG), FSH–LH5 (FSH with 5mg LH), FSH–LH10 (FSH with 10mg LH), or FSH–LH20 (FSH with 20mg LH). FSH–LH was administered as previously described, while 100IU of hCG was given at 0h and 24h. Hormone treated gilts showed increased (P<0.05) medium and large follicle development, estrus (>70%), ovulation (100%), and ovulation rate (>30 CL) compared to saline. There was an increase (P<0.05) in the proportion of hormone-treated gilts with follicular cysts at Day 5, but these did not persist to Day 22. These gilts also showed an increase in poorly formed CL (P<0.05). FSH alone or with small amounts of LH can induce medium follicle growth but greater amounts of LH at the same time is needed to sustain medium follicles, stimulate development of large follicles and induce estrus and ovulation in prepubertal gilts.

Urinary gonadotrophins: a useful non-invasive marker of activation of the hypothalamic pituitary-gonadal axis

BackgroundNon-invasive screening investigations are rarely used for assessing the activation and progression of the hypothalamic-pituitary gonadal axis through puberty. This study aimed to establish a normal range for urinary gonadotrophins in children progressing through puberty.MethodsUrine samples were collected from 161 healthy school children (76 boys, 85 girls) aged 4–19 yrs. Height and weight were converted to standard deviation score. Pubertal status, classified by Tanner staging, was determined by self-assessment. Urinary gonadotrophins were measured by chemiluminescent microparticle immunoassay. Results were grouped according to pubertal status (pre-pubertal or pubertal).ResultsOf the 161 children, 50 were pre-pubertal (28 boys; 22 girls) and 111 were pubertal (48 boys; 63 girls). Overall, urinary gonadotrophins concentrations increased with pubertal maturation. All pre-pubertal children had a low urinary LH:Creatinine ratio. LH:Creatinine ratios were significantly higher in pubertal compared to pre-pubertal boys (p<0.001). In girls, FSH:Creatinine ratios were significantly higher in the pubertal group (p = 0.006). However, LH:FSH ratios were a more consistent discriminant between pre-pubertal and pubertal states in both sexes (Boys 0.45 pubertal vs 0.1 pre-pubertal; girls 0.23 pubertal vs 0.06 pre-pubertal).ConclusionUrinary gonadotrophins analyses could be used as non-invasive integrated measurement of pubertal status which reflects clinical/physical status.

Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. A Cochrane review

Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. A Cochrane review

Comparison of transforming growth factor β1 concentrations in the ovaries of rats stimulated by human menopausal gonadotropin or recombinant follicle-stimulating hormone

To compare the effects of human menopausal gonadotropins (hMG) and recombinant follicle stimulating hormone (rFSH) on transforming growth factor (TGF) β1 concentration in the rat ovary. Twenty-one fertile Wistar-Albino rats were divided into 3 groups of 7. Groups 1, 2 and 3 were injected with saline, hMG or rFSH, respectively, over 5 days, after which they underwent ovariectomy. Hematoxylin and eosin (H&E) staining was used for histological examination. TGF β1 staining levels in ovarian stroma, vessel walls, granulosa cells of Graafian follicles and corpus luteum cells were investigated immunohistochemically. On histological examination, the number of smaller antral follicles was higher in the control group, while there were more and larger antral follicles in the hyperstimulated groups. There were statistically significant differences in staining in vessel walls and granulosa cells between the control and stimulated groups. Both stimulation protocols caused an increased TGF β1 concentration in vessel walls, while there was weak staining in granulosa cells in the treatment groups compared to the control group (p<0.05). There were no significant differences in staining scores between the two treatment groups (p>0.05). The effects of two different gonadotropin preparations on TGF β1 concentrations in different localizations in the rat ovaries are comparable. It may be postulated that the luteinizing hormone (LH) content of hMG contributes little or nothing to the TGF β1 mediated angiogenesis.

Live Birth Following Resection of Multiple Submucous Myomas: A Unique Case Report

Uterine leiomyomas are by far the most common benign uterine tumours present in almost 25 % women of reproductive age. However fibroids are an infrequent cause of infertility being the sole cause in less than 3 % of infertile couples [1]. Uterine fibroids especially submucous leiomyomas may be associated with infertility as well as with subfertilty and pregnancy losses. Some researchers have speculated that the location of fibroids within the endometrial cavity may interfere with sperm transport and/or implantation [2]. One study has calculated a 10 % rate of pregnancy complications in women with fibroids [3]. Though being an infrequent cause of infertility and pregnancy complications, it is still extremely rare to have a pregnancy, that too uneventful in patients with extreme distortion of uterine cavity due to multiple intramural and submucosal fibroids. We would like to report such a case. Patient first presented in 1998 at 28 years of age with secondary infertility and failure to conceive for 1 year. She was married for 4 years and had undergone medical termination of pregnancy 2 years earlier. On investigations, she had regular ovulatory cycles; hysterosalpingogram confirmed bilateral tubal patency and the semen parameters were normal. Pelvic ultrasound showed a uterus with numerous intramural and submucous fibroids of variable size, the largest being 3 × 3 cm. There were no other factors contributing to infertility. She was subjected to six-cycles of COH with IUI, using Clomiphene for 3 cycles urinary gonadotrophins for other 3 cycles. These were unsuccessful. Pelvic ultrasound revealed increasing size and number of myomas. In view of above finding and inability to conceive, she was taken up for operative laparoscopic and hysteroscopic resection of myomas, wherein eight submucosal myomas were resected, the largest on the right lateral wall measuring 3 × 3 × 3 cm. Diagnostic laparoscopy revealed multiple subserous and intramural myomas on the posterior wall and right cornua. Both the tubes were patent. Three more cycles of controlled ovarian hyperstimulation with intrauterine insemination were attempted to no avail. Pelvic ultrasound again revealed a number of submucous myomas. Two injections of depot GnRh-agonist were administered at four weekly intervals and hysteroscopic loop resection of fourteen submucous myomas was done (Fig. 1). Due to suboptimal preovulatory endometrium, IVF was delayed till endometrium was 7 mm and carried out 8 months later. However, at the time of embryo transfer the endometrium was only 5.4 mm triple layered. She failed to conceive and discontinued any further management. She next came to us 10 months later at 35 years of age with a naturally conceived pregnancy. Despite our apprehensions and USG again confirming an extremely unhealthy milieu interior for the conceptus she continued her pregnancy uneventfully except for mild PIH. She was taken up for an elective LSCS at 37 weeks of gestation and a live female baby was delivered. The placenta was however partially adherent and removed piecemeal because the entire uterine cavity was riddled with fibroids from 0.3 to 4 cm in size, a few of which presented themselves in the surgeon’s hands. This case brings a ray of hope to those managing seemingly hopeless cases of leiomyomas. Fig. 1 View of submucous myomas at time of second hysteroscopic resection S submucous myoma, U uterine cavity

Present and Future of Recombinant Gonadotropins in Reproductive Medicine

Pharmacological ovarian stimulation has a major role in reproductive medicine and has been used in anovulatory patients and in the induction of multifollicular development required for the procedures of assisted reproductive techniques (ART). Currently, gonadotropins are the most important tools to proceed with ovarian stimulation for all purposes, including ART and anovulation disorders, like hypogonadotropic hypogonadism and hypothalamic hypophyseal dysfunction. Gonadotropin preparations derived from human urine have been used clinically since the early 1960s and the first urine-derived preparation containing only FSH (urofollitropin) became available in 1983. More recently, the application of recombinant DNA technology has resulted in the development of recombinant FSH produced in mammalian cells. In the last period, LH became available by recombinant DNA technology and is now a new option for protocols of ovarian stimulation. Treatment with gonadotropins has been shown to be effective in males affected by hypogonadotropic hypogonadism. This success has resulted in attempts to utilize FSH therapy in oligozoospermic men, aimed at obtaining a quantitative increase in sperm count. The purpose of this review was to examine the pharmacological aspects and different clinical applications of recombinant gonadotropins (FSH, LH, hCG) in the treatment of female infertility in all its aspects and their use also in the treatment of male infertility. This review will trace these events, from the past through to the present, and conclude with a glance towards the future.

Modeling Follicle Stimulating Hormone Levels in Serum for Controlled Ovarian Hyperstimulation I: Comparing Gonadotropin Products

Despite the dangers of gonadotropin administration, our understanding of serum levels of gonadotropins in our patients is poor. We created a mathematical model of gonadotropin administration in order to learn about the temporal profiles of Follicle Stimulating Hormone (FSH) levels in patients related to the doses of different gonadotropin products administered. Model parameters for each product were determined from published pharmacokinetic information available from the manufacturers. For each product, serum levels of FSH rose then fell following a single injection of FSH. When a gonadotropin dose was injected repeatedly (daily), each injection resulted in a peak level of FSH that was higher than the level attained from the previous injection. Daily FSH peaks rose asymptotically, requiring 3-10 days to approach the maximum. The maximum averaged 3.5 times the peak of the first injection. Decline of FSH following the final injection required 3-10 days to approach the baseline. Time courses and peak values of FSH using different gonadotropin preparations varied widely. Knowledge of the slow changes of FSH that occur during modeled FSH administration will provide a framework for understanding the gonadotropin profiles that occur in patients during controlled ovarian hyperstimulation.