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PubMedDate not supplied

The role of growth hormone (GH), GH-receptor and GH-binding protein in reproduction and ovulation induction.

In the last decade the potential importance of intraovarian regulators of follicular development has been recognized, and the effects of various growth factors on granulosa cell responses to gonadotropins have been extensively investigated. Ovarian responses to exogenous gonadotropins were improved by adjuvant growth hormone (GH) treatment of GH-deficient patients, and responses to hMG were apparently predicted by estimated GH reserve. However, the results of different studies of GH/hMG cotreatment were equivocal. Therefore, a randomized, prospective, cross-over study protocol between GH/hMG/hCG versus hMG/hCG was undertaken. Whereas 18 pregnancies were achieved in the 32 clonidine negative patients (56%) either in the GH/hMG cycle (13) or in the succeeding one (5), no benefit was detected in 10 clonidine positive patients from the GH/hMG combination. The recently described GH-binding protein (BP) may reflect the GH-receptor. GH-BP levels were evaluated in the sera and follicular fluids (FF) of patients undergoing ovulation induction with either hMG/hCG or GH/hMG/hCG. GH-BP increase in serum correlated with E2 and progesterone (P4) concentrations. The FF GH-BP correlated with serum GH-BP levels and was dose-dependent, highly specific, of high affinity, and low capacity. Lower FF GH-BP levels were measured in older compared to younger women, while increased values were obtained both in patients with elevated E2 concentrations in serum and in FF, and when more than 5 oocytes were retrieved. Longitudinal measurements of GH-BP levels showed an initial sharp increase during early gestation, followed by a gradual decrease from the 2nd trimester to term. The late gestational decrease in GH-BP levels may be attributed to the decreasing hCG concentrations, and/or to the increasing secretions of placental lactogen and GH with advancing gestation. Primary increased GH-BP in unexplained infertility may suggest a new mechanism whereby excessive GH-BP levels may prevent GH from binding to its receptor and thus decrease intraovarian IGF-1 production. Whereas GH-BP significantly increased in correlation with moderately (300-1500 pg/ml, 1100-5500 pmol/l), or with severely increased (> 1500 pg/ml, > 5500 pmol/l) E2 concentrations, the serum IGF-1 levels increased with moderately elevated but decreased at severely increased E2 concentrations, as measured in ovarian hyperstimulation (OHSS). This observation may suggest IGF-1's involvement in a mechanism by which OHSS is detrimental to early conception. The clonidine test may identify patients who may benefit from this combination, during the GH/hMG cycle and possibly also during the succeeding cycle.

Carrier Proteins↗
PubMed1999

Luteinizing hormone activity supplementation enhances follicle-stimulating hormone efficacy and improves ovulation induction outcome.

Although FSH is essential to stimulate ovarian folliculogenesis, increasing physiological and clinical evidence suggests that moderate LH stimulation may also be critical for optimal follicle and oocyte development. Conversely, a clinical trend exists toward conducting controlled ovarian hyperstimulation (COH) in a LH-depleted environment, as recently developed gonadotropin preparations are devoid of LH activity, and endogenous LH is suppressed with GnRH analogs in most COH cycles. To investigate the role of LH activity during COH we supplemented highly purified (HP) FSH with low dose hCG in GnRH agonist-suppressed women. Twenty normoovulatory women were pretreated with a GnRH agonist and after 2 weeks were randomly assigned to receive HP FSH (150 IU/day) alone (group A; 10 patients) or combined with hCG (50 IU/day; group B; 10 patients). The HP FSH dose was increased after 14 days only in cases of inadequate response. Treatment was monitored with pelvic ultrasound and daily hormone determinations. None of the patients of group B and 8 of group A required more than 14 days of treatment and increments of the FSH dose. Folliculogenesis and 17beta-estradiol (E2) secretion progressed more rapidly and evenly in group B. Although preovulatory follicle number and E2 concentrations were comparable, patients in group B required a shorter stimulation time (12.5+/-0.6 vs. 17.3+/-0.7 days in group A; P < 0.0001) and a lower HP FSH dose (1725+/-84 vs. 2670+/-164 IU in group A; P < 0.0001). Serum levels of LH, E2, progesterone, and testosterone did not differ between the 2 groups; serum FSH was higher in group A. We conclude that LH activity promotes folliculogenesis in synergy with FSH in the mid- to late follicular phase and that low dose hCG coadministration optimizes COH by 1) enhancing FSH action, 2) accelerating ovarian follicle development, 3) shortening COH duration, 4) lowering HP FSH requirements, and 5) reducing COH cost. Thus, moderate LH activity in the follicular phase plays a positive physiological and clinical role in folliculogenesis and ovulation induction.

Adult↗
PubMed1996

The importance of endogenous feedback for monofollicular growth in low-dose step-up ovulation induction with follicle-stimulating hormone in polycystic ovary syndrome: a randomized study.

OBJECTIVE: To evaluate the role of endogenous feedback in monofollicular growth during low-dose gonadotrophin therapy in polycystic ovary syndrome (PCOS) by measuring FSH levels in a group of patients cotreated with a GnRH agonist (GnRH-a) (group B) compared with patients not cotreated with an agonist (group A). DESIGN: Prospective randomized study. SETTING: University tertiary care Reproductive Endocrinology Unit. PATIENTS: Women with clomiphene citrate-resistant PCOS. MAIN OUTCOME MEASURES: Follicle-stimulating hormone, E2, and inhibin levels, follicular growth. RESULTS: In group A, FSH levels decreased significantly from 7.3 mIU/mL (conversion factor to SI unit, 1.00) at day -5 to 5.9 mIU/mL at day 0 (day that hCG was administered) despite a constant dose, whereas they remained at a level of 7.4 mIU/mL in group B. The rate of monofollicular growth was significantly higher in group A (80%) than in group B (22%). No significant differences in E2 levels or inhibin levels were found between the groups. CONCLUSIONS: The absence of a decrease of FSH during GnRH-a treatment in association with a lower rate of monofollicular growth suggests that endogenous feedback during low-dose step-up ovulation induction in PCOS plays an important role. The absence of this feedback mechanism in the presence of normal inhibin levels suggests that negative feedback control by inhibin during follicular stimulation is minimal.

Adult↗
PubMed2000

Cancer risk associated with subfertility and ovulation induction: a review.

OBJECTIVE: Over the past decades the use of fertility drugs (FDs) has greatly increased. Recently, the possible association between the use of FDs and risk of cancer has aroused great concern. In this paper, we critically review the available epidemiologic studies. METHODS: We identified papers published between 1966 and 1999 that examined FDs and specific causes of subfertility in relation to the risks of cancers of the ovary, breast, endometrium and thyroid, and melanoma. RESULTS: Although present insights into the pathogenesis of hormone-related malignancies suggest a possible association between the use of FDs and the risk of specific cancers, this has not been convincingly demonstrated in epidemiologic studies. With regard to cancer risk in relation to the cause of subfertility, the only consistent association observed is an increased risk of endometrial cancer for women with subfertility due to hormonal disorders. While positive findings in some studies on FDs and ovarian cancer risk have aroused serious concern, the associations observed in most of these reports appear to be due to bias or chance rather than being causal. The most important sources of bias are inadequate confounder control for both parity and causes of subfertility. CONCLUSIONS: To discriminate between the possible carcinogenic effects of various ovulation induction regimens, subfertility disorders, and reproductive characteristics associated with subfertility, future studies should include large populations of subfertile women with sufficient follow-up time. In such cohort studies the cause of subfertility should be measured adequately (based on medical records) and information about reproductive characteristics should be collected for all cohort members. Such studies should also include a group of subfertile women with an indication for FD use but not so treated.

Adolescent↗
PubMed2001

Ovulation induction and risk of endometrial cancer: a pilot study.

OBJECTIVE: To determine whether women with endometrial carcinoma are more likely to have been exposed to fertility drugs, in particular clomiphene, than healthy population controls. STUDY DESIGN: A nationwide case-control, pilot study. About 128 living women 35-64 years old, with a histologically confirmed diagnosis of endometrial carcinoma that was first diagnosed and reported to The Israel Cancer Registry between 1 January 1989 and 31 December 1992 were enrolled. The controls were 255 women from the same dialing areas selected by random digit dialing. A variety of demographic and clinical parameters were compared between cases and controls. A multivariate logistic model, controlling for age, was used to assess the independent effects of factors found to be significantly associated with endometrial cancer on univariate analysis. RESULTS: About 7 women with endometrial carcinoma (5.5%) and 10 healthy controls (3.9%) reported that they had used any fertility drug (crude odds ratio (OR) 1.4; 95% confidence interval (CI) 0.47-4.2). Use of fertility drugs did not meet the criteria for entry into the logistic model. The following parameters were found to be independently associated with endometrial cancer controlling for age, European-American background OR=2.2, (95% CI 1.3-3.7, P=0.004); nulliparity OR=2.7 (95% CI 1.1-6.5, P=0.03); history of infertility OR=1.8 (95% CI 1.0-3.3, P=0.05); BMI> or =27 OR=2.3 (95% CI 1.4-3.9, P=0.001). The use of oral contraceptives and IUD were found to be protective, OR=0.29 and 0.37, respectively, (95% CI 0.14-0.61, P=0.001 and 0.19-0.70, P=0.003, respectively). CONCLUSIONS: We found no evidence that the use of ovulation induction agents, including clomiphene citrate, are associated with a higher risk of endometrial carcinoma. The association between infertility drugs and endometrial carcinoma should be examined in other, larger studies.

Case-Control Studies↗
PubMed2007

Why does ovarian surgery in PCOS help? Insight into the endocrine implications of ovarian surgery for ovulation induction in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex disorder with heterogeneity of clinical and endocrine features. Ovarian surgery for ovulation induction has been used in the management of clomiphene citrate-resistant anovulatory women with PCOS. Various types of ovarian surgery have been employed (wedge resection, electrocautery, laser vaporization, multiple ovarian biopsies and others) and all procedures result in an altered endocrine profile after surgery. The mechanism behind the reversal of endocrinological dysfunction in PCOS after ovarian surgery remains incompletely understood. This review scans the literature systematically to identify the endocrine changes after ovarian surgery in PCOS, in order to glean some knowledge of the mechanism involved. After ovarian surgery in PCOS, a rapid reduction in serum levels of all ovarian hormones is seen, in combination with increased serum levels of pituitary hormones. Folliculogenesis is then initiated and ovarian hormone production increases, synchronically with a reduction of pituitary hormones. Continuation of follicle growth in subsequent cycles after ovarian surgery occurs in an environment with less androgens and lower LH and FSH levels compared with pretreatment levels. The endocrine changes found after ovarian surgery in PCOS women seem to be governed by the ovaries themselves. Rapid reduced secretion of all ovarian hormones restores feedback to the hypothalamus and pituitary, resulting in appropriate gonadotrophin secretion. Initiation of follicular development seems to be induced by increasing FSH levels following a reduction of the follicle excess and (intra-ovarian) androgen levels. Additionally, anti-Müllerian hormone and gonadotrophin surge attenuating factor probably have a role in the endocrine changes.

Endocrine System↗
PubMed1991

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.

Adult↗
PubMed1991

Prognostic appraisal of success and failure in an in vitro fertilization program by transvaginal Doppler ultrasound at the time of ovulation induction.

In 323 stimulated cycles of women participating in in vitro fertilization treatment, a transvaginal Doppler examination was performed on the day of ovulation induction to investigate the value of blood flow velocimetry of the uterine artery. The results showed a significantly lower pulsatility index in patients who conceived (n = 42) compared with those who did not become pregnant (n = 272). The differences were especially marked during the first cycles. These results suggest that studies of the uterine hemodynamic response are useful in appraising the likelihood of success of implantation after embryo transfer.

Journal Article↗
PubMed1986

Follicular stimulation versus ovulation induction in juvenile primates: importance of gonadotropin-releasing hormone dose.

We evaluated the dose of GnRH administered by 1-min pulsatile infusion necessary to achieve follicle growth vs. the dose needed for ovulation induction. Doses of 6.0, 0.6, and 0.06 micrograms GnRH were given to juvenile monkeys iv in 1 min once per h for 4 consecutive months. Monkeys receiving hourly 6.0-micrograms doses of GnRH had cyclic elevations of serum estradiol and had menses, but did not ovulate, as evidenced by lack of a corpus luteum at laparoscopy and consistently low progesterone concentrations. These monkeys ovulated only when hCG was administered near midcycle as a surrogate LH surge. In contrast, monkeys receiving 0.6-microgram doses of GnRH frequently had normal ovulatory menstrual cycles and characteristic elevations of progesterone during the luteal phase. Typically, juvenile monkeys receiving hourly 0.06-microgram doses of GnRH initially had development of a dominant follicle contemporaneous with a rise of serum estradiol, but never ovulated or had any subsequent follicular growth or elevated steroidogenic activity. In summary, ovarian follicular development and steroidogenesis in juvenile monkeys can be initiated by doses of GnRH ranging from 0.06-6.0 micrograms/h, although spontaneous ovulation and normal luteal function occurred frequently only with the 0.6 micrograms/h pulses of GnRH. Thus, the dose range of pulsatile GnRH needed for follicle growth is much broader than that required for induction of ovulatory menstrual cycles.

Animals↗
PubMed1984

The role of subcutaneous luteinising hormone releasing hormone in the induction of ovulation.

Induction of ovulation using pulsatile luteinising hormone releasing hormone (LHRH) has been performed in 53 anovulatory women who had previously failed to respond to clomiphene. Pelvic ultrasound imaging prior to treatment provided an accurate means of predicting the subsequent response to subcutaneous and intravenous therapy and was of particular value in differentiating patients with ovarian enlargement due to multiple intraovarian follicles. Subcutaneous administration was appropriate in the majority of patients. Thirty-eight conceptions have been confirmed.

Adult↗
PubMed1977

[Ovulation induction by cyclofenil (author's transl)].

The ovulation-inducing action of cyclofenil was investigated in 135 sexually mature women aged 20--35 years. The patients were only included in the trial if no ovulation in 2 consecutive cycles with the following criteria: basal temperature, cervix score, ascorbic acid retention, basophil count, serum hormone levels, e. g. LH and progesterone and the estrogens in the 24-hour urine could be determined. Ovulation was only considered to have occurred when all the parameters named indicated it. The lack of ovulation was accompanied by amenorrhea in 21 of the 135 patients. The ovulation rate in the 241 cycles observed was 101, corresponding to 42%. In the 114 patients with anovulatory cycles, the ovulation rate in the 184 cycles observed was 95, corresponding to 50%. In the 21 amenorrheic patients, ovulation occurred 6 times in the 57 cycles observed. Nausea or vomiting occurred as side effects in only 2 cases.

Adult↗
PubMed2000

The role of gonadotropins in follicular development and their use in ovulation induction protocols for assisted reproduction.

During the 1960s, hypogonadotropic patients with polycystic ovary syndrome and those with clomiphene citrate resistance were the first to achieve pregnancy after urinary human menopausal gonadotropin (hMG) administration plus preovulatory human chorionic gonadotropin injection, with cumulative pregnancy rates ranging from 40% to 80% after six to 12 treatment cycles. Ever since, dramatically more progress has been achieved regarding methods and medication in assisted conception techniques, involving both a rapidly increased number of subfertile couples, as well as many practitioners in obstetrics and gynecology. The purpose of this review was to highlight the most crucial historical steps of this remarkable process, by emphasizing the role of gonadotropins in ovulation induction protocols according to the various clinical categories of subfertile patients. In the late 1970s, urinary hMG was the most widely used gonadotropin for ovarian stimulation during in vitro fertilization-embryo transfer for assisted reproduction. The often concurrent problems of premature luteinizing hormone (LH) surges and premature luteinizations, and thus cancellations of the cycles, were efficiently overcome by 'reversible medical hypophysectomy', performed by gonadotropin releasing hormone (GnRH) analogs, introduced in 1982. According to its initiation and duration, GnRH analog use was divided into three protocols: the long, most widely used, protocol, which was the best for suppression of endogenous, high tonic LH levels, especially in polycystic ovary syndrome and normogonadotropic patients; and the short and ultra-short protocols, which were mainly used in poor responders to ovarian stimulation treatment, older or hypergonadotropic patients with ovarian failure, because of the well-known 'flare-up phenomenon'. Recently, GnRH antagonists, which directly do not permit GnRH action by binding to the GnRH gonadotropic cell receptors, have been used, but no final results from large, multicenter clinical trials that are still being undertaken have yet been achieved. Various sub-products of urinary hMG have been produced since the 1980s, with the intention of eliminating most or all of the LH, such as a form with a 3:1 proportion ratio between follicle stimulating hormone (FSH) and LH, as well as a form resulting in the removal of almost all of the LH, the 'pure' urinary FSH. Finally, in the mid-1990s, recombinant pure FSH was produced in vitro from hamster ovarian cell cultures. The theoretical basis for the broad use of pure urinary FSH and recombinant FSH is that the very low endogenous LH levels after pituitary desensitization are sufficient for proper theca steroidogenesis; still, data in the literature and clinical experience may be controversial upon that issue. From the clinical point of view, clinicians nowadays tend to stimulate polycystic ovary syndrome patients with recombinant FSH plus the application of GnRH analogs in a long protocol. However, in poor responders, patients in whom ovulation is resistant to clomiphene citrate, those older than 40 years or hypergonadotropic patients with ovarian failure, urinary hMG, because endogenous LH levels are obviously not sufficient for proper steroidogenesis in the theca cells of the follicles of these patients, is necessary in add to the administration of GnRH analogs in a short or ultra-short protocol. Regarding normogonadotropic women (the majority of patients), most authors agree with the long-protocol application of GnRH analogs. In these patients, it is not certain whether recombinant FSH alone is sufficient for the best possible induction or whether exogenous LH administration in the form of urinary hMG still remains necessary.

Female↗
PubMed1998

Multinucleation in normally fertilized embryos is associated with an accelerated ovulation induction response and lower implantation and pregnancy rates in in vitro fertilization-embryo transfer cycles.

OBJECTIVE: To determine if multinucleation in normally fertilized embryos is indicative of poor developmental or clinical pregnancy prognosis and to examine the ovulation induction characteristics associated with multinucleation. DESIGN: Retrospective review. SETTING: A tertiary care institution. PATIENT(S): Patients undergoing IVF-ET cycles (exclusive of other assisted reproductive technologies). MAIN OUTCOME MEASURE(S): Cycles in which embryos had at least 1 multinucleated blastomere were compared with cycles in which all blastomeres exhibited no nucleus or a single nucleus (control). RESULT(S): When >50% of transferred embryos contained multinucleated blastomeres there was a significant reduction in implantation (3.4% vs. 14.7%), clinical pregnancy (9.1% vs. 29.1%), and live birth rates (7.5% vs. 27.6%) when compared with transfers of control embryos. In conjunction with this finding, multinucleate cycles had higher E2 levels and more follicles on the day of hCG administration, a higher number of oocytes retrieved, a higher fertilization rate, and more embryos transferred per patient than did the cycles that produced control embryos. When multinucleated embryos were present, but not transferred, the developmental capacity of the sibling embryo was reduced. CONCLUSION(S): The evaluation of nuclear status using simple light microscopy is predictive of embryo developmental capacity and should be included in the embryo scoring system. The presence of multinucleated blastomeres in normally fertilized embryos is associated with a more effusive response to gonadotropin therapy and is indicative of a poor developmental outcome and lower clinical pregnancy rates.

Adult↗
PubMed2000

Ovulation induction for polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the commonest cause of anovulatory infertility. Various factors influence ovarian function, and fertility is adversely affected by an individual being overweight or having high serum concentrations of LH. Strategies to induce ovulation include weight loss, oral anti-oestrogens (principally clomiphene citrate), parenteral gonadotrophin therapy and laparoscopic ovarian surgery. There have been no adequately powered randomized studies to determine which of these therapies provides the best overall chance of an ongoing pregnancy. Women with PCOS are at risk of ovarian hyperstimulation syndrome (OHSS) and so ovulation induction has to be monitored carefully with serial ultrasound scans. The recognition of an association between hyperinsulinaemia and PCOS has resulted in the use of insulin sensitizing agents, such as metformin, which appear to ameliorate the biochemical profile and improve reproductive function.

Journal Article↗
PubMed1986

The value of the cervical score in monitoring ovulation induction for in vitro fertilization: a prospective double-blind study.

The present study was designed to determine the accuracy of the cervical score for the timing of human chorionic gonadotropin (hCG) administration in in vitro fertilization patients compared to the timing of hCG administration based upon estradiol and ultrasound measurements. Forty-two patients undergoing ovulation induction with human menopausal gonadotropin (hMG)/hCG for in vitro fertilization were studied. A total of 192 cervical scores was obtained together with plasma estradiol levels and pelvic sonography. hCG was given based on estradiol and ultrasound results without knowing the cervical score. An independent decision to give hCG was made based on the cervical score only following a mean of 2.5 days of a cervical score of 9-12 without the examiner's knowledge of estradiol and ultrasound results. This decision was theoretic and was not considered for the actual timing of hCG. In 16 (38%) of the cases this decision coincided with that based on estradiol and ultrasound. In 24 (57%) of the cases there was a 1-day gap. A direct correlation was found among the cervical score, the plasma estradiol concentration, and the mean diameter of the two leading follicles (P less than 0.001). The overall distribution of the cervical score grouped according to estradiol levels (less than 200, 201-400, and greater than 401 pg/ml) was significantly different (P less than 0.001). The proportion of "mature" cervical scores (score of 11-12) in the three different estradiol groups was 15.6, 34.5, and 68.0%, respectively. In conclusion, independent decisions to give hCG based on cervical score or estradiol and ultrasound were coincident +/- 1 day in 95% of the cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Cervix Uteri↗