Ovarian Overstimulation Research Articles

Inhibin Inactivation in Female Mice Leads to Elevated FSH Levels, Ovarian Overstimulation, and Pregnancy Loss.

Inhibins are members of the transforming growth factor-β family, composed of a common α-subunit disulfide-linked to 1 of 2 β-subunits (βA in inhibin A or βB in inhibin B). Gonadal-derived inhibin A and B act in an endocrine manner to suppress the synthesis of follicle-stimulating hormone (FSH) by pituitary gonadotrope cells. Roles for inhibins beyond the pituitary, however, have proven difficult to delineate because deletion of the inhibin α-subunit gene (Inha) results in unconstrained expression of activin A and activin B (homodimers of inhibin β-subunits), which contribute to gonadal tumorigenesis and lethal cachectic wasting. Here, we generated mice with a single point mutation (Arg233Ala) in Inha that prevents proteolytic processing and the formation of bioactive inhibin. In vitro, this mutation blocked inhibin maturation and bioactivity, without perturbing activin production. Serum FSH levels were elevated 2- to 3-fold in InhaR233A/R233A mice due to the loss of negative feedback from inhibins, but no pathological increase in circulating activins was observed. While inactivation of inhibin A and B had no discernible effect on male reproduction, female InhaR233A/R233A mice had increased FSH-dependent follicle development and enhanced natural ovulation rates. Nevertheless, inhibin inactivation resulted in significant embryo-fetal resorptions and severe subfertility and was associated with disrupted maternal ovarian function. Intriguingly, heterozygous Inha+/R233A females had significantly enhanced fecundity, relative to wild-type littermates. These studies have revealed novel effects of inhibins in the establishment and maintenance of pregnancy and demonstrated that partial inactivation of inhibin A/B is an attractive approach for enhancing female fertility.

Ovarian superstimulation with FSH in Wagyu breed bovine donors impacts folicular dynamics but does not improve the amount of embryos

The increase of the world population generates the need to raise the production of food of vegetal and animal origin. In Brazil, livestock farming has evolved, demonstrating the important role of the country in the production of food. In this way, researchers of this productive chain have been looking for technologies related to production and reproduction, above all, to the use of reproduction biotechnologies, seeking to increase the production of different bovine breeds. Thus, the objective of this research was to investigate the efficacy of ovarian FSH super stimulation in bovine Wagyu oocyte donor females on follicular dynamics and in vitro embryo production. Twelve Wagyu animals, aged 12 to 24 months, randomly distributed in a crossover design were used in two groups: Group 1= animals not stimulated with FSH and Group 2= animals stimulated with FSH. The follicular, oocyte and embryonic variables were evaluated. It was observed that ovarian overstimulation in Wagyu oocyte donor cows with FSH improved the mean and large follicles but reduced the rate of oocyte recovery and, despite the best percentage of viable oocytes, there was no improvement in the amount of embryos produced in vitro.

Highly Purified Human Menopausal Gonadotropin (Menopur®): A Profile of Its Use in Infertility

Menopur® is a highly purified, urine-derived, human menopausal gonadotropin containing both follicle stimulating hormone (FSH) and luteinizing hormone (LH) activity. It is an effective option for controlled ovarian stimulation (COS) in assisted reproductive technology protocols and for ovulation induction (OI) in anovulatory infertility, and is associated with a different endocrine profile from that of recombinant (r) FSH in these settings (in terms of serum levels of FSH, androgens and/or estradiol). When used for COS in women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), Menopur® was as good as rFSH in terms of pregnancy rates (despite being associated with a lower oocyte yield) and was found to improve some aspects of embryo quality in the IVF (but not ICSI) setting; using Menopur® in combination with highly purified urinary FSH resulted in similar reproductive outcomes as Menopur® alone. Data for Menopur® in OI are limited, but suggest ovulation rates may be as good as those with rFSH + rLH (in type 1 anovulation) and rFSH (in type 2 anovulation). Moreover, compared with rFSH, Menopur® appeared to be associated with a less pronounced follicular response and a lower risk of ovarian overstimulation.

Optimal FSH usage in revascularization of allotransplanted ovarian tissue in mice

BackgroudOvarian transplantation is a useful method for preserving the fertility of young women with cancer who undergo radiotherapy and chemotherapy. Follicle-stimulating hormone (FSH) is use to protect transplanted ovarian tissues from ischemia injury through promoting revascularization after transplantation, but the side effect of high level FSH is ovarian overstimulation leading to substantial follicular loss. In this study, we investigated the optimal usage of FSH on revascularization in the in vitro cultured ovarian tissues before and after transplantation.ResultsFSH mainly exhibited an additive response in the gene and protein expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and follicle stimulating hormone receptor (FSHR) with its raised concentrations (0.15 IU/ml, 0.30 IU/ml and 0.60 IU/ml) and prolonged treatment (3 h, 6 h, 12 h, 24 h). The concentrations with 0.60 IU/ml FSH could obviously promoted the expression of VEGF, bFGF and FSHR, but under this concentration FSH could also overstimulated the ovarian tissue leading to follicular loss. With the increase of culture time, the gene and protein expression of VEGF and bFGF both were up-regulated in all of the FSH added groups, but FSHR expression decreased when culture time exceeded 12 h. So we chose 0.30 IU/ml FSH added concentration and 6 h culture time as the FSH usage condition in functional revascularization verification experiment, and found that under this condition FSH promoted 2.5 times increase of vascular density in treated group than in control group after ovarian tissues transplantation.ConclusionOvarian intervention with 0.30 IU/ml FSH for 6 h is an optimal FSH usage condition which could accelerate the revascularization in the allotransplanted ovarian tissue and can not produce ovarian overstimulation.

Hypothesis: Persistently Elevated hCG Causes Gestational Ovarian Overstimulation Associated With Prolonged Postpartum Hyperandrogenism in Mothers of Aromatase-Deficient Babies

Aromatase deficiency due to a CYP19A1 defect leads to fetoplacental inability to convert androgens into estrogens. Pregnant mothers experience virilization caused by excess nonaromatized fetal androgens entering the maternal circulation. Biochemical normalization is believed to take place shortly after delivery. We report prolonged postnatal hyperandrogenism and enlarged multicystic ovaries in the mother of an affected 46,XX infant and hypothesize a possible pathogenetic mechanism. We investigated the mother on days 12 and 20 after delivery. FSH, LH, T, estradiol (E2), androstenedione (A), dehydroepiandrosterone-sulfate (DHEA-S), and human chorionic gonadotropin (hCG) plasma levels were obtained, and ovarian ultrasonography and magnetic resonance imaging were performed. T (1040 ng/dL), A (6940 ng/dL), and E2 (2787 pg/mL) levels were markedly elevated on day 12 after delivery, whereas LH and FSH were suppressed (<0.1 IU/L). On day 20, all hormones had decreased significantly; however, T, A, and E2 still remained 3.5-, 2.2-, and 1.4-fold elevated, respectively, as compared to upper reference values. hCG (18.9 U/L) was still increased. DHEA-S was normal on both occasions. Sonography and magnetic resonance imaging revealed enlarged ovaries, with several cysts up to 4 cm. There was no history of polycystic ovary syndrome. We hypothesize that persistent ovarian overstimulation by hCG had occurred in the mother during pregnancy, leading to prolonged autonomous excess production of androgens during the first weeks after delivery. As a causative mechanism, we propose that gestational hyperandrogenism and hypoestrogenism reduced inhibition of placental GnRH and hCG secretion by progesterone, resulting in persistently elevated hCG.

Internal jugular vein thrombosis due to distant malignancies: two case reports and literature review

The internal jugular vein is an uncommon site of spontaneous venous thrombosis. Most cases usually result from intravenous drug abuse, jugular vein catheterisation, neck dissection, a hypercoagulable state associated with malignancy (Trousseau's syndrome), neck injury or ovarian overstimulation syndrome. In this paper, we present and discuss two cases of spontaneous jugular vein thrombosis associated with breast and lung malignancies. The possibility of Trousseau's syndrome due to distant malignancy should be considered by otolaryngologists and appropriately investigated.

The impact of hormonal therapy for infertility on the age at menopause

Objectives: To look for possible association between past history of ovulation induction and age at menopause. Design: Women attending our postmenopausal outpatient clinic were asked to fill questionnaires with demographic data, obstetrical history (including treatment for infertility), and medical details related to menopause. Patients: The study group ( n=31) consisted of women with a history of ovulation induction, and a control group ( n=200) included women who did not experience such intervention. Results: The age at the final menstrual bleeding was 46.4±5 in the study group, and 50±4 for the control group ( P<0.001). This difference was most prominent for women who had induction of ovulation prior to age 35 years: they entered menopause at age 43.8±5 years. Smoking had a weak effect on the age at menopause (48.5±4 for current, vs. 49.9±4 for non- or past-smokers; P<0.03). Conclusions: This retrospective and preliminary study raises the question whether hormonal manipulations and ovarian over-stimulation during fertility treatments could be a risk factor for premature menopause.

Ovarian Overstimulation and Cystic Formation in Premenopausal Tamoxifen Exposure: Comparison between Tamoxifen-Treated and Nontreated Breast Cancer Patients

Aim.Tamoxifen is the antihormonal treatment of choice for premenopausal breast cancer patients with advanced breast disease. Its premenopausal administration has been shown to induce supraphysiological 17β-estradiol serum levels and to be associated with the presence of persistent, bilateral functional ovarian cysts. However, these abnormalities have not yet been compared to controls. In this study we evaluated the possibility that the above hormonal and/or ovarian abnormalities are more frequent among premenopausal breast cancer patients treated with tamoxifen than among similar nontreated patients, and thus they may be attributed to tamoxifen effect.Methods.We evaluated serum hormone levels of 17β-estradiol, follicular-stimulating hormone, lutenizing hormone, and progesterone, the presence of ovarian cysts, and various demographic and clinical characteristics in 20 premenopausal breast cancer patients treated with tamoxifen (study group) and compared them to those observed in 12 similar nontreated patients (control group).Results.Ovarian cysts were found in 80% of the study patients and only in 8.3% of the control patients (P= 0.001). The incidence of oligomenorrhea was nearly significantly higher in the study than in the control group (50 and 16.7%, respectively;P= 0.0651). Various serum hormone levels tested were not found to be significantly different between the two groups, except for 17β-estradiol serum levels as detected on days 14 and 21 of the menstrual cycle, which were significantly higher among the study than in the control patients. (Day 14 serum estradiol: 757.7 ± 372.0 pg/mL versus 206.5 ± 275.0 pg/mL,P= 0.0012. Day 21 serum estradiol: 300.0 ± 134.5 pg/mL versus 96.5 ± 71.5 pg/mL,P= 0.0008.)Conclusions.Tamoxifen treatment increases the incidence of ovarian cysts and the significantly higher 17β-estradiol serum levels in premenopausal breast cancer patients.

Tamoxifen treatment in premenopausal breast cancer patients may be associated with ovarian overstimulation, cystic formations and fibroid overgrowth

Tamoxifen treatment in premenopausal breast cancer patients may be associated with ovarian overstimulation, cystic formations and fibroid overgrowth

Endocrine Response Determines the Clinical Outcome of Pulsatile Gonadotropin-Releasing Hormone Ovulation Induction in Different Ovulatory Disorders*

To accrue systematic information in different ovulatory disorders on the precise relationship among endocrine response, clinical outcome, and the occurrence of complications, we treated 114 patients with pulsatile GnRH (2.5-5.0 micrograms, iv, every 60 min) for 187 cycles and compared them to 20 normal menstrual cycles. Thirty of these patients had primary hypogonadotropic amenorrhea (PHA; 40 cycles), 33 had other forms of hypogonadotropic hypogonadism (HH; 55 cycles), and 51 had polycystic ovary syndrome (PCOS; 92 cycles). Daily blood samples were drawn for hormone determinations. In PCOS, 50 cycles were preceded by GnRH analog suppression. PHA treatment cycles were characterized by the reestablishment of a normal endocrine pattern, almost no dose-related endocrine differences, elevated ovulatory (93%) and conception rates (23%), and no multiple pregnancies. In the HH subjects the ovulatory (91%) and pregnancy rates (31%) were high; however, while the lower GnRH dose elicited a normal endocrine pattern, the 5-micrograms dose induced excessive folliculogenesis and high estradiol levels and was associated with most of the multiple pregnancies of this study (three of four). GnRH analog suppression was successfully used to avoid recurrence of ovarian over-stimulation in two HH subjects. Finally, GnRH analog suppression in PCOS permitted normalization of the follicular phase endocrine pattern, achievement of good ovulatory (76%) and pregnancy (28%) rates, and avoidance of multiple pregnancies; however, luteal phase steroid secretion was abnormal, and the abortion rate remained elevated (43%). Obesity was associated with a reduced ovulatory rate in PCOS, but not in hypogonadotropic, subjects. Thus, we can conclude that in pulsatile GnRH ovulation induction: 1) a profound hypogonadotropic condition, whether spontaneous as in PHA or induced with GnRH analogs as in other ovulatory disorders, is associated with optimal menstrual cycle restoration, high ovulatory and conception rates, and virtually absent risks of multiple pregnancy; 2) residual hypothalamic activity in HH may be responsible for supraphysiological pituitary-ovarian stimulation and result in multiple pregnancy unless a low GnRH dose (2.5 micrograms/bolus) or GnRH analog pretreatment is employed; 3) obesity does not affect treatment outcome in hypogonadotropic patients; and 4) the high spontaneous abortion rate in PCOS may be related to corpus luteum dysfunction.

Comparison of ovarian stimulation regimens for in vitro fertilization (IVF) with and without a gonadotropin-releasing hormone (GnRH) agonist: Results of a randomized study

In order to diminish the cancellation rate due to a premature endogeneous LH surge and/or to a poor ovarian response and thus increasing the pregnancy rate, a GnRH agonist (Buserelin) was applied in patients starting their first ovarian stimulation with gonadotropins for IVF. All patients suffered from tubal infertility and were not older than 40 years. Each woman was allocated randomly to one of three groups: the conventional treatment with hMG alone (group I), patients from group II started the hMG treatment shortly after the LH rise caused by the GnRH agonist and patients in group III commenced the hMG treatment when an hypogonadotropic state was achieved after a long treatment of Buserelin. All male partners had a normal spermiogram. A reduction of poor responders to the superovulation is seen in the short-term group (6%), compared with the other two groups (14%). In some cases from group III ovarian cyst formation led to the cancellation of the treatment. The long-term group differs significantly from the other two in the duration of the gonadotropin stimulation and the number of ampoules hMG used. A severe ovarian overstimulation syndrome was not observed. There is no difference in the number of retrieved oocytes and the fertilization rate among the three groups. The pregnancy rate per cycle or per patient in the group with a short-term GnRH-agonist regimen is significantly higher compared to that of the group using the conventional hMG treatment.

Combined luteinizing hormone releasing hormone analogue and exogenous gonadotrophins for the treatment of infertility associated with polycystic ovaries

This study was designed to compare the results of treatment with, firstly, exogenous gonadotrophins, with (57 cycles) and without (65 cycles) pretreatment with a superactive analogue of luteinizing hormone releasing hormone (LHRH) and, secondly, pure follicle stimulating hormone (FSH) (50 cycles) with those of human menopausal gonadotrophin (HMG) (72 cycles) in 46 women with clomiphene-citrate-resistant anovulation associated with polycystic ovaries. Patients randomly allocated to the analogue group received buserelin (Suprefact, Hoechst, UK, Ltd, Hounslow, Middlesex), 800 micrograms/day by nasal insufflation and when hypogonadism was achieved, patients were again randomly allocated for ovarian stimulation with either FSH or HMG. Controls received FSH or HMG alone. Patients pretreated with the analogue had similar pregnancy and ovulation rates, needed larger doses and more days of gonadotrophin therapy and had more ovarian overstimulation than those receiving no pretreatment. The role of superactive LHRH analogues for induction of a single ovulation for in-vivo fertilization is thus uncertain. Pure FSH had no advantages over HMG, the LH content of HMG having no deleterious effect on the ovary.

Ovulation induction with pulsatile human menopausal gonadotropin (HMG) administration

A computerized pump for continuous pulsatile HMG administration was used with 5 patients having prolonged anovulatory infertility, for 14 consecutive cycles. All of these women had previously failed to respond to various treatment regimens, or repeatedly developed ovarian overstimulation syndrome. In 12 out of 14 cycles, ovulation was detected by hormonal and ultrasonic evaluation, and pregnancy was achieved in 2 out of 5 cases. A mild form of overstimulation was observed in only 3 out of 14 cycles. A summary of the results of the present and similar previously published series demonstrated overall ovulation and pregnancy rates of 75% and 23.5% respectively. We concluded that inducing ovulation by administering pulsatile HMG is an appropriate alternative method of treatment when ovulation and conception fail with conventional regimens.

Induction of Ovulation and Fertility in Amenorrheic Women by Pulsatile Low-Dose Gonadotropin-Releasing Hormone

Abstract In functional hypothalamic amenorrhea, failure of ovulation probably results from deficient hypothalamic secretion of gonadotropin-releasing hormone (GnRH). We treated 14 infertile women in whom this condition was resistant to clomiphene with pulses of 5 to 15 μg of GnRH administered subcutaneously by portable pumps at 90-minute intervals in 36 cycles of treatment. Ovulation occurred in 30 cycles (83 per cent) and was followed by normal luteal function in 24. Singleton pregnancy occurred after 13 (54 per cent) of these cycles. Ovarian ultrasound consistently showed a single dominant follicle, and follicular-phase levels of gonadotropins and urinary estrone glucuronide were in the normal range in all cycles of treatment except two in which mild ovarian overstimulation occurred. Plasma profiles of GnRH and luteinizing hormone were highly pulsatile after subcutaneous administration of GnRH, and mean peak plasma levels of GnRH were comparable to those in pituitary portal blood. We conclude that treat...

Induction of Ovulation and Fertility in Amenorrheic Women by Pulsatile Low-Dose Gonadotropin-Releasing Hormone

In functional hypothalamic amenorrhea, failure of ovulation probably results from deficient hypothalamic secretion of gonadotropin-releasing hormone (GnRH). We treated 14 infertile women in whom this condition was resistant to clomiphene with pulses of 5 to 15 micrograms of GnRH administered subcutaneously by portable pumps at 90-minute intervals in 36 cycles of treatment. Ovulation occurred in 30 cycles (83 per cent) and was followed by normal luteal function in 24. Singleton pregnancy occurred after 13 (54 per cent) of these cycles. Ovarian ultrasound consistently showed a single dominant follicle, and follicular-phase levels of gonadotropins and urinary estrone glucuronide were in the normal range in all cycles of treatment except two in which mild ovarian overstimulation occurred. Plasma profiles of GnRH and luteinizing hormone were highly pulsatile after subcutaneous administration of GnRH, and mean peak plasma levels of GnRH were comparable to those in pituitary portal blood. We conclude that treatment with low-dose subcutaneous pulses of GnRH is a safe, effective, and physiologic method of restoring reproductive function in hypothalamic amenorrhea and that it has advantages over gonadotropin therapy.

Ectopic pregnancy following treatment with human gonadotropins

After treatment with human gonadotropins, 289 anovulatory women with apparently normal fallopian tubes became pregnant 379 times. Ten ectopic pregnancies in nine women were diagnosed, for an incidence of 2.7% of all conceptions. All the ectopic pregnancies were found in the fallopian tubes. Four patients had also an intrauterine pregnancy. Five of the patients showed ovarian overstimulation, and hormonal modifications at the time of ovulation might explain the high incidence of tubal gestation.

Ovarian function in the ewe after active immunization against testosterone.

The secretion rates of testosterone measured during the last half of the oestrous cycle in 2 Merino crossbred ewes with utero-ovarian autotransplants were 1.95 +/- 0.34 ng/min and 2.48 +/- 0.63 ng/min. The secretion rate of testosterone was not correlated with the secretion rate of oestradiol or androstenedione in either ewe. Welsh Mountain ewes were actively immunized against testosterone-3-(O-carboxymethyl)-oxime-bovine serum albumin (testosterone-3-BSA) or BSA alone (controls). Immunization against testosterone-3-BSA (5 ewes) resulted in anovulation (2 ewes) and the disruption of oestrous cycles and irregular ovulations (2 ewes). The ovaries showed morphological and endocrinological evidence of over-stimulation. Numerous large non-atretic follicles were present and in those ewes still ovulating the numbers of corpora lutea (ovulation rate) were increased. The concentrations of androstenedione and of oestradiol in the ovarian venous plasma were also markedly increased when compared to those in control ewes. The plasma binding capacity for steroids and the jugular venous concentrations of steroids were higher in immunized ewes. The binding capacity of follicular fluid for testosterone was similar to that of jugular venous plasma from the same ewe. These results show that immunization against testosterone-3-BSA leads to a disruption of ovarian cycles and ovarian over-stimulation.

Quintuplet pregnancies.

Five quintuplet pregnancies, following induction of ovulation with clomiphene and HMG-HCG, are the subject of this communication. In 3 women, pregnancy was associated with ovarian overstimulation, and two patients required emergency surgery because of torsion of an ovarian cyst. Two women aborted in mid-trimester, while the other 3 delivered by cesarean section at 33-35 wk gestation. 15 babies were born, weighing 700-2200 g. 8 infants suffered from respiratory distress syndrome and 5 babies were born with correctable malformations. 13 newborns survived, and all are mentally and physically well-developed. Four of the 5 women conceived again. The management of the patients during multiple gestation and the outcome of pregnancy are discussed.

Embryo Transplantation in Cattle

Fourteen true repeat breeders with entirely normal oestrous cyclicity more than 1 year after calving and 14 control donor cows were superovulated with PMSG (2000 i.u.) and flushed non-surgically 6–8 days after the superovulatory heat. The superovulatory response was identical for the 2 groups such as assessed by the number of corpora lutea (9.4 ± 1.8 C.L. per repeat breeder and 9.1 ± 1.5 per control cow), occurrence of ovarian overstimulation (polycysts), presence of a non-countable amount of corpora lutea, negative outcome of the flushings and the number of recovered embryos (5.8 ± 1.0 embryos per repeat breeder and 6.0 ± 1.8 embryos per control cow). The most pronounced difference between the 2 categories of animals was related to the fertilization rate of embryos. In the repeat breeder group only 2.4 embryos per cow or 41 % were fertilized, whereas the control animals attained a fertilization rate of 4.9 embryos or 82 %. Since most factors liable to interfere with the fertilization process were identical for both groups (age, breed, nutritional and management conditions, semen quality, dose, AI-technician e.g.), it is believed that intraovarian, follicular, or follicular-dynamic conditions were responsible for producing a high proportion of non-fertilizable oocytes.

Estrogen monitoring and the prevention of ovarian overstimulation during gonadotropin therapy

The results of therapy with human menopausal gonadotropin (HMG) was compared in patients controlled by the development of fern formation with patients monitored by daily total estrogen excretion. The percentage of anovulatory cycles and pregnancies were high with both methods. There were less multiple pregnancies and cases of ovarian enlargement when estrogen monitoring was utilized. Of most significance was the fact that there were no cases of triplet pregnancy or cases of massive ovarian enlargement with or without ascites when estrogen monitoring was utilized.