Abnormal Steroid Research Articles

A novel case of a raised testosterone and LH in a young man

A 19 year old male attended his GP with a history of “fluid retention”, lack of libido and erectile dysfunction. He was found to have a high serum testosterone, and a raised luteinising hormone. After further investigations, the patient admitted to taking a supplement called ActivaTe Xtreme™, obtained from an internet source, to address his low libido. ActivaTe Xtreme™ contains active ingredients which increase serum testosterone levels by several independent mechanisms that are not associated with luteinising hormone suppression. Urine analyses for synthetic anabolic steroids were negative, and urinary testosterone, epitestosterone and other androgens were normal. This biochemical pattern is not the same as that seen with anabolic steroids (i.e. raised testosterone, suppressed luteinising hormone and abnormal urine steroid profile). The issue of self medication with performance enhancing compounds needs to be carefully considered in order to avoid expensive and invasive investigations, missing an underlying pathology or misdiagnosing a patient. This case also raises the spectre of yet another “performance enhancing” product that may cause difficulty for those trying to ensure that sport remains on a “hormonally” equal basis.

Ovarian Hyperstimulation Syndrome Prevention Strategies: Luteal Support Strategies to Optimize Pregnancy Success in Cycles with Gonadotropin-Releasing Hormone Agonist Ovulatory Trigger

Gonadotropin-releasing hormone agonist (GnRHa) administration for the induction of oocyte maturation during in vitro fertilization treatment is effective in the prevention of ovarian hyperstimulation syndrome (OHSS). However, some studies have reported a lower ongoing pregnancy rate after GnRHa trigger. The excellent conception rates reported in recipients receiving embryos originating from donor cycles or in women receiving frozen embryos originating from fresh cycles during which GnRHa was used to induce oocyte maturation suggest that it does not adversely affect the quality of the oocyte or embryo. A defective corpus luteum function resulting from the relatively short endogenous luteinizing hormone surge may be detrimental to endometrial receptivity. Aggressive luteal phase support and monitoring is therefore essential in view of the overwhelming evidence suggestive of abnormal luteal phase steroid profile. This may be achieved by the use of adequate estradiol and progesterone supplementation in the luteal phase and the first trimester. An alternative approach is the use of adjuvant low-dose human chorionic gonadotropin, although caution should be exercised in view of the associated risk of OHSS development.

Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing's syndrome

ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare and heterogeneous condition characterized by abnormal steroid production. Cortisol secretion can be regulated by aberrant hormone receptors. A large series of patients with AIMAH were evaluated to provide information on the prevalence and profile of aberrant regulations, in relation with the functional status. Thirty-two consecutive patients with AIMAH were prospectively studied: 10 had a Cushing's syndrome (CS), and 22 had a subclinical CS (SCS). A baseline endocrine evaluation was followed by an in vivo protocol in search of aberrant cortisol responses (seven provocative tests). An acute inhibition test with the somatostatin analog octreotide was also performed. At least one aberrant cortisol response was identified in 28 of 32 (87%) patients. The overall prevalence of aberrant responses was independent of the functional status. Responses to the upright posture and to metoclopramide were frequently observed (67 and 56% respectively). A glucagon response was frequently observed in the SCS group (58%). A cortisol inhibition by octreotide was specifically found in the three CS patients who positively responded to the mixed meal, and was observed also in 12 of 13 (92%) patients with SCS. Cortisol responses indicative of aberrant receptor expression were highly prevalent in AIMAH. Thorough phenotyping of AIMAH may help uncover the underlying pathophysiology.

Abnormal Urinary Steroid Profiles in Four Hypertensive Obese Children

There is a poorly understood association between obesity and hypertension. We demonstrated abnormalities of adrenal androgen and cortisol metabolites in four hypertensive obese children. Four males (aged 10 to 15 years) were evaluated for systolic blood pressures consistently above the 99.6th percentile. All were overweight with BMI ranging from 27-35. Clinical examinations, renal ultrasound and DMSA scans were normal. Plasma electrolytes, renin, aldosterone, cortisol, testosterone, ACTH and TSH were normal. 24-Hour urinary steroid profiles showed a generalised excess of adrenal androgen and cortisol metabolites in all cases. Relevant recognised disorders of adrenal androgen and cortisol metabolism were excluded. There is no clinical condition explaining these abnormal urinary steroid profiles. These results support previous findings and provide new data on abnormal urinary adrenal androgen excretion in obese hypertensive patients. Further studies may determine the relationship between obesity, hypertension and the observed abnormalities of urinary steroid excretion.

Abnormal Urinary Steroid Profiles in Hypertensive Obese Children

Abnormal Urinary Steroid Profiles in Hypertensive Obese Children

Ethylglucuronide as a potential marker for alcohol‐induced elevation of urinary testosterone/epitestosterone ratios

The potential influence of alcohol consumption on endogenous steroids has already been described in the literature. In those studies the ethanol level after ingestion was monitored using its concentration in blood, urine or saliva. Corresponding methods are not commonly used in anti-doping laboratories. Ethylglucuronide (EtG), which can be easily detected by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), appears to be a more suitable parameter for this purpose. It is slowly excreted into the urine and indicates alcohol intake for a much longer period than blood or urinary alcohol and it is therefore routinely used for legal purposes as an alcohol consumption marker. In pharmacokinetic studies that aimed to establish calculation models after ethanol intake, the formation of EtG was observed to coincide with elevated urinary testosterone/epitestosterone (T/E) ratios. Similarly, large amounts of EtG were correlated with abnormal steroid profiles found in routine doping samples. In this pilot study, several cases with significantly elevated T/E ratios were associated with urinary EtG concentrations higher than 50 microg/mL. These findings confirmed recent intake of ethanol in considerable amounts and suggest a connection to changes in specific steroid profile parameters. Owing to the ease with which procedures to determine EtG can be carried out, and the potential for such procedures to be introduced into screening schemes, the inclusion of this marker in the final evaluation of suspicious outliers in T/E ratio longitudinal studies would seem to be very useful.

Heritable forms of hypertension

Among the causes of secondary hypertension are a group of disorders with a Mendelian inheritance pattern. Recent advances in molecular biology have unveiled the pathogenesis of hypertension in many of these conditions. Remarkably, the mechanism in every case has proved to be upregulation of sodium (Na) reabsorption in the distal nephron, with accompanying expansion of extracellular volume. In one group, the mutations involve the Na-transport machinery in distal tubule cells themselves: the distal convoluted tubule (DCT) cell and the principal cell of the collecting duct. Examples include Liddle’s syndrome, with an activating mutation of epithelial Na channel (ENaC); two types of Gordon’s syndrome, with mutations in two regulatory kinases [with no lysine (K) serine/threonine protein kinases (WNK)1 or WNK4]; and apparent mineralocorticoid excess (AME), with an inactivating mutation in the glucocorticoid-metabolizing 11β-hydroxysteroid dehydrogenase type 2 enzyme (11HD2). In another group, abnormal adrenal steroid production leads to inappropriate stimulation of the mineralocorticoid receptor (MR) in the distal nephron. The pathophysiology may involve inappropriate production of aldosterone [in glucocorticoid-remediable aldosteronism (GRA) and familial hyperaldosteronism type II (FH II)], of cortisol (in familial glucocorticoid resistance), or of other steroid metabolites (in congenital adrenal hyperplasia and GRA). In contrast to earlier beliefs, hypertension in many of the inherited disorders may be mild, and electrolyte and acid-base abnormalities are often not present. Monogenic hypertension should therefore enter the differential diagnosis of any child or adolescent with hypertension. Plasma renin activity (PRA) is the appropriate screening tool for all types of inherited hypertension.

Somatomedin-C/IGF-I, insulin and prolactin levels in Ullrich-Turner's syndrome.

To clarify the pathogenesis of growth retardation in patients with Ullrich-Turner's syndrome (TS) we have investigated basal SmC/IGF-I, insulin and prolactin concentrations. Compared with 56 age matched healthy controls basal SmC/IGF-I concentration in 51 patients with TS older than 9-11 years was significantly lower (age group 13-14 years; TS 273 +/- 47 and controls 479 +/- 114 ng/ml). Mean basal prolactin level in 43 patients with TS (406 +/- 211 microU/ml) was significantly higher (p less than 0.01) than in 192 female controls (age 3-11 years; 264 +/- 176 microU/ml). Basal insulin concentration in 28 TS patients in comparison to 20 healthy children of a control group was significant higher (TS 18 +/- 8 microU/ml; controls 9 +/- 4 microU/ml; p less than 0.01). It seems that neither insulin nor prolactin are relevant stimulators of Smc/IGF-I in man, especially in patients with gonadal dysgenesis. Considering these results we speculate that despite higher prolactin and higher insulin levels in TS, the lower SmC/IGF-I concentrations may be predominantly related to the abnormal sex steroid secretion.

Nomenclature for alleles of the cytochrome P450 oxidoreductase gene

Recent focus on the cytochrome P450 oxidoreductase (POR) gene has resulted in the discovery of numerous new polymorphic alleles. Many of these were found [1–6] because of their association with steroidogenic disorders and congenital skeletal malformations resembling the phenotype of Antley-Bixler syndrome [7], whereas other alleles have been found as a consequence of sequencing the POR gene in normal unrelated individuals [8,9]. The association of POR variants with clinical phenotypes is the result of POR serving as the major electron donor for cytochrome P450 (CYP) enzymes with important endogenous functions in hormone biosynthesis. Consequently, defective POR alleles can be the cause of abnormal glucocorticoid, mineralocorticoid, and sex steroid synthesis [10], thus leading to a form of congenital adrenal hyperplasia. In addition, POR deficiency can cause skeletal defects, the mechanism of which is yet unknown but has been suggested to result from impaired sterol synthesis [11] because of decreased electron flow from POR to lanosterol 14-alpha-demethylase (CYP51A1) and squalene monooxygenase (SQLE). In addition, as POR is equally important as an electron donor to CYP enzymes involved in the metabolism of drugs, POR variants may affect drug bioavailability. The effect of POR mutations on the activity of some drug-metabolizing CYP enzymes has been documented in vitro [12–14], but not yet in vivo. In addition, POR is an electron donor for heme oxygenase, cytochrome b5, and several additional small molecules that can be directly metabolized by POR without CYP enzymes. Thus, an increasing focus on the importance of POR in drug response and adverse drug reactions is to be expected. Until now, no systematic guidelines have been proposed for the naming of POR alleles. To standardize POR allelic nomenclature, the Human CYP Allele Nomenclature Chair and Committee have taken the initiative to devise a system for the designation of POR alleles that follows the guidelines for CYP allelic star (CYP*) nomenclature (http://www.cypalleles.ki.se/criteria.htm). The POR allele nomenclature web page (http://www.cypalleles.ki.se/por.htm) was launched in September 2008, listing 35 different alleles. On this POR web page, the alleles are presented together with their corresponding nucleotide and amino acid changes, and the phenotypic consequences observed by in vitro and in vivo studies. Among the more important POR variants are POR*2 and *5 (Arg457His and Ala287Pro, respectively), the former being the most frequent mutation in Japanese and Chinese POR-deficient patients [5,15], whereas the latter is the POR mutation most frequently found in Caucasians. Alleles with frameshift mutations (POR*9, *10, and *20–24), deletions, insertions, and several of the alleles that result in amino acid substitutions are also associated with in vivo phenotypes, as is a splice defect in the POR*3 allele. To maintain a common nomenclature system within the field, fellow scientists investigating POR polymorphisms are highly recommended to submit novel POR allelic variants to the Human CYP Allele Nomenclature Committee (http://www.cypalleles.ki.se/criteria.htm) by contacting the Webmaster for designation and reservation of novel POR allele names. The authors of this Letter, a number of whom have identified the novel POR alleles, are supportive of this new nomenclature system, and will use this system in their future work.

Drug testing data from the 2007 Pan American Games: δ13C values of urinary androsterone, etiocholanolone and androstanediols determined by GC/C/IRMS

The main purpose of this article is to show the application of the CG/C/IRMS in real time during competition in the steroid confirmation analysis. For this reason, this paper summarizes the results obtained from the doping control analysis during the period of the 2007 Pan American Games held in Rio de Janeiro, Brazil. Approximately 5600 athletes from 42 different countries competed in the games. Testing was performed in accordance to World Anti-Doping Agency (WADA) technical note for prohibited substances. This paper reports data where abnormal urinary steroid profiles, have been found with the screening procedures. One 8 mL urine sample was used for the analysis of five steroid metabolites with two separate analyses by gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS). Urine samples were submitted to GC/C/IRMS for confirmation analysis to determine the 13C/ 12C ratio of selected steroids. Fifty-seven urine samples were analyzed by GC/C/IRMS and the δ 13C values (‰) of androsterone, etiocholanolone, 5β-androstane-3α, 17β-diol (5β-diol), 5α-androstane-3α, 17β-diol (5α-diol) and 5β-pregnane-3α, 20α-diol (5β-pdiol), the endogenous reference compound are presented. One urine sample with a testosterone/epitestosterone (T/E) ratio of 4.7 was confirmed to be positive of doping by GC/C/IRMS analysis. The δ values of 5β-diol and 5α-diol were 3.8 and 10.8, respectively, compared to the endogenous reference compound 5β-pdiol, which exceeded the WADA limit of 3‰. The results obtained by CG/C/IRMS confirmation analyses, in suspicious samples, were conclusive in deciding whether or not a doping steroid violation had occurred.

Erectile Dysfunction and Comorbidities in Aging Men: An Urban Cross‐Sectional Study in Malaysia

Erectile dysfunction (ED), lower urinary tract symptoms (LUTS), cardiovascular disease (CVD), depression, and androgen deficiency are common conditions affecting aging men over 50 years. However, data were limited in developing countries. To investigate the prevalence of ED, LUTS, chronic diseases, depression, androgen deficiency symptoms, and lifestyle of aging men in Malaysia, and to examine their associations with sociodemographic factors. ED, LUTS, chronic diseases, depression, positive Androgen Deficiency in the Aging Male (ADAM) questionnaire A randomized survey of 351 men using structured questionnaires consisting of self-reported medical conditions, International Index for Erectile Function-5, International Prostate Symptom Score, Geriatric Depression Scale-15, and St Louis University questionnaire for ADAM. Blood samples were taken for glucose, lipid, prostate specific antigen (PSA), and hormones. Mean age was 58+/-7 years. Prevalence of ED was 70.1% (mild ED 32.8%, mild to moderate ED 17.7%, moderate ED 5.1%, and severe ED 14.5%). There were 29% of men with moderate and severe LUTS; 11.1% had severe depression; 25.4% scored positive on ADAM questionnaire; 30.2% self-reported hypertension, 21.4% self-reported diabetes mellitus; 10.8% self-reported coronary artery disease; 19.1% were smokers; and 34% consumed alcohol. There were 78.6% of men that are overweight and obese; 28.8% had a fasting blood sugar (FBS) >or=6.1 mmol/L, 70.1% had total cholesterol >5.2 mmol/L, 19.1% had total testosterone >or=11.0 nmoL/L, 14.0% had calculated free testosterone <0.0225 nmoL/dL; 4% had PSA >4 microg/L; 9.4% had insulin-like growth factor-1 (IGF-1) level below age specific range, 5.1% had abnormal sex hormone binding globulin (<15 nmoL/L and >70 nmol/L). ED was found to be significantly associated with LUTS, depression (P<0.001 respectively). Similarly, LUTS was significantly associated with depression and ADAM questionnaire status (P<0.001 respectively); and ADAM questionnaire status was also significantly associated with depression (P<0.001). ED, LUTS, depression, and androgen deficiency symptoms are common in urban aging men. As these conditions are possibly interrelated, strategies for early disease prevention and detection are warranted when one disease presents.

Diagnosis of the adrenogenital syndrome caused by 11beta-hydroxylase deficiency using gas chromatographic-mass spectrometric analysis of the urinary steroid profile

In 5-7% of all cases of congenital adrenogenital hyperplasia (AGH) there is 11 beta-hydroxylase deficiency (11 beta-HM). Its clinical picture is characterised by hyperandrogenism and, in some cases, arterial hypertension. The diagnosis of the enzyme deficiency depends on a reliable method of analysing the hormone in plasma and urine. As little is known and data often contradictory about the pattern of urinary steroid excretion in 11 beta-HM, these steroid metabolites were measured by a highly specific method. The pattern of urinary excretion of steroids was determined by gas chromatography and mass spectrometry (GC/MS) in 16 children and adults (11 males, 5 females: mean age 9(8)/12 [2/12-20(3)/12] years) with 11 beta-HM. In all patients there was greatly increased excretion of tetrahydrated (TH) and hexahydrated (HH) metabolites of 11-desoxycortisol (S) and desoxycorticosterone (DOC). The excretion of THS and THDOC was extremely increased in all patients. The metabolites 5 alpha-THS as well as 20 alpha- and 20 beta-isomers of HHS, not normal found in healthy persons, were present in 15 patients (94%), while the 20 alpha- and 20 beta-isomers of 5 alpha-HHS were demonstrated in 14 (88%). For the first time, 20 alpha- and 20 beta-isomers of 5 alpha-HHS were shown to be typical urinary steroid metabolites in 11-HM. The excretion of cortisol metabolites is typically decreased in 11 beta-HM. No corticosterone metabolites were found. The urinary steroid excretion pattern, measured by GC/MS, is a noninvasive, highly specific and nonselective method in the differential diagnosis of abnormal steroid metabolism.

Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Studies suggest that the presence of testosterone exacerbates, whereas the absence of testosterone attenuates, the development of nondiabetic renal disease. However, the effects of the absence of testosterone in diabetic renal disease have not been studied. The study was performed in male Sprague-Dawley nondiabetic, streptozotocin-induced diabetic, and streptozotocin-induced castrated rats (n=10 to 11 per group) for 14 weeks. Diabetes was associated with the following increases: 3.2-fold in urine albumin excretion, 6.3-fold in glomerulosclerosis, 6.0-fold in tubulointerstitial fibrosis, 1.6-fold in collagen type I, 1.2-fold in collagen type IV, 1.3-fold in transforming growth factor-beta protein expression, and 32.7-fold in CD68-positive cell abundance. Diabetes was also associated with a 1.3-fold decrease in matrix metalloproteinase protein expression and activity. Castration further exacerbated all of these parameters. Diabetes was also associated with a 4.7-fold decrease in plasma testosterone, 2.9-fold increase in estradiol, and 2.1-fold decrease in plasma progesterone levels. Castration further decreased plasma testosterone levels but had no additional effects on plasma estradiol and progesterone. These data suggest that diabetes is associated with abnormal sex hormone levels that correlate with the progression of diabetic renal disease. Most importantly, our results suggest an important role for sex hormones in the pathophysiology of diabetic renal complications.

Novel Endocrine Disrupter Effects of Classic and Atypical Antipsychotic Agents and Divalproex: Induction of Adrenal Hyperandrogenism, Reversible with Metformin or Rosiglitazone

To ascertain an association between the a priori known insulin resistance caused by antipsychotic agents and divalproex and adrenal hyperandrogenism and to determine whether the associated hyperandrogenism is reversible with insulin sensitizers. We studied 26 consecutive psychiatric inpatients (22 women and 4 men) receiving the aforementioned medications, who were referred to us for a consultation. They ranged in age from 19 to 79 years and had a mean body mass index (SEM) of 32.35 +/- 1.26 kg/m2. Between 8 AM and 9 AM, blood samples were collected for 17-hydroxyprogesterone, 17-hydroxypregnenolone, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate, 11-deoxycortisol, luteinizing hormone and follicle-stimulating hormone (in reproductive age women), estrone, estradiol (in reproductive age women), free testosterone (in women), deoxycorticosterone, and sex hormone-binding globulin (SHBG), which were measured by radioimmunoassay, after chromatography if necessary. For intact, premenopausal women, measurement of the abnormal steroid metabolite or SHBG level was repeated during prednisone therapy (5 mg at bedtime) to document the likely adrenal origin of the abnormality. Men, women who had undergone bilateral oophorectomy, and postmenopausal women had hyperandrogenism of adrenal origin by default. Clinical features included central obesity, acanthosis, hirsutism, alopecia, type 2 diabetes mellitus, and oligomenorrhea. We found reversed estrone/estradiol ratios in 4 patients, decreased SHBG in 4, increased 17-hydroxy-pregnenolone in 8, increased 17-hydroxyprogesterone in 2, increased deoxycorticosterone in 2, increased DHEA sulfate in 1, increased 11-deoxycortisol in 4, increased androstenedione in 1, and reversed ratios of luteinizin hormone to follicle-stimulating hormone in 2. The bio-chemical abnormalities were corrected in 8 of 8 patients receiving metformin and in 2 of 2 patients receiving rosiglitazone. Insulin resistance caused by antipsychotic agents and divalproex is associated with adrenal hyperandrogenism. Metformin and rosiglitazone correct the biochemical abnormalities detected without compromising their psychotropic effect. Adrenal androgen synthesis may be increased by hyperinsulinemia-induced hyperphosphorylation of P450c17 alpha, resulting in an increase in its 17,20-lyase activity, which magnifies the effects of any distal steroidogenic enzyme defects. Treatment with metformin or rosiglitazone prevents excess adrenal androgen synthesis.

505 POSTER Serum adipokine levels in colorectal cancer patients

Adrenocortical tumors (ACTs) are common, and most are benign adrenocortical adenomas (ACAs). Malignant adrenocortical carcinoma (ACC) is a rare tumor type and is observed at the rate of one or two cases per million annually. ACTs are classified as either ACAs or ACCs by histopathologic methods that are based on nine Weiss scoring criteria, including the nuclear grade, mitotic rate, presence of necrosis, and others. In this review, we describe the findings of studies that have examined the molecular basis of ACTs, and we compare transcriptome analysis with other diagnostic approaches. ACTs are occasionally difficult to classify. Therefore, molecular techniques, such as microarray analysis, have recently been applied to overcome some of these diagnostic problems. We also discuss the likelihood of the diagnosis and discernment between ACAs and ACCs based on the molecular tests. To show the recent progress in understanding the etiology of ACTs, we highlight the relationship between genetic analysis and transcriptome analysis. We attempt to understand the role of abnormal cell growth and steroid hormone secretion. Genetic and transcriptome analyses have improved our understanding of ACTs considerably, yet many unanswered questions remain.

Gender Difference in Age-Related Number of Corticotropin-Releasing Hormone-Expressing Neurons in the Human Hypothalamic Paraventricular Nucleus and the Role of Sex Hormones

Previous studies have shown that the total number of corticotropin-releasing hormone (CRH)-stained neurons in the human hypothalamic paraventricular nucleus (PVN) increases with age. To determine whether this age-related change depends on gender and whether circulating sex hormones play a role, we analyzed the total number of CRH-immunoreactive neurons by means of immunocytochemistry and image analysis in the postmortem hypothalamic PVN of 22 control subjects (11 males and 11 females) between the ages of 22 and 89 years, and of 10 subjects with abnormal sex hormone status. Our data show that men have a significantly larger number of CRH neurons than women (p = 0.004) and that the total number of CRH neurons increases significantly with age, but only in male controls (p = 0.032), not in female controls (p = 0.733). Female controls do not show a significant change in the total number of CRH neurons either before or after the age (50 years) of menopause (p = 0.792). Male subjects with low testosterone levels due to castration showed significantly fewer CRH neurons than well-matched intact males (p = 0.008), while castrated male-to-female (M-F) transsexuals with estrogen replacement showed normal numbers of CRH neurons. One male case, who had high estrogen levels due to an estrogen-producing tumor, showed a large number of CRH neurons. Thus, although circulating androgens and estrogens both seem to play a stimulatory role with respect to CRH neurons, the age-dependent increase in the number of CRH neurons in the PVN of men, which has been interpreted to reflect activation of the CRH neurons with age, seems to result from factors other than age-related changes of circulating sex hormone levels.

Developmental and Genetic Outcomes in Children Conceived Through Assisted Reproductive Technologies

After completing this article, readers should be able to: 1. Describe the outcomes of assisted reproductive technologies (ART) for singleton, twin, and other multiple births. 2. Describe the role of fertility in adverse outcomes seen with ART births. 3. Review the association of birth defects with ART. 4. Delineate the association of disease of genomic imprinting with ART. 5. Describe the relationship between ART and the subsequent incidence of neurodevelopmental sequelae. In the 1977 ruling “Carey v. Population Services International,” the United States Supreme Court ruled that the decision to bear children is constitutionally protected. (1) Significant interest already had been shown in the development and improvements of in vitro fertilization (IVF) for infertile couples. The first human pregnancy and human birth using IVF were reported by Steptoe and Edwards in the United Kingdom. (2) Their work resulted in the first baby born via reproductive technologies, Louise Brown, born on July 25, 1978, at Oldham General Hospital in Oldham, United Kingdom. (3) She was born via a planned cesarean section, and her birthweight was 2.61 kg. The first successful viable IVF in the United States was performed by Jones and Seager-Jones in 1981 in Norfolk, Virginia. (4) Assisted reproductive technologies (ART) have seen a recent surge in popularity. The Centers for Disease Control and Prevention (CDC) reported that 122,872 cycles of ART were initiated in 2003, resulting in the delivery of 48,756 neonates, (5) accounting for approximately 1% of all neonates delivered in the United States. The percentage is higher in many countries, including Denmark, where it is estimated that 5% of all deliveries are with the assistance of ART. (6) Couples pursue ART for myriad reasons, including tubal transport factors, ovulatory dysfunction, uterine factors, endometriosis, male- and female-specific factors, and when a cause of infertility is unknown. (5) It would be very …

Obesity and Sex Steroid Changes across Puberty: Evidence for Marked Hyperandrogenemia in Pre- and Early Pubertal Obese Girls

Peripubertal obesity is associated with abnormal sex steroid concentrations, but the timing of onset and degree of these abnormalities remain unclear. The objective of the study was to assess the degree of hyperandrogenemia across puberty in obese girls and assess overnight sex steroid changes in Tanner stage 1-3 girls. This was a cross-sectional analysis. The study was conducted at general clinical research centers. Thirty normal-weight (body mass index for age < 85%) and 74 obese (body mass index for age >or= 95%) peripubertal girls. Blood samples (circa 0500-0700 h) were taken while fasting. Samples from the preceding evening (circa 2300 h) were obtained in 23 Tanner 1-3 girls. Hormone concentrations stratified by Tanner stage were measured. Compared with normal-weight girls, mean free testosterone (T) was elevated 2- to 9-fold across puberty in obese girls, whereas fasting insulin was 3-fold elevated in obese Tanner 1-3 girls (P < 0.05). Mean LH was lower in obese Tanner 1 and 2 girls (P < 0.05) but not in more mature girls. In a subgroup of normal-weight Tanner 1-3 girls (n = 17), mean progesterone (P) and T increased overnight 2.3- and 2.4-fold, respectively (P <or= 0.001). In obese Tanner 1-3 girls (n = 6), evening P and T were elevated, and both tended to increase overnight [mean 1.4- and 1.6-fold, respectively (P = 0.06)]. Peripubertal obesity is associated with hyperandrogenemia and hyperinsulinemia throughout puberty, being especially marked shortly before and during early puberty. P and T concentrations in normal-weight Tanner 1-3 girls increase overnight, with similar but less evident changes in obese girls.

Sex hormone-binding globulin expression in the endometria of women with polycystic ovary syndrome

To evaluate the protein and messenger RNA expression of sex hormone-binding globulin (SHBG) in endometria from women with polycystic ovary syndrome (PCOS). Case-control study. Hospital research unit. Thirty-three women with PCOS, and 17 fertile, healthy women of similar age to those with PCOS. Endometrial and blood samples were obtained from women with PCOS (PCOSEs) and from control women (CEs) during the proliferative phase of the menstrual cycle. Expression studies for SHBG (immunohistochemistry and reverse transcription-polymerase chain reaction). Hormonal studies for determining sex steroids (T, P, and E(2)) and SHBG concentration. Insulin sensitivity was assessed by composite insulin sensitivity index (ISI(composite)). In stroma, the protein expression of SHBG was lower in PCOSEs than in CEs. Epithelial cells had a similar expression of SHBG protein in both groups. Messenger RNA of variant 548 base pairs (wild-type) tended to be lower in PCOSEs compared to CEs. When PCOSEs were classified by insulin resistance, the PCOSEs with normal insulin sensitivity showed an expression of stromal SHBG similar to that observed in CEs. The low SHBG expression in the stromal compartment of endometria from women with PCOS with insulin resistance may contribute to generate an abnormal steroid milieu in the endometria of these women.

Corticotropin-releasing hormone neurons in the paraventricular nucleus of the human hypothalamus in subjects with normal and abnormal sex hormone status

In order to determine the role of peripheral sex hormone levels in the expression of corticotropin-releasing hormone (CRH) neurons, we investigated by means of immunocytochemistry the number of CRH neurons in the hypothalamic paraventricular nucleus (PVN) in postmortem material of young and old subjects with normal and abnormal sex hormone conditions. Clinical data and nuclear androgen receptor (AR) immunoreactivity (ir) in the hypothalamic medial mamillary nucleus (MMN) were used as an estimate for changes in circulating sex hormone levels. It was confirmed that nuclear AR-ir staining in the MMN is a good estimate for abnormal peripheral androgen levels and that the CRH neurons in the hypothalamic PVN are activated with age in male subjects. Male subjects with lower testosterone levels due to castration showed significantly fewer CRH neurons than age-matched male controls. Castrated male-to-female (MF) transsexuals with estrogen replacement showed normal numbers of CRH neurons, while one male case, which had high estrogen levels due to an estrogen-producing tumor, even showed a high number of CRH neurons in the PVN. Results of the present study suggested that the activation of CRH neurons during aging in male subjects results from factors other than changes in endogenous peripheral sex hormone levels. Since estrogens can prevent the drop of CRH cell number following castration in MF transsexuals, and more CRH neurons were found in the case of an estrogen-producing tumor, estrogen seems to play a stimulating role in the activity of CRH neurons in the PVN. The stimulatory effect of androgens on CRH neurons seems to occur via an indirect effect following aromatization into estrogens.