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Three female adolescents are presented with delayed or incomplete secondary sexual development due to primary ovarian failure. All three patients had normal blood leukocyte and ovarian tissue karyotypes. The importance of performing a diagnostic laparoscopy with ovarian biopsy in the setting of chromosome competent ovarian failure (CCOF) is emphasized.
Demographic data from the United States show the need for testing ovarian reserve in a population that is increasingly delaying reproduction. The childless rate for U.S. women over the age of 35 has nearly doubled to 25% since 1925. Yet, in 1994 approximately one-third of all first births were by women over the age of 35. The first-line treatment for the aging effect on the ovarian reservoir of oocytes is ovulation induction. Study results reveal that a delivery rate of only 2.4% was achieved at age 42, and in 119 cycles of therapy in women above that age there were no live births. The clomiphene citrate challenge test is one method of dynamic testing of ovarian reserve. It has the advantages of simplicity and reduced cost when compared with the gonadotropic stimulatory test. In one test group utilizing the clomiphene citrate challenge test only 4.8% conceived at any age following an abnormal test. As a prognostic test with an approximate 95% accuracy rate for negative predictive value it has much to offer. With oocyte donation becoming more widespread as an acceptable method of achieving pregnancy, clomiphene citrate challenge testing should be performed more frequently, in order to spare couples the emotional and financial sequelae of multiple attempts at ovulation induction and IVF when expected pregnancy rates fall below a level acceptable to both patient and physician.
The clomiphene citrate challenge test (CCCT), a means of assessing ovarian reserve, was shown by several studies to have an excellent predictive value for achieving conception in natural cycles, during ovulation induction and in-vitro fertilization cycles. Accordingly we elected to study the cycle to cycle variability of CCCT so as to determine the reliability of a single CCCT result. Two groups of patients were studied, the first (n = 40) were those patients who were performing the test because it was indicated, and the second (n = 24) were those who were receiving clomiphene citrate for ovulation induction. In both groups CCCT intercycle variability was significant in 75% of the cases, but this variability altered the prognostic values of the test in only 40% of the first group. In conclusion, our study showed a high percentage of intercycle variability of CCCT but further studies are needed to evaluate the influence of this variability on potential conception.
In this pharmacokinetic and dose-escalation study of the carboplatin/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combination, patients were randomly assigned to receive paclitaxel either as a 1-hour or a 3-hour infusion. The 1-hour infusion was feasible, with maximum tolerated doses similar to those previously reported for a 3-hour infusion. Using patients' age, height, plasma creatinine, and plasma creatine kinase provided an improved estimate of the glomerular filtration rate compared with the more traditional creatinine-based formulas according to population analysis of data derived from glomerular filtration rate estimates performed by an isotope method. Studies of the p53 gene sequence of ovarian tumors at diagnosis suggest that p53 mutations are a potent predictor of response to subsequent treatment with carboplatin.
OBJECTIVE: To systematically review the value of the clomiphene citrate challenge test (CCCT) in the prediction of poor ovarian response and pregnancy in IVF. DESIGN: Systematic review. SETTING: All studies that evaluated the CCCT in the prediction of poor ovarian response or pregnancy after IVF. PATIENT(S): Infertility population undergoing an IVF treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Poor ovarian response, nonpregnancy. RESULT(S): From the literature we identified and analyzed 12 studies on the CCCT according to preset criteria. In predicting poor response, the sensitivity and specificity of the CCCT varied from 35% to 93% and 47% to 98%, respectively. In predicting nonpregnancy, the sensitivity and specificity varied from 13% to 66% and 73% to 97%, respectively. Because of heterogeneity among studies, a summary receiver operating characteristics (ROC) curve could not be estimated. Back-to-back comparison of the CCCT with basal FSH was possible in six studies. In predicting poor response, the sensitivity of the CCCT increased to some extent, whereas specificity did not increase or even diminished. In predicting nonpregnancy, the CCCT also showed an increase in sensitivity, counteracted by a decrease in specificity. CONCLUSION(S): Summary estimates of test accuracy for the CCCT in IVF are not possible, because of heterogeneity among individual studies. A subanalysis of studies comparing basal FSH and the full CCCT showed that the CCCT has hardly any additional value.
Fertility and results of infertility therapies are submitted to amajor drop in relation with the age of the female patient and her so-called ovarian reserve. Although there is no clear definition of what is exactly the ovarian reserve, the consequence of its decline is a greater difficulty to produce ovocytes with a capacity of becoming living embryos after fertilization. Several tests have been developed to assess the ovarian reserve in order to evaluate the prognosis of spontaneous fertility, the results of infertility therapy and assisted procreation techniques, and to make necessary technical adaptations. Basal determinations of FSH, estradiol and inhibin B at day 3 of the cycle an all reflect the ovarian potential, but only FSH reflects a decline infecundability reliable enough to be used as a screening test. Challenge tests such as the clomiphene citrate, the exogenous FSH or the GnRH challenge tests have the purpose to reveal an exaggerated liberation of FSH or an insufficient secretion of estradiol after stimulation. None of these tests have demonstrated a better sensibility together with a higher specificity and they should be considered as evaluating tools in specific cases only. In conclusion, assessing the ovarian reserve has become a clinical necessity in the following situations: ovulation defect, unexplained infertility, before undergoing ovarian stimulation for assisted procreation, in particular in women above the age of 35. This assessment can be made by determining the basal FSH level on day 3 of a cycle and should be renewed every year.
BACKGROUND: The presence of a wide range of tests of ovarian reserve suggests that no single test provides a sufficiently accurate result. Many tests are used without reference to an evidence base. So far, individual studies conducted on these tests are too small to give precise estimates of prognostic accuracy. OBJECTIVES: To systematically assess the accuracy of the available tests of ovarian reserve in terms of prediction of fertility outcomes. SEARCH STRATEGY: The search will be conducted using the name of the respective index test being studied (as listed on the MESH database), if more than 2000 citations are listed, 'ovary' and or 'ovarian', 'fertility' and or 'reserve' will be combined with the original search term as required. Studies of the accuracy of tests of ovarian reserve will be obtained without language restrictions from 1980 to 2005 using the following electronic databases and Ovid software: MEDLINE, EMBASE, PUBmed, Biological extracts, Pascal, Cochrane Library (CDSR, DARE, CCTR, HTA), Best Evidence databases, SCISEARCH, Conference Proceedings (ISI Proceedings, Healthstar, Current Contents, Science Citation Index, Cancerlit and Econlit and NHS Economic Evaluation database. The National Research Register, the Medical Research Council's Clinical Trials Register, MEDION, DARE, and the US Clinical Trials register. SELECTION CRITERIA: Studies will be selected if accuracy of tests are compared with a reference standard and include data that can be abstracted into a two-by-two table to calculate sensitivity and specificity. The studies to be included in this review will examine one of the following index 'tests' within a study population of women undergoing assisted reproductive technology: * Clinical variables--age, history of cancelled cycles. * Basal blood tests--follicle-stimulating hormone (FSH), lutenising hormone (LH), FSH:LH ratios, estradiol (E(2)), inhibin A and B, progesterone (P(4)), P(4):E(2) ratios, antimullerian hormone, testosterone, vascular endothelial growth factor, insulin-like growth factor-1:insulin-like growth factor binding protein-1 ratios. * Dynamic tests--clomiphene citrate challenge test, gonadotropin analogue stimulating test, exogenous FSH ovarian reserve test. * Ultrasound tests-antral follicle count, ovarian volume, ovarian stromal peak systolic velocity, including waveform and pulsatility index, ovarian follicular vascularity. * Histology--ovarian biopsy. Data collection and analysis Two independent reviewers will perform quality assessment and data extraction. Prognostic accuracy will be determined by calculating positive and negative likelihood ratios for the following outcomes or reference standards: live birth, ongoing pregnancy, clinical pregnancy, biochemical pregnancy, embryos available for transfer, eggs obtained at oocyte retrieval, cycles cancelled prior to oocyte retrieval. Main results and conclusions N/A.
Intermittent administration of parathyroid hormone (PTH) has been shown to be an anabolic agent for animal and human skeletons. In previous studies, PTH has been used concurrent with, or subsequent to, the onset of bone loss. However, it is entirely possible that PTH may be used as an anabolic agent in a situation where there is stable skeletal remodeling. Increasing bone mass at this time might confer long-lasting beneficial effects when bone loss begins, for example, subsequent to the loss of ovarian function. To test this hypothesis, we evaluated the effects of administering rat PTH(1-34) (80 microg/kg/day, subcutaneously [s.c.]) to 6-month-old rats for a 2-week period prior to ovariectomy, and followed the natural occurrence of bone loss over a 14-week period. To determine the effects of estrogen intervention on bone gained by PTH treatment, one group was repleted with 17beta-estradiol (10 microg/kg/day via s.c. implant). Serial measurements of bone mass in vivo at the distal femur were obtained at 2-week intervals using dual-energy X-ray absorptiometry, while histologic and mechanical strength data were obtained from excised proximal tibiae and distal femurs after sacrifice. Two weeks of PTH treatment resulted in an increase of bone mineral density (BMD), mechanical strength, and cancellous bone volume (CnBV/TV). Four weeks after PTH withdrawal, significant residual beneficial effects on BMD and strength, irrespective of ovarian status, were observed. However, 14 weeks after PTH withdrawal, although there were still residual effects on CnBV/TV in ovariectomized animals pretreated with PTH, the PTH effects on BMD and mechanical strength had been lost. Estradiol repletion during the rapid bone loss phase following ovariectomy prevented the reduction in BMD associated with either ovariectomy or PTH withdrawal. Our results suggest that: treatment of rats with PTH prior to ovariectomy produces an increase in BMD and strength, these beneficial effects extend for a period of at least three times the treatment duration, the BMD that is lost when PTH is discontinued equates to the amount accrued during the PTH treatment, estrogen replacement can be used to maintain the bone gained as a result of PTH treatment.
To evaluate the efficacy, safety and tolerance of the GnRH-analogue Buserelin in the treatment of endometriosis, we started a non-comparative study of 52 patients with various stages of endometriosis. The dosage of 900 mcg/d was administered 3 times daily intranasally for 6 months. The degree of the disease was evaluated before and at the end of treatment by pelviscopy and biopsy. A regression of the implant score was found in 88% of patients. The mean AFS score was reduced from 17.4 +/- 1.9 before medication to 7.2 +/- 8.2 after therapy. Endometriosis related complaints were significantly improved during treatment. After 6 months 75% of the patients were without lower abdominal pain, 98% without dysmenorrhoea, and 85% without dyspareunia. As a result of the induced low level of oestrogen, 60% of the patients claimed hot flushes, 12% sweating, reduced libido, and dry vagina. Bleeding (spotting, break-through bleeding, menstruation) occurred in 40% during the first month, and was continuously reduced during the following period. Before, during and after therapy, venous blood samples were drawn to check laboratory tests for blood count, clotting parameters, clinical chemistry, serum electrolytes, as well as liver and lipid metabolism. All values stayed within the normal range without significant changes. In the follow-up period of at least 12 months, we achieved an uncorrected pregnancy rate of 41% in the group of 34 women with primary or secondary infertility.
BACKGROUND: Ovarian activity should ideally be assessed by serial non-invasive methods that require simple procedures for sample collection and storage. Measurement of urinary oestrone-3-glucuronide and pregnanediol-3 alpha-glucuronide is a non-invasive method available for assessment of ovarian activity, but transport of large numbers of urine samples is cumbersome and samples need to be stored frozen. An alternative sample collection, transport and storage procedure that is easier to handle and requires no or minimal cold storage facilities will particularly benefit studies in which ovulatory activity needs to be assessed in field settings. OBJECTIVE: To evaluate the feasibility of using paper impregnated with urine as an alternative to liquid urine for the measurement of oestrone-3-glucuronide and pregnanediol-3 alpha-glucuronide concentrations in the assessment of ovarian activity. METHODS: Urine samples collected daily throughout regular menstrual cycles were stored as liquid urine at -20 degrees C, and as paper impregnated with urine, in the refrigerator for 3 to 12 months or at room temperature for 1 to 6 months. Oestrone-3-glucuronide and pregnanediol-3 alpha-glucuronide concentrations were measured in these urine samples by enzyme immunoassay. Values obtained were correlated using Spearman's correlation test. RESULTS: The pattern of oestrone-3 glucuronide and pregnanediol-3 alpha-glucuronide concentrations estimated using paper impregnated with urine followed that of liquid urine in all storage conditions used. Values obtained by two methods correlated significantly (p < 0.001 to 0.0001) though the paper impregnated with urine gave slightly higher values. CONCLUSIONS: Paper impregnated with urine can be used to facilitate sample collection, transport and storage of urine when oestrone-3-glucuronide and pregnanediol-3 alpha-glucuronide measurements are required in a large number of serial samples to assess ovarian activity.
It is well known that the transient excessive increase of serum prolactin level is harmful for the mechanism of ovulation or the steroidogenesis of the ovaries. The pathogenesis of latent or occult hyperprolactinemia (OHP) has been investigated recently. The present study was conducted to determine the diagnostic standard of OHP, and to elucidate the efficacy of bromocriptine administration for the treatment of OHP and other ovulatory disturbances. 110 cases of hypothalamic anovulations were selected from 385 cases of infertile patients by the LH-RH and TRH loading tests. Bromocriptine (5mg/day) was administered to all of the subjects for more than three months, and the efficacy of the bromocriptine administration was investigated. Follicular development was observed by transvaginal ultrasonography (mature follicular diameters > or = 20mm), and also luteal function was estimated by the duration of the luteal phase in the BBT charts (high phase > or = 12 days), the mid-luteal serum estradiol (> or = 200pg/ml) and progesterone (> or = 10ng/ml) levels. The subjects were divided into two groups: group A, bromocriptine effective patients (63 cases) and group B, bromocriptine non effective patients (47 cases). The results of the LH-RH and TRH loading tests were compared between these two groups. Serum prolactin levels at 30 min. after TRH loading (PRL30) in group B (61.5 +/- 28.3 vs. 38.0 +/- 19.3ng/ml, p < 0.01). At the cut-off points of 50, 60 and 70ng/ml over in the values of the PRL, the efficacies of the bromocriptine administration were 77.4, 78.9 and 88.5%, respectively. From these facts, it was thought suitable that the diagnostic standard of OHP was PRL30 > or = 70ng/ml, and values of PRL30 from 50 to 70ng/ml were borderline cases of OHP. The efficacy of the bromocriptine administration in the cases without OHP (n = 57) was also investigated. Serum LH levels at 30 min. after LH-RH loading (LH30) were compared between the cases of the bromocriptine effective (n = 22) and non effective (n = 35). As a result, the LH30 of the former was significantly higher than that of the latter (96.5 +/- 64.2 vs. 45.1 +/- 31.5mIU/ml, p < 0.005). In conclusion, the diagnostic standard of OHP was determined as PRL30 > or = 70ng/ml (borderline: 50 > 70ng/ml), and bromocriptine administration was effective not only in cases of OHP, but also in cases of hyperreactivities of LH (so-called endocrinological PCOD).
With recent progress in endocrinology and in procreation physiology, the importance of kinetics of pituitary gonadotropin has been increasing, and the measurement method has been improved. In the present study, however, we found inconsistency in measured LH values between IRMA (SPAC-S LH) as the conventional method and CLEIA (IMMULYZE LH) as the newly developed method. The inconsistency between the SPAC-S LH value and the IMMULYZE LH value was observed in 10.0% of the healthy group and in 12.5% of the patient group. The cause of this discrepancy was due to a reaction of the SPAC-S LH of the intact LH monoclonal antibodies to the LH with the abnormal structure beta chain by two point mutation in the LH beta gene. The response of LH-RH test varied depending on the measurement reagent of LH in patients who had the LH with the abnormal structure beta chain, which made it difficult to determine the lesion and histological grading regarding the ovulation mechanism. Therefore, in patients with abnormal beta chain, an accurate treatment protocol was indeterminate. In this study, although a relationship between various gynecological diseases and the point mutation of LH was not clarified, we suggest that LH of the abnormal structure beta chain may cause excessive secretion in the early stage, and lead to some effect on physical activities.
Endocrinological studies on stressed climacteric women and some cases of gonadal dysfunction were carried out by analysing blood levels of adrenocorticotropic hormone (ACTH), beta-lipotropin (beta-LPH) and beta-endorphin (beta-EP) after the administration of synthetic corticotropin releasing factor (CRF, CRF test). Our results can be summarized as follows: 1. The responsiveness to CRF in perimenopausal and ovariectomized women rose and it corresponded with those of post gonadectomy in testicular feminization. 2. Responsiveness to CRF was decreased as estrogen levels decreased with the patient's age, and a similar tendency was observed in gonadal dysfunction. 3. Climacteric women with non-specific complaints have a higher responsiveness to CRF than that of postmenopausal women without complaints. Subjects with a high K.I score and with severe hot flush showed higher responsiveness to CRF than other subjects. These data suggest that CRF and its related hormones may be correlative with stress and hot flushes in climacteric periods and endogenous CRF may play an important psychosomatic role by regulating the hypothalamo-pituitary-adrenal function where there is decreased estrogen.
We performed gonadotropin releasing hormone agonist (GnRHag) tests on 23 consecutive hyperandrogenic girls 9.9-17.5 years of age who were referred to our pediatric endocrinology clinic with symptoms suggestive of PCOS. They were compared to contemporaneously studied groups of adult normal and hyperandrogenic women. We found that hyperandrogenic adolescents had clinical and endocrine features similar to those of hyperandrogenic adults. However, there were some noteworthy unique features of adolescent hyperandrogenism, such as presentation in mid-childhood with premature pubarche and the occasional diagnosis before the age of 10 years. Some differences between adolescents and adults were statistically significant, for example, pelvic ultrasonography was not as helpful in the diagnosis of FOH as it is in adults. Nevertheless, a number of questions about the development of the ovarian dysfunction remain to be answered. For example, we are unable to diagnose ovarian dysfunction before puberty or in early puberty, and the relationship of "physiologic adolescent anovulation" to PCOS remains to be defined.
OBJECTIVE: To examine whether the magnitude of the rise in inhibin B levels after gonadotropin challenge is associated with subsequent response to ovarian stimulation during IVF. DESIGN: Inhibin B serum levels after EFORT (exogenous follicle-stimulating hormone ovarian reserve test). SETTING: Academic clinical practice. PATIENT(S): Serum samples from women who had undergone ovarian reserve screening with FSH in preparation for IVF. Thirteen of these women had a poor response in IVF (canceled cycle for low estradiol and/or no oocytes retrieved), and 19 had a good response (> or =10 oocytes retrieved). INTERVENTION(S): EFORT test. MAIN OUTCOME MEASURE(S): Baseline (day 3) serum E(2) (bE(2)), FSH (bFSH), and inhibin B (bInhB) levels and inhibin B and E(2) levels 24 hours after EFORT (DeltaInhB and DeltaE(2)). RESULT(S): The mean bInhB and DeltaInhB levels were significantly higher in good vs. poor responders. The odds ratio of having a good response for women with a DeltaInhB of 202 pg/mL was 51.8 times (95% CI = 6.1-1,244) the corresponding odds for women with a DeltaInhB of 49 pg/mL. As expected, DeltaE(2) was also significantly higher in good vs. poor responders; however, combination of DeltaE(2) plus DeltaInhB did not improve the odds for predicting IVF response. CONCLUSION(S): Our data suggest that DeltaInhB after EFORT may provide a method for predicting ovarian response to hyperstimulation in a subsequent IVF cycle.
Predicting ovarian response to stimulation constitutes a pivotal task in the organization of a successful in-vitro fertilization (IVF) programme. The purpose of the current study was to determine whether a new ovarian reserve test, the exogenous follicle stimulating hormone ovarian reserve test (EFORT), could improve the predictive value of the classical follicle stimulating hormone (FSH) measurements on cycle day 3 of ovarian stimulation regarding results of IVF. In this prospective study, 52 IVF candidates aged 27-42 years underwent 52 consecutive IVF cycles. These women received 300 IU of purified FSH i.m. on cycle day 3. Blood samples were taken just before the injection to measure plasma FSH and oestradiol; 24 h later, plasma oestradiol concentration was determined. Two menstrual cycles later, ovarian stimulation was performed for IVF using a time-release gonadotrophin-releasing hormone agonist (GnRHa) and human menopausal gonadotrophin (HMG). For the interpretation of the EFORT results, we considered the post-FSH plasma oestradiol increment (delta E2) and the baseline plasma FSH values (bFSH). The results of these two parameters were compared with the subsequent quality of the ovarian response to stimulation for IVF and the pregnancy outcome. Our results indicated a statistically significant improvement of the predictive value of the bFSH on the ovarian stimulation outcome when the EFORT parameters (bFSH and delta E2) were analysed synergistically.(ABSTRACT TRUNCATED AT 250 WORDS)
The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.
BACKGROUND: Few studies have determined the impact of a lifetime history of major depression on an early transition to menopause. METHODS: Reproductive and psychiatric interviews and early follicular-phase blood specimens were obtained at study enrollment and every 6 months during 36 months of follow-up from 332 women with and 644 women without a history of major depression, 36 to 45 years of age. We used menstrual cycle markers to determine inception of perimenopause, defined as time from study enrollment to a follow-up interview with: (1) 7-day or more change in menstrual cycle length; (2) a change in menstrual flow amount or duration; or (3) amenorrhea lasting at least 3 months. RESULTS: Women with a history of depression had 1.2 times the rate of perimenopause of women with no such history (95% confidence interval, 0.9-1.6). Compared with nondepressed women, depressed women with more pronounced depressive symptoms at study enrollment (Hamilton Rating Scale for Depression scores >8) had twice the risk of an earlier perimenopausal transition. Among the women with greater depressive symptoms (Hamilton scores >8), those who also reported use of antidepressants had nearly 3 times the risk of an earlier perimenopausal transition (hazard ratio, 2.7; 95% confidence interval, 1.5-4.8) of nondepressed women. Women with a lifetime history of depression also had higher follicle-stimulating hormone and luteinizing hormone levels and lower estradiol levels at study enrollment and during the follow-up period after adjustment for covariates. CONCLUSION: A lifetime history of major depression may be associated with an early decline in ovarian function.