Low LH Levels Research Articles

Luteal blood flow in patients undergoing GnRH agonist long protocol

BackgroundBlood flow in the corpus luteum (CL) is closely related to luteal function. It is unclear how luteal blood flow is regulated. Standardized ovarian-stimulation protocol with a gonadotropin-releasing hormone agonist (GnRHa long protocol) causes luteal phase defect because it drastically suppresses serum LH levels. Examining luteal blood flow in the patient undergoing GnRHa long protocol may be useful to know whether luteal blood flow is regulated by LH.MethodsTwenty-four infertile women undergoing GnRHa long protocol were divided into 3 groups dependent on luteal supports; 9 women were given ethinylestradiol plus norgestrel (Planovar) orally throughout the luteal phase (control group); 8 women were given HCG 2,000 IU on days 2 and 4 day after ovulation induction in addition to Planovar (HCG group); 7 women were given vitamin E (600 mg/day) orally throughout the luteal phase in addition to Planovar (vitamin E group). Blood flow impedance was measured in each CL during the mid-luteal phase by transvaginal color-pulsed-Doppler-ultrasonography and was expressed as a CL-resistance index (CL-RI).ResultsSerum LH levels were remarkably suppressed in all the groups. CL-RI in the control group was more than the cutoff value (0.51), and only 2 out of 9 women had CL-RI values < 0.51. Treatments with HCG or vitamin E significantly improved the CL-RI to less than 0.51. Seven of the 8 women in the HCG group and all of the women in the vitamin E group had CL-RI < 0.51.ConclusionPatients undergoing GnRHa long protocol had high luteal blood flow impedance with very low serum LH levels. HCG administration improved luteal blood flow impedance. This suggests that luteal blood flow is regulated by LH.

21-Hydroxylase Deficiency Associated with Male Infertility: Report of 2 Cases with Gene Analyses

We treated two patients with male infertility due to 21-hydroxylase deficiency. Endocrinologic examinations disclosed low levels of LH and FSH, with elevated ACTH and 17-OH-progesterone in both. In addition, a small testicular tumor was found in Case 1, which disappeared after adrenal replacement. Suppressed gonadotropin levels caused by increased androgen seemed to underlie the sperm dysfunction in these patients. Dexamethasone and then clomiphene were administered in Case 1, and dexamethasone in Case 2. Spermatogenesis was somewhat improved in both patients and pregnancy achieved in Case 2, though spontaneous abortion later occurred.

Abstract P5-11-13: Tamoxifen and Ovarian Function

Abstract Background: to study and compare ovarian function (clinical and biological data) among premenopausal breast cancer patients receiving tamoxifen alone (group I) or tamoxifen following chemotherapy (group II), because some studies suggest that amenorrhea is an insufficient parameter to define menopausal status. Material and methods: between 1999 and 2003, 138 premenopausal patients, treated for early breast cancer, were included: 68 patients in the group of tamoxifen alone and 70 patients in de group of tamoxifen administered after chemotherapy (6 cycles of FEC 100 on day 1 every 3 weeks -5 fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2- or 4 cycles of EC on day 1 every 3 weeks -epiadriamycine 75 mg/m2, cyclophosphamide 500 mg/m2-). All patients had a confirmed premenopausal status (biological data) at the entry of the study. The median age in group I was 44.5 (36 to 48) and 42 in group II (35 to 47.5). In group I, all were stage I and in group II, 34 were stage I and 36 were stage II. They were followed prospectively every 3 months for 3 years: date about menses, physical examination and blood tests (LH, FSH, 17-bêta-estradiol). Vaginal echography was added every 6 months. After 3 years, prospective evaluation was closed. Retrospective evaluation of all data was performed in 2009. Results: three patients were out of study in the group I and 2 were out of study in the group II. According to clinical data, patients were devided in 4 subgroups: a: regular menses (≥10 cycles/year) b: spaniomenorrhea (5 to 9 cycles/year) c: severe spaniomenorrhea (1 to 4 cycles/year) d: complete amenorrhea. The number of patients in each subgroup is respectively: - For group I (65 patients): 3 (4%), 19 (29%), 38 (58%) and 5 (8%). - For group II (68 patients): 2 (3%), 21 (30%), 38 (55%) and 7 (10%). The most interesting parameter to be studied wass the estradiol levels. Median values of estrogen levels For patients of subgroup a, tamoxifen mimicked an ovulatory cycle such as observed in patients receiving citrate of clomifen. For patients of subgroup b, the variations corresponded to nearly a normal ovulatory cycle. For patients of subgroups c and d, tamoxifen induced low levels of estradiol, LH and FSH, and very few variations. Estrogen levels did not to seem have an impact on disease free survival rate after 3 years of follow-up (100% in group I and 98.6% in group II and after 5 years (98.5% and 97%). In the two groups I and II, estrogen levels from patients of subgroups a and b were significantly higher than in subgroups c and d (p &amp;lt; 0.001). Conclusion: amenorrhea is an insufficient parameter to define menopausal status of patients receiving tamoxifen. Low estradiol level must be coupled to other biological parameters to characterize endocrine status. These data are very important in the choice of endocrine therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-13.

POEMS: A Rare Cause of Low SAAG Refractory Ascites

Purpose: Clinical Case: 67yo WF with no known liver disease presented with refractory ascites, LE edema, and acute renal failure. Six months before admission she developed peripheral neuropathy, ascites, right-sided pleural effusion and shortness of breath. Diuretic therapy led quickly to renal dysfunction requiring diuretic discontinuation and a requirement for serial therapeutic paracenteses. She underwent pleurodesis for her pleural effusion. A right heart catheterization revealed mild pulmonary hypertension but normal cardiac function. PMHx: hypothyroidism. SocHx: no alcohol. FHx: no liver disease. PE: cachectic-appearing, no jaundice or scleral icterus, no stigmata of chronic liver disease. Abd: distended, moderate ascites, NT, no palpable hepatosplenomegaly. Ext: 1+ edema to knees bilaterally. Neuro: significantly decreased lower extremity vibratory and pinprick sensation. Labs: WBC 3,500/mL, HCT 31%, Plt 224,000/mL, alb 2.6 g/dL; liver function tests were normal. Diagnostic paracentesis performed on admission revealed a SAAG of 0.4. CEA, CA 19-9, CA-125 and ascitic cytology, AFB stain, and amylase were all normal. CT of chest/abd/pelvis done to screen for malignancy and/or carcinomatosis showed hepatosplenomegaly and sclerotic bone lesions of sternum, clavicle, and iliac wings. EGD and colonoscopy were nondiagnostic, including small bowel biopsies for celiac disease and rectal biopsies for amyloid. An SPEP and IFE showed a monoclonal M spike of 0.5g/dL with lambda light chain present. Nerve conduction studies confirmed a severe diffuse demyelinating sensorimotor polyneuropathy in the lower extremities. Further testing showed low levels of FSH and LH. Severe symptomatic bradydysrhythmias with syncope in the hospital required pacemaker implantation. Given her polyneuropathy, hepatosplenomegaly, endocrinopathy, monoclonal gammapathy and sclerotic bone changes, concern for POEMS syndrome was raised. A bone marrow biopsy was consistent with multiple myeloma. She was discharged home with plans to initiate therapy for multiple myeloma. Discussion: POEMS syndrome is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. It is associated with polyneuropathy, organomegaly, endocrinopathy of various forms, monoclonal gammopathy, and skin changes. The acronym POEMS captures several dominant features of the syndrome but other important features may include elevated levels of VEGF, sclerotic bone lesions, ascites, pulmonary hypertension, and cardiac conduction disturbances. Treatment is directed at the underlying plasma cell dyscrasia. In this case, ascites was one of the main presenting features. Therefore, POEMS syndrome needs to be included in the differential diagnosis of low SAAG ascites.

Bimanual mirror movements in a patient with Kallmann Syndrome

Introduction: Kallmann (olfactogenital) syndrome results from a congenital defect of the migration of GnRH-producing neurons and those of the olfactory bulb; a symptom combination of hypogonadotropic hypogonadism and hyposomia/anosmia is obligatory. Further optional symptoms may include a movement disorder, optic atrophy, color blindness, deafness, cleft lip and palate or renal agenesis. Kallmann syndrome is more frequent in boys (1:7500) than in girls (1:50,000). Sporadic as well as familial cases with different inheritance modalities have been described. The X-linked type represents about 11–14% of the cases. Synkinesia or mirror movements appear in 85% of patients with X-linked Kallmann syndrome (2) Case report:: We report a 16 year old patient who was presented to the ENT-department as a small child due to lack of taste sense; by the review of delayed sexual development later in his teenage years low levels of FSH, LH und Testosterone led to the suspicion of Kallmann syndrome. The presentation in the neurologic clinic took place because of peculiar mirror movements, which he had since he could remember. During the examination we noticed involuntary simultaneous mirror movement of the contralateral hand each time he purposely moved the other hand. Consistent with Kallmann syndrome his cranial MRI demonstrated hypoplasia of the olfactory bulb. Two possible Mutations in KAL1 and KAL2 (FGFR1) genes were examined and found to be negative. Discussion: Congenital or beyond the 10th year persisting mirror movements occur as a rare isolated form or in the context of neurogenetic syndrome like Klippel-Feil- and Kallman syndromes; these are different from acquired/symptomatic mirror movements occurring after damage to the central nervous system (3). Electrophysiological studies suggest that congenital mirror movements could be the result of simultaneous activation of crossed corticospinal pathways with origin in both right and left motor cortices (4,5). Ipsilateral corticospinal connections seem to be normal in the ontogenity; persistence of mirror movements is attributed to a defect in the transcallosal inhibition, which normally correlates with completed myelination of the corpus callosum (6). It is hypothesized that the migration of inhibitory transcallosal fibres in patients with Kallmann syndrome and synkinesia could be defective (7).

Use of recombinant human luteinizing hormone for ovulation stimulation in in vitro fertilization-embryo transfer

To evaluate application of recombinant human luteinizing hormone (r-hLH) used in ovarian stimulation of assisted reproductive technique and impact on outcome of pregnancy. From Apr. to Jul. 2009, 123 patients with low LH level (< 1 U/L) at day 3 of menstruation and down-regulation of pituitary function undergoing in vitro fertilization-embryo transfer (IVF-ET) in Reproductive Medical Center, Provincial Hospital Affiliated to Shandong University were enrolled in this study, whom were classified into 66 cases treated by r-hLH in r-hLH group and 57 cases without r-hLH treatment in non-r-hLH group. In the mean time, 145 patients with normal level of serum LH (1 - 2 U/L) not given by r-hLH treatment and undergoing IVF-ET were matched as control group. Total amount of gonadotropin, estradiol levels and LH levels on the administration of human chorionic gonadotropin (hCG), number of oocytes retrieved, number of 2PN zygotes, rate of high quality embryos, the rates of implantation and clinical pregnancy were compared among these three groups. The level of serum LH on the day of hCG administration were (1.59 ± 0.77) U/L in r-hLH group, (0.54 ± 0.25) U/L in non-r-hLH group and (2.39 ± 1.01) U/L in control group, which reached statistical difference between every two groups (P < 0.05). The rates of high quality embryo were 59.36% in r-hLH group, 57.79% in non-r-hLH group, which were significantly lower than 65.94% in control group, respectively (P < 0.05). The rates of 2PN were 67.62% in r-hLH group and 68.32% in control group, which were significantly higher than 62.84% in non-r-hLH group, respectively (P < 0.05). The rates of implantation of 29.77% in r-hLH group were significantly higher than 18.26% in non-r-hLH group (P < 0.05). The total amount of gonadotropin, estradiol level on the day of hCG administration, the number of oocytes retrieved, and clinical pregnancy rate were not significantly different among those three groups (P > 0.05). The administration of recombinant human luteinizing hormone in patients who are profoundly suppressed after down-regulation with long protocol can get more quality embryos, the higher rates of 2PN and implantation.

Ganirelix for luteolysis in poor responder patients undergoing IVF treatment: a Scandinavian multicenter ‘extended pilot study’

To enhance oocyte yield and pregnancy outcome in poor responder women undergoing IVF treatment, daily low dose GnRH antagonist administration was given during the late luteal phase to induce luteolysis and possibly secure a more synchronous cohort of recruitable follicles. An open extended pilot study in four Scandinavian fertility centers was done including 60 patients. Poor response was defined as when < or = 5 follicles developed in a preceding cycle following a long agonist protocol with the use of > 2000 IU FSH. GnRH antagonist (ganirelix) was given, 0.25 mg s.c. daily, from days 3 to 5 before expected start of menstruation and continued for 4-7 days. On cycle day 2-3 a starting dose of rFSH (300-400 IU/day) was given. At a leading follicle diameter of 14 mm, ganirelix administration was resumed until final oocyte maturation was induced with 10,000 IU hCG. GnRH antagonist only marginally affected the intercycle FSH rise; basal levels of FSH remained similar to those seen after 4 days of antagonist administration. The protocol effectively induced low LH levels and luteolysis, but daily administration of 350 IU rFSH (median) for 11 days only led to the collection of 3 oocytes in 49 oocyte retrievals resulting in 5 pregnancies (4 delivered). Despite GnRH antagonist administration in the late luteal phase and menstrual bleeding, FSH was not sufficiently reduced to secure a more synchronic cohort of recruitable follicles. Novel GnRH antagonists more specifically targeting FSH release may improve the stimulation results in poor responders.

Oral contraceptive pretreatment significantly reduces ongoing pregnancy likelihood in gonadotropin-releasing hormone antagonist cycles: an updated meta-analysis

Ongoing pregnancy rate (PR) per randomized woman was found to be significantly lower in patients with oral contraceptive (OC) pill pretreatment (relative risk: 0.80, 95% confidence interval [CI]: 0.66-0.97; rate difference: -5%, 95% CI: -10% to -1%; fixed effects model) after pooling data from six randomized controlled trials encompassing 1,343 patients. Duration of stimulation (weighted mean difference [WMD]: +1.33 days, 95% CI: +0.61-2.05) and gonadotropin consumption (WMD: +360 IUs, 95% CI: +158-563) were significantly increased after OC pretreatment, but there was no statistically significant gain in the number of cumulus-oocyte complexes (WMD: +0.6 cumulus-oocyte complexes, 95% CI: -0.08-1.25).

1377 THE UTILITY OF CLOMIPHENE CITRATE IN HYPOGONADAL MEN OVER 50 YEARS OF AGE

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Medical and Non-Surgical Therapy I1 Apr 20101377 THE UTILITY OF CLOMIPHENE CITRATE IN HYPOGONADAL MEN OVER 50 YEARS OF AGE Darren Katz, Alex Mueller, Kelly Park, and John Mulhall Darren KatzDarren Katz More articles by this author , Alex MuellerAlex Mueller More articles by this author , Kelly ParkKelly Park More articles by this author , and John MulhallJohn Mulhall More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1006AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Clomiphene citrate (CC) is being used increasingly in the treatment of hypogonadism (HG) due to the absence of concerns regarding testicular atrophy and hypospermatogenesis. To date, it has been employed largely in younger men concerned about fertility. This analysis was undertaken to review our experience with CC use in the older hypogonadal male. METHODS Men ≥50 years of age with documented HG who were candidates (baseline T<300 ng/dl, LH≤8, ADAM score≥3) and opted for CC therapy constituted the study population. If the baseline T levels were abnormal, T (total and free), SHBG, estradiol and prolactin levels were subsequently measured. When low serum T was confirmed, bone densitometry (BD) was performed. Demographic, comorbidity and treatment data were recorded. Patients were commenced on CC 25mg QOD and were titrated to CC 50mg QOD if required. If T levels still remained low, CC was increased to a maximum of 50mg QD before switching patients to testosterone supplementation. Follow-up was every 6 months (clinical evaluation and hormonal levels) with an annual BD and ADAM questionnaire. Comparison was made between baseline and treatment parameters and multivariable analysis was conducted to define predictors of successful response to CC. RESULTS 96 men with a mean age 61±7 (50-70) years were analyzed. Comorbidities: hypertension 36%, diabetes 14%, dyslipidemia 39%. Baseline/treatment levels were: total T 242±47/492±200; Estradiol 42±16/39±24; LH 2.8±2.6/7.8±2.9 (p<0.01 for all). With CC administration, 76% of men achieved a total T>300 ng/dl. On the ADAM questionnaire, mean ‘yes' responses went from 7±1.5 to 4±3 (p<0.01) on CC. At baseline, 74 (77%) had abnormal BD (58 osteopenia, 16 osteoporosis). After 12 months CC administration, repeat BD revealed 56% of men remained abnormal (48 osteopenia, 6 osteoporosis), but mean T scores improved significantly (p<0.01). Predictors of achieving total T levels ≥400ng/dl are presented in the Table. Table 1. Predictors of achieving total T levels ≥400ng/dl. OR CI P Age <55y 6.1 1.9-13.6 <0.01 LH ≤2.0 10.4 3.2-21 <0.01 ≤2 comorbidities 1.8 1.2-3.9 <0.05 Diabetes 0.4 1.8-4.4 <0.01 CONCLUSIONS These data illustrate that CC is an effective therapeutic option for older men with hypogonadism. Those patients responding best to CC are younger, healthier, non-diabetic and have low LH levels. New York City, NY© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e532 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Darren Katz More articles by this author Alex Mueller More articles by this author Kelly Park More articles by this author John Mulhall More articles by this author Expand All Advertisement Advertisement Loading ...

Disruption of the Single Copy Gonadotropin-Releasing Hormone Receptor in Mice by Gene Trap: Severe Reduction of Reproductive Organs and Functions in Developing and Adult Mice

Mutations in the GnRH receptor gene (GNRHR) can result in hypogonadotropic hypogonadism in humans. Unlike most mammals, mice lack a second form of GnRH (GnRH2) and a type 2 GnRH receptor. To determine whether the GnRH receptor is critical at all stages of reproduction and whether this receptor has additional physiological functions in developing and adult mice, we have generated mice from an embryonic stem cell line containing a retroviral vector with multiple stop codons inserted into intron 1 of the Gnrhr gene. This gene trap insertion resulted in the disruption of exon 2 and exon 3 of the Gnrhr gene. The insertion also contained a lacZ gene that was used as a reporter for GnRH receptor expression in these mice. This model has a similar phenotype to the clinical syndrome of hypogonadotropic hypogonadism. Null Gnrhr mice had small sexual organs, low levels of FSH, LH, and steroid hormones, failure of sexual maturation, infertility, and inability to respond to exogenous GnRH. However, the defective GnRH receptor did not prevent morula/blastocyst development, implantation, masculinization of fetal male mice, or maintenance of early pregnancy. The phenotype of this null Gnrhr mouse was more severe than models in the literature, including the N-ethyl-N-nitrosourea-induced Gnrhr mutant, the kisspeptin (Kiss1) knockout, and the kisspeptin receptor (Gpr54) knockout. In terms of gonadal morphology, adult gene trap-Gnrhr null mice demonstrate a complete cessation of reproduction and serve as an important model for understanding GnRH/GnRHR physiology.

High basal LH levels in combination with low basal FSH levels are associated with high success rates at assisted reproduction

The objective of this study was to evaluate the associations of basal gonadotrophins with pregnancy and delivery rates at IVF/ICSI. A prospective observational study was conducted at a university-affiliated private infertility centre. Patients were 745 women, who underwent 1328 IVF/ICSI treatment cycles. Basal FSH, basal LH and combinations of FSH and LH versus treatment data and pregnancy and delivery rates were measured. Combinations of FSH and LH gave significantly better information than the LH:FSH ratio, or each gonadotrophin alone: highest mean pregnancy rate (39%) was achieved in women with low FSH (<6.7 U/l) and with high LH levels (>4.9 U/l), whereas pregnancy rate was lowest (22%) in women with high FSH and low LH levels. Pregnancy rates were intermediate (27-28%) if FSH and LH were either both low or both high (P for trend = 0.0004). Associations to delivery rates and measures of ovarian response and embryo quality followed the same pattern. Basal LH modifies and improves the information given by basal FSH alone. Low FSH level combined with high LH probably reflects a well-preserved ovarian reserve and is associated with the highest success rates at IVF/ICSI.

Effect of several estrogens on serum gonadotropin levels in postmenopausal women.

To study the effect of several estrogens on serum gonadotropin levels in postmenopausal women blood samples taken from postmenopausal women treated with either ethinyl estradiol mestranol 1-hydroxethinyl estradiol-1.3-diacetate or 17-dioxanyl estradiol for 12-27 days were radioimmunoassayed for serum FSH and LH levels. Doses of 20 mcg/day of ethinyl estradiol began to lower FSH levels on the second day of treatment and lowered LH levels after 13 days. FSH levels stayed suppressed after cessation of the treatment but LH levels rebounded quickly. Ethinyl estradiol at higher doses caused quicker declines in both FSH and LH levels. Mestranol at 50 mcg/day produced significant decreases in FSH and LH levels starting on day 5 of treatment without rebound after cessation of treatment. Hydroxethinyl estradiol at 50 mcg/day caused a stronger decrease in FSH and LH levels than the other estrogens starting on day 2 without rebound. Dioxanyl estradiol at 200 mcg/day failed to inhibit FSH or LH levels in a significant manner and a strong LH rebound was seen within 1 day after cessation of treatment. This LH rebound similar to that seen with ethinyl estradiol at 20 mcg/day is probably due to a drop in the circulating levels of these exogenous estrogens. It is concluded that estrogens of the 17-hydroxy chemical group are necessary to inhibit pituitary gonadotropin secretion. In small doses these estrogens primarily suppress serum FSH only but both FSH and LH at higher doses.

LH supplementation in down-regulated women undergoing assisted reproduction with baseline low serum LH levels

LH supplementation in down-regulated women undergoing assisted reproduction with baseline low serum LH levels

Oral contraceptive pretreatment in women undergoing controlled ovarian stimulation in ganirelix acetate cycles may, for a subset of patients, be associated with low serum luteinizing hormone levels, reduced ovarian response to gonadotropins, and early pregnancy loss

Oral contraceptive pretreatment facilitated scheduling of pure FSH/GnRH antagonist cycles but in a small subset of patients was associated with low serum LH levels, reduced ovarian response, and early pregnancy loss. Supplementation with LH could be examined as a possible way to improve cycle outcome.

Restoration of ovulation after unilateral ovariectomy in a woman with McCune–Albright syndrome: a case report

McCune-Albright syndrome (MAS) is characterized by peripheral precocious puberty, café-au-lait spots, and polyostotic fibrous dysplasia. This syndrome is due to a post-zygotic mutation of the GNAS1 gene with mosaic distribution and unilateral predominance. Clinical manifestations depend on the tissues carrying the mutation. We describe the ovarian function before and after unilateral ovariectomy in a woman with MAS and bilateral distribution of the GNAS1 gene mutation. A 33-year-old patient, previously diagnosed as having MAS, presented irregular menstrual cycles (30-180 days) and monophasic temperature curves. Transvaginal ultrasound and blood tests were repeated at 3-day intervals over 3 months. Findings included a persistent quiescent left ovary, a persistent polycystic right ovary, constantly high estradiol-17beta (E2) levels, and very low FSH and LH levels. She also presented severe persistent pelvic pain. Because of unilateral ovarian activity, a unilateral right ovariectomy was performed as well as biopsy of the remaining left ovary. A GNAS1 gene mutation was identified in both ovaries. A regular monthly menstrual cycle was immediately restored. On day 3 of the menstrual cycle, E2 level was 30 pg/ml, FSH level was 7.5 mIU/ml, and LH level was 6.4 mIU/ml. On day 17, pelvic ultrasound showed one follicle of 25 mm in the left ovary. On day 21, the progesterone level was 13.1 ng/ml. This is the first report of ovulation being restored following unilateral ovariectomy in an adult patient suffering from severe MAS with GNAS1 gene mutation identified in both ovaries.

Recombinant LH supplementation to recombinant FSH during the final days of controlled ovarian stimulation for in vitro fertilization. A multicentre, prospective, randomized, controlled trial

The purpose of this multicentre, multinational trial was to study whether rLH supplementation to recombinant FSH (rFSH) during the late follicular phase increased pregnancy rates. After down-regulation with nafarelin, 526 women were randomized on Day 1 of stimulation to use either rFSH (Gonal-F) alone (n = 261) or to continue after Day 6 of stimulation with both rFSH (Gonal-F) and rLH (Luveris) (n = 265) from Day 6. The starting dose of rFSH was 150-225 IU/day according to age below or above 35 years. Ongoing pregnancy rate at week 10-12 was 28.7% after rFSH alone and 27.2% after rFSH + rLH. This showed no evidence of a difference. Administration of rLH significantly (P< 0.001) increased serum LH. Ongoing pregnancy rates in patients with low LH levels (<33 percentile) on Days 1 and 6 of stimulation showed no difference between the group treated with rFSH only (23.9% low Day 1 LH; 22.1% low Day 6 LH) versus rFSH + rLH (25.0% low Day 1 LH; 28.9% low Day 6 LH). Supplementing rFSH with daily doses of 75-150 IU of rLH during the second half of the follicular phase showed no evidence of increasing the ongoing pregnancy rates in the general population. (ClinicalTrials.gov, trial number: KF02-035/03).

Abnormal Sex Chromosome Constitution and Longitudinal Growth: Serum Levels of Insulin-Like Growth Factor (IGF)-I, IGF Binding Protein-3, Luteinizing Hormone, and Testosterone in 109 Males with 47,XXY, 47,XYY, or Sex-Determining Region of the Y Chromosome (SRY)-Positive 46,XX Karyotypes

Growth is a highly complex process regulated by the interaction between sex steroids and the GH IGF-axis. However, other factors such as sex chromosome-related genes play independent roles. The aim of the study was to evaluate the role of abnormal chromosome constitution for longitudinal growth in relation to reproductive hormones, IGF-I, and IGF binding protein (IGFBP)-3. The study was conducted at an outpatient clinic, Copenhagen University Hospital. Participants included 86 47,XXY males, 14 46,XX-males, and nine 47,XYY. Standing and sitting height, serum levels of reproductive hormones, IGF-I, and IGFBP-3 were measured. In boys with 47,XXY and 47,XYY karyotypes, growth was accelerated already in childhood, compared with healthy boys. 46,XX-males were significantly shorter than healthy boys but matched the stature of healthy girls. In 47,XXY sitting height to height ratios were lower than expected, whereas body proportions in 46,XX-males and 47,XYY were normal. In all subjects serum levels of IGF-I and IGFBP-3 were within normal limits. The boys with 46,XX and 47,XXY karyotypes presented with low normal testosterone and elevated LH levels after puberty, whereas the sex hormone secretion of the 47,XYY boys remained normal. We found accelerated growth in early childhood in boys with 47,XXY and 47,XYY karyotypes, whereas 46,XX-males were shorter than controls. These abnormal growth patterns were not reflected in circulating levels of IGF-I and IGFBP-3. The boys with 46,XX and 47,XXY karyotypes developed hypogonadism in puberty, but androgen secretion in 47,XYY boys remained normal. The abnormal stature of these patients may be a result of abnormal gene expression due to the underlying chromosome aberration resulting in excessive expression of growth-related genes.

Initiation of GnRH antagonist on Day 1 of stimulation as compared to the long agonist protocol in PCOS patients. A randomized controlled trial: effect on hormonal levels and follicular development

BACKGROUND The optimal time for GnRH antagonist initiation is still debatable. The purpose of the current randomized controlled trial is to provide endocrine and follicular data during ovarian stimulation for IVF in patients with polycystic ovarian syndrome (PCOS) treated either with a long GnRH agonist scheme or a fixed day-1 GnRH antagonist protocol. METHODS Randomized patients in both groups (antagonist: n = 26; long agonist: n = 52) received oral contraceptive pill treatment for three weeks and a starting dose of 150 IU of follitropin beta. The primary outcome was E(2) level on Day 5 of stimulation, while secondary outcomes were follicular development, LH during ovarian stimulation and progesterone levels. RESULTS Significantly more follicles on days 5, 7 and 8 of stimulation, significantly higher estradiol (E(2)) levels on days 1, 3, 5, 7 and 8 and significantly higher progesterone levels on days 1, 5 and 8 of stimulation were observed in the antagonist when compared with the agonist group. E(2) was approximately twice as high in the antagonist when compared with the agonist group on day 5 of stimulation (432 versus 204 pg ml(-1), P lt; 0.001). These differences were accompanied by significantly lower LH levels on days 3 and 5 and significantly higher LH levels on days 1, 7 and 8 of stimulation in the antagonist when compared with the agonist group. CONCLUSIONS In PCOS patients undergoing IVF, initiation of GnRH antagonist concomitantly with recombinant FSH is associated with an earlier follicular growth and a different hormonal environment during the follicular phase when compared with the long agonist protocol.

Avaliação da função das células beta pancreáticas através do modelo matemático de HOMA em portadoras de síndrome dos ovários policísticos: comparação entre obesas e não-obesas

PURPOSE: to evaluate the effect of obesity on b-cell function in patients with polycystic ovary syndrome (PCOS). METHODS: this cross-section study evaluated 82 patients with PCOS selected consecutively, at the moment of the diagnosis. We compared 31 PCOS obese women (BMI >30 kg/m2) to 51 age-matched PCOS nonobese patients (BMI <30 kg/m2). Using fasting glucose and insulin levels, homeostatic model assessment values for insulin resistance (HOMA-IR and QUICKI) and percent b-cell function (HOMA-%b-cell) were calculated. As secondary variables, the age at PCOS diagnosis, age of menarche, hormonal levels (testosterone, prolactin, FSH and LH), total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol were also analyzed. RESULTS: menarche was significantly earlier in obese PCOS patients (11.7±1.8 years) than in nonobese patients (12.67±1.86 years) (p<0.05). Obese patients presented lower LH levels (7.9±5 mIU/mL) than did nonobese patients (10.6±6 mIU/mL) (p<0.05). Both groups presented mean HDL cholesterol levels below 50 mg/dL. Obese patients presented significantly higher baseline insulin levels (32.5±25.2 mIU/mL) and fasting blood glucose levels (115.9±40.7 mg/dL) than did nonobese patients (8.8±6.6 mIU/mL and 90.2±8.9 mg/dL, respectively) (p<0.01). Of the obese PCOS patients, 93% presented insulin resistance versus 25% of nonobese PCOS patients (p<0.01). Eighty-six perecent of the obese women had hyperfunction of b-cell versus 41% of nonobese with PCOS (p<0.0001). CONCLUSIONS: obese PCOS patients presented higher prevalence of insulin resistance and hyperfunction of b-cell than did nonobese PCOS patients.

Fetal gonadotrope cell origin of FSH‐secreting pituitary adenoma – insight into human pituitary tumour pathogenesis

The pathogenesis of human pituitary adenomas remains unclear, but we report a case of FSH-secreting pituitary adenoma whose monohormonal phenotype suggests it was of fetal origin. A 28-year-old woman presented with abdominal discomfort and irregular menses, enlarged multicystic ovaries and elevated serum oestradiol, with sustained high-normal FSH and low LH levels. Endocrine studies were performed before and after curative surgery, with assessment of tumour hormone secretion in vitro, and immunostaining of tumour tissue for a series of gonadotrope proteins. Immunocytochemistry showed that tumour cells were monohormonal for FSH. Normal components of gonadotrope signalling pathways were expressed, including oestrogen receptor-alpha, activin receptors, secretogranin-II and chromogranin-A. beta-glycan, the putative inhibin coreceptor, was absent. Tumour culture in vitro confirmed secretion of FSH with minimal LH, that was unsuppressed by oestradiol or inhibin-A. Human fetal pituitary tissue contained FSH-only cells at 18 weeks gestation, whereas normal adult pituitary tissue contained only bihormonal gonadotropes. We propose that this pituitary adenoma represents an indolent tumour of monohormonal fetal gonadotrope cells that originated early in gestation. Pituitary tumours may therefore arise from abnormal persistence of fetal cell types, with extremely slow growth over many years until reaching a size threshold to generate an endocrine syndrome. Understanding fetal pituitary architecture and function may be more informative for new insights into pituitary tumour pathogenesis than classical theories of cancer biology that invoke unrestrained cell proliferation.