The effect of Covid-19 mRNA vaccine on serum anti-Müllerian hormone levels.

STUDY QUESTION: Does the administration of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine have an association with ovarian reserve as expressed by circulating anti-Müllerian hormone (AMH) levels? SUMMARY ANSWER: Ovarian reserve as assessed by serum AMH levels is not altered at 3 months following mRNA SARS-CoV-2 vaccination. WHAT IS KNOWN ALREADY: A possible impact of SARS-CoV-2 infection or vaccination through an interaction between the oocyte and the somatic cells could not be ruled out, however, data are limited. STUDY DESIGN, SIZE, DURATION: This is a prospective study conducted at a university affiliated tertiary medical center between February and March 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study population included reproductive aged women (18-42 years) that were vaccinated by two Pfizer-BioNTech Covid-19 vaccines (21 days apart). Women with ovarian failure, under fertility treatments, during pregnancy, previous Covid-19 infection or vaccinated were excluded from the study. Blood samples were collected for AMH levels before the first mRNA vaccine administration. Additional blood samples after 3 months were collected for AMH and anti-Covid-19 antibody levels. Primary outcome was defined as the absolute and percentage change in AMH levels. MAIN RESULTS AND THE ROLE OF CHANCE: The study group consisted of 129 women who received two mRNA vaccinations. Mean AMH levels were 5.3 (±SD 4.29) µg/l and 5.3 (±SD 4.50) µg/l at baseline and after 3 months, respectively (P = 0.11). To account for possible age-specific changes of AMH, sub-analyses were performed for three age groups: <30, 30-35 and >35 years. AMH levels were significantly lower for women older than 35 years at all times (P = 0.001 for pre and post vaccination AMH levels versus younger women). However, no significant differences for the changes in AMH levels before and after vaccinations (Delta AMH) were observed for the three age groups (P = 0.46). Additionally, after controlling for age, no association was found between the degree of immunity response and AMH levels. LIMITATIONS, REASONS FOR CAUTION: Although it was prospectively designed, for ethical reasons we could not assign a priori a randomized unvaccinated control group. This study examined plasma AMH levels at 3 months after the first vaccination. It could be argued that possible deleterious ovarian and AMH changes caused by the SARS-CoV-2 mRNA vaccinations might take effect only at a later time. Only longer-term studies will be able to examine this issue. WIDER IMPLICATIONS OF THE FINDINGS: The results of the study provide reassurance for women hesitant to complete vaccination against Covid 19 due to concerns regarding its effect on future fertility. This information could be of significant value to physicians and patients alike. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by Sheba Medical Center institutional sources. All authors have nothing to disclose. TRIAL REGISTRATION NUMBER: The study protocol was approved by the 'Sheba Medical Center' Ethical Committee Review Board (ID 8121-21-SMC) on 8 February 2021 and was registered at the National Institutes of Health (NCT04748172).

Ovarian stimulation: is there a long-term risk for ovarian, breast and endometrial cancer?

Adverse effects have been related to infertility treatments. Infertility in general, and female infertility in particular, is a well established risk factor for cancer development, especially ovarian, breast and endometrial cancer. This article addresses the possible association between infertility and cancer development, with an emphasis on the influence of infertility treatments, through a meticulous search of the literature published thus far. While results regarding the possible association of infertility, ovulation induction medications and invasive ovarian cancer show no increased risk and are reassuring, results for increased risk for breast cancer and endometrial cancer following exposure to ovarian stimulation medications are inconclusive. Larger population studies with longer periods of follow-up and better adjustment for confounding factors are needed.

MRgFUS for pain relief as palliative treatment in recurrent cervical carcinoma: a case report.

INTRODUCTION: Focused ultrasound under real-time MR guidance and control (MRgFUS) can be used for the thermal ablation of tissue. Currently this technique is used clinically for the noninvasive treatment of uterine leiomyomas and is in clinical evaluation for breast cancer, adenomyosis and other indications. MRgFUS is being tested for pain relief in patients suffering from bone metastases. This is the first case to report on MRgFUS for pain relief in patients suffering from recurrent cervical carcinoma. CASE REPORT: A 29-year-old patient with recurrent squamous cell carcinoma of cervix following radical hysterectomy, chemotherapy and radiation was treated by MRgFUS due to pelvic mass unresponsive to conventional treatment that caused intractable pain. Following two treatments the patient experienced a marked reduction in pain and increase in Karnovsky Performance Status (KPS) from 50% to 80%. DISCUSSION: Palliative treatment of pain with noninvasive MRgFUS in cases of recurrent cervical carcinoma may be a safe and efficient alternative to other invasive techniques.

Clinical improvement and shrinkage of uterine fibroids after thermal ablation by magnetic resonance-guided focused ultrasound surgery.

OBJECTIVE: Hysterectomy or myomectomy are the accepted treatments for symptomatic uterine fibroids. Heat ablation of uterine fibroids has been shown to be an effective alternative treatment. The aim of this study was to determine the clinical efficacy of non-invasive thermal ablation by transcutaneous magnetic resonance-guided high-intensity focused ultrasound (MRgFUS) for the treatment of symptomatic uterine fibroids. METHODS: In this prospective study, MRgFUS ablation of uterine fibroids was performed in 35 symptomatic women scheduled for hysterectomy. Clinical symptoms, patient satisfaction and uterine size were determined at 1 month and 6 months after the procedure. RESULTS: This outpatient procedure was very well tolerated by all women. Sixty-nine percent (24/35) of the treated patients reported either significant or partial improvement in symptoms. Treated fibroids decreased in volume by 12% and 15% at 1 and 6 months, respectively. Minor transient side-effects were observed in two women. Six women underwent hysterectomy during the follow-up period. CONCLUSION: This study demonstrates the clinical efficacy of MRgFUS ablation of uterine fibroids. This novel, non-invasive surgical approach may offer an alternative therapy for women with uterine fibroids.

Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury.

BACKGROUND: Chemotherapy destroys primordial follicles and can lead to ovarian atrophy. Although reports indicate that apoptosis is the mechanism responsible for follicle loss, additional pathways can be involved. This study investigates the damage in human ovaries after administration of non-sterilizing doses of chemotherapy. METHODS: In a blind study, pathological changes in ovarian tissue harvested for cryopreservation were evaluated. The study group comprised young non-sterile cancer patients, previously exposed to chemotherapy who were (mean +/- SD), when compared with non-exposed patients. RESULTS: Thirty-five cancer patients aged 28.7 +/- 6.74; 17 were previously exposed to non-sterilizing chemotherapy and 18 were not. In all samples, primordial follicles were present. In previously exposed patients, damage to cortical blood vessel and proliferation of small vessels was observed. The cortex showed focal areas of fibrosis with disappearance of follicles (sensitivity 76%, positive predictive value 75% for <37 years old patients). Older patients, not exposed to chemotherapy (5/7) showed similar pathological changes. CONCLUSIONS: Injury to blood vessels and focal ovarian cortical fibrosis are aspects of ovarian damage caused by chemotherapy. These findings indicate a potential additional mechanism of damage to the direct apoptotic effect of chemotherapy on follicles. The possibility that these changes are involved in ageing ovaries should be further investigated.

Elevated day 3 FSH/LH ratio due to low LH concentrations predicts reduced ovarian response.

Adequate ovarian response, essential for successful IVF, cannot be accurately predicted. This study retrospectively reviewed all patients undergoing IVF from 1998 to 2001. Inclusion criteria were age <41 years at treatment onset and a basal day 3 serum FSH concentration <12 IU/l. Women with FSH or=3 in group 1 and <3 in group 2 (controls). Age at treatment initiation, basal serum day 3 FSH and LH concentrations, peak serum oestradiol concentration, number of retrieved and fertilized oocytes and pregnancy rate were analysed. Groups 1 (n = 41, 111 IVF treatment cycles) and 2 (n = 596, 1,434 IVF treatment cycles) were similar in term of woman's mean age. Group 1 had significantly higher mean basal day 3 FSH concentration (P < 0.01) and significantly lower oestradiol concentrations at oocyte retrieval (P < 0.01), mean number of oocytes retrieved and fertilized (P < 0.01) and pregnancy rate (P = 0.016). The same trend persisted after excluding 98 patients with basal FSH concentrations >8 IU/l. In conclusion, elevated day 3 FSH/LH ratio is associated with an inferior outcome in IVF treatment cycles and may be used as an additional predictor for decreased ovarian response.

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.

Pregnancy and live birth after focused ultrasound surgery for symptomatic focal adenomyosis: a case report.

Adenomyosis is a benign disease whose symptoms mimic those of uterine leiomyoma. Hysterectomy is the treatment of choice; conservative surgery is difficult to perform and can damage the uterine structural integrity. We report the case of a 36-year-old woman who had difficulty conceiving because of profuse menometrorrhagia. An 84 cm3 uterine tumour was diagnosed on ultrasonography as leiomyoma, and conservative myomectomy was planned. Magnetic resonance imaging (MRI) corrected the diagnosis to focal adenomyosis. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) destroyed a significant part of the tumour. Following an uncomplicated MRgFUS treatment, a non-perfused volume of 33 cm3 was measured. At 6 weeks, the patient experienced a significant reduction in menometrorrhagia and a marked decrease in tumour size (about 50%). She conceived spontaneously and, after an uneventful pregnancy, gave birth at term to a healthy infant via normal vaginal delivery. No structural uterine abnormality was detected after her delivery. This report highlights the difficult diagnosis and new therapeutic considerations of adenomyosis. MRgFUS seems to have the potential to precisely and effectively treat focal adenomyosis without damage to surrounding healthy myometrium, allowing for normal reproduction. Further studies are needed to assess the overall safety and long-term effectiveness of MRgFUS for the non-invasive treatment of adenomyosis.

First human exposure to FSH-CTP in hypogonadotrophic hypogonadal males.

BACKGROUND: This is the first report of human exposure to the novel compound follicle stimulating hormone (FSH)-C-terminal peptide (CTP) 'FSH-CTP' (Org 36286), a long-acting recombinant FSH like substance, consisting of the alpha-subunit of human FSH and a hybrid beta-subunit. The latter is composed of the beta-subunit of human FSH and the C-terminus part (CTP) of the beta-subunit of human chorionic gonadotrophin (HCG). METHODS: In this phase I, non-blind, multi-centre study, 13 hypogonadotrophic hypogonadal male subjects were enrolled to test the safety of FSH-CTP in terms of antibody formation in humans. Furthermore, the pharmacokinetic profile of this new compound was determined. Subjects were injected four times with 15 microg FSH-CTP with an interval of approximately 4 weeks between each injection. RESULTS: No drug related (serious) adverse events occurred. No antibodies against FSH-CTP or chinese hamster ovary (CHO)-cell derived proteins were detected and measurement of local tolerance demonstrated that s.c. administration of FSH-CTP is well tolerated and no increase in intensity of injection-site responses was observed after repeated exposure to FSH-CTP. After the first and third injection, FSH-CTP serum concentrations were determined. Overall mean (+/- SD) C(max) was 0.426 (+/- 0.116) ng/ml, mean t(1/2) and AUC(0-infinity) were 94.7 (+/- 26.2) h and 81.5 (+/- 18.8) ng.h/ml respectively. Compared with recFSH (Puregon), the half life of FSH-CTP was increased 2-3 times. Following the first and third injection a clear rise in serum inhibin-B concentrations were observed. CONCLUSIONS: The use of FSH-CTP is safe and does not lead to detectable formation of antibodies. Furthermore, the pharmacokinetic and dynamic profile of FSH-CTP may lead to the development of new, more convenient regimens for the treatment of male and female infertility.

Management of women with polycystic ovary syndrome who experienced premature luteinization during clomiphene citrate treatment.

OBJECTIVE: To determine the preferred treatment modality in patients with PCOS who experienced premature luteinization during CC treatment. DESIGN: Prospective randomized study. SETTING: Tertiary medical center. PATIENTS: Twenty-two infertile women with PCOS demonstrating premature luteinization during at least two consecutive CC cycles. INTERVENTIONS: Randomized induction of ovulation either with FSH alone or with GnRH agonist combined with FSH for a single treatment cycle. MAIN OUTCOME MEASURES: Premature luteinization was defined as serum progesterone >1.5 ng/mL before hCG administration. RESULTS: Premature luteinization occurred in eight of the 10 patients (80%) in group A and in two of the 12 patients in group B (16.6%). This result corresponds to the higher mean (+/-SD) progesterone level present in group A patients as compared to those in group B (2.0 +/- 1.2 ng/mL vs. 1.2 +/- 0.6 ng/mL, P=0.03). No pregnancies were achieved in group A, whereas the pregnancy rate per cycle observed in group B was 33.3% (4/12). On the day of hCG administration, the maximum mean (+/-SD) estradiol level was significantly lower (P<0.0001) in group A (210.6 +/- 37.9 pg/mL) than in group B (600.3 +/- 253.8 pg/mL). The treatment duration and the number of FSH ampules used did not differ between the groups. CONCLUSIONS: Pituitary desensitization with GnRH analog in combination with FSH is superior to FSH-only treatment in PCOS patients who demonstrate premature luteinization during CC treatment.

Effects of gonadotrophin-releasing hormone agonists on human ovarian steroid secretion in vivo and in vitro-results of a prospective, randomized in-vitro fertilization study.

The aim of this prospective randomized study was to compare the effects of two gonadotrophin-releasing hormone (GnRH) agonists, buserelin and triptorelin, on human ovarian follicular steroidogenesis, oocyte fertilization and IVF treatment outcome. Ovulatory, healthy women undergoing IVF were treated either with human menopausal gonadotrophin (HMG) alone or with HMG and one of the two GnRH agonists. Serum and follicular fluid hormonal concentrations and cultures of luteinizing granulosa cells obtained during follicular aspiration were analysed. GnRH agonist treatment significantly affected steroidogenesis both in serum and follicular fluid. In follicular fluid, progesterone and oestradiol concentrations were significantly elevated while testosterone concentrations were significantly lower in the triptorelin group. The ratios of testosterone/progesterone, oestradiol/progesterone but not oestradiol/testosterone concentrations were significantly affected by GnRH agonist administration. Similarly, the steroidogenic activity of luteinizing granulosa cells in vitro was significantly decreased in women treated with GnRH agonists. Women treated with GnRH agonists had significantly more fertilized oocytes and cleaving embryos. The results indicate a marked effect of GnRH agonists on the pattern of ovarian follicular steroidogenesis that cannot be explained solely by changes in gonadotrophin concentrations.

Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study.

OBJECTIVE: This study was undertaken to compare the efficacy and safety of intravenous administration of atosiban versus ritodrine for the treatment of preterm labor. STUDY DESIGN: Women with preterm labor and intact membranes diagnosed at 23 to 33 gestational weeks (n = 247) were randomly assigned to treatment arms and received atosiban (6.75 mg intravenous bolus, 300 microg/min for 3 hours, then 100 microg/min intravenously) or ritodrine (0.10-0.35 mg/min intravenously) for as long as 18 hours. Tocolytic effectiveness was assessed in terms of the numbers of women who had not been delivered after 48 hours and after 7 days. Safety was assessed in terms of maternal side effects and neonatal morbidity. Secondary outcomes included mean gestational age at delivery and mean birth weight. An intent-to-treat analysis was performed with the Cochran-Mantel-Haenszel test. RESULTS: The proportion of women who had not been delivered at 48 hours was 84.9% (n = 107) in the atosiban group and 86.8% (n = 105) in the ritodrine group. At 7 days 92 women had still not been delivered in both the atosiban (73.0%) and ritodrine (76.0%) groups. Neither of these differences was statistically significant. The incidence of maternal cardiovascular side effects was substantially lower in the atosiban group (4.0% vs 84.3%, P <.001). In addition, intravenous therapy was terminated more frequently as a result of maternal adverse events in the ritodrine group (29.8%) than in the atosiban group (0.8%). The overall occurrences of fetal adverse events in the two treatment groups were comparable. Neonatal morbidity was similar between the treatment groups after adjustment for unbalanced enrollment of women with multiple pregnancies and for gestational ages within treatment groups. CONCLUSION: Atosiban was comparable in clinical effectiveness to conventional ritodrine therapy but was better tolerated than ritodrine, with no evidence of significant maternal or fetal adverse events. Neonatal morbidity, which was similar between the two treatment arms, was apparently related to the gestational age of the infant rather than to the exposure to either tocolytic agent.

Anti-cardiolipin antibodies in fetal blood and amniotic fluid derived from patients with the anti-phospholipid syndrome.

The aim of this study was to investigate whether, in patients with antiphospholipid syndrome, anticardiolipin antibodies pass from mother to offspring sera and amniotic fluid. Eleven patients with antiphospholipid syndrome (study group) and 11 healthy controls, matched by maternal and gestational age (control group) were prospectively examined for the presence of anticardiolipin antibodies in the cord blood during labour, and amniotic fluid during vaginal or Caesarean delivery. Three neonates (27.3%) in the study group had anticardiolipin antibodies in the cord blood, while none had them in the control group. Anticardiolipin antibodies were detected in the amniotic fluid in six (54.5%) of the study group pregnancies, compared with none in the control group. No adverse neonatal outcome was noted except for significantly lower (P < 0.0006) mean birth weight in the study group. Anticardiolipin antibodies can pass the placenta and be detected in fetal cord blood and amniotic fluid. This finding might be used in the future for the assessment of pregnancies with antiphospholipid syndrome.

Combined somatostatin analog and follicle-stimulating hormone for women with polycystic ovary syndrome resistant to conventional treatment.

This study was undertaken to determine whether somatostatin analog in combination with human urinary follicle-stimulating hormone (FSH) improves ovulatory performance in patients with polycystic ovarian syndrome (PCOS) who failed to respond to FSH alone. A comparative prospective study was performed in six insulin-resistant, hyperandrogenic, PCOS women treated with somatostatin analog combined with FSH for one cycle. Individual ovulatory performance was compared to the cumulative ovulatory response of three previous cycles. Somatostatin analog was administered subcutaneously by means of an infusion pump, providing a total daily dose of 200 micrograms starting from days 1-3 of the cycle. Induction of ovulation with FSH was initiated on day 5 of the stimulated cycle. Vaginal ultrasonography for follicular surveillance was performed before the pump setting and during the treatment cycle. A significant decrease in insulin, insulin-like growth factor (IGF-I), growth hormone (GH) and luteinizing hormone (LH) was observed during the combined somatostatin analog-FSH treatment cycles. The follicular growth patterns and the incidence of ovarian hyperstimulation syndrome (OHSS) was not affected. These observations suggest that adjuvant therapy with somatostatin analog may have a beneficial effect on the hormonal response of PCOS patients to gonadotropin induction of ovulation.

Cancer incidence in a cohort of infertile women.

Among 2,496 infertile Israeli women treated between 1964 and 1974, 143 cancer cases were observed as compared with 116.1 expected (standardized incidence ratio (SIR) = 1.2, 95% confidence interval (CI) 1.0-1.5) through 1991. Site-specific analysis revealed 12 ovarian cancers versus 7.2 expected (SIR = 1.6, 95% CI 0.8-2.9), 21 endometrial cancers versus 4.3 expected (SIR = 4.85, 95% CI 3.0-7.4), and 59 breast cancers versus 46.6 expected (SIR = 1.3, 95% CI 0.96-1.6). Sensitivity analysis revealed that confounding was unlikely to explain the raised risk of endometrial cancer, but nulliparity might explain the increased risk of ovarian cancer. The excess of endometrial cancer was prominent among patients with normal estrogen production but progesterone deficiency (SIR = 9.4, 95% CI 5.0-16.0). The risk for ovarian cancer was similar among the total groups of treated and untreated patients (SIR = 1.7 vs. 1.6). The standardized incidence ratio for endometrial cancer was higher among the treated group than the untreated group, although not significantly. Treatment with ovulation-inducing drugs does not appear to increase the risk for ovarian cancer, but its role cannot be completely excluded.

Adjunctive growth hormone during ovarian hyperstimulation increases levels of insulin-like growth factor binding proteins in follicular fluid: a randomized, placebo-controlled, cross-over study.

GH increases circulating insulin-like growth factor I (IGF-I), which can promote the growth and differentiated function of ovarian granulosa and theca cells. Reported studies of GH as an adjunct to menotropin stimulation in women, largely those with ovarian dysfunction, have not consistently shown a benefit of GH, despite increases in serum and follicular fluid IGF-I. We hypothesized that changes in intrafollicular IGF-binding proteins (IGFBPs), which can antagonize IGF actions on granulosa cells, may underlie the inconsistent effects of GH. In the present study of GH, administered in double-blind, placebo-controlled, cross-over fashion to regularly cycling women undergoing in vitro fertilization, we found that follicular fluid levels of IGFBP-1, -3, and -4 and serum levels of IGFBP-3, as well as follicular fluid and serum IGF-I, were significantly increased in the GH-treated cycles, when compared with the placebo cycle of the same patient. We suggest that the net increase in intrafollicular IGFBPs in GH cycles may mitigate the potential beneficial effect of increased IGF-I.

Outcome of hysteroscopic resection of submucous myomas for infertility.

OBJECTIVE: To examine the reproductive outcome after operative hysteroscopic resection of submucous myomas in women for whom no other infertility factor was identified. DESIGN: Fifteen infertile women with submucous myomas underwent an intensive workup to exclude other causes of infertility. Operative hysteroscopy for resection of the submucous myomas was performed using a rigid 26 French resectoscope (Karl Storz GmbH & Co., Tuttlingen, Germany). SETTING: Academic tertiary referral center. RESULTS: The mean +/- SD duration of the procedure was 25.5 +/- 5.6 minutes. No operative or postoperative complications occurred and all patients were discharged within 6 hours. The follow-up period was 12.0 +/- 4.2 months (mean +/- SD). Seven women conceived (pregnancy rate of 47%) and six of them subsequently delivered at term. CONCLUSION: The results of this study indicate that operative hysteroscopy achieved a pregnancy rate comparable to myomectomy via laparotomy. These results suggest that operative hysteroscopy is the procedure of choice for the resection of submucous myomas in infertile women.

Endogenous catecholamines suppress thyrotropin secretion during the early follicular phase of the menstrual cycle.

The physiological role of hypothalamic catecholamines in the regulation of TSH secretion in humans has not been studied extensively. We administered the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine (AMPT) to five women in the early follicular phase (one of menstrual cycle days 2-5) of the menstrual cycle and compared TSH secretion patterns to those in five women at the same time in the cycle who did not receive AMPT. From 0800-1600 h, volunteers had an i.v. line placed, through which blood was withdrawn every 15 min for TSH and PRL determinations. AMPT (500 mg) was administered to the study group at 0800 h and again at 1000 h. Baseline TSH concentrations at 0800 h were not significantly different between the control and treatment groups. In keeping with its characteristic circadian secretion pattern, TSH in the control group was 1.72 +/- 0.23 mIU/L at 0800 h, declined to 1.02 +/- 0.11 mIU/L by 1600 h, and was significantly less than the 0800 h value at all time points beyond 1115 h. The decline in TSH was observed in all five controls. By contrast, TSH in the AMPT group rose from an 0800 h value of 1.99 +/- 0.09 mIU/L to a peak of 3.30 +/- 0.86 IU/L by 1245 h, and was significantly higher than that at 0800 h in the treated group from 1130-1315 h. The increase in TSH was observed in all five women who received AMPT. There were significant differences between the mean TSH concentrations in the AMPT-treated (2.51 +/- 0.09 mIU/L) vs. the control group (1.28 +/- 0.09 mIU/L; P < 0.0001) for the entire study. The effectiveness of AMPT was demonstrated by an elevation of mean PRL concentrations from a baseline of 16.67 +/- 2.55 micrograms/L to a peak of 138.7 +/- 21.6 micrograms/L. We conclude that endogenous catecholamines tonically inhibit TSH secretion in the early follicular phase. These data suggest modulation of TRH by tuberoinfundibular dopamine at the hypothalamic and/or pituitary level.

The effect of serum follicular phase luteinizing hormone concentrations in habitual abortion: correlation with results of paternal leukocyte immunization.

A prospective study was carried out on 153 couples with recurrent abortions who desired pregnancy. The object was to determine the incidence of raised luteinizing hormone (LH) levels; to compare the outcome of further pregnancies in habitually aborting women with and without raised circulating LH concentrations; and to assess whether the efficacy of paternal leukocyte immunization is affected in the presence of raised LH concentrations. Of the 153 women with recurrent abortions (> 3) included in this study, 56 (36.6%) had follicular phase serum LH concentrations > 10 mIU/ml. Of the 103 pregnancies that were followed prospectively, 65 (63.1%) resulted in a birth of a live infant. There was no significant relationship between the pregnancy outcome and LH concentrations. Women who underwent immunization with paternal leukocytes had significantly more live births (75.8%) than those who were not immunized (43.6%). However, the live birth rate was lower after paternal leukocyte immunization in the presence of raised LH concentrations or a raised LH/follicle stimulating hormone (FSH) ratio.

Induction of aromatase in human granulosa cells by both follicle stimulating hormone and insulin-like growth factor-I involves tyrosine phosphorylation.

Evaluation of the intracellular signalling mechanisms of follicle stimulating hormone (FSH) and insulin-like growth factor-I (IGF-I) was performed in luteinized and non-luteinized human granulosa cells. A severalfold increase in estradiol production from androstenedione was induced by both hormones in these cells, while only FSH led to a concomitant increase in cAMP. IGF-I bound specifically to its receptor in these cells. Specific tyrosine kinase inhibitors (tyrphostins) blocked the effects of both FSH and IGF-I on aromatase activity without altering FSH-induced cAMP accumulation. These findings demonstrate an involvement of a tyrosine kinase pathway in the intracellular signalling mechanism of the IGF-I effect on aromatase activity. Furthermore, since FSH induction of aromatase activity can be blocked by a tyrosine kinase inhibitor without affecting the level of cAMP production, it can be suggested that tyrosine kinase(s) act downstream of cAMP production and protein kinase A activation.