Minimal ovarian stimulation for IVF: appraisal of potential benefits and drawbacks.
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Embryo Transfer↗
Biomedical subjects
W F Crowley
Publications and source records attributed to W F Crowley.
X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females.
X-linked adrenal hypoplasia congenita (AHC) is a disorder associated with primary adrenal insufficiency and hypogonadotropic hypogonadism (HH). The gene responsible for X-linked AHC, DAX1, encodes a member of the nuclear hormone receptor superfamily. We studied an extended kindred with AHC and HH in which two males (the proband and his nephew) were affected with a nucleotide deletion (501delA). The proband's mother, sister, and niece were heterozygous for this frameshift mutation. At age 27 yr, after 7 yr of low dose hCG therapy, the proband underwent a testicular biopsy revealing rare spermatogonia and Leydig cell hyperplasia. Despite steadily progressive doses of hCG and Pergonal administered over a 3-yr period, the proband remained azoospermic. The proband's mother, sister (obligate carrier), and niece all had a history of delayed puberty, with menarche occurring at ages 17-18 yr. Baseline patterns of pulsatile gonadotropin secretion and gonadotropin responsiveness to exogenous pulsatile GnRH were examined in the affected males. LH, FSH, and free alpha-subunit were determined during 12.5-24 h of frequent blood sampling (every 10 min). Both patients then received pulsatile GnRH (25 ng/kg) sc every 2 h for 6-7 days. Gonadotropin responses to a single GnRH pulse iv were monitored daily to assess the pituitary responsiveness to exogenous GnRH. In the proband, FSH and LH levels demonstrated a subtle, but significant, response to GnRH over the week of pulsatile GnRH therapy. Free alpha-subunit levels demonstrated an erratic pattern of secretion at baseline and no significant response to pulsatile GnRH. We conclude that 1) affected males with AHC/HH may have an intrinsic defect in spermatogenesis that is not responsive to gonadotropin therapy; 2) female carriers of DAX1 mutations may express the phenotype of delayed puberty; and 3) although affected individuals display minimal responses to pulsatile GnRH, as observed in other AHC kindreds, subtle differences in gonadotropin patterns may nevertheless exist between affected individuals within a kindred.
Adolescent↗
Is obesity an outcome of gonadotropin-releasing hormone agonist administration? Analysis of growth and body composition in 110 patients with central precocious puberty.
Concern has been raised that children with central precocious puberty (CPP) are prone to the development of obesity. Here we report longitudinal height, weight, and body mass index (BMI) data from 96 girls and 14 boys with CPP before, during, and after GnRH agonist (GnRHa) administration. Skinfold thickness (n = 46) and percent body fat by dual energy x-ray absorptiometry (n = 21) were determined in subsets for more accurate assessment of body composition and to validate the use of the BMI SD score as an index of body fatness in our subjects. Before the initiation of therapy (PRE), the girls with CPP had a mean BMI SD score for chronological age (CA) of 1.1+/-0.1 and for bone age (BA) of 0.1+/-0.1. By the end of the study, 12-24 months after the discontinuation of GnRHa, the mean BMI SD score was 0.9+/-0.1 for CA and 0.6+/-0.1 for BA. At the visit when GnRHa was discontinued, 41% and 22% of the girls had a BMI SD score for CA more than the 85th and 95th percentiles, respectively, indicating that obesity was present at a high rate among our subjects; the BMI SD score for CA at the PRE visit was its strongest predictor. Indeed, 86% of the girls with BMI SD score for CA above the 85th percentile when GnRHa was discontinued also had BMI SD score for CA above the 85th percentile at the PRE visit. The proportion of boys with elevated BMI SD score for CA was also high. Fifty-four percent and 31% of the SD scores were greater than the 85th and 95th percentiles after 36 months of GnRHa therapy; the BMI SD score for CA PRE had been above the 85th percentile in 71% of these overweight subjects. Obesity occurs at a high rate among children with CPP, but does not appear to be related to long term pituitary-gonadal suppression induced by GnRHa administration. Children with CPP should have a baseline BMI SD score calculated, and those at risk for obesity should be counseled appropriately.
Adolescent↗
Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadism or pubertal delay.
Although delayed puberty is relatively common and often familial, its molecular and pathophysiologic basis is poorly understood. In contrast, the molecular mechanisms underlying some forms of hypogonadotropic hypogonadism (HH) are clearer, following the description of mutations in the genes KAL, GNRHR, and PROP1. Mutations in another gene, DAX1 (AHC), cause X-linked adrenal hypoplasia congenita and HH. Affected boys usually present with primary adrenal failure in infancy or childhood and HH at the expected time of puberty. DAX1 mutations have also been reported to occur with a wider spectrum of clinical presentations. These cases include female carriers of DAX1 mutations with marked pubertal delay and a male with incomplete HH and mild adrenal insufficiency in adulthood. Given this emerging phenotypic spectrum of clinical presentation in men and women with DAX1 mutations, we hypothesized that DAX1 might be a candidate gene for mutation in patients with idiopathic sporadic or familial HH or constitutional delay of puberty. Direct sequencing of DAX1 was performed in 106 patients, including 85 (80 men and 5 women) with sporadic HH or constitutional delay of puberty and patients from 21 kindreds with familial forms of these disorders. No DAX1 mutations were found in these groups of patients, although silent single nucleotide polymorphisms were identified (T114C, G498A). This study suggests that mutations in DAX1 are unlikely to be a common cause of HH or pubertal delay in the absence of a concomitant history of adrenal insufficiency.
DAX-1 Orphan Nuclear Receptor↗
The Reproductive Endocrine Associates of the Massachusetts General Hospital: fifteen years of integrated clinical practice and investigation.
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Adult↗
Insights into hypothalamic-pituitary dysfunction in polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is characterized by menstrual dysfunction and hyperandrogenism in the absence of other known causes. While the pathogenesis of PCOS remains elusive and is likely to involve abnormalities in several systems, there has long been an association of abnormal gonadotropin secretion with this disorder. In recent studies we have determined that 94% of women meeting the broad criteria for PCOS have an increased LH/FSH ratio. Several lines of evidence suggest that the mechanisms underlying the increased LH/FSH ratio in PCOS include an increased frequency of GnRH secretion. Decreased sensitivity to progesterone negative feedback on the GnRH pulse generator may play a role in this neuroendocrine defect. Additional factors which may contribute to the low to normal FSH levels in the face of increased LH include chronic mild estrogen increases and possibly inhibin. In addition to these effects on the differential control of FSH, there is increased pituitary sensitivity of LH secretion to GnRH. Both estrogen and androgens have been proposed as candidates mediating these effects. Superimposed on these underlying abnormalities in gonadotropin secretion is a marked inhibitory effect of obesity on LH secretion which may be mediated at either a pituitary or hypothalamic level.
Female↗
Hypogonadotropic hypogonadism.
This article outlines the changing pattern of gonadotropin-releasing hormone (GnRH)-induced gonadotropin secretion across sexual development, a knowledge of which is critical to understanding GnRH secretion in pathologic states such as hypogonadotropic hypogonadism. The clinical presentation, differential diagnosis, and treatment of hypogonadotropic hypogonadism in humans are discussed. Particular emphasis is placed on the contribution of frequent sampling studies of gonadotropin secretion and genetic studies to understanding the pathophysiology and clinical heterogeneity of isolated GnRH deficiency in humans.
Aging↗
Gonadotropin pulsations across development.
Initiation and maintenance of the reproductive axis in the human is contingent upon the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. In man, tracking endogenous GnRH secretion relies on frequent peripheral sampling of three glycoprotein products of the gonadotrope, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and free alpha-subunit (FAS). FAS is superior to LH as a surrogate marker of GnRH secretory dynamics in those circumstances where GnRH secretion is rapid or where the pituitary LH response is low. The pattern of GnRH secretion is constantly changing across development; from high levels during the neonatal period, through a period of quiescence in mid-childhood, followed by sleep-entrained reactivation of the reproductive axis at the onset of puberty, ultimately culminating in the adult pattern of pulsatile secretion which in the male is approximately every 2 h and in the female varies with the stage of the menstrual cycle. This episodic mode of secretion allows differential impact of feedback mechanisms on the GnRH neurons and facilitates the maintenance of the reproductive axis during periods of stress by allowing frequency and amplitude modulations.
Animals↗
Is GnRH reduced at the midcycle surge in the human? Evidence from a GnRH-deficient model.
Recent studies indicate that the midcycle gonadotropin surge in the human occurs without an increase in hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency. In addition, previous studies employing a GnRH antagonist to provide a semiquantitative estimate of endogenous GnRH secretion suggest that the overall amount of GnRH secreted is decreased at the time of the surge. To investigate the hypothesis that a normal gonadotropin surge can be generated in the human with a decreased amount of GnRH at the midcycle, 7 GnRH-deficient subjects underwent two cycles of a physiologic regimen of intravenous pulsatile GnRH therapy. In the control cycle, 75 ng/kg/bolus of GnRH, a dose known to be sufficient for folliculogenesis, was administered throughout the cycle, using physiological frequencies. In a second cycle, the bolus dose of GnRH was decreased by one-half log order to 25 ng/kg just prior to the luteinizing hormone surge and returned to 75 ng/kg after documented ovulation. All cycles were ovulatory. The peak luteinizing hormone level (77.4 +/- 9.7 vs. 67.5 +/- 17.6 IU/l) did not differ between the control and decreased GnRH cycles. There was no difference in the peak serum estradiol level (475.8 +/- 144.1 vs. 493.2 +/- 93.0 pg/ml), follicular phase length (15.0 +/- 1.3 vs. 14.8 +/- 0.6 days), or progesterone level (22.4 +/- 5.1 vs. 34.8 +/- 5.7 ng/mg) on day 6 of the luteal phase in the control and decreased GnRH cycles, respectively. Three pregnancies were achieved in each of the control and reduced GnRH cycles. We conclude that a decreased overall amount of GnRH generates a normal midcycle gonadotropin surge and has no significant impact on luteal phase adequacy or fertility. These results provide further evidence that a decrease in endogenous hypothalamic GnRH secretion may occur at the midcycle in normal women. This study also provides evidence that the GnRH requirements for normal follicular and luteal phase dynamics may well be greater than those required for generation of a normal midcycle gonadotropin surge and ovulation in women.
Adult↗
Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations.
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Animals↗
Exaggerated free alpha-subunit levels during pulsatile gonadotropin-releasing hormone replacement in women with idiopathic hypogonadotropic hypogonadism.
The goals of this study were to determine whether women with idiopathic hypogonadotropic hypogonadism (IHH) respond to pulsatile GnRH replacement therapy with exaggerated glycoprotein free alpha-subunit (FAS) levels, as reported in GnRH-deficient men, and to determine whether this pattern is unique to congenital GnRH deficiency or is also characteristic of patients with hypogonadotropic hypogonadism caused by other factors. GnRH was administered i.v. at a physiologic frequency and dose (75-100 ng/kg.bolus) to women with IHH (n = 11; n = 6 with anosmia); acquired GnRH deficiency secondary to treatment for cranial tumors (AHH; n = 7); and secondary hypothalamic amenorrhea (HA; n = 8). Results were compared with 24 normal cycling women. Gonadotropins, sex steroids, and FAS levels were measured in samples drawn daily across induced or normal menstrual cycles in patients or normal women, respectively. Samples were drawn at the same time of day and were collected 45 min after a GnRH bolus in patients. All women ovulated in response to pulsatile GnRH. There were no differences in the patterns of LH or gonadal steroid secretion between any of the patient groups (IHH, AHH, and HA). The patterns of LH and FSH secretion in the induced patient cycles were not different from normal women, with the exception of lower midcycle FSH levels in IHH women (P < 0.002). However, the daily dynamic secretion of FAS was exaggerated in IHH (compared with AHH, HA, and normal) women (P < 0.002). The increase in FAS levels in IHH was dependent on cycle stage, with the greatest difference observed during the early (P < 0.005) and midfollicular phase (P < 0.05) and the early luteal phase (P < 0.05). There was no difference in FAS between groups during the late follicular phase, at the midcycle, or in the midluteal and late luteal phase. This exaggerated FAS response to GnRH replacement in IHH was demonstrated in repeat cycles in two patients. Conclusions are: 1) Women with IHH respond to pulsatile GnRH replacement with an exaggerated secretion of FAS, which seems to be modified by gonadal factors; 2) this exaggerated FAS response, which is similar to that seen in GnRH-deficient men, is unique to congenital GnRH deficiency, and it is not observed in patients with acquired or secondary hypogonadotropic hypogonadism, suggesting that IHH patients may be missing a factor, in addition to GnRH, which normally restrains FAS secretion; and 3) the FAS response may prove to be a useful marker to distinguish constitutional delay of puberty from congenital GnRH deficiency.
Adolescent↗
A two-site chemiluminescent assay for activin-free follistatin reveals that most follistatin circulating in men and normal cycling women is in an activin-bound state.
Follistatin (FS) is a monomeric protein that binds and regulates the bioavailability of activin. Previously, we found circulating levels of total FS to be similar in men and cycling women. Because relative amounts of activin-bound and free FS are important considerations in determining activin bioavailability, we asked here whether the relative proportions of these two changed during different physiologic states. For this, we developed a two-site, solid-phase, immunochemiluminescent assay for free FS. The assay recognizes the 288 or 315 amino acid variants of human FS and has a detectable limit of 1 ng/mL. Inhibin, transforming growth factor-beta, or alpha-2-macroglobulin do not cross-react or interfere in this assay. Preincubation of FS with activin results in dose-dependent loss of immunoreactivity, confirming specificity of the assay for free FS. Human follicular fluid, pituitary extract, and serum with added FS dilute parallel with the recombinant human FS-288 standard. Recovery of recombinant human FS-288 from serum is quantitative. Using this assay, we found circulating concentrations of free FS to be at or below the detection limit of the assay throughout the menstrual cycle. Comparison of circulating total and free FS levels in postmenopausal or cycling women and normal men suggested that at least 90% is activin-bound. In contrast, measurable quantities of free FS were found in follicular fluid and pituitary extracts. The results of this study, showing that most circulating FS is normally activin-bound, argue against an endocrine role for FS and suggest that a major role of circulating FS is to bind and neutralize the bioactivity of circulating activin. The roles of FS as a local autocrine or paracrine regulator of activin in target tissues, where FS exists in free form, or as an endocrine regulator in human pathophysiology, warrants further investigation.
Activins↗
Clinical review 96: Differential control of gonadotropin secretion in the human: endocrine role of inhibin.
Although considerable strides have been made in charting the physiology and pathophysiology of inhibin in the human, further progress awaits the development of recombinant inhibin suitable for administration in human studies. Measurements of total serum inhibin, although inadequate to chart the dynamic changes associated with normal and disordered pituitary-gonadal function, have proven to be of value as indices of ovarian tumor activity. Although the roles of specific dimeric inhibin measurements in clinical practice have not been clearly established, advances in our understanding of inhibin physiology and pathophysiology in the human suggest that inhibin B may have value as a marker of Sertoli cell function in men with infertility and as a prognostic indicator in women undergoing ovulation induction therapy.
Adult↗
Absence of mutations in the FSH receptor in ovarian granulosa cell tumors.
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Female↗
Activin: an endocrine or paracrine agent?
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Activins↗
Adult-onset idiopathic hypogonadotropic hypogonadism--a treatable form of male infertility.
BACKGROUND: Men with isolated gonadotropin-releasing hormone (GnRH) deficiency typically present with an absence of pubertal development. We describe an adult-onset form of idiopathic hypogonadotropic hypogonadism that develops after puberty. METHODS: We studied 10 men (age, 27 to 57 years) with normal sexual maturation, idiopathic infertility, sexual dysfunction, low serum testosterone concentrations, and apulsatile secretion of luteinizing hormone on frequent blood sampling. All the men had otherwise normal anterior pituitary hormone secretion and sellar anatomy. We compared the results of semen analyses and measurements of testicular volume, serum testosterone, inhibin B, and gonadotropins in these men with the results in 24 men with classic GnRH deficiency before and during GnRH-replacement therapy and in 29 normal men of similar age. RESULTS: Serum gonadotropin concentrations in the men with adult-onset GnRH deficiency were similar before and during pulsatile GnRH administration to those in the men with classic GnRH deficiency. However, as compared with men with classic GnRH deficiency, men with adult-onset hypogonadotropic hypogonadism had larger mean (+/-SD) testicular volumes (18+/-5 vs. 3+/-2 ml, P<0.001), serum testosterone concentrations (78+/-34 vs. 49+/-20 ng per deciliter [2.7+/-1.2 vs. 1.7+/-0.7 nmol per liter], P=0.004), and serum inhibin B concentrations (119+/-52 vs. 60+/-21 pg per milliliter, P<0.001). Treatment with GnRH reversed the hypogonadism and restored fertility in each of the five men who received long-term therapy. CONCLUSIONS: The recognition of adult-onset hypogonadotropic hypogonadism in men as a distinct disorder expands the spectrum of GnRH deficiency and identifies a treatable form of male infertility.
Adult↗
Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency.
Isolated GnRH deficiency is a heritable condition characterized by a functional deficit in GnRH secretion. Familial cases with different modes of inheritance have been described, and the gene responsible for the X-linked form (KAL-1) has been identified. However, sporadic cases with no documented family history of GnRH deficiency account for the majority of the affected patients. For this reason, we sought to determine the frequency with which KAL-1 gene mutations occur in patients with sporadic GnRH deficiency. Only 1 of 21 patients with sporadic GnRH deficiency was found to bear a defect in the KAL-1 gene (a deletion of 14 bases starting at codon 464). Three types of polymorphic single base substitutions with no apparent correlation with GnRH deficiency were also detected in several patients. In each of 3 different patients with an X-linked mode of inheritance, 3 genetic defects, 2 point mutations and a small intragenic deletion, were detected. These defects consist of a single base mutation introducing a stop codon at position 328, a single base mutation resulting in a phenylalanine to leucine substitution at position 517, and a 9-base deletion at the 3'-exon-intron splice site of exon 8, respectively. All identified genetic defects occur within the fibronectin type III repeats of the predicted protein encoded by the KAL-1 gene. In conclusion, our study indicates that the incidence of genetic defects within the coding region of the KAL-1 gene in patients with sporadic GnRH deficiency is low (5-8%), thus supporting the idea that the X-linked form of inheritance represents the least common form of the disease.
Base Sequence↗
Presence of activin, inhibin, and follistatin in epithelial ovarian carcinoma.
Activin induces proliferation in epithelial ovarian carcinoma cell lines, whereas follistatin (FS), an activin binding protein, inhibits this action. To test the hypothesis that activin production, in excess of inhibin and FS, results in cell proliferation in epithelial ovarian tumors, messenger RNA (mRNA) expression of the activin family of proteins, FS, and activin type I and II receptors was examined in 25 primary epithelial ovarian tumors and tumor epithelium in culture (n = 7) using RT-PCR. Activin A was measured in the serum of ovarian cancer patients, and activin A, total inhibin, and FS protein secretion was measured from primary epithelial tumors in vitro. The effect of activin and FS on cell proliferation was assessed by measuring [3H]thymidine incorporation. All results were compared with normal ovarian epithelium. All epithelial ovarian tumors expressed mRNA for the alpha, beta A, and beta B subunits; FS 288 and 315; and the activin type IA, IB, II, and IIB receptors. beta A mRNA expression, as assessed using semiquantitative RT-PCR, was 3-fold greater in cultured tumor epithelium than in primary tumors (band density 0.86 +/- 0.17 vs. 0.28 +/- 0.09; P < 0.01). In addition, beta A mRNA was abundantly expressed in normal epithelium in culture (n = 2), whereas only trace amounts were seen in 2/9 primary epithelial samples. Activin protein was secreted by 24/25 primary epithelial ovarian tumors (range 0.2-155.8 ng/mL). In contrast, total inhibin was secreted by only 2/25 (range 0.01-0.92 ng/mL), whereas free FS was not detectable in the medium of any tumor (< 0.5 ng/mL). Treatment with activin or FS did not consistently affect cell growth. Measurement of serum activin A in a subset of subjects and in 27 additional subjects with epithelial ovarian carcinoma (n = 33) revealed preoperative activin A levels > 3 SD above the mean for pre- and postmenopausal women in 13/33 (39%) subjects. We conclude that in epithelial ovarian cancer: 1) beta A subunit mRNA is expressed, 2) activin protein is secreted more frequently than inhibin and in greater quantities than FS, 3) beta A subunit mRNA expression is greater in neoplastic and normal epithelium in culture than in the primary tissue, 4) the majority of tumors in culture do not respond to activin or FS treatment with proliferation, and 5) serum activin levels may reflect tumor secretion in some patients. Thus, activin A appears to be available as an autocrine/paracrine factor in epithelial ovarian tumors and may contribute to circulating levels, but its role in tumorigenesis has yet to be defined.
Activins↗