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W F Crowley

Publications and source records attributed to W F Crowley.

At least 73 records · Page 4Linked to original sources
PubMed1995

Homologous desensitization of gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone secretion in vitro occurs within the duration of an endogenous GnRH pulse.

A pulsatile GnRH signal is required for the maintenance of LH and FSH secretion. Studies in animals and in perifused pituitary cells have shown that continuous exposure to GnRH leads to decreased gonadotropin secretion and a blunted secretory response to subsequent pulses of GnRH, a process referred to as homologous desensitization. In the current study, we demonstrate that the duration of continuous GnRH exposure required to desensitize the gonadotrope in vitro is less than the durations of most in vivo GnRH pulses. Perifused male rat pituitary cells were tested with 20-sec pulses of 100 nM GnRH at 5-min intervals before, immediately upon termination of, and after GnRH infusions of varying concentration and duration. Desensitization in response to a GnRH infusion was calculated as the decrease in the LH response to the pulse of GnRH immediately after the infusion (Dsn pulse) compared to the mean LH response to GnRH pulses before and after the infusion. Gonadotropes were completely desensitized after a 2-min infusion of 10 nM GnRH (P < 0.05), the shortest duration tested. Endogenous GnRH pulses, by contrast, average more than 5 min in length. When the duration of GnRH infusion was held constant at 4 min, a concentration response for GnRH-induced desensitization was observed. Gonadotropes were desensitized by GnRH concentrations as low as 1 nM (P < 0.05), and maximal desensitization was observed with 5 nM GnRH. To determine the recovery period for GnRH-induced desensitization, a second series of experiments was performed. Experiments were conducted as described above, except the cells were perifused with medium that did not contain GnRH (recovery) for varying periods between the GnRH infusion and the Dsn pulse. A small response (16% of control) to the Dsn pulse of GnRH was observed after 1 min of recovery, and the response was not different from the control value (P > 0.05) after a 3-min recovery period. This recovery period is consistent with the ability to respond to endogenous GnRH pulses, which rarely exceed two per h. We conclude that GnRH-induced secretory desensitization and recovery occur within endogenous GnRH pulse durations and interpulse intervals, respectively. These data raise the possibility that homologous desensitization occurs under some in vivo conditions, providing an unexpected mechanism for physiological regulation of gonadotropin secretion.

Animals↗
PubMed1995

Extragonadal alpha-inhibin precursor proteins circulate in human male serum.

The role of inhibin as a negative feedback regulator of pituitary FSH secretion in men remains controversial inasmuch as serum inhibin and FSH levels are often not correlated, in part because of the known alpha-inhibin subunit cross-reactivity of the most widely used inhibin antiserum (Monash #1989). The objective of this study was to identify the nature of these alpha-inhibin proteins in male serum using antisera specific for the alpha-inhibin precursor. Three polyclonal antisera were raised against synthetic peptide fragments from the proregion (amino acids 21-35 = precursor alpha inhibin (PIN) 1 and 42-56 = PIN 2) and alpha-N segment (113-127 = PIN 3) of the human alpha-inhibin precursor protein. These antisera were then used in individual RIAs with the homologous peptide as both standard and radioligand. Because pure human alpha-inhibin subunit proteins are not available, recombinant alpha-inhibin medium and porcine follicular fluid were used as reference preparations in the PIN assays. All assays were specific for alpha-inhibin proteins, i.e. 1) they showed no significant cross-reactivity with other alpha-inhibin peptide fragments, dimeric 32-kDa inhibin, recombinant activin, FSH, human albumin, or the inhibin binding proteins alpha-2 macroglobulin and follistatin, and 2) they recognized native protein in alpha-inhibin precursor-containing porcine follicular fluid and in medium from a recombinant alpha-inhibin-only secreting cell line. Furthermore, immunoreactivity of all serum proteins seen by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting with the PIN antisera was abolished or significantly reduced (40-100%) by preincubation of each PIN antiserum with the homologous peptide. Serial dilutions of serum from normal, GnRH-deficient, and castrate males exhibited equivalent displacement curves in each precursor (PIN) assay, and there were no significant group differences in PIN 2 immunoreactivity between normal (n = 14), GnRH-deficient (n = 8), and castrate men (n = 3). Western blotting of serum samples from a normal and a GnRH-deficient male revealed immunoreactive proteins of approximately 57 and 29 kDa under reducing conditions with all three PIN antisera. An additional 40-kDa protein was observed with the pro-alpha-inhibin antisera, PIN 1 and 2, and a protein of more than 97 kDa was seen with the PIN 2 antiserum.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Defective regulation of glycoprotein free alpha-subunit in males with isolated gonadotropin-releasing hormone deficiency--a clinical research center study.

During long term replacement with a GnRH regimen that restores their gonadotropin and sex steroid levels to normal, men with idiopathic hypogonadotropic hypogonadism (IHH) exhibit excessive secretion of pituitary free alpha-subunit (FAS). To characterize further the dose and duration of exogenous GnRH required to elicit this response, FAS, LH, FSH, and testosterone were determined during the first 8 weeks of GnRH administration in 10 men with IHH. The GnRH dose was increased stepwise every 2 weeks from 5 to 100 ng/kg every 2 h. Hormonal responses were compared with normative data for both pubertal boys and adult men. Low baseline levels of LH (mean +/- SEM, 0.9 +/- 0.03 IU/L), FSH (2.5 +/- 0.4 IU/L), FAS (148 +/- 21 ng/L), and testosterone (2.5 +/- 0.3 nmol/L) increased progressively after GnRH replacement. Mean FAS levels and pulse amplitudes significantly exceeded those in normal adult men by 4-6 weeks when their LH responses to GnRH administration remained below adult norms. By week 8 (50 ng GnRH/kg every 2 h), mean levels of LH, FSH, and FAS (13.7 +/- 2.1 IU/L, 15.4 +/- 4.0 IU/L, 627 +/- 75 ng/L, respectively) significantly exceeded adult male concentrations (P < 0.03). However, mean LH and FSH concentrations were not significantly different from midpubertal controls, in whom FAS levels were comparable to those in normal adults, verifying the excessive nature of FAS secretion relative to intact gonadotropins in the IHH patients. As this imbalance between FAS and dimeric gonadotropin secretion was established early in the current study when low doses of GnRH presumably resulted in low levels of receptor occupancy in vivo, it does not appear to result from partial pituitary desensitization induced by pharmacological GnRH stimulation. Rather, it appears to represent an inherent property of the GnRH-deficient state that is unmasked when GnRH input to the pituitary is restored. Further work will be necessary to elucidate the mechanism of this apparent defect in FAS regulation in GnRH-deficient men.

Adolescent↗
PubMed1995

Serum follistatin levels in women: evidence against an endocrine function of ovarian follistatin.

Follistatin is a monomeric protein first identified in and isolated from ovarian follicular fluid. Evidence that follistatin might be an ovarian endocrine hormone functioning in a negative feedback fashion to modulate pituitary FSH production is based primarily on in vitro experiments. To examine the possible role of follistatin as an endocrine agent in vivo, we sought to relate circulating levels of follistatin to ovarian activity in women. Therefore, we developed a specific and sensitive homologous RIA using antiserum generated against recombinant human follistatin for the measurement of total follistatin in the presence or absence of activin. Follistatin was measured quantitatively (106 +/- 6% recovery) using calibration standards ranging from 0.4-25 ng/tube and up to 400 microL/tube serum. Furthermore, all of the endogenous follistatin measured in human serum could be removed by adsorption to activin-coated plates. Using this homologous RIA, human follicular fluid (100-600 ng/mL; n = 75) contained 3-150 times more follistatin than serum (4-35 ng/mL), an observation consistent with the notion that serum follistatin originates from the gonad. However, further studies of follistatin levels across the normal menstrual cycle (mean +/- SE, 8.09 +/- 0.73; n = 72 daily samples from 4 women), in pregnant women (17.49 +/- 1.34; n = 8), in daily samples from 20 women undergoing ovarian stimulation by exogenous FSH (9.90 +/- 0.62; n = 119), in postmenopausal women including two ovariectomized individuals (9.57 +/- 0.43; n = 8), and in GnRH-deficient women (9.85 +/- 0.50; n = 6) failed to support the hypothesis that serum levels of follistatin reflect ovarian activity in women. Levels of follistatin measured in serum collected across normal menstrual cycles did not fluctuate. However, the roughly nanomolar concentrations of follistatin measured suggest a physiological role for this protein. Follistatin at nanomolar concentrations may be capable of binding and inactivating circulating activin and perhaps in this way limiting the biological activity of activin to local autocrine or paracrine mechanisms. Measurement of peripheral levels of follistatin apparently represents only a first, albeit crucial, step in the study of the physiological significance of this protein in human reproduction.

Endocrine Glands↗
PubMed1995

Midcycle levels of sex steroids are sufficient to recreate the follicle-stimulating hormone but not the luteinizing hormone midcycle surge: evidence for the contribution of other ovarian factors to the surge in normal women.

The midcycle surge of LH and FSH is critical for final oocyte maturation and ovulation. In normal women, this gonadotropin surge follows a gradual increase in estradiol levels (E) and is concomitant with a small increase in progesterone (P) levels. However, whether sex steroids alone are sufficient to induce the complex neuroendocrine interactions underlying this switch from negative to positive feedback is unknown. In this study, physiological midcycle levels of E, with and without periovulatory levels of P (E+P and E, respectively) were infused into 18 normally cycling women in their early to midfollicular phases. The resulting sex-steroid-induced gonadotropin responses were then compared with 118 spontaneous midcycle surges in 81 normal women. The sex steroid levels achieved by the infusions were within the normal ranges for the spontaneous midcycle surge. However, neither women who received E alone nor those who received E+P had LH responses that achieved those of spontaneous LH surges in the normal menstrual cycle (NMC) [82.7 +/- 16.23 IU/L E (mean +/- SEM), 69.7 +/- 12.01 IU/L E+P vs. 121.7 +/- 6.23 IU/L NMC, P < 0.05 E and P < 0.005 E+P vs. NMC]. In contrast, peak FSH levels evoked by E and P matched the spontaneous FSH peaks (19.0 +/- 2.1 IU/L E, 24.5 +/- 4.0 IU/L E+P vs. 23.3 +/- 0.9 IU/L NMC, P = 0.07 E and P = 0.71 E+P vs. NMC). In conclusion, sex steroids alone do not seem to be sufficient to stimulate the normal midcycle LH surge. We hypothesize that other ovarian factors, which are missing in the midfollicular phase, are required for the generation of the normal midcycle surge of LH.

Adolescent↗
PubMed1994

The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence.

BACKGROUND: Although the medical complications associated with multiple-gestation pregnancies have been well documented, little is known about the effects of such pregnancies on the use of health care resources and the associated costs. This is an important issue because of the increasing use of assisted-reproduction techniques, which commonly result in multiple-gestation pregnancies. METHODS: We determined hospital charges and the use of assisted-reproduction techniques (such as induction of ovulation, in vitro fertilization, and gamete intrafallopian transfer) for 13,206 pregnant women (11,986 with singleton pregnancies, 1135 with twin pregnancies, and 85 with more than two fetuses) who were admitted for delivery to Brigham and Women's Hospital, Boston, in 1986 through 1991 and their 14,033 neonates (11,671 singletons, 2144 twins, and 218 resulting from higher-order multiple gestations). RESULTS: After we controlled for variables known to affect hospital charges, the predicted total charges to the family in 1991 for a singleton delivery were $9,845, as compared with $37,947 for twins ($18,974 per baby) and $109,765 for triplets ($36,588 per baby). Assisted-reproduction techniques were used in 2 percent of singleton, 35 percent of twin, and 77 percent of higher-order multiple-gestation pregnancies; such procedures were approximately equally divided between induction of ovulation alone and in vitro fertilization or gamete intrafallopian transfer. CONCLUSIONS: Multiple-gestation pregnancies, a high proportion of which result from the use of assisted-reproduction techniques, dramatically increase hospital charges. If all the multiple gestations resulting from assisted-reproduction techniques, dramatically increase hospital charges. If all the multiple gestations resulting from assisted-reproduction techniques had been singleton pregnancies, the predicted savings to the health care delivery system in the study hospital alone would have been over $3 million per year. Although assisted reproduction provides tremendous benefits to families with infertility, the increased medical risks entailed by multiple-gestation pregnancies and the associated costs cannot be ignored. We suggest that more attention be paid to approaches to infertility that reduce the likelihood of multiple gestation.

Adolescent↗
PubMed1994

Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women.

To investigate the contribution of hypothalamic gonadotropin-releasing hormone (GnRH) secretion to the midcycle gonadotropin surge in the human, the response of luteinizing hormone (LH) to competitive GnRH receptor blockade achieved by administration of a range of doses of a pure GnRH antagonist was used to provide a semiquantitative estimate of endogenous GnRH secretion. The LH response to 5, 15, 50, and 150 micrograms/kg s.c. of the NAL-GLU GnRH antagonist ([Ac-D-2Nal1,D-4ClPhe2,-D-Pal3,Arg5,D-4-p-met hoxybenzoyl-2-aminobutyric acid6,D-Ala10]GnRH, where 2Nal is 2-naphthylalanine, 4ClPhe is 4-chlorophenylalanine, and 3Pal is 3-pyridylalanine) was measured in normal women in the early and late follicular phases of the menstrual cycle, at the time of the midcycle LH surge and in the early luteal phase. LH decreased in a dose-response fashion after administration of the GnRH antagonist in all cycle phases (P < 0.0001). When this suppression was expressed as maximum percent inhibition, there was no difference in response during the early and late follicular and early luteal phases. However, at the midcycle surge, there was a leftward shift of the dose-response curve with significantly greater suppression of LH at the lower antagonist doses in comparison to the other cycle phases (P < 0.005), but no difference at the highest dose. Thus, we draw the following conclusions. (i) There is a consistently greater degree of LH inhibition by GnRH antagonism at the midcycle surge at submaximal degrees of GnRH receptor blockade than at other phases of the menstrual cycle in normal women. (ii) This leftward shift of the dose-response relationship to GnRH receptor blockade suggests that the overall amount of GnRH secreted at the midcycle surge is less than at other cycle stages. (iii) These data confirm the importance of pituitary augmentation of the GnRH signal at the time of the midcycle gonadotropin surge in the human.

Adolescent↗
PubMed1994

Development of a bioassay for FSH using a recombinant human FSH receptor and a cAMP responsive luciferase reporter gene.

FSH exerts its actions primarily by increasing cAMP levels via a G protein-linked transmembrane receptor. We report the development of a bioassay for FSH using a cell line that stably expresses the human FSH receptor and a cAMP responsive human glycoprotein hormone alpha subunit luciferase reporter construct. Receptor activation by FSH was measured by changes in luciferase activity. The cell line was shown to express 1.6 x 10(4) receptors per cell which bound FSH with high affinity (Kd 2.76 x 10[-9] M). Human pituitary FSH caused a dose-dependent increase in cAMP (ED50, 190 mIU/ml) and luciferase (ED50, 31.5 mIU/ml) activity. The sensitivity of the bioassay was less than 0.6 mIU/well. Postmenopausal serum, rat, ovine and bovine FSH elicited a dose-dependent increase in luciferase activity. There was no significant stimulation by highly purified human LH or recombinant human TSH. This cell line should be useful in the determination of bioactive FSH and characterization of serum FSH inhibitors.

Animals↗
PubMed1994

Gonadotropin-releasing hormone and its analogs.

GnRH and its analogues have led to exciting new avenues of therapy in virtually every subspecialty of internal medicine as well as in gynecology, pediatrics, and urology. Since their discovery in 1971, it has been demonstrated that GnRH and its analogues enable medical professionals to influence the hypothalamic-pituitary-gonadal axis in two distinct classes of therapeutic applications. The first provides natural sequence GnRH in a pulsatile fashion via portable infusion pumps to mimic the normal physiology of hypothalamic GnRH secretion and restores reproductive potential to infertile men and women with disorders of endogenous GnRH secretion. The second mode uses long-acting GnRH agonists administered in a depot delivery to produce a paradoxical desensitization of pituitary gonadotropin secretion which, in turn, results in a complete ablation of the reproductive axis. This biochemical castration induced by GnRH agonist administration is a safe, effective, complete, and reversible method of removing the overlay of gonadal steroids from a variety of diseases which they are known to exacerbate. These diseases include endometriosis and uterine fibroids in women, prostate cancer in men, and precocious puberty in both sexes. This review examines the physiologic and pharmacologic principles underlying the advances produced by these agents, the mechanism of action of GnRH and its analogues at the cellular level, and the individual therapeutic applications to which these analogues have been applied. Because virtually every subspecialty of medicine will be touched by the GnRH analogues, this review provides an overview and background of their use.

Female↗
PubMed1994

Characterization of unique binding kinetics of follistatin and activin or inhibin in serum.

Serum binding proteins (BPs) have been identified for several peptide and protein hormones, and their presence has significant implications for the biological action of the hormone. Follistatin (FS) has been identified as an activin- and inhibin-BP in tissues, serum, and follicular fluid of several species, including humans. In this study, the binding kinetics of FS for activin and inhibin were characterized in human serum using gel filtration chromatography and compared to those of pure recombinant hormones using chromatography and a new solid phase assay. When complexed with radiolabeled activin or inhibin, FS eluted at a volume corresponding to a mol wt range of 67,000-150,000, an elution volume identical to the lower mol wt BP peak observed in serum. Furthermore, kinetic analyses of recombinant FS binding to activin using a solid phase assay revealed that 1) the FS-activin interaction is of high affinity, similar to or exceeding that estimated for activin binding to its receptor; 2) binding to activin is essentially irreversible at physiological pH; and 3) the potency of inhibin is approximately 500- to 1000-fold lower than that of activin in the FS binding assay. The lack of FS-[125I]activin complex reversibility observed in the solid phase assay was confirmed using a modified gel filtration chromatography protocol. Thus, preincubation of pure FS or serum with unlabeled activin for 2 h eliminated all binding of subsequently added labeled activin despite a much longer incubation period. However, when labeled activin was incubated with FS for 2 h, subsequent addition of unlabeled activin or inhibin was unable to displace labeled activin from FS, again demonstrating a lack of reversibility. Finally, to map this high affinity interaction, overlapping synthetic peptides were used to compete with labeled activin for FS binding. Two potential contact sites between FS and activin were identified, one near the N-terminus (amino acids 15-29) and the other near the C-terminus (amino acids 99-116). Given its apparently irreversible nature, high affinity, and ability to neutralize activin's biological activity, FS is quite different from the typical hormone-BP. These unique properties of FS undoubtedly attest to the potency of activin in many physiological and developmental settings and, therefore, to the importance of BPs, such as FS for regulating activin's bioactivity, distribution, and/or clearance.

Activins↗
PubMed1994

Human follicular fluid contains pro- and C-terminal immunoreactive alpha-inhibin precursor proteins.

The majority of immunoactive inhibin in human follicular fluid (hFF) is devoid of pituitary cell bioactivity and is hypothesized to contain alpha-inhibin monomeric proteins known to cross-react with an inhibin antiserum (Monash 1989). The aim of this study was to define more precisely the nature of these inhibin-immunoreactive proteins using alpha-inhibin sequence-specific antisera. First, a polyclonal antiserum was raised to precursor amino acids 21-35 (PIN-1) and was used in a RIA to measure pro-alpha-inhibin-immunoreactive proteins. Western blotting was used to confirm these findings. Secondly, the binding epitope of the Monash antiserum was defined by peptide analysis to be located within the C-terminus (precursor amino acids 326-341) of alpha-inhibin, and this assay was then used to monitor the presence of C-terminal sequences. Similar levels of pro-alpha-inhibin immunoreactivity (PIN-1 RIA; N-terminus alpha-inhibin precursor) were detected in hFF collected from women with normal menstrual cycles during the follicular phase and from multiple follicles from a woman undergoing ovarian hyperstimulation during an in vitro fertilization (IVF) protocol. Western blotting with the PIN-1 antibody confirmed the presence of immunoreactive proteins of 57,000 and 29,000 mol wt in the follicular fluids of both normal cycle and IVF follicles. However, ovarian hyperstimulation elevated intrafollicular C-terminal immunoreactivity (Monash RIA) compared to that in normal cycle hFF. Furthermore, intrafollicular estradiol and progesterone were significantly correlated to C-terminal activity in follicles from IVF, but not in normal cycles. These data show that 1) both pro- and C-terminal alpha-inhibin proteins are secreted into follicular fluids from normal and IVF cycles, suggesting that alpha-inhibin precursor proteins may be physiologically relevant in the process of folliculogenesis; and 2) IVF and normal cycle follicular fluids differ in their production and processing of inhibin.

Amino Acids↗
PubMed1994

A comparison of 13 different immunometric assay kits for gonadotropins: implications for clinical investigation.

To determine whether the new immunometric (sandwich) assays for gonadotropins achieve the alleged improvements over RIAs, we compared 13 commercial kits for LH and FSH with our established and validated polyclonal RIAs. Although the kits claimed detection limits as low as 0.05 IU/L, when sensitivity was tested with a uniform hormone standard (the Second International Reference Preparation of human menopausal gonadotropin urinary standard) and the requirement that the limit must be determined from a detectable standard point rather than the variance around zero, only 4 kits surpassed the detectability achieved by the existing LH and FSH RIAs. Seven of the 10 LH kits tested displayed greater than 10% cross-reactivity with either the alpha- or LH beta-subunit. The relationship between the kit standard and the Second International Reference Preparation of human menopausal gonadotropin uniform standard in each kit was nonlinear, so that attempts to compare results between assays with simple multiplication factors are inaccurate. Only 2 assays were designed to eliminate a hook effect. The following conclusions were reached. 1) Most available gonadotropin immunometric assays do not yet offer features not already available in existing validated polyclonal research assays. 2) Conversion of data from one assay to another is not straightforward. 3) Many of the manufacturers' claims do not appear justified. 4) Determination of the detection limit and other immunometric assay characteristics requires standardization of criteria. We propose the following minimum criteria for validating gonadotropin immunometric assays: 1) a uniform definition of the detection limit based on the lowest distinguishable standard concentration, 2) determination of the standard concentration at which a hook occurs, 3) determination of cross-reactivity to subunits as well as intact gonadotropins, and 4) establishment of an adequate normative data base.

Adult↗
PubMed1994

Relatively low levels of dimeric inhibin circulate in men and women with polycystic ovarian syndrome using a specific two-site enzyme-linked immunosorbent assay.

The endocrine feedback role of dimeric inhibin on FSH secretion from the pituitary has been well established in many species; however, evidence that inhibin is an important endocrine regulator of FSH in the human is more tenuous. One potential explanation for the equivocal data may be that the inhibin immunoassay used most widely in the human is a heterologous assay with an antiserum that exclusively recognizes the inhibin alpha-subunit in both its monomeric form and in inhibin dimers. The aim of the present study was to quantify serum inhibin levels in a variety of fertile and infertile men and women using a new ultrasensitive enzyme-linked immunosorbent assay that is specific for the dimeric form (alpha/beta) only. The specificity of the present assay was demonstrated by the absence of significant cross-reactivity with Mullerian inhibiting substance, transforming growth factor-beta, activin, FSH, LH, hCG, TSH, and hCG alpha and with the alpha-subunit of inhibin. The assay was sensitive to 1 pg/mL, and serial dilutions of human male and female serum samples paralleled the recombinant 32-kilodalton (kDa) dimeric inhibin standard curve. Complete recovery of exogenous recombinant 32-kDa inhibin added to serum was obtained. Mean serum inhibin levels ranged from a low of 5.7 +/- 0.6 pg/mL in the early follicular phase to 49.0 +/- 11.2 pg/mL in the midluteal phase of the normal menstral cycle and were elevated during ovulation induction (1250 pg/mL) and pregnancy (500 pg/mL). Interestingly, mean levels of dimeric inhibin in women with polycystic ovarian syndrome (PCOS) were indistinguishable from normal follicular phase. The most striking observation was the extremely low mean inhibin levels (< 2 pg/mL) found in normal men, GnRH-deficient men before any pulsatile GnRH treatment, and men with Klinefelter's syndrome, all of which were indistinguishable from levels observed in postmenopausal women. These observations in the male raise the possibly that 1) some forms of circulating and bioactive inhibin in the human are not detected by this assay due to either their conformation or the presence of a unique binding protein for endogenous inhibin that does not bind to recombinant 32-kDa inhibin; or 2) dimeric inhibin is not a major endocrine regulator of FSH in the human male. In addition, the relatively high dimeric inhibin levels at midcycle and in the luteal phase of the normal menstrual cycle, after gonadotropin stimulation, and during pregnancy suggest that dimeric inhibin is predominantly produced by dominant follicles, corpora lutea, and placental tissues.

Adult↗
PubMed1994

The midcycle gonadotropin surge in normal women occurs in the face of an unchanging gonadotropin-releasing hormone pulse frequency.

The midcycle gonadotropin surge is a critical event in normal reproductive cycles and requires functional integration of the hypothalamus, pituitary, and ovary. To determine whether a change in GnRH frequency occurs coincident with the onset or termination of the surge in normal women, 20 studies were performed at a sampling interval of every 5 min for up to 36 h. The frequency of pulsatile GnRH secretion was assessed by the use of two surrogate markers of its secretion, LH and free alpha-subunit (FAS). The timing of the studies was prospectively determined by serial ultrasound and previous cycle history, whereas measurements of LH, FSH, estradiol, and progesterone in daily blood samples were used retrospectively to locate the frequent sampling study in relation to the day of ovulation in each individual. The frequent sampling studies were divided into late follicular phase (LFP; days -4 to -2) and early, mid-, and late portions of the midcycle surge (days -1 to 1) in relation to the 95% confidence limits of the LH peak derived from daily samples in 69 normal ovulatory women. The patterns of LH and FAS secretion were pulsatile at all times during the midcycle surge. The amplitude of LH pulsations increased from the LFP and early surge to the midportion of the midcycle surge (5.9 +/- 6 and 15.1 +/- 5 vs. 39.0 +/- 3 IU/L; P < 0.0001) and decreased from the mid- to the late portion of the surge (13.4 +/- 5 IU/L; P < 0.0001). Likewise, the amplitude of FAS pulse increased from the LFP and early surge to the midportion of the surge (82.4 +/- 59 and 153.1 +/- 50 vs. 421.4 +/- 35 ng/L; P < 0.0001) and decreased from the mid- to the late portion of the surge (190.8 +/- 49 ng/L; P < 0.0002). Although there was excellent concordance of pulsatile secretion of LH and FAS, significantly more pulses of FAS were detected than of LH (P < 0.0001). There was no change in frequency (expressed as interpulse interval) between the LFP and the early and midportions of the surge for LH (70.0 +/- 8, 67.5 +/- 7, and 65 +/- 5 min, respectively) or FAS (55.1 +/- 7, 54.6 +/- 6, and 60.0 +/- 4 min). However, there was an increase in LH interpulse interval (decrease in pulse frequency) in the late portion of the surge (87.0 +/- 6 min) compared to the early and midportions of the surge (P < 0.02 and P < 0.0005, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Potential for fertility with replacement of hypothalamic gonadotropin-releasing hormone in long term female survivors of cranial tumors.

Dysfunction of the hypothalamic-pituitary axis presenting as hypogonadotropic amenorrhea is a common sequelae of treatment for cranial tumors with surgery and/or radiation. We hypothesized that the site of the defect in this condition is hypothalamic, rather than pituitary, in the majority of patients. Nine women with acquired hypogonadotropic hypogonadism after treatment with transphenoidal pituitary surgery (n = 3), transphenoidal surgery plus conventional radiotherapy (XRT; n = 1), hypothalamic surgery plus XRT (n = 2), or XRT with or without noncentral nervous system surgery (n = 3) underwent assessment of endogenous pulsatile LH secretion and a standard GnRH test followed by iv administration of a physiological replacement regimen of exogenous GnRH. A total of 25 cycles were completed at doses of 75 or 100 ng/kg.bolus. Ovulation occurred in 78% of patients, with all ovulatory patients who desired fertility becoming pregnant. The hormonal responses in these cycles did not differ from the patterns of sex steroids and gonadotropins in normal women. The response to pulsatile GnRH was not influenced by GH deficiency or PRL abnormalities. Of the two patients who failed to ovulate, there was no evidence of folliculogenesis in one, whereas the second consistently developed follicles, but proved incapable of mounting a LH surge despite adequate preovulatory estradiol levels. Both patients had a history of pituitary radiation and surgery. There was no consistent relationship between the results of GnRH testing and the pattern of pulsatile LH secretion. However, the only patient who failed to achieve folliculogenesis was the only patient without a FSH response to GnRH testing and an apulsatile baseline study. Hypothalamic GnRH deficiency is the etiology of hypogonadism in the majority of patients after treatment with hypothalamic or pituitary surgery or cranial irradiation. Therefore, exogenous pulsatile GnRH represents a physiological replacement therapy that completely restores normal gonadotropin dynamics, resulting in ovulation and fertility.

Adolescent↗
PubMed1993

An overview of the diagnostic considerations in polycystic ovarian syndrome.

The past ten years have been particularly exciting with regard to the elucidation of the pathophysiology of PCOS. It appears that PCOS is about to yield some of its mysteries and to have some of its discrete subsets defined, as Cushing syndrome did 50 years ago. However, future studies of PCOS will require a complex interplay of clinical investigation, molecular and genetic probes, increasingly refined anatomic observations, and fundamental neuroendocrine studies. Each observer has a bias, which must be acknowledged in his/her studies. However, a true synthesis of the abnormalities characteristic of PCOS must continually be sought, for only through a comprehensive view of this syndrome will we come to understand its true pathophysiology; and only then can rational therapies be designed.

Androgens↗