Zeev Shoham

Results of ovulation induction using human menopausal gonadotropin or purified follicle-stimulating hormone in hypogonadotropic hypogonadism patients

Objective To compare ovarian performance and hormonal levels, after ovulation induction, in patients with isolated hypogonadotropic hypogonadism, using two different gonadotropin drugs. Design Patients were treated during consecutive cycles, using the same stimulation protocol, with human menopausal gonadotropin (hMG) in the first treatment cycle and purified follicle-stimulating hormone (FSH) in the second one. Setting Specialist Reproductive Endocrine Unit. Patients, Participants Nine patients with isolated hypogonadotropic hypogonadism. Main Outcome Measure Duration of stimulation, number of leading follicles, serum estradiol (E 2 ) concentration and endometrial thickness at the time of human chorionic gonadotropin administration, and the occurrence of ovulation. Results Compared with hMG, treatment with purified FSH required significantly more ampules of drug ( P P 2 concentrations ( P P P Conclusion This study in isolated hypo gonadotropic hypogonadism patients is consistent with the two-cell two-gonadotropin hypothesis, that both gonadotropins are required to accommodate their synergistic action for appropriate steroidogenesis. In treating this group of patients, the superior efficacy of hMG compared with purified FSH preparation is beyond question.

Luteinizing hormone : its role, mechanism of action, and detrimental effects when hypersecreted during the follicular phase

OBJECTIVE To review studies that have examined the role of LH, its mechanism of action, and its detrimental effects when hypersecreted during the follicular phase. DESIGN Important published studies related to this topic were identified through a computerized bibliographic search. PATIENTS, PARTICIPANTS Review of the need for LH during the follicular phase is based on animal models and women with hypogonadotropic hypogonadism. The association of hypersecretion of LH during the follicular phase with low rates of fertilization and high rates of pregnancy loss is based on clinical studies conducted in patients treated by IVF and ET and by induction of ovulation. The possible mechanism by which the effects occur is based on in vitro studies. RESULTS The results of the studies cited in this review are consistent with the two-cell two-gonadotropin hypothesis implying that synergistic action of both FSH and LH is required for appropriate steroidogenesis. It also seems that, whatever the underlying mechanism, a raised serum LH concentration during the follicular phase confers a substantial risk of infertility and early pregnancy loss. CONCLUSION By reviewing the literature it appears that LH exhibits an important role in the development of the growing follicle and maturation of the oocyte. It also seems that hypersecretion of LH during the follicular phase implies adverse effects on the fertility process. To further test this hypothesis, we now need systemic assessment of the methods of therapy used for treating patients with polycystic ovary syndrome, in relation to LH secretion and outcome of pregnancy.

Intravenous albumin for the prevention of severe ovarian hyperstimulation syndrome in an in vitro fertilization program : a prospective, randomized, placebo-controlled study

OBJECTIVE To evaluate the efficacy of i.v. administration of human albumin solution for the prevention of severe ovarian hyperstimulation syndrome (OHSS). DESIGN A prospective, randomized, placebo-controlled study comparing the effects of i.v. administration of human albumin solution versus sodium chloride 0.9% solution at the time of oocyte retrieval with patients undergoing IVF-ET who are at high risk for the development of severe OHSS. SETTING Specialized assisted reproduction unit. PATIENTS Thirty-one patients undergoing IVF-ET who had serum E2 levels of 1,906 pg/mL (> 7,000 pmol/L) and multiple follicular development on the day of hCG administration. INTERVENTIONS After hCG administration, patients were randomized to receive i.v., either 50 g of human albumin diluted in 500 mL of sodium chloride 0.9% or 500 mL of sodium chloride 0.9% at the time of oocyte retrieval. MAIN OUTCOME MEASURES Ovarian size as measured by pelvic ultrasonography, development of ascites, serum E2 concentrations during the luteal phase, and results of the IVF-ET cycles. RESULTS Although no patient who had received human albumin solution developed severe OHSS, there were four such cases in the control group. All four were hospitalized with marked ascites and ovarian enlargement. There were no significant differences between the two groups comparing serum E2 levels on the day of hCG administration and during the luteal phase, the number of oocytes retrieved, fertilization, and pregnancy rates. CONCLUSIONS Our preliminary results suggest that the administration of human albumin solution may help to prevent the development of severe OHSS in high-risk patients. Further research is needed to assess the potential of this novel approach.

Polycystic ovarian syndrome: safety and effectiveness of stepwise and low-dose administration of purified follicle-stimulating hormone.

OBJECTIVE An attempt to induce ovulation with a single dominant follicle in polycystic ovarian syndrome (PCOS) patients. DESIGN Comparing ultrasound and estradiol (E2) measurements during treatment with a low-dose protocol (using purified follicle-stimulating hormone, starting with 75 IU/d and increasing every 7 days by 37.5 IU/d) with those obtained following treatment with a conventional protocol using the same drug. SETTING Specialist Reproductive Endocrine Unit. PATIENTS PARTICIPANTS: Eight PCOS patients of whom six had failed to respond adequately to the conventional protocol. MAIN OUTCOME MEASURE Rate of cancellation of cycles, number of leading follicles, and serum E2 concentration at the time of ovulation. RESULTS Treatment with the low-dose protocol resulted in a significant reduction in the number of leading follicles (P less than 0.04), serum E2 concentrations (P less than 0.0002), and a higher rate of ovulation. As a result, five patients conceived compared with none in the conventional protocol. CONCLUSION Using the low-dose protocol permitted induction of ovulation safely and successfully in a selected group of PCOS patients who were previously difficult to treat with the conventional ovulation induction protocol.

Epidemiology, etiology, and fertility drugs in ovarian epithelial carcinoma: Where are we today?

OBJECTIVE To review studies that have examined the epidemiology and etiology of the development of epithelial carcinoma of the ovary. DATA IDENTIFICATION Important published studies related to the topic were identified through a computerized bibliography search. CONCLUSION A review of the literature reveals that the etiology of epithelial ovarian cancer is probably multifactorial and that genetic, environmental, hormonal, and viral factors appear to be directly or indirectly related to the development of the disease. An attempt to implicate specific agents has not produced conclusive results. However, based on large epidemiologic studies, it seems that there is a clear trend of decreasing risk with increasing number of pregnancies, deliveries, use of oral contraceptives, and the duration of breast feeding. An increased risk was found to be associated with ovarian dysfunction leading to infertility and exposure to asbestos and talc. The recent observation that infertile women who used fertility drugs might experience an increased risk for the development of epithelial ovarian cancer should be examined very carefully because of the small number of patients in the study, lack of appropriate information about the type of infertility, drugs used, dosage, and duration of treatment. Because there are no screening tests that are consistently accurate enough to detect ovarian cancer at an early stage, translating the current information into disease prevention requires careful clinical evaluation with a routine follow-up of patients at risk.

HORMONAL PROFILES FOLLOWING CLOMIPHENE CITRATE THERAPY IN CONCEPTION AND NONCONCEPTION CYCLES

The hormonal profiles following clomiphene citrate (CC) administration during a single cycle were compared in infertile women who conceived and in those who did not. Of 41 treated patients, ovulation was assumed to have occurred in 28 and was confirmed by clinical pregnancy in five. In the 28 women who presumably ovulated, two distinct patterns of hormonal secretion were observed. A normal response was exhibited by 17 patients (including the five who became pregnant). The other 11 patients exhibited an abnormal response, characterized by significantly higher luteinizing hormone (LH)/follicle‐stimulating hormone (FSH) ratios than in the normal response group from day 9 until the occurrence of the LH peak (days 9 and 10, P > 0.05; days 11 and 12, P > 0.001), and significantly higher oestradiol (E2) levels throughout the cycle (P > 0.01). In addition, in comparison with the normal response group their LH levels during the follicular phase were significantly higher (P > 0‐05) but their LH peaks at ovulation were significantly lower (P > 0.02). Moreover, their progesterone levels, in contrast to those in the normal response group, began to increase prior to the LH peak and remained high during the early and mid‐luteal phases. None of the women who exhibited this abnormal gonadotrophin response to CC therapy achieved a clinical pregnancy. Exposure to high LH levels in the follicular phase following CC therapy seems to reduce the rate of fertilization and/or to contribute to early embryonic loss.

The luteinizing hormone surge—the final stage in ovulation induction: modern aspects of ovulation triggering

OBJECTIVE To compile updated information regarding gonadotropin secretion, specifically the physiology of the midcycle LH surge, in natural cycles and under various ovulation induction protocols. DATA IDENTIFICATION AND SELECTION Studies that deal with the clinical aspects of LH surge manipulation or substitution were identified through literature and Medline searches. RESULTS Three major regulatory factors have been identified as participants in the induction of the midcycle gonadotropin surge. These are hypothalamic GnRH secretion, ovarian and adrenal steroids, and less well-characterized ovarian peptide hormones. Gonadotropin-releasing hormone pulsatility is regulated by a complex mechanism that integrates multiple neurotransmitters and sex steroids. Estradiol plays a central role in the pituitary secretion of LH, which also is influenced by P concentrations. Gonadotropin surge attenuating factor also has been implicated in the regulation of timing and amplitude of the LH surge. Human chorionic gonadotropin is used extensively as a LH surrogate, but its use is associated with a number of disadvantages. Induction of an endogenous LH surge through use of the flare effect of GnRH analogues has been examined more recently and has been found to have several advantages. Recombinant human LH is in the final stages of clinical testing. CONCLUSION Although much is known about the physiology of the midcycle LH surge and its variations under different clinical conditions, new approaches to the induction or substitution of the LH surge currently are being examined and learned. The introduction of recombinant gonadotropins into clinical practice is likely to influence ovulation induction and IVF practice to a significant degree in the near future.

Ovarian carcinoma during pregnancy: A study of 23 cases in Israel between the years 1960 and 1984

Data from a study on malignant ovarian tumors in pregnancy in Israel are presented. During the 25-year period of the survey, 23 new cases of malignant ovarian tumors during pregnancy were diagnosed, representing an incidence of 0.12/100,000 females over the age of 14; over half of the patients were in their third decade of life at the time of diagnosis of the tumor. Ovarian malignant tumors during pregnancy are more prevalent in Jewish women of European-American origin than in those of Asian-African descent. Borderline carcinomas were found in 35% of our patients; epithelial invasive tumors were found in 30%; the other tumors were dysgerminoma (17%), granulosa cell tumor (13%), and undifferentiated carcinoma (5%). Most of the patients (74%) were diagnosed in stage I. In three cases, ovarian cancer was diagnosed during surgery for tubal pregnancy, and in two during cesarean section at term. In early-stage disease and low-potential-malignancy tumors, surgery can be conservative; thus, 14 of 23 bore a live child. In advanced disease, aggressive surgery, chemotherapy, and/or radiotherapy should be instituted. Factors affecting prognosis were age of patient, histologic type of tumor, and clinical stage of disease. Overall, the survival is much better than that for ovarian tumors in general, because most of the tumors are of low potential malignancy and are diagnosed at an early stage.

Is it possible to run a successful ovulation induction program based solely on ultrasound monitoring? The importance of endometrial measurements

OBJECTIVE To attempt the monitoring of ovulation induction solely with ultrasound (US). DESIGN Using serial US measurements to monitor ovulation induction using human menopausal gonadotropin and human chorionic gonadotropin (hCG), in comparison with estradiol (E2) concentrations that became available at the end of each cycle. SETTING Specialist Reproductive Endocrine Unit. PATIENTS, PARTICIPANTS Twenty hypogonadotropic and 29 ultrasonically diagnosed polycystic ovary patients. MAIN OUTCOME MEASURE Follicular growth, uterine measurements, endometrial thickness, and serum E2 concentrations. RESULTS Follicular growth, uterine measurements, and endometrial thickness correlated strongly with E2 concentrations (P less than 0.0001). The endometrium on the day of hCG administration was significantly thicker (P less than 0.01) in the conception (n = 27) compared with the nonconception cycles (n = 87), whereas no significant difference were observed in serum E2 concentrations. No pregnancy was observed when hCG had been administered when the endometrial thickness was less than or equal to 7 mm. Midluteal endometrial thickness of greater than or equal to 11 mm was found to be a good prognostic factor for detecting early pregnancy (P less than 0.008). CONCLUSIONS Serial US examinations used alone have proven to be safe and highly efficient. It also has a unique ability to detect pregnancy in the midluteal phase.

Cotreatment with growth hormone for induction of spermatogenesis in patients with hypogonadotropic hypogonadism

Objective To induce spermatogenesis by cotreatment with growth hormone (GH) and gonadotropin therapy in patients with hypogonadotropic hypogonadism who had failed to respond adequately to conventional treatment. Design Cotreatment with GH (4 IU) and human menopausal gonadotropin, 150IU of follicle-stimulating hormone and 150IU of luteinizing hormone (LH), three times a week, and human chorionic gonadotropin, 2,500 IU, two times a week for 24 weeks after unsuccessful treatment for 12 weeks with either pulsatile LH-releasing hormone or gonadotropins. Setting Specialist Reproductive Endocrine Unit. Patients, Participants Seven patients, four of whom had failed to respond adequately to the conventional treatment. Main Outcome Measures Serum testosterone (T), estradiol, and sperm production, testicular and semen volume, and serum insulin-like growth factor-I and inhibin concentrations. Results Of the four patients who received cotreatment with GH, three increased T secretion (>11 nmol/L) within a relatively short period of time, two produced adequate amount of sperm (13 and 12 × 10 6 /mL), and one of them impregnated his wife. One patient did not respond. Conclusion The results offer a new approach to the problem of induction of spermatogenesis in patients who respond poorly to conventional treatment because cotreatment with GH enhanced T secretion and sperm production in a relatively short period of time.