Prevalence and risk factors for obstetric haemorrhage in 6730 singleton births after assisted reproductive technology in Victoria Australia.

BACKGROUND: Obstetric haemorrhages have been reported to be increased after assisted reproduction technologies (ART) but the mechanisms involved are unclear. METHODS: This retrospective cohort study compared the prevalence of antepartum haemorrhage (APH), placenta praevia (PP), placental abruption (PA) and primary post-partum haemorrhage (PPH) in women with singleton births between 1991 and 2004 in Victoria Australia: 6730 after IVF/ICSI, 24 619 from the general population, 779 after gamete intrafallopian transfer (GIFT) and 2167 non-ART conceptions in infertile patients. Risk factors for haemorrhages in the IVF/ICSI group were examined by logistic regression. RESULTS: The IVF/ICSI group had more APH: 6.7 versus 3.6% (adjusted OR 2.0; 95% CI 1.8-2.3), PP: 2.6 versus 1.1% (2.3; 1.9-2.9), PA: 0.9 versus 0.4% (2.1; 1.4-3.0) and PPH: 11.1 versus 7.9% (1.3; 1.2-1.4) than the general population. APH, PP and PA were as frequent in the GIFT group as in the IVF/ICSI group, but were less frequent in the non-ART group. Within the IVF/ICSI group, fresh compared with frozen thawed embryo transfers (FET) was associated with more frequent APH (1.5; 1.2-1.8) and PA (2.1; 1.2-3.7) and the odds ratio increased with number of oocytes collected (1.02; 1.00-1.04). Endometriosis patients had more PP (1.7; 1.2-2.4) and PPH (1.3; 1.1-1.6) than those without endometriosis. FET in artificial cycles was associated with increased PPH (1.8; 1.3-2.6) compared with FET in natural cycles. CONCLUSIONS: Obstetric haemorrhages are more frequent with singleton births after IVF, ICSI and GIFT. The exploratory analysis of factors in the IVF/ICSI group, showing associations with fresh embryo transfers in stimulated cycles, endometriosis and hormone treatments, suggests that events around the time of implantation may be responsible and that suboptimal endometrial function is the critical mechanism.

Pregnancies conceived using assisted reproductive technologies (ART) have low levels of pregnancy-associated plasma protein-A (PAPP-A) leading to a high rate of false-positive results in first trimester screening for Down syndrome.

BACKGROUND: First trimester screening (FTS) for Down syndrome combines measurement of nuchal translucency, free beta-human chorionic gonadotrophin and pregnancy-associated plasma protein-A (PAPP-A). The aim of this study was to undertake a detailed analysis of FTS results in singleton pregnancies conceived using assisted reproductive technologies (ART) and non-ART pregnancies. METHODS: A record linkage study compared outcomes in 1739 ART-conceived and 50 253 naturally conceived pregnancies. RESULTS: Overall, significantly lower PAPP-A levels were detected in ART pregnancies (0.83 multiples of median, MoM) than in controls (1.00 MoM) (t-test P < 0.001). This difference remained after excluding complicated pregnancies. Analysis of factors affecting PAPP-A levels suggested fresh compared with frozen embryo transfers and use of artificial cycles compared with natural cycles for frozen transfers were associated with lower values. The adjusted odds ratio (AdjOR) for receiving a false-positive result was 1.71 (95% CI 1.44-2.04; P < 0.001) for ART pregnancies compared with non-ART pregnancies, and this leads to a higher AdjOR (1.24, 95% CI 1.03-1.49; P = 0.02) for having a chorionic villous sampling (CVS) or amniocentesis. CONCLUSIONS: ART pregnancies have reduced FTS PAPP-A levels leading to an increased likelihood of receiving a false-positive result and having a CVS/amniocentesis. Lower PAPP-A may reflect impairment of early implantation with some forms of ART.

The thymus-adrenal connection: thymosin has corticotropin-releasing activity in primates.

Endotoxin-free thymosin fraction 5 elevated corticotropin, beta-endorphin, and cortisol in a dose- and time-dependent fashion when administered intravenously to prepubertal cynomolgus monkeys. Two synthetic component peptides of thymosin fraction 5 had no acute effects on pituitary function, suggesting that some other peptides in thymosin fraction 5 were responsible for its corticotropin-releasing activity. In agreement with these observations, total thymectomy of juvenile macaques was associated with decreases in plasma cortisol, corticotropin, and beta-endorphin. These findings indicate that the prepubertal primate thymus contains corticotropin-releasing activity that may contribute to a physiological immunoregulatory circuit between the developing immunological and pituitary-adrenal systems.

Factors affecting low birthweight after assisted reproduction technology: difference between transfer of fresh and cryopreserved embryos suggests an adverse effect of oocyte collection.

BACKGROUND: Data show that differences exist in the birthweight of singletons after frozen embryo transfer (FET) compared with fresh transfer or gamete intra-Fallopian transfer (GIFT). Factors associated with low birthweight (LBW) after assisted reproduction technology (ART) were studied. METHODS: Birthweight, distribution of birthweight, z-score, LBW (<2500 g), gestation and percentage preterm (<37 weeks) for singleton births >19 weeks gestation, conceived by ART or non-ART treatments (ovulation induction and artificial insemination) between 1978 and 2005 were analysed for one large Australian clinic. RESULTS: For first births, the mean birthweight was significantly (P < 0.005) lower, and LBW and preterm birth more frequent for GIFT (mean = 3133 g, SD = 549, n = 109, LBW = 10.9% and preterm = 10.0%), IVF (3166, 676, 1615, 11.7, 12.5) and ICSI (3206, 697, 1472, 11.5, 11.9) than for FET (3352, 615, 2383, 6.5, 9.2) and non-ART conceptions (3341, 634, 940, 7.1, 8.6). Regression modelling showed ART treatment before 1993 and fresh embryo transfer were negatively related to birthweight after including other covariates: gestation, male sex, parity, birth defects, Caesarean section, perinatal death and socio-economic status. CONCLUSIONS: Birthweights were lower and LBW rates higher after GIFT or fresh embryo transfer than after FET. Results for FET were similar to those for non-ART conceptions. This suggests IVF and ICSI laboratory procedures affecting the embryos are not causal but other factors operating in the woman, perhaps associated with oocyte collection itself, which affect endometrial receptivity, implantation or early pregnancy, may be responsible for LBW with ART.

Serum follicle-stimulating hormone, luteinizing hormone, and prolactin during the induction of ovulation with exogenous gonadotropin.

To examine the gonadotropic milieu presiding over recruitment and selection of a dominant follicle during gonadotropin induction of ovulation, four patients were studied over nine cycles of human pituitary gonadotropin (hPG) therapy. These hypogonadotropic subjects received a routine schedule of hPG injections monitored by daily urinary estrogen and pregnanediol determinations. Serum FSH, LH, and PRL profiles were measured in daily morning blood samples throughout each menstrual cycle. hPG therapy produced markedly abnormal gonadotropin patterns. Mean serum FSH levels were above the upper limit of the normal serum FSH range and no early or midfollicular FSH peaks occurred. The FSH-LH ratio was abnormally high for 8 days before ovulation. Progressive and marked elevations of serum PRL developed during hPG treatment. A bimodal luteal phase serum PRL profile appeared with peak values of 40.7 +/- 5.6 ng/ml (mean +/- SE) 1 day and 42.0 +/- 3.0 ng/ml 9 days after the LH peak. We conclude that: 1) Current gonadotropin treatment regimens to induce ovulation produce radioimmunoassayable serum FSH, LH, and PRL profiles which are qualitatively and quantitatively abnormal, and 2) Excessive FSH levels and the elevated FSH-LH ratio orchestrate aberrant folliculogenesis and result in the clinical problems of multiple ovulation and hyperstimulation.

The presence of lactogen receptors in human chorion laeve.

Lactogen receptors have been identified in human chorion laeve and possibly placenta but not other periplacental tissues. The receptors show the same hormonal specificity, and similar binding parameters (affinity 0.47 x 10(9) l/m, capacity 175 fmol3/mg) to lactogen receptors in mammary gland and liver. The presence of these receptors, suggests they may play a role in mediating an action(s) of amniotic fluid prolactn in chorion laeve, such as osmoregulation.

Circulating immunoreactive oxytocin during the human menstrual cycle comes from the pituitary and is estradiol dependent.

The aims of this study were to 1) evaluate the relative contributions of hypothalamic and ovarian oxytocin (OT) to peripheral serum concentrations and 2) determine the relationship between serum OT and ovarian steroid concentrations. Four groups of women were studied: 1) women with spontaneous cycles (n = 4) and normal serum estradiol (E2), progesterone, LH, and FSH levels; 2) in vitro fertilization (IVF) patients (n = 8) undergoing ovarian hyperstimulation; 3) agonadal oocyte-recipient patients (n = 6) receiving replacement E2 and P therapy; and 4) postmenopausal women (n = 21). Peripheral serum samples were collected daily during a menstrual cycle from the normal and agonadal women and for 6 days before ovulation in the IVF group. Serum immunoreactive OT was measured by specific RIA after Sep-Pak extraction; the assay sensitivity was 0.6 pmol/L. Serum OT in the women with normal cycles increased during the follicular phase, reaching a peak 1 day after the LH surge, and decreased in the luteal phase [days 7, 16, and 21, 10.7 +/- 3.5 (mean +/- SE), 25.7 +/- 5.7, and 13.2 +/- 2.5 pmol/L, respectively; P less than 0.05]. Serum OT levels were higher in IVF patients before ovulation than in women with spontaneous cycles, but lower than those in the agonadal women, who had a peak value (49.1 +/- 9.6 pmol/L; P less than 0.05) on day 13 of E2/progesterone replacement therapy. Serum OT was positively correlated (r = 0.68, normal women; r = 0.91, oocyte recipients) with serum E2 values during the first part of the cycle (P less than 0.01). A similar positive correlation between serum OT and E2 was found in the postmenopausal women (r = 0.83). We conclude that serum OT before and around the time of ovulation comes mainly from the pituitary, and not from the ovary, and is E2 dependent.

Is the luteo-placental shift a myth? Analysis of low progesterone levels in successful art pregnancies.

Progesterone (P4) is considered vital to the maintenance of human pregnancy, but the minimal concentration of P4 necessary to sustain human pregnancy remains unclear. The aim of this study was to examine endocrine profiles for serum P4, 17 beta-estradiol (E2), and human (h) beta-CG in early pregnancy from a group of assisted reproductive technologies (ART) patients. These subjects delivered normally but had P4 concentrations below the fifth percentile of the normal singleton pregnancy range from 2 weeks after ART. Normal ranges of these hormones were determined from 118 consecutive ART pregnancies which resulted in singleton births. Values below the fifth percentile (P4 < 35.9 nmol/L at 4 weeks gestation) were considered abnormal. Eight patients who subsequently delivered normally, with serum P4 values below this criterion at 4 weeks gestation, were found. They had serum P4 values at 4 weeks gestation ranging from 1.9-29.9 nmol/L, and their mean P4 values at 5 weeks (30.2 +/- 9.2 nmol/L; mean +/- SE) and 6 weeks gestation (48.0 +/- 10.2 nmol/L) remained below the fifth percentile. No statistically significant increase in serum P4 concentrations occurred between 7 and 11 weeks gestation in these women. Their mean E2 value in serum at 4 weeks gestation (382 +/- 73 pmol/L) was also below the fifth percentile but their mean beta-hCG concentration was within the normal range. We conclude that successful human pregnancy is possible with serum P4 values within the anovulatory range in early gestation and that, in individual patients, serum P4 concentration of 2 nmol/L can be sufficient to maintain human pregnancy.

Messenger ribonucleic acid expression of the insulin-like growth factors and their binding proteins in uterine fibroids and myometrium.

Fibroids (leiomyomata) are the most common tumors in women, but their etiology is unknown. The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) may be important in the growth of these benign neoplasms. We have examined the presence of mRNA encoding both IGF-I and IGF-II and IGFBP-1, -2, and -3 in fibroids and corresponding myometrium from 20 women undergoing hysterectomy for symptomatic uterine fibroids. Northern blots of total cellular RNA were probed with oligonucleotides for IGF-I, IGF-II, IGFBP-2, and IGFBP-3 and a human IGFBP-1 cDNA. Western ligand blotting was also used to detect the presence of IGFBP proteins in both fibroid and myometrium. The data showed that in fibroids compared to myometrium, 1) the relative abundance of IGF-I mRNA was not different, but there was an increase in the relative abundance of IGF-II mRNA (P < 0.001); 2) IGFBP-1 mRNA was undetectable in fibroids and detectable in only 1 specimen of myometrium; 3) there was no difference in the relative abundance of IGFBP-2 mRNA, but there was an increase in the relative abundance of IGFBP-3 mRNA in myometrium (P < 0.05). By Western ligand blotting, both IGFBP-2 and -3 proteins were present. Our data show that the mRNAs encoding IGF-I, IGF-II, IGFBP-2, and IGFBP-3 are expressed in both fibroids and myometrium and that fibroids express more IGF-II and less IGFBP-3 mRNA than myometrium. We postulate that the net effect of the changes seen is to increase the bioavailability of free (bioactive) IGF, which may then play a major role in promoting fibroid tumor growth.

Chronic idiopathic polyhydramnios: evidence for a defect in the chorion laeve receptor for lactogenic hormones.

Binding of human GH (hGH) to the lactogenic receptor of human chorion laeve has been compared in membrane preparations from normal pregnancies and those complicated by chronic idiopathic polyhydramnios. Specific binding of [125I]hGH was significantly lower (mean +/- SE, 1.64 +/- 0.28%; n = 5) in chronic idiopathic polyhydramnios than in normal pregnancies (2.93 +/- 0.4%; n = 16). Scatchard analysis data were consistent with a reduced lactogenic hormone receptor concentration being the explanation for this reduced hGH binding. By contrast, the specific binding of [125I]insulin to its receptor was unchanged when chorion laeve from hydramniotic pregnancies (7.29 +/- 1.98%; n = 4) was compared with that from normal pregnancies (8.63 +/- 1.35%; n = 7). We conclude that a lactogenic hormone receptor defect exists in the chorion laeve of pregnancies complicated by chronic idiopathic polyhydramnios. Such impaired binding for PRL may explain the development of excessive amniotic fluid volumes, which is characteristic of this complication of pregnancy.

Circulating immunoreactive inhibin levels during the normal human menstrual cycle.

Serum inhibin concentrations were measured daily by RIA in six normal women throughout one menstrual cycle. The RIA was specific for inhibin, and inhibin subunits and related proteins cross-reacted minimally in it. In the early to midfollicular phase, inhibin levels changed little, while in the late follicular phase, inhibin levels rose, in parallel with estradiol (r = 0.43; P less than 0.05; n = 22), to a peak level of 714 (407-1267) U/L (geometric mean +/- 67% confidence limits) coincident with the midcycle LH and FSH surges. An inverse relationship was found between serum inhibin and FSH during the mid- to late follicular phase (r = 0.42; P less than 0.01; n = 45). Inhibin levels rose further during the luteal phase to a peak level of 1490 (1086-2028) U/L 7-8 days after the LH surge, and they correlated positively with serum progesterone (r = 0.76; P less than 0.001; n = 49) and inversely with serum FSH (r = 0.43; P less than 0.01; n = 49) throughout the luteal phase. We conclude that 1) circulating inhibin is detectable throughout the normal menstrual cycle; 2) in the late follicular phase, inhibin levels rise in parallel with estradiol, consistent with the concept that both are products of the maturing follicle; 3) in the luteal phase, the profile of inhibin suggests that it is a secretory product of the corpus luteum; and 4) the inverse relationship between inhibin and FSH in the follicular phase is consistent with the inhibin hypothesis, while at midcycle there is loss of the inhibitory effect of inhibin on FSH secretion. The inverse relationship between FSH and inhibin during the luteal phase suggests a hitherto unsuspected role for inhibin in the feedback regulation of FSH secretion.

Serum inhibin levels in polycystic ovary syndrome: basal levels and response to luteinizing hormone-releasing hormone agonist and exogenous gonadotropin administration.

Serum inhibin levels were measured by RIA twice weekly for 4 weeks in 5 women with the polycystic ovary syndrome (PCOS). These were compared to those in 10 women with normal menstrual cycles. Serum inhibin levels were similar in the 5 PCOS women (mean, 199; range, 126-266 U/L) and were not significantly different from those in the normal women during the early follicular phase (227; 100-485 U/L) or midfollicular phase (243; 143-412 U/L) of their cycles. Inhibin levels were higher (P less than 0.001) in the late follicular phase (408; 227-732 U/L), at midcycle (623; 367-1058 U/L), and during the midluteal phase (1245; 898-1727 U/L) in the normal women compared to those in the PCOS group. Serum inhibin levels were also measured in PCOS (n = 8) and infertile (n = 14) women after the rise and subsequent diminished gonadotropin secretion that occurred during LHRH agonist administration. In both groups, serum LH and FSH increased after initiation of LHRH agonist administration; this increase was accompanied by parallel rises in serum estradiol and inhibin before suppression (PCOS women: r = 0.71; P less than 0.001; n = 108; infertile women: r = 0.42; P less than 0.05; n = 163). All hormone levels, including inhibin, decreased during continued LHRH administration. Five PCOS women underwent ovulation induction using combined LHRH agonist and human menopausal gonadotropin administration. Serum estradiol and inhibin rose in parallel in response to exogenous gonadotropins (r = 0.92; P less than 0.001; n = 77). In conclusion, we found no evidence of a primary defect in ovarian inhibin physiology in women with PCOS in terms of either basal or gonadotropin-stimulated (exogenous or endogenous) secretion.

Vaginal progesterone administration before ovulation induction with exogenous gonadotropins in polycystic ovarian syndrome.

We studied the value of vaginal progesterone (P4) in suppressing serum LH concentrations and restoring normal luteal phase serum LH concentrations before administration of exogenous gonadotropins in anovulatory women with the polycystic ovarian syndrome (PCOS). P4 (50 mg every 12 h) was administered by vaginal suppository to 9 women (18 cycles) for 14 days before ovulation induction with human menopausal gonadotropin (hMG) and hCG. Serum LH, FSH, estradiol, P4, and PRL levels were measured daily. A biphasic effect on LH secretion occurred during P4 administration. Peak serum LH levels occurred on day 5 (125% of basal levels; P less than 0.05) of vaginal P4 suppository use, followed by a progressive fall (P less than 0.05) to 79% of basal levels, but serum LH levels were still higher than those in normal women despite achieving physiological luteal phase P4 concentrations. Ovulation occurred in 56% of cycles after P4 and hMG/hCG treatment and in 65% of control cycles after hMG/hCG alone. In 7 women, serum LH was measured at 10-min intervals for 6 h before and after vaginal P4 administration for 10 days. LH pulse frequency decreased from 7.4 +/- 1.1 to 4.4 +/- 1.2 pulses/6 h (P less than 0.01), and LH pulse amplitude increased from 3.8 +/- 1.8 to 6.1 +/- 2.9 IU/L (P less than 0.01) after P4 administration. We conclude that vaginal P4 (50 mg every 12 h) 1) produces serum P4 concentrations within the normal range for the luteal phase of the menstrual cycle; 2) elevates serum LH, but not FSH, within 5 days; 3) decreases LH pulse frequency and increases LH pulse amplitude after 10 days, but does not normalize serum LH values; and 5) fails to improve the results of subsequent ovulation induction with exogenous gonadotropins in patients with PCOS.

Toward removing uterine fibroids without surgery: subcutaneous infusion of a luteinizing hormone-releasing hormone agonist commencing in the luteal phase.

Intermittent sc injection of a LHRH agonist reduced uterine fibroid size in 5 women. Commencement of the LHRH agonist buserelin on day 21 of the menstrual cycle induced a marked increase in plasma LH and FSH concentrations, followed by rises in estradiol (E2) and progesterone. LH and FSH levels fell to within the normal range by 120 h after beginning buserelin, despite continuing administration of the agonist. After menstruation, marked sustained suppression of cyclical gonadotropin and steroid concentrations occurred: mean values of FSH, LH, and E2 were 4.9 +/- 0.5 (+/- SE) mIU/ml, 5.9 +/- 0.6 mIU/ml, and 47.9 +/- 10.8 pg/ml, respectively, during the 20 weeks of buserelin treatment. During treatment, E2 concentrations remained below 50 pg/ml in 98 of 116 weekly observations. Uterine fibroids shrank after 8 or 10 weeks of buserelin administration, as assessed by ultrasound or gynecological examination. Compared to their initial volume, mean uterine fibroid volume after 20 weeks of buserelin infusion decreased from 220 +/- 51 to 98 +/- 26 cm3, which was 39.4 +/- 6.9% of the pretreatment volume. We conclude that sc administration of a LHRH agonist beginning in the luteal phase markedly reduced the size of uterine leiomyomata, suppressed, but did not abolish, pituitary and ovarian function, and warrants further evaluation as an option or adjunctive therapy to uterine myomectomy or hysterectomy.

The stimulation of prostaglandin production by two antiprogesterone steroids in human endometrial cells.

Endometrial stromal cells and isolated endometrial glands obtained from women during days 6-26 of the ovarian cycle were cultured for 24 h in the presence of the progesterone antagonists 17 beta-hydroxy-11 beta-[4-dimethylaminophenyl]17 alpha-[1-propynyl] estra-4,9-dien-3-one (RU486) and 17 beta-hydroxy-11 beta-[4-dimethylaminophenyl] 17 alpha-[3-hydroxy-1-propenyl]estra-4,9-dien-3-one (ZK 98734). Both steroids stimulated prostaglandin F2 alpha (PGF2 alpha) production by stromal cells in a dose-dependent manner, in doses ranging from 10-1000 nM. Progesterone (100 nM) inhibited RU486 stimulation, except at the highest dose of antiprogestin. PGE2 was produced in smaller amounts than PGF2 alpha, but, when measurable, it also increased in the presence of RU486. In contrast, RU486 did not increase PG production by endometrial glands. In an experiment to determine the effect of pretreatment, stromal cells were incubated for 24 h with 1000 nM progesterone or RU486 (all with 100 nM 17 beta-estradiol) with either 30 or 6 microM arachidonic acid. These six batches of cells were incubated for a second 24 h with either progesterone or antiprogestin. Cells pretreated with the higher dose of arachidonic acid had a marked increase in PGF2 alpha production during the second 24 h only when also pretreated with progesterone. This finding suggests that progesterone allows an accumulation of PG precursor in a suitable accessible pool. Pretreatment with progesterone also allowed a greater conversion of PG to its 13,14-dihydro-15-keto metabolite. These results suggest that antiprogesterone steroids may act as menstrual regulators by: stimulating endogenous PG production within the endometrial stromal cells and inhibiting PG catabolism.

Increased adrenocorticotropin, cortisol, and arginine vasopressin secretion in primates after the antiglucocorticoid steroid RU 486: dose response relationships.

The antiglucocorticoid steroid, RU 486, elevated plasma ACTH concentrations when administered im at 0700 h in a dose of 1.0 mg/kg in nonhuman primates (Macaca fascicularis; P less than 0.05). The duration, but not the magnitude, of this response increased after 5.0 mg/kg RU 486 im; release of ACTH did not rise further after 10 mg/kg. Peak ACTH elevations occurred 1-2 h after RU 486 administration. Plasma cortisol concentrations peaked 4 h after RU 486 administration and the response was significant only after 5.0 mg/kg RU 486. Plasma arginine vasopressin (AVP) concentrations also increased after RU 486 but the increase occurred only after the 10.0 mg/kg dose (P less than 0.05). The AVP elevation was greatest 4 h after 10 mg/kg RU 486 and was abolished by dexamethasone pretreatment. We conclude that: 1) RU 486 elevates plasma ACTH, cortisol, and AVP concentrations in a manner which is both dose and time dependent, 2) ACTH release occurred at an order of magnitude lower dose than did AVP release, and 3) plasma AVP changes after RU 486 are glucocorticoid dependent.

Pituitary autonomy in hyperprolactinemic secondary amenorrhea: results of hypothalamic-pituitary testing.

Twenty-seven women with secondary amenorrhea of greater than six months duration were subjected to multiple testing of hypothalamo-pituitary function. They were divided into normo-prolactinemic (Group 1 mean serum prolactin (PRL) 9.8 ng/ml; range 6.8 to 13.0 ng/ml; n=9) and hyperprolactinemic (Group 2 mean 37.5 ng/ml; range 19.2 to 93.7 ng/ml; n=18) groups on the basis of 4 weekly baseline determinations. Group 2 had significantly (P less than .05) lower serum LH and urinary pregnanediol levels than did Group 1; there was no statistical difference between the groups in serum FSH, T4, T3 or urinary estrogen measurements. Two women in Group 2 were found to have a pituitary chromophobe adenoma. Group 2 women showed no significant rises in serum PRL following stimulation tests with thyrotropin releasing hormone (TRH, 200 microng iv) and metoclopramide (10 mg orally), which caused significant responses in Group 1. The TSH response to TRH was, however, preserved in Group 2, while it was subnormal in Group 1 subjects. Both groups showed similar FSH and LH responses to luteinizing hormone-releasing hormone (LHRH, 25 microng iv). No significant suppression of serum PRL was seen in Group 2 patients given L-Dopa (500 mg orally),, which produced a significant response (P less than 0.05) in Group 1 subjects, while all patient showed marked reduction in serum PRL values following 2-bromo-alpha-ergocryptine (CB-154, 2.5 mg orally). When compared with other Group 2 members, the 2 cases with proven pituitary adenomata gave similar responses to the stimulation-inhibition tests and were not clearly distinguished on this basis. We conclude: 1. The pattern of PRL responses to dynamic tests, although of pathophysiological interest an autonomous pituitary lesions in patients with hyperprolactinemic secondary amenorrhea. 2. Such dynamic tests, although a pathophysiological interest, provide no clinical information additional to that provided by the mean basal serum PRL value. 3. In clinical practice, such dynamic tests should be confined to patients with mean serum PRL levels at around the upper limit of the normal range.

Characteristics of an antiluteinizing hormone isoantibody produced during gonadotropin induction of ovulation.

Production of an antihuman LH antibody was suspected in a woman with isolated LH deficiency who received human pituitary gonadotropin (hPG) to induce ovulation and who developed secondary drug failure associated with very high "serum LH' values. Binding of [125I]LH to various dilutions of the patient's serum was demonstrated by precipitation with polyethylene glycol or sheep antihuman immunoglobulin G (anti-IgG) but not by precipitation with sheep antihuman immunoglobulin M (anti-IgM). Unlabeled LH competitively displaced [125I]LH from a 1:200 final dilution of the patient's serum, and indicated a single class of binding sites with a binding affinity of 1.5 X 1011 M-1 and a binding capacity of 84 ng LH/ml serum. The isoantibody was reactive against antigenic determinants in hPG, LH, and hCG but not against human FSH. Further examination showed binding to the beta, but not the alpha, subunit of two LH preparations and to beta hCG. It is concluded that repeated administration of hPG to this patient with isolated LH deficiency evoked IgG isoantibody formation against the beta subunit of LH.

Occult ovarian failure: a syndrome of infertility, regular menses, and elevated follicle-stimulating hormone concentrations.

Ten women with infertility, regular menses, and elevated plasma FSH concentrations after a failed in vitro fertilization attempt were studied throughout a spontaneous menstrual cycle. Plasma estradiol, progesterone, inhibin, LH, and FSH concentrations were measured by RIA on days 1, 8, 15, and 22 and compared with the ovarian steroid and gonadotropin profiles obtained from seven endocrine-normal women. The elevated FSH concentrations in the hypergonadotropic group were not associated with significant changes in E2 and P4, but an increase in LH concentrations was found on days 1, 8, and 22 (medians of 18 and 4, 17 and 6, and 7 and less than 3 U/L for the hypergonadotropic and normal groups, respectively; P less than 0.01). Their plasma inhibin concentrations [213, 242, 747, and 561 U/L (median values on days 1-7, 8-14, 15-21, and 22-28)] were normal. Autoantibodies to adrenal, thyroid, or ovary were present in five (50%) women, and antiovarian antibodies were present in 4. Two women gave a family history of thyroid disease, and one woman was hypothyroid. Repeat assessment 3-6 months revealed persistently elevated FSH concentrations in five (63%) of eight women; the other three had normal ovarian steroid and gonadotropin concentrations. The triad of infertility, regular menses, and elevated plasma FSH concentrations describes a group of women with occult ovarian failure, a condition of compensated granulosa cell function, which may be an early stage of premature ovarian failure. These women with occult ovarian failure had an impaired response to ovarian hyperstimulation and may be at increased risk of developing polyglandular autoimmunity.

An analysis of plasma estradiol concentrations during clomiphene citrate-human menopausal gonadotropin stimulation in an in vitro fertilization-embryo transfer program.

We report here a range of plasma estradiol (E2) concentrations suitable for use in an in vitro fertilization (IVF) program. This range was derived from nonparametric analysis of plasma E2 levels using plasma E2 measurements beginning 10 days before the anticipated day of the midcycle LH surge (midpoint), as calculated from each patient's six previous menstrual cycles, during which time the patients all received the same ovarian stimulation regimen. The regimen consisted of 100 mg clomiphene citrate/day for 5 days, beginning 10 days before the anticipated midpoint, plus 150 IU human menopausal gonadotropin, commencing the day after clomiphene. A consecutive series of 102 IVF conception cycles induced in this standardized fashion were analyzed in this study. The 5th-95 percentile envelope of plasma E2 concentrations was derived as a valid clinical indicator of satisfactory folliculogenesis during IVF treatment. Five women had plasma E2 concentrations below the 5th percentile of the E2 range on at least 3 consecutive days of ovarian stimulation, while six women had E2 levels above the 95th percentile of this range on at least 3 consecutive days. This plasma E2 range defined objectively the diagnoses of ovarian hyperstimulation and inadequate stimulation in an IVF program. These criteria should help clinicians in managing ovarian responses during IVF superovulation stimulation treatment.