Infertility, ovulation induction treatments and the incidence of breast cancer--a historical prospective cohort of Israeli women.

CONTEXT: Ovulation induction drugs may be associated with increased breast cancer risk. Results so far have been inconclusive. OBJECTIVE: To evaluate the association between infertility, exposure to ovulation induction drugs and the incidence of breast cancer. DESIGN: Historical prospective cohort and nested case-control study. SETTING: Institutional practice PATIENTS: About 5,788 women attending five infertility centers in Israel between 1964 and 1984. INTENTION: Abstracting of medical records and telephone interviews. MAIN OUTCOME MEASURE: Breast cancer incidence was determined through linkage with the National Cancer Registry database. Standardized incidence ratios (SIRs) and 95% confidence intervals were computed by comparing the observed to the expected cancer rates in the general population. In addition, a nested case-control study within the cohort was performed with interviews of breast cancer cases and two matched controls. RESULTS: The study cohort included 120,895 women years of follow-up. Compared to 115.2 expected breast cancer cases, 131 cases were observed (SIR = 1.1; 95% CI 0.9-1.4). Risk for breast cancer was significantly higher for women treated with clomiphene citrate (SIR = 1.4; 95% CI 1.0-1.8). Similar results were noted when comparisons were carried out between treated and untreated women, and when multivariate models were applied. In the nested case-control study, higher cycle index (OR = 2.2; 95% CI 1.0-4.8) and treatment with clomiphene citrate (OR=2.7; 95% CI 1.3-5.7) were associated with higher risk for breast cancer. CONCLUSION: Infertility and usage of infertility drugs in general are not associated with increased risk for breast cancer. However, for infertile women treated with clomiphene citrate, breast cancer risk is elevated.

A case of hypergonadotrophinaemia associated with very high isolated concentrations of immunologically and biologically active luteinizing hormone.

A very rare case of a menstruating infertile woman with isolated luteinizing hormone (LH) hypergonadotrophinaemia is presented. There were no signs indicating the presence of a pituitary microadenoma, and LH had normal bioactivity and normal molecular weight. Likewise, no mutation was detected in the coding region of the LH beta-chain gene. In a non-stimulated cycle and a clomiphene citrate cycle, the patient developed an unruptured cyst. The patient ovulated and conceived twice following the addition of human chorionic gonadotrophin. A partial resistance at the ovarian LH receptor site, perhaps caused by a mutation, is a possible explanation for these findings. Another possibility is a malfunction in the signal transduction system of LH beyond the receptor level.

The effect of the hypoestrogenic state, induced by gonadotropin-releasing hormone agonist, on Doppler-derived parameters of aortic flow.

The effect of the hypoestrogenic state, induced by a GnRH agonist (GnRH-a), on cardiac function in healthy young women, was evaluated by Doppler echocardiography performed before treatment and when serum 17 beta-estradiol levels were suppressed by GnRH-a to 36.7 pmol/L. The following parameters of aortic flow were measured: peak flow velocity, ejection time, and acceleration time. Additional parameters calculated were flow velocity integral, cardiac index, and mean acceleration. The study group included 15 menstruating women, aged 25-42 yr (mean, 33 yr), with symptomatic fibroids, endometriosis, or scheduled for in vitro fertilization, who were treated with a GnRH-a. There were significant decreases in peak flow velocity (99 +/- 11 vs. 86 +/- 11 cm/s; P = 0.0004) and cardiac index (3.0 +/- 0.7 vs. 2.5 +/- 0.5 L/min.m2; P = 0.002). A decrease that did not reach statistical significance was noted in flow velocity integral (18.9 +/- 2.7 vs. 16.5 +/- 3.4 cm; P = 0.07). Mean acceleration was decreased significantly (12.6 +/- 2.6 vs. 10.8 +/- 1.8 m/s.s; P = 0.01), but no significant changes in acceleration time (81 +/- 16 vs. 83 +/- 10 ms; P = 0.7) or ejection time (296 +/- 25 vs. 295 +/- 27 ms; P = 0.8) were observed. These results indicate that estrogen deprivation is associated with smaller stroke volume and flow acceleration and might suggest that hypoestrogenism has a direct effect on cardiovascular performance.

Inhibitory effect of a highly potent antagonist of LH releasing hormone (SB-75) on the pituitary gonadal axis in the intact and castrated rat.

The biological potency of the new, highly potent antagonist [AC-D-Nal (2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10] LH-RH (SB-75) on the pituitary-gonadal system of female castrated and intact ovulating rats was tested. Administration of a single dose (50-100 micrograms/kg BW) of the antagonist SB-75 inhibited effectively the elevated gonadotrophin levels for 48 h. Pituitary LH and FSH content was not affected by SB-75 treatment. When administered in the early afternoon of the proestrus to intact cycling rats, SB-75 blocked the preovulatory LH surge as well as the primary and secondary FSH surges. However, the secondary FSH surge was not affected by SB-75 treatment when administered on the evening of proestrus suggesting its independence from the LH-RH mechanism. A group of ovariectomized rats was chronically treated with D-Trp6-LH-RH after having been pretreated by administration of a single dose of the antagonist. The initial stimulatory release of LH and FSH initiated by injection of the LH-RH agonist was significantly reduced by pretreatment with the LH-RH antagonist. We conclude that the LH-RH antagonist SB-75 may be used effectively in the field of reproductive dysfunction and endocrinological oncology and may become an invaluable physiological probe in studying the hormonal dynamics of the reproductive endocrine axis.

Combined transvaginal tubal catheterization and adhesiolysis of filmy uterine synechiae performed with a newly developed device under the guidance of digital road mapping fluoroscopy.

Transcervical fallopian tube catheterization is rapidly gaining favor as a minimally invasive diagnostic and therapeutic technique. On occasion, the presence of filmy adhesions not identified on HSG obstruct the passage of the cannula to the cornual angle. We describe the design and operative characteristics of a new transcervical adhesiolysis device that if used under the guidance of DRM mapping, can restore the shape of the uterine cavity and allow completion of the procedure during the same session.

Another look at co-treatment with growth hormone and human menopausal gonadotrophins in poor ovarian responders.

The objective of this study was to evaluate whether a combined human growth hormone (HGH) and human menopausal gonadotrophin (HMG) treatment can improve ovulation induction in poor ovarian responders. Ten patients aged 28-43 years and requiring > 25 ampoules of HMG for ovulation were admitted to the study. Pituitary growth hormone reserve was evaluated by clonidine stimulation and insulin tolerance tests before commencement of treatment. The patients underwent one treatment cycle with D-tryptophan-6-luteinizing hormone-releasing hormone (D-Trp6-LHRH) and HMG and another cycle with D-Trp6-LHRH, HMG and HGH. Serum HGH, insulin-like growth factor (IGF)-I and oestradiol were measured throughout the two treatment cycles and follicular maturation was assessed by ultrasonographic studies. All patients tested showed no elevation of their serum HGH concentration during a clonidine test, but showed an adequate response during insulin tolerance tests. No significant difference was found in the number of HMG ampoules, duration of treatment, number of leading follicles, and serum oestradiol concentration between the two treatment cycles. Co-treatment with HGH and HMG did not improve ovarian performance in poor ovarian responders. No correlation was found between the results of HGH pituitary function tests and the ovarian response to gonadotrophins.

Digital road mapping image--a novel fluoroscopic real-time guide for selective transcervical catheterization in the treatment of proximal tubal obstruction.

Ten infertile women 20 to 40 years of age, with a standard HSG diagnosis of unilateral proximal tubal obstruction, underwent a transvaginal catheterization and recanalization of the fallopian tubes. To set a fluoroscopic real-time guidance technique for improving the results of transvaginal catheterization and recanalization of the fallopian tubes and to increase its marginal safety, catheterization was performed under digital road mapping guidance. Transcervical catheterization resulted in an immediate patency of the obstructed tube in all 10 women. Three women conceived 2 to 3 months after the procedure. The improved catheterization technique enables good results in the diagnosis and treatment of proximal tubal obstructions.

Calcium homeostasis, bone metabolism and safety aspects during long-term treatment with a GnRH agonist.

Thirty-five women with symptomatic fibroids were treated with monthly injections of 3.2 mg microcapsulated D-Trp-6-LHRH for 6 months. During treatment serum 17 beta-oestradiol levels decreased, falling to castration levels associated with a reduction in the volume of the fibroids. In 16 patients a complete calcium homeostasis and bone metabolism work-up was carried out during treatment and subsequently for a 6-month follow-up period. Bone mineral content (BMC) and Compton bone densitometry readings remained unchanged. There were significant increases in serum calcium phosphate and alkaline phosphatase concentrations. A slight although not significant increase was observed in osteocalcin and parathyroid hormone (PTH) serum levels. Serum 1,25(OH)2D3 values decreased significantly after 3 months of treatment. Urinary hydroxyproline/creatinine and calcium/creatinine ratios as well as 24-h urinary calcium values increased significantly during the treatment period but decreased rapidly to pretreatment values after 3 months in the follow-up period. The endocrine changes induced by the GnRH-agonist treatment were associated with reversible biochemical signs of increased bone turnover and no significant changes in bone mass, suggesting that the treatment can be administered safely for a period of 6 months in patients with oestrogen-dependent diseases.

Pregnancy outcome following early exposure to maternal luteinizing-hormone-releasing hormone agonist (buserelin).

A human pregnancy exposed to a luteinizing-hormone-releasing hormone agonist (buserelin) in its early stages is reported. The possible mechanisms leading to conception under this mode of treatment and its consequences are discussed.

Induction of ovulation with D-Trp6-LHRH combined with purified FSH in patients with polycystic ovarian disease.

Seventeen patients with polycystic ovarian disease (PCOD) and evidence of mild or severe ovarian hyperstimulation syndrome (OHSS) during therapy with CC/hCG, FSH/hCG or hMG/hCG were treated with D-Trp6-LHRH until medical gonadectomy was attained. Under the suppressive therapy with the GnRH agonist (GnRHa) ovulation was induced with FSH/hCG. In 15 out of 17 patients, ovulatory cycles were obtained with this new modality of treatment. Seven patients conceived (3 viable pregnancies and 4 early abortions) after the 1st treatment cycle. Fourteen of the 17 patients demonstrated symptoms of mild OHSS which did not require hospitalization. Only 1 patient developed severe OHSS after the combined treatment. Our results suggest that therapy with GnRHa, especially in its delayed release formulation, is effective for the prevention of severe ovarian hyperstimulation in PCOD patients undergoing treatment with menotropins for the induction of ovulation.

Diagnosis of a small ovarian tumor (androgen secreting) by magnetic resonance: a new noninvasive procedure.

Virilizing ovarian tumors are rare and establishing their exact location before operation is difficult. We report a case in which a small left ovarian tumor was seen with magnetic resonance imaging.

Sonographic monitoring of ovarian volume during LHRH analogue therapy in women with polycystic ovarian syndrome.

Polycystic ovarian disease is characterized by menstrual disorders, infertility, obesity, and large ovaries. Large ovaries with multiple cysts are the direct cause of the high incidence of ovarian hyperstimulation during ovulation induction. Lately, gonadotropin-releasing hormone (GnRH) analogues have been employed to decrease ovarian steroidogenesis and thus reduce the incidence of ovarian hyperstimulation. In this study the ovarian size was ultrasonographically assessed during chronic GnRH analogue treatment, revealing a significant reduction in ovarian volume. This decrease in volume results in a reduced incidence of hyperstimulation, and we think the ultrasonic scanning can be effectively used to assess the success of GnRH treatment.

Fetal kidney size related to gestational age.

Fetal renal anatomy was assessed in 660 apparently normal fetuses. The problems of technique of visualization of the kidneys are outlined. A correlation of fetal kidney length and gestational age is presented. The results are presented to be used as an adjunct in establishing fetal gestational age, as well as the assessment of normal renal morphology in routine obstetric ultrasound assessment.

The effect of serum prolactin levels on ovarian steroidogenesis.

In order to assess the effect of hyperprolactinemia on ovarian steroidogenetic potential, a group of anovulatory hyperprolactinemic patients and a control group of anovulatory normoprolactinemic women were submitted to exogenous gonadotropin (hMG) stimulation under identical experimental conditions. Serum 17 beta-estradiol (E2) concentrations were determined before and after hMG stimulation. The mean basal serum E2 levels in the hyperprolactinemic group (22.7 +/- 3.3 pg/mL, mean +/- 1 SE) were significantly lower than in the normoprolactinemic control group (48.7 +/- 8.4 pg/mL, P less than .01). A significant negative correlation (r = -.6157, P less than .01) between basal serum E2 levels and basal serum prolactin (hPRL) concentrations was found. Following hMG stimulation, the serum E2 increment (delta E2) from basal E2 levels in the control group (491 +/- 91 pg/mL) was significantly higher than the increment in the hyperprolactinemic group (182 +/- 48 pg/mL, P less than .01), and a significant negative correlation was observed between basal serum hPRL levels and the logarithm of delta E2 (r = -.4744, P less than .05). Our results suggest that chronic hyperprolactinemia induces ovarian refractoriness to exogenous gonadotropin stimulation and substantially reduces its steroidogenetic potential.

Induction of ovulation in amenorrheic patients with gonadotropin-releasing hormone and human menopausal gonadotropin.

In five hypothalamic amenorrhea patients who underwent chronic intermittent gonadotropin-releasing hormone (GnRH) therapy for induction of ovulation, small doses (2 to 4 ampules/day) of human menopausal gonadotropin (hMG) were administered 9 to 32 days after the start of GnRH treatment. In seven treatment cycles, the addition of hMG initiated a sudden rise of 17 beta-estradiol concentrations, followed by a luteinizing hormone and follicle-stimulating hormone surge and ultrasonographic evidences of ovulation. Four of five patients conceived (singleton pregnancies) after the first or second treatment course. There were no clinical signs of ovarian hyperstimulation. Combined therapy of GnRH and hMG may be useful, therefore, for the treatment of hypothalamic amenorrhea patients who demonstrate prolonged follicular phases or luteinized unruptured follicle syndrome under chronic treatment with pulsatile GnRH alone.