Prolonged inhibition of presynaptic catecholamine synthesis with alpha-methyl-para-tyrosine attenuates the circadian rhythm of human TSH secretion.

OBJECTIVE: Originating from the pituitary gland, TSH secretion is regulated predominantly by thyroid-releasing hormone (TRH) neurons located in the hypothalamus. Norepinephrine and dopamine have important effects in modulation of TSH secretion. An inhibitor of catecholamine synthesis, alpha-methyl-para-tyrosine (AMPT) has been used in several studies of the regulation of human TSH secretion. The short-term effects (<8 hours) of low doses of AMPT include stimulation of pituitary TSH secretion by selective lowering of brain dopamine levels. After prolonged administration of AMPT (>24 hours), theoretically both dopamine and norepinephrine levels are lowered significantly in the brain, although this has not been reported previously. METHODS: Nine subjects (five women and four men) received a total of five 1-g doses of AMPT or five 50-mg doses of promethazine (active placebo) over 28 hours in a randomized, double-blind, placebo-controlled crossover design in which the active and control tests were separated by 4-6 weeks. Blood samples were obtained over 24 hours (18 time points) on day 2 of each condition. RESULTS: Changes in prolactin secretion and 6-hydroxymelatonin sulfate excretion indirectly showed the effects of AMPT on dopamine and norepinephrine. The typical circadian rhythm of TSH secretion was blunted by AMPT throughout the night; at ten time points, the difference between the two groups was statistically significant (P <.01). The long-term effects of repeated doses of AMPT were inhibition of TSH secretion and significant attenuation of the circadian rhythm of TSH. Additionally, AMPT induced low norepinephrine levels, which counteracted the stimulatory effect of low dopamine levels on TSH. CONCLUSION: Through its inhibitory effect on TRH, norepinephrine appeared to be involved in the regulation of TSH.

Measuring human chorionic gonadotropin in the absence of implantation with use of highly sensitive urinary assays for intact beta-core and free beta epitopes.

OBJECTIVE: To determine if human chorionic gonadotropin (hCG) can be absorbed from the uterine cavity in the absence of an embryo. DESIGN: Prospective study. SETTING: University-based assisted reproduction program. PATIENT(S): Eight functionally agonadal patients (age range, 33-46 years) who were taking hormone replacement therapy so that they could receive donated oocytes. INTERVENTION(S): Intrauterine instillation of 50 microL of hCG (10,000 IU) during a mock cycle before an attempt at oocyte donation. MAIN OUTCOME MEASURE(S): Spot urine measurements of different hCG epitopes (intact beta, beta-core, and free beta) at timed intervals (12, 20, 44, and 68 hours after instillation). RESULT(S): All hCG epitopes were detected in the urine at the first sampling interval, and levels decreased in subsequent sampling intervals. Measurement of the serum hCG level confirmed that systemic absorption had occurred and that the urine measurements were not a result of specimen contamination through the cervix. CONCLUSION(S): hCG may be systemically absorbed into the blood through the uterine cavity, even in the absence of implantation, and its metabolites may be measured with use of highly sensitive urinary assays.

Bilateral serous cystadenofibromas clinically simulating hyperreactio luteinalis following controlled ovarian hyperstimulation and in vitro fertilization.

We report a case of bilateral serous cystadenofibromas clinically simulating hyperreactio luteinalis during a normal pregnancy resulting from controlled ovarian stimulation and in vitro fertilization. Incomplete regression at 2-year follow-up prompted surgical intervention. This case demonstrates that the clinical and sonographic features that have been associated with hyperreactio luteinalis are not specific for this condition and emphasizes the need for close clinical follow-up in all presumptive cases for which a histologic diagnosis has not been established.

Anesthesia practices in the United States common to in vitro fertilization (IVF) centers.

PURPOSE: Our purpose was to characterize and describe anesthesia practice in programs performing IVF in the United States. METHODS: We used a telephone survey requiring respondents to be either the program director, a physician, or a nurse familiar with the practice. Two hundred seven (78%) Society of Assisted Reproductive Technology (SART) registered programs agreed to participate. Programs were divided by geographic region and type of practice (academic versus private). RESULTS: Ninety-one private (68%) and 41 academic (56%) programs used personnel provided by the Department of Anesthesiology. Conscious sedation was performed most commonly (95%). The remaining 5% used primarily either general, regional, or local anesthesia. Typical recovery times were 90 to 120 min. Average costs of anesthetic administration were $300- $400 and were similar among groups except for the Eastern academic programs, with a higher mean cost of $543. Programs using personnel from anesthesiology reported higher costs compared to programs utilizing their own staff ($391 +/- 15 vs $157 +/- 11; P < 0.05). Complications were infrequent (< 10%); no hospitalizations or serious life-threatening incidents were reported. CONCLUSIONS: A large number of programs safely used their own trained personnel to deliver anesthesia, and realized a significant reduction in cost.

The addition of norethindrone acetate to leuprolide acetate for ovarian suppression has no adverse effect on ovarian stimulation.

PURPOSE: Our goal was to determine if the addition of norethindrone acetate (NETA) to leuprolide acetate (LA) has an adverse effect on controlled ovarian stimulation (COH) during in vitro fertilization (IVF). METHODS: Forty-one consecutive patients undergoing COH and IVF were divided into two groups and evaluated. Group 1 consisted of 18 patients who did not become pregnant following two cycles (one of each protocol). Group 2 consisted of 23 patients who became clinically pregnant following one cycle from either protocol. The standard protocol consisted of LA (1 mg) injected subcutaneously from the first day of menses until day 8 or when ovarian suppression was evident, at which time the dose was halved and COH was initiated. The study protocol was identical except 10 mg of NETA was given orally with LA for the first 8 days. Ovarian stimulation was similar in each protocol. RESULTS: No adverse effect on ovarian stimulation was evident on the addition of NETA to LA. No differences were noted in days of stimulation, peak estradiol (E2) level attained, peak E2-to-oocyte ratio, dosage of exogenous gonadotropins, number of aspirated oocytes, fertilization rate, or oocyte and preembryo quality. CONCLUSIONS: The addition of NETA does not attenuate COH in women undergoing IVF.

Successful pregnancy in a familial Mediterranean fever patient following assisted reproduction.

We conclude that untreated women with FMF have up to a 30% incidence of infertility due to ovulatory dysfunction and peritoneal adhesions. Some of these women conceive during ovulation induction with or without insemination. We have described the first case of a successful and normal pregnancy in a patient with FMF following in vitro fertilization (IVF) while on prophylaxis colchicine therapy after other treatments for infertility were unsuccessful.

Pregnancy in a woman with Turner mosaicism following ovarian stimulation and in vitro fertilization.

We conclude that women with Turner mosaicism (46XX/45XO) and normal FSH levels may have an adequate ovarian reserve and undergo attempts at traditional assisted reproduction. At the time of retrieval an ovarian biopsy may be performed in order to evaluate directly the ovarian karyotype. A successful pregnancy resulted from oocytes retrieved from the gonad demonstrating a normal karyotype.

A combination of norethindrone acetate and leuprolide acetate blocks the gonadotrophin-releasing hormone agonistic response and minimizes cyst formation during ovarian stimulation.

A protocol utilizing both leuprolide acetate (LA) and norethindrone acetate (NETA) in subjects undergoing ovarian suppression prior to follicle aspiration proved more effective than LA alone in reducing the incidence of ovarian cyst formation without affecting clinical outcome. Patients (n = 105) undergoing ovarian stimulation followed by follicle aspiration and in-vitro fertilization (IVF) were prospectively randomized and studied. Study measures included ovarian suppression days, days of human menopausal gonadotrophin (HMG) stimulation, serum oestradiol concentrations, number of cycles developing de novo cysts (>15 mm), number of induced flare responses (day 8 oestradiol >=50 pg/ml), number of office visits, total dose exogenous gonadotrophins, number oocytes retrieved, and clinical pregnancy and delivery rates per retrieval. Patients undergoing IVF received either LA alone (n = 58; controls) or LA and NETA (n = 47; study group) for the first 8 days of their cycle. Results comparing NETA/LA versus LA demonstrated: serum oestradiol 20.7 +/- 3.9 versus 57.3 +/- 9.4 pg/ml respectively on day 8 of ovarian suppression (P P < 0.01); and only three individuals (6.4%) using NETA/LA developed ovarian cysts >15 mm compared to 15 (25.9%) controls (P < 0.01). No differences were observed for days of stimulation, peak oestradiol attained, total dosage of exogenous gonadotrophins, or number of aspirated oocytes. Neither were there differences in the clinical pregnancy (26.8 versus 22.6%) nor in delivery rates (19.5 versus 20. 8%). We conclude that the addition of NETA to LA enhances ovarian suppression and lessens ovarian cyst formation, thereby significantly decreasing the overall cost per cycle.

The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome.

Adrenal hyperandrogenism is a common feature of patients with polycystic ovary syndrome (PCO). This may be due to enhanced adrenal sensitivity to ACTH. Because enhanced ovarian androgen secretion does not appear to explain this phenomenon, we explored the role of estrogen in inducing enhanced adrenal sensitivity, in that a state of relative hyperestrogenism exists in PCO. Eight patients with PCO and seven matched controls received ovine corticotropin-releasing hormone (oCRH; 0.1 micrograms/kg) iv before and after hypoestrogenism was induced by leuprolide acetate (LA; 1 mg, sc, each day). In patients with PCO, a third oCRH test was repeated after transdermal estradiol (E2; 0.1 mg) had been applied for a week, during which time LA was continued. At baseline, patients with PCO had increased responses of 11 beta-hydroxyandrostenedione and dehydroepiandrosterone (P < 0.03 and P < 0.02) and increased delta maximal ratios of androstenedione (A4)/ACTH and dehydroepiandrosterone/ACTH (P < 0.01) after oCRH treatment. After LA administration to patients with PCO, these ratios were significantly suppressed (P < 0.01) and returned to baseline after E2 was added. There were no changes in controls. Steroid ratio responses to oCRH suggested that 17,20-desmolase activity (delta maximum change in the ratio of A4/17-hydroxyprogesterone) was lowered with estrogen suppression and increased again after transdermal E2 administration. There was a significant positive correlation between changes in E2 levels and delta maximum change in the ratios of A4/17-OHP after oCRH treatment, signifying 17,20-desmolase activity (r = 0.58, P < 0.02). In conclusion, these data provide evidence that estrogen is at least one factor that influences adrenal androgen sensitivity in PCO and may help explain the frequent finding of adrenal hyperandrogenism in this syndrome.

High dosages of gonadotropins are associated with poor pregnancy outcomes after in vitro fertilization-embryo transfer.

OBJECTIVE: To compare the pregnancy outcomes during IVF-ET when different dosages of hMG are used after follicular phase suppression with leuprolide acetate (LA). DESIGN: Retrospective chart review. SETTING: Hospital-based IVF-ET program. PATIENTS: From January 1990 to December 1992, 264 cycles reached ET after LA downregulation and gonadotropin stimulation. RESULTS: Higher doses of gonadotropins, as measured by both average daily dose and total dose per cycle, were associated with lower clinical pregnancy rates. This effect was independent of age, basal FSH level, endometrial thickness, maximal E2 levels, number of eggs retrieved, and embryos transferred. CONCLUSION: High dosages of exogenous gonadotropins are associated with lower pregnancy rates in IVF-ET.

A possible bimodal effect of estrogen on insulin sensitivity in postmenopausal women and the attenuating effect of added progestin.

OBJECTIVE: To determine the effects of estrogen and of added progestin on carbohydrate tolerance in postmenopausal women. DESIGN: An insulin tolerance test (ITT) was used to assess insulin resistance in healthy post-menopausal women and to determine the effects of oral estrogen with and without added progestin on insulin sensitivity. SETTING: A menopause research clinic at a University Medical Center. PATIENTS: Fifteen healthy postmenopausal and nine premenopausal women were studied after having not received any hormone preparations for > or = 4 weeks. INTERVENTIONS: All subjects received a baseline ITT and postmenopausal women were then randomized to receive either 0.625 mg conjugated equine estrogen, 0.625 mg conjugated equine estrogen/10 mg progestin, or 1.25 mg conjugated equine estrogen for 2 months at which time a second ITT was performed. In the former two groups the women were treated for an additional 4 months to assess the long-term effects of treatment and had a third ITT performed at the end of 6 months. MAIN OUTCOME MEASURES: Fasting serum insulin and glucose were measured and K(itt) values were obtained at each visit in each group. RESULTS: Forty-four percent of nonobese healthy postmenopausal women were found to have insulin resistance. The three groups differed significantly in their K(itt) responses. Estrogen replacement improved insulin sensitivity (K(itt) increased by 25%). However, 1.25 mg of conjugated equine estrogen caused a 24.7% decrease in K(itt) values and progestins attenuated the beneficial effects of 0.625 mg conjugated equine estrogen from baseline values (K(itt) decreased by 17.0%). Two- and 6-month values did not differ. CONCLUSIONS: Insulin resistance is prevalent in healthy postmenopausal women. A moderate dose of estrogen appears to increase insulin sensitivity but higher doses may attenuate this benefit and progestins may cause a decrease in insulin sensitivity.

Time-resolved fluoroimmunoassay compared with radioimmunoassay of luteinizing hormone.

OBJECTIVE: To determine if fluoroimmunoassay (FIA) of serum luteinizing hormone (LH) is more useful clinically than a conventional radioimmunoassay (RIA) because it has been suggested that FIA closely reflects biological activity. DESIGN: Comparison of serum LH measurements by RIA and FIA during various perturbations in normal ovulatory women and in women with polycystic ovarian syndrome (PCOS). SETTING: Normal ovulatory subjects were healthy volunteers and women with PCOS were untreated and newly diagnosed outpatients in our Reproductive Endocrinology/Infertility Clinic, Women's Hospital, at the Los Angeles County+University of Southern California Medical Center. PARTICIPANTS: Fifty-three normal ovulatory women, ages 20 to 35, and 27 women with PCOS, ages 21 to 35. All were in good health and received no other medications during the study period. RESULTS: Fluoroimmunoassay of serum LH reflected status of known altered bioactivity better than with a conventional RIA. This was most evident during conditions of gonadotropin suppression and in patients with PCOS. An excellent correlation was found between values of FIA and RIA. CONCLUSIONS: The measurement of LH by FIA is clinically useful, specifically when a change in biological activity of LH is sought.

Increased circulating levels of immunoreactive beta-endorphin in polycystic ovary syndrome is not caused by increased pituitary secretion.

OBJECTIVE: Our purpose was to investigate the source and role of elevated levels of immunoreactive beta-endorphin in polycystic ovary syndrome. We wished to determine whether immunoreactive beta-endorphin secretion in patients with polycystic ovary syndrome is influenced by body weight and whether the pituitary release of immunoreactive beta-endorphin with corticotropin-releasing hormone is related to luteinizing hormone levels or adrenal androgen secretion. STUDY DESIGN: Eighteen patients with polycystic ovary syndrome and 10 ovulatory controls were studied. Each subject received 1 microgram/kg intravenous corticotropin-releasing hormone and an oral glucose tolerance test on alternate days. Levels of plasma immunoreactive beta-endorphin, corticotropin, luteinizing hormone, cortisol, adrenal androgens, and insulin were measured. RESULTS: Although immunoreactive beta-endorphin levels were elevated in patients with polycystic ovary syndrome (p < 0.01), incremental responses after corticotropin-releasing hormone were similar to controls and were not influenced by body weight. Serum luteinizing hormone levels were not affected by corticotropin-releasing hormone and did not correlate with immunoreactive beta-endorphin levels. Adrenal androgen responses after corticotropin-releasing hormone were increased in patients with polycystic ovary syndrome (p < 0.01) but were not correlated with immunoreactive beta-endorphin secretion. After oral glucose was given, elevated fasting insulin levels increased significantly in patients with polycystic ovary syndrome (p < 0.01), as did immunoreactive beta-endorphin levels (p < 0.05). The increases in insulin and immunoreactive beta-endorphin levels were correlated (p < 0.05). CONCLUSIONS: Pituitary secretion of immunoreactive beta-endorphin is normal in patients with polycystic ovary syndrome, and pancreatic secretion appears to be increased. Corticotropin-releasing hormone does not influence luteinizing hormone levels, and adrenal androgen sensitivity is not influenced by immunoreactive beta-endorphin secretion.

Estrogen improves psychological function in asymptomatic postmenopausal women.

Estrogen treatment of postmenopausal women has been suggested to improve mood and psychological function. However, this remains controversial because previous studies involved heterogeneous groups, were not double blind, and included women who were also experiencing somatic symptoms that were relieved by estrogen. A randomized double-blind study was carried out comparing the effects of placebo and conjugated equine estrogens (0.625 and 1.25 mg) on psychological function over 3 months in 36 asymptomatic women, aged 45-60. The tests included the Minnesota Multiphasic Personality Inventory-168, the Profile of Adaptation to Life, and the Beck Depression Inventory. Memory was assessed directly by the Wechsler Adult Intelligence Scales, measuring both digit span and digit symbol. All women were well-adjusted psychologically. The income management scale of the Profile of Adaptation to Life improved (P less than .05) with estrogen, as did the Beck Depression Inventory (P less than .05), but these results were not dose-related. Memory assessed prospectively by the Wechsler Adult Intelligence Scales was not affected significantly. These results suggest that estrogen use may improve the overall quality of life in postmenopausal women.

Comparison of intermittent and continuous use of a gonadotropin-releasing hormone antagonist (Nal-Glu) in in vitro fertilization cycles: a preliminary report.

The agonistic effect of the gonadotropin-releasing hormone agonist often necessitates an extended period of treatment, resulting in a longer treatment cycle and increased cost. We have evaluated the intermittent use of a gonadotropin-releasing hormone antagonist, Nal-Glu, and have designed a new, simplified protocol for its use in in vitro fertilization. Seven women who had previously undergone treatment with leuprolide acetate and human menopausal gonadotropins were treated with Nal-Glu. Leuprolide acetate, 1 mg/day subcutaneously, was administered in the midluteal phase until down regulation was achieved (estradiol less than 30 pg/ml). Human menopausal gonadotropins, three to four ampules per day intramuscularly, was administered in conjunction with 500 micrograms subcutaneous leuprolide acetate. In the treatment cycles Nal-Glu (50 micrograms/kg/day) was administered intramuscularly on cycle day 1 or 2 for 3 days to achieve down regulation. Human menopausal gonadotropins, three to four ampules intramuscularly, was then administered daily without the antagonist. Nal-Glu was resumed when the follicles reached 14 to 16 mm and was continued until the day of human chorionic gonadotropin administration. Compared with leuprolide acetate-human menopausal gonadotropins cycles, the days required for down-regulation with Nal-Glu were significantly shortened (20.6 +/- 4.1 vs 1.6 +/- 0.3 days, p less than 0.001), as was total cycle length (31.3 +/- 5.8 vs 11.0 +/- 1.0 days, p less than 0.01). The mean number of days of treatment with human menopausal gonadotropins, the mean number of ampules of human menopausal gonadotropins, peak estradiol levels, the number of oocytes, and the percent of oocytes fertilized were not statistically different. No luteinizing hormone surges were detected with Nal-Glu in serum or urine. Nal-Glu was well tolerated, and five pregnancies have resulted. We conclude that intermittent administration of Nal-Glu is highly effective in achieving down-regulation and blocking spontaneous luteinizing hormone surges. Compared with leuprolide acetate-human menopausal gonadotropins cycles, an equally high oocyte and embryo yield may be anticipated. This new protocol substantially decreases cycle length and increases patient convenience.

The gonadotropin-releasing hormone antagonist (Nal-Glu) acutely blocks the luteinizing hormone surge but allows for resumption of folliculogenesis in normal women.

The gonadotropin-releasing hormone antagonist offers several advantages over the use of the agonist and allows several physiologic questions to be addressed. In this study, we evaluated the ability of Nal-Glu to acutely inhibit the luteinizing hormone surge and prevent ovulation. We also assessed whether recovery of the follicle would be possible after several days of gonadotropin deprivation and estradiol decrement. Eight normal ovulatory women were randomized to control or Nal-Glu-treated cycles (50 micrograms/kg intramuscularly) for 3 to 4 days. Monitoring was carried out with daily vaginal ultrasonographic scans and serum estradiol levels and twice-daily serum luteinizing and follicle-stimulating hormone levels. Nal-Glu acutely inhibited the luteinizing hormone surge and ovulation, even when administered as late as the onset of the luteinizing hormone surge. Evidence was provided that spontaneous follicular rescue recurred in eight of 10 cycles after 3 to 4 days of Nal-Glu administration. Although an estradiol to follicular size dissociation occurred with Nal-Glu, subsequent ovulation occurred in 5.1 +/- 0.6 days after the last Nal-Glu dose. The decrement in estradiol after Nal-Glu administration correlated negatively with the days required for subsequent ovulation to occur (r = 0.77, p less than 0.05). The subsequent luteal phase also was normal in terms of length and progesterone levels. These data confirm the potency and efficacy of Nal-Glu in acutely inhibiting gonadotropins and extends our knowledge on the physiologic characteristics of the dominant follicle.

Ovarian stimulation.

Papers related to ovarian stimulation for in vitro fertilization were reviewed from the period of April 1990 to March 1991. Most of the literature pertained to regimens using gonadotropin-releasing hormone agonists. Other areas of interest included information on the impact of cryopreservation, norethindrone for cycle synchronization, and human chronic gonadotropin for luteal support during in vitro fertilization. The adjunctive use of growth hormone to increase ovarian responsivity was also reported on. The effect of ovarian stimulation on endometrial development during in vitro fertilization was also discussed. In general, although there are several new regimens for inducing multiple follicular development in in vitro fertilization, it appears that there is no consensus on an ideal regimen. This in large part is related to heterogeneity among patient populations.